Pediatric Hypertension [5th ed. 2023] 3031062302, 9783031062308

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Joseph T. Flynn Julie R. Ingelfinger Tammy M. Brady Editors

Pediatric Hypertension Fifth Edition

Pediatric Hypertension

Joseph T. Flynn • Julie R. Ingelfinger • Tammy M. Brady Editors

Pediatric Hypertension Fifth Edition

With 104 Figures and 111 Tables

Editors Joseph T. Flynn Department of Pediatrics University of Washington School of Medicine Seattle, WA, USA

Julie R. Ingelfinger Pediatric Nephrology Unit Mass General for Children at MGB Harvard Medical School Boston, MA, USA

Division of Nephrology Seattle Children’s Hospital Seattle, WA, USA Tammy M. Brady Department of Pediatrics Division of Pediatric Nephrology Johns Hopkins University School of Medicine Baltimore, MD, USA

ISBN 978-3-031-06230-8 ISBN 978-3-031-06231-5 (eBook) https://doi.org/10.1007/978-3-031-06231-5 1st edition: © Humana Press 2004 2nd edition: © Springer Science+Business Media, LLC 2011 3rd edition: © Springer Science+Business Media New York 2013 4th edition: © Springer International Publishing AG 2018 © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland.

Preface to the Fifth Edition

The importance of good cardiovascular health in adulthood is obvious but cannot be overemphasized, especially for children with health problems such as obesity and elevated blood pressure. This new edition of Pediatric Hypertension emphasizes data that have appeared over the last several years that are relevant to children with elevated blood pressure, as well as to children with obesity and other health challenges. Cross-sectional and longitudinal studies in large cohorts have led to notable advances in the field of pediatric hypertension. While there is still much work remaining, important knowledge gaps have been narrowed by new studies. Advances include improved understanding of which blood pressure thresholds lead to intermediate outcomes in children such as left ventricular hypertrophy, changes in carotid intima media thickness, and other markers as well as long-term cardiovascular outcomes in adults; enhanced assessment and interpretation of noninvasive measures of cardiovascular disease risk and early vascular aging; recognition of nontraditional cardiovascular disease risk factors in youth such as the role of early life stress; and the evolving description of the neurocognitive sequelae of hypertension. Further, the results of work over the last several years have demonstrated the importance of emergency preparedness and adaptability in the face of natural disasters and pandemics. These substantial advancements, some of which challenge prevailing thought and have already prompted changes in professional society and expert clinical recommendations, are summarized in this Fifth Edition. As with the Fourth Edition, this current text is part of the Springer Major Reference Work program, which is available both in print and online, a format that allows for real-time updating. In addition to new chapters that address the topics noted above, this Edition provides updates to previously published chapters, including those exploring the epidemiology of hypertension; the genetic, perinatal, and lifestyle contributions to pediatric blood pressure and hypertension; secondary causes of hypertension and comorbidities; and the practical and pragmatic approaches to auscultatory, home, and ambulatory blood pressure measurement. We are proud of the breadth of topics covered in this Edition of Pediatric Hypertension. It truly does take a village, and we are most grateful to our expert contributors, who shared their expertise and time to make this Edition as compelling and current as we believe it to be. We hope that this text will not

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only inform and educate existing clinicians and experts immersed in the field, but that it will also inspire students and trainees to choose a career that focuses on cardiovascular health promotion across the lifespan. Seattle, USA Boston, USA Baltimore, USA December 2022

Joseph T. Flynn Julie R. Ingelfinger Tammy M. Brady

Preface to the Fourth Edition

We are delighted to present this expanded fourth edition of Pediatric Hypertension, which is intended to capture and update the ongoing progress in childhood hypertension. There is a growing recognition that adult cardiovascular disease has its origins in childhood, supported by many recent studies. Additionally, the assessment of the short-term sequelae of childhood hypertension is providing new and important data, reviewed herein. Further, there are increasing numbers of studies that are delineating mechanisms of blood pressure elevation in the young. While the obesity epidemic appears to be leveling off (at least in the United States), it remains an important contributor to the higher prevalence of childhood hypertension reported in recent years; numerous epidemiologic studies have become available since publication of the third edition of this text and are detailed here. With publication of this new fourth edition, we hope to bring further focus on the importance of understanding and addressing the role of the obesity epidemic in pediatric hypertension. As our publisher, Springer, has transitioned this text to its Major Reference Work program, which is available not only in print but also online, which allows for continual updating, we have been able not only to retain the topics covered in previous editions of Pediatric Hypertension but also to add new chapters that address additional and important aspects of childhood hypertension. One new chapter addresses the controversy over routine childhood blood pressure screening raised by the 2014 US Preventive Services Task Force Report. Obesity hypertension is now covered in two chapters, one focusing on mechanisms and the other on clinical aspects. Another important mechanism of cardiovascular disease, vascular dysfunction, is covered in a new chapter in the first section of the text. We also now address the important topic of home blood pressure measurement, while continuing to cover casual and ambulatory blood pressure measurement in detail. Expanded chapters on ESRD-related hypertension, substance-induced hypertension, hypertension in oncology patients, and hypertension in young adults should be of substantial interest to clinicians who care for such patients. We have also expanded the section on hypertension research with a new chapter on cohort studies and meta-analyses and their role in studying childhood hypertension. Finally, we have added a short Appendix summarizing the major changes of the 2017 American Academy of Pediatrics clinical practice guideline on childhood hypertension, which was completed as this new edition was in progress. vii

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Preface to the Fourth Edition

It is impossible to put together a comprehensive text such as Pediatric Hypertension without more than “a little help from our friends.” We are greatly indebted to our returning authors as well as to our new authors, all of whom were asked to contribute to the text because of their acknowledged expertise in childhood hypertension. We also thank Daniela Graf and Rebecca Urban from Springer for helping keep everyone on task. We are certain that you will agree that the tremendous amount of work that has been devoted to this edition of Pediatric Hypertension has led to a comprehensive and useful text, which we hope you will consult often in your clinics and research laboratories. Seattle, WA, USA Boston, MA, USA Boise, ID, USA

Joseph T. Flynn Julie R. Ingelfinger Karen M. Redwine

Preface to the Third Edition

We are excited to offer you this third edition of Pediatric Hypertension. Interest in childhood hypertension has increased markedly since the publication of the prior editions of this text, fueled in part by the increase in the prevalence of hypertension in children and adolescents, owing to the obesity epidemic. Investigators have continued to explore many aspects of hypertension in the young, resulting in better understanding of the mechanisms, manifestations and management of this important clinical problem. Cardiovascular disease remains the leading medical cause of death in the world. Only by understanding important risk factors such as hypertension at the earliest stages of disease, during childhood, can substantial progress at eradicating this disease be made. In this edition, we have retained most of the topics from the prior two editions, but have made some important additions and replacements that we feel will increase the usefulness of the text to clinicians and researchers alike. New clinically oriented chapters on obesity-related hypertension, endocrine hypertension and renovascular hypertension should help guide the evaluation and management of these major causes of hypertension in the young. A new chapter on models of hypertension should help both researchers and clinicians to better understand the investigative approaches that have been employed to study childhood hypertension. There are also new chapters on hypertension in pregnancy and ethnic influences on hypertension in the young, which should be of particular interest to those who care for large numbers of teens and minority patients, respectively. A text such as this would not have been possible without contributions from many busy people, all of whom are acknowledged experts in the field. We are profoundly grateful to our colleagues who agreed to contribute chapters to this text, especially those who willingly took on new topics only 2–3 years after writing their chapters for the second edition! It has been a privilege to work with such a talented and generous group of collaborators, and we are sure that you will agree that their efforts have resulted in an enhanced third edition. Seattle, WA, USA Boston, MA, USA Princeton, NJ, USA

Joseph T. Flynn Julie R. Ingelfinger Ronald J. Portman

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Preface to the Second Edition

Interest in pediatric hypertension dates back nearly half a century, when it was first recognized that a small percentage of children and adolescents had elevated blood pressures – and in those days, the same normal values for adult blood pressure were utilized in children! The many advances since that time have led to a much clearer understanding of how to identify, evaluate, and treat hypertensive children and adolescents. At the same time, many questions remain: What causes hypertension in children without underlying systemic conditions? What are the long-term consequences of high blood pressure in the young? What is the optimal therapy of childhood hypertension? and Does such treatment benefit the affected child or adolescent? Can we identify children at risk of developing hypertension and intervene to prevent its occurrence? Readers conversant with the history of hypertension in the young will recognize that these questions were being asked decades ago and may still be unanswered for many years to come. The first text focusing on pediatric hypertension was published in 1982. The book you are about to read is a direct descendant of that first effort to summarize what is known about hypertension in the young. We are fortunate to have been given the first opportunity to produce a second edition of such a text, which reflects the increased interest in hypertension in the young that has developed since the publication of the first edition of Pediatric Hypertension. Many chapters from the first edition have been revised and updated by their original authors; others have been written by new authors. New chapters on topics of recent interest in pediatric hypertension such as the metabolic syndrome and sleep disorders have been added. We hope that the reader will find this new edition of Pediatric Hypertension to be an up-to-date, clinically useful reference as well as a stimulus to further research in the field. It is also our hope that the advances summarized in this text will ultimately lead to increased efforts toward the prevention of hypertension in the young, which, in turn, should ameliorate the burden of cardiovascular disease in adults. We thank our many colleagues who have taken time from their busy schedules to contribute to this text – and we are sure that you will agree with us that their combined efforts have resulted in a valuable reference to those interested in hypertension in the young. Seattle, WA, USA Boston, MA, USA Princeton, NJ, USA

Joseph T. Flynn Julie R. Ingelfinger Ronald J. Portman xi

Preface to the First Edition

More than a quarter of a century has elapsed since the first Task Force on Blood Pressure Control in Children was published in 1977. Since that seminal publication, normative data have been obtained for both casual and ambulatory children’s blood pressure. Blood pressure measurement in infants, children, and adolescents, once an afterthought, has become routine. Pediatric Hypertension discusses the many aspects of pediatric hypertension – a multidisciplinary subspecialty that is comprised of pediatric nephrologists, cardiologists, endocrinologists, pharmacologists, and epidemiologists. Although some areas of our discipline have become well established, others, such as routine use of ambulatory blood pressure recording and well-designed trials in pediatric hypertension, are still emerging. Accordingly, we have included chapters that focus on aspects of blood pressure control and hypertension in the very young that are particularly relevant to those caring for infants, children, and adolescents. Pediatric Hypertension opens with chapters concerning blood pressure regulation in the very young: the transition from fetal life to infant circulation, the factors that regulate blood pressure in early childhood, and the chronobiology of pediatric blood pressure. We then move on to the assessment of blood pressure in children. The book addresses both casual and ambulatory blood pressure measurement methodologies and norms, as well as the epidemiology of hypertension in children. Definitions of hypertension in children, predictors of future hypertension, risk factors, and special populations are discussed at length. Comprehensive chapters on both primary and secondary hypertension in children point out differences in presentation of hypertension in the pediatric, in comparison to the adult, population. The contributions of genetics to the understanding of hypertension are presented, as well as those events during gestation and perinatal life that may influence the development of later hypertension. Risk factors that are discussed include the influences of race and ethnicity, diet, obesity, and society. Special populations, including the neonate with hypertension and the child with chronic renal failure or end-stage renal disease, are each discussed in a separate chapter. In those chapters, the pathophysiology insofar as it is known is also considered. This text concludes with a section that focuses on the evaluation and management of pediatric hypertension. Suggestions for evaluation are presented, and both nonpharmacologic and pharmacologic therapy are discussed xiii

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at length. The 1997 Food and Drug Administration Modernization Act, which offers extension of market exclusivity in return for approved clinical trials of medications with pediatric indication, has had a major impact on the conduct of pediatric antihypertensive medication trials. The current status of such pediatric antihypertensive trials is presented. In the appendix, the reader will find the latest tables for the definition of hypertension in children from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, to be published in Pediatrics in the summer of 2004. We hope that Pediatric Hypertension provides a catalyst for more interest in pediatric hypertension as well as a guide for the interested clinician or clinical researcher already active in this discipline. Very shortly, the results of additional trials concerning new antihypertensive agents in children will be available with the mandate that new antihypertensive medications be evaluated in children. An update by the Task Force on Blood Pressure Control in Children will also be completed in 2004. A number of groups that have a special interest in blood pressure and its control in the very young will continue to contribute to the field, among them, most notably, the International Pediatric Hypertension Association; the National Heart, Lung, and Blood Institute; the American Society of Hypertension; and the American Society of Pediatric Nephrology. These initiatives will lead to a better understanding of the definition, causes, consequences, prevention, and treatment of pediatric hypertension. In addition to advances in molecular and genetics laboratories, new technologies in assessment of human cardiac and vascular anatomy and physiology will help to elucidate the pathophysiology of hypertension and its response to management. In so doing, our hope is that the trend towards reduction in cardiovascular morbidity and mortality will continue for the current generation of children. Finally, we wish to acknowledge the pioneering work of so many in the field of pediatric hypertension that has given us the foundation and tools to advance our field. International Pediatric Hypertension Association

Ronald J. Portman, M.D. Jonathan M. Sorof, M.D. Julie R. Ingelfinger, M.D.

Contents

Part I Regulation of Blood Pressure and Pathophysiological Mechanisms of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Neurohumoral and Autonomic Regulation of Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Empar Lurbe and Josep Redon

1

3

2

Cardiovascular Influences on Blood Pressure . . . . . . . . . . . . Manish D. Sinha and Phil Chowienczyk

21

3

Vasoactive Factors and Blood Pressure in Children . . . . . . . Ihor V. Yosypiv

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4

Ions and Fluid Dynamics in Hypertension . . . . . . . . . . . . . . . Avram Z. Traum

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5

Uric Acid in the Pathogenesis of Hypertension . . . . . . . . . . . Daniel I. Feig

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6

Insulin Resistance and Other Mechanisms of Obesity Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vidhu Thaker and Bonita Falkner

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7

Monogenic and Polygenic Contributions to Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Julie R. Ingelfinger

8

Antenatal Programming of Blood Pressure . . . . . . . . . . . . . . 133 Andrew M. South

9

Familial Aggregation of Blood Pressure and the Heritability of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Sujane Kandasamy and Rahul Chanchlani

10

The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Dawn K. Wilson, Tyler C. McDaniel, and Sandra M. Coulon

11

Endothelial Dysfunction and Vascular Remodeling in Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Julie Goodwin xv

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Adverse Childhood Experiences and Their Relevance to Hypertension in Children and Youth . . . . . . . . . . . . . . . . . . . 217 Julie R. Ingelfinger

13

Salt Sensitivity in Childhood Hypertension . . . . . . . . . . . . . . 229 Coral D. Hanevold

14

Early Vascular Aging in Pediatric Hypertension Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Mieczysław Litwin

Part II Assessment of Blood Pressure in Children: Measurement, Normative Data, and Epidemiology . . . . . . . . . . . . 271 15

Methodology of Office Blood Pressure Measurement . . . . . . 273 Tammy M. Brady

16

Value of Routine Screening for Hypertension in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Joseph T. Flynn

17

Development of Blood Pressure Norms and Definition of Hypertension in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Bonita Falkner

18

Ambulatory Blood Pressure Monitoring Methodology and Norms in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Elke Wühl

19

Methodology and Applicability of Home Blood Pressure Monitoring in Children and Adolescents . . . . . . . . . . . . . . . . 345 George S. Stergiou and Angeliki Ntineri

20

Epidemiology of Hypertension and Cardiovascular Disease in Children and Adolescents . . . . . . . . . . . . . . . . . . . 367 Elyse O. Kharbanda

Part III Hypertension in Children: Etiologies and Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 21

Ethnic Differences in Childhood Blood Pressure . . . . . . . . . . 389 Joshua Samuels and Xamayta Negroni-Balasquide

22

Obesity Hypertension: Clinical Aspects . . . . . . . . . . . . . . . . . 405 Ian Macumber and Joseph T. Flynn

23

Hypertension in Children with Type 2 Diabetes or the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 Grace Kim and Joseph T. Flynn

24

Primary Hypertension in Children . . . . . . . . . . . . . . . . . . . . . 439 Manpreet K. Grewal, Tej K. Mattoo, and Gaurav Kapur

Contents

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25

White Coat and Masked Hypertension . . . . . . . . . . . . . . . . . 461 Yosuke Miyashita and Coral D. Hanevold

26

Hypertension in Chronic Kidney Disease . . . . . . . . . . . . . . . . 477 Susan M. Halbach

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Hypertension in End-Stage Kidney Disease: Dialysis . . . . . . 499 Franz Schaefer

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Hypertension in End-Stage Kidney Disease: Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Tomáš Seeman

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Renovascular Hypertension, Vasculitis, and Aortic Coarctation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 Kjell Tullus and Jelena Stojanovic

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Endocrine Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Perrin C. White

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Neonatal and Infant Hypertension . . . . . . . . . . . . . . . . . . . . . 573 Janis M. Dionne

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Obstructive Sleep Apnea and Hypertension in Children Amee Revana and Alisa A. Acosta

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Hypertension in the Pregnant Teenager . . . . . . . . . . . . . . . . . 615 Tracy E. Hunley and Deborah P. Jones

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Neurocognition in Childhood Hypertension Marc B. Lande and Juan C. Kupferman

35

Stroke and Childhood Hypertension . . . . . . . . . . . . . . . . . . . 659 Juan C. Kupferman, Marc B. Lande, and Stella Stabouli

36

Medication and Substance-Induced Hypertension: Mechanisms and Management . . . . . . . . . . . . . . . . . . . . . . . . 683 Sandeep K. Riar and Douglas L. Blowey

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Hypertension in Oncology and Stem Cell Transplant Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 Benjamin L. Laskin and Sangeeta R. Hingorani

38

Hypertension in Older Adolescents and Young Adults . . . . . 723 Matthew B. Rivara

39

Hypertension in the Developing World Vera H. Koch

. . . 601

. . . . . . . . . . . . . 645

. . . . . . . . . . . . . . . . . 739

Part IV Evaluation and Management of Pediatric Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753 40

Diagnostic Evaluation of Pediatric Hypertension . . . . . . . . . 755 Nicholas Larkins and Derek Roebuck

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Sequelae of Hypertension in Children and Adolescents . . . . 771 Donald J. Weaver Jr. and Mark M. Mitsnefes

42

Cardiovascular Assessment of Childhood Hypertension Edem Binka and Elaine M. Urbina

43

The Role of ABPM in Evaluation of Hypertensive Target-Organ Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805 Stella Stabouli and Vasilios Kotsis

44

Exercise Testing in Hypertension and Hypertension in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827 Carissa M. Baker-Smith and Takeshi Tsuda

45

Nonpharmacologic Treatment of Pediatric Hypertension . . . 843 Stephen R. Daniels and Sarah C. Couch

46

Pharmacologic Treatment of Pediatric Hypertension . . . . . . 857 Michael A. Ferguson and Deborah R. Stein

47

Management of Hypertensive Emergencies . . . . . . . . . . . . . . 883 Craig W. Belsha

48

Hypertension Care During Emergencies and Pandemics . . . 899 Joyce P. Samuel and Bradley K. Hyman

Part V

. . . 785

Hypertension Research in Pediatrics . . . . . . . . . . . . . . . . . . 907

49

Hypertensive Models and Their Relevance to Pediatric Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 Julie R. Ingelfinger

50

Cohort Studies, Meta-analyses, and Clinical Trials in Childhood Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921 Nicholas Larkins and Jonathan Craig

51

Changes in Drug Development Regulations and Their Impact on Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945 Elizabeth J. Thompson, Kevin D. Hill, Rachel D. Torok, and Jennifer S. Li

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959

About the Editors

Dr. Joseph T. Flynn MD, MS, is the Dr. Robert O. Hickman Endowed Chair in Pediatric Nephrology; Professor of Pediatrics, University of Washington; and Chief, Division of Nephrology, Seattle Children’s Hospital. He is an internationally recognized expert in the treatment of hypertension in children and recently chaired the American Academy of Pediatrics Subcommittee that developed the updated clinical practice guideline on high blood pressure in children and adolescents. Dr. Flynn served on the Council of the International Pediatric Nephrology Association from 2010 to 2019, and also on the Council of the American Society of Pediatric Nephrology, including 2 years as ASPN President (2012–2014). He currently is a board member of the Renal Physicians Association and a member of the Nephrology sub-board of the American Board of Pediatrics. He currently serves as one of the Editors-in-Chief of the journal Pediatric Nephrology and is a member of the editorial boards of Hypertension, Blood Pressure Monitoring, and The Journal of Pediatrics. He has contributed chapters to all five editions of the Pediatric Hypertension and edited the three previous editions.

Julie R. Ingelfinger MD, is Professor of Pediatrics at Harvard Medical School, Senior Consultant in pediatric nephrology at Mass General for Children at MGB, and Deputy Editor of the New England Journal of Medicine. She is an internationally recognized hypertension specialist and consultative pediatric nephrologist. Her commitment to teaching has been reflected by receiving the Henry L. Barnett Award from the AAP in 2009, the Founders Award from the American xix

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About the Editors

Society of Pediatric Nephrology in 2012, the National Kidney Foundation’s Honors Award in 2018, the Alumni Lifetime Achievement Award from Albert Einstein College of Medicine (2018), and the Barbara T. Murphy Award from the American Society of Nephrology (2022). Dr. Ingelfinger has been involved in studies of the intrarenal renin angiotensin aldosterone system (RAAS) for many years. Her current projects focus on the role of the intrarenal renin angiotensin system in disease states and the role of maternal diabetes in kidney development and perinatal programming. She is interested in innovative ways to teach writing and communication and has been an editor of Pediatric Hypertension in each of its five editions. Dr. Tammy M. Brady MD, PhD, is Associate Professor of Pediatrics at Johns Hopkins University School of Medicine where she serves as Vice Chair for Clinical Research and as the Associate Director of the Welch Center for Prevention, Epidemiology and Clinical Research. She has focused her career on improving the care of children at increased cardiovascular disease risk through research and clinical innovation. She serves as the Medical Director of the Harriet Lane Kidney Center Pediatric Hypertension Program, and she directs a multidisciplinary obesity hypertension clinic (ReNEW clinic; Reversing the Negative cardiovascular Effects of Weight). Dr. Brady is an expert in blood pressure measurement and blood pressure device validation. She is the co-chair of the Association for the Advancement of Medical Instrumentation (AAMI) Sphygmomanometer committee, the American professional society that develops American National Standards and technical reports regarding sphygmomanometer devices. She was Chair of a two-day meeting at the WHO where published guidance and specifications on blood pressure measuring devices were updated. She is also Co-chair of the American Medical Association’s Validated Device Listing Committee.

Contributors

Alisa A. Acosta Department of Pediatrics Renal Section, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX, USA Carissa M. Baker-Smith Nemours Cardiac Center, Nemours Children’s Hospital, Wilmington, DE, USA Craig W. Belsha SSM Health Cardinal Glennon Children’s Medical Center, Saint Louis University, St. Louis, MO, USA Edem Binka Division of Pediatric Cardiology, University of Utah, Salt Lake City, UT, USA Douglas L. Blowey Pediatric Nephrology, Children’s Mercy Hospital, University of Missouri, Kansas City, MO, USA Tammy M. Brady Department of Pediatrics, Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Rahul Chanchlani Division of Nephrology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada Phil Chowienczyk Kings College London British Heart Foundation Centre, London, UK Sarah C. Couch Department of Rehabilitation, Exercise and Nutrition Sciences, University of Cincinnati Medical Center, Cincinnati, OH, USA Sandra M. Coulon West Texas Veterans Healthcare System, Big Spring, TX, USA Jonathan Craig College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia Stephen R. Daniels Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO, USA Janis M. Dionne Division of Nephrology, Department of Pediatrics, University of British Columbia, BC Children’s Hospital, Vancouver, BC, Canada Bonita Falkner Departments of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA xxi

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Daniel I. Feig Division of Nephrology, Department of Pediatrics, University of Alabama, Birmingham, AL, USA Michael A. Ferguson Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Joseph T. Flynn Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA Division of Nephrology, Seattle Children’s Hospital, Seattle, WA, USA Julie Goodwin Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA Manpreet K. Grewal Division of Nephrology and Hypertension, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA Susan M. Halbach Division of Nephrology, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, USA Coral D. Hanevold Division of Nephrology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA Kevin D. Hill Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Sangeeta R. Hingorani Division of Nephrology, Seattle Children’s Hospital, Seattle, WA, USA Tracy E. Hunley Pediatric Nephrology, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA Bradley K. Hyman Department of Pediatrics- Division of Pediatric Nephrology & Hypertension, McGovern Medical School at University of Texas Health Science Center, Houston, TX, USA Julie R. Ingelfinger Pediatric Nephrology Unit, Mass General for Children at MGB, Harvard Medical School, Boston, MA, USA Deborah P. Jones Pediatric Nephrology, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA Sujane Kandasamy Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, ON, Canada Gaurav Kapur Division of Nephrology and Hypertension, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA Pediatric Nephrology, Central Michigan University, Detroit, MI, USA Elyse O. Kharbanda Research, HealthPartners Institute, Minneapolis, MN, USA Grace Kim Division of Endocrinology and Diabetes, Seattle Children’s Hospital, Seattle, WA, USA Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

Contributors

Contributors

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Vera H. Koch Pediatric Nephrology, University of Sao Paulo Medical School, São Paulo, Brazil Department of Pediatrics, Pediatric Nephrology Unit, Instituto da Criança Hospital das Clinicas, University of São Paulo Medical School, Sao Paulo, Brazil Medical Residency, University of Sao Paulo Medical School, Sao Paulo, Brazil Vasilios Kotsis Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece Juan C. Kupferman Department of Pediatrics, Division of Pediatric Nephrology and Hypertension, Maimonides Medical Center, Brooklyn, NY, USA Marc B. Lande Department of Pediatrics, Division of Pediatric Nephrology, University of Rochester Medical Center, Rochester, NY, USA Nicholas Larkins Department of Nephrology and Hypertension, Perth Children’s Hospital, Nedlands, WA, Australia Paediatrics Division, Medical School, University of Western Australia, Perth, WA, Australia Benjamin L. Laskin Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Jennifer S. Li Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Mieczysław Litwin Department of Nephrology and Arterial Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland Empar Lurbe Pediatric Department, Consorcio Hospital General, University of Valencia, Valencia, Spain CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain Ian Macumber Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Division of Nephrology, Children’s Hospital Los Angeles, Los Angeles, CA, USA Tej K. Mattoo Departments of Pediatrics (Nephrology) and Urology, Wayne State University School of Medicine, Detroit, MI, USA Tyler C. McDaniel Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA Mark M. Mitsnefes Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Yosuke Miyashita Department of Pediatrics, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

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Contributors

Xamayta Negroni-Balasquide Department of Pediatrics, University of Puerto Rico Medical Science Campus, San Juan, PR, USA Angeliki Ntineri Third Department of Medicine, Sotiria Hospital, School of Medicine, Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, Athens, Greece Josep Redon CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain Cardiovascular and Renal Research Group, INCLIVA Research Institute, University of Valencia, Valencia, Spain Amee Revana Department of Pediatrics, Pulmonary and Sleep Medicine Section, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX, USA Sandeep K. Riar Pediatric Nephrology, Children’s Mercy Hospital, University of Missouri, Kansas City, MO, USA Matthew B. Rivara Division of Nephrology, Department of Medicine, Kidney Research Institute, University of Washington, Seattle, WA, USA Derek Roebuck Medical School, University of Western Australia, Perth, WA, Australia Department of Medical Imaging, Perth Children’s Hospital, Nedlands, WA, Australia Joyce P. Samuel Department of Pediatrics- Division of Pediatric Nephrology & Hypertension, McGovern Medical School at University of Texas Health Science Center, Houston, TX, USA Joshua Samuels Department of Pediatrics, University of Puerto Rico Medical Science Campus, San Juan, PR, USA Franz Schaefer Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany Tomáš Seeman Department of Pediatrics, Charles University Prague, 2nd Medical Faculty, Prague, Czech Republic Department of Pediatrics, Dr. von Hauner Children’s Hospital, LMU Munich, Munich, Germany Manish D. Sinha Department of Paediatric Nephrology, Evelina London Children’s Hospital, Guys & St Thomas’ NHS Foundation Trust, London, UK Kings College London British Heart Foundation Centre, London, UK Andrew M. South Department of Pediatrics, Section of Nephrology, Brenner Children’s, Wake Forest University School of Medicine, Winston Salem, NC, USA Stella Stabouli Department of Pediatrics, Aristotle Thessaloniki, Hippocratio Hospital, Thessaloniki, Greece

University

of

Contributors

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Deborah R. Stein Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA George S. Stergiou Third Department of Medicine, Sotiria Hospital, School of Medicine, Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, Athens, Greece Jelena Stojanovic Great Ormond Street Hospital for Children, London, UK Vidhu Thaker Divisions of Molecular Genetics, and Pediatric Endocrinology, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA Division of Endocrinology, Boston Childrens Hospital, Harvard Medical School, Boston, MA, USA Elizabeth J. Thompson Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Rachel D. Torok Department of Pediatrics, University of Pittsburgh Medical Center, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Avram Z. Traum Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA Department of Pediatrics, Harvard Medical School, Boston, MA, USA Takeshi Tsuda Nemours Cardiac Center, Nemours Children’s Hospital, Wilmington, DE, USA Kjell Tullus Great Ormond Street Hospital for Children, London, UK Elaine M. Urbina Preventive Cardiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA Donald J. Weaver Jr. Department of Pediatrics, Division of Nephrology and Hypertension, Atrium Health Levine Children’s, Charlotte, NC, USA Perrin C. White Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center and Children’s Medical Center, Dallas, TX, USA Dawn K. Wilson Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA Elke Wühl Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany Ihor V. Yosypiv Department of Pediatrics, Tulane University, New Orleans, LA, USA

Part I Regulation of Blood Pressure and Pathophysiological Mechanisms of Hypertension

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Neurohumoral and Autonomic Regulation of Blood Pressure Empar Lurbe and Josep Redon

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Neural Components of BP Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Autonomic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Sympathetic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Parasympathetic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Baro- and Chemoreflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Humoral Components of BP Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renin-Angiotensin-Aldosterone System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Atrial Natriuretic Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Apelin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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The Kidney, Fluid Volume, and Salt Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 The Vasculature and Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

E. Lurbe (*) Pediatric Department, Consorcio Hospital General, University of Valencia, Valencia, Spain CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain e-mail: [email protected] J. Redon CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain Cardiovascular and Renal Research Group, INCLIVA Research Institute, University of Valencia, Valencia, Spain e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_1

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E. Lurbe and J. Redon Circadian Variation of Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Abstract

Keywords

Maintenance of BP requires the coordinated regulation of many components that interact in an interdependent network that ultimately controls the main determinants of BP, cardiac output, peripheral resistance, and blood volume. Neurohumoral and autonomic mechanisms are key components of a complex network. The central nervous system, organized into multiple levels of integrative centers, regulates sympathetic activity and vasopressin release in response to nervous and humoral input. The autonomic system, by means of the efferent sympathetic and parasympathetic pathways, regulates heart rate, vasoconstriction, and activation of the reninangiotensin-aldosterone system. Humoral components, angiotensin II, aldosterone, and atrial natriuretic peptides regulate vasoconstriction and sodium excretion. Short-term regulation of cardiac output and peripheral resistance is interconnected by autonomic nervous system reflexes with the intervention of baroreceptors. Mid-term control is achieved by the interplay between sympathetic nervous traffic, humoral systems, and the kidney, controlling vascular peripheral resistance and blood volume. The kidney, through both pressure-natriuresis and arteriolar mechanisms, as well as by flow-mediated vasodilatation and myogenic reactivity, participates broadly in the process. Finally, a circadian rhythm of BP levels is regulated by a clock mechanism driven by the suprachiasmatic nucleus, which is stimulated directly by light. Advances in molecular biology techniques and genetic experimental models continue to provide more precise information about these complex networks.

Angiotensin II · Atrial natriuretic peptides · Baroreflex · Blood pressure · Circadian rhythm · Endothelin · Nitric oxide · Sympathetic activity · Parasympathetic · Vasoconstriction · Vasopressin Abbreviations

ACE1 ACE2 ACh ADMA ALD Ang I Ang I–7 Ang II Ang III Ang IV AngIVr ANGN ANP ANS Apr AS AT1r AT2r BNP BP CNP CNS CV CVLM DMV eNOS EP ErB GABA ILM

Angiotensin-converting enzyme 1 Angiotensin-converting enzyme 2 Acetylcholine Asymmetric dimethylarginine Aldosterone Angiotensin I Angiotensin 1–7 Angiotensin II Angiotensin III Angiotensin IV Angiotensin IV receptor Angiotensinogen Atrial natriuretic peptide Autonomic nervous system Apelin receptor Apelinergic system AT1-receptor AT2-receptor Brain natriuretic peptide Blood pressure C-type natriuretic peptide Central nervous system Circadian variability Caudal ventrolateral medulla Dorsal motor nucleus of the vagus Nitric oxide synthase Epinephrine Endothelin receptor B Gamma-aminobutyric acid Intermediate lateral medulla

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MCA4R MR NA NEP NO NOX NPRA NPRB NTS OVLT PRR PSN PVN RAAS RGS RVLM SNA

Melanocortin Mineralocorticoid receptor Nucleus ambiguus Norepinephrine Nitric oxide NADPH oxidase Natriuretic peptide receptor A Natriuretic peptide receptor B Nucleus of tractus solitarius Organum vasculosum of the lamina terminalis Prorenin receptor Parasympathetic nucleus Paraventricular nucleus Renin-angiotensin-aldosterone system Regulator of G protein signaling Rostral ventrolateral medulla Sympathetic nervous activity

Introduction Intravascular pressure, known as blood pressure (BP), is necessary in order to create blood flow that transports oxygen and nutrients to body organs. Required to achieve this crucial function, many components are orchestrated in an interdependent network. The determinants of BP are cardiac output, peripheral resistance, and blood volume (Fig. 1). Diverse elements, Fig. 1 Basic scheme of main factors controlling BP and their interactions

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neurological (central nervous and autonomic systems), humoral (circulating peptides), baroreceptors and chemoreceptors, arteries, heart, and kidneys, are crucial to maintain the equilibrium of the system. In the short-term, cardiac output and peripheral resistance are interconnected by autonomic nervous system reflexes. In the mid-term, vascular peripheral resistance and blood volume control are achieved through the interplay between sympathetic nervous system activity (SNA), humoral systems, and the kidney. The mission of each of these components mentioned above, as a sensor or as an effector, is regulated and/or modulated by complex organspecific mechanisms (Fig. 2). Dysregulation in one or more BP determinants produces a response by the system to restore BP values, returning to equilibrium. However, if the dysregulation persists, the feedback set point will need to be reset; if it is elevated, a hypertensive state develops. The complexity of the interactions among the different systems in hypertensive patients or animal models is well represented in Page’s mosaic concept, which reflects the many interactions of the mechanisms involved in hypertension (Page 1949). The mosaic theory has been continuously updated since Page created it with the addition of new elements due to advances in the knowledge of the physiopathology of BP regulation (Page 1974; Harrison et al. 2021).

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Fig. 2 Determinants, effectors – sensors and modulators of BP regulation

In the 1970s, Guyton and Coleman published a model of BP regulation that attempted to provide concepts to explain the mechanism for longterm BP control, based on the link between blood pressure and sodium balance (Guyton et al. 1972), and subsequent updates have refined the model. In it, nevertheless, the role of the nervous system was specifically lacking (Guyton 1990). Currently, it is recognized that integrated neurohumoral and autonomic mechanisms are the central components that coordinate the control process even when their activity is modulated by other relevant physiological and pathological processes (Pluznick 2017; Raizada et al. 2017; Carnagarin et al. 2019; Yang et al. 2020; Madhur et al. 2021). This chapter reviews the most relevant mechanisms involved in determining BP levels – effectors and sensors. The anatomy and function of each of the elements requires an individual description, and the present chapter emphasizes their interplay in driving BP regulation.

Neural Components of BP Regulation Both the central nervous system (CNS) and autonomic nervous system (ANS) play key roles in BP regulation (Johnson et al. 2015). Generally, while they integrate multiple afferent and efferent elements, the CNS predominantly commands the level of activation and the ANS predominantly executes the orders.

Central Nervous System Several structures of the CNS are involved in BP control, organized as multiple levels of integrative centers (Ghali 2017a). Usually, these centers respond to signals received through neurogenic afferent connexons or circulating humoral peptides from the blood. The integration of all these elements results in SNA and vasopressin release (Fig. 3).

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Fig. 3 Main central and autonomic neural pathways in BP regulation. Elements controlling the role of the CNS receiving signals from forebrain structures, baroreceptors, chemoreceptors, homeostatic parameters, and organs, through autonomic fibers, cranial nerves, as well as from humoral factors in areas with an absent blood-brain barrier. In response, sympathetic and parasympathetic systems are activated or blunted. Sympathetic activity is exerted

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by the interaction of neurons from the lamina terminalis, PVN, RVLM, CVLM, and NTS transmitting signals to the preganglionic fibers of the ILM and then to the ganglionic ones that innervate vessels and organs. Parasympathetic activity is exerted by the NTS which recruits neurons in the NA and DNV innervating sinus node and the heart-lungs, respectively. Sympathetic activity and humoral peptides interact both in CNS and in systemic actions (see text).

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Sympathetic Activity Activation of the sympathetic nervous system produces not only an increase in the heart rate and vasoconstriction of the arterioles, but it also increases renin production in the juxtaglomerular apparatus of the kidney. The most relevant nodes and pathways of the SNS include the nucleus of tractus solitarius (NTS), the rostral (RVLM) and caudal ventrolateral medulla (CVLM), and the intermedium lateral medulla (ILM). Furthermore, elements present in the lamina terminalis of the third ventricle (circumventricular organ) and dorsomedial hypothalamus are also involved in SNA (Briant et al. 2016). Although the above nodes and pathways have direct functions in establishing SNA, the NTS and the RVLM play the key roles. The NTS, located in the dorsomedial medulla, contains different neuronal clusters that receive the diverse afferent sensory signals (Martinez and Kline 2021). The NTS is the first relay station for general visceral afferents, and it has a critical position in the initiation and integration of a wide variety of reflexes controlling cardiovascular and respiratory functions, matching the process of tissue perfusion and pulmonary ventilation. From the NTS, efferent sympathetic fibers go to the RVLM and efferent parasympathetic (PSN) fibers projected in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA) from which fibers emerge to innervate the heart and vessels (CutsforthGregory and Benarroch 2017; Zanutto et al. 2010). The RVLM integrate information from PVN, NTS, and baroreflexes (Ghali 2017b). The lamina terminalis of the third ventricle, formed by the subfornical organ and the organum vasculosum of the lamina terminalis (OVLT), is a small structure juxtaposed to the third ventricle that has connections to the hypothalamus, limbic system, thalamus, and cerebral cortex

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(Fry and Ferguson 2021), and with a practically nonexistent blood-brain barrier. Consequently, this lack of a blood-brain barrier exposes the neurons to humoral factors – angiotensin II among others (Leenen 2014) – facilitating their detection of signals from the circulating blood. Beginning at the lamina terminalis, the downstream SNA pathways involve the PNV, upper cervical spinal cord, and the RVLM. In addition, the SNA pathways also impact other processes that, in part, contribute to BP regulation, such as thirst, secretion of antidiuretic hormone, and vascular reactivity in the skin vessels. SNA is generated through different neurotransmitters. Fast SNA is transmitted by mechanisms in which glutamate or gamma-aminobutyric acid (GABA) binds to ligand-gated ionotropic receptors, opening the ion channels of the neurons to initiate membrane depolarization and generate the potential action in the relevant axon. The response depends on the quantity of presynaptic neurotransmitter, postsynaptic receptors, and the level of activity in the intraneuronal signaling pathways. In the mid-term SNA, angiotensinogen (ANGN) neurons play an important role. In them, angiotensin II (Ang II) is released in the synaptic cleft and binds to the AT1-receptor (AT1r). This receptor stimulates a G protein signaling pathway with activation of NADPHoxidases (NOX) increasing intracellular reactive oxygen species (ROS). The final result is the activation of several mechanisms and gene expressions in the neurons transmitting the signals (Leenen et al. 2017). Evidence of the relevance of a more slowly acting pathway which maintains the stimulation elicited by Ang II is available nowadays. This slow-acting pathway involves aldosterone (ALD) and the mineralocorticoid receptor (MR), elements co-localized in the ANGN neurons.

ä Fig. 3 (continued) Green arrows show afferent pathways, and black arrows show efferent pathways. CVLM caudal ventrolateral medulla, DNV dorsal nucleus of the vagus, GN ganglionic, ILM intermediolateral medulla, NA

nucleus ambiguus, NTS, PVN paraventricular nucleus, PSNA parasympathetic nervous activity, RVLM rostral ventrolateral medulla, SNA sympathetic nervous system activity

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Vasopressin Vasopressin, a potent antidiuretic and vasoconstrictor hormone, intervenes in the control of plasma volume. It is produced in the PVN and the supraoptic nucleus that contain magnocells and parvocells (Pittman 2021). The magnocells project to the neurohypophysis which secretes vasopressin when a reduction in blood volume or changes in natremia are detected. The parvocells of the PVN project to the lower brainstem and spinal cord in two separate ways. One is the RVLM excitatory pathway, and the other is the CVLM modulatory pathway of SNA (Koba et al. 2018; Brown et al. 2020). In addition to the above mechanisms, stimulation of neuronal vasopressin-receptors by hyperosmolarity and stress is implicated in SNA (Carmichael and Wainford 2015). Melanocortin The melanocortin system, MC4R, also appears to modulate SNS activity in response to various stimuli that are accompanied by sympathetic overactivity. The regions with the greatest abundance of MC4R are all important sites for the regulation of autonomic function: PVN, lateral hypothalamus, amygdala, NTS, DMV, and preganglionic sympathetic neurons of the intermediolateral medulla (ILM) (do Carmo et al. 2017). The MC4R, induced by leptin in the presence of obesity, has been implicated in SNA (da Silva et al. 2019).

Autonomic Nervous System The autonomic nervous system, previously defined functions, integrates visceral afferent inputs with descending influences from forebrain areas. The ANS is involved in homeostasis, emotions, and responses to survival, and its relevance on BP regulation has been acknowledged based on multiple experimental, pharmacologic, and clinical studies (Dampney 2016). The autonomic system is composed of the efferent sympathetic and parasympathetic, the visceral afferents, and the enteric nervous system. Both sympathetic and parasympathetic go through preganglionic neurons and autonomic

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ganglions. While preganglionic neurons use acetylcholine (ACh) as their neurotransmitter, the autonomic ganglionic fiber uses ACh or norepinephrine (NEP) (Benarroch 2020).

Sympathetic Activity The sympathetic preganglionic neurons are located in the ILM in the spinal column from thoracic 1 to lumbar 3 segments. With the potential of being activated by the segmental visceral or somatic afferents, they work in different ways to mediate sympathetic responses driven by inputs coming from the hypothalamus and the upper part of the medulla. The preganglionic sympathetic axons arrive at paravertebral, prevertebral, terminal ganglia, and adrenal medulla. Paravertebral and prevertebral ganglia innervate tissues and organs releasing NEP. The adrenal medulla releases epinephrine (EP) into the blood (Coote and Spyer 2018). Norepinephrine and EP stimulate specific receptors (Farzam et al. 2021), the adrenoreceptors α1,2 and β1,2,3 in the heart, vessels, bronchus, bladder, and uterus. Activation of the postsynaptic α1 receptor by NEP and EP produces vasoconstriction and changes in renal hemodynamics, while the α2 presents pre- and postsynaptically, reducing the liberation of NEP and decreasing SNA. Activation of β1 by EP, which binds with greater affinity than does NE, increases heart rate, cardiac contractibility, and drives renin release. Therefore, the effects of SNA are the increment of peripheral resistance, cardiac output, and renin-angiotensin-aldosterone system (RAAS) activity. In contrast, the β2 receptor, activated by epinephrine, produces mild smooth muscle relaxation. Although the β3 receptor plays a role in metabolic components, it has none in BP control. The SNA is of special relevance to BP control in the innervation of the kidney. The sympathetic fibers in the kidney, both efferent and afferent with a proportion of approximately 90% and 10%, respectively, penetrate along the renal artery wall. In the kidney ilium, they branch out and penetrate the cortex and the juxtaglomerular area (Ana Lusch et al. 2014). Renal SNA efferent increases tubular reabsorption of water and

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sodium, renin release, renal vascular resistance, and it reduces glomerular filtration. The afferent signal travels to the CNS boosting SNA. The relevance of renal SNA in BP regulation is emphasized by the use of renal denervation to reduce BP values in patients with hypertension that is difficult to control (Azizi 2021), even in the absence of an antihypertensive drug regimen (Mahfoud et al. 2021).

Parasympathetic Activity In contrast to the widely spread SNS, the PSN has the preganglionic neurons in the visceral efferent part of the brainstem and in the sacral spinal region (Garamendi-Ruiz and Gómez-Esteban 2019). The ganglia are outside or within the wall of the target organs in which ACh exerts the function through the muscarinic receptors, μ1,2,3. The structure of the PSN results in organ-specific reflexes. Relevant for BP regulation are those driven by the vagus nerve which provides preganglionic innervation to autonomous ganglia in the thorax. Fibers emerging from the DMV innervate ganglia of the heart and lungs, whereas neurons of the NA innervate ganglia of the sinus node in the heart with a reduction in heart rate (Standish et al. 1994).

Baro- and Chemoreflexes The principal mechanism for the short-term control of BP is the baroreflex, providing continuous buffering of acute changes in BP by sympathetic vasomotor and cardiovagal outputs (Lauder et al. 2020). The arterial baroreceptors are located in the wall of the carotid sinus and the aortic arch, innervated by the glossopharyngeal and the vagus nerves, respectively. Under normal resting conditions, heart rate is regulated by the NA, providing a tonic vagal activity controlling beat-to-beat in the sinus node of the heart, and the SNA influences the peripheral resistance. An increment in stretch by pulse pressure stimulates the afferent synapse on neurons of the NTS initiating a response which inhibits the SNA, producing

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vasodilatation. In parallel, cardiovagal neurons of the NA produce bradycardia. In response to a decrease in pulsatile blood pressure, the afferent input of the baroreceptor decreases with an increment in SNA, which results in vasoconstriction and tachycardia due to a reduction in vagal tone. In addition, as a result of the relationship between cardiovagal output and respiration, heart rate decreases during inspiration and increases during expiration. A second task integrated with breathing is the regulation of tissue perfusion. Cardiac output, BP, and SNA can be modified according to necessity in response to signals coming from the arterial chemoreceptors (Iturriaga et al. 2021). These chemoreceptors, located in the carotid body and in the aortic wall, respond mainly to PO2 in the blood and less to PCO2 and pH. The generated output signals travel through the glossopharyngeal and vagus nerves to the NTS and the dorsal respiratory group, composed of inspiratory neurons located in the medulla. The response, controlled by the RVLM, differentially regulates cardiac output, BP, and the perfusion of organs (Guyenet et al. 2010). Furthermore, the signals of the carotid body and aortic chemoreceptors interact with signals from the pCO2 neuron-sensitive in the CNS, contributing to the modification of the SNA.

Humoral Components of BP Regulation Besides the activity of the nervous system, humoral factors also play a key role in BP regulation. Neural and humoral mechanisms continuously interact; both become either activated or downregulated (Fig. 4). This interaction results in mid-term control of peripheral resistance and blood volume.

Renin-Angiotensin-Aldosterone System The renin-angiotensin-aldosterone system (RAAS) regulates many vital body functions, making it one of the key mechanisms in BP regulation. Although

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Fig. 4 Main humoral system in BP regulation. Peptides stimulate or decrease diverse mechanisms in the vessels (vasoconstriction/vasodilatation) and in the kidney (diuresis and sodium reabsorption). Angiotensin II activates the SNA which in turn contributes to the activity of systemic

peptides. Shaded blue promotes BP reduction, and shaded white promotes BP increment. GN ganglionic, ILM intermediolateral medulla, NTS, PVN paraventricular nucleus, RVLM rostral ventrolateral medulla, SNA sympathetic nervous activity

the relevance to BP regulation was the first to be recognized, its role in many other physiological processes extends its importance. Continuous research has identified both the components of the system, peptides and receptors, as well as the intracellular mechanisms its activation triggers (see ▶ Chap. 3, “Vasoactive Factors and Blood Pressure in Children”). Precursors and enzymes for the formation and degradation of biologically active peptides form a complex network ubiquitous in the body.

The peptides of the system not only produce systemic action as an endocrine achievement but also work locally in a paracrine/intracrine manner (Leenen et al. 2017). The initial RAAS components are prorenin and renin (RN), produced mainly in the juxtaglomerular apparatus in response to a low sodium concentration in the distal tubule or reduction in the renal perfusion pressure or increased activity of the SNS. There is a circulating RAAS and local tissue RAASs. In the circulating RAAS, once secreted in its inactive

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form, prorenin, binds to the prorenin receptor (PRR), activating renin, which then cleaves the peptide angiotensin I (Ang I) from angiotensinogen, which is synthesized in the liver. Subsequently, angiotensin-converting enzyme (ACE1), present in the endothelial pulmonary cells and within multiple tissues, cleaves two amino acids from the C-terminus of Ang I resulting in angiotensin II (Ang II), the most active peptide of the RAAS. Of note, ACE1 also reduces bradykinin concentration. Ang II is further cleaved into other peptides – (i) angiotensin 1–7 (Ang I–7) by the action of the angiotensin-converting enzyme 2 (ACE2), which cleaves one amino acid from the C-terminus of Ang II; (ii) angiotensin III (Ang III) by the enzyme aminopeptidase A in the CNS; and (iii) angiotensin IV (Ang IV) a peptide converted from angiotensin III by the angiotensin IV receptor (AngIVr) (Fig. 5) (Carey 2013; Shu et al. 2021). The actions elicited by the peptides described above originate in three G protein-coupled receptors: the angiotensin II type 1 receptor (AT1r), the

angiotensin II type 2 receptor (AT2r), and the MAS receptor. Also present is one Ang IV binding site, a type II transmembrane zinc protein (Karnik et al. 2015). The distribution of these receptors in the CNS is variable. The AT1-receptors are present not only in areas poorly protected by the blood-brain barrier, the circumventricular organs, but also in other areas, such as the supraoptic, preoptic, and ventral medial nuclei, indicating the relevance of the neuronal synthesis of the RAAS elements. The AT2r are located in areas distinct from those of the AT1r (Guimond and Gallo-Payet 2012). Moreover, the AngIVr, although similarly distributed as the AT2r, are also present in the hippocampus, a location at which no other AT-receptors exist. The principal effects of RAAS peptides in BP regulation are the following:

Fig. 5 Renin-angiotensin-aldosterone system: active peptides, enzymes, receptors, and non-active peptides. Prorenin binds to the prorenin receptor (PRR), activating renin, which then cleaves angiotensinogen to produce angiotensin I, which is then cleaved to angiotensin II by ACE1. Subsequently, ACE2 cleaves angiotensin II to produce angiotensin 1–7, aminopeptidase A produces angiotensin III, which through the receptor ATIVr is converted in

angiotensin IV. These four peptides then are able to bind to three G protein-coupled receptors, AT1r, AT2r, and MASr, and a type II transmembrane zinc protein ATIVr. Angiotensin II binding to AT1r stimulates aldosterone synthesis and secretion. Active peptides (black square), enzymes (light blue square), receptors (dark blue square), and nonactive peptides (red)

• Angiotensin II exerts its action mainly by stimulating the AT1r. This increases intracellular MAP kinase inducing gene expression,

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producing vasoconstriction and aldosterone secretion in the cortical layer of the adrenal glands. It regulates water and electrolyte balance, peripheral resistance, and BP levels. Besides vasoconstriction, Ang II induces cellular growth and cell migration, inflammation, and oxidative stress by activating other intracellular mechanisms. Activation of the AT2r partly reduces the contraction induced by the AT1r by inhibiting cell proliferation and releasing nitric oxide (NO). Besides its systemic action, Ang II is secreted in the CNS at synaptic clefts, contributing to stimulation of the postsynaptic AT1r and consequently boosts SNA (Hussain and Awan 2018). • Angiotensin 1–7, in contrast to Ang II, through coupling with the MAS-receptor and AT2r, can restore endothelial function by increasing endothelial nitric oxide synthase (eNOS) and inhibiting NOX. Additionally, as a partial antagonist of AT1r, Ang 1–7 also contributes to the final effect of vasodilation. Furthermore, Ang 1–7 may be a regenerative agent in the cardiovascular system, since it stimulates endothelial and endothelial-progenitor cells (Roks et al. 2011; Diz et al. 2011). • Angiotensin III, through AT1r and AT2r, increases SNA and vasopressin release, and is more potent than Ang II in the brain (Huber et al. 2017). • Angiotensin IV is critical for dopamine and acetylcholine release, and appears relevant for enhancing memory, but not BP regulation (Gard 2008). The RAAS, as the key humoral component of BP regulation, exerts its impact by increasing peripheral resistance through vasoconstriction and by controlling blood volume through actions in the kidney and in stimulating aldosterone secretion (Ames et al. 2019). In the CNS, components of the RAAS exert both systemic and local actions. Systemic actions of the RAAS are driven by the concentration of Ang II in the blood and within the CNS has greatest effect in those areas of the brain in which there is a minimal or nonexistent blood-brain barrier. Further, a local tissue RAAS exists in the CNS in which components are

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synthesized de novo. Astrocytes are the main angiotensinogen source in the brain, and neurons have an intracellular RAAS with membranebound receptors, as well as receptors in neuronal mitochondria and nuclei (Sumners et al. 2020; Cosarderelioglu et al. 2020). Angiotensin II and Ang III in the adrenal gland stimulate the synthesis and secretion of aldosterone, which promotes transepithelial sodium transport, chloride reabsorption, and potassium/magnesium secretion in the kidney. Aldosterone activity is mediated by the activation of the mineralocorticoid receptor (MR), ubiquitous in many cellular systems (Bollag 2014). Due to its low selectivity, MRs bind not only aldosterone but also cortisol in humans. The distribution of this receptor in many organs involved in cardiovascular homeostasis, such as the brain, heart, kidney, and vessels, explains why, in addition to modifying sodium reabsorption, the MR mediates other relevant physiological actions triggered by cortisol binding (Sztechman et al. 2018; please also see ▶ Chap. 2, “Cardiovascular Influences on Blood Pressure”). Among these is a prolonged response in presynaptic neurons of the ILM triggered by binding of aldosterone to the MR (Nakagaki et al. 2012).

Atrial Natriuretic Peptides Atrial natriuretic peptides (ANPs) are a group of hormones that contribute to BP regulation throughout the vascular tree, kidney, and neural tissues. After the description of the first ANP, two other peptides, the brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), were identified. While ANP is mainly synthesized in the cardiac atria, BNP is synthesized in cardiac ventricles, and CNP is synthesized in the endothelial vascular cells and the CNS. Once synthesized, these peptides bind to plasma membrane receptors, receptor A (NPRA) and B (NPRB). While NPRA is activated by both ANP and BNP, NPRB is only activated by CNP. ANP increases the glomerular filtration rate and inhibits sodium and water reabsorption in

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the kidney, resulting in natriuresis and diuresis (Goetze et al. 2020). Moreover, these natriuretic peptides decrease renin secretion and aldosterone synthesis in the adrenal gland, produce relaxation of vascular smooth muscle cells, and increase vascular permeability. Thus, they counteract the actions of Ang II and vasopressin (Hodes and Lichtstein 2014). Natriuretic peptide receptors are broadly expressed in the CNS, and their presence in the area of the lamina terminalis of the third ventricle suggests that the ANPs can be synthetized by neurons or bound from the circulation. Although no central relevant mission in BP control has been identified, they seem to modulate the activation of Ang II and vasopressin in the CNS (dos Santos Moreira et al. 2017).

The Apelin System Recently, a novel apelinergic system (AS) with a putative role in water homeostasis and blood pressure regulation has been described (Janssens et al. 2021; Chapman et al. 2021). This system, composed of the two short-lived peptide ligands, apelin and elabela, and a G protein-coupled apelin receptor, appears to possess activity reciprocal to that of the RAAS. Apelin receptors (Apr), identified in endothelial cells, vascular smooth muscle, and cardiomyocytes, once stimulated, produce arterial and venous vasodilatation (Gupta et al. 2016). In the kidney, they increase renal blood flow and diuresis with mechanisms linked to NO generation. Vasopressin, apelin, and the receptors are co-localized in the hypothalamus; they also interact in the CNS.

The Kidney, Fluid Volume, and Salt Intake The kidney is the main organ that modulates volume homeostasis, in close relation with neurohumoral factors. As discussed above, renin secretion by the juxtaglomerular apparatus and sympathetic activation by the efferent and afferent nerves contribute to BP regulation. The other main contributor is the pressure-natriuresis curve.

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The pressure-natriuresis curve is a mechanism whereby BP elevation increases diuresis and natriuresis to restore equilibrium (O’Connor and Cowley 2010). Changes in renal interstitial pressure and in proximal tubular sodium transporters largely control sodium reabsorption (Palmer and Schnermann 2015). Renal medullary blood flow is relatively poorly autoregulated, and when kidney perfusion increases, glomerular efferent arterioles of the juxtamedullary nephrons augment the flow to the vasa recta. Consequently, capillary hydrostatic pressure increases and is transmitted to the renal interstitium (Sadowski and Bądzyńska 2020). This pressure increment produces a rapid reduction in sodium reabsorption in the proximal tubule by internalization of apical Na+/H+ exchanger isoform 3 and the sodium-phosphate cotransporter along the microvilli of the proximal tubule. Under normal conditions, the proximal tubule reabsorbs two-thirds of the filtered sodium (McDonough 2010). Concurrently, the RAAS and SNA contribute to the dynamic intracellular transposition of the sodium transporters. Further, washout of the medullary solute gradient contributes to the volume regulation in the distal nephrons (Franco and Oparil 2006). Excess salt intake is rapidly eliminated by the kidney, although when the capacity is reduced or overload occurs, intravascular volume will increase. Relatively reduced sodium excretion capacity is present in about 25% of people, categorized as salt-sensitivity (Päivä et al. 2006). In such persons, reduced flow-mediated vasodilation is observed as a consequence of several elements – enhanced vasoconstriction, decreased capacity to modulate SNA, and increased asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor that reduces NO activity (Päivä et al. 2006). Sodium accumulation in the dermal and lymphatic interstitium and other tissues, stored in hypertonic concentrations with proteoglycans, may activate immune reactions (Wiig et al. 2013). The putative role of sodium stored in this manner is not yet well understood (Chachaj and Szuba 2020). Changes in body water/sodium balance are also controlled by ANPs and the CNS. Atrial natriuretic peptide induces natriuresis and diuresis

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by increasing the glomerular filtration rate and inhibiting sodium reabsorption, thereby counteracting the activity of the RAAS (Bie and Evans 2017). Through fibers from the lamina terminalis and the VIIth, IXth, and Xth cranial nerves, the CNS receives information about extracellular fluid osmolarity, sodium concentration, volume receptors, arterial/cardiopulmonary baroreceptors, sense of taste, and BP. Once integrated in the NTS, this information triggers appropriate sympathetic, endocrine, and behavioral responses.

The Vasculature and Nitric Oxide The vascular structure and function of arteries and arteriolar vessels are key elements of BP regulation. Peripheral resistance in the vasculature is determined by the caliber, reactivity, and elasticity of vessels. Autonomic activation, circulating humoral factors, and mechanical forces generate an environment in which endothelial and smooth muscle cells establish the caliber of the vessels. Additionally, changes in the muscular layer and extracellular matrix of vessels form the basis of vascular remodeling, which increases peripheral resistance. Beyond responses to various extravascular stimuli, the endothelium modulates vascular tone by synthesizing and releasing vasoactive factors with vasodilatory capacity (NO, prostacyclin, hyperpolarizing factor, low level endothelin-1) or through vasoconstriction (thromboxane A2, high level endothelin-1). Peripheral resistance increases due to the action of circulating Ang II, catecholamines, vasopressin, high levels of endothelin-1, and thromboxane A2. This is modulated by the intracellular machinery present in the endothelial and small muscle cells. In endothelial cells, the small GTPase RhoA and the downstream target Rho kinase reduces the bioavailability of NO, favoring vasoconstriction. On the other hand, in the smooth muscle cells, the G signaling proteins (RGS) 1 and 2, and the RhoA increase vasoconstriction. Furthermore, the activation of potassium channels (Shvetsova et al. 2021) produces cellular hyperpolarization, increasing vasorelaxation and counteracting contraction induced by different

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vasoconstrictors (Jackson 2017) and SNA (Martínez et al. 2009). Endothelin-1, produced and released by the endothelial cells, in low levels stimulates the endothelin receptor B (ErB), which in turn increases the synthesis of vasodilatory NO and prostacyclin PGI2, relevant to limiting the vasoconstriction produced for the stimulation of endothelin receptor A (Kostov 2021). The vasodilatory capacity of arterial vessels differs, depending on their structure: large arteries, branched or arteriolar. While the large vessels utilize preferent NO, the arteriolar ones use the endothelium-dependent hyperpolarization factor, which through the myoendothelial junctions is transmitted to the smooth muscle cells (Lemmey et al. 2020). Flow-mediated vasodilatation is an endothelial mechanism which involves generation of NO by eNOS, prostacyclin, and the opening of calcium-sensitive potassium channels (Tomiyama et al. 2017). Laminar flow elongates fibers in the direction of flow and activates mechano-sensors, G protein-coupled receptors, in the endothelial surface (Hu et al. 2021). In contrast, turbulent flow, which is generated in bifurcations, activates inflammatory pathways (Amaya et al. 2015). The vasodilatation induced by NO can be blunted by the production of reactive oxygen species (ROS) and by the presence of asymmetric-dimethylarginine (ADMA) (Tsikas 2020). Activation of NOX by Ang II, in the vessels, produces superoxide and other ROS, inactivating NO and the cofactor for NO synthase, tetrahydrobiopterin, producing vasoconstriction (Pautz et al. 2021). The impact of ROS from other sources is not relevant for BP regulation. An endogenous competitive inhibitor of NO synthase, the posttranslational modification of arginine, ADMA, reduces the vasodilatory capacity (Jankovic et al. 2017; Poeggeler et al. 2021). Beside the flow-induced vasodilatation, smooth muscle cells are able to change the status of vasoconstriction or vasodilatation in response to intravascular pressure. In this myogenic reactivity, several mechanisms have been implicated (Kim and Hong 2021), among them the role of a variety of transient receptor potential channels (Liu et al. 2021) which are in charge of

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maintaining the resting membrane potential and the intracellular calcium dynamics in smooth muscle cells.

Circadian Variation of Blood Pressure Recent evidence supports the concept that cardiovascular and kidney function have variations through the circadian clock. Under normal conditions, BP rises during the morning, starting to increase about 1 h prior to awakening, reaching its highest level later, which is maintained until late afternoon. Thereafter, BP decreases progressively until its nadir, around 3:00 AM (Costello and Gumz 2021). Circadian variation (CV) in the brain, heart, kidney, and vessels prepares the transition from sleep to activity. This pattern seems independent of an individual’s sleep/wake or fasting/feeding patterns, although recent studies have challenged the total independence of CV. Physical activity impacts CV, increasing BP during activity and decreasing it with night’s rest (Bass and Lazar 2016). The presence of hypertension-mediated organ damage, mainly in the kidney, blunts the physiological BP nocturnal fall (Redon and Lurbe 2008). Circadian rhythm in the levels of peptides (melatonin, plasma renin activity, ACE activity, Ang II, aldosterone, ANP, NO, endothelin-1) with activity on BP regulation around the clock has been described (Zhang et al. 2021). Melatonin is inhibited by light; plasma renin and ACE activity, Ang II and aldosterone peak just before the usual time of awakening; ANP is antiphase to BP; and NO increases during wakefulness, the early stages of sleep deprivation and the diurnal increment of endothelin-1. If these changes are in response to BP oscillation or play a relevant role in the circadian variability it is not well established for some of them. In mammals, CV control is located in the suprachiasmatic nucleus (SCN) which is stimulated directly by light through the retinal hypothalamic tract (Dibner et al. 2010). Astrocytes of the SCN generate a complex light-induced mechanism involving glutamate as the neurotransmitter, which

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induces a circadian secretion of neurotransmitters, stimulates SNA, and reduces PSNA activity. The gears of the clock are composed of activators, CLOCK and BMAL1, that induce the expression of their own repressors, PER and CRY, forming a negative feedback loop (Allada and Bass 2021). The duration of the stimulus is regulated posttranslationally, including phosphorylation by kinases. Once astrocytes become activated, they synchronize the peripheral clock genes located mainly in the kidney, brain, heart, and vessels resulting in rhythms of clock gene expression (Patke et al. 2020). This system regulates the diurnal rhythm of many biochemical pathways with the rhythmic production/secretion of peptides and hormones with cardiovascular and renal actions (Lecarpentier et al. 2020).

Conclusion Blood pressure control involves the interaction of multiple systems with a close link between neurohumoral and autonomic mechanisms to maintain in equilibrium the main BP determinants, cardiac output, peripheral resistance, and blood volume. Overall, the CNS paces the activity of the different mechanisms implicated, processing and responding to stimuli coming from both cortical, subcortical, and visceral signals, as well as from circulating humoral factors. Autonomic functions, coupled with humoral peptides, execute the orders mainly in the vessels, kidney, and heart, which themselves possess complex mechanisms of autoregulation that modulate the received inputs. Advances in molecular biology techniques and genetic experimental models continue to provide more precise information about the intracellular signals that regulate cellular communication among these many systems.

Cross-References ▶ Cardiovascular Influences on Blood Pressure ▶ Vasoactive Factors and Blood Pressure in Children

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2

Cardiovascular Influences on Blood Pressure Manish D. Sinha and Phil Chowienczyk

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Relevance of BP Level During Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Hemodynamic Phenotypes of Primary Hypertension and Their Clinical Relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Components of Blood Pressure: Static and Pulsatile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Pulsatile Components of Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Physiological Changes in CO, SVR, and HR During Childhood . . . . . . . . . . . . . . . . . . . . 26 Evidence for a “Hyperdynamic State” in Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Evidence of a Vascular Change in the Early Phase of Hypertension . . . . . . . . . . . . . . . 28 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Abstract

M. D. Sinha (*) Department of Paediatric Nephrology, Evelina London Children’s Hospital, Guys & St Thomas’ NHS Foundation Trust, London, UK Kings College London British Heart Foundation Centre, London, UK e-mail: [email protected] P. Chowienczyk Kings College London British Heart Foundation Centre, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_3

The study of hemodynamic mechanisms in children and young people with primary hypertension has been neglected historically. An understanding of the abnormalities in the function of the large arteries, the left ventricle, and their interaction may be important to elucidate the development and observed effects of hypertension. In this chapter, we discuss cardiovascular influences that determine blood pressure; highlighting the static and pulsatile components of blood pressure and review the published literature evaluating hemodynamics in children with hypertension. We compare 21

22

M. D. Sinha and P. Chowienczyk

findings in hypertensive children with those with normotension. Increasing data support a cardiac and large artery component in early hypertension in children and young people. Increase in cardiac output appears to be the earliest identifiable abnormality in children and young people (CYP) with increased systemic vascular resistance (SVR) in hypertensive young adults. Given the tracking of hypertension from children to adults, the finding of a cardiac/aortic rather than peripheral vascular changes associated with primary hypertension has implications for the etiology of hypertension both in children and adults. It also has implications for the best treatment in children.

Introduction Primary hypertension (PH) is a major health burden globally and one of the main contributors to excess morbidity and mortality, accounting for a 1/3rd of ischemic heart disease and 2/3rds of strokes among adults (Egan et al. 2019). In children and young people (CYP), there is an increasing prevalence of PH, mirroring the childhood obesity epidemic, with a steady increase over the last two decades (Litwin and Kułaga 2021; Lurbe et al. 2016; Song et al. 2019). Thus, although the prevalence of PH is reported between 3% and 5% in those aged 6000 pre-pubertal, 9–11-year-olds were evaluated. CO or SVR were not measured when the participants were aged 9–11 years. The investigators reported that compared with those with normal weight, overweight, and obese children (~20% of the study cohort), had significantly higher BP, HR, larger brachial artery diameter, higher flow-mediated dilation, and lower pulse wave velocity. In a subsequent report from the same cohort (Park et al. 2018), including 2110, 17-year-olds, the authors reported increased BP was associated with an increase in both CO (SV and HR) and SVR, with higher quintiles of systolic BP associated with higher SV, higher HR, and higher SVR. The proportional contribution made by SV, HR, and SVR to mean arterial pressure differed little by systolic BP quintile; and

55

51

86

Normal weight OW/ Obese weight

Pierce et al. (2013)

38 38 24

Male (%) 46 91 80

141

NTN 531 Pre-HTN 65 HTN 127

Subjects NTN ISH SDH

Sample size 722 93 135

Urbina et al. (2011)

Study ID, year McEniery et al. (2005)

17

17

17 19 20

Age (years) 20 20 20

30

21

29.4 34.1 38.7

BMI (kg/m2) 23.1  3.6 25.7  4.1 25.7  4.3

132/62

125/63

111/66 119/68 129/73

BP, mmHg 115/71 146/78 141/95

_

68  1

_

_

_

70  2

83  1

_

_

_

PWV (m/s) 5.8  0.3 6.3  0.4 6.0  0.5

66  1 _

SVR (mmHg. min/L) 12.6  4.6 12.5  3.4 15.9  4.3

62  2

SV (ml/s) 83  2 93  24 78  18

81  1

HR (bpm) 68  11 69  12 75  10

5.8  0.9 6.4  1.1 7.1  1.3

CO (L/min) 6.9  1.9 8.1  1.9 6.8  1.7

66  11 70  10 72  12

PP, mmHg 44  8.1 66  7 46  9

81  8 45  11 86  8 51  11 91  11 56  14

MAP, mmHg 85  7 99  6 111  7

Table 1 Summary of key hemodynamic findings in young adults with primary hypertension

(continued)

ISH had higher MAP, PWV, CO and SV compared with NTN group. Those with SDH, had the highest MAP and SVR and lower CO. HR higher in pre-HTN and HTN groups compared to NTN. Obese/ overweight had 7% higher cfPWV but. 5% lower crPWV. No difference in HR between groups. PWV measured but raw data not reported

Main Findings (s)

2 Cardiovascular Influences on Blood Pressure 29

Subjects

Sample size

Male (%)

Age (years) M/F 22/23

BMI (kg/m2) M/F 22.4/22.5

BP, mmHg male female 112/ 107/ 69 69 124/ 123/ 72 74 131/ 122/ 79 82 148/ 143/ 88 96

MAP, mmHg M/F 80/78

PP, mmHg M/F 44/38

CO (L/min) M/F 7.5/6.2

HR (bpm) M/F 63/66

SV (ml/s) M/F 105/85

SVR (mmHg. min/L) M/F 907/1055

PWV (m/s) M/F 5.6/5.4

Main Findings (s)

NTN

1489

27

Both sexes exhibited significantly higher HR and Elevated 464 74 22/22 23.3/23.8 83/84 52/50 8.2/6.8 64/69 110/85 855/1031 5.7/5.6 CO with worsening S1 HTN 693 66 23/24 25.1/23.8 87/89 52/39 8.5/6.6 66/71 113/83 883/1127 6.0/5.8 HTN phenotype. S2 HTN 499 71 26/28 26.6/26.4 97/105 59/46 9.0/6.9 70/75 116/83 905/1311 6.5/6.9 Units of SVR in Dynes x s/cm5 BMI, body mass index; BP, blood pressure; MAP, mean arterial pressure; PP, pulse pressure; CO, cardiac output; HR, heart rate; SV, stroke volume; SVR, systemic vascular resistance; PWV, pulse wave velocity; NTN, normotension; ISH, isolated systolic hypertension; SDH, systodiastolic hypertension; Pre-HTN, prehypertension; AIx, augmentation index; OW, overweight; cfPWV, carotid femoral PWV; crPWV, carotid radial PWV; S1 HTN, stage 1 hypertension; S2 HTN, stage 2 hypertension; M/F, male/female

Study ID, year Nardin et al. (2018)

Table 1 (continued)

30 M. D. Sinha and P. Chowienczyk

Subjects

60

73 73 53

15

15 15 15

CKD þ HTN RV HTN PH NTN

Cheang et al. (2019)

45 55 55

60 62 38

NTN HTN WCH

Tokgoz et al. (2018)

44

52

23

39

32

37

53 58

57 54

101 53

38 45

67 34 48

61 85 21

NTN ObeseHTN ObeseNTN

50 47

Male (%)

68 19

Sample size

Wojtowicz et al. (2017)

Zahka et al. NTN (1981) ObeseNTN HTN NTN Chirico et al. HTN (2015) NTN GarciaEspinosa HTN et al. (2016) Pierce et al. Healthy (2016) weight Overweight

Study ID, year

12 14 12

13

14 13 14

16

15 15

16

16

11 11

15 12 13

14 15

20 26 21

21.4 21.2 22.7

122/63 128/67 103/52

125/75

111/69 118/78 114/69

109/76

103/71 114/80

0.11 2.76 3.8

124/59

115/60

105/57 119/63

141/94 91/55 111/71

115/69 117/71

BP, mmHg

29

22

21.2 25.1

28.7 19.8 26.4

24.6 26.9

BMI Age (years) (kg/m2)

56  2 65  3

77  1 78  1

50  12 3.6  1.2 59  13 3.6  1.2 62  10 3.8  1.2 51  1 3.7  1.2

88  9 92  11 74  6

73.6  29

64  34 79  36

64  15 66  14

88  38 56  12 61  15

79  26 86  28

(ml/s)

SV

73  1.2 50  7 83  1.2 47  5 73  1.2 51  6

78  1.3 47  9

83  9 83  11 81  8

4.9  0.5 4.8  0.5 5.0  0.4

95  9

74  19

33  10 5.4  1.9

87  10

67  13 72  22

32  9 4.3  1.5 34  12 6.3  1.7

64  2

82  7 91  9

4.3  0.2

3.6  0.1

61  2

77  14 80  13

48  7 56  9

68  7 77  9

4.9  0.7 5.3  0.7

76  17 76  9 85  10

110  20 47  21 6.6  3.0 67  4 36  5 4.2  0.8 84  5 40  6 5.2  1.2

HR (bpm) 72  11 71  11

46  9 46  9

84  9 86  8

CO (L/min) 5.7  1.9 6.0  1.8

PP, mmHg

MAP, mmHg

Table 2 Summary of key hemodynamic findings in children and adolescents with primary hypertension

25  5.5 24  4.3 20  3.6

27  5.3

16.1  5.2

18.9  6.7 14.5  4.1

1512

1786

13.8  2.4 14.6  2.6

16.6  8.1 18  4 17  5

14.8  5.2 14.3  4.4

SVR (mmHg. min/L)

4.3  0.4 5.3  0.6 5.1  0.4

5.0  0.74

4.7  0.3 5.1  0.67

5.2  0.1

5.2  0.1

4.9  0.7 5.2  0.8

(m/s)

PWV Main finding

Cardiovascular Influences on Blood Pressure (continued)

Increased CO in HTN compared to NTN children, including in subgroup analysis excluding obesity CO higher and peripheral resistance lower in overweight. Units of SVR in Dynes x s/cm5 Obese-HTN group had significantly higher PWV and CO compared to both other groups. HR, SV, SVR and PWV were not significantly different between the groups. BMI shown as BMI z-score No difference in 24 hr. DBP, HR or CO between groups. Hemodynamics measured using 24-hour monitor. Cardiovascular co-morbidities including obesity excluded. Renal HTN associated with increased SVR and normal arterial compliance (C). PH had decreased C and normal SVR. RV HTN had both increased SVR and C. SV shown as ml/m2

Increase in CO in HTN compared with NTN children

No significant difference in CO and HR between groups. SVR calculated from results in study

2 31

66 30 22 70

NTN HTN

NTN Pre-HTN HTN Severe HTN

Li et al. (2020a)

Obrycki et al. (2020)

76 80 82 74

15 16 15 16

14 15

10

61

46 71

11

107/62 137/71

117/65 130/71 136/73 139/65

0.02 0.88 1.28 1.11

117/72

112/70

BP, mmHg

21 22.8

23.7

18

BMI Age (years) (kg/m2)

53

Male (%)

76  10 90  15

MAP, mmHg 80  16 85  14

4.5  0.4 4.8  0.5

4.9 6.2 6.8 6.7

72  13 71  12 71  14 73  11

73  11 81  15

HR (bpm)

CO (L/min)

45  12 4.5  1.6 66  17 5.3  1.5

PP, mmHg

65 82 94 89

63  18 64  17

63  12

62  12

(ml/s)

SV

1 1 0.9 0.9

18  6.2 19.3  6.1

1.1  0.1

1.1  0.1

SVR (mmHg. min/L)

5.5 5.8 6 6.1

5.9  1.3 5.9  1.1

4.6  0.3

4.4  0.3

(m/s)

PWV

35% had hypertensive ambulatory BP profile. 24 hr. PWV score highest in overweight HTN group. Hemodynamics measured using 24-hour monitor HTN group had higher CO, HR, increased proximal aortic stiffness PWV 3.3  1.4 versus 2.5  0.8 m/s; P < 0.005) and LV ejection velocity compared to NTN. No significant difference in SVR between groups Hemodynamics measured using 24-hour monitor. BMI shown as BMI z-score; Units of SVR unclear

Main finding

BMI, body mass index; BP, blood pressure; MAP, mean arterial pressure; PP, pulse pressure; CO, cardiac output; HR, heart rate; SV, stroke volume; SVR, systemic vascular resistance; PWV, pulse wave velocity; NTN, normotension; HTN, hypertension; WCH, white coat hypertension; CKD, chronic kidney disease; RV HTN, renovascular hypertension; PH, primary hypertension; Pre-HTN, prehypertension; LV, left ventricular; Amb-preHTN, ambulatory prehypertension

Healthy 51 weight Overweight 31

50 31

Subjects

Stabouli et al. (2020)

Sample size

Study ID, year

Table 2 (continued)

32 M. D. Sinha and P. Chowienczyk

2

Cardiovascular Influences on Blood Pressure

those with the highest BP level had the highest BMI. As was discussed eloquently in an accompanying editorial, the initial hyperkinetic hemodynamic profile observed in pre-pubertal children had now changed to one with an increase in SVR although if and when this change had happened remained unknown (Falkner 2018). Early vascular changes in older adolescents were described by Urbina et al. in a large cohort of hypertensive and normotensives (Urbina et al. 2011). The investigators reported a stepwise increase in arterial stiffness measures including reduction in large artery compliance, increase in pulse wave velocity, and augmentation index with worsening BP levels (Urbina et al. 2011). These findings have been confirmed by other investigators with those with hypertension having higher arterial stiffening when compared with normotensives (Cilsal 2020; Kollios et al. 2021; Lurbe et al. 2012; Peluso et al. 2017; Stergiou et al. 2010). Other reports have highlighted obese hypertensives to have higher PWV when compared with nonobese normotensive adolescents (GarciaEspinosa et al. 2018; Kulsum-Mecci et al. 2017; Močnik et al. 2016). There are several datasets that provide evidence of the vascular tree being involved in CYP with PH. A recent systematic review highlighted the evidence for early development of arteriopathy in CYP with PH and suggests a disparity between structural (as assessed by carotid intima medial thickness, cIMT) and functional (as assessed by carotid-femoral PWV, PWVcf) impairment of the arterial tree (Azukaitis et al. 2021). Studies have also described neurocognitive involvement in those with PH highlighting impact of hypertension on the vascular tree (Uddin et al. 2021). Finally, both macrovascular and microvascular components of the arterial tree are impacted by early hypertension as shown in a recent study by Rogowska and colleagues, who reported close association between macrovascular injury expressed as increased cIMT and microcirculation injury expressed as increase of foveal avascular zone in retina (Rogowska et al. 2021). The precise hemodynamic characteristics involved remain unclear, but these phenomena represent a process of early vascular aging represented by increased

33

cIMT, PWV, and decreased flow-mediated dilation (Litwin and Feber 2020). To characterize the static and pulsatile components more precisely, Li and colleagues recently reported a comprehensive evaluation of central hemodynamics in young adolescents with PH and compared them with normotensive peers (Li et al. 2020a). Those with hypertension were predominantly male and ~2/3rd on antihypertensive medications. The investigators measured left ventricular outflow tract (LVOT) velocities and ejection volumes by echocardiography and additionally performed detailed pressure waveform studies including wave separation and waveintensity analysis. In those with hypertension, an increase in MAP was associated with an increase in HR and CO but not by SVR. Hypertensive adolescents also had higher flow and volume velocities across the LVOT, with a proportional increase in the ratio of forward and backward waves (Pf/Pb). Pulse pressure was ~40% higher in the hypertensive and associated with a proportional increase in central PWV and flow rate across the LVOT. The authors concluded that an increase in both steady-state and pulsatile BP are mainly due to cardiac rather than arterial properties in early PH. The cardiac overactivity was characterized by an increased heart rate and left ventricular ejection velocities with increased proximal pulse wave velocity. Evidence of change in ventricular contractility patterns was published by Gu and colleagues, who recently reported on changes in early systolic function as measured by first-phase ejection fraction (EF1), defined as the ejection fraction up to the time of maximal left ventricular rate of contraction (Gu et al. 2021). In children with primary hypertension, early systolic function was impaired with reduced EF1 in those with higher left ventricular mass index compared with normotensive children. This reduction of EF1 was associated with prolonged myocardial wall stress and increased E/e’ ratio (a surrogate marker of diastolic function) (Gu et al. 2021). Table 3 summarizes published studies reporting on pulsatile hemodynamics in PH in CYP (Cheang et al. 2019; García-Espinosa et al. 2016; Li et al. 2020a; Pierce et al. 2016; Urbina et al. 2011).

Healthy weight Overweight

CKD þ HTN RV HTN PH NTN

NTN HTN

Pierce et al. (2016)

Cheang et al. (2019)

Li et al. (2020a)

Oscillometric and tonometry devices

Tonometry and echocardiography

48  7 56  9

56  2

65  3

115/60

124/59

Tonometry and echocardiography

59  13 62  10 51  1

45  12 66  17

122/63 128/67 103/52

107/62 137/71

Magnetic Resonance Imaging

50  12

125/75

105/57 119/63

Measurement method(s) Tonometry and echocardiography

PP, mmHg 45  11 51  11 56  14

BP, mmHg 111/66 119/68 129/73

No difference in AIx and AP

No difference in carotid AIx

Pf higher with some rise in Pb thought to be due to increased Pf. No difference in Pb:Pf ratio

Pf higher but Pb same so reflection coefficient lower in overweight. No difference in reflected wave transit time

Pulsatile components measured plus result Augmentation index Wave analysis Significant stepwise increase in AIx@75 from NTN to pre-HTN to HTN groups No difference in Both Pf and Pb higher in AIx@75 HTN, no difference in ratio, or reflection coefficient

LVOT flow at first systolic shoulder (U1) higher in HTN group

Peak aortic flow higher in overweight. Aortic impedence higher in overweight when adjusted for resistance (to account for body size) Computed aortic compliance lower in PH and renovascular HTN compared to controls

Ventricular outflow/aortic dynamics

Renal HTN associated with increased SVR and normal arterial compliance. PH had decreased compliance and normal SVR. RV HTN had both increased SVR and compliance Increase in pulsatility was explained by increased proximal aortic stiffness and increased left ventricular ejection velocity

Rise in central BP explained by rise in both forward and backward pressure wave components rather than increaser SVR or wave reflection BMI, cardiac output, and Pf are all correlates of increased LV mass in adolescents

Conclusion Pre-HTN in addition to HTN is associated with increased arterial stiffness

BP, blood pressure; MAP, mean arterial pressure; PP, pulse pressure; NTN, normotension; preHTN, prehypertension; HTN, hypertension; AIX, augmentation index; AIx@75, augmentation index at heart rate of 75 bpm; AP, augmentation pressure; Pf, forward pressure wave peak; Pb, backward pressure wave peak; LV, left ventricular; CKD, chronic kidney disease; RV HTN, renovascular hypertension; PH, primary hypertension; LVOT, left ventricular outflow tract

NTN HTN

Subjects NTN Pre-HTN HTN

Garcia Espinosa et al. (2016)

Study ID, year Urbina et al. (2011)

Table 3 Summary of key pulsatile hemodynamic findings in children and young people with primary hypertension

34 M. D. Sinha and P. Chowienczyk

2

Cardiovascular Influences on Blood Pressure

35

Fig. 4 Summary of possible hemodynamic mechanisms in primary hypertension in children and youth. An increase in early left ventricular ejection and aortic flow velocity (Ao flow) together with increased aortic pulse wave velocity (PWV) may cause an increase in pulse pressure (PP). Increased heart rate (HR) and stroke volume (SV) may lead to an increase in cardiac output (CO) which together with

normal or increased systemic vascular resistance (SVR) leads to an increase in mean arterial pressure (MAP). The increase in PWV may be primary or secondary to pressure dependence and increased MAP (dashed line). All these mechanisms could be caused by an increase in sympathetic drive, but many other potential underlying causes highlighted are possible. (Adapted from Li et al. 2020b)

Figure 4 integrates available data and represents a summary of our current understanding of hemodynamics in PH in CYP (Li et al. 2020b); an increase in MAP in early PH, a result of an increase in CO (and HR and SV), with less contribution of an increase in SVR; and the increase in PP, a result of changes in the LV contractility and increase in central PWV. As a result, different values of PP arise for the same value of MAP and represent the dynamic interaction of the ventricular–vascular coupling during heart contraction (Mayet and Hughes 2003). The cause of these changes remains unclear, but the sympathetic nervous system (SNS) is thought to be involved. Although not discussed in this chapter, it is important to remember that these hemodynamic patterns in PH are seen in a complex environment with data highlighting the role of several regulatory mechanisms (Coffman 2011) including genetic studies that have highlighted the heritability of BP components (Warren et al. 2017), the central role of the kidneys (Guyton 1991; Meneton et al. 2005), hypertension as an immune disorder (Litwin et al. 2013) [80], and the mechanisms highlighted in obesity and hypertension including the role of the dysfunctional adipocyte,

leptin-mediated SNS activation, and increased renin-angiotensin-aldosterone system (RAAS) activity (Brady 2017).

Conclusion In conclusion, cardiovascular influences on blood pressure remain underevaluated but may be of critical importance in understanding the development and consequences of pediatric hypertension. Increasing data support a cardiac and large artery component in early hypertension in children and young people. Increase in cardiac output appears to be the earliest identifiable abnormality in CYP with increased SVR in hypertensive young adults. Primary hypertension and obesity-related hypertension share several similarities, and it is likely that the duration and severity of obesity influences observed cardiovascular hemodynamics. The transition from systolic hypertension in CYP to diastolic hypertension in young adults is poorly understood but remains important to understand. An improved understanding of the involved hemodynamic component, “cardiac” as opposed to “vascular,” may help develop more focused

36

treatment strategies. Longitudinal studies and treatment trials targeting different hemodynamic phenotypes are needed to understand the clinical relevance of observations to date.

Cross-References ▶ Early Vascular Aging in Pediatric Hypertension Patients ▶ Endothelial Dysfunction and Vascular Remodeling in Hypertension ▶ Insulin Resistance and Other Mechanisms of Obesity Hypertension ▶ Ions and Fluid Dynamics in Hypertension ▶ Neurohumoral and Autonomic Regulation of Blood Pressure ▶ Salt Sensitivity in Childhood Hypertension ▶ The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation ▶ Vasoactive Factors and Blood Pressure in Children

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Vasoactive Factors and Blood Pressure in Children Ihor V. Yosypiv

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Renin-Angiotensin-Aldosterone System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Angiotensinogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Prorenin, Renin, and (Pro)renin Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Angiotensin-Converting Enzyme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Angiotensin II Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Angiotensin-Converting Enzyme 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Developmental Aspects of the RAAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Aldosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Kallikrein-Kinin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Arginine Vasopressin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Endothelium-Derived Vasoactive Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endothelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natriuretic Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vasoactive Factors and Developmental Programming of Hypertension . . . . . . . . . . . . . . . . Urotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renalase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51 51 52 52 53 53 54

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

I. V. Yosypiv (*) Department of Pediatrics, Tulane University, New Orleans, LA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_2

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Abstract

Control of arterial blood pressure (BP) is accomplished by the net effect of vasodilator and vasoconstrictor substances. This chapter presents updated data on the ontogeny of the most relevant vasoactive systems in the systemic circulation and in the developing kidney, and highlight how any alteration in the integrity of vasomotor control may lead to deregulation of BP and associated hypertension in children. Keywords

Renin · Angiotensin II · ACE · Kallikrein · Nitric oxide · Endothelin · Urotensin II · Prorenin receptor

angiotensinogen (AGT), to generate Ang I [Ang-(1–10)] (Fig. 1). Ang I is then converted to Ang II [Ang-(1–8)] by angiotensin-converting enzyme (ACE). ACE expression on endothelial cells of many vascular beds including the kidney, heart, and lung allows systemic formation of Ang II, the most powerful effector peptide hormone of the RAAS, active throughout the circulation and locally, within tissues (Kobori et al. 2007). Most of hypertensinogenic actions of Ang II are attributed to the AT1 receptor (AT1R). Binding of prorenin to the (pro)renin receptor induces a conformational change of prorenin, facilitating the conversion of AGT to Ang I (Nguyen et al. 2002). ACE2, a homologue of ACE, acts to promote Ang II degradation to the vasodilator peptide Ang-(1–7) (Brosnihan et al. 1996). Ang-(1–7) acts via its cognate receptor, Mas, to counteract Ang II-AT1R-mediated effects (Santos and Ferreira 2007).

Introduction Vasoactive peptide systems play a critical role in the regulation of arterial blood pressure (BP). Inappropriate stimulation or deregulation of a cross-talk among diverse vasomotor factors often contributes to or accounts for development of hypertension, cardiovascular, and kidney disease in children. Understanding how derangements in vasoactive factor systems lead to such health problems might potentially prevent future disease. This chapter reviews newer advances in physiology, biochemistry, pathophysiology, and function of the renal and systemic vasoactive systems with special emphasis on their role in the pathogenesis of hypertension in children.

Renin-Angiotensin-Aldosterone System The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the regulation of arterial BP. Emerging evidence suggests that local tissue-specific formation of components of the RAAS is of major importance in the regulation of the angiotensin (Ang) levels in many organs (Navar et al. 2002). The components of the RAAS are shown in Fig. 1. Renin cleaves its substrate,

Angiotensinogen Angiotensinogen (AGT) is formed and constitutively secreted into the circulation by the hepatocytes (Fukamizu et al. 1990). In addition, AGT mRNA and protein are expressed in kidney proximal tubules, central nervous system, heart, adrenal gland, and other tissues (Ingelfinger et al. 1990; Lynch and Peach 1991). Although AGT is the only substrate for renin, other enzymes can cleave AGT to form Ang I or Ang II (Fig. 1) (Yosipiv and El-Dahr 1996). Expression of the AGT gene is induced by Ang II, glucocorticoids, estrogens, thyroxine, and sodium depletion (Lynch and Peach 1991; Kobori et al. 2007). Importantly, A/G polymorphism at -217 in the promoter of the AGT gene appears to play a significant role in hypertension in AfricanAmericans (Jain et al. 2002). A significant association of a T704➔C (Met235➔Thr) variant in exon 2 of the AGT gene with primary hypertension was reported in the cross-sectional study in Salt Lake City and Paris (Jeunemaitre et al. 1992). Recent meta-analysis indicated significant association between A-6G and A-20C polymorphisms in the AGT promoter and hypertension in the Chinese populations (Gu et al. 2011).

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Vasoactive Factors and Blood Pressure in Children

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Angiotensinogen

Renin/(pro)renin receptor Renin

Cathepsin G Tonin tPA

Ang I

Cathepsin G, A Chymase CAGE

Prorenin

Ang-(1-9)

ACE2 ACE

Ang II

Hypertension

Bradykinin

ACE2, PEP, PCP

ACE, NEP

Ang-(1-7)

AMPA

Ang III AMPN

Ang IV

AT1R Vasoconstriction Cell proliferation Cell hypertrophy Antinatriuresis Fibrosis Atherosclerosis Inflammation Release of: - Aldosterone - Endothelin - Vasopressin

Fig. Ang Ang tPA,

1 The Renin-Angiotensin-Aldosterone System. II, angiotensin II; CAGE, chymostatin-sensitive II-generating enzyme; AMPN, aminopeptidase N; tissue plasminogen activator; ACE, angiotensin

Prorenin, Renin, and (Pro)renin Receptor Renin is synthesized as preprorenin in juxtaglomerular cells of the afferent arterioles of the kidney (Hackenthal et al. 1990). The human renin gene encoding preprorenin is located on chromosome 1 (Miyazaki et al. 1984). Cleavage of a 23 amino acid signal peptide at carboxyl terminus of preprorenin generates prorenin, which is then converted to active renin by cleavage of 43-amino acid N-terminal prosegment by proteases (Paul et al. 2006). The kidney secretes both renin and prorenin into the peripheral circulation. Plasma levels of prorenin are approximately 10-fold higher than those of renin (Danser et al. 1998). Renin release is controlled by baroreceptors in the afferent arterioles of the glomeruli, chloride-sensitive receptors in the macula densa (MD) and juxtaglomerular apparatus, and renal sympathetic nerve activity in response to

AT2R

Mas

Vasodilatation Anti-proliferation Anti-hypertrophy Anti-fibrosis Anti-thrombosis Anti-angiogenesis

converting enzyme; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; NEP, neprilysin; PCP, prolyl-carboxy-peptidase; PEP, prolyl endopeptidase

changes in posture or effective circulating fluid volume (Fig. 2) (Lorenz et al. 1993, Burns et al. 1993). Inhibition of renin secretion in response to an increase in NaCl at the MD is adenosine-dependent, whereas stimulation of renin release by a low perfusion pressure depends on cyclooxygenase-2 and neuronal nitric oxide (NO) synthase (NOS) (Kim et al. 2006). In contrast, changes in AGT synthesis occur more slowly and thus are less responsible for the dynamic regulation of plasma Ang I and Ang II than renin (Brasier and Li 1996). In addition, the circulating concentrations of AGT are more than 1000 times greater than the plasma Ang I and Ang II levels (Navar et al. 2002). Therefore, renin activity is the rate-limiting factor in Ang I formation from AGT (Paul et al. 2006). Although Ang II can be generated from AGT or Ang I via renin/ACEindependent pathways (Yosipiv and El-Dahr 1996), the circulating levels of Ang II primarily reflect the consequences of renin action on AGT.

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Angiotensinogen Renin Ang I

Reduced arterial pressure Reduced NaCl delivery to MD

Ang II AT1R

Aldosterone

Vasoconstriction Sodium and volume retention Increase in blood pressure

Fig. 2 Renin-angiotensin-aldosterone system in vasoconstriction, renal sodium and water retention. Renin is secreted in response to reduced arterial pressure or NaCl delivery to macula densa (MD) and cleaves angiotensinogen to Ang I. Ang II is converted to Ang II

by ACE. Ang II acts via the AT1 receptor (AT1R) to increase blood pressure by arteriolar vasoconstriction and stimulate aldosterone secretion. Ang II and aldosterone also cause renal sodium and water retention leading to suppression of renin release

The renin/prorenin-(pro)renin receptor complex has emerged as a newly discovered pathway for tissue Ang II generation. In addition to proteolytic activation, prorenin may be activated by binding to (pro)renin receptor (PRR) (Nguyen et al. 2002). The (pro)renin receptor (PRR) is expressed on mesangial and vascular smooth muscle cells and binds both prorenin and renin. Binding of renin or prorenin to the PRR induces a conformational change of prorenin facilitating catalytic activity and the conversion of AGT to Ang I (Nguyen et al. 2002). A direct pathological role of the PRR in hypertension is suggested by the findings of elevated BP in transgenic rats that overexpress the human PRR (Burcklé et al. 2006). An important role for the PRR in the pathogenesis of hypertension in humans is supported by the findings that a polymorphism in the PRR gene is associated with a high BP in men (IVS5 þ 169C > T) and left ventricular hypertrophy in women (+1513A > G) (Hirose et al. 2009, Hirose et al. 2011). Two singlenucleotide polymorphisms in the PRR gene (rs296815; rs5981008) were reported to be significantly associated with hypertension in adult Caucasians (Brugts et al. 2011).

bradykinin (BK) (Figs. 1 and 3). There are two ACE isozymes, somatic and testicular, transcribed from a single gene by differential utilization of two distinct promoters (Kumar et al. 1991). Human somatic ACE contains 1306 amino acids and has a molecular weight of 140–160 kilodaltons (kDa). In the kidney, ACE is present as ectoenzyme in glomerular vascular endothelial and proximal tubular cells. ACE localized in glomerular endothelium may regulate intraglomerular blood flow, whereas ACE expressed in the proximal tubular epithelia and postglomerular vascular endothelium may play an important role in the regulation of tubular function and postglomerular circulation. An important role for ACE in normal kidney development and the regulation of BP is evident from the findings that ACE mutations are linked to an autosomal recessive renal tubular dysgenesis (RTD), a severe disorder of renal tubular development characterized by persistent fetal anuria, pulmonary hypoplasia, and refractory arterial hypotension (Gribouval et al. 2005). The human ACE gene contains a polymorphism consisting of either an insertion (I) or deletion (D) of a 287bp Alu repetitive sequence in intron 16. It has been demonstrated that allelic ACE variation is responsible for 47% of the variance of plasma ACE activity (Rigat et al. 1990). Notably, D allele and the DD genotype have been reported to be associated with elevated levels of ACE and a higher risk of left ventricular hypertrophy and hypertension in humans (Higaki et al. 2000). In addition, ACE enzymatic activity, ACE D allele frequency

Angiotensin-Converting Enzyme Angiotensin-converting enzyme (ACE) is involved in the posttranslational processing of many polypeptides, the most notable of which are Ang I and

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Vasoactive Factors and Blood Pressure in Children

Fig. 3 The Kallikreinkinin system. Bradykinin (BK) is generated from kininogen by tissue kallikrein and is degraded by kininase I to Des-Arg9BK that acts via the B1 receptor (B1R) to cause tissue injury and inflammation. BK acts via the B2 receptor (B2R) to cause vasodilation, natriuresis, and pain

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Kininogen Tissue kallikrein

Bradykinin Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Kininase I

Kininase I Kininase II (ACE)

Des-Arg9-Bradykinin

B1R Vasodilatation Inflammation Tissue injury

and systolic BP were higher in low birth weight (LBW) compared with normal birth weight children (Ajala et al. 2012). Thus, ACE DD genotype can be an important factor in association between LBW and high BP levels.

Angiotensin II Receptors Ang II acts via two major types of G proteincoupled receptors (GPCR): AT1R and AT2R. In rodents, AT1R has two distinct subtypes, AT1A and AT1B, with greater than 95% amino acid sequence homology (Iwai and Inagami 1992). In the kidney, AT1R mRNA has been localized to proximal tubules, the thick ascending limb of the loop of Henle, glomeruli, arterial vasculature, vasa recta, arcuate arteries, and juxtaglomerular cells (Tufro-McReddie and Gomez 1993). Activation of the AT1R increases BP in three ways. First, via direct vasoconstriction and increase in peripheral vascular resistance; second, by stimulation of Na+ reabsorption via NHE3 at the proximal nephron and by NHE3 and bumetanidesensitive cotransporter 1 (BSC-1) at the medullary thick ascending limb of the loop of Henle, and third, via stimulation of aldosterone biosynthesis and secretion by the adrenal zona glomerulosa (Fig. 2) (Holland et al. 1995; Goodfriend et al. 1996). AT1R activation also stimulates

B2R Vasodilatation Natriuresis Inflammation Edema Pain

vasopressin and endothelin secretion, the sympathetic nervous system, and proliferation of vascular smooth muscle and mesangial cells (Gasparo et al. 2000; Berry et al. 2001). The AT2R has 34% homology with AT1A or AT1B receptors (Inagami et al. 1993). AT2R is expressed in the glomerular epithelial cells, proximal tubules, collecting ducts, and parts of the renal vasculature of the adult rat (Miyata et al. 1998). In contrast to AT1R, AT2R elicits vasodilation by increasing the production of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) either by stimulating formation of bradykinin or by direct activation of NO production (Siragy and Carey 1997, Abadir et al. 2003). In addition, the AT2R promotes renal sodium excretion and inhibits proliferation in mesangial cells (Siragy and Carey 1997, Gross et al. 2000). Thus, the AT2R might oppose AT1R-mediated effects on blood pressure, cardiovascular and renal growth, fibrosis, and remodeling, as well as RBF, fibrosis, and sodium excretion.

Angiotensin-Converting Enzyme 2 ACE2, a homologue of ACE, is abundantly expressed in the kidney and acts to counterbalance ACE activity by promoting Ang II degradation to the vasodilator peptide Ang-(1–7)

46

(Brosnihan et al. 1996). Ang-(1–7) acts via the GPCR Mas encoded by the Mas protooncogene and counteracts Ang II-AT1R-mediated effects (Santos and Ferreira 2007). An important role for ACE2 in the regulation of BP is suggested by the findings of a decreased ACE2 expression in the kidney of hypertensive rats and a reduction of BP following genetic overexpression of ACE2 in their vasculature (Rentzsch et al. 2008). Although ACE2-null mice are normotensive and have normal cardiac structure and function, they exhibit enhanced susceptibility to Ang II–induced hypertension (Gurley et al. 2006). Studies in mice have demonstrated that, during Ang II infusion, administration of recombinant ACE2 (rACE2) results in Ang II degradation and a decrease in BP (Wysocki et al. 2010). The mechanism of rACE2 action results from an increase in systemic, not kidney or cardiac tissue, ACE2 activity and from the lowering of plasma Ang II rather than the attendant increase in Ang-(1–7). Thus, increasing ACE2 activity may provide a new therapeutic target in states of Ang II overactivity. Moreover, Mas-deficient mice exhibit increased BP, endothelial dysfunction, and an imbalance between NO and reactive oxygen species (Xu et al. 2008). Other major degradation products of Ang II include Ang III [Ang-(2–8)], Ang IV [Ang-(3–8)]. These peptides have biological activity, but their plasma levels are much lower than those of Ang II or Ang-(1–7) (Haulica et al. 2005).

Developmental Aspects of the RAAS The developing metanephric kidney expresses all the components of the RAAS (Table 1). The activity of the renal RAAS is high during fetal and neonatal life and declines postnatally (Yosipiv and El-Dahr 1995). Immunoreactive Ang II levels are higher in the fetal and newborn kidney than in the adult rat kidney (Yosipiv and El-Dahr 1995). The ontogeny of AT1R and AT2R mRNA in the kidney differs. AT2R mRNA is expressed earlier than AT1R, peaks during fetal metanephrogenesis, and rapidly declines postnatally (Norwood et al. 1997, Garcia-Villalba et al. 2003). AT1R mRNA

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expression increases during gestation, peaks perinatally, and declines gradually thereafter (Norwood et al. 1997, Kakuchi et al. 1995). ACE mRNA and enzymatic activity are expressed in the developing rat kidney, where they are subject to regulation by endogenous Ang II and bradykinin (Yosipiv et al. 1994, Kakuchi et al. 1995). In addition, the developing kidney expresses considerable ACE-independent Ang II-generating activity (Yosipiv and El-Dahr 1995, Yosipiv and El-Dahr 1996), which may compensate for the low ACE levels in the early metanephros (Yosipiv et al. 1994). ACE2 mRNA and protein are expressed in the developing mouse kidney as early as on E12.5 (Song et al. 2012). Ang II, acting via the AT1R, exerts a negative feedback on ACE2 in the developing metanephros. In the mouse kidney, PRR mRNA is expressed in the intact ureteric buds (UBs) isolated from embryonic (E) day E11.5 wild-type mouse kidneys (Song et al. 2013b). In the whole metanephros, PRR mRNA and protein are detected from E12.5 while PRR immunostaining is present in the UB, a precursor of the renal collecting system and the cap mesenchyme, which contains nephron progenitors, on E13.5 (Table 1). Kidney PRR protein levels are high throughout gestation and decline gradually during postnatal development. On E16.5 and E18.5, PRR immunostaining is most prominent in the tubules, which resemble morphologically collecting ducts followed by glomerular mesangium (Song et al. 2013b). In human neonates, PRR immunoreactivity is present in the glomeruli, proximal tubules, collecting ducts, and arteries (Terada et al. 2017). The levels of PRR protein expression in neonatal kidney correlate inversely with gestational age and are higher in premature compared with full-term neonates (Terada et al. 2017). These findings suggest that PRR may play an important role in kidney development in humans. To circumvent the early lethality of the global PRR knockout in mice and to drive deletion of PRR in specific lineages of the developing kidney, recent studies used a cre-lox conditional targeting approach and demonstrated that PRR is critical for normal kidney development and function. PRR deletion in mice podocytes using the Nphs2

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Vasoactive Factors and Blood Pressure in Children

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Table 1 Expression of the renin-angiotensin system components during metanephric kidney development AGT Mouse:

E12

E14

UB, SM

UB, SM, PT

E15

E16

E19

References

Rat: UB, SM

UB, SM, PT

PT

26 126

Renin Mouse: precursor cells present M of entire kidney M, close to V and G V, G Rat: V V V ACE Rat: PT, G, CD ACE2 Mouse UB, G, PT PT AT1 Mouse: UB, M UB, G UB, V PT, UB, SM, G PT, DT 85 Rat: G, UB, SM SM PT, CD, G AT2 Mouse: MM MM, SM Medullary SM, under renal capsule Rat: MM Condensed M Medulla, G, V PRR Mouse: UB UB, CM UB T, G T,G

127 48 70 192 26 98 85 98 194

AGT, angiotensinogen; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AT1/ AT2, angiotensin II receptors; UB, ureteric bud; M, mesenchyme; MM, metanephric mesenchyme; SM, stromal mesenchyme; PT, proximal tubule; DT, distal tubule; G, glomeruli; V, renal vessels; CD, collecting duct; PRR, (pro)renin receptor; T, tubule

promoter results in massive foot process effacement, proteinuria, and nephrotic syndrome (Oshima et al. 2011, Riediger et al. 2011). PRR ablation in the UB epithelia using the Hoxb7 promoter leads to kidney hypoplasia, reduced kidney function, polyuria, and a reduced capacity to acidify the urine (Song et al. 2013a). Inactivation of the PRR in nephron progenitors using Six2 promoter (Six2PRR/) results in small kidneys, reduced nephron endowment, and early postnatal death (Song et al. 2016). Reduced PRR gene dosage in heterozygous Six2PRR+/ is associated with decreased glomerular number and development of hypertension at 2 months of age (Song et al. 2018). Reduced glomerular number may be associated with reduced filtration surface area, thus limiting sodium excretion and leading to higher blood pressure or inappropriate activation of other vasoactive systems. Conditional PRR deletion in Foxd1+ stromal progenitors in mice leads to a marked decrease in the intrarenal arterial and arteriolar development (fewer and thinner vessels with a marked decrease in the expression of renin) with the subsequent decreased number of glomeruli and

delay in nephron differentiation (Yosypiv et al. 2019). Thus, stromal PRR is crucial for the proper morphogenesis of the nephrovascular structures of the mammalian kidney. The role of the ACE2-Ang-(1-7)-Mas axis and the PRR in developmental origins of hypertension remains to be determined. Functionally, Ang II, acting via the AT1R, counteracts the vasodilator actions of bradykinin on the renal microvasculature of the developing rat kidney (El-Dahr et al. 1995). Premature infants exhibit markedly elevated plasma renin activity (PRA), which is inversely related to postconceptual age (Richer et al. 1977). In healthy children, PRA is high during the newborn period and declines gradually toward adulthood. In chickens (Gallus gallus), renin mRNA is detected in the kidney at low levels by quantitative polymerase chain reaction (qPCR) at E13 (Hoy et al. 2020). In post-hatch day (D) D4 and D30 maturing chicks, renal renin expressions increased 2-fold and 11-fold, respectively. Renin expression is clearly visible by in situ hybridization in the juxtaglomerular (JG) area

48

in D4 and D30 chicks, but not in E13 embryos (Hoy et al. 2020). While renin gene expression continues to increase in chickens with maturation, its expression in rodents is high toward the end of gestation and in newborns but decreases after maturation. Since the time scale of nephron development differs among chickens and rodents, however, the comparison of renin expressions among these species at the comparable ontogenic stages of these species is difficult. The early and broad appearance of renin in the renal vascular system during early ontogeny suggests that renin has evolved as a local hormone regulating vascular growth and possibly functions such as the control of vascular tone. In the vascular system of rodent fetal kidneys, renin-secretory cells and renin gene expression (Gomez et al. 1989) are widely distributed in renal arteries and arterioles. As the renal arterial tree develops, renin mRNA-containing cells are finally localized to the juxtaglomerular (JG) cells at later stages of kidney development. Interestingly, new findings provide evidence that dysregulated macrophage signaling in response to vitamin D deficiency is sufficient to cause hypertension by a microRNA-specific mechanism that enables communication from innate immune cells to JG cells to cause renin-mediated hypertension (Oh et al. 2020). Pharmacologic or genetic interruption of the RAAS during development alters BP phenotype and causes a spectrum of congenital abnormalities of the kidney and urinary tract (CAKUT) in rodents and RTD, renal failure and other abnormalities (e.g., hypocalvaria) in humans (Table 2) (Gribouval et al. 2005). Therefore, RAAS inhibitors should not be used during pregnancy and postnatally until nephrogenesis is completed. Beyond these periods of life, high activity of the RAAS coupled with persistent expression of the renal AT1R provide the foundation for the use of the classical RAAS inhibitors (ACE inhibitors and AT1R antagonists) in the treatment of children with RAAS-dependent hypertension (e.g., renovascular hypertension). In addition, RAAS inhibitors may be beneficial in children with primary hypertension and particularly in obese adolescents, who exhibit elevated plasma renin activity (Flynn 2011). Recent availability of a

I. V. Yosypiv

direct inhibitor of (pro)renin receptor offers new possibilities in antihypertensive therapy in children that remain to be explored (Flynn and Alderman 2005).

Aldosterone Ang II, acting via the AT1R, stimulates an increase in transcription and expression of the rate-limiting enzyme in the biosynthesis of aldosterone, CYP 11B2 (aldosterone synthase), in the zona glomerulosa of the adrenal glands (Holland et al. 1995). Aldosterone stimulates reabsorption of Na+ and secretion of potassium by principal cells in the collecting duct. In turn, the retained Na+ is responsible for increased extracellular fluid volume that increases BP. Secretion of aldosterone is stimulated by high plasma potassium concentration and adrenocorticotropic hormone (ACTH), and inhibited by atrial natriuretic peptide (ANP) (Vinson et al. 1991). Aldosterone-dependent Na+ reabsorption is due to upregulation of epithelial Na+ channel-α (alfa) (ENaCα (alfa)) subunit gene expression and increased apical density of ENaC channels due to serum- and glucocorticoid-induced kinase-1 (Sgk1)-induced disinhibition of Nedd4-2-triggered internalization and degradation of ENaC (Debonneville et al. 2001). Aldosterone downregulates the expression of histone H3 methyltransferase Dot1a and the DNA-binding protein Af9 complexed with chromatin within the ENaCα (alfa) 50 -flanking region (Zhang et al. 2007). In addition, aldosterone-induced Sgk1 phosphorylates Ser435 of Af9, causing disruption of the protein–protein interactions of Dot1a and Af9. This results in hypomethylation of histone H3 Lys79 and release of transcriptional repression of the ENaCαb gene. The important role of aldosterone in childhood hypertension is underscored by the ability of mineralocorticoid receptor antagonists not only to effectively reduce elevated BP due to hyperaldosteronism (e.g., adrenal hyperplasia), but to offer survival benefits in heart failure and augment potential for renal protection in proteinuric chronic kidney disease.

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Table 2 Effect of genetic inactivation of the renin-angiotensin system genes in mice on the renal and blood pressure phenotype Gene AGT

Function of gene Renin substrate

Renin

Enzyme that generates ANG I from AGT

ACE

Enzyme that generates ANG II from ANG I

AT1A/B

Ang II receptor

AT1A

Ang II receptor

AT1B AT2

Ang II receptor Ang II receptor

PRR

Renin/prorenin receptor

Renal phenotype Vascular thickening Interstitial fibrosis Delayed glomerular maturation Hypoplastic papilla Hydronephrosis Reduced ability to concentrate urine Arterial wall thickening Interstitial fibrosis Glomerulosclerosis Hypoplastic papilla Hydronephrosis Arterial wall thickening Hypoplastic papilla and medulla Hydronephrosis Reduced ability to concentrate urine Decreased kidney weight Delayed glomerular maturation Arterial wall thickening Interstital fibrosis Tubular atrophy Hypoplastic papilla and medulla Hydronephrosis Reduced ability to concentrate urine Normal or mild papillary hypoplasia Normal Duplicated ureters Hydronephrosis Decreased ureteric bud branching and nephron number, renal hypoplasia fewer and thinner renal arteries and arteriols

Glucocorticoids Glucocorticoids are vital for normal development and control of hemodynamic homeostasis. Cortisol or dexamethasone infusion increases BP in the fetal sheep (Fletcher et al. 2002). Dexamethasone increases BP in wild-type serum and glucocorticoid-inducible kinase (Sgk) Sgk1+/+ mice but not in Sgk1/ mice (Boini et al. 2008), indicating that hypertensinogenic effects of glucocorticoids on BP are mediated, at least in part, via Sgk1. A higher ratio of cortisol to cortisone in venous cord blood is associated with higher systolic blood

Blood pressure Very low

References 81,89,95

Very low

158

Very low

96

Very low

107,108

Moderatelylow Normal High

83

Unknown

196, 198, 200

101 82,125

pressure later in life in humans (Huh et al. 2008), suggesting that increased fetal glucocorticoid exposure may account for higher systolic BP in childhood. However, no differences in BP and cardiovascular function are detected at school age in children treated as neonates with glucocorticoids for chronic lung disease (de Vries et al. 2008). It is possible that the functional consequences of glucocorticoid therapy during neonatal life may manifest only later in life. Deleterious effects of elevated endogenous glucocorticoids on childhood BP are apparent, for example, in Cushing’s disease or glucocorticoid-remediable aldosteronism.

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Kallikrein-Kinin System The kallikrein-kinin system (KKS) is another group of proteins that plays an important role in the regulation of blood pressure. Kinins, including bradykinin (BK), are formed from kininogen by kininogenase tissue kallikrein (Fig. 3). Bradykinin is degraded by ACE-kininase II, the enzyme that also converts Ang I to Ang II (Erdös and Oshima 1974). Kinins act by binding to B1 (B1R) and B2 (B2R) receptors. The B1R is activated by Des-Arg9-BK produced from BK by kininase I and mediates tissue injury and inflammation (Marceau et al. 1998). The renal and cardiovascular effects of BK are mediated predominantly by the B2R. Kininogen is expressed in the ureteric bud and stromal interstitial cells of the E15 metanephros in the rat (El-Dahr et al. 1993). Following completion of nephrogenesis, kininogen is localized in the collecting duct. The main kininogenase, true tissue kallikrein, is encoded by the KLK1 gene (Clements 1994). Transcription of the KLK1 gene is regulated by salt and protein intake, insulin, and mineralocorticoids. Expression of the renal KLK1 gene is suppressed in chronic phase of renovascular hypertension. In the developing rat kidney, kallikrein mRNA and immunoreactivity are present in the connecting tubule (El-Dahr et al. 1998). In the mature kidney, tissue kallikrein mRNA is expressed in the distal tubule and glomeruli. Thus, BK can be generated intraluminally from kininogen present in the collecting duct or in the interstitium. BK generated intraluminally causes natriuresis, whereas interstitial BK may regulate medullary blood flow (Siragy 1993). The proximity of the distal tubule to the afferent arteriole may allow kallikrein or BK to diffuse from the distal tubular cells and act in a paracrine manner on the preglomerular microvessels (Beierwaltes et al. 1985). The human B1R and B2R genes are located on chromosome 14 and demonstrate 36% genomic sequence homology (McEachern et al. 1991). Both B1R and B2R are members of the seven transmembrane GPCR families. During metanephrogenesis, the B2R is expressed in on both luminal and basolateral aspects of collecting ducts suggesting that activation of B2R is important for renal tubular growth

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and acquisition of function (El-Dahr et al. 1997). The expression of B1R is inducible rather than constitutive. In contrast to B2R, B1R is not expressed in significant levels in normal tissues (Marceau et al. 1998). Although BK does not appear to be a primary mediator of the maturational rise in RBF in the rat, its vasodilatory effects in the developing kidney are tonically antagonized by Ang II AT1R (El-Dahr et al. 1995). Stimulation of the B2R during adult life stimulates production of nitric oxide and prostaglandins resulting in vasodilation and natriuresis (Siragy 1993). The importance of the KKS in the regulation of BP is underscored by the finding of elevated BP in mice that lack the B2R (Beierwaltes et al. 1985). Moreover, B2R-null mice are prone to early onset of saltsensitive hypertension (Cervenka et al. 1999). Interestingly, B1R receptor blockade in B2R-null mice produces a significant hypertensive response, indicating that both receptors participate in the development of hypertension. In keeping with this hypothesis, single-nucleotide polymorphisms in the promoters of both B1R and B2R genes have been reported to be associated with hypertension in African-Americans, demonstrating that the two receptors play a role in BP homeostasis in humans (Cui et al. 2005). The direct potential role of the KKS in childhood hypertension is further highlighted by studies showing that endogenous bradykinin contributes to the beneficial effects of ACE inhibition on BP in humans (Gainer et al. 1998).

Arginine Vasopressin Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and released in response to increased plasma osmolality, decreased arterial pressure, and reductions in circulating blood volume. Three subtypes of vasopressin receptors, V1R, V2R, and V3R, mediate vasoconstriction, water reabsorption, and central nervous system effects, respectively. In addition, stimulation of the V2R induces endothelial NOS expression and promotes NO production in the renal medulla, which attenuates the V1R-mediated vasoconstrictor effects

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(Szentivanyi et al. 2000). In adult species, AVP supports arterial BP when both the sympathetic system and the RAAS are impaired by sympathetic blockade (Peters et al. 1990). Treatment with a V1R antagonist has no effect on arterial BP in fetal sheep (Ervin et al. 1992). In contrast, antagonism of the V1R during hypotensive hemorrhage impairs the ability of the fetus to maintain BP (Kelly et al. 1983). Thus, endogenous AVP has little impact on basal hemodynamic homeostasis of the fetus, but plays an important role in vasopressor response to acute stress such as hemorrhage.

Endothelium-Derived Vasoactive Factors Nitric Oxide Hypertension is associated with abnormal endothelial function in the peripheral, coronary, and renal vasculature. Nitric oxide (NO) is an important mediator of endothelium-dependent vasodilation. NO enhances arterial compliance, reduces peripheral vascular resistance, and inhibits proliferation of vascular smooth muscle cells (Cowley et al. 2003). The major source of NO production in the rat kidney is the renal medulla, where NO regulates medullary blood flow, natriuresis, and diuresis (Jin et al. 2004). NO promotes pressure natriuresis via cGMP (Taddei et al. 1996). The effects of Ang II or AVP on medullary blood flow are buffered by the increased production of NO, indicating that endogenous NO tonically counteracts the effects of vasoconstrictors within the renal medullary circulation. Interestingly, endothelial dysfunction is not only a consequence of hypertension, but may predispose to the development of hypertension. In this regard, impaired endothelium-dependent vasodilation has been observed in normotensive children of patients with hypertension as compared with those without a family history of hypertension (Taddei et al. 1996), demonstrating that an impairment in NO production precedes the onset of hypertension. Acute antagonism of NO generation leads to an increase in BP and decreases RBF in the fetal sheep (Yu et al. 2002). In fetal rat kidneys, endothelial NO synthase (eNOS) immunoreactivity is first detected in the

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endothelial cells of the intrarenal capillaries on E14 (Han et al. 2005). These findings suggest that eNOS may play a role in regulating renal hemodynamics during fetal life. Moreover, eNOS-knockout mice exhibit abnormal aortic valves, congenital atrial and ventricular septal defects, indicating that eNOS-derived NO plays an important role in the development of the circulatory system (Teichert et al. 2008). The effect of intrarenal infusion of the NO antagonist L-NAME on decreases in RBF and GFR is more pronounced in the newborn than in the adult kidney (Solhaug et al. 1996). These effects of NO may act to oppose high RAAS activity present in the developing kidney. Similar to NO, hydrogen sulfide (H2S) is a gasotransmitter that has been recently revealed as playing a role in cardiovascular physiology. H2S-knockout mice develop age-dependent hypertension, whereas administration of H2S donors attenuates the hypertensive response via decreased renin production in a rat two-kidney one-clip renovascular hypertension model (Lu et al. 2010).

Asymmetrical Dimethylarginine Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of eNOS (Kielstein and Zoccali 2005). Infusion of ADMA increases BP, renal vascular resistance, and decreases renal plasma flow during adulthood. ADMA levels in fetal umbilical venous plasma are higher than in maternal plasma (Maeda et al. 2003). However, low resistance to umbilical blood flow is maintained despite substantially higher fetal ADMA levels, which, by implication, has led to speculation that NO must be a key modulator of fetal vascular tone. Hypertensive children had higher plasma ADMA levels as compared with normotensives children in one study (Goonasekera et al. 2000). In contrast, plasma ADMA levels did not differ between normotensive and hypertensive young adults (Päivä et al. 2008). Moreover, plasma ADMA correlates negatively with vascular resistance (Päivä et al. 2008), suggesting that in a physiological setting ADMA levels in people with elevated vascular tone may decrease to compensate for inappropriately high resistance.

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Endothelin Endothelins (ETs) are vasoconstrictor peptides produced by endothelial cells (Lüscher et al. 1992). Three ETs have been described – endothelin-1 (ET-1), -2 (ET-2), and -3 (ET-3). The hemodynamic effects of ET-1 are mediated by ETA and ETB GPCRs. In the kidney, ET-1 mRNA is expressed in the glomeruli and medullary collecting ducts (Ujiie et al. 1992). ET receptors are located in podocytes, glomeruli, afferent and efferent arterioles, and in the proximal tubule, medullary thick ascending limb and collecting duct (Yamamoto et al. 2002). Activation of the ETB receptor results in natriuresis and vasodilation via release of NO and PGE2, whereas the ETA receptor mediates renal vasoconstriction (Hirata et al. 1993). In the fetal lamb, ETA and ETB receptors expressed on vascular smooth muscle cells mediate vasoconstriction, whereas ETB receptors located on endothelial cells mediate vasodilation (Arai et al. 1990). In the renal circulation of fetal sheep, ET-1, acting via the ETB receptor, results in vasodilation (Fujimori et al. 2005). However, ETA receptormediated vasoconstriction also contributes to the regulation of the fetal renal vascular tone (Fineman et al. 1994). The critical role for the renal ET-1 and ETA/ETB receptors in the regulation of systemic BP is demonstrated by the finding of increased BP in mice with collecting duct-specific knockout of either ET-1 or both ETA and ETB receptors (Ahn et al. 2004, Ge et al. 2008). Moreover, BP in these knockouts increases further with high salt intake, indicating that combined ETA /ETB receptor deficiency leads to salt-sensitive hypertension.

Natriuretic Peptides Natriuretic peptides include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), urodilatin, and Dendroaspis-type natriuretic peptide (DNP) (Hirsch et al. 2006, de Bold et al. 1981). Natriuretic peptides act through binding to three guanylyl cyclase-linked receptors: NPR-A,

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NPR-B, and NPR-C (Levin et al. 1998). In the adult heart, ANP and BNP are stored in atrial and ventricular myocytes, respectively, released in response to atrial stretch, increased BP, atrial tachycardia or increased osmolality (Levin et al. 1998, Brenner and Stein 1989), and are rapidly degraded in the lung and kidney by neutral endopeptidase (Roques et al. 1993). ANP and BNP decrease the secretion of renin and aldosterone, and antagonize the effects of Ang II on vascular tone and renal tubular reabsorption to cause natriuresis, diuresis, a decrease in BP, and intravascular fluid volume (Hunt et al. 1996). ANP and BNP peptide levels are higher in fetal than adult ventricles, suggesting that the relative contribution of ventricular ANP is greater during embryonic as compared to adult life (Zeller et al. 1987, Wei et al. 1987, Hersey et al. 1987). ANP and BNP mRNA is expressed on E8 in the mouse and increases during gestation, suggesting that both ANP and BNP play a role in the formation of the developing heart. Circulating ANP levels are higher in fetal as compared to adult rat or sheep (Wei et al. 1987, Cheung 1995). Infusion of ANP into the circulation of the lamb fetus decreases BP and causes diuresis. ANP secretion during postnatal development is stimulated in response to similar physiological stimuli as in the adult animal and can be induced by Ang II infusion, volume loading, hypoxia, or increase in osmolality (Rosenfeld et al. 1992). Plasma levels of ANP are higher in preterm as compared with term infants (Bierd et al. 1990). In full-term infants, circulating ANP levels increase during the first week of life and decrease thereafter (Weil et al. 1986). Thus, the initial postnatal increase in ANP may mediate diuresis during the transition to extrauterine life. Subsequent decrease in plasma ANP may serve to conserve sodium, which is required for rapid growth. Although BP remains normal in BNP-null mice (Tamura et al. 2000), ANP-null mice develop hypertension later in life (John et al. 1995). Mice lacking NPR-A receptor exhibit cardiac hypertrophy and have elevated BP, indicating that the ANP and BNP play an important role in the regulation of myocyte growth and BP homeostasis during development (Knowles et al. 2001).

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Vasoactive Factors and Developmental Programming of Hypertension

The U-II receptor is a seven-transmembrane, G protein–coupled receptor encoded on chromosome 17q25.3 in humans (Ames et al. 1999). Ligand binding of the receptor results in G protein–mediated activation of PKC, calmodulin, and phospholipase C with evidence also linking MAP kinases ERK1/2, the Rho kinase pathway, and peroxisome proliferator–activated receptor α in the intracellular signaling cascade. Human prepro-U-II mRNA is expressed in the brain, spinal cord, kidney, spleen, small intestine, thymus, prostate, pituitary, and adrenal gland. U-II is the most potent mammalian vasoconstrictor identified to date and is tenfold more potent than endothelin-I in the isolated rat thoracic aorta (Ames et al. 1999). It circulates in the plasma of healthy individuals, and acts as a circulating vasoactive hormone and as a locally acting paracrine or autocrine factor in cardiovascular regulation (Affolter and Webb 2001). The kidney is a major site of U-II production and urinary concentrations of U-II in humans are approximately three orders of magnitude higher than plasma concentrations (Matsushita et al. 2001). In the kidney, U-II is present in the smooth muscle cells and endothelium of arteries, proximal convoluted tubules, and particularly the distal tubules and collecting ducts (Shenouda et al. 2002). Changes in the concentration of U-II in the plasma and urine have been found in a number of diseases. Plasma U-II is elevated in hypertensive adult patients compared to normotensive controls and correlate with the severity of hypertension (Zhu et al. 2015), suggesting that U-II may have a role in hypertension in humans. Higher urinary U-II levels have been reported in adult patients with primary hypertension, glomerular disease and hypertension, and patients with renal tubular disorders, but not in normotensive patients with glomerular disease (Matsushita et al. 2001). Plasma immunoreactive U-II levels are increased in children with congenital heart disease (CHD) and concentrations increase further after cardiopulmonary bypass (CPB) (Simpson et al. 2006). Thus, U-II may be an important mediator in the cardiovascular dysfunction that affects children with CHD early after CPB. Animal studies demonstrated that enhanced tonic UT-II activation may contribute to

An inverse relationship between birth weight or maternal undernutrition and adult BP led to the concept of developmental programming of hypertension (Barker and Bagby 2005). The tissuespecific brain RAAS was upregulated in the fetus of dams fed a low protein (LP) diet, and hypertensive adult offspring of LP-fed dams have evidence of an increased pressor response to Ang II (Pladys et al. 2004). This and other studies suggest that inappropriate activation of the RAAS may link exposures in fetal life to childhood and adult hypertension. Interestingly, LP maternal diet has been reported to result in a decreased methylation of the promoter region of the AT1BR in offspring in the rat (Bogdarina et al. 2007). It is conceivable that epigenetic modifications of AT1BR gene may be one mechanism by which changes in the RAAS lead to developmental programming of hypertension. LP diet or caloric restriction during gestation has been associated with a decrease in the renal kallikrein activity, blunted vasorelaxation to NO donor infusion, an increase in vascular superoxide anion concentration, and a decrease in superoxide dismutase activity in the offspring (Brawley et al. 2003). In addition, heterozygous eNOS offspring of eNOS-null mothers exhibit impaired endotheliumdependent vasodilation as compared to heterozygous offspring of eNOS+/+ mothers (Longo et al. 2005). These observations indicate that impairment in endothelium-dependent vascular function is associated with developmentally programmed hypertension and that maternal eNOS genotype modulates the offspring’s predisposition to hypertension. Further studies are needed to establish the mechanisms by which alterations in antenatal environment impacts vasoactive factor systems and their interplay to program hypertension during postnatal life.

Urotensin II Human urotensin-II (U-II) is a cyclic peptide of 11-amino acids cleaved from a larger prepro-UII precursor peptide of about 130 amino acids.

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renal dysfunction in pre-hypertensive spontaneously hypertensive rats (SHR).

Renalase Renalase, an amine oxidase expressed in the kidney, heart, liver, and brain, metabolizes catecholamines. Anesthetized BP and heart rate are reported as higher in renalase-null as compared to wild-type littermates (Barker and Bagby 2005). Available data suggest that renalase deficiency is associated with increased sympathetic tone and resistant hypertension. Further, recombinant renalase is a potent antihypertensive agent that has some promise as a potential option for treating hypertension in chronic kidney disease (Desir 2012).

Conclusion Various vasoactive substances regulate cardiovascular homeostasis during development, and new ones are still being discovered. Many cardiovascular factors exert pleiotropic actions both systemically and within diverse organ systems. Continuous discovery of new vasoactive substances and more complete knowledge of their role during development improve our understanding of the developmental origin of hypertension and cardiovascular disease and help to minimize their impact on the nation’s health. Further work is needed to more precisely define the role of emerging cardiovascular regulatory factors and their growing relevance to a number of conditions in animal models of human disease and in human diseases including hypertension.

Cross-References ▶ Antenatal Programming of Blood Pressure ▶ Endocrine Hypertension ▶ Endothelial Dysfunction and Vascular Remodeling in Hypertension ▶ Monogenic and Polygenic Contributions to Hypertension ▶ Neurohumoral and Autonomic Regulation of Blood Pressure

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58 Teichert AM, Scott JA, Robb GB et al (2008) Endothelial nitric oxide synthase gene expression during murine embryogenesis: commencement of expression in the embryo occurs with the establishment of a unidirectional circulatory system. Circ Res 103:24–33 Terada T, Urushihara M, Saijo T et al (2017) (pro)renin and (pro)renin receptor expression during kidney development in neonates. Eur J Pediatr 176:183–189 Tufro-McReddie A, Gomez RA (1993) Ontogeny of the renin-angiotensin system. Semin Nephrol 13: 519–530 Ujiie K, Terada Y, Nonoguchi H et al (1992) Messenger RNA expression and synthesis of endothelin-1 along rat nephron segments. J Clin Invest 90:1043–1048 Vinson GP, Laird SM, Whitehouse BJ et al (1991) The biosynthesis of aldosterone. J Steroid Biochem Mol Biol 39:851–858 Wei Y, Rodi CP, Day ML et al (1987) Developmental changes in the rat atriopeptin hormonal system. J Clin Invest 79:1325–1329 Weil J, Bidlingmaier F, Döhlemann C et al (1986) Comparison of plasma atrial natriuretic peptide levels in healthy children from birth to adolescence and in children with cardiac diseases. Pediatr Res 20: 1328–1331 Wysocki J, Ye M, Rodriguez E, González-Pacheco FR et al (2010) Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension 55:90–98 Xu P, Costa-Goncalves AC, Todiras M et al (2008) Endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice. Hypertension 51:574–580

I. V. Yosypiv Yamamoto T, Hirohama T, Uemura H (2002) Endothelin B receptor-like immunoreactivity in podocytes of the rat kidney. Arch Histol Cytol 65:245–250 Yosipiv IV, El-Dahr SS (1995) Developmental regulation of ACE gene expression by endogenous kinins and angiotensin II. Am J Phys 269:F172–F179 Yosipiv IV, El-Dahr SS (1996) Activation of angiotensingenerating systems in the developing rat kidney. Hypertension 27:281–286 Yosipiv IV, Dipp S, El-Dahr SS (1994) Ontogeny of somatic angiotensin-converting enzyme. Hypertension 23:369–374 Yosypiv IV, Lopez M, Song R et al (2019) Stromal prorenin receptor is critical for normal kidney development. Am J Physiol Regul Integr Comp Physiol 316: R640–R650 Yu ZY, Lumbers ER, Simonetta G (2002) The cardiovascular and renal effects of acute and chronic inhibition of nitric oxide production in fetal sheep. Exp Physiol 87: 343–351 Zeller R, Bloch KD, Williams BS et al (1987) Localized expression of the atrial natriuretic factor gene during cardiac embryogenesis. Genes Dev 1:693–698 Zhang W, Xia X, Reisenauer MR et al (2007) Aldosteroneinduced Sgk1 relieves Dot1a–Af9-mediated transcriptional repression of epithelial Na+ channel alpha. J Clin Invest 117:773–783 Zhu L, Sui L, Wu et al (2015) Association between essential hypertension and three vasoactive peptides, urotensin II, endothelin and adrenomedullin. Clin Exp Hypertens 37:604–608

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Ions and Fluid Dynamics in Hypertension Avram Z. Traum

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Sodium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NHE Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NKCC Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The NCCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ENaC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Na+/K+ ATPase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60 60 62 62 63 63

Calcium Flux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Regulation of Ion Flux: The Role of α-Adducin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Sodium Distribution and Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Abstract

Ion transport is known to be involved in the genesis of hypertension and is utilized therapeutically. However, the mechanisms behind sodium flux that may lead to hypertension are incompletely understood. Target proteins of diuretic agents, monogenic forms of hypertension, and

genetic disorders of renal salt wasting have all provided insight into these pathways. In this chapter, we review some of these channels and their relevance to human hypertension. We explore the role of the cytoskeletal protein adducin in the regulation of sodium transport. We examine the function of the osmotically inactive sodium compartment and its regulation, and hormonal alterations affecting this compartment in salt-sensitive hypertension.

A. Z. Traum (*) Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA Department of Pediatrics, Harvard Medical School, Boston, MA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_4

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Keywords

Adducin · Extracellular volume · Liddle syndrome · Osmotically active sodium · NHE transporters – NKCC2, NCCT, and ROMK · Na+/K+ ATPase · Na+/Ca2+ exchanger (NCX) · Osmotically inactive sodium · Ouabain · Rostafuroxin · Salt sensitive · Sodium channel · Tenapanor · Vascular endothelial growth factor-C (VEGF-C) · NT-proBNP

Introduction Among the many determinants of blood pressure, ion transport has long been considered important, with its role considered central to the basic understanding and clinical management of hypertension. For decades, clinicians have counseled their hypertensive patients to limit salt intake. Such an approach has been codified in clinical guidelines and forms the backbone of what has been termed therapeutic lifestyle modifications (Chobanian et al. 2003; National High Blood Pressure Education Program Working Group on High Blood Pressure in and Adolescents 2004; Eckel et al. 2014; Flynn et al. 2017; Whelton et al. 2018). Sodium restriction has been studied in clinical trials as an effective measure for control of moderately elevated blood pressure (Akita et al. 2003; Obarzanek et al. 2003). In addition to sodium restriction, the role of natriuresis been translated into therapy as thiazide diuretics have assumed the role of first-line pharmacologic therapy for hypertension in adults (ALLHAT Collaborative Research Group 2000; Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial Collaborative Research 2003). At a more basic level, an expanding list of genes has been implicated in monogenic forms of hypertension – genes that typically encode proteins that affect renal tubular sodium handling, reviewed elsewhere in this book (see Part I, “Regulation of Blood Pressure and Pathophysiological Mechanisms of Hypertension,” ▶ Chap. 7, “Monogenic and Polygenic Contributions to Hypertension”). Moreover, mutations leading to renal salt wasting, as observed in Bartter and

Gitelman syndromes, are associated with normal or low blood pressure. While monogenic conditions associated with high or low blood pressure provide insight into the pathogenesis of hypertension, these comprise only a small fraction of the overall number of persons with hypertension. More broadly, however, pathogenic changes in ion transport have been implicated in both animal models (see Part V, “Hypertension Research in Pediatrics,” ▶ Chap. 49, “Hypertensive Models and Their Relevance to Pediatric Hypertension”) and in human studies of primary hypertension, suggesting a role for altered structure and function of ion transporters that provide additional rationale for the success of such measures as salt restriction and diuretics in treating hypertension. In this chapter, we will review some of the ion channels studied in hypertension and their relevance to clinical practice. Both channel function and structure will be considered. We will also discuss alterations in sodium distribution and their impact on blood pressure regulation.

Sodium Channels Given the importance of salt in the management of blood pressure, sodium channels have been extensively studied as potential therapeutic targets in both animal models of hypertension and in clinical research. All known relevant channels expressed along the length of the tubule have been studied. These include a variety of sodium transporters – the Na+/H+ exchangers (NHEs), the Na+-K+-2Cl
cotransporter (NKCC), the Na+-Cl
cotransporter (NCC), as well as the epithelial sodium cotransporter (ENaC) and the sodium-potassium ATPase (Na+/K+ ATPase). See Table 1.

NHE Transporters Na+/H+ transporters have been localized throughout the body. They play a major role in cell volume regulation and the transcellular movement of

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Table 1 Sodium transporters along the renal tubule Transporter Na+/H+ exchangers (NHEs) Na+-K+-2Cl– cotransporter (NKCC) Epithelial sodium cotransporter (ENaC) Na+ Cl–cotransporter (NCC) Sodium-potassium ATPase (Na+ K+ ATPase)

Intrarenal location Proximal tubule and TAL TAL

Cellular location Apical

Collecting duct Distal tubule

Apical

Multiple segments

Basolateral

Apical

Apical

TAL Thick ascending limb of the loop of Henle

sodium and osmotically driven water. There are nine NHEs; the NHE1 transporter is ubiquitous, while NHE3 is primarily expressed in the kidney. Both NHE1 and NHE3 have been the focus of much study with respect to hypertension. Specifically, the localization of NHE1 to red blood cells (RBCs) has facilitated its study in humans and in rat models, such as the spontaneous hypertensive rat (SHR). NHE1 activity is increased in multiple cell types in the SHR, including RBCs, platelets, leukocytes, skeletal muscle, vascular smooth muscle cells, and renal tubular epithelial cells. However, increased NHE1 activity was not seen in RBCs or proximal tubular cells of a second rat model of hypertension, the Milan hypertensive strain (MHS). RBC Na+/H+ transport has been examined in humans as well and appears to correlate with renal sodium retention in hypertensive persons (Diez et al. 1995). The differential effect in SHR versus MHS strains aligns well with human studies, as approximately half of the patients studied had increased RBC Na+/H+ activity (Canessa et al. 1991; Fortuno et al. 1997). Such increased Na+/H+ activity likely reflects a systemic effect, as it has also been demonstrated in skeletal muscle in both SHR (Syme et al. 1991) and in humans with hypertension (Dudley et al. 1990). In contrast to NHE1, the NHE3 transporter has a more restricted distribution but does include the

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proximal tubule, while RBC expression of NHE3 has not been reported. In SHR, NHE3 activity is increased (Hayashi et al. 1997), though mRNA expression is not altered. However, this enhanced activity may be related to decreased expression of the NHE regulatory factor 1 (NHERF1) (Kobayashi et al. 2004), which normally inhibits the activity of NHE transporters, suggesting that NHE3 changes are unrelated to gene expression or structure per se. Kelly et al. (1997) studied the relative contributions to sodium transport of NHE1 and NHE3 in proximal tubule cells of SHR. Their studies revealed equal activity of both proteins. While NHE1 protein expression was similar to that of normotensive wild-type controls, NHE3 expression was increased by 50% in SHR. An earlier study (Schultheis et al. 1998) of the NHE3 knockout mouse showed findings of proximal renal tubular acidosis with salt wasting, polyuria, and lower blood pressure, in spite of increases in both renin expression and aldosterone levels. These knockout mice also demonstrated diarrhea, related to absent intestinal expression of NHE3, the other major site of expression. Using NHE3-deficient mice with transgenic rescue of the Nhe3 gene in the small intestine, blood pressure was decreased and response to angiotensin II infusion was blunted, further demonstrating the role of NHE3 in the renal tubule (Li et al. 2015). Human studies of NHE3 in hypertension are limited. Zhu et al. (2004) studied polymorphisms in SLC9A3 (the gene encoding NHE3) to determine its association with hypertension in an ethnically diverse group of 983 persons, including some with normal and others with elevated blood pressure. None of six polymorphisms studied was associated with hypertension, although only a subset of the gene sequence was interrogated. Given the small sample size and limited portion of the gene studied, further work is necessary to evaluate the role of SLC9A3 in predicting human hypertension. Inhibition of intestinal NHE3 channels has been studied as a therapeutic approach to hypertension. Tenapanor is an NHE3 inhibitor; when administered orally, it acts locally in the intestine

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to block sodium uptake. In wild-type rats and healthy humans, tenapanor led to an increase in stool sodium and a reduction in urine sodium (Spencer et al. 2014). In rats with chronic kidney disease (CKD) using a 5/6 nephrectomy model, tenapanor prevented the rise in blood pressure and albuminuria seen with the high-salt diet. Rats treated with tenapanor also had lower left ventricular mass relative to vehicle-treated rats, suggesting that control of blood pressure benefited the heart (Spencer et al. 2014). A second NHE3 inhibitor showed a modest reduction in blood pressure in mice but blunted the hypertensive effect of angiotensin II (Li et al. 2019). Disappointingly, a small placebo-controlled trial of tenapanor in patients with end-stage renal disease showed no difference in interdialytic weight gain and pre-dialysis blood pressure (Block et al. 2016). Tenapanor was approved by the FDA in 2019 for the treatment of irritable bowel syndrome with constipation. It has also been studied as a treatment for hyperphosphatemia in chronic kidney disease as it blocks intestinal phosphate absorption, demonstrating efficacy in reducing serum phosphate levels in several randomized controlled trials (Block et al. 2017, 2019; Pergola et al. 2021; Inaba et al. 2022).

electrolyte wasting and volume depletion. Biochemically, the hallmark of this disease is elevated plasma renin activity and aldosterone level with low to normal blood pressure. Perhaps more clinically relevant are studies by the same group on participants in the Framingham Heart Study, which identified mutations in genes encoding NKCC2, NCCT, and ROMK, which appeared to be protective against hypertension (Ji et al. 2008). Similar to NHE transporters, the NKCC has also been studied in RBCs in animal models and in humans with hypertension. There is higher activity in RBCs in MHS rats compared to controls, and these animals demonstrate a greater natriuretic response to bumetanide (Salvati et al. 1990). Since this strain has normal expression levels of NKCC2 mRNA and protein (Capasso et al. 2008), it seems unlikely that the increased activity is unrelated to increased gene transcription. Higher levels of NKCC1 activity have been documented in hypertensive humans, but that finding accounts for only a fraction of patients with low-renin hypertension (Cusi et al. 1991; Cusi et al. 1993; Cacciafesta et al. 1994). However, patients with elevated NKCCl activity also have an exaggerated response to furosemide (Righetti et al. 1995).

NKCC Transporters

The NCCT

The NKCC family consists of two related proteins, NKCC1 and NKCC2. The first is expressed in a wide variety of tissues, while the second is primarily found in the kidney. In many tissues, both of these channels are activated by shrinkage of cell volume and, conversely, inhibited by cell swelling. The importance of NKCC2 is related primarily to its role in net sodium and chloride reabsorption in the thick ascending limb of the loop of Henle, and its inhibition by diuretics such as furosemide. This transport system is responsible for approximately 25% of tubular sodium reabsorption. Lifton’s group reported that mutations in the gene encoding the NKCC2 protein (SLC12A1) cause type 1 Bartter syndrome (Simon et al. 1996), a severe form of Bartter syndrome that has antenatal manifestations with polyhydramnios, prematurity, and postnatal

Given the widespread use and success of thiazides in treating hypertension, the sparse data on this transporter in both animal models and human hypertension is surprising. Capasso et al. demonstrated increased NCCT mRNA expression in MHS rats, in contrast to NKCC2 and NHE3 mRNA expression, which was not increased (Capasso et al. 2008). Mutations in the NCCT gene (SLC12A3) were also found to be protective against the development of high blood pressure in Framingham Heart Study participants (Ji et al. 2008). Similarly, heterozygote first-degree relatives of patients with homozygous mutations in NCCT (Gitelman syndrome) had significantly lower blood pressures than controls matched for age, gender, and body mass index (Fava et al. 2008).

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ENaC Activating mutations in genes encoding the epithelial sodium channel cause Liddle syndrome, perhaps the best-known monogenic form of hypertension. The ENaC is a protein complex of three subunits. The regulation of ENaC has been elucidated over the past decade, and includes a complex interaction of intracellular proteins including serum- and glucose-regulated kinase (SGK1) and neural precursor cell expressed, developmentally downregulated 4-2 (Nedd4-2). The putative role of ENaC has also been studied in nongenetic forms of hypertension. The Dahl salt-sensitive rat strain has been shown to exhibit increased activity of intrarenal ENaC. Specifically, in cell cultures of collecting ducts from these strains, sodium transport was enhanced as compared to control strains and was augmented by aldosterone and dexamethasone (Husted et al. 1996). In follow-up experiments to elucidate whether the effect was due to ENaC or to Na+/K+ ATPase, sodium transport was unaffected by the Na+/K+ ATPase inhibitor ouabain, suggesting increased ENaC activity as the cause (Husted et al. 1997). Liddle syndrome is caused by mutations in the genes encoding the ß- and γ-subunits of EnaC (see ▶ Chap. 7, “Monogenic and Polygenic Contributions to Hypertension”). These mutations result in truncated proteins without the C-terminal end, a segment that is essential for intracellular regulation, and leave ENaC constitutively activated and unaffected by homeostatic stimuli such as aldosterone. Aside from this rare genetic disease, a number of studies have attempted to assess the contribution of ENaC to primary hypertension. Persu et al. studied ß-ENaC variants in hypertensive families Persu et al. (1998). After determining the most common changes observed in the last exon, they assessed the frequency in a French cohort of 525 patients. Although these changes were seen in only 1% of White persons, the frequency increased up to 44% in those of African ancestry. However, only a fraction of those variants led to changes in sodium flux when studied in Xenopus oocytes (Persu et al. 1998). A relatively common variant in ß-ENaC, T594M, has been examined in a number of studies.

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This variant was first reported by Su et al. (Su et al. 1996) and found in 6% of 231 African American subjects but in none of the 192 Caucasians studied. This variant leads to loss of protein kinase C inhibition, providing a putative mechanism for its effect (Cui et al. 1997). A second study identified an association between this same variant and hypertension in 348 blacks in a study from the UK (Baker et al. 1998). The frequency of this variant was 8.3% among hypertensive persons and 2.1% in those with normal blood pressure. However, a larger study (n ¼ 4803) that included a large black population reported no relationship between this variant and hypertension (Hollier et al. 2006). Moreover, administration of amiloride to those with this variant did not demonstrate any differential effect as compared to those with wild-type ß-ENaC. Thus, the role of ENaC variants in hypertension remains to be fully elucidated.

Na+/K+ ATPase The ubiquitous Na+/K+ ATPase solute pump generates the driving force for a myriad of transport processes. In the renal tubule, the pump results in net sodium gain, facilitating epithelial sodium reabsorption along the length of the renal tubule. Earlier studies revealed increased Na+/K+ ATPase activity in MHS kidney extracts as compared with controls (Melzi et al. 1989). This phenomenon was due to increased activity of the pump per se, since pump number was not increased, as assessed by the number of ouabain binding sites (Parenti et al. 1991). In contrast to primary overactivity of this pump, Blaustein et al. (2009) proposed an alternative model, based on an unidentified endogenous ouabain-like substance. They hypothesized that salt retention leads to production of this ouabain-like substance, which then increases vasomotor tone due to the linked effects of the Na+/K+ ATPase and calcium flux (Haupert 1988). While acute administration of ouabain to rats may induce protective effects, such as increased generation of nitric oxide in response to acetylcholine, chronic administration in the rat model

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induces hypertension that blunts the effects of acetylcholine and generates endothelial dysfunction (Cao et al. 2009). An endogenous ouabainlike substance has been isolated from MHS and mammalian hypothalamus (Murrell et al. 2005).

Calcium Flux Sodium and calcium flux are interrelated, most notably due to the effects of the Na+/K+ ATPase and cross talk with the Na+/Ca2+ exchanger (NCX). This effect has been harnessed therapeutically with the use of digoxin to increase myocardial contractility. Inhibition of the Na+/K+ ATPase leads to an increase in intracellular sodium levels with secondary redistribution of calcium due to NCX (Blaustein 1993). The resulting rise in intracellular calcium improves contractility in cardiac myocytes and vascular smooth muscle cells (VSMCs). This link has been further established on a cellular compartment level with colocalization of Na+/K+ ATPase and NCX. It should be noted that differing Na+/K+ ATPase subtypes likely mediate this effect, with the α2 subtype having the greatest affinity for endogenous ouabain and its effect on VSMCs (Ferrandi et al. 1992; Tao et al. 1997). In mice, expression of the α2 subtype with a shortened N-terminus is dominant negative for expression of wild-type full length α2 pumps (Song et al. 2006). When this dominant negative α2 pump was expressed using a smooth muscle-specific myosin promoter, reduced pump function and elevated blood pressure were observed (Blaustein et al. 2009). Conversely, mice that overexpress the α2 pump within smooth muscle have significantly lower blood pressure than α2 wild-type mice and mice with α1 overexpression (Pritchard et al. 2007). The relation between these transporters suggests a sequence by which increased salt and water intake leads to volume expansion, followed by secondary release of endogenous ouabain (Hamlyn et al. 1996; Blaustein et al. 2009). The inhibition of the Na+/K+ ATPase attempts to prevent further sodium retention by the kidneys. However, within VSMCs, this effect enhances

A. Z. Traum

calcium uptake via NCX with a resultant increase in intracellular calcium and vasoconstriction. Furthermore, because of membrane depolarization related to Na+/K+ ATPase inhibition, L-type calcium channels would be activated leading to further calcium influx, resulting in a net increase in vascular tone. The effects of ouabain on the α2 pump subtype as described above lead to increased vascular tone. However, the α1 pump found in the renal tubular epithelium leads to net sodium retention and would theoretically be inhibited by ouabain. This discordance can be explained by the differential effects of physiological levels of ouabain on the different pump isoforms. As noted, ouabain inhibits the α2 pump, leading to calcium influx into VSMCs and increased vascular tone. In contrast, ouabain may have a net stimulatory effect in the kidney at the α1 pump via stimulation of epidermal growth factor receptor and subsequent phosphorylation and activation of the α1 pump (Haas et al. 2000; Liu et al. 2000). Thus the differential effect on isoforms of the Na+/K+ ATPase leads to a net increase in blood pressure (Ferrari et al. 2006). An exciting outgrowth of this research is the development of an inhibitor of the Na+/K+ ATPase for the treatment of hypertension. Rostafuroxin (PST 2238) is a steroid compound that competitively binds to Na+/K+ ATPase and inhibits the effects of ouabain. In MHS rats, rostafuroxin lowered blood pressure compared to vehicle. This effect was also seen in control rats treated with ouabain, deoxycorticosterone acetate, and salt-treated rats in a remnant kidney model (Ferrari et al. 1999, 2006). A recent phase II clinical study in hypertensive patients showed no effect of five different doses on blood pressure lowering (Staessen et al. 2011). However, when stratified by genotype, rostafuroxin showed a significant drop in blood pressure (Lanzani et al. 2010). Patients with variants in genes encoding enzymes for ouabain synthesis, ouabain transport, and the cytoskeletal protein adducin responded to all doses of rostafuroxin, in contrast to patients receiving losartan, hydrochlorothiazide, or placebo. In a follow-up study, subjects were randomized to rostafuroxin or

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losartan, and further stratified by genetic background (Chinese enrolled in Taiwan vs. Italian) and adducin genotype. They found that only the Italian subjects with specific genotypes responded to rostafuroxin and had a differential response as compared to losartan (Citterio et al. 2021).

Regulation of Ion Flux: The Role of α-Adducin While multiple channels have increased activity that leads to net sodium reabsorption and hypertension in both animal and human studies, the exact mechanism of this regulation remains unclear. The transporters studied generally do not have increased levels of mRNA or protein, and the association studies for specific polymorphisms in these models have provided conflicting data. However, the cytoskeleton has been implicated as having a role in this altered functional activity. Adducin, which is a heterodimeric cytoskeleton protein, and has an alpha subunit plus either a beta or gamma subunit, is ubiquitously expressed. Adducin is found in both rats and humans, and its association with salt-sensitive hypertension has been described in both. Adducin mutations in both α- and β-subunits have been associated with hypertension in MHS rats (Bianchi et al. 1994), leading to increased Na+/K+ ATPase activity in renal tubular epithelium (Tripodi et al. 1996). This group later described that MHS rats with these mutations did not have the expected endocytosis of Na+/K+ pumps in response to dopamine (Efendiev et al. 2004), which may reflect a broader alteration in clathrin-dependent endocytosis (Torielli et al. 2008). Other groups have shown that in a variety of rat models of hypertension, genes encoding adducin subunits have been found within quantitative trait loci for hypertension (Orlov et al. 1999). As described above, rostafuroxin reduces blood pressure in hypertensive MHS rats (Ferrari et al. 1999, 2006) and humans (Lanzani et al. 2010) with adducin mutations. α-Adducin polymorphisms have been described in salt-sensitive human hypertension

65

as well. In an Italian study of 936 persons, including hypertensive siblings, hypertensive individuals, and normotensive controls, the G460W polymorphism was studied, with a significant association seen in this population (Cusi et al. 1997). Interestingly, this relationship was not seen in a cohort of 375 Scottish patients (Kamitani et al. 1998) or 507 Japanese patients (Kato et al. 1998). A study of 232 Ukrainian patients also did not show a relationship between hypertension and this polymorphism, although did show an increased risk of hypertension in those patients with BMI in the overweight and obese categories and this polymorphism (Yermolenko et al. 2021). A meta-analysis of the G460W in Chinese Han population found an association between this polymorphism and the presence of hypertension (Li 2012). A larger meta-analysis of this polymorphism of 33 studies including 40,432 subjects found a relationship only in those of Asian descent (Jin et al. 2019). A cohort study of Italian high school students was utilized to study the relationship between several polymorphisms associated with hypertension in adults including α-Adducin rs4961 (Bigazzi et al. 2020). This polymorphism was not associated with blood pressure but did show a higher urine Na+/K+ ratio in males. The role of α-adducin polymorphisms in hypertension will require further elucidation, especially given the possible antihypertensive effects of rostafuroxin in this population.

Sodium Distribution and Blood Pressure An additional factor in the salt-mediated regulation of blood pressure is the distribution of sodium itself. Sodium intake leads to volume expansion, but distribution to other body compartments exists to offset this effect in rise in blood pressure. Osmotically active sodium refers to the changes seen in total body water with sodium intake. In contrast, osmotically inactive sodium describes sodium distribution that does not alter volume and may protect against sodium-induced changes in blood pressure.

66

This concept was studied in the Dahl saltsensitive (SS) rat strain (Titze et al. 2002). Compared to the Dahl salt-resistant strain and the Sprague Dawley (SD) rats, when fed a high-salt diet, SS rats had an expected increase in total body water, total body salt, and blood pressure. To study the osmotically inactive sodium compartment, bone sodium content was investigated. The SS strain showed an increase in bone sodium content, but the bone sodium to total body sodium ratio (bone Na/TBS) actually dropped in these animals compared to the other strains. This ratio was also inversely correlated with total body water and blood pressure in the SS rats, while no relationship was seen in other strains. Thus, in the SS rats the osmotically inactive bone sodium compartment was inadequate to handle the high-salt diet and contributed to the development of hypertension (see also Part I, “Regulation of Blood Pressure and Pathophysiological Mechanisms of Hypertension,” ▶ Chap. 10, “The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation”). These investigators later studied the role of skin in SD rats as a compartment for osmotically inactive sodium (Titze et al. 2003). Ovariectomized rats were compared to male and fertile female SD rats based on observation of differential salt sensitivity in females compared to males. While all groups showed an increase in skin sodium after a high-salt diet, the ovariectomized rats showed a smaller increase. Similarly, the ratio of skin sodium to total body sodium did not change in ovariectomized rats while it rose in fertile female and male rats. In contrast, the Dahl strains showed no change in skin sodium content. They later demonstrated that this osmotically inactive sodium storage was related to increased skin glycosaminoglycan (GAG) content, and that genes regulating GAG expression could be actively induced by salt loading (Titze et al. 2004). The regulation of sodium in this compartment may be further connected to hormonal mechanisms within local macrophages (Machnik et al. 2009). In this study, high-salt intake in SD rats led to expression of the angiogenic factor vascular endothelial growth factor-C (VEGF-C) and increased lymphatic channel production, as well as greater skin GAG content. Depletion of macrophages blunted this effect and exacerbated

A. Z. Traum

the hypertension of salt loading in these rats with extracellular volume expansion. The relation between skin sodium content and blood pressure has been studied in humans. Using 23 Na MRI, sodium content was measured in skin and muscle in a cohort of hypertensive and normotensive individuals (Kopp et al. 2013). Skin sodium content increased in parallel with age and blood pressure. In the same study, humans with refractory hypertension also had higher skin and muscle sodium. Spironolactone treatment led to both an improvement in blood pressure and decrease in muscle sodium content. The role of VEGF-C in salt-sensitive hypertension has also been studied in humans. In a cohort of adults with mild chronic kidney disease and proteinuria, a high-salt diet was associated with a rise in VEGF-C levels and blood pressure (Slagman et al. 2012). In healthy individuals, the rise in VEGF-C did not achieve statistical significance (p ¼ 0.07), and blood pressure was unchanged. Extracellular volume and NT-proBNP levels followed a similar pattern in both groups. The investigators conclude that VEGF-C may serve as a marker of salt-sensitive hypertension (see also Part I, “Regulation of Blood Pressure and Pathophysiological Mechanisms of Hypertension,” ▶ Chap. 13, “Salt Sensitivity in Childhood Hypertension”). They further investigated the role of VEGF-C using sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptor signaling and causes hypertension as a side effect of therapy in humans (Lankhorst et al. 2017). WKY rats were fed normal and high-salt diets, both before and after sunitinib administration. BP rose both with a high-salt diet and with sunitinib, and the combination led to an even greater increase. Skin sodium rose with high-salt diet and further with the combination. Skin sodium content correlated with BP rise.

Conclusions Aberrant ion transport is a critical component in the pathogenesis of hypertension. The research presented here reflects only a subset of the

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published data in this field. It also represents an exciting area of potential study in children and adolescents with primary hypertension, many of whom are salt sensitive. The role of rostafuroxin remains to be established in the treatment of hypertension, but establishes a new class of agent that more directly targets a potential mechanism of hypertension without the complicating metabolic side effects of thiazides. The role of adducin mutations and polymorphisms has yet to be investigated in pediatric hypertension and presents an untapped avenue for further investigation.

Cross-References ▶ Hypertensive Models and Their Relevance to Pediatric Hypertension ▶ Monogenic and Polygenic Contributions to Hypertension ▶ Salt Sensitivity in Childhood Hypertension ▶ The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation

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A. Z. Traum Tao QF, Hollenberg NK, Price DA, Graves SW (1997) Sodium pump isoform specificity for the digitalis-like factor isolated from human peritoneal dialysate. Hypertension 29(3):815–821 Titze J, Krause H, Hecht H, Dietsch P, Rittweger J, Lang R, Kirsch KA, Hilgers KF (2002) Reduced osmotically inactive Na storage capacity and hypertension in the Dahl model. Am J Physiol Renal Physiol 283(1): F134–F141 Titze J, Lang R, Ilies C, Schwind KH, Kirsch KA, Dietsch P, Luft FC, Hilgers KF (2003) Osmotically inactive skin Na+ storage in rats. Am J Physiol Renal Physiol 285(6):F1108–F1117 Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH, Dietsch P, Hilgers KF (2004) Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol 287(1):H203–H208 Torielli L, Tivodar S, Montella RC, Iacone R, Padoani G, Tarsini P, Russo O, Sarnataro D, Strazzullo P, Ferrari P, Bianchi G, Zurzolo C (2008) Alpha-Adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption. Am J Physiol Renal Physiol 295(2): F478–F487 Tripodi G, Valtorta F, Torielli L, Chieregatti E, Salardi S, Trusolino L, Menegon A, Ferrari P, Marchisio PC, Bianchi G (1996) Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 97(12): 2815–2822 Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr (2018) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol 71(19): e127–e248 Yermolenko S, Chumachenko Y, Orlovskyi V, Moiseyenko I, Orlovskyi O (2021) The association between Gly460Trp-polymorphism of AlphaAdducin 1 Gene (ADD1) and arterial hypertension development in ukrainian population. Int J Hypertens 2021:5596974 Zhu H, Sagnella GA, Dong Y, Miller MA, Onipinla A, Markandu ND, MacGregor GA (2004) Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential hypertension. J Hypertens 22(7): 1269–1275

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Uric Acid in the Pathogenesis of Hypertension Daniel I. Feig

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 The History of Uric Acid and Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Animal Models of Hyperuricemic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Uric Acid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proximal Tubular Urate Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pediatric Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78 81 82 83

Clinical Trials in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Clinical Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Abstract

Over the last century uric acid has been considered a possible risk factor for hypertension and cardiovascular disease. Only in the last two decades; however, have animal models and clinical trials supported a more mechanistic link. Results from animal models suggest a two-phase mechanism for the development of

D. I. Feig (*) Division of Nephrology, Department of Pediatrics, University of Alabama, Birmingham, AL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_5

hyperuricemic hypertension in which uric acid induces acute vasoconstriction by activation of the renin angiotensin system, followed by uric acid uptake into vascular smooth muscle cells leading to cellular proliferation and secondary arteriolosclerosis that impairs pressure natriuresis. This acute hypertension remains uric acid-dependent and sodium independent, whereas the chronic hypertension becomes uric acid-independent and sodium dependent. Clinical trial data has resulted in significant uncertainty. Small clinical trials, performed in adolescents with newly diagnosed hypertension, demonstrate that reduction of serum uric 71

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acid can reduce blood pressure, whereas in older patients no effect has been observed. While more research is clearly necessary, the available data suggest that uric acid may be involved in the onset of hypertension in children and adolescents. Keywords

Uric acid · Hypertension · Endothelial dysfunction · Vascular smooth muscle · Clinical trials

Introduction Hypertension is the leading cause of premature death and cardiovascular disease worldwide(Mills et al. 2020). The prevalence of hypertension and cardiovascular disease has not decreased over the last several decades despite important advances in monitoring and therapeutic options. Hypertension remains underdiagnosed, and even when treatment is offered, control rates are below 50% in most populations. The failure of conventional approaches to stem the cardiovascular disease epidemic emphasizes the need to identify early risk factors that may be amenable to interventions that prevent rather than treat hypertension. Serum uric acid represents one such candidate. The first observed association between serum uric acid and hypertension dates to a treatise by Frederick Mohamed published in 1879 (Mahomed 1879). Over more than 140 years since, numerous studies have documented the association (summarized in Table 1). Recent clinical trials have demonstrated mixed results in regard to the role of uric acid in the development of hypertension. In small clinical trials in adolescents, uric acid-lowering therapy results in a significant reduction of ambulatory blood pressure in newly diagnosed hypertension (Feig et al. 2008) and in obese individuals with elevated BP (Soletsky and Feig 2012). In similar trials in older adults, uric acid reduction has not changed blood pressure (McMullan et al. 2017) but did result in improvement in endothelial function (Gaffo et al. 2021). Several potential mechanisms link serum uric acid to the development of

hypertension. These include activation of the renin-angiotensin-aldosterone system, oxidative stress, endothelial dysfunction, and induction of renal afferent arteriolopathy (Piani et al. 2021). Population genetic studies have also provided conflicting evidence. Polymorphisms in genes for the enzyme xanthine-oxidoreductase, which is involved in the production of intracellular uric acid, have been associated with hypertension. In contrast, polymorphisms in genes that transcribe urate transporters that regulate extracellular concentrations and excretion of uric acid have not consistently been associated with blood pressure. This dichotomy could explain some of the variable results of clinical trials on the effect of agents that lower uric acid levels on blood pressure, as none have accounted for changes in intracellular uric acid levels. The prevailing data, at the time of this writing, suggest that while medications that lower uric acid should not be first-line agents for blood pressure control, control of uric acid in children and adolescents through non-pharmacologic measures may have salutary effects on long term blood pressure and cardiovascular outcomes.

The History of Uric Acid and Hypertension The possibility that uric acid may be a cause of hypertension has been considered for more than a century. In the 1870s Frederick Mahomed postulated that hypertension resulted from a circulating toxin that caused an increase in blood pressure and subsequently damaged the vasculature of the heart and kidneys (Mahomed 1879). While he suggested several candidate molecules, he proposed that uric acid is an important mediator and published the first sphygmograph tracings showing a subject with gout that increased systemic blood pressure (Mahomed 1879). A few years later Alexander Haig also linked uric acid with elevated blood pressure and actually wrote a textbook that suggested a diet that would lower uric acid and control blood pressure in the general population (Haig 1897). In 1897 Nathan Davis, in an address to the American Medical Association, proposed that gout was a major cause of hypertension that manifested as arteriolar disease,

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Table 1 Epidemiology of uric acid and hypertension Study or first author Israeli heart Fessel Gruskin Moscow Children’s study Brand Hungarian Children’s Kaiser Permanente University of Utah NHANES Olivetti heart study CARDIA study Osaka health survey Hawaii-LAHiroshima study Feig Osaka factory study Osaka health survey Okinawa Bogalusa heart

Framingham Normative aging study ARIC

Beaver dam survey Health professional follow-up

Population 10,000 Israeli men, age 17–25 enrolled at military induction 224 white males in Western US, age > 35 Yrs 55 adolescents, racially mixed US population 145 Caucasian children in Moscow, age 8–17 hypertension

Risk of hypertension Twofold risk at 5 Yrs

References Kahn et al. (1972)

Greater increase in SBP at 4 Yrs Higher uric acid, higher BP

Fessel et al. (1973) Gruskin (1985)

Uric acid >8 mg/dL predicts severe

Rovda (1992)

Uric acid, SBP rise a linear relation Uric acid predicts adolescent hypertension Twofold risk at 6 Yrs

Brand et al. (1985)

Twofold risk at 7 Yrs

Hunt et al. (1991)

619 adult males from southern Italy

Uric acid predicts adolescent hypertension Twofold risk at 12 Yrs

Goldstein and Manowitz (1993) Jossa et al. (1994)

5115 black men and women age 18–30 6356 Japanese men age 35–60

Increased risk at 10 Yrs Twofold risk at 10 Yrs

Dyer et al. (1999) Taniguchi et al. (2001)

140 Japanese American males age 40–69

3.5-fold risk at 15 Yrs

Imazu et al. (2001)

175 racially diverse children, age 6–18 in Texas 433 nonobese Japanese men age 18–40

Uric acid >5.5 mg/dL predicts hypertension 1.0 mg/dl "27 mmHg SBP at 5 Yrs 1.6-fold risk at 6 Yrs

Feig (2003)

4286 men and women age 35–50 in the Framingham cohort 17,643 Hungarian children, age 6–19 2062 adult men and women in the Kaiser Permanente multiphasic health checkup cohort in northern California 1482 adult men and women in 98 Utah pedigrees 6768 healthy children age 6–17

2310 male office workers in Japan, age 35–59 4489 Japanese men and women, age > 30 577 black (58%) and white (42%) children enrolled at age followed until age 18–35 3329 men and women in the Framingham cohort 2062 healthy men age 40–60 at enrollment 9104 mixed race (black and white) men and women age 45–64 Yrs at enrollment. 2520 white men (44%) and women (56%) age 43–84 in Wisconsin 750, mostly white men in Massechussetts

1.7-fold risk at 13 Yrs " risk for diastolic HTN at 11 Yrs 1.6-fold at 4 Yrs

Torok et al. (1985) Selby et al. (1990)

Masuo et al. (2003) Nakanishi et al. (2003) Nagahama et al. (2004) Alper Jr. et al. (2005)

1.5-fold at 21 Yrs

Sundstrom et al. (2005) Perlstein et al. (2006)

1.5-fold at 9 Yrs

Mellen et al. (2006)

1.65-fold at 10 Yrs

Shankar et al. (2006)

1.08-fold at 8 Yrs

Forman et al. (2007)

(continued)

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Table 1 (continued) Study or first author MRFIT Nurses health Qingdao port health Jones Leite

Grayson Silverstein

GOCADAN Fadrowski

Population 3073 men age 35–57 Yrs 1496 women, racially diverse, age 32–52 7220 men (74%) and women (26%) in Quingdoa China mean age 37 141 children age 7–18, 64% male, 71% black 1410 men and women in Milan, Italy, young cohort 42–59 Yrs, older cohort 60–74 55,607 adults, meta-analysis of 18 prospective studies 108 racially diverse children, age 6–18 in Texas and Washington DC. 1078 Alaskan native Americans with CKD II-III 6036 adolescents, age 11–17 evaluated in NHANES

interstitial kidney injury, and myocardial hypertrophy(Davis 1897). In 1909, Henri Huchard hypothesized that the vascular lesions associated with hypertension had three causes: elevated uric acid levels, elevated lead levels, and intake of fatty meats, which also would result in increased uric acid levels (Huchard 1909). In 1913, Desgrez reported the first animal model evidence supporting the link between uric acid and hypertension, noting that uric acid infusions increased blood pressure in a rabbit model(Desgrez 1913). In 1915 Urodonal, a drug consisting of theobromine and methenamine, was introduced in France as a treatment intended to lower uric acid levels and control blood pressure; however, it was eventually proven ineffective. Nevertheless, at the end of the nineteenth century and the first two decades of the twentieth century uric acid was already linked with hypertension and cardiovascular diseases. Interest in the possible link between hypertension and uric acid waxed and waned during much of the twentieth century. While some cardiovascular risk trials measured uric acid and suggested an association between uric acid and hypertension, or cardiovascular disease (Table 1), two factors led most investigators to conclude that uric acid was an associated surrogate marker for more important risk

Risk of hypertension 1.8-fold at 6 Yrs 1.9-fold at 6 Yrs

References Krishnan et al. (2007) Forman et al. (2009)

1.39 for men, 1.85 for women at 4 Yrs 2.1-fold risk in adolescence by ABPM Increased risk in middle age, not elderly

Zhang et al. (2009) Jones et al. (2009) Leite (2011)

1.41-fold risk each 1 mg/dL uric acid Linear association between SBP and uric acid in children on renal replacement therapy 1.2-fold age-adjusted risk

Grayson et al. (2011)

Uric acid >5.5 mg/dL, 2.03fold risk

Loeffler et al. (2012)

Silverstein et al. (2011) Jolly et al. (2012)

factors such as obesity, diabetes, and chronic kidney disease (CKD)(Culleton et al. 1999). The first was a lack of a plausible physiological mechanism, and the second was that despite consistent correlation, the link between serum uric acid levels and cardiovascular disease was not always statistically independent of other factors such as hypertension, kidney disease, and diabetes. In the 1980s, uric acid was removed from some common laboratory panels, markedly reducing the available epidemiologic data on uric acid in otherwise well patients and those suffering from cardiovascular disease. That move was made because of the majority of serious side effects from the urate-lowering drug, allopurinol, were observed in patients with asymptomatic hyperuricemia (Gutierrez-Macias et al. 2005) and was intended to reduce risk of unnecessary medication side effects associated with the treatment of asymptomatic hyperuricemia.

Animal Models of Hyperuricemic Hypertension While significant epidemiological evidence supported the hypothesis that uric acid may be associated with hypertension, it was not deemed

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Uric Acid in the Pathogenesis of Hypertension

important until the experiments of Johnson and colleagues in 2001, established a plausible mechanism. Using a rat model of pharmacologicallyinduced hyperuricemia, the increased serum uric acid level results in hypertension within 2 weeks. The increases in SBP and DBP are proportional to those of uric acid. These abnormalities can be ameliorated by uric acid lowering drugs (allopurinol or benziodarone). Early hypertension is completely reversible with urate reduction, but prolonged hyperuricemia results in irreversible sodium sensitive hypertension that becomes uric acid independent (Mazzali 2001, 2002). Early hypertension is mediated by increased intrarenal renin and reduction of circulating plasma nitrates (Gersch et al. 2007; Kang et al. 2001; SanchezLozada et al. 2007; Sautin et al. 2007), leading to a phenotype of excessive vasoconstriction that can be reversed by reduction of uric acid or by reninangiotensin system blockade. The latter, irreversible hypertension, is secondary to altered

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intrarenal vascular architecture. Uric acid enters vascular smooth muscle cells (VSMC) via the URAT1 channel, resulting in the activation of kinases, nuclear transcription factors, cyclooxygenase 2 (COX-2) generation, and the production of the growth factor PDGF, and inflammatory proteins, C-reactive protein, monocyte chemoattractant protein-1, resulting in the VSMC proliferation, shifted pressure natriuresis, and sodium-sensitive hypertension (Kanellis et al. 2003; Kang et al. 2002; Kang and Johnson 2003; Price et al. 2006; Watanabe et al. 2002). If this scenario is recapitulated in humans, this model suggests that there may be an initial period of reversible hypertension (Fig. 1). Another implication of this model is that if VSMC proliferation and a shifted pressure natriuresis curve were present but another mechanism leading to established hypertension, such as aging or atherosclerosis, were already present, urate-lowering therapy would be expected to have a very limited impact.

Phase 1: Acute Vasoconstriction Uric Acid Increased renin Decreased NO

Reversible Sodium resistant

Phase 2: Arteriolar Wall Hypertrophy Uric Acid Vascular smooth muscle proliferation mediated by PDGF and MCP-1 Fig. 1 Mechanisms of uric acid-mediated hypertension. Animal model data suggest that hyperuricemia leads to hypertension in a stepwise fashion. The effects of uric acid on the blood vessel are shown here. The first phase is direct, uric acid- dependent activation of the renin-angiotensin system and down-regulation of the nitric oxide production, leading to vasoconstriction. At this stage, uric acid reduction results in vascular relaxation and improved blood pressure. The second phase, which

Irreversible Sodium sensitive

develops over time, is uric acid-mediated arteriolosclerosis. Uric acid uptake into vascular smooth muscle cells causing the activation and elaboration of PDGF and MCP-1. This results in the autocrine stimulation of vascular smooth muscle cell proliferation, vascular wall thickening, loss of vascular compliance, and a shift in pressure natriuresis. This process is not reversed by the late reduction of uric acid and causes permanent sodium sensitive hypertension.

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Epidemiology Numerous longitudinal cardiovascular risk trials have evaluated the possible relation between serum uric acid levels, hypertension, cardiovascular disease, and chronic kidney disease (see Table 1). As early as 1972, the Israeli Heart Trial, which evaluated the medical data of young adults inducted into the armed services, demonstrated that the highest tertile of serum uric acid was associated with double the risk of incident hypertension within 5 years (Kahn et al. 1972). That association was robust across racial groups, with similar findings in African Americans noted in the CARDIA trial (Dyer et al. 1999) as well as in several trials demonstrating the same association in Asians and Asian Americans(Imazu et al. 2001; Masuo et al. 2003; Nagahama et al. 2004; Nakanishi et al. 2003; Taniguchi et al. 2001). Several studies on children and adolescents, particularly the Hungarian Children’s Study (Torok et al. 1985), the Moscow Children’s Hypertension Study (Rovda 1992), and the National Health And Nutrition Examination Survey (NHANES) (Goldstein and Manowitz 1993), in the 1980s and early 1990s, demonstrated a particularly strong association between uric acid and hypertension. Studies specifically of older and elderly patients have had more variable results(Culleton et al. 1999; Nefzger et al. 1973; Saito et al. 2000; Staessen 1991). Notably, some of the studies found that the association between uric acid and cardiovascular (CV) risk did not retain significance in certain multiple regression models, particularly if the risk conferred by hypertension was controlled in the model(Culleton et al. 1999; Moriarity et al. 2000; Sakata et al. 2001; Simon 2006). One explanation may be that the CV risk caused by uric acid functions through the development of hypertension; alternatively, there may be a preferential effect in the young. In the past two decades, new epidemiological studies have rekindled an interest in the link between uric acid and hypertension. Three longitudinal studies in Japanese subjects showed an association between serum uric acid and incident hypertension. Nakanishi et al. demonstrated a 1.6-fold increased risk of new hypertension

D. I. Feig

over 6 years in young adult office workers whose serum uric acid levels were in the highest tertile (Nakanishi et al. 2003). Tanaguchi et al. demonstrated a twofold increased risk of new hypertension over 10 years associated with elevated uric acid in the Osaka Health Study (Taniguchi et al. 2001). Matsuo et al. evaluated the linear association of serum uric acid and systolic blood pressure, finding an average increase of 27 mm Hg per 1 mg/dl increase in serum uric acid among non-obese young men (Masuo et al. 2003). In an ethnically diverse population within the Bogalusa Heart Study, higher childhood and young adult serum uric acid levels were associated with incident hypertension and progressive increase in blood pressure, even when within the normal range (Alper Jr. et al. 2005). A post-hoc analysis from the Framingham Heart Study also suggested that a higher serum uric acid level is associated with an increased risk of rising blood pressure (Sundstrom et al. 2005). Taken together, the preponderance of evidence supports a close epidemiologic association between uric acid and hypertension that is robust across ethnic racial and anthropomorphic categories but may be attenuated in the elderly. A general association between uric acid and cardiovascular morbidity and mortality has also been extensively studied. While hard cardiovascular endpoints are not immediately applicable to child health, as they occur long after childhood, one of the primary goals of screening for hypertension and its cofactors is to mitigate long-term risk. Many of the large longitudinal cardiovascular health studies, including the Bogalusa Heart Study(Alper Jr. et al. 2005), the Atherosclerosis in Communities study (ARIC)(Mellen et al. 2006), the Multiple Risk Factor Intervention Trial (MRFIT) (Krishnan et al. 2007), The Framingham Heart Study (Sundstrom et al. 2005), and others have assessed the association of elevated serum uric acid on cardiac morbidity, cardiac mortality, and all-cause mortality. A curated selection of representative studies is listed in Table 2. As there are >3200 reports of the epidemiologic association between hyperuricemia and cardiovascular risk published since January 2000, a

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Table 2 Epidemiology of uric acid and cardiovascular disease Study or first author Lehto Liese Alderman Fang

Franse Verdecchia Mazza Wang Bickel Weir Niskanen Athyros Hakoda Suliman Bos Culleton Moriarity Sakata Simon URRAH mg/dL

Population 1017 diabetics, mean age 58 Yrs followed for 7 Yrs 1044 healthy adults, 50–60 Yrs, followed for 8 yr 7978 hypertensive adults mean age 53 Yrs, followed for 6 yrs 5926 healthy adults mean age 48, followed for 16 Yrs 4327, elderly adults, mean age 71, followed for 5 Yrs 1720 adults with hypertension, mean age 51 Yrs, followed for 4 Yrs 3282 healthy adults, mean age 74, followed for 14 Yrs 1873 Chinese adults mean age 66 Yrs, followed for 3 Yrs 1017 with coronary artery disease, mean age 62 followed for 2.2 Yrs 2482 stroke patients, mean age 72, follow up 2 Yrs 1423 healthy Finnish adults, mean age 53 Yrs, followed for 12 Yrs. 1600 adults with hypertension and congestive heart failure, mean age 59, followed for 3 Yrs 10,615 atomic bomb survivors mean age 49 followed for 25 Yrs 294 adults with ESRD, mean age 53, followed for 3 Yrs 4385 adults in Rotterdam study, above age 55 Yrs followed for 8.5 Yrs 6763 adult men, mean age 47, followed for 4 Yrs, Framingham cohort 13, 504 healthy adults, mean age 50, followed for 8 Yrs 8172 healthy adults, mean age 49, followed for 14 Yrs 2763 women, mean age 66, followed for 4 yrs 22,714 adults, assess for serum uric acid threshold associated with >20% increase in risk for CV morbidity or mortality

comprehensive review of these studies is beyond the scope of this chapter. The preponderance of data suggests a close association with longitudinal hyperuricemia and myocardial infarction, stroke, and cardiovascular mortality. The debate regarding whether uric acid is linked to the causation of cardiovascular disease has been fueled by the observation that the disease only sometimes

CV Risk OR 1.91, independent on MR OR 1.7–2.8, independent on MR OR 1.5, independent on MR OR 3.0, independent on MR

OR 1.5, independent on MR OR 1.9, independent on MR OR 1.6, independent on MR OR 1.34, independent on MR OR 2.7, independent on MR OR 1.3, independent on MR OR 4.8, independent on MR OR 3.0, independent on MR OR 1.8, independent on MR OR 1.3, independent on MR OR 1.7, independent on MR OR 4.1, not independent on MR OR 3.0, not independent on MR OR 2.3, not independent on MR OR 1.1, not independent on MR Uric acid cutoffs were 4.7 5.6 mg/dL for mortality and CV morbidity, respectively

References Lehto et al. (1998) Liese et al. (1999) Alderman et al. (1999) Fang and Alderman (2000) Franse et al. (2000) Verdecchia et al. (2000) Mazza et al. (2001) Wang et al. (2001) Bickel et al. (2002) Weir et al. (2003) Niskanen et al. (2004) Daskalopoulou et al. (2004) Hakoda et al. (2005) Suliman et al. (2006) Bos et al. (2006) Culleton et al. (1999) Moriarity et al. (2000) Sakata et al. (2001) Simon (2006) Virdis et al. (2020)

remains after multiple regression analysis (Sanchez-Lozada et al. 2020). It is important to remember, however, that if the impact of uric acid on cardiovascular morbidity is largely, or even in part, driven by its effect on blood pressure, statistical regression that excludes the effect of hypertension will attenuate the evident association (Piani et al. 2021). The recent Uric Acid Right

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D. I. Feig

for Heart Health (URRAH) study reviewed the association between serum uric acid levels and cardiovascular mortality and morbidity with the goal of defining risk-level targets for future interventional trials. URRAH found that serum uric acid levels of 4.7 mg/dL and 5.6 mg/dL were the cutoffs for an increase of greater than 50% in hazard ratios for cardiovascular mortality and morbidity, respectively (Virdis et al. 2020).

Uric Acid Metabolism The precise causes of hyperuricemia in the young are not well established; however, many possibilities exist and probably co-exist. Uric acid is the endpoint of purine metabolism in humans. Xanthine, adenine, and guanine are metabolized by xanthine oxidase to uric acid. Most mammals have the enzyme uricase, which metabolizes uric acid to the more soluble enzyme allantoin. However, allantoin was lost during primate evolution (Fig. 2). Increased uric acid can result from decreased kidney function; in general, children with CKD and ESRD have higher serum uric acid levels (Silverstein et al. 2011). Genetic polymorphisms in anion transporters such as SLC22A12, which encodes for uric acid anion

transporter 1 (URAT-1) (Graessler et al. 2006) and SLC2A9, which encodes for GLUT9, anion transporters with an affinity for uric acid (McArdle et al. 2008; Parsa et al. 2012), can lead to hyperuricemia by altering proximal tubular urate clearance. Approximately 15% of uric acid clearance takes place in the GI tract; consequently, small bowel disease can also contribute to increased serum uric acid levels (Cannella and Mikuls 2005). Diets rich in fatty meats, seafood and alcohol increase serum uric acid levels (Lee et al. 2006; Schlesinger 2005), and obesity confer a threefold increased risk of hyperuricemia (Hwang et al. 2006). There are also numerous medications that alter the renal clearance of uric acid, even in the presence of normal glomerular filtration rate, including loop and thiazide diuretics(Reyes 2005). Finally, as uric acid is the endpoint of the purine disposal pathway, impairment of the efficiency of purine recycling metabolism or overwhelming the recycling pathway with excessive cell death or cell turnover will increase serum uric acid (Masseoud et al. 2005) (Table 3). Serum uric acid levels also correlate with sweetener consumption (Rho et al. 2011). Sweetener consumption in the USA has dramatically increased since the introduction of high fructose

Purines (Adenine, Guanine) Hypoxanthine

•O2-

Xanthine Oxidase

Xanthine

Xanthine Oxidase

•O2-

Uric Acid Mutation Urate oxidase (Uricase)

Primates Fig. 2 Metabolism of uric acid. Uric is the endpoint of purine metabolism in humans. Guanine and adenine are metabolized to xanthine, and then to uric acid by the enzyme xanthine oxidoreductase, sometimes simply referred to as xanthine oxidase. Non-primate mammals

Allantoin

Non-primates have the enzyme uric acid oxidase, or uricase, that further metabolizes uric acid to allantoin though this enzyme is not present in humans and great apes, resulting in higher serum levels of uric acid

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Uric Acid in the Pathogenesis of Hypertension

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Table 3 Clinical trials of effect of uric acid lowering therapy on blood pressure Study Feig

Kanbay

KostkaJeziorny Soletsky

Population/intervention 30 newly hypertensive adolescents treated with allopurinol randomized crossover design (4 weeks) 97 adults with asymptomatic hyperuricemia, without gout open-label, treated with allopurinol (16 weeks) 66 adults with stage 1 hypertension treated with allopurinol (8 weeks)

60 obese adolescents with hyperuricemia, elevated BP randomized to allopurinol, probenecid, or placebo (8 weeks) Assadi 44 adolescents with newly diagnosed hypertension randomized to enalapril alone or enalapril plus allopurinol (8 weeks) Higgins 80 adults with recent ischemic stroke randomize to allopurinol or placebo (12 months) Kim 179 adult men with gout and serum uric acid >8.0 mg/dL randomized to allopurinol at 300 mg/d, febuxostat 40, 80, and 120 mg/dL (4 weeks) Madero 72 overweight, pre-hypertensive adults, randomized allopurinol or placebo (4 weeks) Segal 110 African American adults with stage 1 hypertension and normal renal function, on thiazide diuretic, randomized to allopurinol or placebo (4 weeks) Tani 160 hyperuricemic hypertensive adults randomized to dose ranging Febuxostat (40, 80, and 120 mg/d) versus placebo (6 months) Borgi 149 obese adults with hyperuricemia and normal BP randomized to placebo, probenecid, or allopurinol (8 weeks) Gundwardhana 121 adults with hyperuricemia, without gout and stage 1 hypertension randomized to placebo or febuxostat 80 mg/d (6 weeks) Jalal 80 adults with CKD3 and hyperuricemia randomize to allopurinol or placebo (12 weeks) McMullan 149 overweight adults with normal BP and serum uric acid >5 mg/dL randomized to allopurinol, probenecid, or placebo (8 weeks) Johnson 212 adults with refractory gout randomized to Pegloticase at either 2 week or 4 week intervals (6 months) Gaffo 99 young adults with stage 1 hypertension randomized to allopurinol or placebo (6-week crossover)

Outcome 20/30 achieved normal BP on allopurinol

References Feig et al. (2008)

Decrease in SBP

Kanbay et al. (2011)

No change in BP

KostkaJeziorny et al. (2011) Soletsky and Feig (2012)

Subjects treated with urate-lowering therapy had a significant reduction in BP Those treated with allopurinol were twice as likely to achieve the BP goal

Assadi (2014)

Patients on allopurinol at lower BP at 1 yr

Higgins et al. (2014)

Patients on higher doses of febuxostat had lower SBP and DBP

Kim et al. (2014)

Patients on allopurinol had lower SBP

Madero et al. (2015)

No statistically significant change in BP over thiazide alone

Segal et al. (2015)

Febuxostat reduced renin activity, and serum aldosterone

Tani et al. (2015)

No change in endothelial function

Borgi et al. (2017)

Sub-group with normal renal function showed SBP reduced with febuxostat No difference in BP

Gunawardhana et al. (2017) Jalal et al. (2017)

No change in BP or renin activity

McMullan et al. (2017)

Mean arterial BP decreased in the frequently treated group, no placebo

Johnson et al. (2019)

No difference in ambulatory BP but significant increase in flow mediated dilation in treatment phase

Gaffo et al. (2021)

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D. I. Feig

corn syrup (HFCS) in the early 1970s (Nakagawa et al. 2006). Fructose raises uric acid rapidly via activation of the fructokinase pathway in hepatocytes (Fox and Kelley 1972). Fructokinase consumes ATP, leading to an increased load of intracellular purines requiring metabolism and disposal through xanthine oxidase-mediated metabolism, ending in uric acid production (Fox and Kelley 1972) (Fig. 3). The administration of large quantities of fructose to rats (60% of their caloric intake) results in hyperuricemia, elevated blood pressure, and the development of preglomerular arteriolopathy (Hwang et al. 1987). Furthermore, lowering uric acid prevents these changes despite ongoing fructose consumption (Nakagawa et al. 2006). It takes a prodigious amount of fructose intake in rats to raise serum uric acid levels, possibly because rats have uricase, an enzyme that metabolizes uric acid to allantoin. In humans, who are genetically deficient in uricase, less fructose consumption is apparently needed to result in hyperuricemia. Human studies show that fructose loading leads acutely to increased serum uric acid levels,

and that chronic increases in fructose consumption lead to chronically increased serum uric acid and increases in blood pressure (Brown et al. 2008). With the nearly universal exposure to sweetened foods and beverages in the pediatric population in much of the world, it is very likely that much of the hyperuricemia noted today, especially that associated with obesity, is dietary rather than genetic in origin(Nguyen et al. 2009). Consistent with this hypothesis, epidemiological studies have shown a relation between fructose intake and serum uric acid levels in most but not all studies (Jalal et al. 2010). One reason some studies may be negative could reflect the action of fructose, as it tends to increase uric acid mostly in the postprandial setting. Since most studies use fasting uric acid levels, it is possible that an elevation in mean 24-hour uric acid would be missed. Jalal and colleagues used the National Health and Nutrition Examination Survey (NHANES 2000–2003) which was a survey of healthy adults in the United States in which direct blood pressure measurement was available as well as dietary intake of fructose as determined by dietary questionnaire.

FRUCTOSE

GLUT5/SLC2A5

ATP

FRUCTOSE FRUCTOKINASE

FRUCTOSE-1-PHOSPHATE

TRIGLYERIDES + ↓PHOSPHATE

ADP

↑ Adenosine Deaminase

AMP

URIC ACID

URIC ACID Fig. 3 Effect of fructose on cellular uric acid metabolism. Fructose enters cells via the high capacity fructose transporter, GLUT5 (encoded by SLC2A5). Fructose raises uric acid rapidly via activation of the fructokinase pathway in hepatocytes. Unlike glucokinase, fructokinase does not respond to end-product inhibition so will mediate

rapid metabolism as long as fructose is available. Fructokinase consumes ATP leading to an increased load of intracellular purines requiring metabolism and disposal through xanthine oxidase mediated metabolism ending in uric acid

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Uric Acid in the Pathogenesis of Hypertension

The major finding in participants was a strong, independent association of fructose intake with elevated systolic blood pressure (Jalal et al. 2010). Interestingly, this association was independent of fasting serum uric acid. In a different study, Nguyen and colleagues also found an independent association of sugary soft drinks with hypertension in adolescents(Nguyen et al. 2009). Perez-Pozo et al. administered 200 g of fructose per day to healthy overweight males with or without allopurinol over a 2-week period(Perez-Pozo et al. 2009). In that study, an increase in serum uric acid was observed in association with a significant increase in daytime systolic, and both 24-hour and daytime diastolic blood pressure occurred. Allopurinol reduced the serum uric acid levels and blocked the blood pressure rise. While the dose of fructose in that study was very high, 25% of the NHANES cohort consumed similar quantities (Jalal et al. 2010).

LUMINAL SURFACE

Transportosome

SMCT 1/2

81

Proximal Tubular Urate Transport Understanding the mechanisms of renal urate handling are useful in both predicting hyperuricemia and developing strategies to manage it. Uric acid is freely filtered through the glomerulus; however, over 90% is reabsorbed in the proximal tubule. Because of its hydrophobicity and negative charge, it is unlikely that there is significant paracellular transport, leaving the transcellular transport as the dominant mechanism (Fig. 4). The most active transporter on the luminal membrane in the proximal tubule is the URAT-1 (urate anion transporter 1), which is a high throughput anion exchanger located at the luminal membrane of the proximal tubule. URAT-1 primarily exchanges luminal uric acid for monocarboxylates, including lactate, nicotinate, and pyrazine carboxylic acid. URAT-1-mediated urate reabsorption is

BASOLATERAL SURFACE

Na+

Organic anions dicarboxylates

Lactate Nicotinate PDZ

OAT1

URAT 1

NET URATE EXCRETION

OAT 4

OAT3

Uric Acid

NET URATE REABSORBTION

dicarboxylates

OATv1 MRP4

fructose

GLUT9L

UAT

Fig. 4 Uric acid transport in the proximal tubule: Solid lines indicate the direction of urate transport, dashed lines the movement of cotransported or counter-transported ions. URAT-1 is a urate/dicarboxylate exchanger that provides most of the reabsorption for filtered uric acid. It is coupled by the PDZ domain containing scaffolding proteins (represented by the dotted box) to SMCT 1 and SMCT 2 which are Na, monocarboxylate cotransporters. This “urate transpososome” results in efficient monocarboxylate reabsorption and excretion yielding net reabsorption of Na and urate. OAT4 is a urate/

dicarboxylate exchanger that may modestly contribute to urate reabsorption. OATv1, MRP4, and UAT, also located on the luminal membrane, are thought to contribute to the active excretion of uric acid (see text). On the basolateral membrane, OAT1 and OAT3 are bidirectional urate/ dicarboxylate exchangers that provide the major pathway for re-entry of uric acid into the circulation. GLUT9 (facilitative glucose transporter 9) is a fructose and uric acid cotransporter present on the basolateral membrane of proximal tubules and several other cell types

82

likely enhanced by structural linkage to sodium/ monocarboxylate cotransporters SMCT-1 and SMCT-2 (Anzai et al. 2007). Scaffolding proteins with PDZ (Post-synaptic density protein, Disc large tumor suppressor, Zona-occludens) protein binding motifs co-localize in SMCT transporters and URAT-1. Monocarboxylate molecules entering the proximal tubular cell through SMCT transporters will then be excreted into the proximal tubule lumen, in exchange for urate, by URAT-1. The results of this channel pairing, called by some groups the “urate transportosome,” are the local intracellular concentration of monocarboxylates to drive urate reabsorption and the net reabsorption of sodium and urate in equal molar concentrations. Some experts have hypothesized that this indirect pairing of urate and sodium reabsorption led to an evolutionary advantage in times of a severely sodium deficient diet and explains the loss of urate oxidase during hominid development (Watanabe et al. 2002). URAT-1 can be inhibited by several pharmacologic agents including benzbromarone, probenecid, losartan, and high dose salicylate. The dominant of the role of URAT-1 in urate reabsorption is demonstrated by patients with hereditary renal hypouricemia in which mutations in URAT-1 lead to increased clearance and serum levels less than 2 mg/dL which is as low as in animals with active urate oxidase (Endou and Anzai 2008). There are several other potential apical membrane urate transporters; however, their relative contribution to uric acid homeostasis is unclear. Organic anion transporter 4 (OAT-4) is an anion/ dicarboxylate exchanger, structurally similar to URAT-1, which may participate in urate reabsorption. OAT-v1 is a voltage-gated anion channel that may contribute to urate secretion into the tubular lumen (Anzai et al. 2008). Uric acid transporter (UAT) is a constitutively active urate channel expressed on the apical pole of proximal tubular cells that also contribute urate efflux proportionate to serum concentrations. MRP-4 is an ATP-dependent urate transporter that may provide modifiable urate excretion(Ichida 2009). OAT-1 and OAT-3 are urate transporters located on the basolateral surface of proximal tubule cells. These dicarboxylate/urate exchangers provide the

D. I. Feig

major pathway for re-entry of uric acid into circulation. It is as yet unknown if or to what degree these transporters are regulated(Ichida 2009). While tremendous strides in the understanding of proximal tubular urate handling have been made in the last 10 years, it remains incompletely understood and the focus of intense study.

Genetic Associations The advances of genomic technology over the past couple of decades have been applied to causes of hyperuricemia, largely as an etiology of gout but occasionally as it relates to hypertension. Genome-wide association studies, performed on populations of European, African American, and Asian descent have identified genes encoding uric acid transporters, including GLUT9, URAT1, and ABCG2, account for 20–40% of the population variability of serum uric acid (Major et al. 2018). These studies have been used to generate a genetic risk score, including 30 genes that correlate with the development of gout; however such data do not explain the development of chronic hypertension (Major et al. 2018). Similarly, mendelian randomization studies have failed to demonstrate a causal relation between serum uric acid and hypertension (Major et al. 2018; Piani et al. 2021). In contrast, studies that have focused on polymorphisms of aldehyde dehydrogenase II (ALDH-2) (86) or xanthine oxidoreductase (XOR) (Cicero et al. 2021; Kei et al. 2018) have shown that these variants are associated with both increased serum uric acid and hypertension. A possible explanation for these divergent results may be the impact of polymorphisms on intracellular rather than extracellular uric acid. Intracellular uric acid concentrations, which do not always directly associated with serum uric acid levels, may be responsible for some of the physiologic effects (SanchezLozada et al. 2020). Urate transporters, which don’t clearly associate with hypertension, are much more impactful on serum levels compared to intracellular concentrations (Piani et al. 2021).

5

Uric Acid in the Pathogenesis of Hypertension

Pediatric Clinical Trials In adolescents, there is a close association between elevated serum uric acid and the onset of hypertension. The Moscow Children’s Hypertension Study found hyperuricemia (>8.0 mg/dl) in 9.5% of children with normal blood pressure, 49% of children with borderline hypertension, and 73% of children with moderate and severe hypertension (Rovda et al. 1990). The Hungarian Children’s Health Study followed all 17,624 children born in Budapest in 1964 over 13 years and found that significant risk factors for the development of hypertension were elevated heart rate, early sexual maturity, and hyperuricemia (Torok et al. 1985). These two studies do not separate the hypertensive children by underlying diagnosis, primary hypertension versus that caused by renal, cardiac, or endocrinologic causes independent of uric acid, so the relationship between serum uric and hypertension may be attenuated somewhat. In a small study, Gruskin (Gruskin 1985) compared adolescents (13–18 years of age) with hypertension to age-matched, healthy controls with normal blood pressures. The hypertensive children had both elevated serum uric acid (mean > 6.5 mg/dl) and higher peripheral renin activity. In a racially diverse population referred for the evaluation of hypertension, Feig and Johnson observed that the mean serum uric acid level in children with white coat hypertension was 3.6  0.7 mg/dl, slightly higher in those with secondary hypertension (4.3  1.4 mg/dl, p ¼ 0.008) and significantly elevated in children with primary hypertension (6.7  1.3 mg/dl, p ¼ 0.000004) (Feig and Johnson 2003). There was a tight, linear correlation between the serum uric acid levels and the systolic and diastolic blood pressures in the population referred for evaluation of hypertension (r ¼ 0.8 for SBP and r ¼ 0.6 for DBP). Each 1 mg/dl increase in serum uric acid was associated with an average increase of 14 mm Hg in systolic blood pressure and 7 mm Hg in diastolic blood pressure (Feig and Johnson 2003). Among patients referred for evaluation of hypertension, a serum uric acid level > 5.5 mg/dl had an 89% positive predictive value for primary hypertension while a serum uric acid 25) and the analysis assumed the null hypothesis for those who did not complete the study. Gunawardhana and colleagues randomized 121 young adults with variable renal function, hypertension, and hyperuricemia to the xanthine oxidase inhibitor febuxostat or placebo (Gunawardhana et al. 2017). In contrast to the McMullan study, this population was younger, mean age of 34 years, and more hyperuricemic, mean 6.7 mg/dL, at the time of enrollment. In the primary analysis of change in 24-hour ambulatory blood pressure monitoring, there was no statistically significant change in blood pressure but in a planned subgroup analysis, individuals with normal renal function had a significant decrease is systolic and diastolic blood pressure when treated with urate-lowering therapy. Gaffo and colleagues studied a younger group of adults, mean age of 28 years (Gaffo et al. 2021). Ninety-nine participants with stage 1 hypertension and mild hyperuricemia were randomized to placebo versus allopurinol in a 6-week cross-over study design. The primary endpoints were ambulatory systolic blood pressure and endothelial function assessed by flow-mediated dilatation. Therapy resulted no statistically significant difference in ambulatory blood pressure compared to placebo; however, flow-mediated dilatation was significantly increased in patients while on allopurinol. As there were no differences in markers of inflammation, the conclusion was that uric acid reduction was likely a direct mediator of the improved endothelial function. While each of these clinical trials is quite small, they do suggest a generalizable pattern. Uric acidlowering therapy does not appear to be a useful general therapy for hypertension in adults. This is particularly true for older patients and those with impaired kidney function. Such patients most likely have additional mechanisms contributing to the development and maintenance of high blood pressure such that alterations in the

D. I. Feig

physiology impacted by uric acid do not represent dominant fact. That younger patients with larger changes in serum uric do respond to uratelowering therapy with lower ambulatory blood pressure (Gunawardhana et al. 2017) and that young patients experience improved endothelial function when treated with xanthine oxidase inhibition (Gaffo et al. 2021) suggest that uric acid control in the young may provide significant preventive benefits in cardiovascular health.

Clinical Summary • In adolescents, it appears that uric acid may contribute to the development of elevated blood pressure. • Hypertension in patients with elevated serum uric acid levels may be responsive to uric acidlowering therapy early in the course of their disease. • Older patients do not appear to have a significant reduction in blood pressure on medications that reduce serum uric acid. • Allopurinol and probenecid have side effect profiles that are inferior to conventional antihypertensive medication so are not optimal alternatives for preventive therapy. • Reduction in dietary sweetener intake may be a useful approach to uric acid reduction, and blood pressure reduction, in select patients.

Implications The combination of epidemiological, animal model, and clinical trials suggest that there may be a causative role for uric acid in some patients with elevated blood pressure. The controversy over such a role for uric acid stems from the lack of a plausible causative mechanism prior to 2001 and its overlap with other more conventional risk factors such as renal disease, diabetes, and obesity. More recent mechanistic studies, however, support the concept that uric acid-mediated activation of the RAAS, a process with rapid onset that can also be rapidly controlled, followed by a more gradual alteration of renovascular geometry and

5

Uric Acid in the Pathogenesis of Hypertension

sodium handling may result in chronic saltsensitive hypertension. Recent clinical trials in adults showing that uric acid reduction does not impact blood pressure in older adults or those with impaired renal function, though it does improve endothelial function in young adults, are consistent with a developmental, step-wise mechanism. The implications of this paired mechanism are twofold. First, it would explain the greater magnitude of effect seen in younger patients. Second, it may represent a unique opportunity in newly diagnosed hyperuricemic hypertension, in which metabolic control may delay or prevent irreversible vasculopathy and permanent future hypertension. The best to approach mild to moderate hyperuricemia remains an open question. The currently available medications, especially allopurinol, are associated with clinically significant, even lifethreatening, side effects that preclude its safe use in populations as large as those at risk for future hypertension. Furthermore, as there are many classes of readily available antihypertensive medications with more optimal safety profiles so direct management of hypertension is reasonable. The caveat to such an approach is the poor actual control rates in both adult and pediatric hypertension with current conventional approaches that bespeaks the need for novel therapeutics. A possible link between fructose intake and serum uric acid may also hold important promise; however, while fructose loading clearly leads to increased serum uric acid and increased blood pressure in clinical trials, the efficacy of fructose reduction has not been proven. A post-hoc evaluation for the PREMIER trial, a large trial of the efficacy of non-pharmacologic therapy for hypertension and cardiovascular risk mitigation, demonstrated that those participants with the greatest reduction in sweetener consumption also had the greatest reduction in blood pressure (Chen et al. 2010); however, additional research is needed to confirm its efficacy.

Cross-References ▶ Cardiovascular Influences on Blood Pressure ▶ Monogenic and Polygenic Contributions to Hypertension

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▶ Nonpharmacologic Treatment of Pediatric Hypertension

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Suliman ME, Johnson RJ, Garcia-Lopez E, Qureshi AR, Molinaei H et al (2006) J-shaped mortality relationship for uric acid in CKD. Am J Kidney Dis Off J Nat Kidney Foundat 48:761–771 Sundstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB et al (2005) Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 45:28–33 Tani S, Nagao K, Hirayama A (2015) Effect of Febuxostat, a xanthine oxidase inhibitor, on cardiovascular risk in Hyperuricemic patients with hypertension: a prospective, open-label, pilot study. Clin Drug Investig 35: 823–831 Taniguchi Y, Hayashi T, Tsumura K, Endo G, Fujii S et al (2001) Serum uric acid and the risk for hypertension and type 2 diabetes in Japanese men. The Osaka health survey. J Hypertens 19:1209–1215 Torok E, Gyarfas I, Csukas M (1985) Factors associated with stable high blood pressure in adolescents. J Hypertension Suppl Off J Int Soc Hypertension 3 (Suppl 3):S389–S390 Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C et al (2000) Relation between serum uric acid and risk of cardiovascular disease in essential

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Insulin Resistance and Other Mechanisms of Obesity Hypertension Vidhu Thaker and Bonita Falkner

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Postulated Mechanisms for Insulin Resistance Leading to Hypertension . . . . . . . . .

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Measurement of Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Insulin Resistance in Obesity-Associated Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism for Obesity-Associated Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95 95 97

Insulin Resistance in Chronic Kidney Disease (CKD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

99

Diabetes, Insulin Resistance, and Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Low Birth Weight and Subsequent Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Genetic Influences on Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Treatment of Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Abstract

V. Thaker (*) Divisions of Molecular Genetics, and Pediatric Endocrinology, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA Division of Endocrinology, Boston Childrens Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] B. Falkner Departments of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_39

Insulin exerts important biological effects on the metabolic regulation of carbohydrates, lipids, and proteins. In addition, it has important influences on the vasculature, kidneys, and the sympathetic nervous system. Insulin resistance (or loss of insulin sensitivity) is typically defined as decreased insulinmediated glucose disposal in the body in response to physiological (endogenous or exogenous) insulin concentrations. Insulin resistance is commonly associated with 91

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obesity, although not all individuals with obesity have insulin resistance, and insulin resistance may be present in persons without obesity. Insulin resistance can have important adverse consequences on the vasculature and blood pressure, thought to be mediated via vascular inflammation, nitric oxide action, sympathetic nervous system, and renal sodium retention. The “gold standard” for measurement of insulin sensitivity is glucose clamp studies, and the most widely used index for insulin resistance is the homeostasis model for insulin resistance (HOMA-IR). The prevalence of insulin resistance and its adverse effects has been found to be higher in children and adolescents with obesity, diabetes, chronic kidney disease, and in those with low birth weight. Modifications in diet, especially the use of DASH diet, physical activity, and drugs such as metformin and liraglutide, have been found to be effective in improving insulin resistance. Surgical treatment has been shown to be effective in youth with severe obesity and diabetes to improve metabolic consequences and should be offered to patients. Genetic and epigenetic mechanisms likely influence insulin resistance and are an active area of research. Keywords

Insulin resistance · Metabolic syndrome · Obesity · Diabetes · Hypertension · Blood pressure · Childhood obesity · Insulin resistance · Endothelial nitric oxide synthase (eNOS) · Endothelial dysfunction · Metabolic syndrome (MetS) · Homeostasis model of insulin resistance (HOMA-IR) · Mitogenactivated protein kinase (MAPK) · Phosphatidylinositol-3-kinase (PI3K) signaling pathway

Introduction Insulin is one of the most potent anabolic hormones that promotes the synthesis and storage of carbohydrates, lipids, and proteins, while

simultaneously inhibiting their degradation and release into the circulation. The principal role of this peptide hormone is the maintenance of the levels of blood glucose within the normal range of approximately 70–180 mg/dL (4–7 mmol/L) through the cycles of feeding and fasting. This regulation occurs by a complex interplay of metabolic processes that govern nutrient absorption by the intestine, and transport and storage into cells during periods of abundance, while allowing glucose production from protein during periods of fasting in three principal tissues – liver, skeletal muscle, and adipose tissue. In addition to the regulation of glucose, insulin exerts important biologic actions in the vasculature and within the kidney. Insulin resistance (or the inverse of insulin sensitivity) is typically defined as decreased insulin-mediated glucose disposal in the body in response to physiological (endogenous or exogenous) insulin levels. Within the target organs, there is decreased glucose uptake and glycogenesis in myocytes, increased lipolysis via decreased anti-lipolytic activity in adipocytes, and decreased inhibition of glycogenolysis and increased gluconeogenesis in hepatocytes. Insulin resistance is commonly associated with obesity, although not all persons with obesity have insulin resistance, and insulin resistance may be present in people without obesity. It may also be seen in certain physiological states such as pregnancy and puberty. Due to the impaired insulin-mediated glucose uptake, greater amounts of insulin are secreted to achieve glucose regulation. The resulting chronic hyperinsulinemia imposes dysregulatory effects on the other target tissues and organs such as kidney and the microvasculature. Hyperinsulinemia is associated with enhanced renal sodium reabsorption. In the context of the vascular system, insulin resistance manifests as endothelial dysfunction, impaired vascular smooth muscle action, and vascular inflammation (Schulman and Zhou 2009). Thus, impairment of the vascular insulin-signaling pathway (vascular insulin resistance) may be a triggering factor in the initiation of cardiovascular disease in insulin resistance syndromes such as obesity and type 2 diabetes.

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Postulated Mechanisms for Insulin Resistance Leading to Hypertension The effects of insulin on the vasculature can result in either vasoprotection or vascular injury, depending on the pathophysiological state and the involved cell types. These diametrically opposite effects appear to be caused by the dosedependent action of insulin on two different pathways. At the relatively lower fasting levels seen in persons with insulin sensitivity (typically 50–150 pM/L), insulin constitutively stimulates the phosphatidylinositol-3-kinase (PI3K) signaling pathway that participates in regulating its metabolic effects and maintaining the vascular tone. In insulin-resistant states, in which the fasting insulin levels may reach nano- to micromolar range, the PI3K pathway is selectively impaired, activating the alternative mitogen-activated protein kinase (MAPK) signaling pathway, increasing vasoreactivity (and leading to hypertension) and vascular growth (with resultant stiffening or hypertrophy), both of which are implicated in the development of long-term macro- and microvascular complications (Schulman and Zhou 2009). The binding of insulin to the insulin receptor substrate (IRS, specifically IRS-1) results in tyrosine phosphorylation activating PI3K that causes NO production via the endothelial nitric oxide synthase (eNOS) activity. NO, in turn, is thought to mediate the vasoprotective effects of insulin including vasodilation, inhibition of vascular smooth muscle cells (VSMC) migration and proliferation, attenuation of inflammatory cell infiltration into the vascular wall, and inhibition of platelet aggregation. This hypothesis is supported by the observation of vasodilation in in vitro aortic preparations, that is impaired in type 2 diabetic mice (Baron et al. 1996). In VSMC, insulin regulates NO production by the inducible NO synthase (iNOS) that maintains vascular tone. Additionally, it inhibits vascular contractility by attenuating increase in cytosolic calcium channels and stimulating the activity of myosin light-chain phosphatase (Schulman and Zhou 2009). It is also possible that these effects are augmented by NO-mediated glucose disposal, as glycemic control itself serves as protection against inflammation.

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The activation of MAPK pathway in the insulin-resistant state results in the stimulation of secretion of the vasoconstrictor endothelin (ET-1) in the vascular endothelium and endothelial expression of cellular adhesion molecules (e.g., plasminogen activator inhibitor-1 [PAI-1], vascular cell adhesion molecule-1 [VCAM-1], monocyte chemoattractant protein-1 [MCP-1], and E-selectin). Together, these molecules exert detrimental effects on the vascular wall by inducing endothelial dysfunction and fostering atherosclerosis. In cultured VSMC, insulin stimulates the expression of angiotensinogen via the MAPK pathway, activating the renin-angiotensin pathway, especially with production of Ang-II and activation of its receptor, AT1R (Kamide et al. 2004). This condition impairs stimulation of the PI3K pathway, and synergistically stimulates the MAPK pathway promoting cardiovascular disease. Hyperinsulinemia also causes vasoconstriction by activation of the sympathetic nervous system and stimulation of secretion of the vasoconstrictor ET-1 in the vascular endothelium (Eringa et al. 2004). In the kidney, insulin has been shown to act on various segments of the nephron, with the predominant action of renal sodium reabsorption. In normal individuals, this may not cause hypertension possibly due to the simultaneous NO-mediated vasodilation. In states of chronic hyperinsulinemia, the vasodilator action is lost with continued sodium reabsorption mediated by sodium transport channels as well as by the activation of the renin-angiotensin-aldosterone pathway, tumor necrosis factor-α, and with-no-lysine kinases (WNK) (Horita et al. 2011). A summary of the mechanisms discussed here can be found in Fig. 1. Evidence from clinical studies on the effects of insulin resistance is discussed in subsequent sections.

Measurement of Insulin Resistance Due to the importance of insulin resistance in physiology and disease, a wide range of measurement methods have been devised. All methods that assess insulin-mediated glucose disposal can be

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Fig. 1 Simplified mechanism of insulin resistance

quantified using combination(s) of insulin and glucose levels in the blood along with other physiological parameters. Most of the currently available methods measure peripheral insulin resistance, mainly in the skeletal muscle, although some methods may give an estimate of the hepatic insulin resistance. Since the assessment of insulin resistance depends on the insulin values, it is worthwhile emphasizing the value of an accurate assay, especially in the lower ranges seen in the fasting state. Besides the importance of using nonhemolyzed samples, it is noteworthy that the insulin values are higher in serum compared to plasma samples, and the difference is proportional to the concentrations. Hence, uniformity of sample ascertainment within a study is important. Additionally, it is beneficial to follow the guidelines of the Insulin Standardization Work Group to report the results in International Units (SI, pmol/L), to maintain the precision, accuracy, and replicability across studies (Marcovina et al. 2007). Fasting insulin levels can provide evidence of compensatory hyperinsulinemia but are not a good measure of peripheral insulin sensitivity. Such levels show wide variability in different persons, not always correlated with the currently accepted reference standards for insulin sensitivity, and, in isolation, are

not a good measure of insulin resistance (LevyMarchal et al. 2010). Clinical features such as acanthosis nigricans can indicate a likelihood of insulin resistance but cannot define it. The classic method for measurement of insulin resistance in adults is the glucose clamp technique (DeFronzo et al. 1979), which has been adapted for children and adolescents. In the hyperinsulinemic euglycemic clamp, insulin (I) is infused in one arm to maintain hyperinsulinemia at a level that suppresses hepatic glucose production (generally an insulin level above 40–60 mU/m2/min in nondiabetic patients with normal BMI, and
80 mU/m2/min in obese persons). The insulin infusion is accompanied by an infusion of 20% dextrose titrated to maintain euglycemia (BG ~80–100 mg/dL). Euglycemia is accomplished through frequent BG measurements in “arterialized blood” from the warmed contralateral extremity. At steady state, the glucose infusion rate is equal to the insulin-mediated glucose uptake rate (M) in mg/kg/min. M is then adjusted for the actual plasma level of steady-state achieved insulin (I). Insulin sensitivity is then expressed as M/I. Higher M/I indicates greater insulin sensitivity and lower M/I is consistent with insulin resistance. Since most of the glucose uptake occurs in skeletal muscles, the glucose

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clamp method may underestimate insulin sensitivity in obese persons. M/I can be adjusted for fat free or lean body mass to achieve a more accurate estimation of insulin-mediated glucose uptake. However, Gniuli et al. have shown that adipose tissue may contribute significantly to insulinmediated glucose uptake in morbidly obese subjects (Gniuli et al. 2010). The frequently sampled IV glucose tolerance test (FSIVGTT) (Bergman et al. 1987) and steady-state plasma glucose (SSPG) (Shen et al. 1970) are other valid measurements in adults that have been studied in limited cohorts of children. These methods are invasive, and several simpler methods, based on the oral glucose tolerance test (OGTT), or fasting plasma glucose and insulin levels, have been developed for larger epidemiological studies (Table 1). The homeostasis model for assessment of insulin resistance (HOMA-IR) is an estimate of insulin resistance derived from fasting glucose and insulin levels. It has been validated as a surrogate measure of insulin resistance with a correlation as high as 0.91 with glucose clamp studies and FSIVGTT (Conwell et al. 2004). HOMA-IR is calculated as fasting insulin (in microU/L)  fasting glucose (mmol/L)/22.5. The calculated HOMA-IR value is an estimate of insulin resistance, unlike the calculated M/I value based on an insulin clamp procedure which measures insulin sensitivity. Therefore, higher HOMAIR values indicate greater insulin resistance, although there is no specific threshold HOMA-IR value that is diagnostic of insulin resistance. Population-based standards are available for children and adolescents older than 12 years of age (Thaker et al. 2021), derived from the analysis of data from 5541 adolescents from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. In the NHANES, the prevalence of insulin resistance was much higher in children with obesity (BMI
95th %tile) compared with those with BMI < 85th percentile. In adjusted comparisons, the levels of HOMA-IR were higher in children with severe obesity (BMI >120% of 95th percentile: median 6.43 [95% CI 5.83–7.03] compared to those with BMI between 95th and 120% of 95th percentile: median 3.53 [95% CI 3.19–3.87] compared to

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1.96 [95% CI 1.85–2.07] with BMI < 85th percentile). There was a 26% (95% CI 15–37) increase in HOMA-IR in 2015–2018 compared to 1999–2002. There was a positive association of HOMA-IR with systolic blood pressure and other measures of cardiometabolic risk. These standards from NHANES can serve as a guide but are not currently recommended for use in individual patients clinically.

Insulin Resistance in ObesityAssociated Hypertension The reference percentiles used to define hypertension in youth were revised in 2017 by the AAP guidelines on the screening and management of hypertension in youth (Flynn et al. 2017). There has been a decrease in the prevalence of high BP and hypertension in the US youth from 1999–2002 to 2017–2018, albeit with consistently higher levels in those with overweight/obesity, boys, and older age group (Hardy et al. 2021). Among children with obesity, the odds of hypertension were 3.05 (95% CI 1.78–5.20) in those 8–12 years of age and 10.13 (95% CI 4.38–23.41) for those between 13 and 17 years of age, clearly indicating the role of obesity. Males between the ages of 13–17 years had higher odds of 4.87 (95% CI 2.43–9.75) compared to girls. It has also been shown that for similar percent body fat, adolescents with obesity have twofold higher fasting insulin level and lower hepatic (~53%) and peripheral (~42%) insulin sensitivity (Arslanian et al. 2018). In a metanalysis of 12 studies, elevated BP in youth was associated with significant cardiovascular morbidity and higher mortality in adulthood – high pulse wave velocity (OR 1.83, 95% CI 1.39–2.40), high carotid intima-media thickness (OR 1.60, 95% CI 1.29–2.00), and left ventricular hypertrophy (OR 1.40, 95% CI 1.20–1.64) (Yang et al. 2020).

Metabolic Syndrome Over 30 years ago, the concomitant presence of obesity, hypertension, type 2 diabetes, and

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Table 1 Summary of the methods for measuring β-cell function and changes Indices (reference) Formulas Based on hyperinsulinemic-euglycemic clamp Insulin sensitivity (IS) IS ¼ M/I (DeFronzo et al. 1979) M ¼ mean glucose infusion rate over steady state/kg body weight corrected for urine glucose loss I ¼ mean steady state plasma concentration at the same time periods Based on frequently sampled intravenous glucose tolerance test Insulin sensitivity (IS) Uses minimal model, with frequently sampled plasma (Bergman et al. 1979) glucose and insulin concentrations after an initial intravenous glucose load and three model parameters. Uses MINMOD software Based on OGTT (75,000 þ (fasting glucose – 2-h glucose) * 0.19 * ISI Gutt BW)/(120 * log ([fasting insulin þ 2-h insulin]/2) * (Gutt et al. 2000)a [fasting glucose þ 2-h glucose]/2), where BW is body weight 10,000/[square root (fasting glucose * fasting insulin) * ISI Matsuda (Matsuda (mean glucose * mean insulin)] and Defronzo 1999)b ISI Cederholm [75,000 þ (fasting glucose – 2-h glucose) * 1.15 * 180 * (Cederholm and Wibell 0.19 * BW]/[120 * log (mean insulin) * mean glucose], 1990)a where BW is body weight 0.226–0.0032 * BMI – 0.0000645 * 2-h insulin – 0.00375 ISI Stumvoll (Stumvoll * 1.5-h glucose et al. 2000)a OGIS (Mari et al. Calculated from OGTT using the formula available at 2001)b www.ladseb.pd.cnr.it/bioing/ogis/home.html 2/([(AUC insulin)  (AUC glucose)] þ 1), where AUC ISI Belfiore (Belfiore insulin and AUC glucose represent the area under the et al. 1998)a insulin curve and area under the glucose curve divided by mean of normal values {[0.137 * 100,000,000/(insulinT0 * glucoseT0 * VD)] þ ISI Avignon (Avignon [100,000,000/(insulinT2h * glucoseT2h * VD)]}/2, where et al. 1999)a VD is the apparent glucose distribution volume ¼ 150 (mL/kg)  BW (kg) 1/[log (sum glucoset0–30–90-120) þ log (sum insulint0–30–90SIisOGTT (Bastard et al. 2007)a 120)] Log sum insulin (Cheng Log (sum insulint0–30–60-120) et al. 2004)b 0.138  (0.00231  BMI)  (0.00118  G120)  SI OGTT (Solomon et al. 2014) (0.0000135  I30)  (0.00000678  I90) Based on fasting samples HOMA-IR (fasting insulin  fasting glucose)/22.5 (Matthews et al. 1985) QUICKI (Katz et al. 1/(log fasting insulin) þ (log fasting glucose) 2000) Fasting insulin 1/fasting insulin

Units M ¼ mg/kg/min; I ¼ mg/dL

mg/min/μU/mL

Glucose ¼ mg/L; BW ¼ kg; Insulin ¼ μU/mL Glucose ¼ mg/dL; Insulin ¼ μU/mL Glucose ¼ mmol/L; BW ¼ kg; Insulin ¼ μU/mL Glucose ¼ mmol/L; BMI ¼ kg/m2; Insulin ¼ pmol/L Conventional or SI units Conventional or SI units

Glucose ¼ mg/dL; Insulin ¼ μU/mL Glucose ¼ mmol/L; Insulin ¼ μU/mL Insulin ¼ μU/mL (μmolkg1min1pM1)

Glucose ¼ mmol/L; Insulin ¼ μU/mL Glucose ¼ mg/dL; Insulin ¼ μU/mL Insulin ¼ μU/mL

Abbreviations: IS: insulin sensitivity; ISI: insulin sensitivity index; BW: body weight; OGIS: oral glucose insulin sensitivity; OGTT: oral glucose tolerance test; BMI: body mass index; AUC: area under curve; VD: volume of distribution; G: glucose; I: insulin; t: time; HOMA-IR: homeostatic model of insulin resistance; QUICKI: Quantitative Insulin Sensitivity Check Index a Based on 2-h OGTT b Based on both 2-h and 3-h OGTT

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atherosclerosis began to be recognized in adults. Originally described as syndrome X by Reaven in 1988, this cluster of conditions is now designated as metabolic syndrome (MetS). Insulin resistance or impaired insulin-mediated glucose uptake has been established as the core abnormality that links the metabolic and hemodynamic abnormalities in this condition. Because insulin resistance has been difficult to quantify clinically, the concept of metabolic syndrome has developed as a strategy to identify persons with multiple cardiovascular risk factors that are linked with insulin resistance (Meigs et al. 1997). Studies have demonstrated a heightened risk for diabetes and cardiovascular disease among adults with metabolic syndrome (Meigs et al. 2006; Li et al. 2021). There has been some variation in the precise definition of MetS regarding both included risk factors and the values considered to be abnormal. Among various definitions, the World Health Organization (WHO) (Alberti and Zimmet 1998) and the National Cholesterol Education Program Adult Treatment Panel III (ATPIII) (Expert Panel on Detection and Treatment of High Blood Cholesterol in 2001) criteria are more commonly used in clinical reports in adults. According to the ATPIII definition, metabolic syndrome is present if an adult meets three of the five following criteria – (1) visceral obesity based on waist circumference, (2) elevated BP, (3) abnormal glucose tolerance, (4) elevated plasma triglyceride, and (5) low high-density lipoprotein (HDL)-cholesterol. Although it has been recognized that abnormal levels in BP, adiposity, and lipids can be detected in childhood, no consistent definition of MetS has been established for children and adolescents. Reports on the prevalence of MetS in children have been based on the modified ATPIII or WHO definitions. Obesity is strongly associated with insulin resistance in childhood and is manifest by relative hyperinsulinemia. Cook et al. investigated the prevalence of MetS in children and adolescents based on data from the NHANES data periods 1988–1994 (Cook et al. 2003). Based on the ATPIII criteria modified for children, the investigators reported an overall childhood

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prevalence of MetS at 4.2%. However, among obese adolescents only, the prevalence was as high as 28.7%. It is of note that the data period 1988–1994 preceded the childhood obesity epidemic and as expected, the increasing prevalence of childhood obesity is associated with higher rates of MetS. In a study on a predominantly obese cohort of children and adolescents, Weiss et al. reported that the prevalence of MetS increased with severity of obesity and reached 50% among severely obese youth (Weiss et al. 2004). Another study on a cohort of children with obesity found elevated BP (
90th percentile), identified by repeated BP measurement, in 37% of the cohort. More boys with high BP had low HDL-cholesterol compared to boys with normal BP (49.4% vs 27.6%). The rates of high BP and low HDL-cholesterol both increased among the more severely obese boys and girls. In a prospective study of 2427 children from three countries with clustering of cardiovascular risk factors, a higher prevalence of carotid intima media thickness (cIMT) was seen with higher number of risk factors, with
3 risk factors resulting in OR of 4.24 (95% CI 2.81–6.39) (Zhao et al. 2020). Pathologic evidence of early atherosclerotic lesions in the aorta and coronary arteries were also identified in autopsy studies in youth following premature death associated with multiple risk factors consistent with MetS (Berenson et al. 1998). These reports indicate that the constellation of metabolic risk factors detectable with obesity-associated hypertension accelerate the risk for cardiovascular disease in early adulthood.

Mechanism for Obesity-Associated Hypertension Multiple theories have attempted to explain the link between obesity and hypertension. It has been proposed that hyperinsulinemia, a consequence of insulin resistance, activates sympathetic nervous system (SNS) activity. Based on experimental models, a potential mechanism for SNS activation could be adipose tissue production of leptin,

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which is commonly elevated in obese individuals. Further support of heightened SNS activity in obese hypertensive children has been developed with application of 24-hour ambulatory blood pressure monitoring (ABPM). Compared to children with hypertension but normal weight, those with obesity have higher heart rates and greater BP variability during ABPM, indicative of a hyperkinetic hemodynamic condition (Sorof and Daniels 2002). In other reports, investigators applied advanced Fourier analysis to 24-h ABPM data and detected variations in the cardiac rhythms in hypertensive children (Litwin et al. 2010). In a longitudinal study on obese hypertensive youth by Niemirska et al., abnormal BP rhythmicity detected before treatment was unchanged with pharmacologic therapy that reduced BP; but the abnormal BP rhythmicity was normalized among patients who lost weight (Niemirska et al. 2013). Overall, the evidence indicates that there is, at least in part, a role of SNS activity in the link between obesity and hypertension in childhood, as well as adulthood. These observations also support the benefit of weight reduction in children and adolescents with obesity-associated hypertension. Dietary sodium has been implicated in obesityassociated hypertension. Using the data from NHANES 2003–2008, Yang et al. demonstrated that for the entire population each 1000 mg/day of sodium intake was associated with 1.0 mm Hg increase in systolic BP, whereas, among the overweight/obese subjects, systolic BP increased 1.5 mm Hg (Yang et al. 2012). They also demonstrated that for the entire cohort the adjusted odds ratios (AOR) comparing risk for prehypertension/ hypertension in the highest sodium intake quartile compared to the lowest was 2.0 (95% CI ¼ 0.95–4.1). However, among the overweight/ obese children, the adjusted AOR for prehypertension/hypertension in the high sodium intake quartile increased to 3.5 (95% CI ¼ 1.3–9.2). The investigators proposed that overweight/obesity and sodium intake appeared to have synergistic effects on risk for high BP. In a more recent review of 12,249 youth enrolled in the NHANES from 2003–2016, the mean sodium intake decreased from 3381–3208 mg/day

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(P < 0.001 for trend), parallel with a small but statistically significant decrease in the BP in this population (Overwyk et al. 2019). However, the higher AOR for high BP/hypertension, especially for youth with obesity remained (AOR 1.18, 95% CI 1.03–1.15). While these declining trends are encouraging, the recommended average sodium intake for children is much higher than the 2300 mg/day, and lower for youth younger than 14 years of age (USDA.gov and HHS.gov 2020). Reducing sodium intake can lower BP, and it is projected that 40% reduction in sodium intake in the US population over 10 years might save at least 280,000 lives (Coxson et al. 2013). Experimental and clinical studies demonstrate that insulin upregulates sodium transport in distal renal tubules. As described earlier, obese children, as well as adults, tend to have relative hyperinsulinemia secondary to obesity-associated insulin resistance. Higher insulin levels enhance sodium reabsorption, a process that can result in higher BP. This concept was supported by Rocchini et al. on a cohort of children with obesity and elevated BP (Rocchini et al. 1989). BP measurements were taken after 2 weeks on a high salt diet and again following a low salt diet. There was a significant decrease in BP on the low salt diet, indicating BP sensitivity to sodium intake. Subsequently the children underwent a weight reduction intervention for several weeks after which the high and low salt diet procedures were repeated. For participants who experienced a modest weight reduction there was less BP reduction indicating a reduction in BP sensitivity to sodium. Among those with no weight change the BP response was the same. These findings support the concept of a renal mechanism with BP sensitivity to sodium likely mediated by insulin. The results also provide evidence that weight loss appears to blunt sodium sensitivity in children with obesity, and that weight loss should be a therapeutic goal in obese children. The literature on dietary salt intake and BP in children is limited compared to that in adults. However, emerging evidence supports a causative role of high sodium intake on elevated BP, especially in the presence of overweight and obesity. A clue to a possible genetic mechanism for renal regulation of sodium sensitivity in children

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with obesity was reported in a study conducted on cohort of children in China (Xi et al. 2013). In this study, the investigators constructed a genetic risk score (GRS) based on six single nucleotide polymorphisms (SNPs) from prior GWAS studies on hypertension. They found an association of three SNPs and the GRS with higher systolic BP and four SNPs with hypertension in the group with obesity, although no association was noted in those with normal weight. Of interest, three of the four SNPs found to be significantly associated with BP have been linked with renal sodium regulation (Xi et al. 2013). Another possible mechanism for obesityassociated hypertension is alteration in microvascular function and structure. Elevations in plasma levels of pro-inflammatory cytokines, such as C-reactive protein (CRP) and interleukin-6 (IL-6), are associated with obesity. Similar elevations of inflammatory cytokines are reported in children with obesity (DeLoach et al. 2014; Weiss et al. 2004). In humans, obesity is associated with accumulation of macrophages in adipose tissue that may contribute to obesity-related inflammation. Support for a causal role of inflammation in development of hypertension is based largely on experimental studies that focus on endothelial dysfunction (Madhur et al. 2010). Exposure of human vascular endothelial cells to CRP in vitro results in decreased expression of endothelial nitric oxide synthase with attenuation of vasodilation in response to provocative stimuli (Venugopal et al. 2002). Recent experimental studies describe a role of perivascular adipose tissue (PVAT) in paracrine signaling of inflammatory cytokines. Excess PVAT contributes to endothelial dysfunction and increased vascular smooth muscle tone. In vitro experiments on PAVT from obese and lean humans demonstrate that vasodilatory capacity is lost in PVAT from obese subjects with concurrent expression of mediators of inflammation and oxidative stress (Greenstein et al. 2009). Thus, microvascular dysfunction, mediated by PVAT-derived inflammation, could contribute to insulin resistance and capillary rarefaction, both of which set the stage for increased vascular resistance and hypertension. The elaborated mechanisms underlying obesityassociated hypertension are likely overlapping or

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acting synergistically. Despite many gaps in the complete understanding of these mechanisms, it is clear that obesity-induced insulin resistance in childhood has many adverse effects that lead to premature adult onset cardiovascular and metabolic disease.

Insulin Resistance in Chronic Kidney Disease (CKD) An association of insulin resistance with CKD has been demonstrated both experimentally and clinically (DeFronzo et al. 1981). The metabolic consequences of insulin resistance/hyperinsulinemia are related to the elevated risk for accelerated atherosclerosis in adults with CKD. Reports from population studies describe an association of MetS with CKD in adults with an increasing prevalence of MetS as kidney function declines (Beddhu et al. 2005; Chen et al. 2004). Several causal factors for insulin resistance have been considered, including uremic toxins, elevated uric acid, and inflammation. Recent studies have developed novel insights on mechanistic pathways in development of insulin resistance in CKD. Adipose tissue serves the endocrine function in the production of several cytokines and hormones designated as adipokines. Adipocytes produce several inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and plasminogen activator inhibitor type-1 (PAI-1), along with adiponectin, a hormone that has anti-inflammatory, anti-atherosclerotic, and insulin sensitizing properties. There is a consistent strong relationship of elevated circulating pro-inflammatory cytokines with obesity. However, plasma levels of adiponectin are significantly lower among obese individuals with normal kidney function compared to normal weight individuals with normal kidney function. While obesity-associated inflammation had been thought to contribute a causal role in the insulin resistance of obesity, recent studies in adults and in children (Weiss et al. 2004) demonstrate that pro-inflammatory cytokines are significantly associated with obesity, but pro-inflammatory

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cytokines do not have an independent association with insulin resistance. These clinical studies, using the insulin clamp procedure (Martinez Cantarin et al. 2011) or oral glucose tolerance test (Weiss et al. 2004), demonstrate a significant independent association of adiponectin with insulin resistance, findings consistent with the insulin sensitizing activity of adiponectin have also been obtained. Despite evidence of insulin resistance in CKD, plasma levels of adiponectin are elevated in patients with CKD, a relation that is independent of obesity or BMI. Several suggested explanations for the opposite relationship of adiponectin with insulin resistance in CKD considered reduced renal clearance of adiponectin, chronic malnutrition, or a response to uremic inflammation (Cui et al. 2011). While adiponectin is secreted by adipose tissue, adiponectin receptors (adipoR1 and adipoR2) are predominantly expressed in muscle and liver where they exert their major antidiabetic functions. A study by Martinez Cantarin et al. reported increased adiponectin secretion in patients with end stage renal disease (ESRD) that was associated with elevated plasma levels of adiponectin (Martinez Cantarin et al. 2013). These investigators conducted studies on human tissues harvested from ESRD patients and healthy kidney donors at the time of renal transplantation. Their data demonstrate an increase in adiponectin protein and mRNA expression level in subcutaneous and visceral adipose tissue, as well as increased mRNA expression of the adiponectin receptors in fat and muscle in ESRD patients compared to controls with normal kidney function. Data in subsequent in vivo and in vitro studies by these investigators demonstrated disruption in the normal adiponectin signaling pathway in muscle cells in uremia, consistent with adiponectin resistance at the postreceptor level (Martinez Cantarin et al. 2014). These reports support the concept that the insulin resistance observed in CKD is a consequence of loss of an adiponectin insulin sensitizing function due to adiponectin resistance. Further studies will be needed to delineate the mechanistic pathway of adiponectin resistance in CKD. Finally, genetic predisposition for insulin resistance may play additional role in the insulin resistance seen in individuals with CKD (Garaduno et al. 2021).

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Diabetes, Insulin Resistance, and Hypertension Majority of patients with type 2 diabetes (T2D) have insulin resistance. Fasting hyperglycemia, the hallmark of T2D, develops with the failure of the pancreatic β-cell to sustain compensatory hyperinsulinemia to maintain glucose homeostasis in the face of insulin resistance (Reaven 2011). Based on the mechanistic links between insulin resistance and hypertension considered above, it is no surprise that many patients with T2D also have hypertension. Additionally, multiple studies have provided evidence that insulin resistance is also involved in the development of adverse long-term micro- and macrovascular complications in patients with type 1 diabetes (T1D), classically considered a disease of insulin deficiency (Nadeau et al. 2010). Cross-sectional studies in youth have shown a high prevalence of hypertension in both T1D and T2D. In the population-based multicenter SEARCH study of youth aged 3–17 years, hypertension was more commonly seen in youth with T2D (35.6%) compared to T1D (14.8%). In both cohorts, each 0.01 unit increase in change in waist-height ratio (a measure of central adiposity) resulted in an adjusted relative risk of 1.53 (95% CI 1.36–1.73) and 1.20 (95% CI 1.00–1.43) for HTN in T1D and T2D, respectively (Koebnick et al. 2020). In the TODAY study, the largest longitudinal systematic multicenter study of youth with T2D, 699 youth between the age of 10 and 17 years with new-onset T2D were randomized to receive metformin alone, metformin and rosiglitazone or metformin and intensive lifestyle management for 4 years in phase 1. Of these subjects, 572 were followed longitudinally for another 10 years in two different phases. Among the 518 youth with data at 15 years, the prevalence of hypertension was 19.2% at baseline that increased to 65.7% at follow-up. Importantly, in adjusted multivariable models, presence of hypertension was associated with higher odds, 1.45 (95% CI 1.16–1.82), of microvascular disease. Previous discussions on the mechanism of insulin resistance and hypertension are also relevant to diabetes. It is postulated that there are differences in insulin sensitivity in various target tissues. In patients with T2D there is resistance to

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insulin-mediated glucose uptake in liver and muscle tissue resulting in hyperinsulinemia. The relative hyperinsulinemia necessary for glucose regulation can disrupt the normal physiology of other tissues that are not resistant to insulin. The renal response to hyperinsulinemia is upregulation of sodium retention (Facchini et al. 1999). Hyperinsulinemia also impacts the sympathetic nervous system, resulting in both vasoconstriction and sodium retention (Reaven et al. 1996). In patients with type 1 diabetes, the lack of endogenous insulin makes it difficult to assess insulin resistance, especially since the simpler tools such as the homeostasis model are not applicable. The association of decreased insulin sensitivity with vascular disease and hypertension was first reported in late 1960s. Martin and Warne described poorer prognosis in patients with clinically evident vascular disease and hypertension, when associated with lower glucose assimilation index, as measured by fall in blood glucose after a standardized dose of intravenous insulin (Martin and Warne 1975). Defronzo et al. demonstrated the presence of hepatic and peripheral insulin resistance in adults with T1D, using euglycemichyperinsulinemic clamp studies (DeFronzo et al. 1982). Newer methods to estimate insulin sensitivity in T1D such as estimated glucose disposal ratio (eGDR) (Williams et al. 2000) and the insulin sensitivity score (IS) (Dabelea et al. 2011), with easily measurable parameters like hypertension, waist-hip ratio, lipid levels, and family history of hypertension were devised based on their correlation with glucose disposal in clamp studies and subsequently validated in independent cohorts. The 10-year historical prospective data obtained from the Pittsburgh Epidemiology of Diabetes Complications Study of 603 patients with T1D (onset below 18 years of age) found that cardiovascular events were related to insulin resistance–related factors rather than to glycemic control per se (Orchard et al. 2003). Analysis of the data collected during the Diabetes Control and Complications Trial (DCCT), a 9-year follow-up study of 1441 participants with T1D designed to compare intensive insulin treatment versus conventional blood glucose management, showed increased risk of both micro- and macrovascular complications in those participants

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with greater insulin resistance at baseline as estimated by lower end. The term “double diabetes” has been coined to describe those patients with T1D who have evidence of insulin resistance, elicited by testing with eGDR (Kilpatrick et al. 2007). In another publication from the DCCT, the prevalence of hypertension and MetS increased most in those patients in the intensive insulin therapy arm who gained the most weight over time (Purnell et al. 1998). Adjusting for the prevalence of MetS and the insulin dose, the risk of developing the complications of diabetes was higher over time in patients with lower baseline eGDRs, showing the relation between insulin resistance and microvascular disease (Kilpatrick et al. 2007). This association has also been consistently demonstrated in youth with T1D. CreeGreen et al. noted higher prevalence of adipose, hepatic, and peripheral insulin resistance measured by hyperinsulinemic clamp, in a cohort of 35 adolescents with T1D when compared with controls (Cree-Green et al. 2018). In another study of 291 patients with T1D, 29.9% (CI 24.6–35.2%) of the participants had hypertension, with higher rates observed among older male patients in association with overweight and obesity and longer diabetes duration, prominently associated with lower insulin sensitivity (Chillarón et al. 2011). In a separate study of 298 youth with T1D (the SEARCH CVD study), lower insulin sensitivity was associated with increasing arterial stiffness, as measured by pulse wave velocity over an average follow-up period of 5 years (Shah et al. 2015). Based on the evidence presented, insulin resistance is a significant and potentially modifiable factor that may contribute to the adverse cardiovascular outcomes seen in both type 2 and type 1 diabetes.

Low Birth Weight and Subsequent Insulin Resistance Low birth weight is now considered to be a risk factor for chronic diseases in later life. This association was first described in an epidemiologic study by Barker et al., who identified lower birth weight among men with premature coronary disease (Barker et al. 1989). The birth weight

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hypothesis proposes that low birth weight, a response to nutritional deprivation within the intrauterine environment, contributes to greater susceptibility to cardiovascular and metabolic diseases in later life, now often called “developmental origins of health and disease,” or DOHaD. Subsequent epidemiologic studies detected modest associations of birth weight to the risk of subsequent cardiovascular disease. In a systematic review of published human studies, Whincup et al. reported that in most populations lower birth weight was associated with increased risk for subsequent development of type 2 diabetes (Whincup et al. 2008). Although insulin resistance is the core metabolic condition underlying metabolic syndrome and type 2 diabetes, the results of clinical investigations to examine the birth weight hypothesis conducted on children have been inconsistent (Li et al. 2001). Variations in obesity, rate of weight gain, secular changes in diet and nutritional patterns, and modest sample sizes explain some of the inconsistent findings. Longitudinal studies beginning in early childhood have identified the relationship of birth weight with later childhood outcomes of obesity, blood pressure, and metabolic risk factors. Conditions reported to be associated with lower birth weight include maternal hypertensive disorders of pregnancy, relative growth rates, maternal and paternal obesity, and 24-h blood pressure variability in childhood. Prospective studies on perinatal programing that begin in the neonatal or perinatal period on offspring of normal pregnancy are limited. A small but rigorous study on a sample of healthy full-term newborn infants was conducted by Lurbe et al. Infants were stratified by birth weight as small (SGA), appropriate (AGA), or large for gestational age (LGA). Blood pressure and weight were measured at 2 days of age, 6 months, 2 years, and 5 years. At 5 years of age a blood sample was obtained for measurement of metabolic parameters. Each birth weight group gained similar amount of weight during each examination interval; and SGA participants remained the smallest and LGA remained the largest. After 6 months, current weight and weight gain were positively associated with birth weight, and there was no association of blood pressure

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with birth weight. However, at 5 years of age, fasting insulin levels were higher in SGA infants who had become heavy as compared to the AGA and LGA infants who also became heavy. The most striking finding was that SGA infants were insulin resistant, irrespective of their weight status at age 5 years, as measured by HOMA-IR, compared to all AGA and LGA infants (Lurbe et al. 2014). These findings in a sample of healthy infants are consistent with the concept that intrauterine factors related to lower birth weight could induce metabolic programming for relative insulin resistance that is sustained, at least in early childhood, regardless of the weight or weight gain. A variety of potential mechanisms that have been considered to explain fetal programing include the changes in the microarchitecture of various organs, changes in transporters or hormonal levels, and epigenetic modification of DNA. Further research is needed to determine the epigenetic modifications in the perinatal period that may be engaged in fetal programing and the potential for intervention.

Genetic Influences on Insulin Resistance Insulin resistance is a polygenic trait determined by both genetics and environment, especially adiposity. The presence of defective insulin secretion and a tendency toward insulin resistance in nondiabetic family members of patients with T2D highlights the importance of genetics with heritability estimates of ~38% (Elbein et al. 1999). Subsequent studies in twins and families have shown that the heritability of traits associated with insulin secretion, such as first-phase insulin secretion by euglycemic clamp, had a higher heritability (0.55–0.58) compared to those of insulin utilization, such as insulin-mediated glucose uptake, or surrogate markers of insulin resistance such as HOMA-IR and fasting insulin. One study also identified genetic influences on the insulin response to three different secretagogues (Simonis-Bik et al. 2009). Two large genome-wide association metanalyses have discovered loci associated with insulin resistance. In a meta-analysis of 52 studies

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comprising of 96,496 individuals without diabetes, Manning et al. identified a total of 50 SNPs, 30 associated with fasting insulin, 19 associated with fasting glucose, and 1 associated with both, 6 of which had not been previously known (Manning et al. 2012). The novel genes identified with these loci, such as IRS-1, PPP1R3B, PCSK1, TNK5, and others, known to be associated with glycogen metabolism, and regulation of insulin, triglycerides as well as HDL levels. In parallel, another meta-analyses of 133,0101 nondiabetic individuals of European ancestry identified 53 loci associated with markers of glycemic traits such as fasting insulin, fasting glucose, and postchallenge glucose concentrations (Scott et al. 2012). Similar studies in African American (Chen et al. 2012), Hispanic (Palmer et al. 2010), and Asian (Hong et al. 2014) populations have either replicated the potential importance of these loci or identified new ones. Some of these loci are associated with genes known to influence insulin function such as insulin receptor (IRS-1) and glucokinase (GCKS), and have a role in T2D, while the function of others such as klotho (KL), topoisomerase (DNA) I (TOP1), etc. remains to be elucidated. In a recent study, Knowles et al. identified a nonsynonymous variant of N-acetyltransferase 2 (NAT2) strongly associated with decreased insulin sensitivity independent of BMI and proved its function in murine adipocyte cell line and in vivo models in mice (Knowles et al. 2016).

Treatment of Insulin Resistance Insulin resistance is intertwined with obesity and other clustered cardiovascular risk factors. Despite the varied definitions of MetS, it is the most used outcome in intervention studies to assess the effects of treatment. Lifestyle intervention comprising of both diet and physical activity play an essential role in preventing and controlling the development of insulin resistance. Verduci et al. performed a systematic study of 85 Italian children with obesity on an one-year long nutritional behavioral intervention consisting of normocaloric diet by age and sex balanced for the macronutrients distribution with emphasis on

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polyunsaturated fats and fiber along with at least 60 min of daily of moderate-to-vigorous intensity physical activity. The investigators observed a significant decrease in both insulin resistance, based on HOMA-IR, and blood pressure level, along with decrease in BMI-z score and increase in HDL (Verduci et al. 2015). Lustig and colleagues provided isocaloric substitution of starch for sugar to restrict fructose intake in 43 children over a 9-day period and observed a statistically significant decrease in the peak insulin levels, insulin AUC during OGTT, and HOMA-IR index with no significant decrease in systolic BP (Lustig et al. 2016). In a longitudinal, randomized, atherosclerosis prevention trial, Nupponen et al. reported the beneficial effects of a dietary intervention strategy provided since infancy in a cohort of children over two decades. Biannual dietary counseling on a balanced macronutrient composition with emphasis on fiber intake, better-quality carbohydrates, whole grains, low sodium, and polyunsaturated fats along with encouragement of physical activity was provided to families of 540 infants with an equivalent control group (Niinikoski et al. 2014). There was a statistically significant lower prevalence of MetS (6–7% v/s 10–14%, p < 0.001) in the intervention group along with lower BP and greater insulin sensitivity compared to the control group (Nupponen et al. 2015; Oranta et al. 2013). Similar benefits of improved insulin sensitivity were also seen with Mediterranean-style diet rich in polyunsaturated fatty acids, fiber, flavonoids, and antioxidants with 60% energy from carbohydrates, 25% fat, and 15% protein compared with a standard diet (Velázquez-López et al. 2014). The eating plan for dietary approaches to stop hypertension (DASH) diet is rich in vegetables, fruits, whole grains, low-fat dairy products, and with low sodium intake resulted in decrease in the rates of metabolic syndrome and hypertension in children with no statistical decrease in HOMA-IR index (Saneei et al. 2013). Based on these data and the importance of maintaining caloric intake to allow for the growth in children, a diet rich in fresh produce, polyunsaturated fats, high fiber, low sodium, and balanced macronutrients is optimal, starting from early childhood.

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Physical activity (PA) is an important lifestyle modification to improve insulin sensitivity. In a systematic review of evidence pertaining to PA and cardiovascular risk factors, Andersen et al. reported that a PA/exercise intervention lasting for at least 30 min, at a frequency of three times/week and intensity sufficient to improve aerobic fitness can be effective in reducing BP in children with hypertension. There was no association between PA and clustered metabolic risk (MetS) in crosssectional studies based on self-report. However, in longitudinal studies such as the European Youth Heart Study and studies that used objective methods of assessing physical activity such as accelerometers, a graded association in MetS z-score was seen through all the PA percentiles (Andersen et al. 2011). The reviewers concluded that moderate-to-vigorous intensity physical activity (MVPA) had to be about 90 min/day to effectively reduce the risk of MetS. Similar findings were noted by Stabelini Neto et al. in a study of 391 Brazilian participants aged 10–18 years. Time spent in MVPA was inversely associated with the continuous risk score for MetS, and the analysis of the ROC curve suggested that the adolescents must perform at least 88 min of MVPA per day for the benefit (Stabelini Neto et al. 2014). In a 10-week intensive weight loss camp for obese Danish children, Grønbæk and colleagues observed a marked weight loss (BMI SDS 0.56 to 0.72  0.21) and improvement in BP and insulin sensitivity measured by OGTT and HOMA index. At 12 months after the intervention, the improvements in BMI and BP were lost, but the improvement in insulin sensitivity remained, highlighting the need for long-term interventions (Grønbæk et al. 2012). Lifestyle interventions are effective, but difficult to maintain. Limited success has been demonstrated in large-scale interventions, especially at the level of the school and community (Mårild et al. 2015). Pharmacological therapy can be a valuable addition for the treatment of clustering of metabolic effects of hyperinsulinemia and insulin resistance. Randomized controlled trials of varying duration ranging from 2–12 months have demonstrated the benefit of metformin in the treatment of excess weight and metabolic parameters. Freemark et al. observed an improvement in BMI

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(0.5 vs 0.9 kg/m2, p < 0.05), fasting glucose, and fasting insulin in 29 obese adolescents with hyperinsulinemia and a family history of T2D when treated with 500 mg metformin twice daily (Freemark and Bursey 2001). Yanovski and colleagues randomized 100 severely obese children between the ages of 6 and 12 years to receive 1000 mg metformin in twice daily dose for 6 months followed by an open-label treatment for 6 months. They reported significant decrease in measures of adiposity such as BMI, BMI z-score, and fat mass at the 6 months’ time. They also observed significant decrease in fasting plasma glucose ( p ¼ 0.007) and HOMA-IR index ( p ¼ 0.006) in the metformin-treated children compared to those treated with placebo. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17% (Yanovski et al. 2011). Similar beneficial results have been seen in other trials of varying duration and doses examining the effects of metformin on the metabolic profile in children with obesity (Luong et al. 2015). The improvements in insulin resistance, measured predominantly by HOMA-IR or other surrogate markers of insulin resistance, have shown improvement in most of such studies. As many of these studies have documented such improvements with associated weight loss, it is difficult to discern the metabolic benefits from the weight loss versus the isolated effect of metformin on improving insulin sensitivity. A multicentered trial of extendedrelease metformin therapy for 48 weeks followed by an additional 48 weeks of observation did not show a significant improvement in insulin indices or body composition, although a small statistically significant decrease in BMI was reported. It is unclear whether this observation is due to the difference in the administration of the therapy, or a true long-term effect (Wilson et al. 2010). Based on the emerging evidence on the influence of genetic makeup on the metabolic benefits of metformin, a recent study reported the influence of polymorphisms in SLC22A1 on the reduction in adiposity and pharmacokinetics in 30 severely obese children with insulin resistance between the ages of 7 and 12 years (Sam et al. 2016). There was no difference in the pharmacokinetics based on the

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genotype, but the change in truncal fat was significantly different between the wild type and the variant genotype. The influence of this and other genetic variants needs further exploration to pave the way for personalized medicine in future. In a retrospective study of 30 children with MetS who received ACE inhibitor compared to 23 control obese children, Bitkin et al. found no significant differences in the weight, BMI, or the BMI SDS, but significant improvements in the BP and insulin levels along with the HOMA-IR and lipid profile in the treated group compared to the controls (Bitkin et al. 2013). Glucagon-like peptide-1 receptor analogues (GLP-1RA) such as liraglutide and semaglutide have emerged as a new class of drugs that potentiate insulin and inhibit glucagon secretion, while increasing gastric emptying and reducing food intake (Drucker 2018). In a randomized, doubleblind, placebo-controlled trial of 21 adolescents between 12 and 17 years and Tanner stages 2–5 with obesity, treated with liraglutide gradually titrated to a maximum of 3.0 mg/day for a total of 5 weeks, the treatment-related adverse effects were same as that seen in adults. The most common treatment-related adverse effects were gastrointestinal disorders, with none severe enough to require discontinuation of therapy (Danne et al. 2017). This study opened the door for subsequent therapeutic trials for youth with T2D as well as obesity. In a 52 week, randomized, placebo-controlled study of 135 youth between the ages of 10 and 17 years with T2D, a daily dose of 1.8 mg of liraglutide decreased the HbA1c levels by 1.30% (Tamborlane et al. 2019). While significant improvements were observed in HbA1c and fasting glucose, this trial did not observe a statistically significant improvement in either BMI z-scores or other secondary outcomes such as blood pressure or lipid levels. In a separate randomized, placebo-controlled doubleblind trial, 151 youth with obesity between the ages of 12 and 17 years received 3.0 mg of liraglutide daily or placebo with intensive lifestyle management. Liraglutide was superior to placebo for change in BMI SDS at 56 weeks. A reduction in BMI of 5% was observed in 51 of 113 participants in the liraglutide group, compared to 20 of 105 in the placebo group (43.3% vs 18.7%), and a

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reduction in BMI of at least 10% was observed in 33 and 9 participants, respectively (26.1 vs 8.1%), with weight regain during the observation period following withdrawal of therapy (Kelly et al. 2020). While no difference was observed in the blood pressure levels at 56 weeks, it is reasonable to project that long-term weight loss will result in reduction in insulin resistance and hypertension as has been observed in long-term evaluation of adults. Metabolic and bariatric surgery (MBS) is increasingly being used as an option for treatment of severe obesity and its metabolic consequences in adolescents. In the most recent guidelines from the American Society for Metabolic and Bariatric Surgery (ASMBS) based on the review of literature from 2009–2017, a strong recommendation was made to use MBS for any youth with severe obesity and cardiometabolic risk factors including insulin resistance and HTN based on the reports that MBS is effective and these conditions are unlikely to resolve without such an intervention (Pratt et al. 2018). In a comparative study of 161 adolescents enrolled in Teen-LABS and 396 adults enrolled in longitudinal assessment of bariatric surgery (LABS) 5 years after undergoing Roux en Y gastric bypass, there were no significant differences in the weight loss between the two groups. However, the adolescents were significantly more likely than adults to have remission of type 2 diabetes (86% vs 53%, risk ratio 1.51, 95% CI 1.21–1.88) and of hypertension (68% vs 41%, risk ratio 1.51, 95% CI 1.21–1.88) (Inge et al. 2019). Bariatric surgery has also been shown to be superior to medical intervention for management of T2D and its long-term consequences such as diabetic kidney disease. In a comparison of the youth with T2D enrolled in the TODAY study of youth with new-onset T2D (see section on “Hypertension and Diabetes”), and Teen-LABS with diabetes kidney disease, hyperfiltration decreased from 27% to 5% in TeenLABS and increased from 21% to 43% in TODAY (OR 15.7, 95% CI 2.6–94.3) at 5-year follow-up. It should be noted that the beneficial improvements of MBS are longer lasting in those who continue physical activity after the performance of the bariatric surgery (Price et al. 2019).

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Conclusion and Future Directions The role of insulin resistance in the development of disease, and interventions to modify it, continue to be an area of intense research. A systematic study to assess the impact of long-term changes in diet and physical activity on both insulin resistance and blood pressure, especially in children with obesity, is critical considering the rising rates of T2D in children. The therapeutic armamentarium of medications for treatment of obesity and its associated metabolic dysfunction is increasing. Exploratory work on the role of omega-3 fatty acids and other supplements and alterations of the microbiome to influence health and disease profile appear to be promising. Finally, the increasing emphasis on personalized medicine is driving efforts to identify genetic and epigenetic variations that will likely influence individualized approach to therapy in the future.

Cross-References ▶ Antenatal Programming of Blood Pressure ▶ Cardiovascular Influences on Blood Pressure ▶ Endothelial Dysfunction and Vascular Remodeling in Hypertension ▶ Familial Aggregation of Blood Pressure and the Heritability of Hypertension ▶ Neurohumoral and Autonomic Regulation of Blood Pressure ▶ Salt Sensitivity in Childhood Hypertension ▶ The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation ▶ Vasoactive Factors and Blood Pressure in Children

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Monogenic and Polygenic Contributions to Hypertension Julie R. Ingelfinger

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Monogenic Forms of Human Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Familial Hyperaldosteronism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glucocorticoid-Remediable Aldosteronism or Familial Hyperaldosteronism Type 1 [OMIM #103900] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Hyperaldosteronism Type 2 OMIM #605635 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Hyperaldosteronism Type 3 [OMIM# 613677] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Hyperaldosteronism Type 4 [OMIM # 617027] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apparent Mineralocorticoid Excess [AME] [OMIM # 218030] . . . . . . . . . . . . . . . . . . . . . . . Mineralocorticoid Receptor Gain-of-Function Mutation (OMIM # 605115) . . . . . . . . . . Steroidogenic Enzyme Defects Leading to Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

116 116 119 119 119 120 120 121

Steroid 11β-Hydroxylase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Steroid 17α-Hydroxylase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Mutations in Renal Transporters Causing Low-Renin Hypertension . . . . . . . . . . . . . 122 Pseudohypoaldosteronism Type II – Gordon Syndrome [OMIM#145260] . . . . . . . . . . . . 122 Liddle Syndrome [OMIM # 177200] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pheochromocytoma-Predisposing Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertension with Brachydactyly [OMIM #112410] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Forms of Mendelian Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

123 123 124 124

When to Suspect Monogenic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Non-Mendelian, Polygenic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Experimental Hypertension as a Tool to Investigate Polygenic Hypertension . . . . . . . . . 125 Human Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

J. R. Ingelfinger (*) Pediatric Nephrology Unit, Mass General for Children at MGB, Harvard Medical School, Boston, MA, USA e-mail: jingelfi[email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_6

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J. R. Ingelfinger Mendelian Randomization Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Candidate Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Candidate Susceptibility Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Variants or Subphenotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Conclusions and Implications for Pediatric Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . 127 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Abstract

This chapter provides an overview of the genetics of hypertension, reviewing rare Mendelian forms of hypertension, which can be explained by mutations in single genes, as well as the genetics of primary hypertension. Different approaches such as candidate gene approaches, linkage studies, and genome-wide association studies are discussed. This chapter is intended as a concise primer for reading the literature in the area of genetics and hypertension. Keywords

Apparent mineralocorticoid excess · Defects in steroidogenesis · Primary hypertension · Familial hyperaldosteronism · Gordon syndrome (pseudohypoaldosteronism type II) · Familial hypertension · Hypertension with brachydactyly · Liddle syndrome · Mendelian hypertension · Low-renin hypertension · Monogenic hypertension · Pheochromocytoma-predisposing syndromes · Polygenic hypertension

Introduction Over two decades have elapsed since the publications in February 2001 that provided the first maps of the human genome (International Human Genome Sequencing Consortium 2001; Venter et al. 2001). While genes involved in a number of rare, monogenic forms of hypertension have been identified, the genetics of primary hypertension continues to require further elucidation, likely because it has multiple genetic determinants. However, many recently developed tools are available

to elucidate the genetic aspects of primary hypertension, and a growing number of studies have identified many genetic associations with the condition, which is widely viewed as a polygenic disorder. This chapter discusses both monogenic and polygenic forms of hypertension. We also discuss the current clinical implications of genetic studies and information in our approach to hypertension (Khandelwal and Deinum 2022; Delles and Padmanabhan 2012; Wei et al. 2017).

Monogenic Forms of Human Hypertension At the onset of the Millennium, genes for a number of monogenic forms of human hypertension were identified via positional cloning (in the past called “reverse genetics”) (Deng 2007; Lander et al. 1995). In this approach, large kindreds with many affected family members are phenotyped, and the mode of inheritance determined – that is, is the disease autosomal recessive, autosomal dominant, sex linked, and codominant, in its clinical transmission? Subsequently, linkage analysis is performed using highly polymorphic genetic markers such as microsatellite markers that occur widely throughout the genome, evenly spaced at approximately 10 centimorgan (cM) intervals. Since most people (about 70%) are heterozygous, the inheritance of alleles can be traced through large pedigrees. In a successful linkage analysis, a specific chromosomal region in the genome linked to the trait is identified. A LOD (logarithm of the odds) score describes the presence of such a region. The generally accepted LOD score indicating linkage is greater than 3.3 (corresponding to a significance level genome wide of 4.5
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(Deng 2007)). Once linkage is identified, a search for known candidate genes in the area of putative linkage commences. A search using additional highly polymorphic markers may also narrow the area of interest, leading to sequences of possible genes within the area. Presently, newer technologies permit more rapid discovery of genes of interest. Many of the genes responsible for monogenic hypertension have been found using whole exome sequencing, based on family history and phenotype (Raina et al. 2019). An increasing number of monogenic forms of hypertension have been identified to date – at least 37 (Kandelwal and Deinum 2021; Padmanabhan and Dominiczak 2021). A number of these are due to gain-of-function mutations (Dluhy 2002a; Lifton et al. 2001), most of which involve the

handling by the kidney of salt and/or the overproduction of mineralocorticoids or increased mineralocorticoid activity (Baudrand and Vaidya 2018). Severe hypertension, often from early life – even infancy – is not unusual in such conditions. Clinical hallmarks include apparent volume expansion and suppressed plasma renin activity with variable hypokalemia. An approach to evaluation of those forms of hypertension associated with hypokalemia and suppressed renin activity is shown in Fig. 1 (Athimulam et al. 2019: Buffolo et al. 2020; Yiu et al. 1997). Gain-of-function mutations in transporters in the distal renal tubules result in hypertension via salt and water retention, initially reported by Wilson et al. in 2001 (Wilson et al. 2001). While mutations and polymorphisms in the genes of various components of the renin-angiotensin-

Fig. 1 Evaluation of patients with hypertension and low plasma renin. Such disorders are either autosomal dominant, generally with a positive family history, or autosomal recessive, generally with a negative family history. Children with glucocorticoid-responsive aldosteronism (GRA), Liddle syndrome, and apparent mineralocorticoid excess (AME) all have normal physical examinations (PE), low plasma renin activity (PRA) or concentration, and hypokalemia. Characteristic urinary steroid profiles and genetic testing distinguish these syndromes. K+, potassium, TH18oxoF/THAD ratio, ratio of urinary

18-oxotetrahydrocortisol (TH18oxoF) to urinary tetrahydroaldosterone (THAD), which has a normal of 0–0.4, and GRA patients >1. THF plus alloTHF/THE ratio of the combined urinary tetrahydrocortisol (THF) and allotetrahydrocortisol (alloTHF) to urinary tetrahydrocortisone (THE), which has a normal of 3β-hydroxysteroid dehydrogenase>17α-hydroxylase and cholesterol desmolase. Patients with the 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase defects have a tendency to retain salt, becoming hypertensive. It is also important to remember that any person with CAH may develop hypertension owing to overzealous steroid replacement therapy.

Steroid 11β-Hydroxylase Deficiency The mineralocorticoid excess in 11β-hydroxylase deficiency (Krone and Arlt 2009; Claahsen-van der Grinten et al. 2022), a form of CAH accompanied by virilization, leads to decreased sodium excretion with resultant volume expansion, renin suppression, and hypertension. Elevated BP is not invariant in 11β-hydroxylase deficiency and most often is discovered in later childhood or adolescence, often with an inconsistent correlation to the biochemical profile (Krone and Arlt 2009; Zachmann et al. 1971). Hypokalemia is variable, but total body potassium may be markedly depleted in the face of normal serum or plasma potassium. Renin is generally decreased, but aldosterone is increased. Therapy of 11β-hydroxylase deficiency should focus on normalizing steroids. Administered glucocorticoids should normalize cortisol and reduce ACTH secretion and levels to normal, thus stopping over secretion of deoxycorticosterone (DOC). Hypertension generally resolves with such therapy. When hypertension is severe, antihypertensive therapy should be used instituted until the BP is controlled; such therapy can be tapered later. Additional mutations can cause this syndrome. For example, a patient with 11β-hydroxylation inhibition for 17α-hydroxylated steroids but with intact 17-deoxysteroid hydroxylation has been reported (Zachmann et al. 1971). Multiple mutations affecting the CYP11B1 gene have been described; these include frameshifts, point mutations, extra triplet repeats, and stop mutation (Claahsen-van der Grinten et al. 2022; Curnow et al. 1993; White et al. 1991).

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Steroid 17α-Hydroxylase Deficiency Abnormalities in 17α-hydroxylase affect both the adrenals and gonads, since a dysfunctional 17α-hydroxylase enzyme results in decreased synthesis of both cortisol and sex steroids (Biglieri et al. 1966). The enzyme P450c17, encoded by CYP17A1, influences both 17α-hydroxylase and 17,20-lyase activities. Thus, mutations in CYP17A1 can result in a distinct but subtle syndrome that includes hypertension. Affected persons appear phenotypically female (or occasionally have ambiguous genitalia), irrespective of their genetic sex, and puberty does not occur. Consequently, most cases are discovered after a girl fails to enter puberty. An inguinal hernia is another reported presentation; the “hernia” in these reports contained gonadal tissue. Hypertension and hypokalemia are characteristic, owing to impressive overproduction of corticosterone (compound B). Symptoms in affected patients are caused by the increased corticosterone and 11deoxycorticosterone. These metabolites are generally excreted into the bile, where they drain into the intestines, and anaerobic bacteria transform them to 21-dehydroxylated forms; in rats, the antibiotic neomycin can block the increased blood pressure. Such observations suggest that corticosterone, and related 5α-pathway products and also derivatives 11-oxygenated progesterone may be involved in the hypertension in this entity (Morris et al. 2014). Glucocorticoid replacement is an effective therapy. However, should replacement therapy fail to control the hypertension, appropriate therapy with antihypertensive medication(s) should be instituted to achieve BP control.

Mutations in Renal Transporters Causing Low-Renin Hypertension Pseudohypoaldosteronism Type II – Gordon Syndrome [OMIM#145260] Pseudohypoaldosteronism type II or Gordon syndrome was first described in the early 1960s, and is a rare form of familial hypertension in which there is often marked hyperkalemia (OMIM

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#145260). Treatment with thiazide diuretics is often successful, as is severe salt restriction or triamterene. Aldosterone receptor antagonists do not correct the observed abnormalities. As thiazides are effective, one would hypothesize that the thiazide-sensitive Na/Cl cotransporter (NCC) would be affected; it turns out to be, but secondarily. The NCC itself is not abnormal. PHAII genes were mapped to chromosomes 17, 1, or 12 (Mansfield et al. 1997). One kindred was found to have mutations in WNK1 – large intronic deletions that increase WNK1 expression. Another kindred with missense mutations in WNK4, which is on chromosome 17, has been described. While WNK 1 is widely expressed, WNK4 is expressed in primarily kidney, localized to tight junctions. WNKs alter the handling of potassium and hydrogen in the collecting duct, leading to increased salt resorption and increased intravascular volume. Patients with WNK4 mutations often have metabolic symptoms prior to the development of hypertension. These may include hypocalcemia and hypercalciuria (with calcium stones) and metabolic bone disease (Mabillard and Sayer 2019). The pathophysiology of Gordon syndrome is more complex than it first seemed (O’Shaunessey 2015). The role of the two serine/threonine kinases that were identified in 2001 as causative – WNK1 and WNK4 –act in a pathway that has other serine/threonine kinases (SPAK and OSR1), and those kinases phosphorylate and activate the Na/Cl cotransporter in the distal tubule, as well as the cotransporters NKCC1 and NKCC2. Patients with Gordon syndrome also have hyperkalemia, and it is now known that WNK1 and WNK4 normally decrease the cell-surface amounts of the secretory K-channel in the collecting duct, ROMK. In addition, it turns out that WNK1/WNK4 mutations are not common among Gordon syndrome families. Recent work shows that other genes may lead to this syndrome – CUL3, which encodes the scaffold protein in a ubiquitin-E3 ligase, Cullin-3, and also KLHL3, which encodes an adaptor protein called Kelch 3. The genotypes found to date correlate with phenotypes. CUL3 is associated with signs and

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symptoms very early in life – and profound potassium abnormalities. Indeed, the initial family described by Gordon had very severe hypertension and, recently, was found to have a CUL3 mutation (Glover et al. 2014). The severity and age at first symptoms appears to be severe-to-mild in this order: CUL3 > KLHL3 > WNK4 > WNK1 (Boyden et al. 2012; O’Shaughnessy 2015; Mabillard and Sayer 2019).

Liddle Syndrome [OMIM # 177200] In 1963, Liddle et al. (1963) described the early onset of autosomal dominant hypertension in a family in whom hypokalemia, low renin, and aldosterone concentrations were noted in affected members. Inhibitors of renal epithelial sodium transport such as triamterene worked well in controlling the hypertension, but inhibitors of the mineralocorticoid receptor did not. A general abnormality in sodium transport seemed apparent, as the red blood cell transport systems were not normal (Wang et al. 1981). A major abnormality in renal salt handling seemed likely when a patient with Liddle syndrome underwent a renal transplant and hypertension and hypokalemia resolved posttransplant (Botero-Velez et al. 1994). While the clinical picture of Liddle syndrome is one of aldosterone excess, aldosterone levels as well as renin levels are very low. Hypokalemia is not invariably present. A defect in renal sodium transport is now known to cause Liddle syndrome. The mineralocorticoid-dependent sodium transport within the renal epithelia requires activation of the epithelial sodium channel (ENaC), which is composed of at least three subunits normally regulated by aldosterone. Mutations in the beta (SCNN1B) and gamma (SCNN1G) subunits of the ENaC have been identified (both lie on chromosome 16) (Hansson et al. 1995; Shimkets et al. 1994). Thus, the defect in Liddle syndrome leads to constitutive activation of amiloride-sensitive epithelial sodium channels (ENaC) in distal renal tubules, causing excess sodium reabsorption. For a recent review, see Ceccato and Mantero (2019).

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Pheochromocytoma-Predisposing Syndromes A variety of RET proto-oncogene mutations and abnormalities in tumor-suppressor genes are associated with autosomal dominant inheritance of pheochromocytomas, as summarized in Table 2 (Dluhy 2002b). A number of paraganglioma and pheochromocytoma susceptibility genes inherited in an autosomal dominant pattern appear to convey a propensity toward developing such tumors (Dluhy 2002b). Both glomus tumors and pheochromocytomas derive from neural crest tissues, and the genes identified in one type of tumor may appear in the other (Neumann et al. 2019). For instance, germ-line mutations have been reported both in families with autosomal dominant glomus tumors (as well as in registries with sporadic cases of pheochromocytoma) (Neumann et al. 2019). In addition, other pheochromocytoma susceptibility genes include the proto-oncogene RET (multiple endocrine neoplasia syndrome type 2 [MEN-2]), the tumor-suppressor gene VHL seen in families with von Hippel-Lindau disease, and the gene that encodes succinate dehydrogenase subunit B (SDHB) (Hudler and Urbancic 2022). The genes involved in some of these tumors appear to encode proteins with a common link involving tissue oxygen metabolism (Hudler and Urbancic 2022). In von Hippel-Lindau disease, there are inactivating (loss-of-function) mutations in the VHL suppressor gene, which encodes a protein integral to the degradation of other proteins – some of which, such as hypoxia-inducible factor, are involved in responding to low oxygen tension. Interestingly, the mitochondrial complex II, important in O2 sensing and signaling, contains both SDHB (succinate dehydrogenase subunit B) and SDHD (succinate dehydrogenase subunit D). Thus, mutations in the VHL gene and SDHB and SDHD might lead to increased activation of hypoxic signaling pathways leading to abnormal proliferation. In multiple endocrinopathy-2 (MEN-2) syndromes, mutations in the RET proto-oncogene lead to constitutive activation (activating mutations) of the receptor tyrosine kinase. The end result is hyperplasia of adrenomedullary

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chromaffin cells (and in the parathyroid, calcitonin-producing parafollicular cells). In time, these cells undergo a high rate of neoplastic transformation. It now also appears that apparently sporadic chromaffin tumors may contain mutations in these genes as well.

Hypertension with Brachydactyly [OMIM #112410] Hypertension with brachydactyly, also called brachydactyly type E with short stature and hypertension (Bilginturan syndrome), was first described in 1973 in a Turkish kindred (Bilginturan et al. 1973). Affected persons have shortened phalanges and metacarpals, as well as hypertension. Linkage studies performed in the 1990s mapped this form of hypertension to a region on chromosome 12p, in the region 12p12.2 to p11.2 (Bähring et al. 1996). Patients with this form of hypertension have normal sympathetic nervous system and RAAS responses. In 1996, some abnormal arterial loops were noted on MRI examinations of the cerebellar region. There was speculation that this abnormality could lead to compression of neurovascular bundles that would lead to hypertension (Bähring et al. 1996). Of the several candidate genes in the region – a cyclic nucleotide phosphodiesterase (PDE3A) – has been found to be causative in both humans and murine models (Maass et al. 2015; Toka et al. 2015). Further, additional mutations have been

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found in PDE3A more recently (Ercu et al. 2020; Li et al. 2020).

Other Forms of Mendelian Hypertension In addition, there have been reports of severe insulin resistance, diabetes mellitus, and elevated BP caused by dominant-negative mutations in human peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor (Meirhaeghe and Maouyel 2004; Fang et al. 2021). PPARγ is important in the differentiation of adipocytes (reviewed in Meirhaeghe and Amouyel 2004). Mutations in PPARγ have been linked to a group of symptoms, including hypertension (Reviewed in Fang et al. 2021). The affected patients have had marked insulin resistance, then developed type 2 diabetes, and have partial lipodystrophy, as well as hypertension. The finding of these patients has been taken widely as a demonstration of the importance of PPARγ in metabolic syndrome and in blood pressure control, since common polymorphisms appear to be associated with hypertension in the general population.

When to Suspect Monogenic Hypertension Table 3 lists those situations in which the astute clinician should consider monogenic hypertension (Dluhy 2002a). These include both clinical

Table 3 When to suspect a hypertensive genetic disorder Patient is a child with marked hypertension, particularly if plasma renin is depressed Patient is an at-risk member of a kindred with a known monogenic hypertensive disorder (e.g., multiple endocrine neoplasia, glucocorticoid-responsive aldosteronism) Patient is a hypertensive child with hypokalemia and first-degree relatives have hypokalemia and/or hypertension Patient has physical findings suggestive of syndromes or hypertensive disorders (e.g., retinal angiomas, neck mass, or hyperparathyroidism in patient with a pheochromocytoma) Patient has onset of hypertension at a young age, and/or a family history of early-onset hypertension Adapted from Dluhy (2002a).

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and laboratory findings that should point toward further evaluation. Significant among these are a strong family history of hypertension and early onset of hypertension, particularly when the BP is difficult to control within the family. Low plasma renin activity, along with hypokalemia, should also point toward the possibility that a defined form of hypertension may be present.

Non-Mendelian, Polygenic Hypertension In 2005 Kearney et al. estimated that at least 1.5 billion people would have hypertension by 2025, which is becoming more common in children and youth (Kearney et al. 2005). Further, the vast majority of persons with hypertension likely have primary hypertension, which is at the intersection of lifestyle and risk genes. The genetic contribution to a prevalent condition such as primary (sometimes termed essential) hypertension is widely considered to involve multiple genes and is thus termed polygenic. In the current genomic era, a variety of studies indicate that thousands of genes may contribute or modify the tendency to hypertension, yet using the data to change outcome has proved elusive, in part because BP is a continuous variable, and the contribution of any one gene appears to be small. Relevant background for considering the genetic factors predisposing toward hypertension follows.

Experimental Hypertension as a Tool to Investigate Polygenic Hypertension Many studies in inbred experimental animals, mainly rats and mice, have aimed to identify genes controlling BP (see ▶ Chap. 49, “Hypertensive Models and Their Relevance to Pediatric Hypertension”). In the 1980s, it was estimated that 5–10 genes control BP (Harrap 1986). In 2000, Rapp summarized available research and estimated that 24 chromosomal regions in

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19 chromosomes were associated with hypertension in various rat strains (Rapp 2000). A review by Delles et al. (2010) noted that candidate QTLs (quantitative trait loci) have been identified on nearly every chromosome.

Human Hypertension A variety of studies have long pointed to a link between human hypertension and genes of the RAAS (summarized in references (Zhu et al. 2003)). However, in common diseases such as hypertension, it may be more productive to consider susceptibility alleles rather than disease alleles per se. Furthermore, some people carrying a particular susceptibility allele may not have the disease, either because they do not have the environmental exposure that causes the condition to develop or because they lack another allele (or alleles) that are needed to cause a given clinical problem. Because there are multiple potential interactions, and susceptibility alleles are generally common, following a given allele through pedigrees is difficult. In such a circumstance, segregation analysis is difficult, particularly if a given susceptibility allele has a small effect. Indeed, linkage with hypertension has been reported on most chromosomes in humans. While linkage analysis may constitute an initial step (Delles and Padmanabhan 2012), it is not as powerful a tool in polygenic conditions as it is in Mendelian diseases, because many people without the disease may carry the susceptibility allele. Using affected siblings (sib pairs) may be helpful to gain more understanding of the possible genetics (Delles and Padmanabhan 2012). A LOD score of greater than 3.6 is taken as evidence of a linked locus, which is often very large (in the range of 20–40 cM). Once a putative linkage is confirmed in a replicate study, finer mapping can be performed to pinpoint the genetic region that contains the putative gene. This is done via linkage nucleotide polymorphisms (SNPs). SNPs occur roughly every 1,000 base pairs and lend

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themselves to automated testing. Using SNPs, a broad region (10–40 cM) can be narrowed to a far smaller region of roughly 1
106 base pairs (The International SNP Map Working Group 2001). More recently, genome-wide screens of the human genome aiming to discover hypertension genes have suggested many loci of interest – by now, thousands (reviewed in Magavern et al. 2021). Such genome-wide screens have included subjects with diverse phenotypes and ethnicity; furthermore, selection criteria have varied. The numbers and composition of families have ranged from single, large pedigrees to more than 2,000 sib pairs from 1,500 or so families. When a BP Genome-wide association study (GWAS) is performed, genetic regions associated with blood pressure-related traits are found (Cabrera et al. 2015). There may be multiple correlations with variants in linkage disequilibrium, and it may not mean that the nearest gene is actually involved. There are many large and collaborating biobanks. For example, the UK Biobank and International Consortium for BP, the million veteran program, and the Estonian Genomic Centre of the University of Tartu (Evangelou et al. 2018). Studies from this group have reported many new loci. Further, the Million Veteran Program and UK Biobank have done additional studies and confirmed them with BioVU (Vanderbilt’s biorepository of DNA extracted from discarded blood collected during routine clinical testing and linked to de-identified medical records) (Giri et al. 2019). Additionally, large groups that are likely to provide further data and discoveries exist, such as the Finnish biobank, FinnGen (500,000 participants), and the UK Accelerating Detection of Disease Cohort (Magavern et al. 2021). A number of present steps are these: 1. Crucial to making sense of the large number of genes found in GWAS studies is to correlate the findings with phenotypic data and gene and environmental exposure information. Importantly, doing so requires a “big data” approach and artificial intelligence techniques as well.

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2. With advances from GWAS techniques, the hope is to find loci of interest and targets within the genome that may lead to candidate pathways that might be “druggable targets,” creating novel therapy. 3. In all the several steps involved in discoveries that may ultimately find a path to clinical translation are depicted in Fig. 3.

Mendelian Randomization Studies Mendelian randomization combines observation and phenotyping with examination of genetic variability. Many investigators feel that MR may be as useful as randomized controlled trials, though others do not. In Mendelian randomization, an observational study looks at specific biomarkers or risk factors (such as BP levels) and genetic findings. The advantage is that confounding is thought to be less problematic (Magavern et al. 2021). Thus, a given genetic variant considered associated with a specific risk factor is chosen, for example, BP levels. Then two other aspects of the variant are required – that the given genetic variant and confounders are not associated and, finally, that the influence of the given genetic variant occurs by means of the risk factor (Emdin et al. 2017). Using this technique a number of studies in hypertensive populations have been performed (see Magavern et al. 2021). A GWAS can discover many loci. For example, a 2018 GWAS included over a million participants that utilized two discovery from the UK Biobank and the International Consortium for Blood Pressure then validation sets from the MVP and the Estonian Genomic Centre of the University of Tartu (Evangelou et al. 2018). The study reported 525 new loci, which increased the number of loci associated with hypertension to 901. A similar study subsequently found 208 additional common variant loci associated with BP and 53 rare variants (Giri et al. 2019).

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Candidate Genes Another approach in assessing polygenic hypertension is to use candidate genes – genes that already have a known or suspected role in hypertension – that are present near the peak of observed genetic linkage (Söber et al. 2009). If the full sequence of the candidate gene is known, then it is relatively easier to go forward. In an early study by Caulfield and colleagues (Caulfield et al. 2003), for example, there were a number of candidate genes that are within the linkage analysis-identified areas on chromosomes 2 and 9. Genes that encode serinethreonine kinases, STK39, STK17B are on chromosome 2q; PKNBETA, a protein kinase, is on chromosome 9q; G protein-coupled receptors on chromosome 9 – GPR107 9q and GPR21 on 9q33; and on 2q24.1 there is a potassium channel, KCNJ3. Use of microarrays to identify differential expression of expressed sequences in tissues from affected and unaffected persons has become common. These arrays are available either as full-length cDNAs or as expressed sequence tags (ESTs).

Candidate Susceptibility Genes A number of genes have become candidates as susceptibility genes, particularly those of the RAAS. A number of such genes were associated with hypertension and cardiovascular regulation in the pre-genomic era. Many associations have been described or imputed, including not only members of the RAAS but many other genes. For example, Izawa et al. (2003) chose 27 candidate genes based on reviews of physiology and genetic data involved with vascular biology, leukocyte and platelet biology, and glucose and lipid metabolism. They then also selected 33 SNPs in these genes, largely related in promoter regions, exons, or spliced donor or acceptor sites in introns and looked at their relationship to hypertension in

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a cohort of 1,940 persons. They found that polymorphisms in the CC chemokine receptor 2 gene were associated with hypertension in men and the TNF-alpha gene was associated with it in women. In a GWAS in African Americans, Adeyemo et al. (2009) suggested that pathway and network approaches might be helpful in identifying or prioritizing various loci.

Variants or Subphenotypes If a particular variant of a complex disease is clinically distinct, then analysis of so-called subphenotypes via positional cloning may be potentially illuminating (Delles and Padmanabhan 2012; Lander and Kruglyak 1995). In such an instance, there may be fewer susceptibility genes involved. However, subphenotypes may be difficult to study, as the physiology involved may be intricate. An example would be salt-sensitive hypertension (Levy et al. 2009). In order to study subjects, it is necessary to perform careful metabolic studies that confirm the subphenotype (hypertension with salt sensitivity) and also is standard during testing.

Conclusions and Implications for Pediatric Hypertension A search for monogenic forms of hypertension is clearly indicated in an infant, child, or teenager with elevated BP and history or signs compatible with one of these diagnoses. If a child is found to have one of the rare forms of monogenic hypertension, there will likely be specific therapy. Few data, however, exist to guide the clinician in terms of the roles polygenic hypertension in children at the present time. Current approaches, summarized in Fig. 2 and in reviews (Delles et al. 2010; Simino et al. 2012; Padmanabhan et al. 2012; Braun and Doris 2012; Hiltunen and Kontula 2012; Cowley et al. 2012; El Shamieh and Visvikis-Siest 2012), would still indicate that the concept of a complex

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Fig. 2 Study designs used to dissect the genetic architecture of common complex traits. This figure shows the flow of studies that utilize candidate gene approaches, genomewide linkage studies, and genome-wide association studies (After Simino J, Rao DC, Freedman BI. Novel findings and

future directions on the genetics of hypertension. Curr Opin Nephrol Hypertens. 2012;21(5):500–7, with permission. Insets for genome-wide linkage and genome-wide association studies are from Graphic Arts, the New England Journal of Medicine, with permission

set of interactions leads to most cases of hypertension. Another approach worth mentioning is that of genome-wide admixture mapping – mapping by admixture linkage disequilibrium (MALD), which is used to detect genes in populations that are mixed, for example, where one group’s ancestors have more of a given disease than another group (Simino et al. 2012). Using a moderate number single-nucleotide polymorphisms (SNPs), this method determines regions in the genome that contain more SNPs from one ancestral group as compared to the others. Then honing down on the area, genes of interest may be found. This approach is very appealing as a means by which to study hypertension in African Americans (Kopp et al.

2008; Genovese et al. 2010). For example, MALD was used to find a linkage peak in persons with African ancestry, which has turned up two apolipoprotein L1 (APOL1) variants in the coding region, as well as an adjacent area in the myosin heavy chain 9 gene (MYH9), which are associated with focal segmental glomerulosclerosis and hypertension. There is no doubt that further genetic mechanisms that lead to primary hypertension remain to be delineated. In the future gene-environment interactions, pathways that involve multiple gene products, as well as epigenetic phenomena, will be explored. Ultimately, there may be pharmacogenetic approaches by which therapy for hypertension may be individualized.

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Fig. 3 This figure notes the promise of big data in making progress toward personalized medicine. Adapted from Magavern et al. (2021)

Cross-References ▶ Endocrine Hypertension ▶ Hypertensive Models and Their Relevance to Pediatric Hypertension

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Antenatal Programming of Blood Pressure Andrew M. South

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Overview of Clinical and Epidemiological Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Select Blood Pressure-Programming Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kidney-Altered Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kidney-Altered Sodium Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kidney-Altered Hormonal Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kidney-Altered Neural Tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

136 136 140 141 144

Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Potential Sex Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

Abstract

Despite how common hypertension is in children, adolescents, and adults, the antecedent mechanisms underlying its origins remain incompletely understood. Increasingly strong evidence from clinical, epidemiological, and

A. M. South (*) Department of Pediatrics, Section of Nephrology, Brenner Children’s, Wake Forest University School of Medicine, Winston Salem, NC, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_57

preclinical studies support the concept of earlylife programming of hypertension within the framework of the developmental origins of health and disease theory. In essence, harmful antenatal exposures cause the fetus (and the intrauterine environment) to alter its physiological, structural, and metabolic development to adapt to this deleterious environment to improve short-term survival. However, if of sufficient severity, number, timing, or duration, such exposure-induced developmental plasticity can program persistent, maladaptive cardiovascular phenotypes that appear later on over the life course and ultimately 133

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increase the risk of developing hypertension. Well-described antenatal exposures can come from a variety of sources – maternal, paternal, fetal, and environmental – and can occur throughout pregnancy, from gametogenesis through birth. These exposures include abnormal maternal-fetal vascular supply and nutrient delivery (both restricted and excess), maternal stress causing increased exposure to endogenous glucocorticoids, inflammation, and exogenous exposures. Programming mechanisms can occur directly or indirectly via placental insufficiency and/or growth restriction; they likely do not simply occur due to low birth weight in isolation. Programming alters organ structure and function, tissue cell type, number, and distribution, blood supply, and hormonal system enzyme, substrate, and receptor expression and function in a variety of cardiovascular tissues including the kidneys, brain, vasculature, and heart. Additional factors further contribute to the programming of hypertension, including epigenetic changes as well as preconception and postnatal exposures. This chapter reviews the preclinical evidence for antenatal factors that result in programmed hypertension, including the complex interactions among these mechanisms, and highlights gaps in the field that limit translation to patient care. Understanding these programming factors has important implications for primordial prevention and treatment strategies. Keywords

Antenatal glucocorticoids · Arterial stiffness · Autonomic dysfunction · Developmental origins of health and disease · Growth restriction · Low birth weight · Nephron number · Placental insufficiency · Preeclampsia · Preterm · Renin-angiotensinaldosterone system

Introduction The mechanistic bases of primary hypertension have been the subject of extensive investigation for at least the past 150 years (Lever and Harrap

A. M. South

1992). In particular, the developmental origins of health and disease theory have been instrumental in advancing our understanding of the origins of primary hypertension (Barker and Osmond 1988, Brenner et al. 1988). However, many of these hypotheses have now been shown to be overly simplistic or biased. Individuals born preterm with extremely low or very low birth weight or who were born small for gestational age often have higher blood pressure as adolescents and young adults compared to term-born peers with birth weight greater than or equal to 2500 grams (Haikerwal et al. 2020; South et al. 2019a). Lower birth weight, preterm birth, and growth restriction are associated with increased risks of altered heart structure and function and coronary artery disease (Lewandowski et al. 2013). Despite many important findings to date, the exact clinical early-life factors that contribute to developing future hypertension remain poorly defined (Nuyt and Alexander 2009). Increasingly strong preclinical, clinical, and epidemiological evidence over the past 40 years has begun to define how antenatal exposures may cause maladaptive alterations to fetal development – physiological, structural, and metabolic – that program adverse cardiovascular phenotypes (Barker and Osmond 1988; Brenner et al. 1988). This developmental plasticity – physiological alterations to adapt to a deleterious environment to improve short-term survival – requires a trade-off leading to maladaptive long-term physiological changes that program an increased risk of disease (Nathanielsz 2006). Antenatal exposures can occur at any point during gestation – from conception and the embryonic period through birth – and can come from a variety of sources (maternal, paternal, fetal, and environmental) (Langley-Evans et al. 1996b). In addition, preconception and postnatal exposures, including during the neonatal period and throughout infancy and later childhood, can have important programming effects that may augment or mitigate the deleterious effects of these antenatal exposures (Siddique et al. 2014). This chapter focuses on exposures that occur during the antenatal period. In both preclinical and clinical studies, it is unclear whether early or midgestation exposures are more deleterious than exposures that occur in the

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perinatal period (i.e., within a few weeks before or after birth). While preterm birth, low birth weight, and growth restriction have all been suggested as generalized proxy risk factors in humans, it is often difficult to parse out the complex contributions of the various mechanisms likely involved (Nuyt and Alexander 2009). It is unknown whether and to what extent simply being born prematurely or having low birth weight – independent of their antecedent causes – is necessary and sufficient to lead to programmed hypertension, or if gestational age, birth weight, or growth restriction either have differential effects on the conferred risk or are intermediate factors on the causal pathway. Furthermore, being born small for gestational age (birth weight less than the tenth percentile for gestational age and sex) is not synonymous with fetal growth restriction in humans, and the timing and type of growth restriction (symmetric vs. asymmetric) can have important later health implications. Similarly, it has been difficult to develop preclinical models that are fully equivalent to human disease; available models mimic similar mechanisms but usually cannot recreate premature birth itself (Vehaskari and Woods 2005). Yet, numerous insightful and well-defined antecedent programming mechanisms, broadly speaking, model placental insufficiency and/or growth restriction – for example, due to abnormalities in maternal-fetal vascular supply and nutrient delivery, maternal stress, inflammation, and exogenous exposures (Fig. 1). These models include maternal hypertension (chronic, gestational, or preeclampsia); maternal diabetes mellitus (chronic or gestational); maternal nutritional status including obesity and undernutrition (global caloric restriction vs. specific macronutrient or micronutrient restriction); hypoxia; and exogenous corticosteroids (Table 1). Antenatal programming can affect several cardiovascular organ systems (often simultaneously), including the kidneys, brain, vasculature, and heart (Table 2). Alterations to organ structure and function, tissue cell number, type, and distribution, blood supply, and enzyme, substrate, and receptor expression and function in numerous hormonal systems can all mediate antenatal programming of blood pressure (Nathanielsz 2006), including the renin-angiotensin-aldosterone system, the hypothalamic-pituitary-

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adrenal axis, mineralocorticoids, and glucocorticoids, and sex hormones. Another important caveat is whether observed programmed changes are relatively appropriate physiological adaptations or represent overt pathophysiological changes. This chapter reviews the preclinical evidence of the effects that these antenatal mechanisms have on the major cardiovascular systems that contribute to programmed hypertension, including increasing evidence for transgenerational programming via epigenetic and related mechanisms.

Overview of Clinical and Epidemiological Evidence Important early-life exposures such as preterm birth and lower birth weight are emerging as risk factors for the development of hypertension across the life course, though the nature and magnitude of this risk remain unknown. Compared to term-born peers, persons born preterm with very low birth weight had higher blood pressure as adolescents and young adults (South et al. 2019a; South et al. 2020). Similarly, young adults born extremely preterm with extremely low birth weight had a greater trajectory of increasing ambulatory blood pressure from 18 to 25 years compared to term-born peers (Haikerwal et al. 2020). Individuals born preterm or small for gestational age have been reported to have altered heart function and structure as young and middle-aged adults (Lewandowski et al. 2013). However, the relative contributions among these exposures that confer the greatest risk for hypertension development remain undefined, and it is unknown if antecedent maternal or fetal conditions such as maternal preeclampsia are the more relevant exposures. Further, additional neonatal and early-life conditions and exposures (e.g., bronchopulmonary dysplasia, catch-up growth during infancy, food insecurity, and adverse childhood experiences) may magnify the risk of hypertension that antenatal programming confers. The underlying mechanisms remain incompletely described clinically but include biochemical pathway programming and alterations to kidney and cardiovascular tissue

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Fig. 1 Graphic causal model of the effects of major antenatal exposures (green with black arrowheads) on programmed hypertension in the offspring (blue with black vertical bar) mediated through alterations to fetal cardiovascular tissues. Solid green nodes denote ancestors of the exposures while solid blue nodes denote ancestors of the outcome. Gray nodes denote intermediate steps; red nodes denote kidney mechanisms; purple nodes denote brain mechanisms; brown nodes denote vascular mechanisms; and orange nodes denote heart mechanisms. For simplicity, not all arrows are drawn, timing of fetal exposure is not incorporated, preconception exposures are minimized, and

postnatal exposures are excluded. In this model, there are direct effects of the exposures on tissue-specific mechanisms and indirect effects mediated through placental insufficiency, lower gestational age at birth, lower weight at birth, and growth restriction. Dec, decreased; Exo, exogenous; FGR, fetal growth restriction; Gest, gestational; HPA, hypothalamic-pituitary-adrenal axis; HTN, hypertension; Inc., increased; Insuff, insufficiency; LV, left ventricular; M, maternal; Na, sodium; P, paternal; RAAS, renin-angiotensin-aldosterone system; Resp, responsiveness; Vasc, vascular; Wt, Weight. (Figure made with Dagitty (http://www.dagitty.net) (Textor et al. 2016))

structure and function (Lewandowski et al. 2013; Sehgal et al. 2020; South et al. 2018; South et al. 2020; South et al. 2019c). Clinical evidence suggests that the risk of programmed hypertension may be enhanced in people who develop obesity in later childhood (supporting the second-hit hypothesis) and in females who may lose some of the premenopausal protective effects of sex hormones (South et al. 2018; South et al. 2019b). There is increasing clinical evidence that programming of blood pressure-regulating hormones such as the renin-angiotensin-aldosterone system may predict development of higher blood pressure years later (South et al. 2019c). However, much more work is needed to better define precise

risks and to inform changes in clinical care and policy to guide primordial prevention and treatment strategies by reconciling the clinical and epidemiological data with that from preclinical models.

Select Blood Pressure-Programming Mechanisms Kidney-Altered Structure and Function Alterations to kidney structure and function (glomerular, tubular, interstitial, and vascular), sodium transport, hormonal signaling pathways,

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Table 1 Overview of select experimental hypertension programming models with and without induced growth restriction in the offspring Animal Rat

Mouse

Guinea pig

Sheep

Baboon Chicken

Antenatal programming event Protein restriction (6–18%) Global undernutrition (40–70%) High (8–30%) or low-salt (0.03%) diet High-fat (20%) diet Diabetes induced by streptozotocin or glucose infusion prior to conception and during pregnancy Uterine artery/vessel ligation Reduced uterine perfusion (35–45%) induced by clipping the aorta between the renal arteries and iliac bifurcation as well as branches of the uterine arteries, including a model that induces maternal preeclampsia L-NAME-induced preeclampsia Antenatal glucocorticoids-mimicking increased maternal endogenous glucocorticoids or clinical administration to promote fetal lung maturity Maternal or fetal hypoxia (10.5–12% oxygen or 25% reduction in fetal PaO2) Protein restriction (6–12%) Global undernutrition (70%) Antenatal glucocorticoids-mimicking increased maternal endogenous glucocorticoids Global undernutrition (18–33%) Uterine artery/vessel ligation Antenatal glucocorticoids-mimicking increased maternal endogenous glucocorticoids Maternal hypoxia (12% oxygen) Natural twinning Global undernutrition (85%) Removal of uterine/endometrial caruncles Umbilico-placental embolization Antenatal glucocorticoids-mimicking increased maternal endogenous glucocorticoids or clinical administration to promote fetal lung maturity Exogenous fetal or maternal cortisol infusion Decreased fetal renal perfusion pressure Fetal uninephrectomy Maternal hypoxia (25% reduction in fetal PaO2) Preeclampsia induced by uterine artery/vessel ligation Embryonic hypoxia (15% oxygen)

and innervation are major sources of blood pressureprogramming mechanisms that have been very well described (Langley-Evans et al. 1996b). Over 50 years ago, Zeman demonstrated that antenatal maternal protein restriction (6 vs. 24% casein) in rats was associated with development of “immature” kidneys in the newborn pups, characterized by fewer and less well-differentiated glomeruli and tubules as well as more connective tissue (Zeman 1968). This congenital reduction in nephron number was similar to that seen in models of acquired severe nephron deficiency, such as 5/6 ablation in male MunichWistar rats. Early work by Brenner, Garcia, Anderson, and others – that loss of functional nephrons past a tipping point precipitates further loss of kidney function – built on Zeman’s initial findings and was applied to the contemporaneous developmental

origins of health and disease theory to develop the idea of antenatal programming of hypertension put forth by Barker and others (Barker and Osmond 1988; Brenner et al. 1988; Zeman 1968). The traditionally held view was that reduced nephron number and function (i.e., oligonephronia) – a consequence of overall reduced kidney mass due to relative growth restriction – primarily drove antenatal hypertension programming (Brenner et al. 1988). This thinking was based on numerous observations, including that (1) nephrogenesis, normally completed by 36 weeks’ gestation in humans, becomes blunted in the extrauterine environment in those born preterm; (2) substantially reduced kidney mass increases systemic arterial and glomerular capillary blood pressure to drive a compensatory increase in glomerular filtration to maintain fluid

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Table 2 Overview of select organ-specific hypertension programming mechanisms Organ Kidney

Brain

Vasculature

Heart

Programming mechanisms Smaller kidney size Abnormal glomeruli: lower number, greater size, hyperfiltration, and sclerosis Abnormal tubulointerstitial development with greater fibrosis Enhanced sodium retention: Alterations in the expression and function of the Na/K-ATPase, Na/H exchanger, Na/K/2Cl cotransporter, Na/Cl cotransporter, and epithelial Na channel Altered intrarenal renin-angiotensin-aldosterone system, mineralocorticoid receptor, and glucocorticoid receptor expression and activity Salt-sensitive blood pressure/impaired pressure natriuresis Enhanced renal vascular responsiveness Enhanced renal sympathetic nerve activity Increased oxidative stress and inflammation Altered structure and size Altered neurovasculature-capillary density and size, tone, and reactivity Autonomic dysfunction-baroreflex sensitivity, heart rate, and blood pressure variability Increased catecholamine production, release, and response Altered hypothalamic-pituitary-adrenal axis expression and activity Altered local renin-angiotensin-aldosterone system, mineralocorticoid receptor, and glucocorticoid receptor expression and activity Greater vascular stiffness and resistance Impaired flow-mediated dilation Enhanced vasoconstrictor response Attenuated vasorelaxation dependent and independent of the endothelium Enhanced myogenic tone Greater vessel wall remodeling with increased collagen content Impaired angiogenesis, capillary rarefaction, and arteriole density Reduced endothelial and smooth muscle cell number and size Altered local renin-angiotensin-aldosterone system, nitric oxide, and prostaglandin expression and activity Increased afterload and systemic vascular resistance Decreased basal and responsive cardiac output and stroke volume Augmented contractility Reduced heart size Left ventricular hypertrophy Increased and decreased ventricular size Increased fibrosis and remodeling Lower cardiomyocyte number and altered cardiomyocyte size Altered cardiac renin-angiotensin-aldosterone system, mineralocorticoid receptor, and glucocorticoid receptor expression and activity

excretion; and (3) progressive glomerular hyperfiltration leads to inadequate sodium excretion resulting in salt-sensitive hypertension (i.e., impaired pressure natriuresis). Subsequently, numerous antenatal mechanisms were shown to contribute to oligonephronia-related programmed hypertension independent of growth restriction in preclinical models. These included alterations to several biochemical pathways important to nephron development and maturation such as cyclooxygenase 2, renin, angiotensin II, WT1, Pax2, WNT, p53, TGF-β, fibroblast growth factors, and matrix metalloproteinases (Baserga et al. 2007;

Bertram et al. 2001; Woods et al. 2001). Bilateral uterine artery ligation-induced growth restriction in pregnant Sprague-Dawley rats at gestational day 19 caused adult-onset hypertension in offspring at 140 days of life (Baserga et al. 2007). Rats exposed to maternal L-NAME-induced preeclampsia from gestational days 14–21 had increased blood pressure and evidence of kidney disease at 6 weeks of age (Habib et al. 2021). Maternal gestational diabetes (streptozotocin administered to pregnant dames on day 0 of gestation or maternal glucose infusion to generate hyperglycemia on days 12–16 of gestation) was associated with persistent adult

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hypertension starting at 6 months of age in rat offspring with reduced nephron number and kidney function (Amri et al. 1999; Nehiri et al. 2008). Maternal generalized undernutrition (50% reduction compared to controls) from gestational days 15–21 in Sprague-Dawley rats increased offspring blood pressure that was associated with lower kidney weight and nephron number at 16 weeks of age (Chou et al. 2008). Rats exposed to maternal low-protein diet (18, 12, 9, and 6% by weight) prior to mating and throughout pregnancy developed hypertension by 9 weeks of age that persisted throughout adulthood in offspring exposed to more severe protein restriction (9 and 6%) (Langley and Jackson 1994). However, adult female rats exposed to uteroplacental insufficiency and postnatal restricted lactation developed reduced glomeruli number and impaired kidney function but did not develop hypertension at 8, 12, or 20 weeks, nor at 18 months (Moritz et al. 2009). Models of antenatal glucocorticoid exposure attempt to mimic growth restriction due to increased fetal exposure to maternal endogenous glucocorticoids as well as exogenous glucocorticoids administered to pregnant women at risk of preterm birth to facilitate fetal lung maturity. In an antenatal dexamethasone-induced growth restriction model, exposed rats demonstrated 60% fewer glomeruli at 20 postnatal days and developed hypertension at 60 postnatal days that was associated with worse kidney function and greater sodium retention compared to controls (Benediktsson et al. 1993). A series of elegant experiments in sheep illuminated the effects of clinically relevant antenatal doses of glucocorticoids administered at approximately 80 days’ gestation, the point at which ovine fetal kidney development reaches the peak of nephrogenesis; offspring in this model did not develop growth restriction. Maternal antenatal betamethasone exposure was associated with 25% fewer glomeruli at term in lambs exposed as fetuses independent of fetal kidney weight (Zhang et al. 2010). Exposed sheep offspring had higher blood pressure as 6-month-old lambs and as adults, but their kidney function did not differ from that of controls until older adulthood and then only in males (Tang et al.

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2010; Zhang et al. 2010). Interestingly, the higher blood pressure did not correlate with nephron reduction severity (Zhang et al. 2010). The cause(s) and timing of fetal growth restriction have differential effects on nephron endowment and the subsequent programming of hypertension. For example, in a study comparing two growth restriction models in rats, maternal antenatal betamethasone administered at gestational days 17–19 led to a severe nephron deficit associated with kidney disease and hypertension, while maternal antenatal low-protein diet (9% fed throughout gestation) was associated with only a modestly lower nephron number in male offspring without corresponding sustained changes in kidney function or blood pressure (Boubred et al. 2016). In a study comparing two sheep models of intrauterine growth restriction, natural twinning was associated with reduced nephron number in the offspring while late-gestational umbilico-placental embolization was not (Mitchell et al. 2004). Similarly, it can be difficult to elucidate the relative contributions of antenatal glucocorticoid exposure versus induced maternal undernutrition. Various antenatal nutritional abnormalities can program effects in the offspring – diets with high or low sodium, fat, vitamins and minerals, and water, though the relative contributions among them are not well defined (Battista et al. 2002). Furthermore, type of low-protein diet – relative to carbohydrate and fat source and composition – likely has differential programming effects. Over the past twenty years, numerous antenatal programming models have consistently demonstrated that altered kidney development could increase blood pressure through a variety of complex mechanisms – and during discrete gestational periods – that reduced nephron endowment or kidney dysfunction cannot sufficiently explain (Baum 2018; Langley-Evans et al. 1996b; Ortiz et al. 2003). A rat model of intrauterine growth restriction via late-gestation placental insufficiency induced by clipping the aorta and bilateral uterine artery branches was associated with low birth weight and persistent hypertension in the offspring that developed by 4 weeks of age with no apparent effect on kidney function (Alexander 2003). Both maternal antenatal low-protein diet

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(9%) throughout pregnancy and dexamethasone administration at gestational days 13 and 14 in rats programmed hypertension without reducing nephron number or kidney size (Ortiz et al. 2003; Pladys et al. 2005). Uterine artery ligationinduced placental insufficiency in a guinea pig model was associated with higher glomerular collagen deposition and reduced tubular spacing despite no difference in glomerular number at 8 weeks of age (Briscoe et al. 2004). The preponderance of evidence supports the fact that renal mechanisms other than low nephron number are just as important to hypertension programming.

Kidney-Altered Sodium Transport Altered kidney sodium handling plays a major role in hypertension development generally, and this is no exception in models of programmed hypertension. Male Wistar Kyoto rats exposed to uteroplacental insufficiency via bilateral uterine vessel ligation at gestational day 18 demonstrated enhanced salt-induced hypertension at 23 weeks of age compared to controls and had corresponding blunted natriuretic responses (Gallo et al. 2018). Programmed alterations at all levels of renal tubular sodium transport are likely major contributors to hypertension development and progression (Baum 2018). Once filtered through the glomerulus, sodium resorption throughout the nephron occurs predominantly through the major apical transporters – the Na/H exchanger in the proximal tubule, the Na/K/2Cl cotransporter in the thick ascending limb, the Na/Cl cotransporter in the distal convoluted tubule, and the epithelial Na channel in the collecting duct. The low intracellular sodium concentration generated by the basolateral Na/KATPase drives each of these transporters. Various preclinical models of programming have demonstrated direct or indirect evidence of alterations in each of these transporters, as well as the Na/KATPase, though significant heterogeneity in the data exists based on the specific animal model and exposure type and timing. Some models have shown that transporter alterations precede increases in blood pressure, while others occur concurrent with or after hypertension development. Many

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but not all models have demonstrated salt-sensitive blood pressure; programmed hypertension can develop through a variety of salt-resistant mechanisms. Maternal antenatal dexamethasone exposure (from gestational day 13 to term) and maternal low-protein diet (9%) in rats were associated with increased renal Na/K-ATPase mRNA and protein expression (Bertram et al. 2001; Wyrwoll et al. 2007). However, this is not a universal observation; sheep exposed to maternal antenatal betamethasone at gestational days 80 and 81 demonstrated no differences in renal cortical Na/KATPase mRNA or protein expression compared to controls at 81 and 135 days’ gestation (Massmann et al. 2006). While these studies did not directly measure Na/K-ATPase activity, increased expression can be consistent with the potential for enhanced sodium reabsorption. Alternatively, rats exposed to a maternal 20% high-fat diet throughout pregnancy and during suckling demonstrated reduced Na/K-ATPase activity at 6 months of age (Armitage et al. 2005). Maternal antenatal dexamethasone administration in rats and sheep was associated with increased Na/H exchanger activity as well as mRNA and protein abundance in the offspring, leading to increased volume absorption in the proximal convoluted tubule and subsequent hypertension (Dagan et al. 2008; Massmann et al. 2006). Basal and angiotensin II-stimulated sodium uptake in isolated proximal tubule cells was greater in adult male sheep offspring exposed to maternal antenatal betamethasone compared to controls and exposed female sheep, in part associated with greater Na/H exchanger protein expression and suppressed nitric oxide production (Su et al. 2015). In rat offspring that developed hypertension, both maternal low-protein diet (6%), provided from gestational day 12 to birth, and maternal dexamethasone, administered between gestational days 15 and 18, were associated with greater medullary Na/K/ 2Cl cotransporter activity at 6 weeks of age (Dagan et al. 2008). While 6% low-protein diet was associated with higher medullary, but not cortical, Na/K/2Cl cotransporter protein abundance at 6 weeks in this rat model, the greater protein abundance was not detectable until 8 weeks in those

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exposed to maternal dexamethasone (Dagan et al. 2008). Interestingly, Dagan et al. found no differences in Na/K/2Cl cotransporter protein in younger offspring who had not yet developed hypertension. Maternal low-protein diet (6%) starting at day 12 of gestation in rats was associated with greater renal mRNA expression and protein abundance of the Na/K/2Cl cotransporter and Na/Cl cotransporter in the offspring at 4 weeks of age that preceded hypertension development (Manning et al. 2002). Further, maternal antenatal dexamethasone exposure was associated with increased Na/Cl cotransporter protein abundance in rat offspring at 8 weeks of age (Dagan et al. 2008). While many of these studies did not demonstrate programmed changes to the epithelial Na channel, maternal protein restriction to 6% during pregnancy has been shown to indirectly enhance epithelial Na channel activity in vivo and to increase sodium transport in the cortical collecting ducts in vitro (Cheng et al. 2012). Furthermore, at three months of age rat offspring exposed to maternal gestational diabetes (maternal streptozotocin or glucose administration during pregnancy) developed salt-sensitive blood pressure responses that preceded hypertension development at 6 months of age, at which point the offspring demonstrated greater cortical β and γ epithelial Na channel subunit and Na/K-ATPase expression (Nehiri et al. 2008). In addition to sodium transporters, strong evidence exists for programming of sodiumregulating hormonal pathways, including aldosterone and the mineralocorticoid receptor. Maternal protein restriction to 6% during the latter half of pregnancy in rats was associated with persistently higher circulating aldosterone concentrations in growth-restricted offspring at 1, 2, and 4 months of age (Vehaskari et al. 2001). Baboon offspring exposed to maternal preeclampsia induced by uterine artery ligation at 5 weeks’ gestation – in the absence of fetal growth restriction – had a greater blood pressure response to high-salt diet compared to unexposed controls at approximately 3 years of age (Yeung et al. 2018). Interestingly, offspring who consumed a 6% high-salt diet for 2 weeks demonstrated reduced serum aldosterone from days 1–7 in both the exposed and control

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groups, but only exposed offspring developed a rebound increase in aldosterone during week 2 of the high-salt diet. These findings occurred despite no difference in plasma renin activity, sodium excretion, or kidney function. Growth restriction due to bilateral uterine artery ligation at gestational day 19 in the rat was associated with decreased renal mRNA and protein expression of the glucocorticoid receptor and mineralocorticoid receptor at day 21 of life (Baserga et al. 2007). Alternatively, maternal antenatal dexamethasone exposure from gestational day 13 to term and maternal 9% protein restriction throughout pregnancy in rats were associated with increased renal glucocorticoid receptor expression in the fetal and neonatal period as well as in juveniles and adults and were associated with hypomethylation of the glucocorticoid receptor gene promoter at 6 months of age (Bertram et al. 2001; Wyrwoll et al. 2007). Importantly, growth restriction-induced programmed suppression of 11-β-hydroxysteroid dehydrogenase – the placental enzyme critical to metabolizing maternal endogenous corticosteroids to regulate fetal steroid exposure – may increase glucocorticoid sensitivity and decrease aldosterone selectivity in offspring in the short and long term (Baserga et al. 2007; Bertram et al. 2001; Wyrwoll et al. 2007). These experiments suggest that growth restriction may sensitize offspring to the deleterious programming effects of maternal glucocorticoid excess. Programming of signaling pathways more proximal to aldosterone (i.e., renin and angiotensin II) also contributes substantially to maladaptive sodium homeostasis.

Kidney-Altered Hormonal Pathways The renin-angiotensin-aldosterone system regulates sodium and volume homeostasis, blood pressure, and inflammation and fibrosis, as demonstrated in many studies. In addition to the angiotensinconverting enzyme/angiotensin II pathway, substantial data exist on programmed alterations to the angiotensin-converting enzyme 2/angiotensin-(1–7) pathway and to some extent additional

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renin-angiotensin-aldosterone system pathways, reviewed recently by South et al. (South et al. 2019c). The majority of the pathways of the reninangiotensin-aldosterone system are highly expressed in the kidneys and to some extent in most cardiovascular tissues. In particular, programmed alterations that upregulate the angiotensin II pathway and/or downregulate the angiotensin(1–7) pathway can contribute to hypertension development (Sehgal et al. 2020). However, the relative contributions of these pathways – or their combined additive or multiplicative effects – remain to be defined. Early work demonstrated that antenatal exposures such as exogenous cortisol infused in fetal lambs at approximately 94 days’ gestation led to alterations in the fetal renin-angiotensin-aldosterone system including enhanced renin responsiveness (Carbone et al. 1995). Decreased fetal renal perfusion pressure at approximately 134 days’ gestation in ovine fetuses was associated with alterations to circulatory renin and prorenin concentrations in the fetus (Rosnes et al. 1998). Maternal antenatal betamethasone at 80 days’ gestation was associated with sustained lower plasma angiotensin II concentrations in exposed sheep as adults (Kantorowicz et al. 2008). Adult sheep exposed to antenatal betamethasone that developed hypertension also demonstrated greater serum angiotensin-converting enzyme activity and maximum velocity but lower serum angiotensin-converting enzyme 2 activity and maximum velocity (Shaltout et al. 2009). An early maternal antenatal protein restriction model (18, 12, 9, and 6%) in the rat demonstrated greater pulmonary angiotensin-converting enzyme activity in all of the exposed groups compared to controls (Langley and Jackson 1994) and, in the 6% restriction group, lower plasma renin activity and greater aldosterone concentrations that developed during the prehypertension stage and which persisted after overt hypertension developed (Vehaskari et al. 2001). Rats exposed to maternal high-salt diet (8%) from gestational days 3–21 demonstrated changes to DNA methylation in the cardiac angiotensin II type 1 receptor at 21 days’ gestation (Ding et al. 2010). However, many models, particularly those of various maternal nutritional deficits, have not

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demonstrated consistent findings pertaining to renin-angiotensin-aldosterone system programming. Some have observed greater plasma renin activity without a corresponding change in circulating aldosterone (Battista et al. 2002; Pladys et al. 2005), while others observed greater plasma angiotensin-converting enzyme activity but no differences in plasma angiotensin II levels or plasma renin activity (Langley-Evans and Jackson 1995). Still others have found higher plasma angiotensin I and angiotensin II concentrations compared to controls (Wang et al. 2015). More proximally, maternal antenatal dexamethasone exposure during embryonic days 14–21 in rats led to higher angiotensinogen hepatic mRNA expression and plasma concentration in female adult offspring (O’Regan et al. 2004). Angiotensin-converting enzyme inhibition with captopril normalized blood pressure in rat offspring exposed to maternal antenatal 9% low-protein diet, suggesting that, regardless of the specific programmed alterations, renin-angiotensin-aldosterone system dysregulation likely plays an important role (Langley-Evans and Jackson 1995). There has been mounting evidence of sustained programmed effects on many of the pathways of the intrarenal renin-angiotensin-aldosterone system in preclinical models and clinical studies (Shaltout et al. 2009; South et al. 2018). In addition to mediating programmed reductions in nephron number and subsequent kidney dysfunction, intrarenal renin-angiotensin-aldosterone system programming contributes to hypertension development. Reduced fetal kidney perfusion alters renal renin and prorenin concentration and expression in ovine fetuses (Rosnes et al. 1998). Maternal antenatal betamethasone exposure was associated with altered renin expression, processing, and secretion in exposed sheep acutely in the fetal period and in later adulthood (Kantorowicz et al. 2008). In utero betamethasone exposure in sheep was also associated with enhanced renal vascular and sodium excretion responsiveness to angiotensin II infusion in males at 1 year of age that was mediated preferentially by the angiotensin II type 1 receptor compared to the type 2 receptor (Contag et al. 2010).

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Rat offspring with programmed hypertension due to maternal antenatal 8.5% protein restriction demonstrated lower renal renin and renal angiotensin II content as newborn pups (Woods et al. 2001). Maternal antenatal high-fat diet (20%) led to lower renal renin activity in offspring at age 6 months (Armitage et al. 2005). At 16 weeks of age, adult male rats exposed to maternal lategestation undernutrition (50% reduction compared to control diet) demonstrated higher blood pressure associated with higher renal angiotensin II and chymase immunoreactivity compared to controls (Chou et al. 2008). Placental insufficiency programs alterations to renal renin expression directly related to renal prostaglandin synthase expression. Renal angiotensin II type 1 and type 2 receptor protein content was low initially and later increased above control levels at day 28 of life prior to hypertension development in rats exposed to maternal antenatal 6% protein restriction (Vehaskari et al. 2004). Maternal antenatal betamethasone was associated with lower ovine fetal renal angiotensin II type 2 receptor expression acutely and at term despite a lack of growth restriction (Massmann et al. 2006). Adult sheep exposed to maternal antenatal betamethasone demonstrated lower proximal tubular angiotensin-converting enzyme 2 activity and expression (Shaltout et al. 2009). Antenatal betamethasone-exposed adult male sheep that underwent uninephrectomy at 12–18 months of age demonstrated impaired renal responses to intrarenal angiotensin-(1–7) infusion, including decreased sodium excretion and possible angiotensin II type 1 receptor activation (Bi et al. 2013). In support of the notion that timing of programming events is critical, late-gestation growth restriction via umbilico-placental embolization in sheep did not affect fetal ovine renal renin, angiotensinogen, or angiotensin II type 1 or type 2 receptor mRNA expression despite a lower nephron number (Zohdi et al. 2007). Maternal dexamethasone administration in rats at gestational days 15 and 18 was associated with greater urinary angiotensin II/creatinine levels in offspring at 4 weeks (prior to hypertension development) and 8 weeks of age (after hypertension development), independent of plasma renin

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activity, plasma angiotensin II, and renal angiotensin II content (Dagan et al. 2010). Components of the renin-angiotensin-aldosterone system measured in the urine are generally acceptable markers of the intrarenal renin-angiotensin-aldosterone system. Maternal 6% protein restriction from gestational day 12 to birth in rats was associated with higher urinary angiotensinogen/creatinine and urinary angiotensin II/creatinine in offspring at 6 months of age that treatment with enalapril starting at 3 weeks of age improved (Mansuri et al. 2015). At 20 weeks of age, growth-restricted rat offspring exposed to maternal bilateral uterine artery ligation at 18 days’ gestation had higher urinary angiotensinogen/creatinine levels that preceded proteinuria development at 32 weeks of age, at which time they also demonstrated higher renal angiotensinogen expression (Murano et al. 2015). Adult sheep offspring exposed to maternal betamethasone at 80 days’ gestation had reduced angiotensinconverting enzyme 2 activity in the urine, mirroring findings in serum and the proximal tubules (Shaltout et al. 2009). Such programmed alterations to intrarenal renin-angiotensin-aldosterone system expression and activity – in particular the angiotensinconverting enzyme/angiotensin II pathway – may lead to sustained increases in sodium absorption throughout the nephron, including that mediated via renal sympathetic nerve regulation of proximal tubule sodium transport. Maternal 50% global nutrition restriction until 77 days’ gestation in sheep was associated with higher angiotensin II type 1 receptor expression in the kidneys of neonatal sheep that paralleled greater glucocorticoid mRNA expression and lower 11-β-hydroxysteroid dehydrogenase mRNA expression (Whorwood et al. 2001). Finally, the renin-angiotensin-aldosterone system is recognized as having an immunomodulatory role in numerous cardiovascular tissues in regulating inflammation and progression to fibrosis. Increased renal oxidative stress and inflammatory cell infiltration precede development of programmed hypertension in adult rat offspring exposed to maternal 6% low-protein diet at gestational day 12 (Stewart et al. 2005). In addition to

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higher blood pressure and greater blood pressure variability, adult sheep offspring exposed to maternal betamethasone at gestational day 80 demonstrated enhanced reactive oxygen species production but blunted nitric oxide production mediated via enhanced angiotensin II type 1 receptor and attenuated Mas receptor function (Gwathmey et al. 2011). Betamethasone exposure in this sheep model was associated with enhanced renal susceptibility to oxidative stress induced by angiotensin II predominantly in the proximal tubule (Bi et al. 2014). The majority of studies have confirmed that programmed upregulation of the angiotensin II pathway, at the expense of angiotensin-(1–7) pathway downregulation, particularly in the kidneys, is a major contributor to programmed hypertension (South et al. 2019c). It is likely that alterations to the renin-angiotensin-aldosterone system, especially that in circulation, are in part secondary physiological responses to changes in sodium reabsorption leading to alterations in extracellular volume (Vehaskari et al. 2001). As with other mechanisms, timing and severity of programming events are important. The fetal renin-angiotensin-aldosterone system response to stimuli, especially renin, varies throughout gestation in numerous animal models, including concentration and activity in circulation and in tissues. Endogenous or exogenous (maternal or placental) angiotensin II feedback modulates the synthesis, content, and secretory sensitivity to stimuli in the majority of renin-angiotensin-aldosterone system components. A lack of a concurrent comprehensive assessment of the major renin-angiotensin-aldosterone system pathways – proximally and distally, systemic and intrarenal – and use of appropriate, well-validated collection, processing, and analytic methods has limited the majority of studies to date (Chappell et al. 2021; Sparks et al. 2020).

Kidney-Altered Neural Tone Programmed central activation of neurohormonal pathways is associated with increased renal sympathetic nerve activity that, coupled with

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programmed enhanced renal nerve responsiveness, may lead to elevated sodium reabsorption. This renal neurohormonal programming mirrors that seen more centrally in programmed autonomic dysfunction with a shift toward sympathetic tone and away from vagal tone. The renal nerves regulate fetal active renin secretion and mRNA responsiveness to beta-adrenergic stimulation at term, though not the response to reduced kidney perfusion (Draper et al. 2000). In uninephrectomized male Wistar rats, renal nerve stimulation increased proximal tubular sodium reabsorption via the Na/H exchanger and in part mediated through the angiotensin II type 1 receptor as well as increased renal angiotensinogen and angiotensin II content (Pontes et al. 2015). In exposed adult male rats, maternal protein restriction to 6% throughout pregnancy starting at gestational day 12 was associated with exaggerated increases in blood pressure and renal sympathetic activity in response to decerebrated physical stress that occurred via the exercise pressor reflex despite no difference in baseline renal sympathetic tone (Mizuno et al. 2013). In this model, treatment with enalapril at age 3 weeks attenuated contraction and stretch-induced increases in blood pressure and renal sympathetic activity, despite no differences in baseline plasma angiotensin II (Mizuno et al. 2014). However, while rat offspring exposed to maternal 6% protein restriction in the latter half of pregnancy demonstrated higher urinary angiotensinogen/creatinine levels, renal denervation at 3 months of age did not change urinary angiotensinogen/creatinine values. A series of elegant experiments by several groups contributed important information about these mechanisms. In an attenuated uterine perfusion model of growth restriction-induced hypertension, bilateral renal denervation reduced blood pressure by 20 mmHg in rats with hypertension compared to sham and prevented hypertension development (Alexander et al. 2005). In maternal antenatal dexamethasone-induced programmed hypertension in the rat (administered gestational days 15–18), bilateral renal denervation at 6 weeks of age normalized blood pressure at 8 weeks of age related to normalized renal protein expression of the type 3 Na/H exchanger,

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Na/K/2Cl cotransporter, and Na/Cl cotransporter (Dagan et al. 2008). Adult rat offspring exposed to maternal 6% low-protein diet throughout pregnancy had blunted renal natriuretic and kaliuretic responses to cerebral epinephrine microinjections that were localized preferentially to more proximal portions of the tubule (Cardoso et al. 2019). In the same rat model, bilateral renal denervation at 8 weeks of age decreased blood pressure by increasing sodium excretion measured at 8 weeks of age (Custódio et al. 2017). Various hormonal programming mechanisms can then feedback to stimulate central nervous systemmediated increased renal sympathetic outflow that may be independent of postganglionic activation.

Brain The autonomic nervous system exerts important direct control over blood pressure and cardiovascular function through control of cardiac output and systemic vascular resistance. It also exerts indirect control by means of kidney-mediated blood volume modulation. Numerous central programming mechanisms have been described that are thought to result in altered brain structure, biochemical pathways, and autonomic cardiovascular control. These include increased catecholamine production, baroreflex-altered sensitivity and “reset,” and increased sympathetic but decreased parasympathetic activity. These central alterations have been observed both in basal tone and in response to various stimuli across the age spectrum. In a rat fetal growth restriction model induced by maternal low-salt diet (0.03% given during the last week of pregnancy), offspring had higher blood pressure from 5 to 12 weeks of age (Battista et al. 2002). Exposed male and female offspring in this model had greater brain size relative to body size compared to controls as fetuses but lower brain size by weight at 1 week of age and as adults at 12 weeks of age (Battista et al. 2002). Maternal 9% low-protein diet throughout pregnancy in rats was associated with offspring cortical capillary density and mean capillary length at day 21 of

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gestation but not as adults (Pladys et al. 2005). Maternal undernutrition with 40% restricted diet throughout pregnancy in rats was associated with hypertension in male offspring at approximately 40 days of age and tonic reciprocal sympathetic excitatory interactions between the paraventricular nucleus and the locus coeruleus (Cayupe et al. 2021). Maternal betamethasone exposure at 80 days’ gestation in sheep was associated with altered cerebral vascular tone and reactivity in vitro in middle cerebral arteries from adult female offspring at 18 months of age (Eckman et al. 2010). Maternal 9% low-protein diet throughout pregnancy in Wistar rats led to blunted nitric oxide-dependent vasorelaxation in the cerebral vasculature independent of endothelial nitric oxide synthase expression and activity in vitro in cortical microvessels from adult offspring (Lamireau et al. 2002). Prenatal hypoxia to 10.5% oxygen from gestational days 5–21 in rats was associated with in vitro enhanced angiotensin II-induced middle cerebral artery vasoconstriction mediated by both angiotensin II type 1 and type 2 receptors and blunted endothelial nitric oxide synthase-mediated vasodilatation in offspring at 5 months of age (Tang et al. 2017). In a sheep model, newborn lambs exposed to maternal earlygestation dexamethasone demonstrated an altered baroreflex response between 10 and 14 days of life associated with increased sympathetic activity and abnormal nitric oxide-mediated compensatory vasodilatation prior to hypertension development (Segar et al. 2006). Young female sheep (approximately 42 days old) exposed to maternal betamethasone at 80 days’ gestation developed enhanced sympathetic and hypothalamicpituitary-adrenal axis responsiveness to sodium nitroprusside-induced blood pressure reduction (Shaltout et al. 2011). These changes occurred in part due to impaired evoked baroreflex sensitivity and preceded overt basal blood pressure differences compared to controls. Higher blood pressure was noted in rat weanling offspring exposed to maternal 9% protein restriction before and during pregnancy, along with changes to the proximal hypothalamicpituitary-adrenal axis including alterations to hippocampal glucocorticoid receptor number and

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binding capacity (Langley-Evans et al. 1996a). Adult female, but not male, rat offspring exposed to maternal high-salt diet (8%) before conception, throughout pregnancy, during lactation, and for 1 week after weaning demonstrated enhanced blood pressure and heart rate responses to stress despite a lack of growth restriction and normal resting blood pressure (Porter et al. 2007). This was associated with increased corticotropinreleasing hormone mRNA expression in the hypothalamic paraventricular nucleus. However, numerous studies have demonstrated normal glucocorticoid levels at baseline and in response to stress in exposed offspring; thus, hypothalamicpituitary-adrenal axis programming, in isolation, may not be a predominant mechanism (LangleyEvans et al. 1996a). The hypothalamic-pituitary-adrenal axis has been shown to regulate the renin-angiotensin-aldosterone system, at least, in part. Such regulation includes the late-gestation cortisol surge affecting angiotensin II type 1 receptor expression in the kidneys and left ventricle (Chen et al. 2005). There is increasingly strong evidence that programmed alterations to the local brain reninangiotensin-aldosterone system contribute to hypertension. At 6 months of age, maternal antenatal betamethasone-exposed female sheep offspring had lower angiotensin-(1–7) concentrations in the cerebral spinal fluid compared to controls that were associated with enhanced activity of an angiotensin-(1–7)-specific neuropeptidase (Marshall et al. 2013b). In a mouse model of maternal low-protein diet (50% reduction) during the latter half of gestation, brains of exposed fetuses demonstrated greater expression of angiotensinogen and angiotensinconverting enzyme mRNA but lower angiotensin II type 2 receptor mRNA and protein expression (Goyal et al. 2010). These authors also observed hypomethylation of the angiotensin-converting enzyme gene promotor region and greater expression of several microRNAs that regulate angiotensin-converting enzyme mRNA translation, further demonstrating a programmed epigenetic mechanism (Goyal et al. 2010). In sheep, maternal administration of dexamethasone in early gestation was associated with fetal hypothalamic angiotensinogen expression and medulla oblongata

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angiotensin II type 1 receptor expression at 130 days’ gestation, and that persisted at 7 years of age (Dodic et al. 2002a). In sheep, maternal cortisol exposure was associated with increased hippocampal mRNA expression of angiotensinogen, angiotensin II type 1 receptor, mineralocorticoid receptor, and glucocorticoid receptor at 130 days’ gestation in the offspring, but these changes were not detectable at 2 months of age (Dodic et al. 2002b). In a fetal sheep model, mild chronic hypoxemia in utero (intratracheal nitrogen to reduce fetal brachial artery PaO2 by 25%) was associated with altered fetal baroreflex sensitivity and enhanced neurologic and cardiovascular responsiveness to umbilical cord occlusion associated with increased binding to the angiotensin II type 1 and type 2 receptors and the Mas receptor in the nucleus tractus solitarius and dorsal motor nucleus of the vagus (Pulgar et al. 2009). Maternal antenatal betamethasone-exposed adolescent and adult sheep had lower Mas receptor protein expression as well as greater angiotensin II content relative to both angiotensin-(1–7) and angiotensin I in the dorsal medulla, an area of the brain critical to baroreflex sensitivity control (Marshall et al. 2013a). Female lambs and male adult rams exposed to maternal antenatal betamethasone at 80 weeks’ gestation demonstrated reduced heart rate variability and increased blood pressure variability compared to controls (Shaltout et al. 2010). These findings were reversed by angiotensin II type 1 receptor blockade and enhanced by Mas receptor blockade, suggesting that the renin-angiotensin-aldosterone system mediates this central cardiovascular dysregulation (Shaltout et al. 2010). Maternal 9% low-protein diet throughout pregnancy in rats was associated with increased angiotensin II receptor expression in cardiovascular regulatory regions of the brain in exposed offspring, and intracerebroventricular angiotensin-converting enzyme inhibitor administration abolished hypertension in programmed offspring (Pladys et al. 2004). All told, the preponderance of evidence confirms that programmed alterations to the brain renin-angiotensin-aldosterone system upregulate the angiotensin II pathway and downregulate the angiotensin-(1–7) pathway – in addition to

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alternative pathways – and thus contribute to hypertension pathophysiology (South et al. 2019c). As with the kidneys, proximal neurohormonal cardiovascular control also regulates vascular function and tone.

Vasculature Clinical and preclinical studies have demonstrated that many antenatal programming mechanisms lead to maladaptive alterations to vascular structure and function in a variety of vascular bed types (conductance vs. resistance vs. capillary) and tissues. Even subtle vascular abnormalities appear to contribute to subsequent development of precocious arteriosclerosis and hypertension, supporting the concept of antenatal programming as a major contributor to premature vascular aging. Identified vascular alterations include impaired endothelium-dependent and endothelium-independent vasodilatation, enhanced vasoconstrictor response, increased myogenic tone, impaired smooth muscle relaxation, increased vessel wall thickening and remodeling with increased collagen content relative to elastin and increases in profibrotic matrix metalloproteinases, impaired angiogenesis, altered capillary rarefaction, and changes in the renin-angiotensinaldosterone system, endothelial nitric oxide synthase, and prostaglandin expression and activity. However, heterogeneity between different models and mechanisms has been observed, and it is often unclear whether vascular changes truly precede development of hypertension or are a consequence of such. A maternal undernutrition-programming model in sheep, characterized by a 15% reduction in global nutrition during the first 70 days of gestation, demonstrated increased fetal femoral artery resistance at baseline and in response to hypoxia (Hawkins et al. 2000). Uteroplacental insufficiency induced via bilateral uterine artery ligation at 18 days of gestation in Wistar Kyoto rats was associated with greater mesenteric arterial stiffness in exposed male offspring fed a postnatal 8% highsalt diet from 20 to 26 weeks of age (Gallo et al. 2018). Sprague-Dawley rats exposed to a model of preeclampsia, reduced uteroplacental perfusion

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pressure, developed transgenerational programmed hypertension and vascular hyperresponsiveness in a sex-dependent manner (Anderson et al. 2006). In this model, clips were applied to the lower abdominal aorta distal to the renal arteries but proximal to the iliac bifurcation as well as branches to the bilateral ovarian arteries in pregnant rats at gestational day 14 to induce an approximately 40% reduction in uteroplacental perfusion pressure. Mild chronic hypoxemia induced by late-gestation intratracheal nitrogen administration for 5 days in pregnant ewes increased responsiveness of femoral arteries to phenylephrine in vitro that were obtained from the exposed ovine fetuses (Kim et al. 2005). Maternal 70% global dietary restriction from gestational days 0–18 in a murine model demonstrated abnormal vascular sympathetic responsiveness in femoral arteries harvested from pups at age 20 days but not consistently in femoral arteries harvested from exposed adult mice at age 200 days (Ozaki et al. 2001). In another murine model comparing two programming mechanisms, both maternal low-protein diet (50% reduction) through 19 days’ gestation and late-gestation dexamethasone (days 10–18) were associated with impaired aortic vasodilatation in vitro from aortic rings obtained from offspring at approximately 6 months of age, though blood pressure did not differ between experimental groups or controls (Roghair et al. 2007). In a rat model of hypoxia-induced growth restriction, characterized by maternal 11.5% oxygen exposure from days 15 to 21 of pregnancy, impaired nitric oxide-mediated flow dilation was observed in young adult (4 months) and aging (12 months) male and female offspring (Morton et al. 2011). Adult sheep offspring that were exposed to maternal antenatal betamethasone at 80 days’ gestation showed brachial arterial endothelial dysfunction mediated by altered endothelin-1 receptor function both in the endothelium and in smooth muscle in vitro from samples obtained at 1–2 years of age (Pulgar and Figueroa 2006). Further, maternal antenatal betamethasone-exposed adult sheep in this model had an enhanced increase in blood pressure and vascular resistance in vivo in response to endothelin-1 infusion via the endothelin-1

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receptor (Lee et al. 2013). Rat offspring exposed to maternal protein restriction (9% throughout pregnancy) demonstrated lower vasodilatorinduced arterial relaxation in vitro – both dependent and independent of the endothelium – in mesenteric artery samples obtained at day of life 87 and 164, despite no between-group differences in contractile responsiveness (Brawley et al. 2003). Maternal undernutrition (50% global nutrition reduction) throughout pregnancy in Wistar rats was associated with abnormal endotheliumdependent vascular reactivity in the aorta in vitro in aortic ring samples obtained from offspring at 14 weeks of age (Franco Mdo et al. 2002). Adult rat offspring exposed to maternal high-fat diet (20–25.7%) before and during pregnancy as well as during lactation had blunted endotheliumdependent small artery relaxation in vitro associated with altered arterial fatty acid content in branches of the femoral artery isolated in female and male offspring at 80, 160, and 180 days of age (Khan et al. 2003). Maternal prepregnancy diabetes (streptozotocin-induced prior to conception) superimposed on a maternal 30% high-fat diet before, during, and after pregnancy in rats magnified this programmed abnormal vascular responsiveness in vitro in isolated femoral arteries from exposed 15-day-old offspring (Koukkou et al. 1998). Interestingly, there is evidence for postnatal adaptive responses in offspring who continue to consume a high-fat diet after birth, at least in rats (Khan et al. 2004). Reduced uteroplacental perfusion pressure at 14 days’ gestation in rats was associated with sustained reductions in endothelium-dependent aortic relaxation in vitro and hypertension starting at 4 weeks of age in exposed male offspring, effects that a postnatal 8% high-salt diet provided to offspring enhanced (Payne et al. 2003). Offspring of female rats fed a 20% high-fat diet before and during pregnancy as well as throughout lactation developed increased aortic stiffness in an organ bath preparation in vitro at 6 months of age that was associated with impaired endothelium-mediated vasodilation, decreased aortic endothelial cell volume, and decreased smooth muscle cell number (Armitage et al. 2005). Placental insufficiency-induced growth

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restriction via midgestation uterine artery ligation in guinea pigs was associated with decreased aortic luminal area and increased tunica media thickness (due to an increase in medial elastic layers) in vitro in tissue obtained from exposed offspring at 8 weeks of age (Briscoe et al. 2004). Maternal 9% low-protein diet throughout pregnancy in a rat model was not associated with arterial remodeling in offspring with programmed hypertension but did induce microvascular alterations including reduced muscle capillary and arteriole density as well as reduced aortic angiogenesis in vitro from samples obtained at 7 and 28 days of life in exposed offspring (Pladys et al. 2005). Maternal food restriction to 50% at gestational day 10 to birth in Sprague-Dawley rats was associated with impaired angiogenesis in renal and mesenteric microvessels as well as in the aorta in vitro in specimens isolated from exposed offspring at day of life 1 and in adulthood (Khorram et al. 2007). In offspring exposed to maternal 9% low-protein diet throughout pregnancy in rats, the lipid peroxidation inhibitor lazaroid, administered to pregnant dams throughout pregnancy, prevented increased blood pressure and prevented enhanced angiotensin II-mediated vasoconstriction in vivo in 10–12 week-old male offspring as well as prevented impaired vasodilatation and microvascular rarefaction ex vivo in carotid artery rings obtained from adult offspring (Cambonie et al. 2007). Early-gestation dexamethasone exposure in sheep was associated with increased coronary artery vasoconstriction and attenuated vasodilation in vitro in coronary arteries isolated from 1-week-old offspring (Roghair et al. 2005). Thus, programming events can induce many vascular alterations, many of which are connected to related programmed changes to the heart.

Heart Numerous programming exposures alter cardiac structure and function directly and secondarily via mechanisms such as increased afterload due to elevated arterial stiffness. In sheep at 9 weeks of age, when the full complement of cardiomyocytes is established, offspring with low birth weight due

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to natural twinning had reduced absolute heart size and cardiomyocyte number in the left ventricle, though there were no differences relative to body or heart weight and no blood pressure differences (Stacy et al. 2009). Growth restriction induced by maternal 9% low-protein diet prior to and throughout pregnancy in rats was associated with smaller absolute heart size and cardiomyocyte number in offspring at birth (Corstius et al. 2005). However, there was no difference in heart size relative to body weight, and the authors did not present data on cardiomyocyte number relative to heart weight. Placental insufficiency in a sheep model consisting of prepregnancy uterine caruncle removal was associated with reduced nutrient delivery to the fetal heart assessed in vivo with microspheres, despite no change in blood flow, leading to adverse fetal cardiomyocyte development (Poudel et al. 2014). Cardiac programming models in ewes who underwent prepregnancy uterine caruncle removal also have demonstrated decreased cardiomyocyte number and an increase in mononucleated cardiomyocytes that are larger relative to heart weight that may persist into young adulthood (Morrison et al. 2007). Depending on the model, differential cardiac alterations have been observed – maternal hypoxia (12% oxygen from 35–65 gestational days), but not maternal nutrition restriction (18–33% reduction in food intake from gestational day 35 to birth), in guinea pigs was associated with reduced cardiomyocyte number in adolescent offspring (Botting et al. 2018). Furthermore, maternal 8.7% low-protein diet during pregnancy and lactation in rats did not affect postproliferative total cardiomyocyte number at 4 weeks of age (Lim et al. 2010). In addition to increased blood pressure in adult offspring, low-protein dietinduced growth restriction in rats was associated with increased cardiac fibrosis and decreased cardiomyocyte number as well as increased cardiomyocyte degeneration in the offspring at 24 weeks of life (Amer et al. 2017). Uteroplacental insufficiency in late gestation induced by bilateral uterine vessel ligation in rats was associated with left ventricular hypertrophy at 35 days of age and increased blood pressure at

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6 months of age, but not cardiomyocyte number, in affected male offspring in the first and second generations, providing further evidence for transgenerational programming (Master et al. 2014). Fetal growth restriction induced by a maternal low-salt diet (0.03%) given during the last week of pregnancy in rats was associated with increased blood pressure from 5 to 12 weeks of age as well as increased ventricular size relative to body size in the fetuses (Battista et al. 2002). However, cardiac ventricle weights were lower in the exposed offspring at 1 week of age and, in males, in adulthood (Battista et al. 2002). Male rats exposed to uteroplacental insufficiency via bilateral uterine vessel ligation at 18 days’ gestation developed greater left ventricular mass relative to total heart weight (but not body weight) and increased left ventricular angiotensin II type 1 receptor mRNA expression at age 6 months after developing higher blood pressure at 10 weeks of age (Wlodek et al. 2008). Eight-week-old guinea pig offspring with growth restriction due to uterine artery ligation around gestational day 28 had higher left ventricular interstitial collagen content, myofiber width, and wall thickness per luminal area with lower luminal area (Briscoe et al. 2004). Rat offspring exposed to maternal low-protein diet (8.7%) throughout pregnancy and lactation had blunted cardiac output and stroke volume responses to beta-adrenergic activation in vivo at 14 weeks of age compared to controls despite no differences in mean arterial pressure or ventricular contractility (Zohdi et al. 2011). The offspring also demonstrated increased vascular resistance and afterload. Antenatal chronic hypoxia (12% oxygen during gestational days 10–20) was associated with enhanced cardiac contractility ex vivo with reduced left ventricular epicardial and endocardial capillary density related to lower endothelial nitric oxide protein expression in vitro in 10-week-old rat offspring (Hauton and Ousley 2009). Adult female rat offspring exposed to maternal 8.7% low-protein diet during pregnancy and lactation demonstrated greater left ventricular interstitial fibrosis (Lim et al. 2006). In a rat model comparing maternal antenatal hypoxia (12% oxygen) to 40% global nutrient restriction at gestational day 15, both groups demonstrated fibrotic

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cardiac remodeling and impaired postischemia/ reperfusion recovery at age 7 months compared to controls, but the hypoxia-exposed group developed these findings by age 4 months compared to both controls and the nutrient-restricted group (Xu et al. 2006). Many preclinical models have demonstrated intracardiac renin-angiotensin-aldosterone system programming. Rat fetuses exposed to maternal high-salt diet of 8% from gestational days 3–21 demonstrated higher cardiac angiotensin II content and angiotensin II-mediated increased S-phase driven by greater angiotensin II type 1 receptor mRNA and protein expression (Ding et al. 2010). They also demonstrated abnormal myofibrils and mitochondria, and the greater expression of cardiac angiotensin II type 1 receptor protein persisted into adulthood. Twenty-one-day-old lambs with growth restriction due to prepregnancy uterine caruncle removal demonstrated higher cardiac angiotensinconverting enzyme 2 mRNA expression and lower angiotensin II type 1 receptor protein expression (Wang et al. 2015). While the significance of this finding is unknown, it could represent a compensatory response to counteract deleterious programming effects (South et al. 2019c), given that at this young age, the lambs lacked cardiac fibrosis or evidence for autophagy. In this same sheep model, growth restriction was associated with greater left ventricular size at 21 days of life, alterations to cardiac insulin and glucose-signaling pathways, and overall abnormal energy metabolism (Wang et al. 2013). Further investigation into precise cardiac programming mechanisms is warranted, especially in relation to programming in other cardiovascular tissues and in conjunction with clinical data.

Potential Sex Differences Preclinical models in several species and clinical studies have often demonstrated conflicting results regarding sex differences in programmed hypertension (Langley-Evans et al. 1996b; Langley and Jackson 1994; South et al. 2018; South et al. 2019a). However, much heterogeneity is related to study design choices and a historic lack of

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interest in directly comparing sex differences. Studies currently are pursuing this line of inquiry, particularly regarding sex differences in reninangiotensin-aldosterone system programming. Adult female rat offspring exposed to maternal 8.5% low-protein diet throughout gestation had normal blood pressure and normal glomeruli number and volume compared to controls, while exposed adult male rat offspring had hypertension and abnormal glomeruli (lower glomerular filtration rate and glomerular number with higher glomerular volume) compared to controls (Woods et al. 2001). In adult sheep exposed to maternal antenatal betamethasone at 80 gestational days, male but not female offspring had lower kidney function and a blunted response to an acute salt load, despite no sex differences in blood pressure (Zhang et al. 2010). Furthermore, adult male but not female sheep offspring exposed to maternal antenatal betamethasone had enhanced proximal tubular sodium uptake (Su et al. 2015). In a rat model of growth restriction and programmed hypertension due to reduced uterine perfusion at gestational day 14 by clipping the aorta and uterine artery branches, male but not female offspring demonstrated increased renal oxidative stress-mediated hypertension at 16 weeks of age (Ojeda et al. 2012). Similarly, male but not female adult sheep offspring exposed to maternal antenatal betamethasone at gestational day 80 (in the absence of growth restriction) demonstrated enhanced renal susceptibility to angiotensin II-mediated oxidative stress (Bi et al. 2014). In a maternal antenatal dexamethasone model in guinea pigs (administered on gestational days 40–41, 50–51, and 60–61), male and female offspring had differential proximal hypothalamicpituitary-adrenal axis-programmed effects at approximately day of life 70 and 80 (Liu et al. 2001). Male rat offspring exposed to maternal modest (70%) global undernutrition during gestational days 0–18 developed hypertension sooner than exposed female offspring (60 days vs. 100 days), and only exposed males had abnormal femoral artery vasoconstrictor responsiveness in vitro compared to controls at 100 and 200 days of life (Ozaki et al. 2001). However, while several models have demonstrated apparent protective effects in exposed

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females compared to males, many others have demonstrated programmed hypertension in females that occurs via different mechanisms compared to males. Male but not female rat offspring exposed to maternal 8.5% protein restriction throughout gestation demonstrated lower renal renin activity and angiotensin II content as pups at day of life 1 compared to controls (Woods et al. 2005), while female but not male rats exposed to antenatal dexamethasone from gestational day 14 to 21 demonstrated higher plasma angiotensinogen concentration and plasma renin activity in adulthood (O’Regan et al. 2004). As with many preclinical models investigating sex differences, sex hormones are believed to play a critical role, though they are likely only one of several mechanisms involved. Furthermore, in many models the sex-specific programming effects occurred at different times across the life course in males compared to females. Female rat offspring exposed to reduced uterine profusioninduced growth restriction at gestational day 14 demonstrated an enhanced hypertensive response to acute angiotensin II infusion compared to controls at 16 weeks of age that ovariectomy at age 10 weeks magnified, whereas there were no differences among any of the groups in response to phenylephrine (Ojeda et al. 2011). Testosterone was shown to possibly modulate programmed hypertension and enhance reninangiotensin-aldosterone system activity in adult male rat offspring exposed to placental insufficiency-induced growth restriction (Ojeda et al. 2007). Maternal antenatal betamethasoneexposed sheep offspring demonstrated differential responses to angiotensin-(1–7) infusion by age: Males had an enhanced natriuretic response compared to females as adolescents at approximately 6 months of age, while females developed the enhanced natriuretic response compared to males as adults at 1.5 years of age (Tang et al. 2010). Programming event severity and timing may influence whether sex differences occur. Finally, additional programming factors that occur postnatally, such as increased adipose tissue in the offspring, likely mediates in part sex differences in programmed hypertension. There is increasing interest in elucidating how an antenatally exposed

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female’s risk of programmed hypertension changes when she herself becomes pregnant.

Conclusion Hypertension contributes in a major way to cardiovascular disease morbidity and mortality. While the exact mechanisms contributing to hypertension development remain undefined, there is robust evidence for the developmental origins of hypertension. Preclinical data demonstrate evidence for a variety of important mechanisms – maternal-fetal vascular supply and nutrient delivery, maternal stress, inflammation, and exogenous exposures – as discussed. Fetal developmental plasticity, wherein short-term alterations to an adverse environment have long-term health consequences, can lead to programmed alterations in tissue structure and function, cell type, number, and distribution, blood supply, and expression and function of numerous enzymes, substrates, and receptors, all of which likely contribute to hypertension development. Programming events appear to occur throughout the antenatal period, as well as preconception and postnatally, and from a variety of sources – maternal, paternal, fetal, and environmental. However, much data are inconsistent, in part due to heterogeneity among studies, including species, genetic background, programming model, timing and duration of exposure, and whether multiple exposures are present (Vehaskari and Woods 2005). The interplay among antenatal exposures likely leads to cumulative additive and multiplicative effects to program hypertension. There likely exist windows of time in which one could mitigate antenatal programmed hypertension via primordial and primary preventative strategies as well as initiating earlier treatment. Several intriguing pathways are emerging or are being refined, including leptin, klotho, fibroblast growth factor 23, uric acid, and APOL1, as well as transgenerational epigenetic programming (Reidy et al. 2018; South et al. 2020; Wang et al. 2015). The interplay of preconception and antenatal exposures with postnatal exposures across the life course is of increasing importance and may

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sensitize individuals to “second hits” such as obesity and future pregnancy in female offspring (South et al. 2018, South et al. 2019a). It should be noted that programming of additional conditions such as diabetes, kidney disease, and lung disease also contributes to hypertension risk. In sum, antenatal events can set the stage for the development of hypertension years or decades before it would otherwise develop.

Cross-References ▶ Cardiovascular Influences on Blood Pressure ▶ Early Vascular Aging in Pediatric Hypertension Patients ▶ Endothelial Dysfunction and Vascular Remodeling in Hypertension ▶ Epidemiology of Hypertension and Cardiovascular Disease in Children and Adolescents ▶ Familial Aggregation of Blood Pressure and the Heritability of Hypertension ▶ Hypertensive Models and Their Relevance to Pediatric Hypertension ▶ Neonatal and Infant Hypertension ▶ Neurohumoral and Autonomic Regulation of Blood Pressure ▶ Salt Sensitivity in Childhood Hypertension

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157 Stewart T, Jung FF, Manning J, Vehaskari VM (2005) Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension. Kidney Int 68(5):2180–2188. https://doi.org/10.1111/ j.1523-1755.2005.00674.x Su Y, Bi J, Pulgar VM, Figueroa J, Chappell M, Rose JC (2015) Antenatal glucocorticoid treatment alters Na+ uptake in renal proximal tubule cells from adult offspring in a sex-specific manner. Am J Physiol Renal Physiol 308(11):F1268–F1275. https://doi.org/10. 1152/ajprenal.00047.2015 Tang L, Bi J, Valego N, Carey L, Figueroa J, Chappell M, Rose JC (2010) Prenatal betamethasone exposure alters renal function in immature sheep: sex differences in effects. Am J Physiol Regul Integr Comp Physiol 299(3):R793–R803. https://doi.org/10.1152/ajpregu. 00590.2009 Tang J, Li N, Chen X, Gao Q, Zhou X, Zhang Y, Liu B, Sun M, Xu Z (2017) Prenatal hypoxia induced dysfunction in cerebral arteries of offspring rats. J Am Heart Assoc 6(10). https://doi.org/10.1161/jaha.117. 006630 Textor J, van der Zander B, Gilthorpe MK, Liskiewicz M, Ellison GTH (2016) Robust causal inference using directed acyclic graphs: the R package ‘dagitty’. Int J Epidemiol 45(6):1887–1894. https://doi.org/10. 1093/ije/dyw341 Vehaskari VM, Woods LL (2005) Prenatal programming of hypertension: lessons from experimental models. J Am Soc Nephrol 16(9):2545–2556. https://doi.org/10. 1681/asn.2005030300 Vehaskari VM, Aviles DH, Manning J (2001) Prenatal programming of adult hypertension in the rat. Kidney Int 59(1):238–245. https://doi.org/10.1046/j.15231755.2001.00484.x Vehaskari VM, Stewart T, Lafont D, Soyez C, Seth D, Manning J (2004) Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol Renal Physiol 287(2): F262–F267. https://doi.org/10.1152/ajprenal.00055. 2004 Wang KC, Lim CH, McMillen IC, Duffield JA, Brooks DA, Morrison JL (2013) Alteration of cardiac glucose metabolism in association to low birth weight: experimental evidence in lambs with left ventricular hypertrophy. Metabolism 62(11):1662–1672. https://doi.org/ 10.1016/j.metabol.2013.06.013 Wang KC, Brooks DA, Summers-Pearce B, Bobrovskaya L, Tosh DN, Duffield JA, Botting KJ, Zhang S, Caroline McMillen I, Morrison JL (2015) Low birth weight activates the renin-angiotensin system, but limits cardiac angiogenesis in early postnatal life. Physiol Rep 3(2). https://doi.org/10.14814/phy2. 12270 Whorwood CB, Firth KM, Budge H, Symonds ME (2001) Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin ii

158 receptor in neonatal sheep. Endocrinology 142(7): 2854–2864. https://doi.org/10.1210/endo.142.7.8264 Wlodek ME, Westcott K, Siebel AL, Owens JA, Moritz KM (2008) Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats. Kidney Int 74(2):187–195. https://doi.org/ 10.1038/ki.2008.153 Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R (2001) Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res 49(4):460–467. https://doi.org/ 10.1203/00006450-200104000-00005 Woods LL, Ingelfinger JR, Rasch R (2005) Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol 289(4):R1131–R1136. https://doi.org/10.1152/ ajpregu.00037.2003 Wyrwoll CS, Mark PJ, Waddell BJ (2007) Developmental programming of renal glucocorticoid sensitivity and the renin-angiotensin system. Hypertension 50(3):579–584. https://doi.org/10.1161/hypertensionaha.107.091603 Xu Y, Williams SJ, O’Brien D, Davidge ST (2006) Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. FASEB J 20(8):1251–1253. https://doi.org/10.1096/fj.05-4917fje

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Familial Aggregation of Blood Pressure and the Heritability of Hypertension Sujane Kandasamy and Rahul Chanchlani

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Evidence of Familial Aggregation of Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Age Dependency of Genetic Effects on BP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Findings of GWAS Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Familial Aggregation of BP and Its Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Future Research Opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Abstract

Within industrialized, high-income nations, it is evident that a pediatric obesity epidemic has taken place. Part of the transition to an increasing number of children and youth with obesity is elevated blood pressure (BP) (hypertension) during childhood and

S. Kandasamy Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, ON, Canada e-mail: [email protected] R. Chanchlani (*) Division of Nephrology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_14

youth. Hypertension is a well-recognized risk factor for chronic kidney and cardiovascular diseases. Childhood hypertension, which is associated with adulthood hypertension and lifelong cardiovascular events, has been increasing over the past two decades. The tracking of BP from childhood to adulthood has led to a renewed focus on etiology, identification, prevention, diagnosis, and management. Within this emerging public health challenge, it is also acknowledged that genetic factors play an important role in a person’s propensity to develop hypertension. This chapter reviews the history and evolution of the field through the exploration of the familial aggregation of childhood BP. We will consider the genetic factors

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related to the familial aggregation of childhood BP as well as maternal factors, birth weight, obesity, health behavior influences, and socio-economic features. We conclude the chapter with a brief discussion of promising future research directions for assessing the genetic risk of BP in childhood. Keywords

Birth weight · Blood pressure · BP regulation across the life-course · Dietary patterning and quality · Dietary potassium intake · Dietary sodium intake · Familial aggregation · Fetal programming · Genetic influence · Genes · Genetic and environmental factors · Genetic markers · Genome wide association studies (GWAS) · Health behavior influences · Heritability estimates · Heritable component · Obesity · Phenotyping processes · Quantitative genetic methods · Risk factors · Single nucleotide polymorphisms (SNPs) · Twin studies

Introduction The concerns about elevated BP in children has been a topic of interest among pediatricians and health researchers, especially with the rising incidence of hypertension that has been documented over the past two decades (DinDzietham et al. 2007; Muntner et al. 2004). A recent meta-analysis of 47 studies reported a pooled global prevalence of 4.0% and 9.7% of hypertension and pre-hypertension among children, respectively (Song et al. 2019). This increasing prevalence has been attributed to the global epidemic of obesity and increase in sedentary behaviors and physical inactivity (Song et al. 2019; Flynn 2013). Importantly, childhood BP remains the strongest indicator for adult hypertension and is associated with an increased risk for cardiovascular disease (CVD) in adulthood (Lauer and Clarke 1989; Bao et al. 1995; Berenson et al. 1998; Chen and Wang 2008). See ▶ Chap. 20, “Epidemiology of Hypertension and Cardiovascular Disease in Children and Adolescents.”

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Evidence of Familial Aggregation of Blood Pressure In the early-to-mid 1900s, clinical case reports developed largely anecdotal evidence for the familial aggregation of elevated BP. By the 1960s/1970s, family and sibling studies illustrated that the familial tendency to high and low BP is established early in life (e.g., Zinner et al. 1971). However, whether shared genes or shared environment was causing this BP aggregation within families remained unknown. This knowledge gap led to more specific research approaches such as twin studies, which helped to focus this question (see Wang and Snieder 2013 for a summary on twin studies). Interestingly, most twin studies found strong evidence for genetic influence (most heritability estimates range from 50–60%) but little evidence for influence of shared family environment on childhood BP. It is estimated that around 50% of the variance in BP is attributed to genetic factors (Wang and Snieder 2013). Even twin studies with large sample sizes and enough power to detect moderate influences of shared environment only found a contribution around 10–20%. Part of the explanation for this is related to the concept that there is a heritable component to seemingly environmental features (e.g., salt intake, physical activity), making it largely conclusive that the familial aggregation of BP is mostly due to genetic (rather than environmental) factors. See ▶ Chap. 7, “Monogenic and Polygenic Contributions to Hypertension.” Furthermore, sex differences in heritability estimates for males and females are very similar; and, despite the lack of a large data pool, there is no current evidence for large differences in BP heritability among different ethnic groups (Snieder et al. 2003), although the specific genes responsible may differ. With some research demonstrating that ambulatory BP estimates are better predictors of cardiovascular outcomes than clinic BP (Verdecchia 2000), more recently conducted twin studies have incorporated large sample sizes and ambulatory BP monitoring (Vinck et al. 2001; Fagard et al. 2003; Kupper et al. 2005). Results from these studies demonstrated that (1) heritabilities were similar for resting and ambulatory (daytime and nighttime) systolic and diastolic BP (around 50%)

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(Vinck et al. 2001); (2) results did not differ between monochorionic and dichorionic twins (Fagard et al. 2003); (3) there is a common genetic influence on day and nighttime BP (systolic and diastolic), with heritability ranging from 44–63% (Kupper et al. 2005).

Age Dependency of Genetic Effects on BP Interestingly, the relation between age and BP level changes is not linear. In fact, different genetic and environmental factors influence BP at different periods across the life-course. This age-dependency has been investigated via cross-sectional twin studies, family studies, and longitudinal studies. Wang and Snieder 2013 provided an overview of these studies, revealing a case for age-dependent trends in heritability and that different genes influence BP in childhood and adulthood. They denoted heritability estimates from family studies ranging between 0.17 and 0.45 for systolic BP and from 0.15 and 0.52 for diastolic BP (Iselius et al. 1983; Tambs et al. 1992; Hunt et al. 1989), while estimates from twin studies were typically in the 0.40–0.70 range for both systolic and diastolic BP (Evans et al. 2003). Most longitudinal studies have confirmed that the same group of genes underlie BP regulation across the life-course, with some data suggesting that there are gene products newly expressed during specific phases of adolescence (e.g., 14–18 years of age) (Kupper et al. 2006). Given such differences, researchers should exercise caution when pooling adolescent and adult participants in large association studies.

Findings of GWAS Studies An advancement within this field is the advent of genome-wide association studies (GWAS), which permit the exploration of mutual relations between genetic factors and BP variations early in life when environmental influences remain minimal. GWAS are used in genetic research to uncover associations between genetic variations and specific diseases of interest. In simple terms, the method scans the genomes of a wide array of individuals seeking

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genetic markers that are predictive of a disease. For example, an early GWAS on BP was conducted by the International Consortium for BP (ICBP) and included 20,000 adults of European ancestry and found 29 loci for adult BP, thereby explaining 0.9% of variance in systolic and diastolic BP (Ehret et al. 2011). This set of results prompted research exploring whether these genetic variants were also associated with BP levels in children and adolescents (e.g., Juhola et al. 2012). Findings confirmed that the genetic markers were (1) associated with BP levels in children; and (2) were predictive of hypertension development in young adults. For example, Oikonen et al. 2011 used data from the Cardiovascular Risk in Young Finns Cohort to determine that the genetic risk score of previously identified 13 Single Nucleotide Polymorphisms (SNPs) were significantly associated with BP levels from childhood to adulthood and at different age groups in childhood. It was also noted that this can explain 0.1–0.2% of the variation in BP. Using the same cohort data, Juhola et al. 2012 demonstrated that 29 loci was an independent predictor for the development of adult hypertension at age 24–45 years. Within the context of these 29 loci, Howe et al. 2013 pooled data from the Avon Longitudinal Study of Parents and Children and the Western Australian Pregnancy Cohort, determining that the genetic risk score was significantly associated with systolic BP at 6 years of age, but showed weak evidence with age. The genetic risk score explained 0.06% of the variation in systolic BP at 6–7 years and 0.23% at 17-years. It is possible that future studies using newly developed quantitative genetic methods (e.g., Genome-wide Complex Trait Analysis) can help answer more detailed genetic research questions regarding the familial aggregation of childhood BP. See Fig. 1 for a summary of these advancements.

Familial Aggregation of BP and Its Associations Lifestyle and genetic factors influence the variation in BP (Havlik et al. 1979; Whelton et al. 2002). Wang et al. (2015) provide a detailed summary of the recent landscape of familial aggregation and

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Fig. 1 Timeline summarizing the history and evolution of the study of familial aggregation of BP in childhood

childhood blood pressure. Building on these works, we aim to review the intersections across the life-course (maternal/gestational influences, birth weight, health behaviors, and socio-economic

influences) as it pertains to childhood/adolescence and compare their heritability (see Fig. 2). Maternal and Gestational Influences: Key maternal and gestational influences on the

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Fig. 2 Venn diagram highlighting the key influences of BP and predisposition related to genetic factors

development of childhood blood pressure have been investigated for ties to genetics, familial life-style factors, and fetal programming consequences. The BP levels of offspring born to mothers with maternal obesity are higher than those of children born to mothers of normal weight (Tan et al. 2015), and maternal hypertension and pre-eclampsia are also known to be positively associated with offspring BP (systolic and diastolic) (Vatten et al. 2003; Geelhoed et al. 2010). Exposures such as smoking during pregnancy have been determined to show a link with offspring systolic and diastolic BP (Högberg et al. 2012), although direct effects have not been confirmed. Prenatal exposure to particulate matter from air pollution has also been linked to hypertension and preterm birth (which are factors linked to higher offspring BP) (Xue et al. 2018; Trasande et al. 2016). There is also some evidence for gestational timing of fetal exposure to particulate

matter in air pollution. For example, Nitrogen Dioxide (NO2) exposure during the third trimester (compared to first and second) was associated with greater DNA methylation and higher BP levels in a pre-adolescent population (Breton et al. 2016). Additional prospective studies are required to further explore the role of other chemicals (e.g., phthalates, bisphenols) on offspring growth and cardio-metabolic outcomes (Philips et al. 2017) and whether there are genetic predispositions to such influences. See ▶ Chap. 8, “Antenatal Programming of Blood Pressure.” Birth Weight: The adverse implications of birth weight across the life-course are related to metabolic and cardiovascular outcomes. For example, high BP in childhood is related to low birth weight, early year developmental catch-up, and adverse intrauterine conditions (e.g., pre-eclampsia) (Lurbe et al. 2009; Bonamy et al. 2012; Wolfenstetter et al. 2012). With an overall heritability of 20–30%

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(Mook-Kanamori et al. 2012; Dubois et al. 2007; Clausson et al. 2000), the birth weight influences of genetic factors are autonomous of the intrauterine environment (e.g., paternal anthropometric features). Wang et al. (2015) explore some examples of twin studies that have demonstrated these genetic variants and shared environmental features that are linked to low birth weight and high BP. Interestingly, recently published multi-ethnic GWAS data exploring birth weight report 60 loci where fetal genotype was associated with birth weight (Horikoshi et al. 2016). Strong genetic correlations were also demonstrated between birth weight and systolic BP and coronary artery disease, linking life-course associations between early growth phenotypes and adult cardiovascular disease to shared genetic factors (Horikoshi et al. 2016). Obesity: Across the life-course, BMI is one of the most important determinants of BP, suggesting that an increase in the prevalence of obesity is contributing to the rising BP cases recently documented within the pediatric population (Muntner et al. 2004). Family and twin studies have demonstrated that the relationship between BMI and BP is threaded together by shared genetic factors. For example, genetic factors modulating BMI account for 6% and 8% of the total variance of systolic BP in adult and pediatric populations, respectively (Schieken et al. 1992; Wu et al. 2011). Howe et al. (2013) described a genetic risk score comprised of 32 BMI loci identified in GWAS that were strongly associated with systolic BP both in children aged 6 and 17. As follow-up, a recent meta-analysis of 57,464 hypertensive cases and 41,256 controls, demonstrated that the first GWAS-identified obesity gene (FTO, located on chromosome 16) was significantly associated with hypertension (He et al. 2014). Man et al. (2020) recently reported a considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP, illustrating the role of pleiotropic genes (genes that exhibit multiple phenotypic expressions). It is recommended that future GWAS analyses aim to explore the specific genes that influence obesity indices and BP to disentangle their joint genetic backgrounds. Health Behavior Influences: Emerging findings indicate that in addition to obesity, factors

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such as diet, limited physical activity, excessive screen time, and sleep disorders are linked to elevated BP in children and adolescents (Falkner et al. 2010). Diet: Dietary patterning and quality related to high sodium intake, low potassium, and high sugar sweetened beverage (SSB) consumption have been associated with high BP in youth (Falkner and Lurbe 2020). A recent meta-analysis demonstrated a positive association between dietary sodium intake and BP in childhood via an increase of 0.8 mm Hg and 0.7 mm Hg increase in systolic and diastolic BP, respectively, with each additional 1 g of sodium intake per day (Leyvraz et al. 2018). Twin studies have observed strong genetic predispositions for sodium intake and salt habits with heritability ranging from 31–34%, after adjustment for other epidemiologic characteristics (Kho et al. 2013). Additional twin studies have denoted similar heritability ranging from 43% to 55% (Ge et al. 2009). An inverse relationship between potassium intake and BP is denoted in a longitudinal study exploring dietary potassium intake on blood pressure in adolescent girls (Buendia et al. 2015) and a cross-sectional analysis in youth aged 12–18 reported that a higher intake of sugar sweetened beverages was linked to higher BP levels (unmodified by presence or absence of obesity) (Nguyen et al. 2009), but we were not able to locate any studies exploring the genetic predispositions to these health behaviors. See ▶ Chap. 10, “The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation.” Sleep Patterns: Sleep disturbance, chronic sleep restriction, poor sleep quality, and sleeprelated conditions (e.g., sleep apnea, see ▶ Chap. 32, “Obstructive Sleep Apnea and Hypertension in Children”) are commonly overlooked risk factors of hypertension in children and adolescents (Navarro-Solera et al. 2015; Hannon et al. 2014; Rodriguez-Colon et al. 2015; Amin et al. 2004). Twin studies illustrate some of the genetic predispositions seen across the lifecourse, including shared underlying mechanisms altering between daytime and nighttime (Wang et al. 2009; Xu et al. 2015). It is hypothesized that this occurs via shifts in gene expression or the deliberate turning key genes on or off, but

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further research is needed to better understand these genetic factors and how they influence BP in children. Socio-economic Influences: Educational attainment is widely used as a surrogate measure for socio-economic status (SES) in various epidemiological studies. Within the CHARGE GeneLifestyle Interactions Working Group, de las Fuentes et al. (2021) performed a GWAS of systolic and diastolic BP, accounting for geneeducational attainment interactions. They identified 81 known and 18 novel BP loci, suggesting that educational attainment may play a role in the genetic architecture of BP. More studies using this approach may help to further our understanding of the possible heritability of SES and its relation to BP in childhood.

Future Research Opportunities Outlined by Wang and Snieder (2017) are four key future directions of genetic studies aiming to assess the risk of hypertension in childhood: (1) Applying adult BP GWAS findings to children (including re-evaluations of the influence of adult GWAS findings on childhood BP); (2) Expanding the sample size of BP GWAS in children; (3) Improving BP prediction using GWAS; (4) Use of improved phenotyping processes (i.e., the combination of multiple approaches to establish accurate phenotypes). With the advancements that have been made from BP GWAS of adult populations, we aim to strategically inch closer to hypertension prediction in early life. Furthermore, to help guide practices that are rooted in principles of equity, we need a concerted effort to explore these genetic predispositions within different ethnic populations, especially those who exhibit a higher prevalence of hypertension in childhood and those who have been historically isolated from clinical and genomic research. This way therapeutic approaches can be tailored to the specific needs of priority populations. More complex genetic analyses (e.g., genome-wide complex trait analysis) can also help elucidate rare variants with large effects, common variants with smaller effects, estimates of genomewide pleiotropy, and the contribution of new

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behavioral or SES-related risk factors (Wang et al. 2015). See section “Research in Pediatric Hypertension” for more details on hypertension research in pediatric hypertension; for example, ▶ Chap. 50, “Cohort Studies, Meta-analyses, and Clinical Trials in Childhood Hypertension.”

Conclusion It is well-known that familial aggregation of BP occurs early in life and is largely due to genetic factors. We highlighted certain key factors across the life-course as these relate to BP in children: the maternal environment, birth weight, obesity, health behaviors, and socio-economic factors and suggest opportunities for future research directions.

Cross-References ▶ Antenatal Programming of Blood Pressure ▶ Cohort Studies, Meta-analyses, and Clinical Trials in Childhood Hypertension ▶ Epidemiology of Hypertension and Cardiovascular Disease in Children and Adolescents ▶ Monogenic and Polygenic Contributions to Hypertension ▶ Obstructive Sleep Apnea and Hypertension in Children ▶ The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation

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S. Kandasamy and R. Chanchlani early genetic etiology of hypertension? Hypertension 3(2):262–269 Geelhoed JJ, Fraser A, Tilling K et al (2010) Preeclampsia and gestational hypertension are associated with childhood blood pressure independently of family adiposity measures: the Avon longitudinal study of parents and children. Circulation 122:1192–1199 Hannon TS, Tu W, Watson SE, Jalou H, Chakravorty S, Arslanian SA (2014) Morning blood pressure is associated with sleep quality in obese adolescents. J Pediatr 164:313–317 Havlik RJ, Garrison RJ, Feinleib M et al (1979) Blood pressure aggregation in families. Am J Epidemiol 110:304–312 He D, Fu M, Miao S, Hotta K, Chandak GR, Xi B (2014) FTO gene variant and risk of hypertension: a metaanalysis of 57,464 hypertensive cases and 41,256 controls. Metabolism 63:633–639 Högberg L, Cnattingius S, D’Onofrio BM, Lundholm C, Iliadou AN (2012) Effects of maternal smoking during pregnancy on offspring blood pressure in late adolescence. J Hypertens 30(4):693 Horikoshi M, Beaumont RN, Day FR et al (2016) Genomewide associations for birth weight and correlations with adult disease. Nature 538(7624):248–252 Howe LD, Parmar PG, Paternoster L et al (2013) Genetic influences on trajectories of systolic blood pressure across childhood and adolescence. Circ Cardiovasc Genet 6:608–614 Hunt SC, Hasstedt SJ, Kuida H, Stults BM, Hopkins PN, Williams RR (1989) Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol 129:625–38. Iselius L, Morton NE, Rao DC (1983) Family resemblance for blood pressure. Hum Hered 33:277–286 Juhola J, Oikonen M, Magnussen CG et al (2012) Childhood physical, environmental, and genetic predictors of adult hypertension: the cardiovascular risk in young Finns study. Circulation 126(4):402–409 Kho M, Lee JE, Song Y-M et al (2013) Genetic and environmental influences on sodium intake determined by using half-day urine samples: the healthy twin study. Am J Clin Nutr 98(6):1410–1416 Kupper N, Willemsen G, Riese H, Posthuma D, Boomsma DI, de Geus EJ (2005) Heritability of daytime ambulatory blood pressure in an extended twin design. Hypertension 45:80–85 Kupper N, Ge D, Treiber FA, Snieder H (2006) Emergence of novel genetic effects on blood pressure and hemodynamics in adolescence: the Georgia cardiovascular twin study. Hypertension 47:948–954 Lauer RM, Clarke WR (1989) Childhood risk factors for high adult blood pressure: the Muscatine study. Pediatrics 84(4):633–641 Leyvraz M, Chatelan A, da Costa BR et al (2018) Sodium intake and blood pressure in children and adolescents: a systematic review and meta-analysis of experimental

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The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation

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Dawn K. Wilson, Tyler C. McDaniel, and Sandra M. Coulon

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Dietary Sodium and Blood Pressure in Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Dietary Potassium and Blood Pressure in Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Nutritional Interventions and Blood Pressure in Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Nutrition and Dietary Adherence in Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Conclusions and Implications for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

Abstract

The prevalence of high blood pressure and cardiovascular risk has increased in youth, given increasing rates of overweight and obesity. Dietary electrolytes influence blood pressure (BP) mechanisms in youth, and previous research indicates that dietary sodium, potassium, and calcium have clinically important effects on

D. K. Wilson (*) · T. C. McDaniel Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA e-mail: [email protected]; [email protected] S. M. Coulon West Texas Veterans Healthcare System, Big Spring, TX, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_15

BP regulation. Electrolyte balance is essential for health, and the beneficial effects of decreasing sodium intake on BP in youth have been strongly supported. Though interventional studies demonstrate that reduced intake of sodium is beneficial for BP, it is not clear whether children and adolescents can adhere to long-term efforts to reduce sodium intake. There is a growing body of evidence that increased potassium and calcium intake also reduces the risk of high BP in youth, and studies suggest that some youth may be more likely to adhere to diets that emphasize adding foods (e.g., foods containing potassium and calcium) rather than eliminating foods as is the case with a reduced sodium diet. The purpose of this chapter is to summarize the nutritional electrolyte-related determinants of blood pressure in children and adolescents, specifically the roles of dietary sodium and 169

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potassium in regulating casual BP, BP reactivity, and circadian BP patterns in youth. Keywords

Electrolytes · Blood pressure · Children · Dietary sodium · Dietary potassium

Introduction Although the prevalence of hypertension (HTN) is relatively low during childhood and adolescence (Sinaiko et al. 1989), an estimated 2.6–3.4% of youth have hypertensive blood pressure (BP) levels, and 5.7–13.6% have prehypertensive BP levels (Ostchega et al. 2009). BP patterns tend to track from childhood to the third and fourth decades of life (Sinaiko et al. 1989), and elevated BP early in life has been associated with increased risk of cardiovascular and renal disease (Berenson et al. 1993). The prevalence of hypertension and, along with it, presumed cardiovascular risk have also increased, given growing rates of overweight and obesity among youth; for example, studies such as one by Obarzanek et al. showing that obese girls have six times the rate of HTN compared to nonobese girls (Obarzanek et al. 2010). Thus, there is a strong need for prevention programs to attempt to reduce these risks in youth (Berenson et al. 1993; Zhu et al. 2008). Modifying intake of dietary electrolytes such as sodium and/or potassium has been an effective approach to BP reduction in adults (Whelton et al. 1997), but there is less evidence for the benefit of this approach in children and adolescents (Sinaiko et al. 1993). Recommendations for the primary prevention of HTN from the American Heart Association, the American Academy of Family Physicians, and the National Heart, Lung, and Blood Institute (American Heart Association 2012, 2014) promote a population approach and an intensive strategy for targeting people at increased risk for developing HTN in early adulthood. Two of these approaches include reducing sodium intake and maintaining an adequate intake of potassium. Globally, sodium consumption among children

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and adolescents exceeds intake recommendations; packaged cereals and meat products, as well as “fast” foods contribute to the problem (Brown et al. 2009). HTN may be further prevented by addressing obesity through weight reduction programs that incorporate physical activity as regular aerobic activity and are strongly recommended as strategies to improve BP (Alpert and Wilson 1992; Sica and Wilson 2001; American Heart Association 2014). Identification of precursors or markers of HTN in youth is acknowledged as important for preventing the development of primary HTN. Two such markers include cardiovascular reactivity (CVR) and ambulatory BP profiles (Alpert and Wilson 1992; Sica and Wilson 2001). Cardiovascular reactivity is a measure of vasoconstriction in response to psychological or physical stressors. As a marker, high reactivity is a consequence of preexisting cardiovascular damage or of heightened sympathetic tone that results in vasoconstriction and/or excessive cardiac output. As a mechanism, hyperreactive BP peaks are proposed to contribute to arteriosclerosis and subsequent HTN by damaging the intimal layer of arteries. Although there is controversy about the predictive value of measured CVR, prospective studies have shown that increases in CVR in response to standardized mental stress are predictive of later development of primary HTN (Roemmich et al. 2007), although efforts to associate increased CVR with physiological correlates of HTN (i.e., left ventricular hypertrophy) have yielded mixed results (Alpert and Wilson 1992; Moseley and Linden 2006). Researchers have assessed the relation between adolescent dietary intake and clustering of cardiometabolic risk in 1369 girls using data from the National Heart, Lung, and Blood Institute Growth and Health Study (Moore et al. 2016). Youth were tracked until they were 17 years old, and findings showed that at the end of adolescence, 35% had developed evidence of at least two cardiometabolic risk factors, and 18% had at least three. Results revealed that adolescent girls who reported high intakes of dairy, fruits, and non-starchy vegetables were almost 50% less likely to have three or more cardiometabolic risk factors in late adolescence. Thus, the study

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The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation

highlights the potential benefits of healthy eating patterns in early adolescence which appear to influence later adolescence cardiometabolic risk. Ambulatory BP profiles serve as another marker and potential predictor or risk factor for HTN in youth. Ambulatory BP monitoring (APBM) is a method for assessing a person’s daily fluctuations in BP and for linking these fluctuations to factors associated with individual differences in BP responses to the natural environment. Previous research indicates that most people have lower BP values at nighttime during sleeping hours and higher BP values during waking hours (Sica and Wilson 2001). In healthy persons, average BP declines by 10–15% or more during sleeping hours. While this circadian rhythm is generally preserved in hypertensive patients, the 24-h BP profile is shifted upward throughout the 24-h period (Verdecchia et al. 1997). When BP does not decline by at least 10% from waking to sleeping, the circadian pattern is considered blunted, or “non-dipping,” and is associated with greater cardiovascular risk (Sica and Wilson 2001). For example, ambulatory BP non-dipping status is a risk factor for the development of end-organ disease in patients with primary HTN – non-dippers have been reported to suffer more frequent occurrences of stroke and left ventricular hypertrophy (LVH) (Devereux and Pickering 1991). Even among healthy AfricanAmerican adolescents, Wilson et al. found that there is a 30% prevalence rate of non-dipping status (Wilson et al. 1996; Wilson et al. 1999c), and other investigators have shown that racial differences in sodium excretion may be due in part to renal retention of potassium (Palacios et al. 2010). These findings have led to investigation of electrolytes in the diet that may influence the ambulatory BP pattern in youth. Previous research has shown that dietary intake of electrolytes such as sodium, potassium, and calcium significantly affects BP in adults, especially in industrialized countries (Espeland et al. 2002). Electrolytes are positively and negatively charged ions that moderate the conduction of electrical signals between cells and influence homeostasis within the body (Allison 2004). Appropriate electrolyte balance (i.e., balance of

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positively and negatively charged conductive ions) is essential for health (Espeland et al. 2002). Previous studies indicate that environmental and genetic factors can influence BP responses in children (Ge et al. 2009; Tobin et al. 2008). Some children as young as 0–3 years of age may already be at higher risk for future cardiovascular complications because their sodium handling is aberrant (Guerra et al. 1997), and stress-induced excretion is a heritable phenotype which differentially affects African-Americans as compared to Caucasians (Ge et al. 2009). Other investigators have demonstrated that salutary changes in dietary electrolytes instituted in the first two decades of life can reduce BP and cardiovascular risk across the lifespan (Couch et al. 2008). The beneficial effects of decreasing sodium intake on BP have stronger support than the effects of increasing potassium, and few studies have actually evaluated the influence of potassium on BP levels in youth (Simons-Morton and Obarzanek 1997). We will now summarize the dietary electrolyterelated determinants of BP in children and adolescents. In particular, we will focus on the role of dietary sodium and potassium in regulating casual BP, BP reactivity, and circadian BP patterns in youth. We will also note the role of calcium intake on BP, as several investigators have demonstrated protective effects of calcium supplementation on BP (van Mierlo et al. 2006) and in youth (SimonsMorton et al. 1997).

Dietary Sodium and Blood Pressure in Youth Previous research has indicated that casual BP level is important in understanding the influence of genetic, environmental, and nutritional factors on the progression and development of HTN in children and young adults. In a national study which included a meta-analysis of 1658 youth (ages 4–18 years), He and MacGregor showed a significant association between sodium intake and systolic BP after adjusting for age, sex, body mass index (BMI), and dietary potassium intake (He and MacGregor 2006). Additionally, Yang et al. (2012) assessed the association between

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normal sodium intake and blood pressure in 6235 children and adolescents aged 8–18 years (51% male) taking part in the National Health and Nutrition Evaluation Survey (2003–2008) and revealed that sodium intake was positively associated with systolic BP levels and with risk for HTN. Further, they found that this relation was stronger in overweight or obese youth. The magnitude of the association was similar to that observed in a meta-analysis that evaluated the effects of sodium reduction on BP responses in youth (SimonsMorton and Obarzanek 1997) in which 25 observational studies that had examined the association between sodium intake and casual BP in children and adolescents were included. Eight of those studies used self-reported measures of dietary intake, and 17 used urinary sodium excretion as a surrogate for sodium intake. Two-thirds (67%) of the studies that included urine collections and controlled for other factors (e.g., age, BMI, weight) in the analysis found a significant positive association with casual BP levels. Three of the four studies that relied on self-reported measures of dietary intake and that controlled for other variables found significant positive associations between dietary sodium and casual systolic BP, diastolic BP, or both. More recently, a systematic review of both experimental and observational studies (n ¼ 6572 adolescents) showed that for each additional gram of sodium consumed daily, there was an increase of approximately 1 mm Hg in SBM and DBP (Leyvraz et al. 2018). Taken together, the studies included in these various meta-analyses provide support for a role of sodium intake on BP regulation in children and adolescents. Thus, interventions that reduce the dietary intake of sodium may be beneficial, although it is not clear whether children and adolescents can adhere to recommendations to reduce sodium intake for the long term. Prior research shows that people at risk for cardiovascular disease such as AfricanAmericans, hypertensive patients, and persons with a positive family history of HTN are a priori more likely to be salt sensitive, i.e., to have an increase in BP in response to high sodium intake (Falkner et al. 1986). Wilson et al. (1999a) examined the prevalence of salt sensitivity in

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normotensive African-American adolescents and characterized 22% of healthy normotensive African-American adolescents as salt sensitive based on their results, which employed definitions established in the adult literature (Sullivan and Ratts 1988). Falkner et al. have also shown that salt-sensitive adolescents with positive family history of HTN had greater increases in BP with salt loading than did adolescents who either were salt resistant or had a negative family history of HTN (Falkner et al. 1986). In another study by Palacios et al., African-American girls showed greater sodium retention in response to a low sodium diet (57 mmol/day) than Caucasian girls. In all, these data suggest that differences in sodium handling may contribute to underlying racial differences in susceptibility to the development of HTN (Palacios et al. 2004). A recent review on salt sensitivity and BP in childhood and adolescence also provided evidence that obesity, low birth weight, diabetes, chronic kidney disease, and race/ethnicity were all risk factors associated with greater salt sensitivity (Hanevold 2021). Several investigators have also examined the relation between salt sensitivity and ambulatory BP profiles in children and adolescents who are normotensive. Wilson et al. (1999b) examined ABPM patterns in normotensive African-American adolescents and found that a significantly greater percentage of salt-sensitive adolescents were classified as non-dippers (BP that did not drop from when awake to when asleep) according to mean BP (5% African-American; >11% Hispanic race T2D ¼ >20% Caucasian; >30% African-American; >14% Hispanic; >12% native American Mean BP (mmHg) ¼ 108/68

Participants’ diets were analyzed using a self-report food frequency questionnaire from which a DASH concurrence score was calculated

In youth with T1D, adherence to DASH was inversely associated with HTN, where as in youth with T2D adherence to the DASH diet was not associated with reductions in the risk of HTN

(continued)

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Table 2 (continued) Authors Mu et al. (2009) People’s republic of China

Intervention Three-group RCT Duration ¼ 3 years/ group Low sodium diet (LS; n ¼ 110) Health behavior education given until salt intake decreased to 50–100 mmol per person Potassium þ calcium capsule (K þ ca; n ¼ 101) families given supplement and asked to eat as usual Control (CTL; n ¼ 114) families asked to eat as usual

Sample baseline demographics N ¼ 325 (F ¼ 152, M ¼ 173) Chinese adolescents from Northwest China with SBP >90th percentile by age and sex Mean age (year) ¼ 20  3.5 Race ¼ 100% Chinese Mean BP (mmHg) ¼ 122/75 (LS); 124/75 (K þ Ca); 124/77 (CTL)

Compliance 24-h UNa: LS achieve 50 mmol/day and the K þ Ca group was compliant

Findings SBP decreased on average by 5.9 mmHg, and DBP decreased 2.8 mmHg in the K þ Ca group. In the LS group, SBP decreased by 5.8 mmHg and DBP decreased by 1.0 mmHg

BMI body mass index, BP blood pressure, CT controlled trial, not randomized, CTL control, DBP diastolic blood pressure, F female, M male, HTN hypertension, LS low sodium diet, MBP mean blood pressure, RCT randomized controlled trial, SBP systolic blood pressure, UNa urinary sodium

reported that youth with type 1 diabetes who adhered to the DASH diet had lower BPs, independent of demographic, clinical, and behavioral characteristics (Gunther et al. 2009). In contrast, Günther et al. did not find that adherence to the DASH diet was associated with such reductions in the risk of hypertension among youth with type 2 diabetes. Thus, the DASH diet may be a promising approach for improving cardiovascular risk factors such as elevated BP in some youth. Further research is needed to better determine the overall rate of compliance with the DASH diet relative to other approaches to reducing sodium intake and/or increasing potassium intake. Some evidence suggests that dietary electrolyte intake plays an influential role in circulatory responses to stress. Falkner et al. (1981) conducted a number of investigations to assess how altering dietary sodium affects CVR. In one small study, they evaluated 15 normotensive adolescent girls for 2 weeks, at rest and during mental arithmetic exercises and before and after adding

10 g of sodium to their diet. Those girls with a positive family history of primary HTN showed an increase in resting baseline and stress BP levels. Those girls with a negative family history did not. These findings have been replicated in young adults (Falkner and Kushner 1990). However, for those young adults with a positive family history of primary HTN, changes from baseline (not from resting) to stress were similar before and after salt loading, with no increase seen due to sodium loading. Sorof et al. (1997) examined whether CVR was inversely related to the dietary intake of potassium in 39 children (17 Caucasian and 22 African-American). At baseline, the 24-h urinary potassium/creatinine ratio varied inversely with diastolic CVR in Caucasian children with a positive family history of HTN; however, CVR was not attenuated by potassium supplementation (1.5 mmol/kg/day of potassium citrate) compared to placebo. The urinary potassium/creatinine ratio was higher in Caucasian children

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than African-American children; dietary potassium-modulated CVR in Caucasian children with a family history of HTN but not in AfricanAmerican children. Consistent with this finding, Wilson et al. (1999c) demonstrated no significant change in BP reactivity in African-American adolescents who adhered to a 3-week high-potassium diet in a study that examined the effects of increasing dietary potassium on BP non-dipping status in salt-sensitive and salt-resistant African-American adolescents. Urinary potassium excretion increased significantly in the treatment group (35  7 to 57  21 mmol/24 h). At baseline, a significantly greater percentage of salt-sensitive (44%) adolescents were non-dippers, based on diastolic BP classifications ( p < 0.04), compared to salt-resistant (7%) adolescents. After the dietary intervention, all of the salt-sensitive adolescents in the high-potassium group achieved a dipper BP status with a drop in nocturnal diastolic BP and no change in daytime BP (daytime 69  5 vs. 67  5; nighttime 69  5 vs. 57  6 mmHg). These results suggest that a positive relation between dietary potassium intake and BP modulation can prevail, although daytime BP may be unchanged by a high-potassium diet. Other investigations have also shown beneficial effects of increasing potassium on BP responses in salt-sensitive populations. For example, Fujita and Ando (1984) demonstrated that salt-sensitive hypertensive patients who were given a potassium supplement (96 mmol/24 h) while on a high sodium diet showed significantly greater decreases in MBP after 3 days when compared to non-supplemented hypertensive patients. Svetkey et al. (1987) demonstrated a significant drop in both systolic and diastolic BP after 8 weeks of potassium supplementation (64 mmol/24 h vs. placebo) among mildly hypertensive patients. Similarly, a 2-year randomized intervention in China found that systolic and diastolic BP decreased on average by 5.9 and 2.8 mmHg, respectively, in an experimental group that used a potassium- and calciuminfused salt substitute. In a comparison group in which sodium intake was restricted, systolic and diastolic BP were reduced by 5.8 and 1.0 mmHg, respectively, indicating that use of the salt substitute was as effective at reducing BP as sodium restriction (Mu et al. 2009).

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A number of reviews on the influence of potassium on BP responses have also shown positive inverse associations between high-potassium intake and BP responses in primarily adult populations (Filippini et al. 2020). The mechanisms underlying BP non-dipping status are unknown. One potential mechanism by which potassium may alter nighttime BP may involve potassium-related natriuresis (Weinberger et al. 1982). Restricting potassium intake has been associated with sodium retention; while potassium supplementation results in natriuresis. Some investigators suggest that the effect of potassium on urinary sodium excretion, plasma volume, and mean arterial pressure could be evidence of a potassium-mediated vasodilatory effect on BP (Linas 1991). If non-dippers have excess SNS activity and increased peripheral resistance during sleep, this potassium-mediated vasodilatory effect could explain the reversal of non-dipping status as in a prior study (Wilson et al. 1999c). Other studies that support this hypothesis show that intrabrachial arterial infusions of potassium chloride increase forearm blood flow and decrease forearm vascular resistance in healthy adults (Fujita and Ito 1993). Potassium supplementation given in combination with a high sodium diet also suppresses the increase in catecholamine responses typically seen in response to salt loading (Campese et al. 1982). Previous studies have shown that total peripheral resistance and norepinephrine responses to stress are greater in offspring of hypertensives than in normotensives (Stamler et al. 1979). Several adult studies have also confirmed that SNS activation occurs in individuals with elevated nighttime BP (Kostic and Secen 1997). In summary, these data support the hypothesis that the SNS may be important in non-dipping BP status.

Nutrition and Dietary Adherence in Youth Several lines of evidence suggest that targeting the family rather than the patient may be important for the successful promotion of healthy dietary adherence in children and adolescents. Previous research has demonstrated moderate aggregation of dietary variables among adolescents and their

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parents (Patterson et al. 1988). Furthermore, because family members often share a genetic predisposition to health risk factors, family involvement may be important in motivating adolescents to improve their long-term eating habits. Parents and peers may serve as role models for adolescents by consuming foods that are healthy and by reinforcing dietary knowledge and behaviors learned in schools (Perry et al. 1988). Recent association studies have shown that heritable variants in genetic coding relate to blood pressure response to a low sodium family-based intervention. In such studies, Chinese families were asked to adhere to either a low sodium diet, a high sodium diet, or a high sodium plus potassium supplementation diet, and the results were correlated with genetic variants. The responsiveness of family members’ systolic and diastolic BPs to the low sodium diet was associated with variants in the renalase (RNLS), serum/glucocorticoid regulated kinase (SGK1), and adiponectin genes (Chu et al. 2016). A genome-wide association study showed preliminary results that the compounding risk of eight heritable variants as associated with changes in BP responses to dietary sodium and potassium intervention, in a dose-response pattern (He et al. 2013). Similarly, genetic variants in the renin-angiotensin-aldosterone also were associated with a dose-response effect on individual BP responses of participants to dietary potassium intake (He et al. 2011). Together, these findings provide foundational evidence that dietary interventions likely interact with genetic predisposing factors to influence BP changes in response to alterations on sodium and potassium intake; however, further validation studies are needed to replicate these findings. Social support from family members may also influence adherence to dietary interventions. Parents may encourage adolescents to adopt healthy dietary behaviors, which in turn may decrease the risk for cardiovascular disease and chronic illness. Wilson and Ampey-Thornhill (2001) examined the relationship between gender, dietary social support (emotional), and adherence to a low sodium diet. Healthy African-American adolescents (N ¼ 184) participated in an intensive 5-day low sodium diet (50 mEq/2 h) as part of an HTN prevention program. Girls who were compliant (urinary sodium

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excretion [UNaV] < 50 mEq/24 h) reported higher levels of dietary support from family members than boys who were compliant (UNaV < 50 mEq/24 h). In contrast, boys who were adherent reported lower levels of dietary support from family members than boys who were nonadherent. In a recent trial that compared two intervention strategies for reducing sodium in families, the investigators found that gradual reduction in sodium was more effective than a gradual reduction plus intensive counseling approach or a standard sodium control condition (Toft et al. 2020). Furthermore, an NHANES study determined that adherence estimates by sodium density were substantially lower than for estimates based on total sodium intake (Hu et al. 2020). Taken together these studies suggest that a gradual lifestyle change that involves family support may be most effective for reducing sodium intake in youth. In a study by Nader et al. (1989), Caucasian, African-American, and Mexican-American families were randomly assigned to a 3-month low sodium, low-fat dietary program or to a no-treatment group. The treatment group showed a greater increase in social support specific to diet than the no-treatment group. In summary, these studies provide evidence that familial support may be important for increasing adolescents’ adherence to healthy dietary programs that could ultimately decrease the risk of HTN and cardiovascular complications. Another way that parents, teachers, and peers may influence adolescents’ adherence with healthy eating habits is through role modeling. Cohen et al. (1989) randomly assigned adolescents to either peer-led or parent-led promotions of a low sodium, low-fat dietary intervention. At the end of the intervention, both groups showed equal effectiveness in changing nutritional habits. The peer-led intervention, however, was more effective in reducing BP. Previous research also suggests that the incorporation of behavioral skills training and developmentally appropriate dietary interventions may be most effective in promoting long-term changes in sodium and/or potassium intake (e.g., increased fruit and vegetable intake). For example, in a study conducted by Gortmaker et al. (1999), 1295 sixth- and seventh-grade students from public

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schools in Massachusetts participated in a schoolbased intervention over 2 years to reduce the prevalence of obesity. The intervention was based on social cognitive theory (SCT) and behavioral choice theory. Treatment sessions were incorporated into the existing curricula, used classroom teachers, and included the students increasing their fruit and vegetable intake. Schools across four study sites were randomized to either the SCT treatment that focused on behavioral skills or a control condition. After 3 years, these intervention schoolchildren exhibited significant changes in improved knowledge, intentions, self-efficacy, dietary behavior, and perceived social reinforcement for healthy food choices. Some studies have provided insight into the importance of targeting eating patterns for improving food choices related to high-potassium/low sodium foods such as fruit and vegetable intake (Simons-Morton et al. 1990). In 943 third to fifth graders, fruit juices accounted for 6.1% of the total food selections for boys and 6.6% for girls. Vegetables accounted for 15.7% of total selection for boys and 16.2% for girls. Fruit was more likely consumed for snacks than for meals, and vegetables were eaten at the same rate for snacks, at lunch, and at supper. Consequently targeting an increase in fresh fruits and vegetables in all meals may be one effective approach to improving electrolyte intake in children. Several studies have demonstrated sex differences in adherence to sodium restriction and dietary potassium supplementation. Sinaiko et al. (1993) reported urinary electrolyte excretion data over the course of a 3-year intervention in fifth through eighth graders. Boys were less likely to comply with a sodium restriction of 70 mmol/day than girls. Subsequently, BP effects were only significant for girls. In a study by Wilson and Bayer (2002), boys were more likely than girls to comply with a 3-week dietary intervention of increasing potassium to 80 mmol/day intake. However, Krupp et al. (2015) assessed the impact that fruits and vegetables (FV) and sodium intake has on BP in 206 adolescent males (n ¼ 108) and females (n ¼ 98). The Krupp et al. (2015) study utilized participants in the Dortmund Nutritional and Anthropometric Longitudinally Designed study, which had data collected in adolescence

D. K. Wilson et al.

(11–16 years) and early adulthood (18–25 years). Interestingly, results revealed sex differences with the impact that FV and sodium had on BP. Specifically, they found that in healthy adolescent girls, higher FV intake was predictive of lower systolic BP, where there was no difference in healthy boys. On the contrary, they found a significant reduction in systolic BP for adolescent boys who consumed less sodium, but there was no difference for adolescent females (Krupp et al. 2015). These studies suggest that boys, in particular, may be more likely to comply with high-potassium diets that emphasize adding foods to the diet, compared to low sodium diets that focus on eliminating foods from the diet. Their findings highlight the importance of understanding sex differences in promoting healthy diets for males and females with regard to blood pressure. Further research is needed to more fully explore the long-term effectiveness of dietary electrolyte interventions in boys versus girls and among youth in general. Finally, researchers conducted a meta-analysis of studies assessing DASH diet adherence (Kwan et al. 2013). They found nine studies that met their search criteria, but there was no consensus on the best method of assessing adherence. The studies included had used an array of assessment methods, from more objective approaches (e.g., urinary excretion) to more subjective measures (e.g., dietary intake assessments). However, they did conclude that the development of effective approaches to measure compliance of the DASH diet should be the focus of future research (Kwan et al. 2013).

Conclusions and Implications for Future Research This chapter has summarized data that indicate that promoting effective nutritional-electrolyte-focused interventions may be useful in the prevention and therapy of hypertension in children and adolescents. Reducing sodium and increasing potassium intake are effective approaches for preventing cardiovascular risk in children and adolescent populations, and research suggests that adherence to high-potassium dietary interventions is higher than that for low sodium diets. The role of dietary

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intake on BP markers suggests that further attention should be paid to promoting positive dietary lifestyle skills in youth. However, other important factors must be considered, including those related to obesity and unhealthy lifestyles. Further, abnormal SNS activity may be linked to the factors that lead to elevated BP as reviewed in this chapter. Promoting healthy diets that target decreasing sodium and increasing potassium may help to decrease SNS activation. Finally, ethnic/minority populations, and especially African-American youth, are at highest risk for developing HTN in early adulthood, and efforts should focus on preventing HTN in these communities. Continued efforts will be needed to address disparities in cardiovascular risk and obesity-related risk in underserved and minority youth.

Cross-References ▶ Ambulatory Blood Pressure Monitoring Methodology and Norms in Children ▶ Cardiovascular Influences on Blood Pressure ▶ Development of Blood Pressure Norms and Definition of Hypertension in Children ▶ Ethnic Differences in Childhood Blood Pressure ▶ Insulin Resistance and Other Mechanisms of Obesity Hypertension ▶ Monogenic and Polygenic Contributions to Hypertension ▶ Obesity Hypertension: Clinical Aspects ▶ Salt Sensitivity in Childhood Hypertension Acknowledgments This work was supported in part by a grant from the National Institutes of Health (R01 HD072153) to Dawn K. Wilson, Ph.D., in part by a training grant from the General Medical Sciences (T32 GM081740) to Tyler C. McDaniel, M.S., and by a grant to Sandra M. Coulon, M.A. (F31 AG039930).

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Wilson DK, Sica DA, Devens M, Nicholson SC (1996) The influence of potassium intake on dipper and nondipper blood pressure status in an African-American adolescent population. Blood Press Monit 1:447–455 Wilson DK, Bayer L, Krishnamoorthy JS, AmpeyThornhill G, Nicholson SC, Sica DA (1999a) The prevalence of salt sensitivity in an African–American adolescent population. Ethn Dis 9:350–358 Wilson DK, Sica DA, Miller SB (1999b) Ambulatory blood pressure nondipping status in salt-sensitive and salt-resistant black adolescents. Am J Hypertens 12: 159–165 Wilson DK, Sica DA, Miller SB (1999c) Effects of potassium on blood pressure in salt-sensitive and saltresistant black adolescents. Hypertension 34:181–186

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Woodruff SJ, Fryer K, Campbell T, Cole M (2014) Associations among blood pressure, salt consumption and body weight status of students from South-Western Ontario. Public Health Nutr 17: 1114–1119 Yang Q, Zhang Z, Kuklina EV, Fang J, Ayala C, Hong Y, Loustalot F, Dai S, Gunn JP, Tian N, Cogswell ME, Merritt R (2012) Sodium intake and blood pressure among US children and adolescents. Pediatrics 130: 611–619 Zhu H, Yan W, Ge D, Treiber FA, Harshfield GA, Kapuku G, Snieder H, Dong Y (2008) Relationships of cardiovascular phenotypes with healthy weight, at risk of overweight, and overweight in US youths. Pediatrics 121:115–122

Endothelial Dysfunction and Vascular Remodeling in Hypertension

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Julie Goodwin

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Role of the Endothelium in Blood Pressure Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Etiologies of Endothelial Dysfunction and Resultant Blood Pressure Derangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

199 199 200 201

Vascular Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemodynamic Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactive Oxygen Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renin-Angiotensin-Aldosterone System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adiponectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MicroRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

202 203 203 205 206 206

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Abstract

The endothelium is a critical mediator of blood pressure homeostasis through its roles in producing and interacting with circulating vasoactive compounds, most notably nitric oxide. Endothelial dysfunction is a marker of cardiovascular disease and may develop under a variety of

J. Goodwin (*) Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_41

conditions seen in the pediatric population, including relatively rare diseases such as chronic kidney disease and acute kidney injury, as well as common conditions, such as childhood obesity. Ongoing endothelial dysfunction eventually leads to adaptive mechanisms that lead to vascular remodeling, by which the structure of resistance vessels is altered, as is systemic blood pressure. Multiple factors central to the functioning and maintenance of the endothelium contribute to and perpetuate vascular remodeling including hemodynamic forces, reactive oxygen species, and the adipokine adiponectin. 195

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Keywords

Endothelium · Endothelial dysfunction · Vascular remodeling · Pediatric hypertension · Nitric oxide · Adiponectin · Reactive oxygen species

Introduction While hypertension is a systemic disease involving many organ systems, there is recent recognition that certain cell types, endothelial cells in particular, may contribute disproportionately to the pathophysiology of this condition. Endothelial cells are uniquely positioned as the first interface between the blood and the blood vessels and are important mediators of inflammation, proliferation, and vascular reactivity. Indeed, endothelial health is both a marker of overall cardiovascular health and reflects the sum of ongoing beneficial and detrimental influences on the vasculature. This chapter reviews the ways in which the endothelium maintains vascular homeostasis, the conditions under which vascular homeostasis becomes deranged and the ensuing vascular remodeling that occurs as a result of prolonged endothelial dysfunction.

Role of the Endothelium in Blood Pressure Homeostasis The endothelium is a critical player in maintaining vascular homeostasis. Though vessel wall resistance has long been recognized as a key variable in blood pressure regulation and primary hypertension (Folkow 1982), more complete understanding of vessel wall biology has clearly identified interactions with the endothelium and circulating vasoactive substances, including nitric oxide (NO), angiotensin II (AII), and endothelin as equally important (Singh et al. 2010). Perhaps the most important of these is nitric oxide, produced in the endothelium by endothelial nitric oxide synthase (eNOS). eNOS is a calcium-dependent enzyme regulated by protein phosphorylation, protein-protein interactions, and its subcellular localization into peri-nuclear and

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plasma membranes (Fulton et al. 2001). NO is recognized to mediate many processes crucial to endothelial and blood vessel health including promotion of vessel wall relaxation and lowering of blood pressure. The mechanism by which eNOS-derived NO modulates blood pressure is complex and is postulated to involve the kidney as well as the blood vessels. eNOS has been shown to be expressed not only in the vascular endothelium but also in certain epithelia in the nephron, including in the thick ascending loop of Henle (Wu et al. 1999). For example, NO has been shown to inhibit the Na-K-2Cl transporter in the thick ascending limb, thereby reducing renal sodium reabsorption in this nephron segment (Guarasci and Kline 1996; Herrera et al. 2006a). Recent studies using a mouse model of collecting duct (CD)-eNOS deficiency have shown that this decrease in CD nitric oxide bioavailability leads to an upregulation of CD renin production and may contribute to the activation of the intrarenal renin-angiotensin system and subsequent hypertension (Curnow et al. 2020). The kidney-protective effects of HMG-CoA reductase inhibitors, colloquially known as statins, may also be tied mechanistically to modulation of NO. For example, pitavastatin was recently shown to increase renal NOS expression and upregulate eNOS activity in both spontaneously hypertensive rats and Wistar-Kyoto rats, while attenuating hypertension (Hu et al. 2018). Multiple laboratories have also demonstrated that increased salt intake in animal models is associated with increased NO in the kidney. This effect likely involves endothelin, as endothelin receptor antagonists have been shown to prevent this high-salt dietinduced increase in eNOS expression (Herrera and Garvin 2005; Herrera et al. 2006a, b; Mount and Power 2006). In addition to its ability to limit sodium reabsorption, eNOS-derived NO has also been shown to lower blood pressure via several discrete signaling pathways. For example, Li et al. have demonstrated that use of a protein kinase C (PKC) inhibitor, midostaurin, in the spontaneously hypertensive rat (SHR) model, can increase eNOS protein, mRNA, and NO bioavailability (Li et al. 2006). PKC activation mediates hypoxia-inducible factor (HIF-1)-induced eNOS

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synthesis in response to hyperoxia, as well as kallistatin-mediated eNOS synthesis (Chao et al. 2017). PKC inhibitors have been discussed as potential anti-hypertensive agents in humans, but clinical studies are still awaited (Khalil 2013; He et al. 2014); theoretically, PKC inhibitors should be able to be targeted to specific vasculature, and this is an attractive avenue for ongoing drug development (Ringvold and Khalil 2017). However, there are some promising data from animal models. For example, the induction of endothelin1 by palmitic acid administration was shown to be neutralized by the PKC inhibitor Gö 6850 in a mouse model of obesity-related hypertension triggered by high-fat diet feeding (Zhang et al. 2018). The Rho/Rho-associated kinase (ROCK) pathway has also received attention as a potential avenue of blood pressure regulation by means of NO. ROCK activation has been found to result in lower levels of eNOS mRNA in cultured cells (Noma et al. 2006; Takemoto et al. 2002), and eNOS-null mice have been shown to have higher levels of ROCK activity as compared to normal mice (Williams et al. 2006). Chronic ROCK activation has been associated with cardiovascular disease, including hypertension, in humans (Soga et al. 2011). However, it is not clear if ROCK activation increases cardiovascular risk or cumulative cardiovascular risk enhances ROCK activity (Soga et al. 2011). A small pilot study of 50 adult patients with idiopathic hyperaldosteronism has recently shown that a 12-week course of eplerenone, an aldosterone antagonist, was able to substantially reduce ROCK activity and increase microvascular endothelial cell function, despite having no effect on systolic or diastolic blood pressure (Kishimoto et al. 2019). The authors postulated that this observation may have been due to confounding comorbidities in these adult patients. Further study of ROCK activity in a pediatric population free from dyslipidemia, diabetes, and poor lifestyle habits would be instructive in further illuminating the relationship between ROCK and cardiovascular disease. Other vasoactive substances that are secreted by the endothelium and contribute greatly to vascular homeostasis are the endothelins. These is a three-member family of small peptides –

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endothelin-1, endothelin-2, and endothelin-3. Endothelin-1 (ET-1) is most important in the vasculature and is produced constitutively (Inoue et al. 1989). It is a powerful vasoconstrictor and can induce inflammatory responses, both key properties in maintaining vascular homeostasis. The molecular identity of this molecule was elucidated in 1988 by Yanagisawa and colleagues (Yanagisawa et al. 1988), but there is much that is still poorly understood. In contrast to NO, which is generally regarded as a disease-inhibiting substance, ET-1 is one of the few endogenous substances, which, when perturbed, may be regarded as disease-promoting by inducing cell proliferation, inflammation, coagulation, and vasoconstriction (Barton and Yanagisawa 2008). ET-1 production is upregulated with age and during the development of aging and chronic disease, tipping the vascular milieu from a protective to a detrimental environment which may initiate and potentiate endothelial dysfunction. Novel oral ET-1 antagonists, including bosentan and macitentan are in clinical use in children with pulmonary hypertension (Ivy and Frank 2021; Aypar et al. 2020; Schweintzger et al. 2020), but there are, as yet, no studies which evaluate the use of these agents in systemic hypertension in a pediatric population. More recently, C-type natriuretic peptide (CNP) has been recognized as important in maintaining vascular homeostasis. Through elegant studies in a mouse knockout model, Moyes and colleagues demonstrated that endothelialspecific deletion of CNP resulted in vascular dysfunction, hypertension, and atherogenesis (Moyes et al. 2014). Those investigations further showed that CNP is a critical component of the non-prostanoid, non-NO vasorelaxation in resistance vessels as well as in preserving the integrity of the blood vessel wall. In addition to its role as a generator of vasoactive substances, the endothelium also contains myriad receptors that allow it to respond to circulating molecules. One of the most relevant of these with respect to blood pressure homeostasis is the glucocorticoid receptor which binds its endogenous ligand, cortisol. There is evidence that confirms the presence of the glucocorticoid receptor

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in the vascular endothelium (Imai et al. 1989; Piovesan et al. 1990), but little is known about its role there. In vitro experiments with endothelial cell culture models have suggested that glucocorticoids regulate vascular reactivity via suppression of the production of vasodilators such as prostacyclin and nitric oxide which would lead to vasoconstriction. However, Provencher et al. demonstrated an increase in angiotensin II receptor levels, yet a decrease in endothelin-1 levels in response to synthetic glucocorticoids in a vascular smooth muscle cell culture model (Provencher et al. 1995); those results would lead to vasodilation. Such contradictory results led the authors to speculate that glucocorticoids may function as modulators of vascular inflammation and not solely as vasoconstrictive agents. Experiments performed to study the role of glucocorticoids and glucocorticoid receptors in the vasculature have compared intact vessels to injured vessels in which the endothelium has been mechanically stripped and hence are devoid of all endothelial function. Wallerath et al. suggest that it is the ability of glucocorticoids to destabilize eNOS mRNA and reduce eNOS protein expression that is responsible for the ensuing hypertension observed in rats treated with dexamethasone (Wallerath et al. 2004). More recent studies in isolated rat aortas showed that, through the glucocorticoid receptor, glucocorticoids could decrease expression of guanosine triphosphate cyclohydrolase 1 (GTPCH1) mRNA, the rate-limiting enzyme in the production of tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthase (Mitchell et al. 2004). However, in that series of studies, eNOS mRNA levels were not significantly different in control vessels than in those treated with dexamethasone. In a mouse model, Goodwin et al. (Goodwin et al. 2011) ablated the glucocorticoid receptor from the vascular endothelium by using Tie-1 Cre, which allows tissue-specific deletion of the receptor. Interestingly, these knockout animals had a small but statistically significant increase in their baseline blood pressure, the source of which could not be entirely explained. In addition, the

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knockout animals were almost completely resistant to glucocorticoid-induced hypertension and conspicuously lacked the pressure natriuresis observed in another model in which the vascular smooth muscle glucocorticoid receptor had been ablated (Goodwin et al. 2008). Intravital microscopy studies done in real-time on resistance vessels from animals lacking the endothelial glucocorticoid receptor revealed a statistically significant decrease in vessel contractility to the glucocorticoid receptor-specific ligand dexamethasone when compared to wild-type animals (Goodwin et al. 2011). The contractility in response to phenylephrine was similar between the two groups (endothelial glucocorticoid receptor knockouts and wild types), suggesting that loss of the endothelial glucocorticoid receptor confers a specific contractile defect in these animals, presumably preventing them from mounting a hypertensive response to systemic dexamethasone. In that study, whole blood nitric oxide levels were not different between the two groups though the possibility of differences in nitric oxide in local vascular beds could not be ruled out (Goodwin et al. 2011). Other investigators have examined nitric oxide derangements with ex vivo studies in rats. In 2009, Aras-Lopez et al. evaluated electrical field stimulation-induced neuronal nitric oxide release in mesenteric arteries of Wistar-Kyoto (WKY) rats, which are normotensive, and spontaneously hypertensive rats (SHRs) and the role of protein kinase C (PKC) in these responses (Aras-Lopez et al. 2009). Through a series of manipulations involving various PKC inhibitors, the authors demonstrated that dexamethasone was able to reduce neuronal nitric oxide release in arteries from SHRs but not WKY rats and that this effect was mediated though activation of glucocorticoid receptors. This study was novel in that it addressed the possibility that glucocorticoids exert their hypertensive effects, at least in part, by altering the neuronal nitric oxide release of the perivascular innervation of these tissues (ArasLopez et al. 2009). Thus, there may be differential effects of glucocorticoids on the various nitric oxide isoforms, which appear to be affected by the overall milieu.

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Endothelial Dysfunction and Vascular Remodeling in Hypertension

Etiologies of Endothelial Dysfunction and Resultant Blood Pressure Derangements Given the clear importance of the vascular endothelium in maintaining normal blood pressure, it is not surprising that endothelial dysfunction would aggravate or even precipitate hypertension. There are several conditions under which endothelial dysfunction develops.

Chronic Kidney Disease It is well-known that the leading cause of death of patients on dialysis, both children and adults, is cardiovascular disease. Perhaps what is less well recognized is that patients with chronic kidney disease (CKD), not yet on dialysis, also have increased cardiovascular risk, in excess of that expected based on the basis of accepted risk factors (Go et al. 2004; Khandelwal et al. 2016). Emerging data suggest that endothelial dysfunction makes a key contribution. Microvascular rarefaction, which is the loss of perfused microvessels that results in a significantly decreased microvascular density, is a key finding in most human and animal studies of CKD and represents permanent loss of endothelial cell homeostasis that paves the way for progressive organ dysfunction (Querfeld et al. 2020). Several endothelial functions have been shown to be defective in uremic states, including derangements in angiogenesis (Jacobi et al. 2006), vascular permeability (Harper and Bates 2003), and endothelial-dependent vasodilation (Verbeke et al. 2011). Deficits in NO bioactivity were also reported in CKD (Baylis 2006), the reasons for which are an active area of investigation. For example, resistance vessels from both humans and rats have been shown to have impaired endothelium-dependent vasodilatation, reduced nitric oxide and cyclin guanosine monophosphate (cGMP) production, and reduced eNOS expression under hyperphosphatemic conditions, a common biochemical milieu in CKD (Stevens et al. 2017). In a rat CKD model using

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5/6 nephrectomy, provision of omega 3 (n-3) polyunsaturated fatty acids (PUFA) was shown to improve endothelial dysfunction by improving NO bioavailability (Zanetti et al. 2017). In a particularly elegant study using the sodium-glucose co-transporter 2 inhibitor (SGLT2) empagliflozin and a co-culture methodology using human microvascular endothelial cells and rat ventricular cardiomyocytes, serum from CKD patients impaired endothelial enhancement of cardiomyocyte function, an effect that could be rescued by empagliflozin, a mechanism mediated mainly via increased eNOS bioavailability (Juni et al. 2021). This study has important implications for the understanding of cardiovascular disease in CKD and will surely become a springboard for future trials. Asymmetric dimethylarginine (ADMA), a metabolite of arginine, is an endogenous inhibitor of nitric oxide synthases, and ι-arginine can be metabolized to ι-citrulline and NO by eNOS, its main substrate. Accordingly, provision of additional arginine, either as an acute or chronic manipulation, results in increased production of nitric oxide and improved endothelial function (Loscalzo 2004). It is known that ADMA is mainly absorbed by endothelial cells with extracellular levels being several fold lower than intracellular levels. Thus, small changes in plasma ADMA are able to change intracellular ADMA and NO levels significantly (Cardounel et al. 2007). Accordingly, the arginine-NO pathway (Fig. 1) is of great interest in the study of endothelial dysfunction. Increased ADMA levels in dialysis patients were first described over two decades ago (Vallance et al. 1992a, b). Over one dozen studies have clearly demonstrated a statistically significant increase in ADMA in patients with CKD compared to controls (Aldamiz-Echevarria and Andrade 2012). Interestingly this increase is also seen in kidney transplant patients, who usually also suffer from varying degrees of endothelial dysfunction, increased levels of reactive oxygen species, and clinically significant hypertension (Zhang et al. 2009). Recent studies have demonstrated that concentrations of ADMA present in patients with

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Fig. 1 Arginine-nitric oxide metabolic pathway illustrating the inhibitory role of ADMA on NO generation. Abbreviations: NO, nitric oxide; NOS, nitric oxide synthase; ADMA, asymmetric dimethylarginine; DDAH1, dimethylarginine dimethylaminohydrolase 1; ROS, reactive oxygen species

kidney failure can decrease NO generation (Kielstein et al. 2004). Further, it has also been shown that in a 5/6 nephrectomy rodent model, the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which metabolizes ADMA, is decreased, while the enzyme protein arginine methyltransferase (PRMT), which catalyzes ADMA, is increased (Matsuguma et al. 2006). In addition to these enzyme imbalances, two additional mechanisms have been postulated to account for the increased ADMA levels found in CKD patients – an increased rate of protein turnover and impaired renal excretion of ADMA (Aldamiz-Echevarria and Andrade 2012). Though the ADMA pathway has not been as well studied in children as in adults, some data in this population exist. Enzyme levels are typically higher in children as compared to adults, due to immaturity of the enzyme system. Increased arginine-to-ADMA ratios, an index for NO, were found to correlate positively with systolic BP, measured by ABPM, and left ventricular (LV) mass in children with early CKD stages 1–3 (Chien et al. 2015). ADMA levels have been shown to be upregulated in children with homocystinuria (Kanzelmeyer et al. 2012) and diabetes (Heilman et al. 2009), both conditions in which blood pressure elevation and endothelial dysfunction are common. Recently, a small study of 105 children (85 with obesity), examined

endothelial function, ADMA-related biomarkers, and traditional risk factors as related to obesity (Lo et al. 2019). Though no statistical differences were found between children with normal weight and those with obesity with respect to the ADMArelated biomarkers, the authors allowed this study was not adequately powered to detect such a change, and this relationships remains an active area of investigation.

Acute Kidney Injury In addition to the smoldering endothelial injury which may persist over years in patients with CKD, endothelial damage may also result from temporally brief but severe episodes of acute kidney injury (AKI). The hallmark of AKI is a reduction in glomerular filtration rate (GFR) resulting from a sustained increase in renal vascular resistance. Evidence from animal models of ischemia/ reperfusion injury supports the notion that endothelial damage contributes to the reduction in renal blood flow in that model system (Sutton et al. 2003). Endothelial dysfunction also has been shown to result in impaired vasodilator capacity due to the impairment of eNOS function, demonstrated by loss of vasodilator responses to bradykinin and acetylcholine in a rodent model (Conger et al. 1988). Furthermore, as one of the

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functions of eNOS in the kidney is to maintain medullary blood flow in response to vasoconstrictors such as angiotensin II (Zou et al. 1998), deranged eNOS function would predispose to hypertension. Surprisingly, it has been noted that renal autoregulation is compromised for up to 7 days following ischemic injury, well beyond the point at which renal blood flow has recovered to pre-injury levels, suggesting that endothelial injury persists despite overall clinical recovery (Conger et al. 1994, 1995). Perhaps this observation contributes to the persistent hypertension that is noted in some patients following AKI episodes despite normalization of serum creatinine. Continued study of the effect of ischemia/reperfusion injury in animal models has recently shown that recombinant ADAMTS13 (rhADAMTS13) might represent a novel therapy for AKI. In one study, rhADAMTS13 was shown to improve endothelial dysfunction by enhanced phosphorylation of eNOS at serine1177 (Zhou et al. 2019).

Obesity In this era of rampant childhood obesity in which nearly 20% of the adolescent population is classified as having obesity (Ogden et al. 2014), endothelial dysfunction is gaining attention as a surrogate marker of cardiovascular disease, even in the pediatric population. The effects of the interaction between hypertension and endothelial function on one another in the pediatric population are complex; furthermore puberty may affect the interaction (Bruyndonckx et al. 2016). Contrary to expectations, studies in obese prepubertal children with obesity have demonstrated greater functional reserve and greater adaptive capacity of the endothelium in response to stress as compared to responses in normal weight children (Radtke et al. 2013a). It has further been shown that HDL cholesterol, commonly regarded as a beneficial molecule with cardioprotective effects, is functionally impaired in obese children in that it is less capable of stimulating eNOS activity compared to its effect in normal weight children (Matsuo et al. 2013). The manipulation of HDL is an active area of investigation; HDL is now known to be a major

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carrier of microRNAs (miRs), small non-coding molecules that regulate the expression of proteincoding genes. Early studies are currently underway in adult patients, though not yet in pediatric patients, to induce a more favorable miR profile via lifestyle modifications, including exercise, to prevent cardiovascular disease (Riedel et al. 2015). However, it is increasingly clear that obesity in childhood can predict endothelial dysfunction and markers of cardiovascular morbidity, including low HDL, later in adult life (Williams et al. 2017). Some studies in animal models suggest a link between obesity, endothelial dysfunction, and immunity. In particular, mice deficient in B cells are protected against obesity-induced hypertension (Tanigaki et al. 2018). Hyposialylated IgG and FcgammaRIIB inhibit VEGF-induced activation of eNOS by altering eNOS phosphorylation, suggesting that supplementation with N-acetylmannosamine (ManNAc), a key biological precursor of sialic acid, may provide a novel therapy to uncouple obesity and hypertension (Peng et al. 2019). The beneficial effects of physical activity on staving off or improving obesity are undeniable, but the relationship between physical activity and endothelial function is not as clear. In prepubertal children, exercise correlates strongly with endothelial function, as assessed by flow-mediated dilation of the brachial artery (Abbott et al. 2002), but this relationship is absent in adolescents (Radtke et al. 2013b). In young adults, the relationship is intuitive: healthy-weight adults stimulate endothelial function with physical activity, while obese individuals have a blunted response (Goran and Treuth 2001). Exercise has also been found to have a beneficial effect on endothelial progenitor cells (EPCs) in animal models via improved EPC proliferation and adherence mediated through the PI3K and pAKT pathways (Peyter et al. 2021). This fact is of particular interest for the pediatric population as it has been shown the children born with IUGR are at increased risk of HTN at all stages of life and demonstrate impaired endothelial-dependent vasodilatation with an altered proteome profile, suggesting early programming of endothelial dysfunction (Krause et al. 2013; Caniuguir et al. 2016). It is unknown whether exercise in obese

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IUGR patients is an effective strategy to mitigate this long-term risk. In addition to the very visible and physical limitations, obesity imposes on general health, and, as described above, on endothelial health, obesity may also be regarded as an endocrinopathy given the increased numbers and activity of adipocytes which are capable of secreting biologically active adipokines. At least two such adipokines, leptin and chemerin, have been found to influence endothelial function. Leptin has been found to induce hypertension and endothelial dysfunction in female mice via an aldosterone-sensitive mechanism (Huby et al. 2016). A more recent study has provided evidence that these sex-specific differences in obesity-induced endothelial dysfunction are driven by progesterone receptor-induced differences in expression of the endothelial mineralocorticoid receptor (MR), suggesting that MR antagonists may be a promising therapy to address obesityrelated endothelial dysfunction in females (Faulkner et al. 2019; Faulkner and Belin de Chantemele 2019). In humans, circulating chemerin levels were correlated closely with endothelial function in obese youth in one study (Landgraf et al. 2012). Interestingly, further examination of chemerin has also shown a pattern of diurnal and sexual dimorphism, with increased nocturnal chemerin levels noted exclusively in overweight/obese female adolescents (Daxer et al. 2017). Several comorbidities often segregate with obesity and may precipitate endothelial dysfunction. These include sleep apnea which is known to impair endothelial function (Li et al. 2013). Indeed, endothelial dysfunction in children with sleep apnea has been associated with higher plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels, an effect that was exacerbated by concomitant obesity (Kheirandish-Gozal et al. 2017). As Lp-PLA2 is recognized as an independent risk factor for cardiovascular disease, the long-term significance of these findings is potentially impactful, but so far unknown. In addition, insulin resistance may lead to endothelial dysfunction or vice versa. In a healthy state, insulin is a strong vasodilator, but in states of insulin resistance, endothelial cells are selectively resistant to this action, thus promoting a

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vicious cycle (Steinberg et al. 1994; Potenza et al. 2005). A recent randomized, double-blind, crossover trial sought to determine whether lowering the level of free fatty acids (FFA), which are associated with insulin resistance, could improve endothelial function as measured by flow-mediated dilation (FMD). By using acipimox, a drug that impairs FFA efflux, the authors demonstrated that they could lower FFA levels in 18 patients with metabolic syndrome to levels observed in 17 healthy controls, but there was no changed in endothelial-dependent FMD observed (Aday et al. 2019). However, since this study was quite small and was powered only to detect a 4% difference in FMD, it is not clear that the same results would be achieved using a larger cohort. In a study of 248 normal children, psychological derangements, including anxiety, depression, and anger, have been reported to contribute to endothelial dysfunction, though the mechanisms are far from clear (Osika et al. 2011). As such problems are highly prevalent in obese children, we would speculate that another mechanism for endothelial dysfunction in the obese child may be through mood derangements.

Vascular Remodeling Ongoing endothelial dysfunction ultimately results in adaptive mechanisms including vascular remodeling, characterized by alterations in the structure of resistance vessels. Vascular remodeling is an active and continuous process involving at least four different cellular processes including cell growth, cell death, cell migration, and extracellular matrix (ECM) synthesis and modification (Renna et al. 2013). Vascular remodeling may be physiological, as in the case of arteriogenesis or angiogenesis which occur during normal human development, or maladaptive, as may occur during vascular disease processes, such as atherosclerosis or hypertension. Vascular remodeling generally involves four cell types – fibroblasts in the adventitia, smooth muscle cells in the media, endothelial cells in the intima, and circulating macrophages (Fang and Yeh 2015).

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Hemodynamic Forces Hemodynamic forces play a major role in endothelial cell health and plasticity. Shear stress, that is, the component of stress coplanar with the vessel cross section, affects endothelial cell morphology. In vivo, there is evidence that cells exposed to steady, uniform flow are aligned with their long axis in the direction of flow and are elongated in shape. In contrast, cells exposed to disturbed flow are rounder and non-uniform in orientation (Langille and Adamson 1981). Shear stress is an important factor in regulating endothelial cell proliferation. Steady flow promotes reduced endothelial cell proliferation while disturbed flow stimulates cell turnover and apoptosis (Davies et al. 1986). Shear stress has been shown to induce other changes in endothelial cells as well including stimulation of migration and angiogenesis, increased expression of glycosaminoglycans (GAGs), and higher expression of key pro-fibrotic genes including fibronectin and collagen III alpha1, with resultant extracellular matrix remodeling (Russo et al. 2020). Collectively, these changes in mechanotransduction and hemodynamic forces affect the endothelium and its microenvironment and predispose vessels to vascular derangements, including hypertension (Russo et al. 2020). Cyclic strain/stretch, which occurs perpendicular to the blood vessel wall and is caused by the pumping of the heart inducing circumferential stress, also predisposes to endothelial migration (Von Offenberg Sweeney et al. 2005); cyclic strain is necessarily increased in hypertension. Endothelial cells respond to changes in hemodynamic forces by altering their production of vasoactive substances. Increases in shear stress generally favor vasodilation mediated by increases in NO and eNOS, though multiple other vasoactive factors including prostaglandin and endothelin-1 are also affected (Hendrickson et al. 1999; Kuchan and Frangos 1993). Data from the Time-2b study, a phase 2 randomized placebocontrolled, double-blind clinical trial which sought to assess the efficacy of an inhibitor (designated AKB-9778) of the endothelial cell-specific receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP), which is known to be upregulated in hypertension, (Carota et al. 2019)

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show that diabetic patients receiving this inhibitor have lower blood pressure than those receiving placebo (Siragusa et al. 2021). These findings were further explored in a diabetic mouse model in which it was shown that VE-PTP inhibition augments eNOS activity both by activation of the CD31/VE-cadherin/VEGFR2 complex, which mediates the endothelial response to shear stress and by dephosphorylation of eNOS Tyr81 (Siragusa et al. 2021). This study suggests that VE-PTP inhibition may represent a novel treatment for endothelial dysfunction-induced hypertension, especially in diabetic patients. Shear stress also affects expression of endothelial cell adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and selectins, which, in turn, may lead to leukocyte adhesion, and platelet aggregation, both important events in the formation of atherosclerotic lesions and indicative of worsening vascular disease (Merten et al. 2000; Gerszten et al. 1998). Hemodynamic forces can also affect production of various endothelial cytokines and growth factors in addition to vasoactive substances. Imbalances in the expression of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-β), interleukin-6 (IL-6), and interleukin-1 (IL-1) can create a domino effect, stimulating vascular smooth muscle cells to migrate and proliferate, creating a pro-inflammatory environment predisposed to progressive vascular disease (Cahill and Redmond 2016). Additional effects of shear stress on endothelial cell phenotypes are relatively recently recognized. For example, changes in DNA methylation, histone acetylation, and microRNA expression have been reported in states of endothelial dysfunction, all of which have been linked with cardiovascular disease (Huynh and Heo 2019).

Reactive Oxygen Species Aberrant modulation of reactive oxygen species (ROS), through changes in cyclic and shear stress, as well as through generation of vasoactive substances, leads to endothelial dysfunction, which is associated with ongoing vascular injury and

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chronic changes. Endothelial cells, and indeed all vascular cells, have the ability to produce ROS, which are relatively unstable oxygen-centered free radicals. ROS are short-lived and difficult to measure directly. It has been shown that in conditions of low shear stress, such as the disturbed flow that results from occlusive vascular disease or stenotic vessels, a signaling cascade is stimulated that results in NAPDH oxidase (Nox) activation and ROS production (Chatterjee et al. 2012). Nox is activated by growth factors, cytokines and vasoactive agents, all of which may be considered pro-hypertensive factors (Montezano et al. 2015b). Angiotensin II (Ang II) appears to be a particularly potent stimulator of Nox. Stimulation of both vascular endothelial and vascular smooth muscle cells with Ang II leads to increased Nox-induced ROS production which in turn activates redox signaling pathways (Raaz et al. 2014). Furthermore, Nox activation is increased in endothelial cells in vitro as well as in intact vessels in human hypertension (Konior et al. 2014; Montezano et al. 2015a). There are currently seven identified isoforms of Nox, all of which are expressed in the vasculature, but each with its own tissue distribution and cellular and subcellular localization (Montezano et al. 2015b). Nox2 has been shown to be a key mediator of endothelial dysfunction and hypertension. Using in vivo studies in a mouse model as well as in vitro assays, Ma et al. demonstrated that expression of the Ca2+-activated Cl channel TMEM16A was increased during angiotensin II-induced endothelial dysfunction and that this was mechanistically related to increased ROS production, increased Nox2-containing NAPDH oxidase production, and augmented Nox2 p22phox protein expression (Ma et al. 2017). The endothelial dysfunction associated with derangements in ROS signaling is mediated by changes in the redox state of ion channels, kinases, cyclases, activated protein kinases, phosphatases and proteins, and transcription factors. There exists a fine balance between these ROS/NO regulatory mechanisms. Steady flow seems to promote the activation of transcription factors important for vessel health including nuclear factor

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(erythroid-derived 2)-like 2 (Nrf2) and Kruppellike factor 2 (KLF2), which, in turn, increase expression of superoxide dismutase (Takabe et al. 2011). Conversely, disrupted flow favors the upregulation of nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) and activator protein 1 (AP-1), which stimulate expression of disease-favoring proteins such as monocyte chemotactic protein 1 (MCP-1) and intracellular adhesion molecule-1 (ICAM-1) (Hsieh et al. 2014). In redox-sensitive proteins, ROS signaling effects are mediated via changes in the specific cysteine residues. These post-translational modifications may include S-nitrosylation, S-glutathionylation, sulfhydration, sulfenylation, disulfide bonds, and sulfinic and sulfonic acid (Choi et al. 2011) and result in changes to protein structure and function, which, in turn, cause myriad cellular effects, including vascular cell proliferation and/or apoptosis. For example, under normal conditions, vascular smooth muscle cells demonstrate very low rates of proliferation. Under pathological conditions such as hypertension, increased levels of ROS influence redox-sensitive cell cycle processes via the aforementioned post-translational modifications resulting in cell proliferation, dedifferentiation, and migration (Rao and Berk 1992). This proliferative phenotype then leads to the increased medial thickness, reduced lumen size, and increased stiffness that are the hallmarks of the detrimental vascular hypertrophy and remodeling observed in hypertension. There is also now an appreciation for the role inflammation can play in stimulating the production of ROS as well as its status as an independent risk factor for endothelial dysfunction and cardiovascular derangements, including hypertension (Barrows et al. 2019; Xiao and Harrison 2020). Specifically, blockade of the NLRP3 inflammasome has garnered particular attention, and it has recently been shown the NLRP3 blockade, through the use of hydrogen sulfide (H2S), can suppress production of ROS and improve hypertension in a rat model (Li et al. 2019). This study and other in vitro data have suggested a variety of drugs may be effective in combating endothelial dysfunction through known NLRP3

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inhibition including statins; hypoglycemic agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors, dulaglutide, acarbose, and fenofibrate; and aspirin (Bai et al. 2020).

Renin-Angiotensin-Aldosterone System Another important contributor to the initiation and maintenance of vascular remodeling is the reninangiotensin-aldosterone system (RAAS). Multiple lines of evidence clearly demonstrate that unchecked RAAS activation is deleterious. In vivo, infusion of Ang II in a rat model increases leukocyte adhesion in resistance vessels (Alvarez et al. 2004) and increases the expression of VCAM-1 in the aorta via transcriptional activation of NF-κB (Tummala et al. 1999). Administration of losartan, an angiotensin receptor blocker, was shown to abrogate the latter effects (Tummala et al. 1999). In studies using human vascular smooth muscle cells (Kranzhofer et al. 1999), and peripheral blood monocytes (Hahn et al. 1994), Ang II induces expression of IL-6, MCP-1, and TNFα. Ang II can directly induce endothelial cell damage by inhibiting cellular regeneration; in addition, Ang II acts as a second messenger, activating the mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) pathways, stimulating cell apoptosis, proliferation, and vascular dysfunction (Becher et al. 2011). Ang II is both pro-fibrotic and pro-oxidant (Qi et al. 2011). Ang II infusion has been further shown to induce production of ROS and activate Nox signaling and redox-sensitive genes (Rajagopalan et al. 1996). Consequently, the endothelium becomes more permeable (“leaky”) and allows migration of inflammatory cells into the blood vessel wall; the dysfunctional endothelium also recruits additional inflammatory cells and cytokines, compounding tissue injury and ultimately leading to vascular disease (Pacurari et al. 2014). As a corollary, RAAS blockade has clearly been shown to improve vascular function and, in particular, endothelial dysfunction. Studies using blockade with either an angiotensin receptor

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blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi) have demonstrated improved NO bioavailability in humans (Mason 2011). Clinically, the reduction in cardiovascular events observed seems to exceed that expected from blood pressure lowering alone, suggesting that concurrent reduction in inflammation and oxidative stress directly improves endothelial dysfunction. Aldosterone has also been shown to promote vascular remodeling. Though the effects of aldosterone on cardiac remodeling are wellestablished, there is recent recognition that aldosterone also contributes directly to vascular remodeling under conditions of endothelial dysfunction (Luther 2016) . Adipocyte-derived growth factors have been shown to stimulate aldosterone secretion (Goodfriend et al. 1999; Ehrhart-Bornstein et al. 2003), and leptin itself is an aldosterone agonist (Ingelsson et al. 2007), perhaps explaining the strong association between obesity and hyperaldosteronism. Aldosterone directly stimulates adipocyte expansion (Urbanet et al. 2015) and decreases adiponectin evidence of expression in vitro (Guo et al. 2008), which is directly correlated with endothelial dysfunction as well as insulin resistance (Wang and Scherer 2008). In vivo studies have proved confusing in trying to assess the effects of aldosterone on endothelial cells. For example, obese mice fed a high-fat diet and isolated aortic rings from lean mice that received short-term aldosterone infusion, both of which were mineralocorticoid receptor (MR) replete, demonstrated impairment in NO-dependent vasodilation, and endothelial dysfunction which could be reversed, in both models, by genetic deletion of endothelial MR (Schafer et al. 2013). This study suggested that endothelial MR is involved in both the regulation of obesity-induced and aldosteroneinduced endothelial dysfunction. Similarly, after a prolonged period of salt/deoxycorticosterone administration, endothelial cell-specific MR knockout mice were protected against cardiac ICAM-1 expression, macrophage infiltration, iNOS upregulation, and collagen deposition compared to controls despite the fact that there was not a significant change in blood pressure (Rickard et al. 2014).

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However, in another murine model, overexpression of the mineralocorticoid receptor in endothelial cells was protective when the mice were subjected to carotid artery injury and observed for thrombosis; this protection was mediated by increased vWF release and endothelial protein C receptor expression (Lagrange et al. 2014). The same investigators also demonstrated increased blood pressure and increased response to vasoconstrictors in this overexpression model (Nguyen Dinh Cat et al. 2010). The authors speculate that aldosterone activates the vascular endothelial MR, in the setting of healthy endothelium, which is anti-thrombotic, but in the setting of an injured or diseased endothelium, aldosterone is pro-thrombotic. Activity of extra-renal MR, including in the vasculature and adipose tissue, and associated high aldosterone levels, favors the development of components of metabolic syndrome such as hypertension and obesity, leading to the recent increased use of MR antagonists in clinical practice to counteract this aldosterone effect (Feraco et al. 2020).

Adiponectin Adiponectin is gaining recognition as a key mediator of endothelial dysfunction and cardiovascular disease. First discovered (Scherer et al. 1995) and cloned (Maeda et al. 1996) about 25 years ago, adiponectin is a small protein hormone that is exclusively produced by adipose tissue and is composed of 244 amino acids. Adiponectin has effects in multiple tissues including the liver, pancreas, and skeletal muscle; in endothelial cells, adiponectin activates the AMP kinase pathway which stimulates NOS production and bioavailability (Wang and Scherer 2008). Adiponectin production is decreased in all inflammatory processes. In humans, there is a strong negative correlation between blood pressure and plasma adiponectin levels (Kazumi et al. 2002; Baden et al. 2013), and adiponectin levels seem to be an independent risk factor for the development of hypertension (Chow et al. 2007). Mounting evidence suggests that endothelial dysfunction may be the common link between hypoadiponectinemia and hypertension.

J. Goodwin

Adiponectin is thought to regulate the enzymatic activity of eNOS via several mechanisms including increased mRNA stability, association with heat shock protein 90 (Hsp90), a scaffolding molecule, and eNOS phosphorylation at Ser1179 (Fulton et al. 1999; Wang and Scherer 2008). In vitro, adiponectin treatment of cultured endothelial cells increases cyclooxygenase-2 (COX-2) expression and activates that Akt-dependent COX-2 signaling pathway (Rojas et al. 2014), which has been shown to protect the heart from ischemia reperfusion injury in coronary artery disease (Szmitko et al. 2007). There are not many studies that have examined the ramifications of hypoadiponectinemia in children, as compared to adults. However, in the few studies that have been completed, adiponectin levels have been found to be statistically lower in obese children (Panagopoulou et al. 2008) and seem to be an independent risk factor for diabetes and cardiovascular disease (Bush et al. 2005; Cruz et al. 2004; Ogawa et al. 2005) – findings that would be anticipated, given data in adults. The most recent study examining this phenomenon in children studied a small group of 74 prepubertal obese children and determined that a decrease adiponectin levels was associated with a decrease in flow-mediated dilatation and an increase in pulse wave velocity and arterial stiffness (Maggio et al. 2018). The question as to whether prenatal adiponectin levels determine post-natal levels and/or contribute to lifetime cardiovascular risk is unresolved and is an active area of investigation.

MicroRNAs In this age of increasing ease of genetic manipulation and broader understanding of the epigenetic determinants of health, microRNAs have emerged as another contributor to vascular remodeling. Several miRs have been well described in endothelial cells and are thought to directly influence vascular remodeling. For example, miR-21 has been shown to regulate proliferation, migration, and tubulogenesis (Dentelli et al. 2010), purportedly through regulation of RhoB (Sabatel et al. 2011).

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Most recently, miR-21 has been implicated in vascular remodeling and perivascular fibrosis via endothelial-to-mesenchymal transition (EndMT), particularly in diabetic patients (Li et al. 2020). miR-126 is also highly expressed in endothelial cells and is known to regulate angiogenesis during embryonic development (Fish et al. 2008) but has also been shown to have anti-inflammatory (van Solingen et al. 2011) and anti-atherogenic roles (Zernecke et al. 2009). miR-155, also found in endothelial cells, can be activated by increases in shear stress, such as may be found in the early stages of vascular remodeling, and in turn inhibits vascular inflammation by downregulation of the gene ETS-1, a transcriptional activator of inflammation (Fang and Yeh 2015). Also of note is miR-221/222, which is highly expressed in both vascular smooth muscle cells and vascular endothelial cells but has differing functions which are dependent on cell type. While this miR aggravates neointimal hyperplasia in smooth muscle cells (Liu et al. 2009), it has been shown to be anti-inflammatory, anti-atherogenic, and antiangiogenic in endothelial cells (Zhu et al. 2011; Poliseno et al. 2006). Circulating endothelial miRs, such as miR cluster 221/222, are emerging as new therapeutic targets for treatment of cardiovascular diseases related to vascular remodeling. Vascular miR-204 is one of the newest players in this arena. It has been shown to promote endothelial dysfunction and impair blood pressure decline during periods of inactivity in a mouse model of diabetes; interestingly, miR-204 was also shown to be sensitive to the microbiome as microbial suppression can decrease vascular expression of miR-204 and improve endothelial cell function (Gaddam et al. 2020). miR-204 is also postulated to be a key link between cardiovascular and renal diseases (Liu et al. 2021).

Conclusions Endothelial dysfunction is recognized as a major risk factor for the development and perpetuation of hypertension in all age groups. Notably, some of the conditions presently increasing among

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children, including obesity and chronic kidney disease, may lead to endothelial dysfunction. Ongoing research efforts and clinical trials continue to uncover novel players in the complex regulatory systems and signaling pathways that direct the functions and fate of endothelial cells, often tipping the balance from the healthy vasculo-protective endothelium to a dysfunctional, disease-promoting endothelium which fuels many cardiovascular diseases. Unchecked endothelial dysfunction leads to maladaptive mechanisms including vascular remodeling, a complex interplay of proliferative and largely pro-inflammatory changes occurring in multiple cell types, which may permanently alter vasculature and systemic blood pressure.

Cross-References ▶ Cardiovascular Influences on Blood Pressure ▶ Cohort Studies, Meta-analyses, and Clinical Trials in Childhood Hypertension ▶ Epidemiology of Hypertension and Cardiovascular Disease in Children and Adolescents ▶ Hypertension in Chronic Kidney Disease ▶ Hypertension in End-Stage Kidney Disease: Dialysis ▶ Hypertension in End-Stage Kidney Disease: Transplantation ▶ Insulin Resistance and Other Mechanisms of Obesity Hypertension ▶ Obesity Hypertension: Clinical Aspects ▶ Obstructive Sleep Apnea and Hypertension in Children

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Adverse Childhood Experiences and Their Relevance to Hypertension in Children and Youth

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Julie R. Ingelfinger

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 ACEs as Compared to Other Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Examples of Studies in Children and Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Examples of Studies in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 What Are the Mechanisms by Which ACEs Effect Changes? . . . . . . . . . . . . . . . . . . . . . 223 Limitations in Studies of ACEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Abstract

The concept of adverse childhood experiences (ACEs) grew out of observations that childhood exposure to neglect, abuse, and a dysfunctional home environment could, in a dose-dependent manner, lead to adverse outcomes impacting future physical and mental health, including hypertension and cardiovascular disease. ACEs, in and of themselves, may lead to at-risk behaviors known to have adverse health implications, e.g., smoking, substance use disorder, early initiation of

sexual activity, early pregnancy, and multiple sex partners. Further, ACEs may lead to altered physiology and epigenetic alterations, making the affected persons at higher risk of illness. Risk scoring systems, adjusted for confounders, have supported the concept that ACEs are important in predicting many illnesses, including cardiovascular disease. The high prevalence of ACEs, up to 60% of the US population having experienced one, and up to 20% four or more, indicates that understanding this concept and the available data is important in the evaluation of children and adolescents with hypertension. This chapter reviews the concept of ACEs and presents relevant data.

J. R. Ingelfinger (*) Pediatric Nephrology Unit, Mass General for Children at MGB, Harvard Medical School, Boston, MA, USA e-mail: jingelfi[email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_58

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Keywords

Adverse childhood experiences (ACEs) · Abuse · Neglect · Dysfunctional home environment · Hypertension · Blood pressure · Kidney disease

Introduction Over the past several years, a variety of studies, most retrospective, have, in the aggregate, suggested that adverse childhood experiences (ACEs) may influence health in later life. For example, relevant to blood pressure (BP), ACEs may increase the risk of later hypertension, and, ultimately, cardiovascular disease and kidney disease (see Godoy et al. 2021; Lin et al. 2021). To date, such evidence is largely epidemiologic, though some supportive scientific studies in inbred rodents and other experimental models lend weight to the importance of ACEs. Further, current data have begun to suggest relevant mechanistic pathways through which these effects may occur. The concept of ACEs grew out of observations that childhood exposure to neglect, abuse, and a dysfunctional home environment could, in a dosedependent manner, lead to at-risk behaviors known to have adverse health implications, e.g., smoking, substance use disorder, early initiation of sexual activity, early pregnancy, and multiple sex partners (Anda et al. 1999). The initial work in what has now become a burgeoning field was pioneered by Felitti and colleagues who studied a large cohort of Kaiser-Permanente patients together with the CDC (Felitti et al. 1998). The investigators developed questionnaires the answers to which created risk scores (now often called “conventional” risk scores) based on seven areas of inquiry about social factors. These scores, adjusted for confounders, have supported the concept that ACEs are important in predicting many illnesses, including cardiovascular disease. The data for that initial study (CDC study, accessed 2022) was unique – it involved over 17,000 southern California members of Kaiser-Permanente and covered two data collection waves from 1995 to 1997 that included physical examinations

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and surveys. Of importance, two-thirds of the participants reported that they had endured at least one ACE. The initial questionnaire from the Kaiser-CDC study was subsequently expanded to cover 10 domains. These additional areas enlarged the classification and concept of ACEs to account for diverse environments, for example, community violence, foster care, racism, bullying, and separation resulting from deportation or immigration. These are categorized as “expanded ACEs” (Cronholm et al. 2015). See Table 1 for summary of conventional and expanded ACEs. While substantial data repeatedly indicate that up to two-thirds of all adults have experienced at least one or more ACEs that can impact later health, health care providers, and indeed the health care system, have had a difficult time acknowledging the existence and power of ACEs in influencing the health of individuals, and, indeed, the population (Krugman 2019). A number of epidemiologic cohort studies have provided evidence that adversity in childhood is associated with increased risk of cardiovascular conditions later in life – higher likelihoods of ischemic heart disease, atherosclerotic cardiovascular disease, and hypertension. Well-known cohorts in which such studies have been conducted have included the Adverse Childhood Experience Study (Felitti

Table 1 Conventional and expanded ACES Conventional ACEs Physical abuse Substance-using household member Emotional abuse Household member with mental illness Witnessed domestic violence Sexual abuse Incarcerated household member Emotional neglect Physical neglect Expanded ACEs Witnessed violence Felt discrimination Neighborhood unsafe Victim of bullying Lived in foster care

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et al. 1998), the CARDIA study (Pierce et al. 2020), and the Nurse’s Health Study II (RichEdwards et al. 2012). While many studies on ACEs are cross-sectional, some longitudinal data about ACEs starting with assessment during later infancy and early childhood and following the participants to evaluate the impact of ACEs on subsequent health are emerging. This chapter explores the concept of ACEs and their role in the development of future hypertension and other chronic diseases in later life.

ACEs as Compared to Other Adverse Events Clearly, many adverse events of various intensities can and do occur during childhood (infancy through age 18 in most studies to date). As ACEs were initially conceived, the adverse events constituted those considered in the realm of neglect, abuse, and dysfunctional homes (Felitti et al. 1998). Such events obviously shape a child’s future in many ways, and, not surprisingly, the concept of ACEs has been expanded (Mersky et al. 2021; Choi et al. 2020; Cronholm et al. 2015; Gooding et al. 2020; Hicken et al. 2021). Additionally, children who live through war, famine, and environmental cataclysms (earthquakes, volcanic eruptions, and tsunamis) have also endured obvious stresses, but these differ from ACEs. Still other types of personal challenges have been considered – a health crisis or accident involving the patient. Further, the locale of one’s childhood is important in the stress surrounding daily experiences – i.e., what is now termed the “built environment” – which impacts later health (Blackwell, et al. 2001). Indeed, growing evidence suggests that these environmental and political issues will have worse long-term implications in persons who have experienced ACEs (Gordon 2021). However, most of the research-identified association about ACEs has focused on the three domains initially denoted: (1) dysfunctional household environment/family, (2) abuse (sexual, emotional, and physical), and (3) neglect. Additionally, poverty, as well as serious childhood health challenges, constitutes risk factors for

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future illness. Further, well-known risk-factors first identified in adults have been associated with ACEs – smoking, physical inactivity and obesity, and alcohol and substance use. And these same risk factors are also linked to chronic diseases that have included CV disease, pulmonary disease, hepatic disease, and cancer (Danese et al. 2009; Dong et al. 2003; Felitti et al. 1998). A difficulty in the interpretation of some of the data supporting the concept of ACEs and future disease is that information about childhood events in many published reports was obtained years later, by recall, and the populations studied do not necessarily lend themselves to generalization of the study findings. However, a rich variety of data are becoming available, and studies carried out in small animal models (see de Miguel et al. 2018) provide some mechanistic support for the concept that ACEs may influence the subsequent development of adult conditions. The Center for Disease Control (CDC) in the USA, through its Behavioral Risk Factor Surveillance System, has noted that, according to a 25-state survey, 61% of adults reported having experienced one or more adverse childhood experiences, and nearly one in six reported having experienced four or more (Merrick et al. 2019). The WISQARS™ – Web-based Injury Statistics Query and Reporting System – available through the CDC has tracked a number of specific ACEs. This system is an interactive, online database and includes data on fatal and nonfatal injury, violent death, and cost of injury data. Importantly, the use of WISQARS™ is freely available to members of the media, public health professionals, and the public. Figure 1 illustrates how the CDC conceptualizes the impact of ACEs over time on health. Other ongoing work has used updated questionnaires and has identified more items that mark whether a given person has experienced ACEs. For example, the Childhood Experiences Survey (CES) focuses on specific experiences/adversities and tests the associations between these various experiences and mental health in adults. The CES has found 17 interrelated events and describes a four-factor solution – direct victimization/household dysfunction, neglect, poverty, and family separation/loss (Choi et al. 2020).

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Fig. 1 Diagram courtesy of the Centers For Disease Control and Prevention

Clinical Studies Most studies concerning ACEs are epidemiologic and provide associational data about subsequent illness or about various stress or vasoactive pathways. Some examples follow:

Examples of Studies in Children and Youth A number of studies about ACEs have focused on effects already evident in children and youth prior to adult life. For example, Pretty et al. carried out a cross-sectional study of 1234 children in middle school (grades 6–8) in a school-based project in which resting BP, heart rate, BMI, and waist circumference were measured (Pretty et al. 2013). In that study, the children’s parents filled out an ACE inventory from the Childhood Trust Events Survey. The investigators then used linear regression models to evaluate the relation between >4 prior ACEs and SBP, HR and BMI, and also the presence of hypertension and obesity. The study controlled for income, family education status, age, sex, and level of physical

activity, as well as for parental hypertension and waist circumference (Pretty et al. 2013). After adjustment, the investigators found that >4 ACEs were associated with higher resting HR, higher BMI, and larger waist circumference, as well as obesity, though confidence intervals were broad (Pretty et al. 2013). The Niagara Longitudinal Heart Study has examined the influence of ACEs on cardiovascular health over time. Wade et al. carried out a pilot study (Rafiq et al. 2020), in 76 persons (18 or older) who were prior participants in the crosssectional Health Behavioural and Environmental Assessment Team (HBEAT) Study, which had examined a cohort of children in grades 5–8 (10–14 years of age) from which a subsample had had in-depth cardiovascular structural and functional measures determined (Wade et al. 2019). The investigators found that 4 or more ACEs were associated with increased arterial stiffness over time, a finding seen in both male and female participants and independent of heart rate change, systolic BP, BMI, and physical activities (Wade et al. 2020). Such data provide a start in documenting the association of ACEs and subsequent adverse cardiovascular abnormalities.

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Death of a parent has widely been considered an adverse childhood experience. Chen et al. (2021) examined the association of death of a parent (obtained from population-based registries) and BP in 48,624 men born in 1949–1951 at the time of compulsory military conscription (1969–1970). The analysis (multivariable least square means of systolic and diastolic pressure) adjusted for gender of the deceased parent, age of the child at parental death. There was no difference overall, though the subgroup of those subjects whose parents had died of natural causes had a marginal increase in the risk of hypertension. A major limitation was that few BPs were recorded (one or two measurements per participant), so generalizability is unclear. Additionally, confounders were also not considered. Though studies starting in childhood and youth are presently limited, ongoing work is likely to provide more data with similar implications – ACEs experienced in childhood and youth will likely be found to have implications for future BP levels and cardiovascular health.

Examples of Studies in Adults There are data from studies among young adults indicating that prior exposure to multiple ACEs is correlated with increased risk of elevated BP during young adulthood. Specifically, the Georgia Stress and Heart study (GSH) found a positive correlation 23 years after the occurrence of specific ACEs, and independent of BMI (Su et al. 2015). Analyses from the Nurses’ Health Study II, a large, complex, and well-run cohort study initiated in 1989 that includes participants who selfdocument many aspects of their lives and provide biosamples, reported that abuse in childhood was associated with an increased risk of developing Type 2 diabetes and other health issues (RichEdwards et al. 2010; Riley et al. 2010). In another large study (45,482 participants), Kreatsoulas et al. extracted data from the 2009 and 2011 Behavioural Risk Factor Surveillance System and were able to obtain complete information on ACEs, health behaviors, and risk

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factors in this cohort of persons aged 18 to 99 years of age (Kreatsoulas et al. 2019). The ACEs were then classified and evaluated as a “cumulative burden.” The authors used multivariable logistic analysis, including stratification for these young adults. One ACE was reported by 52% of participants, and two such events by 25%. The authors noted that a second ACE was associated with hypertension, diabetes, and dyslipidemia. Findings were most pronounced in young adult participants (Kreatsoulas et al. 2019). In the Southern Community Cohort Study (n ¼ 38,200 participants in 12 states in the southeastern USA), following adjustment for confounding there was a positive association for all chronic conditions examined other than hypertension in persons reporting 4 ACEs as compared to those reporting none (Sanderson et al. 2021). Other associations relevant to cardiovascular disease included a positive relation with ACEs and stroke, myocardial infarction, and elevated cholesterol levels. In a retrospective study of 17,337 adult members of a health plan, Dong et al. carried out a logistic regression analysis, using age, sex, race, and education level (Dong et al. 2004), and noted that roughly half of ischemic heart disease variance can be explained by “traditional” risk factors – smoking, lack of exercise, and diabetes mellitus, but that ACEs might explain the shortfall in risk factor-related ischemic heart disease. The same group also reported an ACEs dose-response relation to self-reported liver disease (Dong et al. 2003). In a cross-sectional study, Crowell et al. examined 210 Black/African Americans and White/European Americans in midlife (mean age 45.8 +/ 3.3 years, range 35–55 years) in a Boston-based cohort study that looked at adverse childhood experiences, as well as metabolic and physical factors related to adult systolic and diastolic BP. Their analyses reported association between ACEs and adult waist-hip ratio, leptin levels, and mean arterial BP as well as systolic and diastolic BP (Crowell et al. 2016). Alastalo et al. examined 1361 nonobese persons born between 1934 and 1944 in Helsinki, Finland, and who had (192) or had not (1169)

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been separated from their parents during World War II (Alastalo et al. 2013). Those who had been temporarily separated had higher systolic BP as adults, and also higher diastolic BP. There were other differences, depending on the age at which separation took place. Anda et al. have found a relation between ACEs and premature death in families (Anda et al. 2009). Using a detailed categorization of ACEs, they found what they term a graded relation between ACEs and premature death. In their discussion, the authors consider the panoply of ACEs, taken together, markers of a stressful childhood environment (Fig. 2). Stress throughout life may be important in cardiovascular health as well. For example, Clemens et al. examined the relation between psychological stress and subsequent cardiovascular health in a cross-sectional design using a probability sample of people in Germany, and they elicited a history of adverse events in adult life, as well as memory of childhood maltreatment (Clemens et al. 2021). The authors found that adverse life events in adult life were associated with adverse CV health events. Of interest, they also found that childhood maltreatment was also “significantly and independently” associated with cardiovascular health in both men and women (Fig. 3).

Fig. 2 Adjusted prevalence of premature death of family member among different age groups by number of ACEs. (From Anda et al. 2009 with permission)

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Koyama et al. randomly recruited 491 older persons, aged 65–84 years in Tokamachi City, Japan (Koyama et al. 2022), and assessed the relation between self-reported ACEs and brain anatomy. Seven brain regions of interest were evaluated via structural magnetic resonance imaging. The authors reported that ACEs were associated with the volumes of brain regions such as anterior cingulate cortex, hippocampus, and amygdala, which are responsible for emotion and self-regulation. While such a study does not directly inform an interaction of ACEs and BP, it does provide indirect evidence of a possible physical association between a history of ACEs and health much later in life. In a recent study of 11,972 people in China, Lin et al. used a questionnaire to assess the presence of any of 12 ACEs and the association with 14 chronic diseases, among them hypertension, heart disease, stroke, and dyslipidemia. Associations were evaluated using logistic regression models and modification by tests for interaction and stratified analyses. Mean age of participants was 59.9 years, and 51.6% were female. The vast majority reported exposure to 1 or more ACEs (80.9%), and 18% had been exposed to 4 or more ACEs. Those exposed to 4 our more ACEs had increased risks of kidney disease and stroke, but not of heart disease or hypertension (Lin et al. 2021).

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Fig. 3 Cardiovascular problems and number of adult stressful life events. Analyzed via Chi2-Tests. From Clemens et al. (2021), with permission

The authors speculated whether the lack of association with hypertension in their study might have been due to the relatively low numbers of persons with obesity. A large systematic review and meta-analysis was performed by Hughes et al. in 2017. These investigators searched five electronic data bases (up to May 6, 2016) for studies that reported health outcomes in adults aged 18 or older that were associated with multiple ACEs (Hughes et al. 2017). The investigators selected articles with risk estimates for four or more ACEs compared to none. Thirty-seven studies (of 11,621 references screened) provided risk estimates for 253,719 persons. Associations were moderate for heart disease (OR 207 [CI 166–259]). In a recent systematic review, Scott et al. reported that ACEs were reported to be associated with higher risk of elevated BP (Scott et al. 2021). In that study, the authors, with the help of a medical librarian, reviewed literature from January 1998 to December 2019; of 1740 papers, 12 (8 cohort studies) were considered to have met the criteria for the study. When self-reported

history of ACEs was reported, 60% of studies had a significant association with ACEs and increased BP, but when the history of ACEs was verified, only 30% did (Scott et al. 2021). Further, 25% of the studies showed an association of ACEs and lower BP. Such a study indicates the difficulties in carrying out analyses in this field.

What Are the Mechanisms by Which ACEs Effect Changes? A number of mechanistic studies intended to explain the physiological and long-term effects of ACEs have involved animal models, particularly maternal separation. Such work has implicated stress and reactive oxygen species (ROS). For example, Ho et al. have shown that such stress results in endothelial abnormalities in which elevated NADPH levels-mediated superoxide production has been observed in an adult murine model (Ho et al. 2016). Fewer studies have been carried out in humans, most often by doing blood tests on persons

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participating in cohort studies. Endothelial function, which is crucial to cardiovascular health, may be adversely impacted by the response to ACEs. Nitric oxide (NO), produced through endothelial NO synthase, is important in maintaining the function of the endothelium. When NO is not bioavailable, it increases the likelihood of vascular dysfunction, important in the development of cardiovascular disease. The increased presence of reactive oxygen species (ROS) also can decrease NO levels. Another important factor is that the NADp-dependent deacetylase, sirtuin 1 (Sirt1), is key to maintenance of endothelial health through regulation of many proteins. Sirt 1 is dependent on NADp also – and regulates NOS3. Studies from the group of Rodriquez and Pollock indicate that a relatively low level of Sirt1 in childhood is a factor in microvascular dysfunction in early adulthood (Rodriguez-Miguelez et al. 2020). Inflammation is hypothesized to occur in response to ACEs (as it does in other stressful settings). Evidence of increased systemic inflammation, as measured by high-sensitivity C-reactive protein (CRP), was identified in the Dunedin Multidisciplinary Health and Development Study (Danese et al. 2007). In that study, more participants noted to have a history of maltreatment or social isolation. There are additional association studies that indicate that biomarkers of stress are increased in persons who have suffered ACEs. For example, Bourassa et al. recently examined three stress biomarkers in 828 persons who participated in the Dunedin cohort – interleukin-6 (IL-6), CRP, and soluble urokinase plasminogen activator receptor (suPAR) and observed that persons who had ACEs had higher suPAR levels at age 45 (Bourassa et al. 2021). Marin and colleagues (Marin et al. 2009) determined stress in 71 children with asthma and 76 children without by using child version of the University of California Los Angeles Life Stress Interview and also measured cytokines IL-4, IL-5, IL-13, and IFN-gamma every 6 months over a 2-year period. They then obtained self-reported asthma symptoms after each study visit. Those children with reported

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higher levels of family stress had higher levels of cytokines IL-4, IL-5, and IFN-gamma as compared with those without stress. The authors interpreted this as supporting the concept that negative life events were important in asthma symptomatology. In recent studies, Jenkins et al. have reported that young adults with history of ACEs in childhood appear to have decreased vascular endothelial capacity, as measured by flow-mediated dilation studies (Jenkins et al. 2021). Further, in a study of 221 healthy adolescents and young adults (mean age 21 years, range 13–20 years), Su et al. reported that endothelin levels were directly related to the number of ACEs (Su et al. 2014). In addition to other measures, the authors examined BP and then also peripheral vascular resistance measures of arteriolar stiffness, and circulating endothelin-1 (ET-1) levels. The authors observed a graded association with ACEs and plasma ET-1 levels. Further, these with two or more ACEs had significantly higher total peripheral resistance, diastolic BP, and pulsewave velocity. Importantly, the observations appeared to be independent of race, age, gender, BMI, and SES in childhood. ACEs may lead to changes in the stress response. For example, Elzinga et al. did a small study in which they compared 33 persons with a childhood history of stress to 47 who had low exposures (Elzinga et al. 2008). They then measured salivary cortisol levels before, during, and following a “psychosocial stress task” in healthy young adults. Those with a history of exposure to adverse events in childhood, particularly the male participants, had a blunted cortisol response. The authors take this to suggest that the hypothalamic-pituitary axis may be affected by adverse events earlier in life. A recent metaanalysis by Brindle and colleagues supports the concept that blunted HPA, and cardiovascular stress response is associated with ACEs (Brindle et al. 2022). There is some evidence that, just as with perinatal programming, ACEs may have transgenerational implications, some of which have implications for cardiovascular health of subsequent generations.

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Genes are activated or turned off by epigenetic modification, for example, through the methylation of cytosine, which alters gene function without changing base sequences. Epigenetic studies are lending credence to the concept that prenatal exposures to adversity result as a result of ACEs. Neves et al. performed a retrospective systematic review of 36 studies in which DNA methylation was determined and then associated with the exposure to ACEs that took place between birth and age 16. In this systematic review, 28 articles found an estimated association with childhood adversity and future physiology and increased risk for psychopathologic illnesses. However, no correlation with “somatic illnesses” was performed at the time of the report (Neves et al. 2019). In a recent report, Folger et al. noted that there was evidence that DNA methylation of certain genes was increased in infants whose mothers had had ACEs, but that home visits to the at-risk neonates could modify the epigenetic changes (Folger et al. 2021). Using the Avon Longitudinal Study of Parents and Children (ALSPAC), Tang et al. explored the association of ACEs with DNA methylation age acceleration and plasma cortisol in 974 subjects. They performed Horvath-estimated DNA methylation age acceleration, as well as baseline plasma cortisol levels in adolescence. They also accessed the ACE International Questionnaire from the WHO that had been collected prospectively from birth to age 14 years. The exposure to four or more ACEs as compared to none appeared to be associated with DNA methylation age acceleration in girls, though not in boys; further, emotional and physical abuse were also associated with DNA methylation age acceleration in girls, but not boys. No specific chronic physical diseases were included in that analysis (Tang et al. 2020). While maternal ACEs have an intergenerational effect through epigenetic effects, these changes may be modifiable (see review by Roubinov et al. 2021). Nwanaji-Enwerem et al. studied the relation between ACEs in mothers during childhood (to age 18) as reported in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study and examined telomere length in leukocytes. Having maternal ACEs was

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associated with a 0.76 or greater acceleration in epigenetic age. The authors adjusted for maternal age at delivery, the use of smoking and alcohol during gestation, the child’s gestational age, parity, and estimated leukocyte proportions (NwanajiEnwerem et al. 2021). In all, they tested 8 epigenetic markers, lending to the strength of their data. However, there was not a validation cohort in the study, a major drawback, although the results are very interesting. Further, mitochondrial alterations may be central to the mechanisms by which ACEs have longterm health effects. Mitochondria respond to stress and may play a major role in the long-term effects of ACEs (Zitkovsky et al. 2021). In sum, concepts through which ACEs effect change are evolving and, once the mechanisms are understood, will provide potential targets through which to modify their effects. Figure 4 displays a current view.

Limitations in Studies of ACEs The occurrence of ACEs in childhood – infancy to age 18 – and their effects in adult life means that investigation to date – given the time span encompassed – consisted of cross-sectional cohort studies or retrospective work. Such studies have, of necessity, certain limitations – often, questions of personal recall, confounding, and the fact that conclusions are associational, not causal. Look-backs at the persons followed prospectively over time such as the Bogalusa Heart Study and the Muscatine Study may provide high-quality associational data but will not permit claims of causation. When ACEs occur very early in life, the concept intersects with that of Developmental Origins of Health and Disease, which holds that early events (that may be exposures that would not typically be labeled as ACEs) lead to alterations in organ development, sufficiently subtle as not to be connected with gross organ maldevelopment. DOHaD events may well include ACEs, and, obversely, DOHaD may certainly be induced by ACEs. Indeed, there are parallels in how these two areas of research and of conceiving potential

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Fig. 4 Relation between ACEs and later illnesses. SNS, sympathetic nervous system; HPA axis, hypothalamic-pituitaryadrenal axis

cause have gone forward. Such overlap should, one might suggest, be considered as conceptually useful, and crosstalk between investigators in these two broad areas would be beneficial.

Conclusion Growing evidence suggests that ACEs may have a profound influence on future health (see Hall et al. 2021). There is a direct association between the number of ACEs a child endures and future risk-taking and future adverse, often chronic health conditions (Obi et al. 2019). The impact may affect not only health, but also educational achievement and occupational success. Among conditions associated with ACEs are obesity, cardiovascular disease, and hypertension. Thus, clinicians and investigators who care for children and youth with hypertension need to become familiar with this relatively young field.

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228 Nwanaji-Enwerem JC, Van der Laan L, Kogut K et al (2021) Maternal adverse childhood experiences before pregnancy are associated with epigenetic aging changes in their children. Aging 13(24): 25653–25669. https://doi.org/10.18632/aging.203776 Obi IE, McPherson KC, Pollock JF (2019) Childhood adversity and mechanistic links to hypertension risk in adulthood. Br J Pharmacol 176:1932–1950 Pierce JB, Kershaw KN, Kiefe CI et al (2020) Association of childhood psychosocial environment with 30-year cardiovascular disease incidence and mortality in middle age. J Am Heart Assoc 9(9):e015326. https://doi. org/10.1161/JAHA.119.015326 Pretty C, O’Leary DD, Cairney J, Sade TJ (2013) Adverse childhood experiences and the cardiovascular health of children: a cross-sectional study. BMC Pediatr 13:208. http://www.biomedcentral.com/1471-2431/13/208 Rafiq T, O’Leary DD, Dempster KS, Caimey J, Wade TJ (2020) Adverse childhood experiences (ACEs) predict increased arterial stiffness from childhood to early adulthood: pilot analysis of the Niagara longitudinal heart study. J Child Adolesc Trauma 13:505–514 Rich-Edwards JW, Spiegelman D, Lividoti Hibert EN, Jun HJ, Todd TJ, Kawachi I, Wright RJ (2010) Abuse in childhood and adolescence as a predictor of type 2 diabetes in adult women. Am J Prev Med 39:529–536. PubMed: 21084073 Rich-Edwards JW, Mason S, Rexrode K et al (2012) Physical and sexual abuse in childhood as predictors of early-onset cardiovascular events in women. Circulation 126(8):920–927. https://doi.org/10.1161/CIRCU LATIONAHA.111.076877 Riley EH, Wright RJ, Jun HJ, Hibert EN, Rich-Edwards JW (2010) Hypertension in adult survivors of child abuse: observations from the nurses’ health study II. J Epidemiol Community Health 64:413–418. PubMed: 20445210 Rodriguez-Miguelez P, Looney J, Thomas J, Harshfield G, Pollock JS, Harris RA (2020) Sirt1 during childhood is associated with microvascular function later in life. Am J Physiol Heart Circ Physiol 318:H1371–H1378. https://doi.org/10.1152/ajpheart.00024.2020

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Salt Sensitivity in Childhood Hypertension

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Coral D. Hanevold

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Definitions and Methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Pathogenesis of Salt Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Phenotype of Salt-Sensitive Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 Diabetes Type 2 and Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Low Birth Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Race and Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Stress and Adverse Childhood Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Interventions for Salt Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Surrogate Markers for Salt Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Abstract

C. D. Hanevold (*) Division of Nephrology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA e-mail: [email protected]

The importance of salt in the genesis and perpetuation of hypertension is well established. However, within the population, there is considerable heterogeneity in the individual blood pressure response to salt intake. Those with little or no change in their BP in response to salt depletion or loading are considered salt

© This is a U.S. Government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_18

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resistant (SR) while those with more significant changes are labeled as salt sensitive (SS). Currently, assessment for SS is impractical, and thus population-wide salt restriction is recommended for all who are hypertensive. This chapter will review definitions of SS, current perspectives on the pathogenesis, and mechanisms involved in inducing SS, explore the phenotype of the SS pediatric hypertensive patient, and outline appropriate interventions. Keywords

Hypertension · Salt sensitivity · Sodium · Potassium · Heritability · Obesity · Diabetes · Insulin resistance · Stress · Low birth weight

Introduction The connection between salt and blood pressure (BP) has been demonstrated in many animal and human studies over the years. The seminal INTERSALT cross-sectional multinational study of 10,000 adults (ages 20–59 years) showed a positive independent relationship between systolic BP and 24-hour urine sodium excretion in individual subjects and urine sodium to potassium ratio (Intersalt Cooperative Research Group 1988). Across all sites, sodium excretion showed a positive correlation with the slope of BP with age. Regarding children and adolescents, a recent meta-analysis confirmed a positive relationship between BP and sodium intake in children ages 0–18 years (Leyvraz et al. 2018). Indeed, for years, sodium restriction has been one of the recommended lifestyle measures for initial treatment of hypertension (HT) in children and adolescents. However, it may be difficult to easily achieve this alteration in diet on an individual level even when motivation may be high due to the finding of HT. Sodium is ubiquitous in commercially prepared and processed food products complicating efforts to reduce intake. Additionally, it is recognized that salt restriction is not uniformly effective for everyone. Clearly, identification of those who are sensitive to the effects of salt on BP and

C. D. Hanevold

thus likely to benefit from salt restriction would allow a more nuanced approach to management.

Definitions and Methodologies In those who are salt sensitive (SS), changes in dietary salt intake result in exaggerated and parallel changes in BP. In salt-resistant (SR) individuals, BP changes little in response to variation in salt intake. The magnitude of BP change that supports SS has varied between studies. The degree of BP change is greater in hypertensive versus normotensive individuals. Recently proposed criteria for the minimal BP change in adults that signifies SS are shown below (Kurtz et al. 2017): • In normotensives, mean arterial pressure (MAP) change
3–5 mm Hg • In hypertensives, MAP change
8–10 mm Hg However, outside of the research environment, these discrete criteria for SS do not reflect the realworld situation. Within the population, the BP response to salt follows a Gaussian curve (Weinberger et al. 1986). The frequency of SS generally is around 50% in hypertensive adults and 25% of normotensive adults with some variability noted depending on the population tested. Please refer to Table 1 for comparison of salt and sodium; intake will be expressed according to the relevant reference. Direct testing of SS requires measurement of BP after exposures to low and high salt intake. Again, as with definitions, protocols vary. As recently reviewed, studies with the greatest reproducibility are characterized by controlled 1–2 weeks intake of low and high salt diets with adherence confirmed by 24-hour urine sodium collections (Kurtz et al. 2017). The salt intake provided in the two conditions should be reasonable and comparable to intakes that might be seen Table 1 Salt and sodium content 1 gram salt ¼ 388 mg sodium 1 gram sodium ¼ 2.6 grams salt 1 mmol sodium ¼ 23 mg sodium

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in free-living individuals. Measurement of BP either in the office or outside the office with ABPM to confirm the response to each diet is required. However, ideal methodology is not uniformly possible due to concerns about patient adherence and financial and time constraints. As a result, investigators may use alternative approaches such as inpatient testing, intravenous or oral saline loading for salt loading, extreme salt restriction coupled with diuretics for salt depletion, and spot urine estimation of sodium excretion. These variations in approach may underlie some of the conflicting results and poor reproducibility. Additionally, although 24-hour urines have traditionally been used to validate adherence to dietary manipulation, newer information may in time cast doubt on their use. There is increasing appreciation of the skin and other tissues as storage depots for excess sodium intake as discussed further below. As seems clear, direct testing for SS in the clinical arena is not feasible and is limited to the research environment where dietary intake may possibly be controlled. There are no guidelines for formal SS testing in pediatric populations. Few studies have been conducted in the pediatric age group. Most studies in children have compared the change in BP upon exposure to a high salt diet for a population of interest to the BP change in controls (Wilson et al. 1999a; Rocchini et al. 1989; Ruys et al. 2018; Simonetti et al. 2008; Mu et al. 2012; Mu et al. 2005; Ye et al. 2004). As shown in Table 2, in the few studies where SS was tested with a dietary protocol, variabilities and limitations include differing definitions of SS, inconsistent use of 24-hour urine sodium excretion to validate compliance, and comparison of BP values after exposure to a high salt diet to BP values on baseline diet rather than a low salt diet (Ruys et al. 2018; Simonetti et al. 2008). The use of furosemidebased protocols in conjunction with saline loading has been limited (Mu et al. 2005; Mu et al. 2012; Ye et al. 2004). However, in contrast to the poor reproducibility of inpatient furosemide-based studies noted in adult studies, Ye et al. reported consistent results in a small outpatient study of 55 adolescents (Ye et al. 2004). Utilizing an outpatient protocol composed of salt loading with

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intravenous saline followed by depletion by oral furosemide, classification of SS was sustained in over 90% of these participants.

Pathogenesis of Salt Sensitivity The concept of salt sensitivity was introduced in the 1970s by Kawasaki and Guyton (Kawasaki et al. 1978; Guyton 1991). Studies by Guyton provided the background to support the critical role for the kidney in sodium handling and implicated abnormalities in sodium excretion in response to volume loading and subsequent pressure changes as the underlying cause of SS HT. When the response to salt loading is normal, volume expansion leads to an increase in cardiac output and BP followed rapidly by natriuresis to restore cardiac output and BP to normal as shown in Fig. 1a. This process is referred to as pressure natriuresis. For those with SS, the response is inadequate due to defects in natriuretic or antinatriuretic mechanisms resulting in sodium retention and continued BP elevation (Elijovich et al. 2016). With time, the salt load is excreted. However, a body of evidence has accumulated over time that challenges this kidney-centric view. More recent studies failed to show an increased cardiac output and sodium retention in human subjects with SS as compared to SR (Kurtz et al. 2018). The “vasodysfunction” concept of SS contends that abnormalities in the vascular response to salt loading serve as the initiating event inducing SS. The normal response to the salt load is a reduction in systemic and renal vascular resistance as shown in Fig. 1b. Studies in humans demonstrate higher systemic vascular resistance, similar cardiac output, and sodium excretion in SS as compared to SR. BP rises due to the increase in systemic vascular resistance rather than retention of sodium. The underlying process(es) through which salt intake alters vascular tone remains to be elucidated. Reduction in nitric oxide generation within the vascular endothelium has been implicated through differing mechanisms (Feng et al. 2017). Feng et al. postulate that a high salt diet leads to excessive production of TGF beta resulting in the generation of oxidative stress and

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Table 2 Characteristics of direct studies of salt sensitivity in children and adolescents (under 18 years of age) Inclusion Risk of special group populations 1 week LS and HS intake Wilson African et al. Americans (1999a) only 2 weeks of HS and LS Rocchini Obese et al. (1989)

1 week of HS intake Ruys et al. Premature (2018) birth Simonetti LBW et al. (2008)

Ages of subjects (years)*

Total/SS subjects

14.2 +/ 1.0

140/31

MAP on low and HS intake


5 mm Hg increase

Yes, each diet

12.5 +/ 0.6

78/60 obese 18 controls

MAP on HS followed by low intake

BP response change with weight loss

Yes, low salt diet

7.9 [7.6–8.3]

63/10 24/9

>5% increase
3 mm Hg increase

No

LBW:11.4 +/ 0.4 NL BW: 11.2 +/ 0.4

MAP on usual diet to HS diet 24-hour MAP on normal diet and HS diet

310/101

MAP change pre/post saline loading and MAP change pre/post sodium depletion

As above As above

Saline**/furosemide based Mu et al. No SS: 9.3 +/ 1.9 (2012) NSS: 9.2 +/ 1.9

Mu et al. (2005) Ye et al. (2004)

Comparisons

Definition of SS

Validation with 24hour Urine Sodium

No

10.6 +/ 1.5

261/56

As above

Sum of MAP changes of
10 mm Hg As above

No

14.9 +/ 1.9

55/31

As above

As above

Yes

N/A (controlled intake)

HS, high salt; LS, low salt; SS, salt sensitive; NSS, non-salt sensitive; LBW, low birth weight; NL BW, normal birth weight; MAP, mean arterial pressure *mean +/- SD or median and [IQR] **Saline loading either by oral or intravenous route (Used with permission Hanevold 2021)

a reduction in nitric oxide availability. Other investigators suggest that exposure to elevated extracellular sodium levels may damage the glycocalyx overlying vascular endothelial cells allowing more sodium entry into the cells via ENaC (Mutchler et al. 2021). The resulting increase in intracellular sodium stabilizes the cytoskeleton rendering it less deformable and inhibits nitric oxide generation. However, there are many mediators of vascular resistance and further research is necessary (Kurtz et al. 2018). The pressure natriuresis process almost certainly explains SS in some individuals. Low nephron number due to premature birth, an adverse maternal

environment, and chronic kidney disease are thought to contribute to an impaired ability to excrete sodium. Beyond reduction in glomerular number and thus reduced filtration area, other processes including renin-independent aldosterone secretion, stimulation of intrarenal renin-angiotensin system (RAS), and inflammation have been found to contribute to enhanced distal tubule sodium reabsorption and SS in chronic kidney disease (Bovée et al. 2020). However, for many individuals worldwide with primary HT, there is growing evidence that suggests derangements in the vascular system may underlie SS for many (Kurtz et al. 2018).

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Acute Salt Load

a

↓ ↑ Intravascular Volume ↓ ↑CO and ↑ BP Natriuresis

NSS

SS

Adequate

Impaired

Baseline BP

↑ BP Persists

Acute Salt Load

b

↓ ↑ Intravascular Volume/↑ CO

NSS ↓↓RVR/PVR

SS Blunted ↓ RVR/PVR

↓

↓

Baseline BP

↑ BP Persists

Fig. 1 Comparison of response to acute salt loads under pressure natriuresis (PN) and renal vasodysfunction models for salt sensitivity (SS). In PN model (a), an acute salt load increases cardiac output (CO), blood pressure (BP) and promptly leads to natriuresis in non-salt sensitive (NSS) individuals while impaired natriuresis results in persistence of increased intravascular volume, CO and BP in SS subjects. In the vasodysfunction model, an acute salt load generates an increase in intravascular volume and CO. In the NSS these changes trigger a significant reduction in renal vascular resistance (RVR) and peripheral vascular resistance (PVR) and BP is unchanged. In the SS reduction in RVR and PVR is attenuated resulting in persistent elevation of BP. (Used with permission Hanevold 2021)

Beyond the kidney and vascular systems, the potential roles of other tissues in the maintenance of sodium balance and injury from SS have been

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increasingly appreciated. Involvement of the immune system in hypertension has long been recognized (Mattson 2019). Early histologic studies noted that lymphocytic infiltration around damaged glomeruli and renal arterioles and small arteries correlated with the severity of injury in hypertensive patients. Subsequent investigations identified interstitial accumulation of CD68 + macrophages, CD4 þ T helper cells, and CD8+ cytotoxic T cells in kidneys from hypertensives with accompanying circulating chemokines. Recent studies have offered insight into possible triggers for the immune system response (Elijovich et al. 2020). Investigators have found that a high salt environment results in sodium entry into antigen-presenting cells (APC) including dendritic cells via ENaC, inducing a state of oxidative stress with subsequent production and accumulation of isolevuglandins. These isolevuglandins cross-link with proteins with subsequent generation of neo-antigenic peptides. These neo-antigens, along with activated dendritic cells, induce differentiation of TH17 cells which produce the pro-inflammatory cytokine IL-17. Elijovich and colleagues identified APC (macrophages, monocytes, and dendritic cells) localized in the salt enriched medullary region in hypertensive patients where they may be activated by the high salt environment, thus inciting the pro-inflammatory response. Moreover, there are indications that renal sodium transporters can be modulated by inflammatory cytokines, including IL-17A and IL-1β. Immune cells are also activated by contact with high sodium environments in the gut, the initial point of entry for dietary sodium. Research shows that excessive salt intake impacts gut microbiota leading to gut dysbiosis (Wilck et al. 2017; Ferguson et al. 2019). These changes have been linked with immune independent and dependent effects that result in the generation of higher BP. Studies in mice demonstrate that exposure to a high salt depletes Lactobacillus from the gut, increases BP, and increases the number of Th17 cells (Wilck et al. 2017). Repletion with Lactobacillus murinus ameliorated these effects. In a follow-up study by the same investigators, healthy adult males treated with

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supplemental salt demonstrated reduction in Lactobacillus species, increase in nocturnal BP, and increase in numbers of TH17 cells. Other investigators have shown that exposure to high salt intake in mice heightens the BP response to low-dose angiotensin II and effects changes in gut dendritic cells that drive production of interferon-gamma and IL-17A by TH17 cells (Ferguson et al. 2019). Furthermore, transfer of fecal microbiota from mice fed a high-salt diet to germ-free mice increased the latter’s BP response to low-dose angiotensin II significantly when compared to transfer from normal salt-fed mice. Plasma levels of the pro-inflammatory cytokines, IL-6, and Il-17 increased significantly after the transfer from high salt-fed but not normal salt-fed. Although much more research into this complex process is needed, it seems clear that the inflammatory response to salt begins in the gut. Recent appreciation of the interstitium and specifically that within the skin, as a storage site for sodium, has challenged our understanding of sodium balance and offers insight into other possible mechanisms for SS HT (Selvarajah et al. 2018). The interstitium is rich in glycosaminoglycans (GAGs) which can bind sodium rendering it non-osmotically active. With salt loading, the buffering ability of the interstitium may be surpassed prompting an adaptive immune response. High salt exposure prompts expression of transcription factor tonicity-responsive enhancer-binding protein (TonEBP) and release of vascular endothelial growth factor C (VEGFC) by recruited macrophages. VEGF-C mitigates the hemodynamic effect of salt on BP by inducing lymphangiogenesis and upregulation of endothelial nitric oxide synthase (eNOS). The former improves the capacity for lymphatic drainage of water and sodium back to systemic circulation for renal excretion while the latter results in vasodilation. A reduced capacity to store sodium in the interstitium may convey a propensity for SS HT. Early work by Titze et al. demonstrated that osmotically inactive sodium accumulation was greater in SR versus SS rats and greater in male versus female rats (Titze et al. 2003). A recent study in humans demonstrated impaired ability

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to alter vascular resistance with sodium loading and depletion in SS individuals compared to SR subjects; the authors suggested that the abnormality in vascular response was linked to differences in salt and water interstitial storage as sodium balance (intake and excretion) was otherwise equal (Laffer et al. 2016). Using ambulatory BP monitoring in a placebo-controlled human trial, Selvarajah et al. demonstrated that skin sodium was significantly increased in men but not in women in response to 1-week high salt diet ingestion of a high salt diet (Selvarajah et al. 2017). Corresponding to their limited accumulation of skin sodium, women showed significant increases in BP, weight, and greater salt sensitivity than men. Further research is required, but regardless, the elucidation of the skin’s role as a storage site for excess sodium has altered the concept of sodium balance. Genetic variations undoubtedly factor into the pathogenesis of SS. Aside from the monogenetic disorders, it has been well appreciated for years that multiple genes have been implicated in causing or contributing to the development of SS. The Genetic Epidemiology Network of Salt Sensitivity evaluated the influence of genetic factors on BP response to dietary sodium interventions in 658 families in rural China (Gu et al. 2007). The heritability, or the proportion of the variance due to genetic factors, of MAP was 34% on free living diets and rose with standardization of diet to 51% for both low and high sodium diets. The heritability for percentage of MAP response were 23% and 33% after the low sodium and high sodium interventions, respectively. These results were consistent with earlier, smaller studies in other populations. Variants in genes influencing renal sodium handling, nitric oxide synthase, intracellular messaging, renin-angiotensin-aldosterone system (RAAS), and others have been identified (Elijovich et al. 2016; Liu et al. 2020). The similarity of the low renin phenotype noted in blacks to that of patients with Liddle’s syndrome has generated great interest in whether genetic mutations in the ENaC might underlie SS in those of African ancestry (Spence and Rayner 2018). Appreciation of the expression of ENaCs beyond the kidney suggests that alterations in ENaC

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function may contribute to SS through effects in vascular endothelium, dendritic cells, and several cell types in the central nervous system (Mutchler et al. 2021; Pavlov and Staruschenko 2017). Ongoing genetic investigations in diverse ethnicities may allow future identification of individuals likely to be SS. Beyond genetic mutations, future research into epigenetic modulations may shed light on familial patterns of HT.

Phenotype of Salt-Sensitive Hypertension Weinberger et al. conducted extensive research several decades ago to delineate the characteristics of SS and SR individuals (Weinberger et al. 1986). In this large US study of 375 normotensive and 192 hypertensive subjects, 26% of normotensive and 51% of hypertensive subjects were classified as SS. The magnitude of the BP change in response to salt was less in normotensive versus hypertensive SS subjects. Further investigation showed that overall, SS individuals were older; among normotensive adults, the frequency of SR was 65% in those under 30 years of age compared to 23% in adults over 50 years of age (Weinberger and Fineberg 1991). Additionally, the increase in BP with age was greater in those with SS versus SR even if normotensive. Importantly, SS hypertensive individuals had significantly lower plasma renin activity values than SR hypertensives at baseline, post salt loading, and post salt depletion (Weinberger et al. 1986). Other identified risk factors for SS include African ancestry, Asian ethnicity, obesity, low birth weight, female sex, insulin resistance, and diabetes (Weinberger et al. 1986; Elijovich et al. 2016; Falkner et al. 1992; Nosadini et al. 1993; Hall et al. 2019; Yatabe et al. 2010; Rocchini et al. 1989; Perälä et al. 2011; de Boer et al. 2008; Graudal et al. 2020; Faulkner and Belin de Chantemèle 2020). As noted above, risk for SS is amplified with age, and thus it is not known when in childhood SS might begin to manifest. Small studies conducted in the USA during the 1980s did not show significant BP changes in normotensive children placed on low sodium and/or high

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sodium diet (Falkner and Michel 1997). However, these studies did not consider responses in individual children. There is evidence to suggest the BP response to salt intake may follow a Gaussian distribution in children as in adults (Miller et al. 1988). In a small study conducted over 30 years ago, 149 white normotensive US children showed a heterogeneous response to salt restriction (under 75 mmol sodium/day or half of usual intake for 12 weeks), despite confirmed adherence. Although the mean age was 10.6 +/ 0.4 SEM for boys and 9.7 +/ 0.4 SEM for girls, the range of ages extended from 2.6 to 19.8 years. The absolute systolic BP change with sodium restriction was quite wide extending from 14 to 16 mm Hg. The absolute BP change demonstrated a normal distribution. Unfortunately, the BP data was not expressed as the percentage change from baseline, a maneuver used by some investigators to adjust for a wide range of ages. A more recent study contends that SS begins in childhood and influences progression of BP over time. Mu et al. evaluated SS in 310 Chinese children with a mean age of 9.2 years using an outpatient 2-day protocol with oral saline loading followed by volume depletion with diuretics (Mu et al. 2012). In this normotensive population, the frequency of SS was 33%, and no significant differences were found when baseline BP, BMI, or sex when SS and SR groups were compared. On follow-up 18 years later, the increase in BP over time was significantly greater in the SS versus the SR cohort. Furthermore, incident HT were greater for the SS cohort as compared to the SR cohort (15.5% vs 6.3% respectively, RR 2.34) while there was no difference in BMI. Of note, persistence of SS at follow-up was not confirmed. Based on this limited information, it seems that SS may be found in some normotensive children. There are no data on the frequency of SS in hypertensive children, and thus it is not known whether the diagnosis of elevated BP or HT conveys risk for SS in youth. However, a recent metaanalysis of six studies of children with elevated BP by Rios-Leyvraz supplies supportive data (Rios-Leyvraz et al. 2019). Pooled data showed that for children with elevated BP with no identifiable cause, each additional gram of salt in the

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diet was associated with a 6.3 mm Hg (CI: 2.9,9.6) higher systolic BP and 3.5 mm Hg (CI: 1.2, 5.7) higher diastolic BP compared to 0.8 mm Hg (0.4, 1.3) and 0.7 mm Hg (0.0, 1.4), respectively, in normotensive children. It should be noted that the number of subjects in the studies evaluating the influence of salt on elevated BP was quite limited (381 combined). Additionally, five of the six studies were conducted more than 25 years ago, and many subjects who were classified as having elevated BPs would now be considered hypertensive. Based on this information and the known risk for SS afforded by HT in adults, it seems reasonable to conclude that SS is more frequent in children with HT than in those with normal BP. Other studies addressing the impact of salt on BP in pediatric populations have focused on risk groups for SS including African ancestry, obesity, history of low birth weight, family history of HT, diabetes, and insulin resistance. These purported high-risk groups will be considered below. Most pediatric studies have been performed in normotensive children. In the absence of studies in children with HT, data for normotensive youth or hypertensive adults in a risk group will be examined.

Obesity Obesity is recognized as one of the leading risk factors for HT in youth. Since the 1980s, the global prevalence of obesity has increased dramatically in children in countries of all income levels. (Mahumud et al. 2021). A recent meta-analysis pooled data for over 7000 children from 47 studies and demonstrated the profound impact of obesity on the frequency of HT (Song et al. 2019). The prevalence for HT was 15.27% in obese and 4.99% in overweight children compared to 1.90% for non-obese children. Studies in adults have identified obesity as a risk factor for SS (Hall et al. 2019). As recently reviewed by Hall et al., excess weight gain is associated with impaired pressure natriuresis due to excessive sodium reabsorption resulting in sodium retention, volume expansion, and elevated BP (Hall et al. 2019). The underlying mechanisms inducing sodium reabsorption involve activation of the renin-angiotensin system (RAS)

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and renal mineralocorticoid activation by aldosterone and/or other factors, stimulation of the sympathetic nervous system (SNS), and kidney compression with visceral obesity. Considering the effect of obesity on salt handling in adults and the cross-sectional studies in children, it seems likely that obesity is a predisposing factor for SS HT in childhood. Yang et al. reviewed NHANES 2003–2008 data on 6235 children aged 8–18 years and found that the effect of salt on BP was amplified in obese children (Yang et al. 2012). In a more recent study, Correia-Costa et al. evaluated the association of sodium intake and BP using 24-hour ABPM in 298 Portuguese children ages 8–9 years (CorreiaCosta et al. 2016). Sodium intake as estimated by 24-hour urine sodium excretion was higher for males than females which may have been due to the higher overall caloric intake in males. Daytime systolic BP showed a positive association with 24-hour sodium excretion in obese and overweight boys but not in girls. Although the study design was enhanced by use of ABPM, the discrepancy in the response between sexes is puzzling. Differences in puberty status may have contributed to the observed gender differences. The influence of obesity on SS and BP in children was assessed directly in the seminal study by Rocchini et al. In this study BP levels after intake of high (>250 mmol/day) and then low (2. Potentially the older age and greater sexual maturity accounts for the higher frequency of SS in this earlier study. Raaijmakers et al. considered whether a history of LBW predisposes to low renin hypertension in a study of Dutch adolescents (11 years of age) with BW under 1000 grams (Raaijmakers et al. 2017). PRA was significantly lower and systolic and diastolic BP significantly higher for the study group in comparison to age matched controls despite no difference in sodium excretion between

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the groups. The odds of having systolic BP readings in the range of prehypertension and HT were 6.43 [CI, 2.52–16.4] and 10.9 [CI, 2.46–48.4] for the ex-preterm group compared to the control subjects. PRA correlated negatively with BP but was not related to the sodium load per nephron (estimated by dividing 24-hour urine sodium by renal length based on ultrasound). The slope of BP versus PRA was similar in the two groups. Renal length and estimated GFR based on cystatin C were significantly less than those born at term. These findings suggested HT in this population is not mediated via the RAS.

Race and Ethnicity Differing frequencies of SS HT between ethnic and racial groups have long been recognized. However, more recently it has been acknowledged that race is a social rather than a scientific construct. Multiple influences may be involved in generating a predisposition to HT in some populations including dietary, socioeconomic, and genetic factors. The designations utilized in the references will be used while recognizing the inadequacies of these labels. Studies conducted in North America, Europe, and Asia have demonstrated the propensity of some racial and ethnic groups to manifest SS (Graudal et al. 2020). Individuals of African ancestry specifically have been identified as a high-risk group. Other identified susceptible groups include Hispanic and Asian populations. However, within populations, there is considerable heterogeneity. For example, Mexican Hispanics have a racial and genetic composition bearing more resemblance to Native Americans while Caribbean Hispanics demonstrate similarities to Africans (Richardson et al. 2013). Similarly, within African and Asian populations, differences in the frequency of HT are found as well (Forrester 2004; Fei et al. 2017). Limited data are available addressing the effect of race or ethnicity on the BP response to sodium intake in childhood. In a study from the early 1990s, Harshfield et al. evaluated 140

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normotensive US youth, ages 10–18 years for an association between casual and ambulatory BP and 24-hour sodium excretion (Harshfield et al. 1991). The slopes relating systolic casual and nocturnal BP with sodium excretion were significantly steeper in blacks compared to whites. This effect remained significant even after adjusting for BMI and sex. Direct testing for SS in a young adult US population of hypertensive and normotensive subjects (ages 18–23 years) was conducted by Falkner et al. (Falkner and Kushner 1990). After oral salt loading for 2 weeks, these investigators found that overall 37% of black and 18% of white subjects were SS. In a younger population limited to normotensive African Americans, ages 13–16 years, Wilson et al. identified 22% as salt sensitive (Wilson et al. 1999a). Studies in adults indicate that black hypertensives manifest a low renin state (Weinberger et al. 1986; Spence and Rayner 2018). This premise was evaluated in children by Tu et al. in a longterm prospective study of 540 black and white children with a mean age of 10.6 years, 221 of whom returned for a follow-up assessment at a mean age of 30.8 years (Tu et al. 2014). PRA and plasma aldosterone concentration (PAC) were lower in blacks compared to whites at both time points and the PAC/PRA was significantly lower in black children compared to whites. Using varying coefficient regression analysis, the investigators were able to estimate the effect of aldosterone on systolic BP in blacks and whites in childhood and in adulthood. In blacks, the effect of PAC on BP was significant and increased the lower the PRA values while the effect was insignificant in whites. Thus, BP sensitivity to aldosterone persisted even as the PRA remained suppressed. Moreover, further analysis demonstrated that PRA and PAC showed greater decline with age in blacks as compared to whites. However, in spite of decreasing PAC values, BP sensitivity to aldosterone intensified with age in blacks but not in whites (Tu et al. 2018). These investigators also directly tested aldosterone sensitivity in a small interventional study of young adult subjects (20 black and 18 white) with a mean age of 27 years (Tu et al. 2014). After 2-weeks of

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treatment with 9-α fludrocortisone, blacks showed significant increases in manual office BP, B-type natriuretic peptide, ambulatory systolic BP, and weight, while whites showed no effect for these measures. Importantly, while suppression of PRA and PAC was noted in both groups, the magnitude of suppression was greater in whites than blacks. The authors suggested that blacks have a reduced capacity to accommodate to the effects of aldosterone due to a baseline state of sodium retention. In another large pediatric study, Yu and colleagues considered the impact of race and adiposity on the RAAS and BP (Yu et al. 2013). In this study of 248 black and 348 white normotensive children, BMI was negatively associated with PRA in blacks and positively associated with PAC in whites. Additionally, in blacks systolic BP levels were significantly higher in those with lower PRA and higher PAC values with no differences noted in whites. Overnight urine samples did not reveal significant differences in sodium or potassium excretion. The authors suggest that blacks tend to be volume expanded relative to whites, a state that may augment the effect of adiposity on BP in a population known to have a high prevalence of obesity (Yu et al. 2013; Ogden et al. 2018). Similarly, an earlier study demonstrated racial differences in sodium handling in normotensive female adolescents aged 11–15 years, matched for age and BMI, after controlled periods on a low and high sodium diet (Palacios et al. 2004). Although no significant difference in BP was noted, black girls retained an average of 0.7 gram/day more sodium than white girls, suggesting storage outside the intravascular space. Additionally, stimulated (by upright posture) PRA and PAC values were significantly lower for black versus white girls while on the high sodium diet. Increased risk for SS in individuals of different ancestries over other groups is likely related to the intersection of lifestyle and genetic determinants. Recent investigations have enhanced our understanding of potential roles for the ENaC channels within the kidney and in extra-renal tissues. In addition to aldosterone, ENaC is also regulated by elevated extracellular and intracellular sodium, post-translational proteolytic cleavage, and lipids (Pitzer et al. 2020). Certainly within the kidney,

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ENaC plays a pivotal role in sodium and potassium handling. Racial differences detected in the function of ENaC have drawn attention to the potential importance of mutations in the genes for subunits of the ENaC channel or genes impacting functionality of ENaC (Spence and Rayner 2018). Indeed some have advocated initiating treatment blocking this channel or the aldosterone receptor in those of African ancestry demonstrating low renin HT (Spence and Rayner 2018). However, of note assessments of the RAS must be interpreted in the context of sodium intake and concurrent antihypertensive medications. As will be discussed in more detail, evidence also suggests SS in blacks is exacerbated by low potassium intake and can be ameliorated or resolved when adequate potassium is included in the diet (Morris Jr. et al. 1999). Recently, Kurtz and colleagues reviewed past evidence of increased SS in normotensive blacks versus whites in the context of potassium intake and found no evidence of SS with salt loading and no significant racial differences when potassium intake met or exceeded the recommended daily intake (Kurtz et al. 2021). In contrast, when potassium intake was inadequate, SS was restored along with racial differences. Although continued investigation is required, it appears that low dietary potassium intake stimulates sodium reabsorption via transporters throughout the tubule, including the sodium chloride cotransporter (NCC) (Rodan 2017). Additionally, potassium may also exert a beneficial effect on BP through reduction of endothelial stiffness and increased availability of nitric oxide (Kurtz et al. 2021). While inadequate potassium intake is common in US children and adults, individuals of African ancestry may be at exceptional risk for inadequate intake (Han et al. 2019; Cohen et al. 2017). Recent analysis of NHANES from 2002 to 2016 show that adult blacks are least likely to meet the recommended daily potassium intake when compared to other groups of adults (Han et al. 2019). Similarly, a recent analysis of US NHANES surveys from 2003 to 2012 showed that only 3.6–5.5% of youth ages 8–18 years met the dietary reference values for potassium intake for age (Cohen et al. 2017).

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Chronic Kidney Disease Although the deleterious influence of salt intake on BP in most individuals with chronic kidney disease (CKD) is well accepted, few studies have directly addressed this issue in children (RiosLeyvraz et al. 2019). In a recent systematic review, Rios-Leyvraz et al. identified only a single study in children ages 18 months to 10 years that showed a positive association between systolic BP and sodium intake in children with CKD. Notably, children with CKD stage 1 due to congenital and solitary functioning kidneys from birth are increasingly recognized as at risk for HT or as having HT if assessed by ambulatory BP monitoring (Yel et al. 2021; Cochat et al. 2019). This population represents a significant portion of society as it is estimated that 1 in 1000 individuals have a solitary kidney (congenital or acquired) (Cochat et al. 2019). Studies in sheep exploring the effect of fetal loss of a kidney have shown increased BP, reduction in PRA, and impairment of sodium excretion, with sodium handling worsening with age (Lankadeva et al. 2014). These studies support the recent findings by investigators who evaluated the association of dietary salt intake and BP in children with a solitary (congenital or acquired) kidney or a hypofunctioning kidney (Yel et al. 2021). They found that salt intake (as estimated by 24-hour urine sodium) correlated positively with 24-hour systolic BP and 24-hour MAP when all groups were combined but only for those with a congenital solitary kidney when each group was considered separately. Of note, the frequency of nocturnal HT was significantly increased for all three groups compared to controls.

Stress and Adverse Childhood Events Recent studies have demonstrated that adverse childhood events (ACE) are linked with cardiovascular disease in adulthood including HT (Su et al. 2015). Subjects with a history of multiple ACE and followed from childhood into adulthood exhibited a steeper rise in BP after age

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30 years compared to those with no ACEs (Su et al. 2015). Based on a prediction model, by age 38 years, systolic and diastolic BPs were 9.3 and 7.6 mmHg higher in subjects with
4 ACE than in those with zero ACEs. The mechanisms through which ACE lead to HT remains to be elucidated. While ACEs have been shown to induce an inflammatory state in humans prior to adolescence, further studies are needed to clarify the mechanisms involved in the progression to cardiovascular disease (Obi et al. 2019). Whether ACE have an effect on risk for SS is not known. Studies in both animals and humans have demonstrated impairment of natriuresis with stressinduced increase in BP (Hanevold and Harshfield 2016). Investigations in animal models have implicated the SNS and RAAS pathways in the genesis of impaired sodium handling during stress-induced BP elevation (Hanevold and Harshfield 2016; Loria et al. 2015). In humans, stress-related changes in sodium handling have been demonstrated in adult and pediatric populations (Hanevold and Harshfield 2016). Studies in normotensive adolescents and young adults have shown impaired excretion or sodium retention during stress in approximately 20% of whites and 33% of blacks. In response to stress, these individuals manifested an increase in BP accompanied by sodium retention and an increase in cardiac output and stroke volume. In contrast, the majority of subjects showed an increase in BP accompanied by an increase in peripheral vascular resistance and sodium excretion. Of interest in those subjects who demonstrated sodium retention during stress, the BP during recovery dropped but did not return to baseline; in contrast in the subjects who excreted sodium during stress, the recovery BP was lower than the baseline value. This phenotype of sodium retention during stress has been associated with race and obesity with mixed findings with regard to family history (Hanevold and Harshfield 2016). An increase in plasma angiotensin II and reduction in urinary endothelin-1 have also been reported with this phenotype (Hanevold and Harshfield 2016). Building on animal studies, treatment of normotensive adults with drugs targeting the RAS has been shown to improve sodium excretion in

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subjects identified as sodium retainers during stress (Hanevold and Harshfield 2016; Harshfield et al. 2018). Implying the need for a second hit, animal studies suggest that the combination of SS and early life stress may influence subsequent BP responses including the response to acute stress (Loria et al. 2015). Dahl SS rats exposed to maternal separation in early life (study group) demonstrated an exaggerated BP response to the combination of a high salt diet and chronic angiotensin II infusion compared to control Dahl SS rats. Although not statistically significant, the augmentation of sodium excretion by combining a high salt diet with the angiotensin II infusion was attenuated in the study rats in contrast to control rats. These investigators also compared the effect of an acute stress on Dahl SS rats with and without past exposure to maternal separation in early life. BP responses to a 3-minute acute stress were similar. However, the rats exposed to maternal separation manifested an impaired recovery with MAP remaining above baseline while MAP dropped below baseline for control Dahl SS rats. A similar incomplete recovery was noted in adolescents and young adults with sodium retention during stress as mentioned above (Hanevold and Harshfield 2016).

Interventions for Salt Sensitivity In addition to limiting salt intake, other dietary interventions may ameliorate SS. As mentioned above, reduction of obesity has been shown to lessen SS (Rocchini et al. 1989). Regarding specific dietary components, the beneficial effect of potassium intake on BP has been recognized for years (Falkner 2017; Kurtz et al. 2021). However, studies directly addressing the effect of a potassium-rich diet or potassium supplementation on SS are limited in adults and children. In a small study conducted in 38 adult normotensive men (24 blacks, 14 white), Morris et al. demonstrated that increasing potassium intake lessened SS, particularly in blacks (Morris Jr. et al. 1999). Mu and colleagues randomized 261 school age children with a mean age of 10 years to receive a

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potassium/calcium tablet or a placebo tablet daily for 2 years followed by testing for SS at study conclusion with a furosemide-based protocol (Mu et al. 2005). Of those identified as SS, 30 children had received the supplement (treated) while 20 children received placebo (untreated). Treated SS children demonstrated a significantly smaller increase in casual BP over time compared to the untreated SS group. Additionally, comparison of 24-hour urine sodium excretion at baseline and study conclusion showed a remarkable increase in treated SS children in response to the intervention. Although these patient numbers are small, these results suggest higher potassium intake over time may lessen the influence of salt on BP. These studies offer some insight into the success of the widely utilized potassium-rich DASH (Dietary Approaches to Stop Hypertension) diet for treatment of HT. Research in murine models offers insight into how low potassium intake may potentiate SS. With potassium restriction, absorption of sodium is enhanced through the NCC resulting in reduced natriuresis, kaliuresis, and higher BP (Hoorn et al. 2020). The effect of potassium intake on blood pressure is greatest when sodium intake is also high as has been demonstrated in several large international studies conducted in adults (Rodan 2017). Moreover, a high potassium intake can also lower BP in SS individuals even if salt restriction is not achieved (Hoorn et al. 2020). Hoorn et al. propose that the antihypertensive effects of angiotensin-converting enzyme inhibitors and ENaC blockers could be due in part to an increase in plasma potassium levels with subsequent inhibition of NCC transporter.

Surrogate Markers for Salt Sensitivity Unfortunately, beyond direct testing for SS, no surrogate methods for identification of SS in the clinical arena have emerged. Early investigations by Weinberger confirmed that SS is a volumeloaded, low renin state (Weinberger et al. 1986). However, from a clinical standpoint, random plasma renin activity (PRA) is generally not helpful. PRA must be interpreted in the context of

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sodium excretion; otherwise a low level may merely reflect the universally high sodium intake seen in most populations. In adults there is literature indicating that blunted dipping on ABPM is supportive of SS HT (Elijovich et al. 2016). However, this finding lacks specificity, and results have been conflicting for adults and adolescents (Elijovich 2016, Wilson et al. 1999b Simonetti et al. 2010). In a study of black adolescents, Wilson et al. showed that blunted dipping was significantly more prevalent in SS normotensive teens compared to SR youth (Wilson et al. 1999b). Furthermore, these investigators demonstrated conversion to a normal dipping pattern in all of the SS subjects after 4 weeks of an increased dietary potassium. Direct testing for SS and SR was performed, but the ABPM studies were performed on their usual sodium intake. In contrast, a population of Swiss normotensive subjects with a mean age of 11.9 years and previously identified as SS did not demonstrate blunted dipping while on a high salt diet despite significant changes in daytime pressures with dietary salt manipulation (Simonetti et al. 2010). The discrepancy in results casts doubt on the reliability of this finding as a marker for SS in children. Identification of unique plasma biomarkers to detect SS using metabolomic and lipidomic profiling is another avenue that may in time allow for a more personalized approach to lifestyle management. In a recent ancillary study of the DASH cohorts, investigators found that SS individuals fed a high sodium (150 meq) diet showed significant changes in plasma tocopherol alpha, 2-ketoisocaproic acid, and citramalic acid measurements when compared to values while on a low sodium (50 meq) diet (Chaundary et al. 2021). Similar changes were not seen in SR individuals. While promising, the significance of these findings is uncertain and further research is indicated. Other promising work on biomarkers is focused on the identification of microRNAs and long non-coding RNAs that are differentially expressed in individuals with SS HT (Zhang et al. 2020). In the future, bio-markers and/or genetic testing may allow clinicians to discern patients most likely to benefit from salt restriction.

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Clinical Implications Although it is impossible to know if an individual child will benefit from salt restriction, restriction of daily sodium intake to under 2–2.3 grams (or a comparable level for age) should be initiated when elevated BP or HT is diagnosed (U.S. Department of Agriculture and U.S. Department of Health and Human Services 2020). While further reduction in sodium intake may be beneficial for BP control, more severe reduction may not be sustainable. A careful diet history should be taken with close attention to consumption of processed foods and frequency of eating outside the home. Counseling on the benefits of a potassium-rich diet should be emphasized. Education of the family about the importance of dietary potassium is key as the intake of potassium is exceptionally poor in many children as reviewed above. Although not recommended for use in SS research, spot urine sodium measurements might be useful to confirm high sodium intake in individuals considered at risk for SS HT. RiosLeyvraz assessed the ability of eight equations to estimate 24-hour urine sodium excretion in healthy Swiss children, ages 6–16 years, on their regular diet (Rios-Leyvraz et al. 2018). The most accurate results were obtained employing the Tanaka and Brown equations and a first morning void. Of note, due to the tendency to overestimate when 24-hour sodium excretion is low, these equations are NOT suitable for evaluating adherence to a low sodium diet.

Conclusion In summary, predisposing factors for SS include LBW, obesity, solitary kidney, CKD, insulin resistance, African ancestry, Asian ancestry, and low potassium intake. The effect of family history of HT, stress, adverse childhood events, and other environmental influences on the risk for SS is uncertain. In the future, identification of SS perhaps through biomarkers or genetic profiling may allow for an individualized approach to prevention and treatment of SS HT.

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Cross-References ▶ Antenatal Programming of Blood Pressure ▶ Ethnic Differences in Childhood Blood Pressure ▶ Familial Aggregation of Blood Pressure and the Heritability of Hypertension ▶ Hypertension in Children with Type 2 Diabetes or the Metabolic Syndrome ▶ Hypertension in Chronic Kidney Disease ▶ Insulin Resistance and Other Mechanisms of Obesity Hypertension ▶ Monogenic and Polygenic Contributions to Hypertension ▶ Obesity Hypertension: Clinical Aspects ▶ Pharmacologic Treatment of Pediatric Hypertension ▶ The Role of Dietary Electrolytes and Childhood Blood Pressure Regulation

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Early Vascular Aging in Pediatric Hypertension Patients

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Mieczysław Litwin

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 The Concept of Early Vascular Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Features of EVA in Hypertensive Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Biological Determinants of Blood Pressure in Childhood and Adolescence. . . . . . . 255 Determinants of EVA in Children with Primary Hypertension . . . . . . . . . . . . . . . . . . . . 256 Altered Body Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Metabolic Abnormalities, Metabolic Syndrome, and Oxidative Stress in Adolescents with PH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Immune Abnormalities and Inflammatory Activation in Children with PH . . . . . 259 Accelerated Biological Maturation and Childhood Hypertension . . . . . . . . . . . . . . . . . 260 Hemodynamic Determinants of EVA in Hypertensive Children . . . . . . . . . . . . . . . . . . . 261 Reversibility of Features of EVA in Children with PH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

Abstract

Primary hypertension (PH) develops in childhood, and its future occurrence may even be determined perinatally. Analysis of the

M. Litwin (*) Department of Nephrology and Arterial Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_59

phenotype of hypertensive children has revealed that PH is a complex of anthropometric and neuro-immuno-metabolic abnormalities, typically found in hypertensive and older adults. Children with elevated blood pressure have shown signs of accelerated biological development, which are closely associated with further development of PH, metabolic syndrome, and cardiovascular disease in adulthood. It is well established that hypertensive children have evident arterial remodeling 249

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detectable as significantly increased carotid intima-media thickness, increased stiffness of large arteries, lower area of microcirculation, and decreased endothelial function. All these abnormalities are typical features of early vascular aging (EVA) as described in adults with PH. Macrocirculatory changes in hypertensive children correspond with those observed in 4–5 years older normotensive individuals. There is close association between macroand microcirculatory remodeling in children with PH. These early vascular changes in hypertensive children are closely associated with features of accelerated biological development and immunometabolic abnormalities observed in older subjects. Such findings indicate that PH in childhood is not only an EVA event but also a premature biological maturation phenomenon. The results of interventional studies, in the general pediatric population, indicate that it is possible to obtain a significant improvement in both arterial remodeling and improving elastic properties of large arteries. In few studies in children and adolescents with PH, intensive non-pharmacological and pharmacological treatment aimed not only at lowering blood pressure but also at normalizing the body composition and normalizing metabolic disorders also resulted in a significant regression of vascular changes. Keywords

Primary hypertension · Children · Early vascular aging · Arterial stiffness

Introduction From a biological and evolutionary perspective, chronic diseases in adulthood such as primary hypertension (PH), cardiovascular disease (CVD), atherosclerosis, type 2 diabetes mellitus (T2DM), or arthritis typically develop in later life (Kirkwood 2017). Thus, the development of PH and its complications in childhood and adolescence may be defined as “premature” or “early.” For years, PH was regarded as disease of adults

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and was only rarely diagnosed in childhood and adolescence. Indeed, the dominant form of arterial hypertension in the pediatric age group was considered to be secondary hypertension. However, population screening programs and routine blood pressure measurements during outpatient visits changed this view. Although secondary hypertension is the dominant form of arterial hypertension in younger children, PH is now recognized as the most common form of hypertension in older children, especially adolescents. In the developed world, the prevalence of arterial hypertension increases with age from 0.2% in neonates to at least 10–11% in 18-year-old adolescents, affecting 4% of all children and adolescents (Song et al. 2019; Symonides et al. 2010). There is substantial sex difference in the prevalence of PH. Among 14–18-year-olds, arterial hypertension occurs with a male-to-female ratio: 3–4:1, and the prevalence is 16–21% among male teens (GuptaMalhotra et al. 2015; Litwin et al. 2010; Obrycki et al. 2020; Symonides et al. 2010). Blood pressure values increase with age from below 90–100 mmHg after birth up to 120 mmHg for systolic blood pressure (SBP) during adolescence. Blood pressure values are similar for both girls and boys until the pubertal growth spurt. However, there is a substantial rise in SBP among boys during the pubertal growth spurt (mean age for European males: 13.8 years) (Fig. 1). These increases are associated with an adaptive increase in arterial wall thickness and arterial stiffness, which can be measured by carotid intima-media thickness (cIMT) and pulse wave velocity (PWV), respectively. Reference values for cIMT and PWV indicate no significant differences between boys and girls until puberty, but both cIMT and PWV significantly increase with the pubertal growth spurt in boys (Doyon et al. 2013). The main predictors of both cIMT and PWV in healthy, normotensive children are age- and sex-adjusted blood pressure, body mass index (BMI), and pulse pressure (Doyon et al. 2013). cIMT and PWV increase further with age after adolescence (The Reference Values for Arterial Stiffness’ Collaboration 2010). Therefore, arterial properties expressed as cIMT and PWV values should be interpreted in relation to age,

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Fig. 1 Blood pressure differences between boys and girls 3–18 years of age. N ¼ 21,332 (OLAF Study, Poland, unpublished data). (Reprinted from Litwin and Kułaga

2021, with permission). (N ¼ 21,332, Abbreviations: DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure)

just as blood pressure values in childhood are. Thus, the structure of the arterial wall and its elastic properties may be interpreted as markers of the biological age of the arteries.

develop in patients with normal blood pressure, independent of hypertension (Table 1). However, hypertension aggravates endothelial injury. In hypertensive patients, both arterio- and atherosclerosis progress with age (Hamczyk et al. 2020). Further, arterial aging is not limited to large arteries but involves the entire arterial system, including the microcirculation, in which rarefication of the microcirculation develops with age and is aggravated by hemodynamic and metabolic factors. What is termed “arterial age” can be assessed by measurement of arterial wall structure and function. In clinical practice, arterial age is described as (1) arterial structure as assessed by cIMT, (2) elasticity as assessed by examining arterial PWV, (3) rarefication of the microcirculation as assessed with capillaroscopy or measurement of retinal vessel caliber, and (4) endothelial function as measured through flow-mediated dilation (FMD) of the brachial artery. Newer techniques such as magnetic resonance imaging have been used for assessment of stiffness in the proximal aorta. However, these techniques are not used routinely in the clinic. Increased cIMT and PWV were found to be clinically important markers for future cardiovascular events and cardiovascular death in adults. Although cIMT and PWV increase with age, there is a wide range of

The Concept of Early Vascular Aging Gradual stiffening of large arteries with age is caused by progressive loss of elastin fibers and changes secondary to atherosclerosis. Large arteries have three layers: intima, media, and adventitia. The intimal layer consists of endothelium and is the site where atherosclerosis develops. However, the structure and function of medial layer is the main determinant of stiffness in large arteries. The medial layer consists of network of elastin fibers, vascular smooth muscle cells, and extracellular matrix. With age and hemodynamic damage caused by pulse pressure to the arterial wall, elastin fibers are replaced by collagen. These changes are modulated by immune-metabolic abnormalities associated with PH and aging. Arteriosclerosis, the stiffening of large arteries with age and increased arterial stiffness observed in arterial hypertension, is mainly caused by adaptive changes in the media. In contrast, atherosclerosis starts with damage to endothelial cells and may

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Table 1 Common features of early vascular aging and early biological maturation in hypertensive children and adults. (Reprinted from Litwin and Feber 2020 with permission) Features Early vascular aging Increased intima-media thickness Increased pulse wave velocity Microcirculation rarefaction Decreased endothelial function Anthropometrical parameters Decreased LBM/BW ratio Visceral obesity Accelerated biological maturation/early biological aging Advanced bone age Earlier menarche Earlier growth spurt Metabolic syndrome and abnormalities typical of metabolic syndrome Oxidative stress Sympathetic overactivity Immune activation Innate immunity More mature T cells with senescence phenotype Extracellular matrix remodeling

Children and adolescents

Adults

+

+

+

+

+ +

+ +

+ +

+ +

+ + + +

– + + a,b +

+ +

+ +

+ +

+ +

+

+

a

On a population level data from retro- and prospective studies showed that accelerated biological maturation is associated with higher blood pressure, development of arterial hypertension, and cardiovascular disease in adulthood b Age is a surrogate for biological maturation

normal values in every age category, including children and adolescents. Moreover, population studies in adults have shown that although arterial stiffness increases with age, not all patients develop either PH or CVD – many may maintain low values of arterial wall thickness and high arterial elasticity until old age. Therefore, while arterial age can be regarded as a marker of biological age, it may not necessarily match a given person’s chronological age.

The relation between blood pressure and arterial stiffness is bidirectional. Thus, increased arterial stiffness may cause elevation of blood pressure, especially of SBP, and that elevated blood pressure may cause an increase of cIMT and arterial stiffness by repetitive hemodynamic injury to the arterial wall, as well as faster loss of elastic fibers. Therefore, it can be assumed that increased stiffness of large elastic arteries assessed as carotid-femoral PWV (cfPWV) and increased cIMT are fingerprints of arterial hypertension. Such findings based on the observations of adults with PH and CVD were the basis of the hypothesis of early vascular aging (EVA) (Nilsson et al. 2008), which has recently been expanded to include a concept of healthy vascular aging (HVA) or even supernormal vascular aging (SUPERNOVA). HVA and SUPERNOVA describe the phenotypes of patients with normal blood pressure, well-preserved arterial structure (low cIMT), and elasticity (low PWV) (Laurent et al. 2019). More detailed analysis of risk factors for EVA as well as protective factors found in patients with HVA and SUPENOVA revealed that not only hemodynamics and pressure injury to arterial wall but rather a cluster of neuroimmuno-metabolic factors may promote cardiovascular injury or protect against CVD. The MARE Consortium study found that middle-aged participants (mean age 52 years) with signs of EVA were not only hypertensive but also displayed anthropometric and laboratory abnormalities typical of metabolic syndrome (MS), whereas participants with signs of HVA were normotensive, leaner, and metabolically healthy (Nilsson et al. 2018). Recently, immune activation and sterile inflammation termed “inflammaging” has been found to be associated with signs of EVA and in general with aging processes (Guzik et al. 2017). This clinical and metabolic phenotype is usually described as a cluster of altered body composition, visceral obesity, hyperinsulinemia/insulin resistance, and elevated blood pressure and is typical among children and adolescents with PH (Litwin and Feber 2020). Such a relation between insulin sensitivity, immune activation, longevity, and development of chronic diseases such as PH may occur in relatively young persons (Arai et al. 2019; Chakraborty et al. 2020). That being said, the first

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report of a relation between hypertension and metabolic disorders was first described 100 years ago (Kyllin 1923). In contrast to adults, children and adolescents with PH have obviously had less exposure to other concomitant CVD risk factors such as smoking, alcohol, chronic hyperlipidemia with widespread atherosclerosis, night-time shift work, or type 2 diabetes mellitus (T2DM). Given the “purity” of PH in childhood, pediatric studies may illuminate the pathogenesis of EVA and CVD at very early stages. The concepts of EVA and HVA together with the findings from pediatric studies are consistent with the hypothesis that PH develops early in life and coincides with metabolic alterations that affect growth rate and biological maturation (Lever and Harrap 1992). According to this hypothesis, rapid growth in childhood is associated with blood pressure elevation and metabolic alterations driving structural and functional vascular changes, which, in turn, trigger a self-perpetuating cycle of vascular remodeling, ultimately leading to sustained hypertension. The relation between premature birth and/or low birth weight with development of CVD and PH in childhood can be viewed as a perinatally programmed and modulates later multi-systemic disturbances earlier than expected, yet with features resembling those observed with aging (Kuh 2007). Altogether, this means that PH in children is not only a sign of EVA including both the macro- and microcirculations, but also a sign of generalized an early biological maturation (EBM) syndrome. More generally, EVA and EBM correspond to the concept of developmental origins of health and disease (DOHaD) consistent with a coherent concept of CVD development.

Features of EVA in Hypertensive Children Features of EVA in children with hypertension include remodeling of the arterial wall, increased arterial stiffness, endothelial dysfunction, and rarefication of the microcirculation. Because both cIMT and PWV increase with age, elevated values for these tests in hypertensive children

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imply that their arteries are biologically older compared to the arteries of normotensive ageand sex-matched peers. Results from the Young Finns Study demonstrated that blood pressure in childhood not only tracked in adulthood but also was associated with higher cIMT and PWV values after 27 years of observation (fourth–fifth decades of life) (Juhola et al. 2013; Aatola et al. 2017). A recent systematic review of longitudinal studies found that elevated blood pressure in childhood was associated with several intermediate markers of CVD/EVA (such as elevated PWV, cIMT, left ventricular hypertrophy, and remodeling) and increased risk of cardiovascular mortality and morbidity (Yang et al. 2020). Children with PH have been shown to have important subclinical arterial injury such as increased cIMT, arterial stiffness, and decreased endothelial function, often apparent at diagnosis (Kollias et al. 2014; Urbina et al. 2018). Analysis of published studies noted that increased cIMT was evident in about 40% (range 38–46%) of adolescents with PH at the time of diagnosis (Litwin et al. 2004, 2006; Urbina et al. 2018; Yang et al. 2018). The meta-analysis by Kollias et al. revealed that hypertensive children had a higher cIMT (on average by 0.03 mm) than normotensive children (Kollias et al. 2014). A recent review of studies in children with PH found that 75% of studies reported faster cfPWV in hypertensive children in comparison with normotensive children (Azukaitis et al. 2021). Others reported a correlation between elevated blood pressure and arterial injury, expressed as increased cIMT and PWV that was already present in children with office and ambulatory prehypertension (Obrycki et al. 2020; Urbina et al. 2011). Comparison of raw, non-indexed data in normotensive and hypertensive adolescents (mean age 14–16 years) revealed a PWV difference of 0.3–0.5 m/s (Litwin and Feber 2020; Obrycki et al. 2020). These differences in cIMT and PWV between hypertensive and normotensive children suggest that both the carotid arteries and aorta of children with PH may have structural and functional features typical for people 4–5 years older (Fig. 2). As previously mentioned, increased cIMT in children has been associated with MS and future CVD risk (Zhao et al. 2020; Yang et al. 2020).

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Fig. 2 Difference in arterial properties between normotensive (black line) and hypertensive subjects (dotted line). Hypertensive adolescents at the age of 15–16 years have similar pulse wave velocity (PWV) and carotid intima

media thickness (cIMT) as normotensive adolescents/ young adults who are 4–6 years older. (Reprinted from Litwin and Feber 2020, with permission)

However, while increased PWV has been associated with the presence of metabolic risk factors in obese children, hypertension was associated with increased PWV independent of obesity; hypertensive children with obesity had higher cfPWV than normotensive children with obesity (KulsumMecci et al. 2017). Similarly, recent systematic reviews using meta-regression found that cfPWV in children was associated with blood pressure level, impaired glucose metabolism, and MS. However, obesity was not consistently associated with cfPWV (Stoner et al. 2020). Taken together, these data suggest that elevated blood pressure is clearly associated with cfPWV (Azukaitis et al. 2021). Available studies have shown a decrease in brachial artery FMD among hypertensive children (Urbina et al. 2018). Studies in both prepubertal and pubertal children with obesity with similar

phenotypes to children with PH also showed a decrease in brachial artery FMD, related to elevated blood pressure (Aggoun et al. 2008; Meyer et al. 2006). In a study by Jurko et al., 20% of adolescents with PH (mean age 16 years) had decreased FMD (Jurko et al. 2018). Interestingly, decreased FMD was also noted in 17% of adolescents with white coat hypertension but none among normotensive controls. Impairment of FMD is associated with metabolic abnormalities and MS, as shown by Civilibal et al. (2014). Rarefication of the microcirculation is another feature of vascular aging that is aggravated by arterial hypertension, indicating that there is interplay between the macro- and microcirculation in the process of EVA (Bruno et al. 2017; Rizzoni et al. 2019). The development of new diagnostic techniques that permit non-invasive assessment of the microcirculation, especially the retinal

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vessels, has made it possible to demonstrate early changes in microcirculation in hypertensive children. Recently, several pediatric reports showed that elevated BP, obesity, and lack of physical fitness are significantly correlated with the narrowing of retinal arterioles in otherwise healthy prepubertal children (Kőchli et al. 2019). A prospective study showed that elevated blood pressure at a baseline exam at a mean age 7.4  04 years predicted narrowing of the retinal arterioles after 4 years, while narrow arterioles at the first exam predicted higher SBP after 4 years (Lona et al. 2020). Microcirculatory rarefication expressed as a retinal foveal avascular zone was significantly associated with macrovascular injury expressed as increased cIMT as it was found in cross-sectional study of hypertensive children (Rogowska et al. 2021).

Biological Determinants of Blood Pressure in Childhood and Adolescence. From the public health perspective, the main determinants of elevated blood pressure in children are (1) body mass index (BMI), (2) waist circumference (WC), (3) sex, and (4) perinatal factors such as prematurity, low birth weight (LBW), and high birth weight (Falkner and Lurbe 2020). A relation between BMI and blood pressure has been observed in children as young as 2–4 years of age (Falkner et al. 2006), even in patients with BMI at the 25th percentile, and becomes evident at BMIs greater than the 85th percentile (Wang et al. 2020). Consequently, the prevalence of arterial hypertension increases with both BMI and WC, reaching as high as 30% in obese adolescents (Flechtner-Mors et al. 2015). The role of perinatal factors such as prematurity and LBW as predictors of hypertension and CVD was first noted by Barker et al. (1989). Both prematurity and LBW, especially in LBW neonates who are small for gestational age (SGA), are associated with the development of metabolic abnormalities typical of MS, as well as with elevated blood pressure (Lurbe et al. 2014). Globally, the rate of prematurity is 9.6%, ranging from 7.5%

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(in more developed countries) to 12.5% (in less developed regions) (Lawn et al. 2010). Given the recent increase in premature and SGA births in the USA, reaching 9.84% and 8.16%, respectively, and greater survival of those born before the 28th week of gestation in developed countries, prematurity, and SGA is an important risk factor of CVD (Heikerwal et al. 2020; Tanne 2017; Schoenardie et al. 2019). Other perinatal risk factors for future hypertension and metabolic abnormalities are linked with maternal health issues, e.g., maternal obesity, gestational diabetes, and hypertension. However, after 5 years of age, the impact of LBW on blood pressure appears to be modified by the patient’s current BMI and metabolic abnormalities (Lurbe et al. 2018). Nevertheless, rapid weight gain and early overfeeding of SGA and/or premature infants have been associated with the development of PH and metabolic abnormalities in prepubertal and pubertal youngsters (Singhal et al. 2007; Vohr et al. 2018). Lurbe et al. found that at 5 years of age even non-obese SGA children had higher insulin levels in comparison with those born with appropriate weight LBW, and LBW itself predicted later blood pressure levels. However, insulin levels were highest among those born SGA who were obese at 5 years of age (Lurbe et al. 2014). In a prospective part of the study, it was found that birth weight was not a predictor of both office and ambulatory blood pressure, and it was current BMI that was associated with blood pressure values. However, insulin levels, insulin resistance, low HDL, and higher uric acid levels were associated with birth weight, which may suggest a long-term effect of perinatal programming on metabolism (Lurbe et al. 2018). However, it is not only LBW but rather prenatal disturbances of intrauterine development that may result in an SGA birth; and LBW is considered a surrogate marker of disturbed intrauterine development. There is a significant association between SGA and development of EVA in adulthood. Sperling and Nilsson found that adults in the fourth decade of life who were born as SGA had significantly greater augmentation indices and higher BP values than adults who were born with weights appropriate for gestational age (AGA) or LBW-AGA (Sperling and Nilsson 2020).

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Similarly, the Tyrol study of EVA found that 16-year-old adolescents who were born as SGA and/or preterm had significantly faster cfPWV than their term-born peers who were AGA (Stock et al. 2018). The same associations were found for arterial remodeling expressed as cIMT in young adulthood (mean age 27 years) as found in ARYA study (Oren et al. 2004). High birth weight (>4.5 kg) is also associated with increased risk of obesity, CVD in adulthood, and T2DM, especially in females. Because of increasing worldwide rate of obesity among women of childbearing age, as well as gestational diabetes, high birth weight would also appear to confer a risk for future CVD (Lurbe and Ingelfinger 2021). The role of perinatal factors in the programming of EVA is supported by data from studies of children conceived by assisted reproductive technologies (ART). In European countries, ART accounts for 0.8–6.1% of all live births (European IVF-Monitoring Consortium 2016). According to some reports, children conceived through ART who were not exposed to well-known perinatal risk factors (such as LBW, prematurity, maternal diabetes, hypertension, or obesity) had a significantly higher prevalence of arterial hypertension, increased PVW, increased cIMT, and lower FMD in comparison with ageand sex-matched peers (Guo et al. 2017; Meister et al. 2018). While some literature reviews reported an increased rate of arterial hypertension in children conceived through ART (Bergh and Wennerholm 2020), a recent meta-analysis did not find significant differences in cIMT if such children were born at term and with normal birth weight (Epure et al. 2020).

Determinants of EVA in Children with Primary Hypertension The typical clinical and laboratory phenotype of adolescents with PH is similar to that of hypertensive adults and consists of cluster of neurologic and immune abnormalities. These include altered body composition, metabolic abnormalities typical of MS, immune and inflammatory

M. Litwin

derangements, and sympathetic system activation. In addition, population and clinical studies revealed that both hypertensive adults and hypertensive children had a history of relatively rapid biological development during puberty, which suggests more advanced biological as compared with chronological age (Table 1). The clinical and laboratory phenotype of hypertensive children and adolescents with PH has shown changes that typically develop with aging as noted in hypertensive adults with EVA. The presence of increased cIMT and PWV, microcirculatory rarefication, and decrease of FMD were closely associated with these abnormalities.

Altered Body Composition One of the most common traits that changes with age is body composition. Starting from the fourth decade of life, body composition gradually increases its fat-to-lean body mass ratio, WC, and visceral adipose tissue (VAT). Data from the Paris Prospective Study 3 have revealed that change in body composition from lean to adipose, expressed as body silhouette from childhood (8 years) to adulthood (45 years), is associated with the development of PH, as well as evident EVA with carotid artery wall remodeling and aortic stiffening (van Sloten et al. 2018). Altered body composition with features typically found in adulthood may occur in hypertensive adolescents. Most affected teens have a BMI that connotes overweight or obesity. However, although studies of prehypertensive and hypertensive adolescents found that increased BMI is not uncommon, 29–50% were obese and 53% were overweight in several studies (Obrycki et al. 2020, Urbina et al. 2019). However, the relation between blood pressure and body composition is bidirectional. For example, the Tecumseh Study showed that 6-year-old children with elevated blood pressure had a high likelihood of future adiposity – expressed as increased skinfold thickness at age 20–24 and hypertension at 31 years; obversely, adiposity at 6 years of age predicted elevation of blood pressure 10 years later (Julius et al. 2000).

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Early Vascular Aging in Pediatric Hypertension Patients

Currently, the “gold standard” for the accurate assessment of body composition is dual X-ray densitometry. Using this technique it was shown that hypertensive adolescents have a relative decrease of lean body mass (Płudowski et al. 2008). Similarly, a population study of Chinese children aged 6–17 years demonstrated that blood pressure level was directly correlated with increasing amounts of fat and associated with increased fat-to-lean body mass (Chen et al. 2019). The latter study also documented metabolic abnormalities typical for MS in both obese and normal weight children that were associated with the amount of VAT rather than with BMI. Analysis of body composition and accompanying metabolic and hemodynamic abnormalities distinguished four phenotypes: (1) normal weight metabolically healthy (NWMH), (2) normal weight metabolically unhealthy (NWMU), (3) metabolically healthy obese (MHO), and (4) metabolically unhealthy obese (MUHO). Chen et al. noted that NWMU and MUHO children had similar blood pressure values but that these were greater than those of NWMH and MHO children (Chen et al. 2019). A study analyzing determinants of hypertension-mediated organ damage (HMOD) including EVA markers in hypertensive adolescents found that WC rather than BMI was positively related to cIMT results (Litwin et al. 2010). In contrast, analysis of studies on obesity and hypertension found that while the prevalence of hypertension is much greater among obese children, only some obese children and adolescents develop hypertension (Litwin and Kułaga 2021). These data indicated that it was not obesity nor the absolute increase of fat mass per se that was most associated with hypertension but rather abnormal visceral fat mass distribution and abnormal fat-to-lean body mass. In a prospective study of children 6–11 years of age, an increasing or persistently high WC was associated with increased cIMT after only 2 years of observation (Wang et al. 2021). The molecular basis of the evolution from a normotensive MHO phenotype to MUHO and hypertension was associated with a disturbed pattern of adipokine secretion. The Beijing Child and Adolescent Metabolic Syndrome study reported

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that higher leptin levels (RR 11.04, 95% CI 1.18–103.35) and leptin-to-adiponectin ratio (RR 9.8, 95% CI 1.11–87.97) were associated with increased risk of development of arterial hypertension in children with an MHO phenotype (Ding et al. 2018). However, a wide range of CI should be noted which suggests both the role of other factors and heterogeneity of studied group.

Metabolic Abnormalities, Metabolic Syndrome, and Oxidative Stress in Adolescents with PH It is estimated that the prevalence of MS in the general adult population, depending on the definition used, varies from 20% to 40%, increases with age, and reaches over 60% in persons over 60 years (Moore et al. 2017; Liu et al. 2021). The prevalence of MS among the general pediatric population has been reported to vary from ~10% in the USA to 0.2–2.8% in European countries (de Ferranti et al. 2004; Ekelund et al. 2009; Ostrihonova et al. 2017). However, the prevalence of MS among European adolescents with PH was 15–20% (in contrast to 2% in control group) and reached values observed in young adults (Litwin et al. 2007, 2010). Adolescents with PH have been reported to have metabolic abnormalities characteristic of MS: (1) hyperinsulinemia and insulin resistance (IR), (2) hyperuricemia, and (3) oxidative stress (OXS). Because these abnormalities typically develop with aging, their appearance in childhood PH suggests an association with altered body composition and VAT. Associations between glycemia, insulinemia, IR, and blood pressure status have been reported in children as young as 4 years of age and increase with age, as does disturbed body composition (Srinivasan et al. 2006). In one prospective study, higher insulin levels and IR at 13 years of age were associated with later blood pressure elevation and dyslipidemia at 16 years of age, and these effects were independent of BMI (Sinaiko et al. 2006). In a cross-sectional study of 113 adolescents with PH, cIMT correlated negatively with adiponectin levels and positively with fasting insulin and IR (Litwin et al. 2007). Further, in

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the same study, carotid wall cross-sectional area, another marker of arterial remodeling, correlated with WC, MS criteria present, and IR. A recent multicenter analysis of data from 2427 children aged 6–17 years noted an association between the number of MS criteria present and increased cIMT (Zhao et al. 2020). Although not part of the definition of MS, a higher-than-normal uric acid level was associated with MS and PH (Sun et al. 2014). In another study, higher serum uric acid levels, even in the upper normal range (>5.5 mg/dl), were noted among adolescents with PH; such a trend was also noted in teens with white coat hypertension and secondary hypertension (Feig and Johnson 2003). Recently, a relation between serum uric acid and blood pressure was addressed in a publication from the SHIP-AHOY study (Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth) which reported a direct correlation of mean uric acid level with BP level; uric acid rose from 5.3 mg/dl to 5.9 mg/dl as BP increased from below the 80th to above the 90th percentile (Urbina et al. 2019). Moreover, Feig et al. reported that treatment with allopurinol in adolescents with PH and serum uric acid levels above 6 mg/dl not only decreased uric acid levels but decreased BP (Feig et al. 2008). In a study of 294 adolescents referred for PH, a subset of 43 (mean age 16 years) with isolated systolic hypertension were followed for a year; among these, a decrease in serum uric acid level was the sole predictor of decrease of central systolic blood pressure – a marker of aortic stiffening (Obrycki et al. 2021). Such findings are concordant with results of observational longitudinal studies in adults that reported a significant association between arterial stiffness and increased serum uric acid levels (Canepa et al. 2017). Taken together, such associational studies suggest a causal relationship between metabolic disorders and the development of hypertension and arterial stiffening. Markers of cellular senescence, especially OXS and inflammatory activators, may be the mediators of metabolic abnormalities closely associated with PH phenotypes. Although only a few clinical studies have reported a putative role

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for OXS in children with PH, such work noted an association of OXS with PH, irrespective of BMI, and correlated with hypertension severity, hypertension-mediated organ damage (HMOD), and other metabolic and immunologic abnormalities. The effect of OXS on endothelial cells has been well described. A small number of clinical studies in the children and teens reported close associations between OXS and markers of EVA; for example, Warolin et al. reported that OXS is associated with visceral obesity, irrespective of BMI and blood pressure (Warolin et al. 2014). In another study, Paripovic et al. noted that children with PH were exposed to greater OXS irrespective of their BMI and that OXS correlated with 24-h SBP and left ventricular hypertrophy (Paripovic et al. 2018). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, enhances SOX (Nair and Gongora 2017). In a study in which age- and sex-matched normotensive and hypertensive children were compared, the hypertensive children had significantly increased serum levels of both symmetric dimethylarginine and ADMA (Goonasekera et al. 1997). The relation between OXS, expressed as serum levels of thiobarbituric acid substances (TBARS), and higher blood pressure was demonstrated in prepubertal children, especially boys as young as 6 years of age (Craig et al. 2018). Moreover, TBARS significantly correlated with cfPWV. Another study noted that 14-year-old hypertensive adolescents had evidence of greater lipid peroxidation in comparison with age- and BMI-matched normotensive children, had significant alterations in OXS markers such as depletion of glutathione in red cells, and had oxidative stress markers that correlated with hypertension severity (Turi et al. 2003). In a study of 86 adolescents with untreated PH, participants with severe ambulatory hypertension and left ventricular hypertrophy had increased TBARS, decreased glutathione, and increased glutathione peroxidase activity (Sladowska-Kozlowska et al. 2012). Moreover, patients with MS had greater OXS levels than those without MS, and ADMA and oxidized LDL-cholesterol correlated with inflammatory activity and serum TBARS concentrations with cIMT. Thus, it appears that OXS is a non-specific

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marker of both metabolic abnormalities typical of MS and of senescence and is a link between EVA, metabolic abnormalities, and inflammaging.

Immune Abnormalities and Inflammatory Activation in Children with PH A relation between immune activation, both of innate and adaptive immune system, and the pathogenesis of PH has been shown in both experimental and clinical studies (Norlander et al. 2018). Inflammaging, a non-specific immune activation, is one of the defining features of senescence and is associated with classic CVD risk factors such as metabolic abnormalities and visceral obesity (Bektas et al. 2018). The role of the immune system in the pathogenesis of PH and EVA is mediated through innate immunity by (1) adipocytokines and (2) matrix metalloproteases and their tissue inhibitors and through adaptive immunity via (3) T cells. Adipocytokines, such as adiponectin and leptin, link the effects of abnormal body composition, metabolic disturbances, and immune abnormalities. Higher adiponectin levels have also been associated with longevity (Arai et al. 2019). A meta-analysis of studies in hypertensive adults showed that adiponectin is higher in normotensive compared to hypertensive persons and that the inverse relation between adiponectin and the risk of PH increases with age and is also operative in persons with normal BMIs (Kim et al. 2013). The results of the prospective Young Finns Study showed that low adiponectin levels measured in childhood and adolescence (8–18 years) predicted cIMT after 21–27 years had elapsed (Saarikoski et al. 2017). The results remained similar when additionally adjusted for insulin levels in childhood, early life smoking, and adiponectin levels in adulthood. Few studies have addressed the role of the immune system in childhood hypertension and its association with EVA. Children with PH have apparent alterations in both innate and adaptive immunity. Children with untreated PH had significantly greater serum concentrations of hsCRP,

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macrophage inflammatory protein-1β (MIP-1β) is regulated upon activation, normal T cell expressed and presumably secreted protein (RANTES) than their normotensive peers, and immune activity was correlated with increased cIMT and the presence of MS (Litwin et al. 2010a). An analysis of 113 children with untreated PH who were examined at the time of the hypertensive diagnosis noted that low serum adiponectin levels correlated negatively with cIMT (Litwin et al. 2007). Adiponectin action is mediated by specific receptors on target cells. More recent work indicated that expression of adiponectin receptors on peripheral blood leucocytes was increased in hypertensive children and was inversely correlated with serum adiponectin levels, irrespective of BMI; study participants with greater expression of adiponectin receptors, a cellular marker of lower activation by adiponectin, had higher values of cIMT (Gackowska et al. 2015). Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are secreted by immune cells to control extracellular matrix remodeling and mediate effects of immune activation on cardiovascular system. The concentration and tissue activity of these molecules increase with age and mediate cardiovascular remodeling with age and in PH. In studies in adults noted that MMP-2 activity in aortic wall correlated with age (McNulty et al. 2005). In both healthy normotensive and hypertensive adults with isolated systolic hypertension serum, MMP-9 was positively associated with cfPWV (Yasmin et al. 2005). Results of a metanalysis of studies on MMPs and TIMPs in hypertensive adults suggest that TIMP-1, MMP-2, and MMP-9 may have a role as biomarkers of cardiovascular remodeling in hypertensive patients (Marchesi et al. 2012). Similarly, pediatric studies have found significantly higher serum levels of MMP-9 in children with untreated PH (Martinez-Aguayo et al. 2016; Niemirska et al. 2016). Moreover, hypertensive children had significantly altered secretion of both MMPs and TIMPs, and TIMP-1 serum concentrations correlated with functional markers of aortic stiffness, such as aortic pulse pressure and augmentation index (Niemirska et al. 2016). In another

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cross-sectional study of the same group of untreated adolescents with PH compared to a control group of normotensive adolescents, an altered gene expression pattern of MMPs and TIMPs in peripheral blood leucocytes was associated with carotid wall cross-sectional area, left ventricular hypertrophy, MS, and visceral obesity (Trojanek et al. 2020). Some studies indicate that adolescents with PH have subtle alterations of adaptive immunity, for example, in their T-cell distribution: increased mature T memory cells and decreased absolute and relative numbers of T regulatory cells (Tregs) in comparison with normotensive peers (Gackowska et al. 2018, 2020). Moreover, the pattern of T-cell subset distribution in children with PH was associated with left ventricular hypertrophy, increased cfPWV, and augmentation index. Such findings suggest that hypertensive children with signs of cardiac and arterial injury noted by increased aortic stiffness may have more rapid biological maturation of the immune system, particularly, of T memory cells (Gackowska et al. 2018). Similarly, adolescents with PH had decreased absolute and relative amounts of Tregs but with increased pool of activated/memory cells, indicating a shift towards more mature Tregs. Further, there was an association between the percentage of more mature, memory Tregs, and markers of aortic stiffness expressed as cfPWV (Gackowska et al. 2020).

Accelerated Biological Maturation and Childhood Hypertension As already discussed, the significant associations between features of immune-metabolic aging and EVA in children with PH indicate premature biological aging. This phenomenon has been shown in studies that have shown a correlation between blood pressure measurements and rate of growth. This phenomenon has been observed in premature infants born at the 28th–29th week of gestational age who exhibit catch-up in blood pressure levels after birth, reaching blood pressure levels of term infants by the 2nd week of postnatal life (Kent et al. 2007, 2009). Another rapid increase of blood

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pressure is observed at pubertal growth spurt. Physiologically, there is a 4–5-year window for the onset of puberty (Abreu and Kaiser 2016). Puberty and its accompanying growth spurt occur earlier in girls (mean age in EU: 12.6 years), than in boys (mean age in EU: 13.8 years). However, boys generally demonstrate a greater and faster rise in blood pressure, especially of SBP (Fig. 1). At puberty, blood pressure curves of both sexes diverge, and significantly higher values are then observed in males until the fifth–sixth decade of life. This physiological phenomenon corresponds to a greater prevalence of PH among males with a predominantly hemodynamic phenotype of isolated systolic hypertension in adolescent males. Epidemiological studies have indicated that more rapid maturation is closely associated with higher blood pressure. The National Health and Nutrition Examination Survey II and III have reported that markers of accelerated biological age such as more advanced bone age, greater number of permanent teeth, and higher WC were all associated with elevated blood pressure (Lauer et al. 1984). In a cross-sectional study in Brazilian adolescents, early maturation (expressed as the age of growth spurt) was strongly associated with greater prevalence of blood pressure in hypertensive range (28%) in comparison with those who matured on time (15.7%) or later (16%) (Werneck et al. 2016). In a prospective study, earlier maturation was associated with a greater BMI and higher blood pressures in adulthood (Hulanicka et al. 2007). Similar observations have been reported in other prospective studies such as the Bogalusa Heart Study and the Fels Longitudinal Study, which showed that an earlier growth spurt was associated with higher blood pressure, adiposity, and significant metabolic abnormalities by young adulthood (Frontini et al. 2003; Sun and Schubert 2009). The Young Finns Study found that women who had menarche at an earlier age had greater risk for PH, MS, and IR in their fourth decade of life (Kivimäki et al. 2008). Similarly, retrospective studies have reported that rapid growth between 8 and 13 years of age was associated with increased adult BP and increased mortality and morbidity

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from CVD, suggesting EVA (Halldorsson et al. 2011; Imai et al. 2013). These observations have been confirmed by clinical studies. Katz et al. reported that faster growth rate and advanced bone age were both associated with higher blood pressure in adolescence (Katz et al. 1980). In another study, the difference between bone age and chronologic age in adolescents with PH was 1.9  0.9 years, was significantly greater in comparison with normotensive peers ( p ¼ 0.006), and was correlated with blood pressure status (normal, prehypertension, ambulatory hypertension, and severe ambulatory hypertension) (Pludowski et al. 2009).

Hemodynamic Determinants of EVA in Hypertensive Children Only a few studies have been published in which the influence of individual hemodynamic components on the development of EVA was analyzed. One of the reports from Young Finns Study revealed that pulse pressure values measured in childhood correlated significantly with cIMT measured 21 years later (Raitakari et al. 2009). Recent analysis of data from 5925 participants in a study of 6 prospective cohorts revealed that SBP values had the best predictive value for adulthood cIMT (Koskinen et al. 2019). Similar results were obtained in smaller, cross-sectional studies of general pediatric population (Lim et al. 2009). Studies in children with PH also revealed that SBP and pulse pressure were the main predictors of cIMT (Litwin et al. 2004, 2006). Recent systematic review of studies in children with PH found that cIMT was determined not only by blood pressure components but also by BMI, visceral fat, immune activation, uric acid, and other classical cardiovascular risk factors (Azukaitis et al. 2021). With regard to arterial stiffness, studies in a general pediatric population have indicated that both SBP and diastolic blood pressure values correlated with PWV values (Lona et al. 2021). Similarly, Stabouli et al. found that both peripheral and central SBP were the main determinants of 24-h PWV independent of weight status

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(Stabouli et al. 2020). The other determinant of cfPWV was increased SBP variability (Stabouli et al. 2015). The recent analysis found that in contrast to cIMT the main determinant of PWV in children with PH was blood pressure but not other cardiovascular risk factors (Azukaitis et al. 2021). The clinical significance of these results is important as the main hemodynamic phenotype of PH is isolated systolic hypertension (Sorof et al. 2002; Litwin et al. 2019).

Reversibility of Features of EVA in Children with PH Chronic kidney disease (CKD) and HutchinsonGilford progeria are examples of diseases that follow the typical features of EVA with increased cIMT, arterial stiffness, and high rate of cardiovascular events in which appropriate treatment improves the morphology and function of the cardiovascular system and reduces the cardiovascular risk (Litwin et al. 2005, 2008; GerhardHerman et al. 2012; Gordon et al. 2014; Schmidt et al. 2018). Prospective studies in children with these diseases have shown that even advanced arterial changes may still be stabilized or improved with normalization of blood pressure, improved metabolic milieu in the case of CKD, and intensive treatment of main hemodynamic and metabolic abnormalities in the case of Hutchinson-Gilford progeria (Litwin et al. 2008; Gordon et al. 2014; Schmidt et al. 2018). Analysis of data from four prospective population studies from Finland, the USA, and Australia has shown that people who had elevated blood pressure in childhood or adolescence, but subsequently had normal BP as adults, had not developed increased cIMT and PWV in their fourth decade of life (Juhola et al. 2013). Further, data from the Bogalusa Heart Study and the Young Finns study showed that normalization of metabolic abnormalities and resolution of youth MS were associated with normal cIMT values in adulthood and decreased risk of T2DM development (Magnussen et al. 2012). Similarly, the prospective Special Turku Coronary Risk Factor Intervention Project for Children showed that

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even a moderate increase in physical activity caused significant improvement of FMD and attenuated cIMT progression in persistently active adolescents compared with those who became sedentary (Pahkala et al. 2011). Such results, as well as clinical observations, indicate that cardiovascular risk and EVA features may at least partially decrease over time if certain nonpharmacological and lifestyle therapeutic measures are introduced. Similarly, there is firm evidence that healthy lifestyle interventions based on school-based or community-based prevention programs are effective not only in terms of improvement of both blood pressure control and macrovascular injury but also on the level of microcirculation as assessed by retinal vessels status (Siegrist et al. 2018). Such positive effects have been observed both in adults and children (Streese et al. 2020). Although many cross-sectional studies have documented EVA in children with PH, few prospective studies have evaluated the effects of treatment in children with PH on EVA markers. Such studies have shown that improvement in endothelial function and arterial wall structure was associated with normalization of metabolic abnormalities, decrease of adiposity markers, and visceral fat. Further data can be obtained from prospective, interventional studies looking at the effects of treatment in obese children who have a similar clinical and laboratory phenotype to PH. Such studies have demonstrated that both dietary intervention and physical exercise in obese, prepubertal children have been associated with a significant increase in FMD and decrease in blood pressure and cIMT (Farpour-Lambert et al. 2009; Woo et al. 2004). Importantly, the extension of the intervention to 1 year resulted in a further improvement in terms of regression of increased cIMT values. Second, dietary intervention together with physical exercise was more effective than dietary intervention alone (Woo et al. 2004). These results have been confirmed in studies that included obese adolescents (Meyer et al. 2006). A recent study by Coach et al. showed that the DASH diet proved more effective than routine care both in terms of decrease of blood pressure and improvement of endothelial function assessed

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by FMD in a cohort of adolescents with PH. These authors reported that even a 6-month DASH diet in adolescents with stage 1 PH led to sustained improvement of dietary habits after 18 months and to significant blood pressure lowering and improvement of endothelial function assessed by FMD in comparison with routine care group (Couch et al. 2021). In a 12-month prospective study of non-pharmacologic and pharmacologic therapy (angiotensin-converting-enzyme inhibitor or angiotensin receptor blockers), subclinical arterial injury (expressed as cIMT and remodelling of carotid wall expressed carotid wall cross sectional area) regressed significantly in 86 adolescents with PH (Litwin et al. 2010b). The main predictors of regression of cIMT and arterial remodeling were the decrease of WC and inflammatory activation (in terms of hsCRP levels). Moreover, further analysis of this study also revealed that the main predictor of decrease in carotid wall crosssectional area was the decline of intraperitoneal VAT assessed by magnetic resonance imaging (Niemirska et al. 2013). There are fewer pediatric data on regression of arterial stiffness. In a prospective study of adolescents with ISH, there was significant decrease of standardized values of cfPWV despite no change in absolute values of cfPWV, after 1 year non-pharmacological antihypertensive therapy (Obrycki et al. 2021). This result may suggest that antihypertensive treatment may cause significant improvement of arterial elasticity in patients at an early stage of hypertensive disease. Recently, Laurent et al. reported that intensive antihypertensive treatment prevented arterial aging in a cohort of hypertensive adults at medium to high cardiovascular risk (Laurent et al. 2021).

Conclusions PH in childhood is associated with adaptive changes in the arterial tree that involves both large arteries and small, resistance vessels. These changes are associated with increased arterial wall thickness as well as increased stiffness of large arteries and rarefication within the microcirculation. Much data

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from both experimental and clinical studies suggest that the phenomenon of EVA in PH is caused not only by hemodynamic injury but rather by exposure to a cluster of immune-metabolic abnormalities and accelerated biological maturation. The pathogenesis of PH and EVA appears to be modulated by pre- and perinatal factors. The common denominator of these disturbances is the phenomenon of EBM, both on systemic, organ and molecular level. Results of large prospective studies in the general population and results of interventional studies in children and adolescents with PH suggest that EVA in its early stage is reversible, at least in part. However, improvement of arterial structure and function is not determined only by blood pressure lowering but also by an improvement of the metabolic milieu and normalization of body composition.

Cross-References ▶ Antenatal Programming of Blood Pressure ▶ Endothelial Dysfunction and Vascular Remodeling in Hypertension ▶ Hypertension in Children with Type 2 Diabetes or the Metabolic Syndrome ▶ Insulin Resistance and Other Mechanisms of Obesity Hypertension ▶ Obesity Hypertension: Clinical Aspects ▶ Uric Acid in the Pathogenesis of Hypertension

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blood pressure according to early, on time, and late maturation in adolescents. J Clin Hypertens 18: 424–430. https://doi.org/10.1111/jch.12699 Woo KS, Chook P, Yu CW, Sung RYT, Qiao M, Leung SSF et al (2004) Effects of diet and exercise on obesityrelated vascular dysfunction in children. Circulation 109:1981–1986 Yang L, Yang L, Zhang Y, Xi B (2018) Prevalence of target organ damage in Chinese hypertensive children and adolescents. Front Pediatr 6:333. https://doi.org/10. 3389/fped.2018.00333 Yang L, Magnussen CG, Yang L, Bovet P, Xi B (2020) Elevated blood pressure in childhood or adolescence and cardiovascular outcomes in adulthood: a systematic review. Hypertension 75:948–955. https://doi.org/ 10.1161/HYPERTENSIONAHA.119.14168 Yasmin N, Wallace S, McEniery CM, Dakham Z, Pulsalkar P, Maki-Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB (2005) Matrix Metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 25:875. https:// doi.org/10.1161/01.ATV.0000151373.33830.41 Zhao M, Caserta CA, Medeiros CCM, López-Bermejo A, Kollias A, Zhang Q, Pacifico L et al (2020) Metabolic syndrome, clustering of cardiovascular risk factors and high carotid intima-media thickness in children and adolescents. J Hypertens 38:618–624. https://doi.org/ 10.1097/HJH.0000000000002318

Part II Assessment of Blood Pressure in Children: Measurement, Normative Data, and Epidemiology

Methodology of Office Blood Pressure Measurement

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Tammy M. Brady

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Blood Pressure Measurement Steps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Patient Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Before the Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Cuff Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Cuff Placement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 Measurement Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Automated Blood Pressure Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Manual Auscultation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leg Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

277 277 277 279

Blood Pressure Measurement in Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Importance of Training and Retraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Device Selection and Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

Abstract

Accurate blood pressure measurement is an essential part of health care, particularly in

T. M. Brady (*) Department of Pediatrics, Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_42

pediatrics. Screening children for elevated blood pressure allows for early identification of abnormalities that may be associated with systemic conditions requiring intervention such as heart or kidney disease. Inaccurate measurement can lead to misdiagnosis: falsely low blood pressure can lead to missed hypertension, which is a lost opportunity for early disease-modifying intervention and treatment, and falsely high blood pressure can lead to 273

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unnecessary testing, treatment, stress, and burden. This chapter reviews the practical aspects of obtaining an accurate blood pressure measurement in a pediatric office setting, with additional attention paid to device accuracy. Keywords

Blood pressure · Cardiovascular disease · Hypertension · Automated device · Aneroid device · Manual auscultation · Validation · Validated device · Calibration · Pediatrics · Children · Youth

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devices, and by individuals with varying levels of expertise. Accurate measurement is therefore dependent on both skill in performing the measurement, which includes proper patient preparation and positioning prior to the actual measurement procedure, and the use of an accurate device. Suboptimal adherence to recommended measurement steps and/or use of inaccurate devices can have a significant impact on the blood pressure value obtained – either leading to a falsely high or falsely low measurement, both of which may have significant consequences.

Blood Pressure Measurement Steps Introduction Accurate blood pressure measurement is essential to the assessment of both health and illness severity. For patients presenting to a health-care provider when unwell, blood pressure measurement is crucial for triaging illness and determining the level of care required. For patients receiving medication treatment, blood pressure is key for assessing tolerance and screening for reactions. For those presenting for preventive care, blood pressure measurement is fundamental for health-care screening. In children, screening blood pressure measurements may help to identify otherwise asymptomatic individuals with kidney or cardiac disease or with other systemic conditions. These screening measurements can improve the outcomes of children with chronic illnesses that might otherwise manifest later and in a more advanced stage. With the clear evidence that blood pressure is a “vital” sign, it is easy to understand the importance of accurate blood pressure measurement. Inaccurate measurement leading to falsely low blood pressure is a missed opportunity for early evaluation and intervention and is a missed opportunity to identify secondary etiologies that impact health in the short and long term. Inaccurate measurement leading to erroneously high blood pressure can lead to unnecessary stress, testing, inconvenience, burden, and stigma to a child and their family. Due to its wide applicability, blood pressure is obtained in a wide variety of settings, with various

In the pediatric age group, most blood pressure measurements are obtained in an office setting in the context of a well-child visit or an urgent care visit. These screening blood pressures can be obtained using an automated device typically employing an oscillometric technique or an aneroid device via manual auscultation. Regardless of device used, there are key steps that need to be followed prior to measurement, which are summarized below (Flynn et al. 2017) and in this short video https://youtu.be/T9J3RE4Eins. While seemingly simple and easy to implement in practice, these steps are infrequently followed (Edward et al. 2020; Rakotz et al. 2017; Padwal et al. 2019) resulting in substantial measurement errors (Kallioinen et al. 2017).

Patient Preparation Before the Measurement Prior to having blood pressure measured, individuals should refrain from caffeine intake, smoking, and exercising for at least 30 min. They should have an empty bladder, and the room should be maintained at a comfortable temperature, avoiding extremes (too hot, too cold). The patient’s arm should be bare for cuff placement, with care taken to avoid upper arm constriction when rolling up sleeves. If necessary, a gown should be provided to keep the arm bare and

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unconstrained during measurement. Providers should ensure the room is quiet during the measurement, in a location remote from loud activity.

Positioning The room in which blood pressure is obtained should be furnished and arranged to facilitate proper patient positioning. All patients should have their back and feet supported with legs uncrossed. This means that they should be provided a chair low enough to the ground to have their feet resting on the floor, either with a backrest or positioned to allow them to rest their back against a wall. To facilitate this, pediatric offices may opt to provide smaller, child-sized chairs for younger children. Alternatively, patients can be provided a foot stool if needed to avoid dangling feet. The chair should be adjacent to a table for their arm to rest on in such a way that the midpoint of the upper arm cuff is at heart level (Fig. 1).

Cuff Selection The importance of using an appropriately sized cuff, individually selected for each patient, cannot be overstated. Miscuffing – i.e., using a cuff that is too small or a cuff that is too large – can lead to measurements that are either falsely high, potentially leading to overdiagnosis of hypertension, or falsely low, potentially leading to underdiagnosis of hypertension, respectively (Muntner et al. 2019;

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Maxwell et al. 1982). The pediatric age group is particularly vulnerable to miscuffing, as cuffs are invariably labeled to indicate age group (infant, child, small adult, adult, large adult and thigh) (Arafat and Mattoo 1999). The National Health and Nutrition Examination Survey data demonstrates that youth 3 years of age and older require a variety of cuffs, with some children 3–5 years of age requiring an adult cuff and some children 12 years of age and older requiring a thigh cuff for accurate measurement based on measured mid-arm circumference (Ostchega et al. 2014). An appropriately sized cuff is one in which the inflatable portion of the cuff (the bladder) encircles 80–100% of the mid-upper arm when applied. When measuring blood pressure by manual auscultation, one needs to also ensure that the width of the bladder is 40–50% of the measured mid-arm circumference (Geddes and Tivey 1976). The optimal way to determine cuff size is by direct measurement of the arm circumference at the midpoint of the upper arm. To obtain this measurement, first measure the length of the arm from the acromion (the bony part of the shoulder) to the olecranon (the bony part of the elbow) and divide this distance by 2. This halfway point is where you should then measure the mid-arm circumference. This measured value should be used to choose the appropriate cuff based on the arm circumference ranges printed on the cuff label. An alternative, less robust way in which to choose a cuff involves turning the cuff 90
so that the width of the cuff can be made to encircle the part of the mid-upper arm. If the cuff selected has a

Fig. 1 Proper patient positioning. (Source: Omron Blood Pressure Monitor BP785 instruction manual, page 25)

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bladder width that encircles at least 40% of the mid-arm and a bladder length that encircles 80–100% of the mid-upper arm, then this cuff is likely appropriate for the individual patient. Careful attention needs to be paid when using a two-piece cuff to ensure that the interior bladder is used for these measurement approximations (not the outer packaging that can be larger than the inflatable portion).

Cuff Placement In order to get an accurate blood pressure, the limb artery needs to be compressed symmetrically, and this can only be done when the cuff is placed with the midpoint of the bladder directly over the artery. In the upper extremity, the midpoint of the bladder should be placed directly over the brachial artery. For leg blood pressures, to be discussed later, the midpoint of the bladder should be placed directly over the popliteal artery (for thigh blood pressures) or over the posterior tibial artery (for calf blood pressures). Prior to cuff placement, the pulse should be located. Then, the bladder should be folded in half with the midpoint of the bladder placed over the artery as identified by the pulse. In the case of upper arm blood pressures, the cuff should be placed 1–2 fingerbreadths above the brachial pulse and should be applied snugly so that no more than 2 fingers can be inserted between the cuff and the skin once the cuff is secured (Fig. 2). A snug fit is important because loosely applied cuffs

Fig. 2 Proper cuff placement and application

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can lead to falsely high BP – a phenomenon called loose-cuff hypertension (Taleyarkhan et al. 2009). Once the cuff is placed, the patient’s arm should be supported in such a way that the midpoint of the cuff is at heart level (4th intercostal space). Poor adherence to any of these premeasurement steps can lead to inaccurate measurements (Table). Sources of Inaccurate Blood Pressure Measurement Effect on SBP Effect on (mmHg) DBP (mmHg) Patient preparation Recent caffeine +3 to +14 +2.1 to +13 intake Recent nicotine +2.8 to +25 +2 to +18 use/exposure Insufficient rest +4.2 to +11.6 +1.8 to +4.3 Bladder +4.2 to +33 +2.8 to +18.5 distension Patient positioning Arm unsupported +4.9 +2.7 to +4.8 Back NS +6.5 unsupported Crossed legs +2.5 to +14.9 +1.4 to +10.8 Arm lower than +3.7 to +23 +2.8 to +12 heart level Supine versus 10.7 to +9.5 13.4 to +6.4 sitting Cuff selection and technique Undercuffing +2.1 to +11.2 +1.6 to +6.6 (too-small cuff) Overcuffing 3.7 to 1.5 4.7 to 1.0 (too-large cuff) Talking +4 to +19 +5 to +14.3 Adapted from J Am Coll Cardiol 2019;73:317–35 (Muntner et al. 2019)

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Measurement Procedure Once these steps are followed, patients should be instructed to rest for 2–5 min prior to having their blood pressure measured, without talking, reading, or using their cell or smart phone. In the ideal scenario, the provider leaves the room for this rest period. After completion of the rest period, blood pressure measurement can begin. Blood pressure can be measured using an automated device, which is not dependent on provider skill other than what is required to initiate measurement on the device, or an aneroid device, which does require significant skill that can only be achieved and maintained by ongoing training. Both devices require testing to determine accuracy at initial purchase and then at regular intervals to ensure that accuracy is maintained. Due to their significant environmental risk and hazard to health, mercury devices should not be used for office blood pressure measurement (2020, Programme 2019). The procedures for determining accuracy are detailed later in the chapter.

Automated Blood Pressure Measurement Automated blood pressure devices can either measure one blood pressure per actuation or, when fully automated, can take three or more blood pressures per actuation separated by 30–60 s after a programmed initial rest period. Fully automated devices allow for unattended blood pressure measurement, a method that is commonly utilized in adult medicine to minimize the potential for white-coat hypertension. Evidence suggests that unattended blood pressure measurement may be a reasonable approach to hypertension screening in pediatric patients as well, particularly when paired with manually auscultated measurements (Hanevold et al. 2020). Blood pressures obtained using an automated device are typically estimated measurements based on arterial oscillations detected by the device cuff. Arterial oscillations are the slight increases and decreases in cuff pressure sensed

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when the pulse volume changes with each heart beat during inflation and deflation. Depending on the device, the cuff will identify the point of maximal oscillation during either inflation or deflation. This measured value, the mean arterial pressure, is then incorporated into a proprietary algorithm to produce an estimated systolic and diastolic blood pressure (Fig. 3; (Cohen et al. 2019)). While most consider the casing that houses the power source and display to be the “device,” the cuffs are an integral part of this system, as they are where the oscillations are sensed. Accuracy of the device is dependent on the use of device-specific cuffs. The use of off-brand cuffs that were not developed for the device can lead to inaccurate measurements and should be avoided.

Manual Auscultation When screening children and adolescents for hypertension, using an automated blood pressure device is a reasonable initial approach. However, any blood pressure measurement found to be  the age-sex-height specific 90th percentile or 120/80, whichever lower, requires confirmation via manual auscultation. This method of blood pressure measurement requires significantly more skill than the automated blood pressure measurement. Additionally, as cuff inflation requires effort on the part of the observer and blood pressure is determined by audible Korotkoff sounds, individuals obtaining manual blood pressure measurements must have adequate dexterity for cuff inflation, good hearing, and access to a high-quality stethoscope. Accurate blood pressure measurement using manual auscultation also depends on excellent vision on the part of the observer and purposeful placement of the aneroid device so that the dial is easily within sight. With manual auscultation, blood pressure is determined by the sounds emitted when an occluded artery becomes unoccluded during cuff deflation. These sounds resulting from increased arterial flow are Korotkoff sounds. The systolic blood pressure is identified as the first of two consecutive “taps”

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Fig. 3 Oscillometric versus auscultatory blood pressure determination

audible during cuff deflation (K1) and the diastolic blood pressure is identified as either the last audible Korotkoff sound (K5), confirmed after allowing the cuff to deflate 10 mmHg below this value, or as the point at which the Korotkoff sounds become

muffled (K4) when the Korotkoff sounds are heard all the way to 0 mmHg or to a nonphysiologic value. Preservation of a quiet environment is particularly important with manual blood pressure measurement.

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Fig. 4 Korotkoff sounds and the auscultatory gap

Some individuals have an auscultatory gap, which is an exaggerated pause or silence between the first 2 or more Korotkoff sounds and subsequent Korotkoff sounds (Fig. 4). Due to this known phenomenon, it is essential to determine the peak inflation level prior to manual blood pressure measurement. This step, detailed below, ensures that the observer will inflate the cuff sufficiently to auscultate the true K1. Insufficient inflation can lead to deflation initiation during the auscultatory gap, leading the observer to interpret the subsequent Korotkoff sounds as the K1 (thus obtaining a falsely low reading by missing the true K1). Manual Blood Pressure Measurement Steps: • Locate the radial pulse, inflate the sphygmomanometer quickly to 60 mmHg, and then inflate slowly in increments of 10 mmHg until the pulse disappears. • The value at which the pulse disappears +30 mmHg ¼ peak inflation level. • Deflate the cuff, wait 30 s, and inflate to peak inflation level. • Deflate at 2–3 mmHg/second to a level that is 10 mmHg lower than the level of the last Korotkoff sound (K5).

– SBP ¼ Onset of at least two consecutive, clear tapping sounds (K1) – DBP ¼ Disappearance of Korotkoff sounds (K5)

Leg Blood Pressure Certain situations warrant blood pressure measurement in the leg. In particular, youth with newly identified high blood pressure should have three limb blood pressures obtained (both arms and one leg) to screen for coarctation of the aorta and midaortic syndrome. The goal of leg blood pressure measurement is to identify any significant blood pressure discrepancies, specifically screening for lower blood pressures in the legs compared to the upper extremities. The systolic blood pressure in the leg is typically 10–20% higher than the systolic blood pressures in the arms. With this in mind, it is best to compare blood pressures obtained in the same manner, i.e., compare automated upper extremity supine BPs to automated lower extremity supine BPs. Or, if manual BPs are preferred, then each extremity

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should have a manual BP measured while in supine or prone position. It is recommended to follow all of the same steps for upper extremity blood pressure measurement with the patient lying on the examination table, resting for 2–5 min prior to measurement. Great care should be taken to ensure that appropriate cuff sizes are used for each extremity and that the cuffs are placed in such a way that allows for equal compression of the corresponding artery. The arteries in the leg are located posteriorly, so the bladder should be positioned accordingly. The cuff should also be at heart level; for leg blood pressures, a support may be needed to ensure proper cuff placement. To obtain a leg blood pressure, one can choose either to obtain a thigh or a calf blood pressure. A reasonable approach is to measure the right arm, left arm, and leg blood pressure sequentially using an automated device for comparison. If obtaining a manual leg blood pressure, this is best done with the cuff placed mid-thigh, patient positioned prone, and the stethoscope positioned over the popliteal artery.

Blood Pressure Measurement in Special Populations Blood pressure measurement in children and adolescents with obesity can be challenging to obtain primarily due to cuff size and placement. Youth with extreme obesity (class II or greater) can have mid-arm circumference measurements that call for a thigh cuff for accurate upper extremity measurements. These larger cuffs, typically encompassing an arm circumference range of 45–52 cm, are not always readily available in pediatric office settings. When they are available, additional challenges remain in regards to proper cuff application. Individuals with obesity are more likely to have conically shaped upper arms, meaning their proximal upper arm circumference is greater than their distal upper arm circumference – sometimes by as much as 20 cm (Palatini and Frick 2012). When this occurs, it is not only difficult to ensure snug cuff placement, but the cuff will often extend pass the

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elbow. A technique to optimize placement includes applying the cuff while the patient’s arm is extended to the side and using a slight crisscross to the end of the cuff when adhering the Velcro. While it’s tempting to use a forearm or wrist device in pediatric patients with obesity, this is not recommended and should be avoided. There are no known wrist devices that have undergone accuracy validation testing in children, these devices are commonly used improperly (as with upper extremity cuffs occluding the brachial artery, wrist cuffs need to be at heart level for accuracy), and radial blood pressures are not equivalent to brachial artery blood pressures. In fact, adult studies have demonstrated that radial blood pressures obtained via invasive lines are often >5 mmHg higher – sometimes >15 mmHg higher – than brachial artery blood pressures obtained in the same manner (Armstrong et al. 2019). Infants are another population in which it is challenging to obtain blood pressures. Fortunately, blood pressure measurement in this age group is infrequently required. When needed, several steps can optimize accurate measurement. Up until 6 months of age, lower extremity blood pressures are reasonable to use in place of upper extremity blood pressures. An appropriately sized and placed cuff remains essential. Placing the cuff and leaving it on for 15 min or more may allow for the infant to adequately quiet after placement. Waiting to inflate the cuff until the infant is sleeping or quietly awake, ideally 1.5 h after the last feeding and the last medical intervention, will increase the odds of a successful measurement. In an office setting, these steps can be achieved with advance planning with the parents. Avoidance of BP measurement while feeding and even while using a pacifier is important, as these activities can lead to an increase in blood pressure by 10–20 mmHg (Dionne et al. 2012). Manual measurement is also most successful with the use of a Doppler device or by radial palpation as Korotkoff sounds can be challenging to hear in small children. Using a Doppler device or palpation will only allow you to assess systolic blood pressure as you will hear/palpate the pulse all the way to 0 mmHg.

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Importance of Training and Retraining Accurate blood pressure measurement relies on skill that requires formal training and retraining to avoid decay over time (Armstrong 2002; Minor et al. 2012). The importance of this training is underscored by studies showing the waxing and waning measurement accuracy that correspond to the proximity to a training event (Bruce et al. 1988). Clinic settings where blood pressure measurement is performed should have systems in place to ensure that all staff have adequate, ongoing training ideally with certification provided to those demonstrating competence (Padwal et al. 2019). The American Medical Association has a free online course, “BP Measurement Essentials: Student Edition” for initial training on proper blood pressure measurement, and another course, “BP Measurement Refresher: Student Edition,” for retraining to maintain proficiency ( 2021).

Device Selection and Maintenance It goes without saying that the blood pressure measurement devices should pass validation testing for accuracy prior to purchase or use in a clinical setting. These validated devices should routinely undergo accuracy checks (automated and aneroid devices) and calibration (aneroid devices only) while in use. There are thousands of automated devices available for purchase for use in a professional/ clinic setting or for use in a home environment. Only a fraction of these devices have undergone formal validation testing for accuracy (Stergiou et al. 2018), with even fewer devices validated in children. Prior to purchasing a device, one should ensure that the device was tested for accuracy using the American National Standards Institute (ANSI)/Association for the Advancement of Medical Instrumentation (AAMI)/International Organization for Standardization (ISO) protocol (Stergiou et al. 2018; O’Brien et al. 2019). The British Hypertension Society validation protocol is acceptable for older devices manufactured prior to 2020.

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Several organizations have developed websites to help identify devices that have undergone appropriate validation testing for accuracy. Some of these are listed below: • American Medical Association: https:// validatebp.org • British and Irish Hypertension Society: https:// bihsoc.org/bp-monitors/ • Hypertension Canada: https://hypertension.ca/ bpdevices • Stride BP: www.stridebp.org Device maintenance requires regular inspection to screen for malfunction and inaccuracy. Automated devices never require calibration to maintain accuracy. Instead, these devices require inspection for wear and tear of the cuff and tubing and require accuracy checks against a reference standard. When parts are in disrepair or damaged, they require device-specific replacement to maintain accuracy. When a device is deemed to be inaccurate during testing, they should be replaced outright. These inspections should occur at least on a yearly basis. Aneroid devices are more prone to losing accuracy due to the intricate system of gears and bellows that can be damaged with rough handling. Accuracy checks of aneroid devices include the same inspection of cuffs and tubing as with automated devices, with additional inspection of the inflation bulb and the aneroid dial face to identify cracks. While at rest the dial needle should be at the 0 mmHg mark; if not, this is a sign the device needs to be calibrated or replaced. Aneroid devices should also undergo accuracy checks against a reference standard every 6 months; if found to be inaccurate, a qualified biomedical engineer may be able to calibrate the device to return it to accuracy. If such an individual is not available for this purpose, then the device needs to be replaced. More information regarding device accuracy checks and calibration can be found in the World Health Organization Technical Specifications for Automated Non-Invasive Blood Pressure Measuring Devices with Cuff (https://apps.who.int/iris/handle/10665/ 331749) (2020).

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Conclusion Accurate blood pressure measurement is key for sustaining health and wellness. Key aspects to accurate measurement include proper patient preparation, positioning, individualized cuff selection, and mastery of the measurement. Observer training and retraining to achieve and maintain proficiency and selection of accuracy validated devices that undergo regular maintenance are similarly important. With accurate measurement in pediatrics, children and adolescents can avoid misdiagnoses of hypertension, the repercussions of which can be significant with long-term consequences.

Cross-References ▶ Diagnostic Evaluation of Pediatric Hypertension ▶ Epidemiology of Hypertension and Cardiovascular Disease in Children and Adolescents ▶ Methodology and Applicability of Home Blood Pressure Monitoring in Children and Adolescents ▶ Neonatal and Infant Hypertension ▶ Obesity Hypertension: Clinical Aspects ▶ Primary Hypertension in Children ▶ Value of Routine Screening for Hypertension in Childhood

References American Medical Association (2021) 3 Tools to Help Health Care Students Accurately Measure Blood Pressure [Online]. https://edhub.ama-assn.org/pages/3tools-for-students-to-accurately-measure-blood-pres sure. Accessed 17 Sept 21 Arafat M, Mattoo TK (1999) Measurement of blood pressure in children: recommendations and perceptions on cuff selection. Pediatrics 104:e30 Armstrong RS (2002) Nurses’ knowledge of error in blood pressure measurement technique. Int J Nurs Pract 8: 118–126 Armstrong MK, Schultz MG, Picone DS, Black JA, Dwyer N, Roberts-Thomson P, Sharman JE (2019) Brachial and radial systolic blood pressure are not the same. Hypertension 73:1036–1041 Bruce NG, Shaper AG, Walker M, Wannamethee G (1988) Observer bias in blood pressure studies. J Hypertens 6: 375–380

T. M. Brady Cohen JB, Padwal RS, Gutkin M, Green BB, Bloch MJ, Germino FW, Sica DA, Viera AJ, Bluml BM, White WB, Taler SJ, Yarows S, Shimbo D, Townsend RR (2019) History and justification of a national blood pressure measurement validated device listing. Hypertension 73:258–264 Dionne JM, Abitbol CL, Flynn JT (2012) Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol 27:17–32 Edward A, Hoffmann L, Manase F, Matsushita K, Pariyo GW, Brady TM, Appel LJ (2020) An exploratory study on the quality of patient screening and counseling for hypertension management in Tanzania. PLoS One 15: e0227439 Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, De Ferranti SD, Dionne JM, Falkner B, Flinn SK, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM, Subcommittee On, S, Management Of High Blood Pressure In, C (2017) Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 140:119 Geddes LA, Tivey R (1976) The importance of cuff width in measurement of blood pressure indirectly. Cardiovasc Res Cent Bull 14:69–79 Hanevold CD, Faino AV, Flynn JT (2020) Use of automated office blood pressure measurement in the evaluation of elevated blood pressures in children and adolescents. J Pediatr 227:204–211.e6 Kallioinen N, Hill A, Horswill MS, Ward HE, Watson MO (2017) Sources of inaccuracy in the measurement of adult patients’ resting blood pressure in clinical settings: a systematic review. J Hypertens 35:421–441 Maxwell MH, Waks AU, Schroth PC, Karam M, Dornfeld LP (1982) Error in blood-pressure measurement due to incorrect cuff size in obese patients. Lancet 2:33–36 Minor DS, Butler KR Jr, Artman KL, Adair C, Wang W, McNair V, Wofford MR, Griswold M (2012) Evaluation of blood pressure measurement and agreement in an academic health sciences center. J Clin Hypertens (Greenwich) 14:222–227 Muntner P, Einhorn PT, Cushman WC, Whelton PK, Bell AA, Drawz PE, Green BB, Jones DW, Juraschek SP, Margolis KL, Miller ER, Navar AM, Ostchega Y, Rakotz MK, Rosner B, Schwartz JE, Shimbo D, Stergiou GS, Townsend RR, Williamson JD, Wright JT, Appel LJ, Inst NHLB (2019) Blood pressure assessment in adults in clinical practice and clinic-based research JACC scientific expert panel. J Am Coll Cardiol 73:319–335 O’Brien E, Stergiou G, Palatini P, Asmar R, Ioannidis JP, Kollias A, Lacy P, McManus RJ, Myers MG, Shennan A, Wang J, Parati G, European Society Of Hypertension Working Group On Blood Pressure, M (2019) Validation protocols for blood pressure measuring devices: the impact of the European Society of Hypertension International Protocol and the development of a Universal Standard. Blood Press Monit 24: 163–166

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Ostchega Y, Hughes JP, Prineas RJ, Zhang G, Nwankwo T, Chiappa MM (2014) Mid-arm circumference and recommended blood pressure cuffs for children and adolescents aged between 3 and 19 years: data from the National Health and Nutrition Examination Survey, 1999–2010. Blood Press Monit 19:26–31 Padwal R, Campbell NRC, Schutte AE, Olsen MH, Delles C, Etyang A, Cruickshank JK, Stergiou G, Rakotz MK, Wozniak G, Jaffe MG, Benjamin I, Parati G, Sharman JE (2019) Optimizing observer performance of clinic blood pressure measurement: a position statement from the Lancet Commission on Hypertension Group. J Hypertens 37:1737–1745 Palatini P, Frick GN (2012) Cuff and bladder: overlooked components of BP measurement devices in the modern era? Am J Hypertens 25:136–138 Programme, U. N. E (2019) Minimata Convention on Mercury [Online]. https://www.mercuryconvention. org/sites/default/files/2021-06/Minamata-Conventionbooklet-Sep2019-EN.pdf. Accessed 17 Sept 21

283 Rakotz MK, Townsend RR, Yang J, Alpert BS, Heneghan KA, Wynia M, Wozniak GD (2017) Medical students and measuring blood pressure: results from the American Medical Association Blood Pressure Check Challenge. J Clin Hypertens (Greenwich) 19:614–619 Stergiou GS, Asmar R, Myers M, Palatini P, Parati G, Shennan A, Wang J, O’Brien E, European Society Of Hypertension Working Group On Blood Pressure, M. & Cardiovascular, V (2018) Improving the accuracy of blood pressure measurement: the influence of the European Society of Hypertension International Protocol (ESH-IP) for the validation of blood pressure measuring devices and future perspectives. J Hypertens 36: 479–487 Taleyarkhan PR, Geddes LA, Kemeny AE, Vitter JS (2009) Loose cuff hypertension. Cardiovasc Eng 9: 113–118 WHO (2020) WHO technical specifications for automated non-invasive blood pressure measuring devices with cuff. World Health Organization, Geneva

Value of Routine Screening for Hypertension in Childhood

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Joseph T. Flynn

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Recognizing Pediatric Hypertension Can Be Challenging . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Different Points of View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 The Evidence Advocating Pediatric Hypertension As a Pathologic Condition . . . Blood Pressure Tracking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Left Ventricular Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carotid Intima-Media Thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arterial Pulse Wave Velocity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microalbuminuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

288 289 290 291 291 291 291

Benefits and Risks of Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

Abstract

Many consensus organizations recommend that all children and adolescents have their blood pressure routinely measured to screen for hypertension. The value of this practice

J. T. Flynn (*) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA Division of Nephrology, Seattle Children’s Hospital, Seattle, WA, USA e-mail: joseph.fl[email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_43

has been questioned based upon a lack of conclusive clinical trial evidence that such routine measurements lead to prevention of adult cardiovascular disease. Additionally, even recognizing elevated blood pressure measurements in childhood can be challenging, which may further weaken the value of routine blood pressure screening. However, ample indirect evidence from longitudinal cohort studies exists that elevated blood pressure early in life is linked to intermediate end-points and may predict the development of adult hypertension. Additionally, elevated childhood blood pressure may be 285

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an early sign of an underlying condition that requires specific treatment. The rationale for routine blood pressure screening in childhood will be discussed in the context of these issues. Keywords

Screening · Guideline · Cardiovascular disease · Secondary hypertension · Electronic health records

Introduction Pediatric hypertension is no longer a rare problem. Its prevalence has climbed steadily over the past several decades, particularly when the impacts of the childhood obesity epidemic and the new normative data in the 2017 American Academy of Pediatrics (AAP) Clinical Practice Guideline (Flynn et al. 2017) are considered (Flynn 2013; Sharma et al. 2018). Given this, today’s primary care providers will almost certainly encounter hypertensive children and adolescents should they decide to look. The central question this chapter addresses is whether they should look. Specifically, it considers the question “does the early identification and treatment of pediatric hypertension provide benefits to patients?” For adults, this question has long been answered in the affirmative. Multiple consensus organizations, including the American Heart Association (AHA), American College of Cardiology (ACC), and the United States Preventative Service Task Force (USPSTF), have recognized hypertension as a significant risk factor for cardiovascular morbidity and mortality (Siu and U.S. Preventive Services Task Force 2015; Arnett et al. 2019). Thus, adults routinely have their blood pressure (BP) screened, and once identified as having hypertension are actively monitored and treated. Essentially every adult hypertension guideline endorses this approach, including those from the ACC/AHA (Whelton et al. 2018), Hypertension Canada (Rabi et al. 2020) and the European Societies of Hypertension and Cardiology (Williams et al. 2019). This has resulted in a general consensus that, in adults,

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hypertension is a disease requiring treatment, so therefore, routine screening is warranted. Unfortunately, no such consensus exists in pediatrics. In fact, national expert committees contradict each other outright, with some recommending routine BP screening for children and others dismissing the practice as lacking value. The discrepancy between adult and pediatric views of BP screening arises from a lack of hard evidence: there is no study that conclusively links elevated childhood BP with an increase in mortality for either those children or the adults they will become. From this perspective, it could be said that childhood hypertension has not been conclusively proven to be a specific disease with adverse long-term consequences. A lack of direct evidence, however, does not imply no evidence at all. Much indirect evidence does exist, the majority of which suggests that hypertensive children become hypertensive adults susceptible to the increased morbidity and mortality that that entails. After a brief examination of the challenges facing recognition of pediatric hypertension, this chapter will explore this evidence in detail. We will also elucidate how the various expert panels charged with determining the utility of pediatric BP screening reached opposite conclusions. The potential benefits of BP screening, including its use in diagnosing secondary hypertension, will then be examined. Finally, we will present recommendations for future study, in hopes that one day the question of whether or not pediatric hypertension is an actual disease process with consequences in adulthood will be definitively answered.

Recognizing Pediatric Hypertension Can Be Challenging Any discussion of pediatric hypertension screening must begin by acknowledging that pediatric hypertension is significantly underdiagnosed. This was first demonstrated in a landmark study by Hansen et al. (2007), who showed that 74% of children meeting the criteria for hypertension during a well-child visit went unrecognized. This percentage of unrecognized BP elevations was

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even higher (87.5%) in a study by Brady et al. (2015), that included children presenting for both preventative care and acute care visits. These findings have been confirmed in multiple other studies (Stabouli et al. 2015; Aliarzadeh et al. 2016; Shapiro et al. 2012), with the prevalence of under-recognition ranging from 73% to 95%. Most recently, in a multicenter quality improvement project, chart review showed poor provider adherence to BP measurement steps, including repeating BPs when elevated at that visit, recording/recognizing BP elevations, scheduling follow-up visits for confirmation of BP elevations, and diagnosing HTN when BP was persitently elevated over 3 visits (Rea et al. 2021). It is clear, then, that many children who meet criteria for hypertension go unrecognized. Various explanations for this under-recognition have been proposed. Some focus on the complexity involved in diagnosing hypertension in childhood (Brady et al. 2010; Mitchell et al. 2011) – making the diagnosis requires triangulating a patient’s age, sex, and height onto percentile tables – whereas others attribute it to the increasing time pressures on primary care providers (Cha et al. 2014). These problems are compounded when one considers that the diagnosis of hypertension in childhood requires that a patient’s BP exceed a certain threshold on more than one occasion. Simply discovering previous values for a patient’s BP may increase both the complexity and duration of an office visit, never mind the additional calculations needed to determine whether past BPs were normal or elevated. Additionally, the known lability of BP measurements in children and adolescents means that BP levels may not remain stable over time (Kaelber et al. 2020), further compounding the challenge of making a diagnosis. Fortunately, there are encouraging signs that the use of electronic health records (EHRs) may increase the rate at which pediatric hypertension is diagnosed. Not only can EHRs automatically determine an individual patient’s threshold for hypertension and easily access past BP measurements, but they can also send providers alerts when hypertension is diagnosed. In the 2015 Brady paper, hypertension recognition increased

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from 12.5% to 42% when EHR alerts were implemented. Although most hypertensive children still went unrecognized, this represents a significant improvement. Additionally, a multicenter quality improvement project demonstrated improved recognition of elevated BP readings during and after implementation of a quality improvement collaborative (Rinke et al. 2019).

Different Points of View Recommendations regarding pediatric blood pressure screening come primarily from North America and Europe. However, neither continent has been able to agree on the sphygmomanometer’s utility as a screening tool. Guidelines published by the European Society of Hypertension (Lurbe et al. 2016) recommend at least annual BP screening for all children aged 3 years and older, whereas the United Kingdom recommends against universal screening (United Kingdom National Screening Committee 2018). Recommendations from the United States have been equally divided. Favoring universal screening, the Task Force on Blood Pressure Control in Children of the National Heart, Lung, and Blood Institute (NHLBI) has recommended at least annual BP measurement in all children 3 years of age and older since the First Task Force Report was released in 1977 (Blumenthal et al. 1977). The NHLBI most recently reaffirmed this position with the publication of its integrated guidelines for cardiovascular disease prevention (National Heart, Lung, and Blood Institute 2011). Following the NHLBI’s decision to defer guideline development to specialty societies, the recommendation to conduct universal BP screening in children starting at the age of 3 became part of the 2017 childhood BP guideline issued by the American Academy of Pediatrics (AAP) (Flynn et al. 2017). Taking an alternative stance since 2003, the United States Preventive Services Task Force (USPSTF) reports finding insufficient evidence to recommend for or against BP screening in children and adolescents (United States Preventative Services Task Force 2003). This “I recommendation” was reaffirmed (United States Preventative

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Services Task Force 2020) after an updated review of the evidence (Gartlehner et al. 2020), ensuring that the discrepancies in the recommendations from these organizations remain unresolved. Compounding this disagreement, the two largest professional societies representing pediatric primary care providers in the United States have also taken opposite sides of the debate. As already mentioned, the AAP issued a clinical practice guideline on childhood hypertension in 2017 that endorses annual measurement of BP starting at the age of 3 years for most children (Flynn et al. 2017). However, in keeping with longstanding policy, the American Academy of Family Physicians (AAFP) has adopted the USPSTF position, and therefore does not recommend screening BP measurements in children under the age of 18 years, and the AAFP did not fully endorse the AAP guideline. Family medicine providers are not necessarily discouraged from checking children’s BP, but are warned about the possibility of false positive readings. Ultimately, the choice of whether or not to screen a given child for hypertension is left to the individual family practitioner. For primary care providers, this is admittedly a perplexing state of affairs. How can thorough reviews of the evidence, performed by these different organizations, reach almost opposite conclusions? How can it be that pediatricians are directed to screen for hypertension, but family medicine providers are allowed not to? The answer lies in the guiding principles of each committee’s review. The overarching goal of any USPSTF review is to assess the balance of benefits and harms of routine screening for the condition in question. In the case of high BP in children and adolescents they concluded “The benefits and harms of screening for BP in children and adolescents are uncertain, and the balance of benefits and harms cannot be determined” (US Preventive Services Task Force 2020). Similarly, the NHLBI Working Group and later the AAP saw as their mandate “to provide recommendations for diagnosis, evaluation, and treatment of hypertension based on available evidence and consensus expert opinion.” Superficially, these groups appear to be engaged in the same endeavor, but a subtle distinction exists: the

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AAP must provide a recommendation regarding the practicalities of BP screening and HTN diagnosis to accomplish their goal, the USPSTF need not. The balance of benefits and harms of pediatric BP screening may be currently unknown and unproven, in which case the USPSTF could (and does) satisfy its mission by saying so. The NHLBI Working Group and AAP, in contrast, must (and do) recommend whether or not to evaluate BPs in children and adolescents. As mentioned, there are no clinical trials that directly link pediatric hypertension to increased mortality in either children or adults. Given the low mortality rate among pediatric patients, designing such a study would require following a large, stringently defined cohort for decades. Even if the logistics could be mastered – no small feat – the results of this hypothetical study would not be available for a generation or more. In effect, then, each organization’s recommendation turns upon the weight placed on the available indirect evidence, which will be considered in the next section.

The Evidence Advocating Pediatric Hypertension As a Pathologic Condition Because of the aforementioned difficulties in designing and conducting a study to determine whether pediatric hypertension is clearly associated with later cardiovascular mortality, researchers have split this research question into more manageable components. The logic behind this rests on the premise that because adult hypertension is associated with mortality, if pediatric hypertension can be associated with adult hypertension, then pediatric hypertension becomes associated with mortality. This approach of indirectly linking pediatric hypertension to adult mortality can also be seen in studies that analyze the association of pediatric characteristics with pathologic findings more typically considered to be “adult” outcomes, or adult precursors to cardiovascular mortality. These “intermediate outcomes” include left ventricular hypertrophy (LVH), increased carotid intimamedia thickness (cIMT), abnormal arterial pulse

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wave velocity (PWV), microalbuminuria, and metabolic syndrome. Again, if pediatric hypertension can be associated with an adverse intermediate outcome, it becomes indirectly linked to adult cardiovascular disease. These linkages are demonstrated in Fig. 1. Splitting the question of whether pediatric hypertension is associated with mortality into two parts is beneficial in that the latter half of each question has already been answered: adult hypertension (Franklin and Wong 2013; Kung and Xu 2015; Sim et al. 2015); LVH (Levy et al. 1990; Verdecchia et al. 2001), increased cIMT (Den Ruijter et al. 2012), elevated PWV (Vlachopoulos et al. 2010), microalbuminuria (Gerstein et al. 2001; Hillege et al. 2002), and metabolic syndrome (Galassi et al. 2006; Gami et al. 2007) have all been associated with increased cardiovascular mortality. However, determining whether pediatric hypertension is associated with any of the above still demands decades of follow-up. Fortunately, a partial answer can be glimpsed by examining the results of large, prospective cohort studies that have been established in several countries. Most of these studies began several decades ago, such that enough data has been collected on the earliest participants to begin elucidating the link between pediatric hypertension and adult outcomes. Indeed, all of the research discussed below is drawn from at least one of these cohort studies, which are summarized in Table 1.

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Blood Pressure Tracking In general, it appears that hypertensive children are more likely than non-hypertensive children to become hypertensive adults. Five studies involving members of the Bogalusa Heart Study, Muscatine Heart Study, Cardiovascular Risk in Young Finns study, and Fels Longitudinal Study all demonstrate significantly increased risk ratios or odds ratios linking elevations in pediatric BP to elevations in adult BP. The first of these was published by Beckett et al. (1992), and involved participants in the Fels Longitudinal Study. It focused on diastolic hypertension and found that 15-year-old males with diastolic BPs greater than 80 mmHg were three times more likely to have diastolic hypertension as adults. The effect was even more pronounced in 15-year-old females, who were four and a half times more likely to have diastolic hypertension as adults. Sun et al. (2007) used data from the Fels Longitudinal Study to look at the effects of systolic BP and found that increased systolic BP during childhood was significantly associated with adult hypertension in males aged 5–13, and in females aged 5–7 and 14–18. Males aged 14–18 and females aged 8–13 had odds ratios suggestive of an association, but these were not statistically significant. Lauer et al. (1993) studied the Muscatine cohort and found that children with BPs greater than the 90th percentile were 2.4 times more likely

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Adult HTN

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Increased LVMI

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Increased cIMT

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Microalbuminuria

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Fig. 1 Potential linkages between pediatric hypertension and adult cardiovascular mortality

Adult Mortality

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Table 1 Major prospective cohort studies investigating risk factors for cardiovascular disease from childhood into adulthood Study Cardiovascular Risk in Young Finns (Young Finns) (Finland) Bogalusa Heart Study (Bogalusa, LA, USA) Muscatine Study Adult Longitudinal Cohort (Muscatine, IA, USA) Childhood Determinants Of Adult Health (CDAH) (Australia) Princeton Follow-up Study (Cincinnati, OH, USA)

International Childhood Cardiovascular Cohort Consortium (i3C) (Multinational) Fels Longitudinal Study (Yellow Springs, OH, USA)

History Began in 1980 with the enrollment of 3596 Finnish children and adolescents. Measurements taken at ages 3, 6, 9, 12, 15, and 18 years. Follow-up continues regularly Began in 1973, now has nine cross-sectional surveys of children aged 4–18 years in the study Initial data collection took place between 1970 and 1981, now has 865 adults with ongoing follow-up Consists of 8498 children aged 7–15 years recruited in 1985. Blood pressures measured at 9, 12, and 15 years. Follow-up is ongoing The Princeton Lipid Control Study evaluated cardiovascular risk factors of 6775 children aged 6–18 years between 1973 and 1976. From 1999 to 2003, follow-up of 1632 original participants was performed Formed in the mid-2000s from researchers involved with the five cohort studies described above, now includes several smaller cohort studies as well A longitudinal study that began in 1929 that annually examines participants. Recruitment continues today (and now includes greatgrandchildren of the original participants)

to be hypertensive as adults when compared to children with normal BPs. Bao et al. (1995) studied the Bogulasa cohort, and found a similar risk ratio of 3.6 when comparing children with BPs above the 80th percentile to those below the 80th percentile. Along the same lines, participants with elevated childhood BP in the Childhood Determinants of Adult Health Study had a 35% increased risk of developing adult hypertension compared to those with normal childhood BP (Kelly et al. 2015). Juhola et al. (2011), using data from the Cardiovascular Risk in Young Finns cohort, examined the positive predictive value (PPV) of using pediatric BP elevations to predict adult hypertension. They obtained a PPV of 0.44, suggesting that about half of the participants who had a BP measurement in the hypertensive range as children were later found to have hypertension as adults. A study conducted in Israel showed much stronger associations between BP in adolescence and adult hypertension (Tirosh et al. 2010). Finally, in a study from the

References Raitakari et al. 2003; Juhola et al. 2011; Aatola et al. 2014

Bao et al. 1995; Hoq et al. 2002; Li et al. 2003; Li et al. 2004; Lai et al. 2014 Lauer et al. 1993; Burns et al. 2009; Schubert et al. 2009 Juonala et al. 2010; Juhola et al. 2013; Kelly et al. 2015 Huang et al. 2008; Schubert et al. 2009

Juonala et al. 2010; Juhola et al. 2013; Urbina et al. 2019

Beckett et al. 1992; Sun et al. 2007; Schubert et al. 2009

International Childhood Cardiovascular Cohort (i3C) Consortium, which combines many of the cohort studies already mentioned, participants who self-reported adult hypertension had higher BP and adiposity as youth (Urbina et al. 2019), providing further evidence that high BP in childhood tracks into adulthood.

Left Ventricular Hypertrophy Only one study investigating the association between childhood BP and adult LVH has been conducted. Utilizing participants in the Bogalusa Heart Study, Lai et al. (2014) evaluated LVH in adults with at least two BP measurements obtained during childhood. They found that as childhood systolic BP increased, the likelihood of adult LVH also increased, even when adjusting for other risk factors. This was a statistically significant finding, with an odds ratio of 1.27 (95% confidence interval 1.04–1.54).

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Carotid Intima-Media Thickness Studies investigating the relationship between childhood BP and adult carotid IMT (cIMT) have demonstrated conflicting results, though the preponderance of evidence suggests that the two are linked. A study by Li et al. (2003), which included participants in the Bogalusa Heart Study, found no relationship between the two. That same year, however, a similar study by Raitakari et al. (2003) involving participants from the Cardiovascular Risk in Young Finns study demonstrated a significant relationship between increasing systolic BP (measured when participants were 12–18 years of age) and increasing cIMT. More recently, additional data from the i3C Consortium have become available. As mentioned previously, these studies combined data from the Young Finns study, the Bogalusa Heart Study, the Muscatine Study Adult Longitudinal Cohort, and the Childhood Determinants of Adult Health study, thereby resulting in more participants and greater power than the individual cohort studies. Using this larger cohort, Juonala et al. (2010) found that, beginning at age 12, systolic BPs were significantly associated with increases in carotid IMT during adulthood. Juhola et al. (2013) later demonstrated that persistently elevated BP beginning at age 12 was significantly associated with increased carotid IMT in adulthood, more so than elevated BP in adulthood alone. Interestingly, the researchers also found that elevated BPs in childhood that resolved by adulthood was not associated with increased carotid IMT, suggesting that treatment of elevated BP in childhood may be effective at preventing end organ damage.

Arterial Pulse Wave Velocity In an early study of arterial PWV, a noninvasive measure of arterial stiffness, Li et al. (2004) found that increases in childhood systolic BP were significantly associated with increases in adult brachial-ankle PWV. Unfortunately, further interpretation of this study is difficult because its results are presented in a confusing fashion: the authors

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provide beta coefficients from the regression model, but it is not clear what type of regression model was used and whether those coefficients are related to differences in means or odds ratios. However, the relationship between childhood BP and adult arterial PWV was strengthened when Aatola et al. (2014) investigated the PWV of participants originally aged 6–15 years in the Young Finns study. They found that those participants with elevated BPs in childhood were 1.7 times more likely to have an elevated arterial PWV than those with normal BPs.

Microalbuminuria Hoq et al. (2002) investigated the relationship between microalbuminuria in adulthood and BP in childhood among participants in the Bogalusa Heart Study. Using a logistic regression model accounting for other risk factors, they found a significant association between the two among Black (with a p-value of 0.05), but not White (p-value of 0.776), participants. BP was also higher in Black participants; whether this explained the difference in microalbuminuria was not further explored by the authors.

Metabolic Syndrome Using data from the Muscatine Study Adult Longitudinal Cohort, Burns et al. (2009) investigated risk factors for development of metabolic syndrome in 730 participants. They found that participants with childhood systolic BPs above the 75th percentile were 2.6 times as likely to develop metabolic syndrome as those participants with childhood systolic BPs below the 50th percentile. Huang et al. (2008) used data from the Princeton Follow-up Study to demonstrate that adults with metabolic syndrome had significantly higher systolic BP in childhood than those without metabolic syndrome. This finding was confirmed in a later study by Schubert et al. (2009) using data from the Princeton Follow-up Study, Muscatine Study, and Fels Longitudinal Study.

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Benefits and Risks of Screening Though the evidence reviewed above is mixed, most studies suggest a connection between pediatric hypertension and worsening intermediate outcomes as adults. Many professional societies endorse the Lifespan Approach to Adult Disease, with the American Heart Association in particular promoting preservation of Ideal Cardiovascular Health starting in childhood. For the sake of argument, let us postulate that pediatric hypertension and adult cardiovascular morbidity and mortality are causally linked. It stands to reason, then, that the diagnosis and treatment of hypertension – if safe and feasible – should be a priority during childhood. The safety of BP screening (and, if necessary, resultant hypertension treatment) was thoroughly investigated by both the NHLBI and USPSTF. In this instance, both committees reached the same conclusion: no significant harms were associated with BP screening, hypertension treatment via lifestyle changes, or hypertension treatment via medication. Safety, then, is not a concern. The only question remaining is whether treating pediatric hypertension prevents cardiovascular morbidity and mortality. Some evidence exists describing the beneficial effects of hypertension treatment during childhood and adolescence on many of the markers of cardiovascular disease delineated above. The best studied of these markers is LVH, and studies by Assadi (2007), Litwin et al. (2010), and Seeman et al. (2007) all have demonstrated improvements in left ventricular mass index (and therefore decreases in LVH prevalence) following hypertension treatment. Litwin et al. also demonstrated a reduction in the carotid IMT and the percentage of children qualifying for a diagnosis of metabolic syndrome with antihypertensive treatment. No such studies exist for the other intermediate outcomes, but it is certainly plausible that improved BP control could reduce arterial PWV and rates of microalbuminuria. Aside from the controversy regarding screening for the prevention of long-term cardiovascular sequelae, screening children’s BP remains beneficial in that this may lead to detection of significant underlying conditions that require specific

J. T. Flynn

treatment. In other words, hypertension in childhood may be secondary in origin, and screening BP measurements may lead to the early diagnosis of a causative problem. Two recent studies (GuptaMalhotra et al. 2015; Flynn et al. 2012) have shown that over half of hypertensive children – particularly younger children – have secondary forms of hypertension. Sometimes, such as with coarctation of the aorta, renal artery stenosis, pheochromocytoma, or chronic kidney disease, hypertension is the major presenting symptom of this underlying condition. Thus, the diagnosis may go undiscovered if BPs are not routinely monitored. The morbidity associated with conditions causing secondary hypertension is clear, but can potentially be reduced with early diagnosis and treatment. Routine BP screening goes a long way toward making that early diagnosis and treatment possible. Even if BP screening serves only to identify those patients with secondary hypertension – a big if, considering the evidence above – it would seem to still be a worthwhile practice.

Future Directions Overall, the cohort studies discussed above have made great progress in linking pediatric hypertension to intermediate outcomes that are themselves conclusively linked to adult cardiovascular disease and mortality. Most of these cohorts began in the 1970s and 1980s and their usefulness has continued to grow over time. Assuming that retention rates remain acceptable, the prevalence of outcomes already studied should only increase. With additional observation time, it is also possible that “hard” cardiovascular outcomes such as myocardial infarction and stroke can be studied. As these cohort studies continue to collaborate and analyze their participants in aggregate (as evidenced by the i3C Consortium), the power of future studies will be enhanced, providing data that could resolve the discrepancies noted above. With enough time and careful documentation, it may even be possible to directly investigate the association between pediatric hypertension and adult mortality. Though causation would not be able to be established given the

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Value of Routine Screening for Hypertension in Childhood

study designs, a correlation between high childhood BP and adult cardiovascular mortality would be very suggestive. The burgeoning use of electronic health records is also encouraging. Though much work remains to be done to improve EHR functionality, usability, and cross-platform compatibility, one can imagine a world in which the prospective cohorts discussed above are instead created retrospectively with a series of database queries. This world relies upon a number of assumptions, however: that the data in question exists (it has to be recorded to be stored in the database), that the data is of high quality, and that decades’ worth of data is available for a given individual. As EHRs become more commonplace, researchers will have to work with informaticists and IT specialists to address these issues.

Conclusions Pediatric hypertension is increasingly common, and its diagnosis requires diligence on the part of primary care providers. However, the consequences of undiagnosed pediatric hypertension are not entirely clear. As such, expert committees differ widely in their recommendations as to whether or not children should have their BP routinely monitored, with some proposing universal, annual screening and others suggesting no routine screening during childhood. The evidence linking pediatric hypertension to undesirable adult outcomes is also sometimes contradictory, and there is no direct evidence that elevated BP in childhood is problematic when those children become adults. However, there is mounting indirect evidence that hypertensive children are at greater risk for cardiovascular morbidity and mortality later in life. Furthermore, routine BP screening allows for the identification of secondary hypertension and the morbidity and mortality it represents. Ongoing analyses of prospective cohort studies and the increasing use of electronic health records should provide more powerful data and insight to hopefully resolve the question of whether or not to routinely perform pediatric BP screening.

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Cross-References ▶ Ambulatory Blood Pressure Monitoring Methodology and Norms in Children ▶ Development of Blood Pressure Norms and Definition of Hypertension in Children ▶ Methodology of Office Blood Pressure Measurement Acknowledgment The author would like to recognize Dr. Michael Semanik for his contributions to the previous edition of this chapter.

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J. T. Flynn noncardiovascular mortality in general population. Circulation 106(14):1777–1782 Hoq S, Chen W, Srinivasan SR, Berenson GS (2002) Childhood blood pressure predicts adult microalbuminuria in African Americans, but not in whites: the Bogalusa Heart Study. Am J Hypertens 15(12): 1036–1041 Huang TT, Nansel TR, Belsheim AR, Morrison JA (2008) Sensitivity, specificity, and predictive values of pediatric metabolic syndrome components in relation to adult metabolic syndrome: the Princeton LRC follow-up study. J Pediatr 152(2):185–190 Juhola J, Magnussen CG, Viikari JS et al (2011) Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study. J Pediatr 159(4):584–590 Juhola J, Magnussen CG, Berenson GS et al (2013) Combined effects of child and adult elevated blood pressure on subclinical atherosclerosis: the International Childhood Cardiovascular Cohort Consortium. Circulation 128(3):217–224 Juonala M, Magnussen CG, Venn A et al (2010) Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium. Circulation 122(24):2514–2520 Kaelber DC, Localio AR, Ross M, Leon JB, Pace WD, Wasserman RC, Grundmeier RW, Steffes J, Fiks AG (2020) Persistent hypertension in children and adolescents: a 6-year cohort study. Pediatrics 146(4): e20193778 Kelly RK, Thomson R, Smith KJ et al (2015) Factors affecting tracking of blood pressure from childhood to adulthood: the childhood determinants of adult health study. J Pediatr 167:1422–1428 Kung HC, Xu J (2015) Hypertension-related Mortality in the United States, 2000–2013. NCHS data brief, no 193. National Center for Health Statistics, Hyattsville Lai CC, Sun D, Cen R et al (2014) Impact of long-term burden of excessive adiposity and elevated blood pressure from childhood on adulthood left ventricular remodeling patterns: the Bogalusa Heart Study. J Am Coll Cardiol 64(15):1580–1587 Lauer RM, Clarke WR, Mahoney LT, Witt J (1993) Childhood predictors for high adult blood pressure. The Muscatine Study. Pediatr Clin N Am 40(1):23–40 Levy D, Garrison RJ, Savage DD et al (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322(22):1561–1566 Li S, Chen W, Srinivasan SR et al (2003) Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 290(17):2271–2276 Li S, Chen W, Srinivasan SR, Berenson GS (2004) Childhood blood pressure as a predictor of arterial stiffness in

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young adults: the Bogalusa heart study. Hypertension 43(3):541–546 Litwin M, Niemirska A, Sladowska-Kozlowska J et al (2010) Regression of target organ damage in children and adolescents with primary hypertension. Pediatr Nephrol 25(12):2489–2499 Lurbe E, Agabiti-Rosei E, Cruickshank JK et al (2016) 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens 34(10):1887–1920 Mitchell CK, Theriot JA, Sayat JG et al (2011) A simplified table improves the recognition of paediatric hypertension. J Paediatr Child Health 47(1–2):22–26 Rabi DM et al (2020) Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children. Can J Cardiol 36(5):596–624 Raitakari OT, Juonala M, Kähönen M et al (2003) Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 290(17):2277–2283 Rea CJ, Brady TM, Bundy DG et al (2021) Pediatrician adherence to guidelines for diagnosis and management of high blood pressure. J Pediatr S0022-3476(21): 01073–01078. https://doi.org/10.1016/j.jpeds.2021. 11.008 Rinke ML, Singh H, Brady TM et al (2019) Cluster randomized trial reducing missed elevated blood pressure in pediatric primary care: project RedDE. Pediatr Qual Saf 5:e187 Schubert CM, Sun SS, Burns TL et al (2009) Predictive ability of childhood metabolic components for adult metabolic syndrome and type 2 diabetes. J Pediatr 155(3):S6.e1–S6.e7 Seeman T, Gilík J, Vondrák K et al (2007) Regression of left-ventricular hypertrophy in children and adolescents with hypertension during ramipril monotherapy. Am J Hypertens 20(9):990–996 Sharma AK, Metzger DL, Rodd CJ (2018) Prevalence and severity of high blood pressure among children based on the 2017 American Academy of Pediatrics Guidelines. JAMA Pediatr 172(6):557–565 Shapiro DJ, Hersh AL, Cabana MD et al (2012) Hypertension screening during ambulatory pediatric visits in the United States, 2000–2009. Pediatrics 130(4):604–610 Sim JJ, Bhandari SK, Shi J et al (2015) Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension. Kidney Int 88(3):622–632 Siu AL, U.S. Preventive Services Task Force (2015) Screening for high blood pressure in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 163(10):778–786 Stabouli S, Sideras L, Vareta G et al (2015) Hypertension screening during healthcare pediatric visits. J Hypertens 33(5):1064–1068

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Development of Blood Pressure Norms and Definition of Hypertension in Children

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Bonita Falkner

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 Outcome of Childhood Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 Prevelance of Hypertension in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Definition of Hypertension in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Normative Blood Pressure Distribution in Children and Adolescents . . . . . . . . . . . . 302 Application of Blood Pressure Normative Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Abstract

The definition of hypertension in children and adolescents is based on analysis of blood pressure (BP) data from a large population of healthy children and adolescents to determine the normative distribution of BP in childhood. Such data were not available prior to the 1970s and measurement of BP was not a standard practice in asymptomatic healthy children at the time. In the absence of reference data on BP levels in healthy children, adult criteria were used. Early

B. Falkner (*) Departments of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 J. T. Flynn et al. (eds.), Pediatric Hypertension, https://doi.org/10.1007/978-3-031-06231-5_10

reports on BP levels in healthy children indicated that the normal range of BP was considerably lower than in adults, and there was a progressive increase in BP levels that corresponded to childhood growth and development. Subsequently, several large observational studies were conducted on healthy children and adolescents. These studies applied uniform methods in BP measurement along with growth measures of height and weight. The combined data from these studies were analyzed to determine the normative distribution of BP from early childhood to late adolescence. In the absence of morbidity and mortality data, hypertension in childhood continues to be defined statistically as systolic or diastolic pressure
95th percentile for sex, age, and height on repeated measurement. For adolescents, hypertension is currently 297

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defined as
130/80 mm Hg, similar to the current definition hypertension in adults. Keywords

Blood pressure · Hypertension · Elevated BP · Children · Adolescents · Growth · Obesity

Introduction Assessment of blood pressure (BP) in children and adolescents, as a measure of health status, is now part of routine clinical practice. Prior to the 1970s, BP was not commonly measured in very young children due to the difficulty in obtaining reliable measurements and the general belief that hypertension was a rare problem in children (McCrory 1952). Since measurement of BP had not yet become routine, high BP was detected only when significant clinical signs or symptoms were present. In the absence of any childhood BP data on which to base an age-appropriate definition of hypertension, adult criteria were the only available thresholds to guide interpretation of measurements. Based on current knowledge about normal BP in healthy children, we now know that the early descriptions of hypertension in the young represented only the most severe cases of hypertension in childhood. The development of specific normal values for BP in childhood has led to a significant shift in our understanding of hypertension in the young. Prior to 1970, it was widely believed that hypertension was always secondary to an underlying cause in children, and that primary, or essential, hypertension did not exist in the pediatric population. Once reference data on BP relative to childhood growth and development was available, this belief changed. There is now a substantial body of normative BP data based on a large, diverse group of children from the United States that enable clinicians to evaluate the BP level in a given child relative to age, sex, and body size. Moreover, the clinician can use the available reference BP data and the clinical characteristics of the child to determine the child’s health status in terms of healthy, having risk factors that warrant preventive intervention, or having a BP level that

B. Falkner

necessitates further evaluation. Some children, especially younger children, do indeed have hypertension secondary to an underlying disorder such as renal disease, endocrine disorders, or cardiac and vascular abnormalities. However, with these advances, it is now known that primary (essential) hypertension can be detected in the young. This important shift in understanding has allowed for efforts focusing on recognizing the early phase of primary hypertension to intervene earlier and modify risk for later adverse cardiovascular events. The advancement in knowledge on childhood hypertension over the past 40 years has developed from a process of accumulating, evaluating, and understanding data on BP levels in children and adolescents. An important outcome of this process is the BP normative data on which the current definitions of normal and abnormal BP levels in childhood are based. BP measures the circulatory pressure exerted by the blood on the arterial walls, and high BP levels are a well-described risk factor for future cardiovascular events. An abnormal BP level may also be indicative of an underlying disorder or may indicate primary hypertension. Today, the definitions of hypertension in childhood rely on normative BP data generated from ~50,000 children without overweight or obesity. This chapter will discuss the development of the BP normative data in childhood and their use in detection, evaluation, and management of hypertension in childhood.

Outcome of Childhood Hypertension Hypertension is a significant health problem to the extent that adverse clinical outcomes can be attributed to or associated with BP measurements that exceed a certain level. Prior to a publication in 1967 by Still and Cottom (1967) little was known about the health consequences of hypertension in childhood. These authors provided one of the first descriptions on the outcome of severe hypertension in children by reviewing cases of children with sustained diastolic BP greater than 120 mm Hg treated at the Hospital for Sick Children at Great Ormond Street from 1954 to 1964. Of the 55 cases reviewed, 31 died, 18 survived with treatment that achieved a

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Development of Blood Pressure Norms and Definition of Hypertension in Children

reduction in BP, and 6 were cured of the hypertension following corrective surgery for an identifiable lesion (coarctation repair, unilateral nephrectomy, pheochromocytoma removal). Of the cases that died, the average duration of survival following diagnosis of hypertension was only 14 months. In this early case review, the sample of children with severe uncontrolled hypertension had a mortality rate of 90% in slightly over 1 year, a mortality rate that is the same as that of malignant hypertension in adults. While these numbers are shocking by today’s standards, the message at that time was that severe hypertension in a child could be as deadly as it was in an adult. The above report and others of that period were limited to children with what would now be considered very severe hypertension. In the absence of BP data on normal children, the conventional adult cut point of 140/90 mm Hg was generally used to define hypertension in children. This practice limited the diagnosis of hypertension in children to those with the most extreme elevations of BP. In children, severe hypertension is frequently associated with renal disease or some other disorder that causes the hypertension. Consequently, for some time the focus of childhood hypertension was on the evaluation for underlying disease, and search for a secondary cause. Subsequent efforts to develop normative data on BP in childhood were a necessary prelude for a shift from the narrow focus of secondary hypertension to a broader perspective that high levels of BP could indicate an early phase of a chronic process. It was established that severe hypertension had an adverse outcome if left untreated. What was yet to be determined was how frequently did hypertension occur, and what level of BP elevation in a child conferred risk for target organ or vessel injury.

Prevelance of Hypertension in Childhood In the last half of the twentieth century, hypertension was established as a significant health problem in adults, and efforts were underway, from both a public health and clinical care perspective, to

299

improve detection and management of hypertension. To a large extent, hypertension had been regarded as a component of aging and a reflection of chronic atherosclerosis. Thus, hypertension appeared to have little relevance in the young. Jennifer Loggie was one of the first to consider the possibility that “essential” hypertension could be detected in adolescents. In a review article, Loggie (1974) discussed the available reports at that time on the prevalence of hypertension in persons 25 years of age or less. Of the five published reports (Heyden et al. 1969; Londe 1966; Wilber et al. 1972; Gallagher et al. 1956; Boe et al. 1957) that attempted to determine the prevalence of hypertension in the young by conducting BP screening on samples of healthy individuals, the prevalence of hypertension ranged from 1% to 12.4%. Table 1 summarizes these reports and denotes the differences in the criteria used to define hypertension, methods of measurement (sitting vs. supine), and the age of the sample examined. The majority of these early reports on hypertension in adolescents and young adults defined hypertension according to a blood pressure level that was similar to values used for adults. However, the report by Londe (1966) examined BP levels in younger children, aged 4–15 years and used a different definition of hypertension. Londe had measured BP on children in his own pediatric clinic, and observed that BP levels increased with age, concurrent with growth and development. He then analyzed the BP data to determine the range of observed systolic and diastolic blood pressure stratified by age and selected the 90th percentile for each age to define abnormal BP. Thus, his reported rates of high BP were consistent with his definition and were slightly above 10%. He also noted that on repeated BP measurement there was regression toward the mean, and the prevalence of persistent systolic or diastolic BP greater than the 95th percentile was much lower at 1.9%. Little attention was given to Londe’s work for some time. However, it is remarkable that his reported prevalence of sustained elevations in systolic or diastolic BP equal to or greater than the 95th percentile in children as 1.9% is close to more contemporary estimates of pediatric hypertension derived from far larger numbers of children.

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Table 1 Reported prevalence of hypertension in persons 25 years of age or less prior to availability of normative dataa Authors Masland et al. (1956) Boe et al. (1957) Heyden et al. (1969) Londe (1966)

Wilber et al. (1972) a

Subjects’ age (year) “Adolescents”

Number screened 1795

Position in which pressure was taken Not stated

Definition of hypertension (mm Hg) 140/90

Prevalence (%) 1.4

15–19

3833

Sitting

150/90

15–25

435

Sitting

140/90

3.01 males 1.04 females 11.0

4–15

1473

Supine

Systolic or diastolic >90th%

15–25

799

Sitting

Systolic or diastolic >95th% (repeated measures) Systolic >160 Diastolic >90

12.4 males 11.6 females 1.9 1.0 1.5

Adapted From Loggie 1974

Definition of Hypertension in Childhood The fundamental problem in defining hypertension in children and adolescents is determining what constitutes normal BP and what constitutes abnormal, or elevated, BP. In adults, the definition of hypertension is based on the approximate level of BP that marks an above average increase in mortality. These cut point numbers for abnormal BP were initially based on actuarial data from life insurance mortality investigations that indicated an increase in death rates occurred when the systolic BP exceeded 140 mm Hg or the diastolic BP exceeded 90 mm Hg. This method to define hypertension was challenged by Master and Marks (1950) in a report published in 1950. These authors argued that defining hypertension by a single number was arbitrary, because hypertension occurred far more frequently in the elderly and was commonly associated with atherosclerosis. They contended that an increase in BP was a reflection of aging, and that the use of one number to define a disorder for all ages resulted in an overdiagnosis of hypertension in the elderly. They proposed a statistical definition based on the distribution of BP readings around the mean, according to sex and age. BP, like most human characteristics, demonstrates a frequency distribution that yields a fairly normal curve. In a normal distribution, roughly two-thirds

of the observations will occur within the range of the statistical mean plus or minus one standard deviation from the mean; and 95% of the observations will be within the range of the mean plus or minus two standard deviations. They proposed that BP that reached a level that was two standard deviations beyond the statistical mean, or greater than the 95th percentile, should be considered abnormal. Master et al. supported their position by examining data obtained from industrial plants in various sections of the country on about 7,400 persons who were considered to be in “average good health and able to work.” Using a statistical method to define the normal range of BP, they described the normal range of systolic BP in males to be 105–135 mm Hg at 16 years of age, rising progressively to 115–170 mm Hg at 60–64 years of age. They also noted a sex difference in the normal range: females had a normal range of systolic BP from 100 to 130 mm Hg at 16 years of age and that increased to 115–175 mm Hg at age 60–64 years of age. The conclusion of these authors was that one static cut point for all led to hypertension being overdiagnosed in adults, particularly in the elderly. Their conclusion was supported, they believed, by demonstrating that large numbers of persons with BP above 140/90 mm Hg were living with BP at that level and were “in average good health and able to work.” A large body of subsequent epidemiological and clinical investigations on hypertension in

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Development of Blood Pressure Norms and Definition of Hypertension in Children

adults has clearly dismissed the conclusion by Master et al. Several expert panels define hypertension in adults according to the level of BP that marks an increase in cardiovascular events and mortality. This definition, for some time, has been systolic BP
140 mm Hg or diastolic BP
90 mm Hg (Joint National Committee on Prevention 1997). These numbers are approximate BP levels above which the risk for morbid events is significantly heightened and the benefits of treatment are established. It is also now recognized that the risk for cardiovascular events attributable to BP level in adults does not begin only at 140/90 mm Hg, but the risk is linear and begins to rise starting a lower BP level. Data derived from the Framingham Study show that adults with a blood pressure in the range of 130/85–139/89 mm Hg have more than double the absolute risk for total cardiovascular events in the subsequent 10 years, than adults with a blood pressure < 120/ 80 mm Hg (Vasan et al. 2001). In response to this emerging epidemiological data, the concept of prehypertension was developed to designate a BP range wherein adults could benefit from preventive lifestyle changes (Chobanian et al. 2003). More recent clinical trials in adults with diabetes, chronic kidney disease, and older adults at high risk for cardiovascular events have developed evidence that support recommendations to treat and achieve BP levels lower than 140/90 mm Hg. As yet, there are no comparable data that provide a direct link between a level of BP in childhood with morbid events at some time later in adulthood. The original report by Masters et al. is the earliest to show that the normal range of BP is lower at age 16–19 years than later in life. Of most significance is that Masters et al. provided a statistical method to define the normal BP range and a method whereby abnormal BP could then be defined in the absence of mortality or morbidity end points. Until the early 1970s, the prevalence of hypertension in children and adolescence was largely unknown. Accurately describing the prevalence of hypertension in the young, however, could not be done without a uniform and consistent definition of hypertension in the pediatric population. Moreover, this definition of hypertension

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could not be developed in the absence of knowledge about what constituted normal BP in children and adolescents. There were some, but quite limited, data on BP levels in asymptomatic healthy children. The available data indicated that the level of BP was considerably lower in young children than in adults, and that there appeared to be a normal rise in BP with age that was concurrent with growth. It was also recognized that due to differences in measurement techniques, there was likely to be considerable variability in the child BP data that was available. Initial efforts to gain a better understanding of the prevalence of hypertension in the young focused on adolescents. Based on a careful examination of her own clinical data derived from children and adolescents that she had evaluated for abnormal BP, Loggie (1974) suggested that essential hypertension was more common in adolescents than had been previously believed. Kilcoyne et al. (1974) made an effort to determine if asymptomatic hypertension could be detected in otherwise healthy adolescents by conducting BP screening on urban high school students. They observed that female students of all races had lower levels of systolic BP than males. Using 140/90 mm Hg as a definition of hypertension, they detected an overall prevalence of 5.4% systolic and 7.8% diastolic hypertension at the initial screening. Follow-up BP screening on those with abnormal measurements demonstrated a decline in prevalence to 1.2% systolic and 2.4% diastolic hypertension. They also noted higher rates of sustained hypertension among Black males. Frequency distributions of systolic BP in the males at successive age levels of 14 years, 16 years, and 18 years demonstrated a progressive rightward displacement with increasing age, which, the authors suggested, indicated a transition to adult characteristics. However, this shift in distribution did not occur in females between 14 and 19 years of age. Based on these data, these investigators suggested that the criteria used to define hypertension in adolescents would be more meaningful if they were based on the frequency distributions of BP levels in an adolescent sample. They proposed that BP values exceeding one standard deviation above the statistical mean would more

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appropriately define hypertension. From their data, one standard deviation above the mean was 132/85 mm Hg for males and 123/82 mm Hg for females. It is of note that, although one and not two standard deviations above the mean were proposed, these BP values are reasonably close to the numbers that Master and Marks (1950) reported to be at the top of the normal range for persons 16–19 years of age (males 135 mm Hg; females 130 mm Hg). Similar early efforts to investigate BP levels and the prevalence of hypertension in healthy adolescents were conducted by other investigators, largely in the context of high school screening projects (Kotchen et al. 1974; Miller and Shekelle 1976; Garbus et al. 1980). From these studies, the investigators determined that the initial prevalence of hypertension, when adult criteria were used, was approximately 5%. This percentage decreased with repeat BP measurement. These reports also noted lower BP levels in adolescent females compared to males. Some difference in BP by race was again reported, with higher BP levels and more hypertension noted among African Americans. An effect of excessive weight on BP was also described. Together these reports emphasized a need to develop a better definition of hypertension in the young – a definition that would be based on BP reference data derived from a large sample of healthy children. The National Heart, Lung, and Blood Institute (NHLBI) recognized the gaps in understanding the normal distribution of BP levels and definition of hypertension in childhood, and directed the National High Blood Pressure Education Program to appoint a Task Force on Blood Pressure Control in Children in the mid-1970s. This Task Force published its first report in 1977 (National Heart Lung, and Blood Institute 1977). The Task Force goals were to (1) describe a standard methodology for measurement of BP in the young; (2) provide BP distribution curves by age and sex; (3) recommend a BP level that is the upper limit of normal; and (4) provide guidelines for detection, evaluation, and treatment of children with abnormal BP. The BP distribution curves in this report were based on data gathered from three observational studies conducted in Muscatine, Iowa;

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Rochester, Minnesota; and Miami, Florida. The total size of the sample was 9,283 children from age 5 through 18 years, with an additional 306 children age 2–5 years. The BP data were presented as percentile curves, by age, for systolic and diastolic BP in males and females, similar to the standard pediatric growth curves for weight and height. These BP curves represented a substantial advancement in understanding of BP levels in the young, particularly for clinicians who care for children. Although based on cross-sectional data, the curves indicated a progressive increase in BP level with age, a trend that is concurrent with increasing height and weight. The BP curves also established a normative range for BP in early childhood that was different than that of adults. Using a statistical definition, the recommended definition of hypertension was a BP level that is equal to or greater than the 95th percentile for age and sex, if verified on repeated measurement. These BP curves, for the first time, provided a clear view on the levels of BP that were outside of the normal range in young children. However, by age 13 years in boys the 95th percentile had reached 140 mm Hg and 90 mm Hg for systolic and diastolic pressure, respectively, with a progressive rise to 18 years, at which age the 95th percentile was over 150 mm Hg systolic and 95 mm Hg diastolic. These numbers seemed to indicate that by early adolescence the adult criteria to define hypertension would be appropriate. However, the BP levels at the 95th percentile provided in this report seemed to be high for older adolescents when compared to the data that had been collected in the preceding high school screening studies. This discrepancy raised concern as to how well these distribution curves truly reflected the normative BP distribution in healthy children and adolescents.

Normative Blood Pressure Distribution in Children and Adolescents The NHLBI recognized the need to obtain a larger body of data on BP levels in the young within the context of childhood growth, and subsequently

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Development of Blood Pressure Norms and Definition of Hypertension in Children

supported several epidemiological studies that prospectively investigated BP levels and BP trends in relation to growth in children and adolescents. These projects were conducted at several sites, applied rigorous detail to the methodology of BP measurement, and examined the anthropometric determinants of BP levels relative to physiological development. As these data emerged, a second Task Force on Blood Pressure Control in Children and Adolescents was convened to reexamine the data on BP distribution throughout childhood and prepare distribution curves of BP by age accompanied by height and weight information. With this new information, the second Task Force also updated the guidelines for detection, evaluation, and management of hypertension in the young in its 1987 report (Report of the Second Task Force on Blood Pressure Control in Children 1987). Table 2 provides the sites that contributed data used to develop the new BP distribution curves. The total number of children on whom BP data were available was over 60,000. This sample included an age range from infancy to age 20 years with a substantial representation of different race and ethnic groups. The BP percentile curves published in the Second Task Force Report again demonstrated a progressive rise in BP that was concurrent with age. Sex differences in BP levels during adolescence were verified. The BP levels in males continued to increase from age 13 through 18 years, whereas the BP levels in females tended to plateau after age 13 years; and the normal distribution was somewhat higher in adolescent males compared to females. Moreover, the entire BP distribution was lower; the 95th percentile

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delineated a BP level that was substantially lower than that described in the previous report. The Second Task Force Report applied the same definition of hypertension that was used in the first Task Force Report, which was systolic or diastolic BP that was repeatedly equal to or greater than the 95th percentile. However, in consideration of how much lower the 95th percentile appeared to be at that time, along with the concern about possibly overdiagnosing hypertension in the young, this report included a classification table for “significant” and “severe” hypertension. According to age strata, BP values between the 95 and 99th percentiles were designated significant hypertension, and BP values that exceeded the 99th percentile were designated severe hypertension. At the time that report was developed, it could seem that the authors were hedging on the definition of hypertension in the young. However, by intention or not, the concept of staging hypertension on the basis of degree of BP elevation was novel and had not yet been considered in the field of adult hypertension. It was not until the publication of the 6th Report of the Joint National Commission in 1997 (Joint National Committee on Prevention 1997) that hypertension stage was introduced as a method to guide patient care and clinical management decisions in adults. Subsequent to the 1987 Task Force Report, additional childhood BP data were collected during the National Health and Nutrition Examination Survey (NHANES) III 1988–1991 and added to the normative database of childhood BP. Other reports were also published on data indicating that children with elevated BP in childhood often developed hypertension in early adulthood

Table 2 Data sources for the second task force report on blood pressure control in children Source Muscatine, IA University of South Carolina University of Texas, Houston Bogalusa, LA Second National Health and Nutrition Examination Survey University of Texas, Dallas University of Pittsburgh Providence, RI Brompton, England

Age (year) 5–19 4–20 3–17 1–20 6–20 13–19 Newborn–5 Newborn–3 Newborn–3

N 4,208 6,657 2,922 16,442 4,563 24,792 1,554 3,487 7,804

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(Lauer and Clarke 1989). Based on increasing support for the concept that the origins of hypertension begin in the young, a rationale for emphasizing BP surveillance in childhood and implementing early preventive efforts began to develop. A reexamination of the national data on childhood BP was necessary to provide substance to such recommendations. Therefore, a third Task Force was convened to update the normative data as well as update the guidelines for management to include increased attention to preventive efforts. The addition of the new BP data and reanalysis of the entire childhood data base resulted in BP distribution curves that were slightly lower, but generally consistent with the findings of the second Task Force. The third report published in 1996, titled “Update on the 1987 Task Force Report,”(Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents 1996) provided further detail regarding the relationship of body size to blood pressure. Analyses indicated that height and body weight, as well as age, were major determinants of BP level with height considered to be the best determinant of BP that was within the normal range. Therefore, it was recommended that height adjustment be applied in the evaluation of BP level. The third “Update” report expanded the presentation of the data by providing tables with the 90th and 95th percentile levels of systolic and diastolic BP for multiple height percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) by age (1–17 years) and sex. These tables provided a better view on the normal BP increase that occurs with increasing height and age. The other modification, which was considered controversial at the time, was changing the designation of diastolic BP from K4 (muffling of the pulse sounds) to K5 (absence of pulse sounds). The rationale for this change was to make the designation of diastolic BP the same in children as in adults. The childhood BP data was reexamined by a fourth Working Group that published expanded BP percentile tables in 2004, in a publication commonly designated the “Fourth Report” (National High Blood Pressure Education Program Working Group on High Blood Pressure in

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Children, and Adolescents 2004). These tables provide the sex, age, and height and BP levels for the 50th and 99th percentile as well as the 90th and 95th percentile. The intent of the Fourth Report was to provide additional guidelines for the detection and clinical management of childhood hypertension. The definition of hypertension in childhood remained the same; systolic and/or diastolic BP
95th percentile verified on repeated measurement. The Fourth Report provided additional precision in the staging of hypertension. Stage 1 hypertension was defined as systolic or diastolic BP between the 95th percentile and 5 mm Hg above the 99th percentile. Stage 2 hypertension is defined as systolic or diastolic BP that is greater than the 99th percentile plus 5 mm Hg. The category of “high normal blood pressure” was replaced with the term “prehypertension.” Prehypertension was defined as systolic and/or diastolic blood pressure
90th percentile (or
120/80, whichever lower) and < 95th percentile. This definition was developed for two reasons: (1) the definition of prehypertension in adults was systolic blood pressure between 120 and 139 mm Hg or diastolic blood pressure between 80 and 89 mm Hg (Chobanian et al. 2003) and (2), beginning at age 13 years, the 90th percentile was higher than 120/80 mm Hg, with the exception of very short young adolescents. The Fourth Report provided additional guidelines for evaluation and treatment of abnormal BP according to these defined stages, as well as recommendations on evaluating other cardiovascular risk factors and target organ damage related to high BP. Following the publication of the Fourth Report, subsequent publications reported data on the prevalence of hypertension based on these definitions. Hansen et al. (2007) applied the above criteria for hypertension and prehypertension to electronic medical record data from well-child care visits in a cohort of over 14,000 primary care patients. With the advantage of having data on repeat BP measurements on separate visits, these investigators determined the prevalence of hypertension to be 3.6% and the prevalence of prehypertension to be 3.4% among children and adolescents between 3 and 18 years of age. In another study that

17

Development of Blood Pressure Norms and Definition of Hypertension in Children

included repeated blood pressure measurements taken in 6,790 high school students 11–17 years of age, the prevalence of hypertension and prehypertension was determined to be 3.2% and 15.7%, respectively (McNiece et al. 2007). In both studies, youth with obesity were more likely to have abnormal BP. In the study on high school students by McNiece et al. (2007), the prevalence of hypertension and prehypertension combined was over 30% in obese boys and from 23% to 30% in obese girls, with prevalence varying by ethnicity. A childhood obesity epidemic was clearly established prior to the Fourth Report in 2004. The association of overweight and obesity with higher BP has been consistently demonstrated in children as well as adults. The impact of the increase in childhood obesity on BP in the United States was demonstrated by Muntner et al. (2004) who compared childhood BP levels from two sequential NHANES periods. Their analysis identified a significant upward trend in BP levels in children and adolescents. The authors determined that the increase in BP level was largely, but not entirely, attributable to the concomitant increase in childhood body mass index (BMI). High BP was most striking among minority groups that also had the highest rates of childhood obesity. Another analysis comparing the same two cohorts demonstrated an overall increase in the prevalence of hypertensive blood pressure from 2.7% in the 1988–1994 survey to 3.7% in the 1999–2002 survey period (Din-Dzietham et al. 2007). Both analyses concurred that the population increase in BP level and prevalence of hypertensive BP among children and adolescents were largely due to the increase in prevalence and severity of childhood obesity. It was also recognized that the association of adiposity and elevated BP was not limited to youth with obesity as defined by a BMI
95th percentile. A study by Tu et al. (2011) demonstrated that the prevalence of elevated BP (>90th percentile) increased four-fold when BMI exceeded the 85th percentile. The BP percentile tables provided in the Fourth Report (2004) are based on child population data mostly collected prior to the child obesity epidemic. To determine the effect of overweight

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and obesity on the BP distribution, Rosner et al. (2008) reexamined the childhood BP normative data after excluding children without a normal weight for height (i.e., those with a BMI
85th percentile). Their analysis of BP data, limited to normal weight children and adolescents, demonstrated somewhat lower BP thresholds for the 90th and 95th percentiles when compared to the BP levels published in the Fourth Report. The BP percentile tables based on age, sex, and height of normal weight children are available in the publication and at http://sites.google.com/a/channing. harvard.edu/bernardrosner/pediatric-blood-press. Although the BP levels in the tables were not markedly lower, these tables and the known adverse effect of overweight and obesity on BP in childhood raised the question of whether the normative BP data in children and adolescents should be based on normal weight children only. Additional advances in epidemiologic, clinical, and translational research on BP and hypertension in youth published after the Fourth Report made it clear that an update of the pediatric hypertension guidelines was needed. However, due to an administrative decision, the NHLBI no longer supported guideline development on hypertension and other clinical conditions related to the NHLBI mission. The American Academy of Pediatrics assumed this role and commissioned a working group to review new evidence subsequent to 2004 and update the guidelines on screening and management of high BP in children and adolescents. An updated clinical practice guideline (CPG) was published in 2017 (Flynn et al. 2017). A key change in the 2017 CPG was that the normative BP tables were based on data only from normal weight (BMI 51 g/m2.7 or LV mass >115 g/BSA for boys LV mass >95 g/BSA for girls or RWT >0.42

No recommendation

Abbreviations: BP blood pressure, HTN hypertension, CKD chronic kidney disease, TOD target organ damage, LV left ventricular, LVMI left ventricular mass index, RWT relative wall thickness, cIMT carotid intima media thickness, PWV pulse wave velocity a Khoury P, et al. 2009 b Jourdan C et al. 2005, Doyon A et al. 2013 c Reusz GS et al. 2010, Elmenhorst J, et al. 2015

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S. Stabouli and V. Kotsis

Ambulatory Blood Pressure including 24-h systolic BP, 24-h systolic BP Parameters and Target Organ Damage index (measured BP/95th percentile BP; values Heart Left Ventricular Hypertrophy Assessment of left ventricular (LV) mass and determination of left ventricular hypertrophy (LVH) by echocardiography remains a cornerstone of TOD assessment in pediatric HTN. Many studies evaluating the prevalence of LVH in hypertensive children and adolescents have used a threshold of LVMI >38.6 g/m2.7 for females and males as this was reported to represent the 95th percentile for children (de Simone et al. 1992). Age- and sex-specific reference values for indexing LV mass and LVMI in children and adolescents are also available and have been used in most recent studies (Khoury et al. 2009). The definition of LVH endorsed by the AAP 2017 CPG is based on the American Society of Echocardiography (ASE) adult recommendations, which uses the threshold of LV mass > 51 g/m2.7 for youth 8 years of age or older or LV mass > 115 g per body surface area (BSA) for boys and LV mass > 95 g/BSA for girls (Flynn et al. 2017). Moreover, left ventricular relative wall thickness (RWT) >0.42 cm is used to further characterize left ventricular geometry, with LVMI and RWT above thresholds indicating concentric hypertrophy. These CPG endorsed thresholds for LVH are greater than the 95th percentile in children and adolescents. In contrast to the US CPG, the ESH 2016 guideline recommends the use of LVMI or RWT  95th for age and sex to define LVH (Lurbe et al. 2016). Most studies that assessed the association of ABPM with LVH have used the pediatric percentile-based thresholds to define LVH, while few others have compared both definitions for LVH with variable results regarding the ability of ABPM to predict LVH (Obrycki et al. 2020). Ambulatory BP have been reported to be more predictive of LVH (LVMI >51 g/m2.7) than office BP in untreated hypertensive children (Sorof et al. 2002). Left ventricular mass index was strongly correlated with several ABPM parameters

1 are elevated), 24-h systolic BP load, daytime systolic BP load, nighttime systolic BP, and nighttime systolic BP load. The prevalence of LVH in this cohort was 27% overall but the prevalence increased up to 47% among patients with both 24-h systolic BP index >1.0 and systolic BP load >50%, suggesting that hypertensive children with severe ambulatory hypertension have increased the probability of having LVH. In children with essential hypertension and similar 24-h BP levels, LVH can be predicted by sex and BMI (Brady 2016; Litwin et al. 2006). In a crosssectional study including a multiethnic group of children and adolescents at risk for hypertension, either because of an elevated office BP level ( 90th percentile) or presence of a first-degree relative with a diagnosis of hypertension, LVMI significantly correlated with 24-h systolic BP standard deviation score (SDS), 24-h systolic BP index, and 24-h systolic BP load, but not with diastolic 24-h BP SDS, nocturnal BP decline or office BP index (Richey et al. 2008). In the same study, 24-h systolic BP load >50% was predictive of increased LV mass, even after adjustment for BMI, and increased LVMI, defined as >90th percentile for age and sex, was positively correlated with BP stage. Children with severe ambulatory hypertension (both mean ambulatory BP >95th percentile and BP load >50%) had significantly greater LVMI and three times greater odds of elevated LVMI than children with normal ambulatory BP. In fact, the odds of having elevated LVMI increased by 54% for each incremental increase of one 24-h systolic BP SDS after controlling for race and BMI and by 88% for each incremental increase of 0.1 in the systolic ambulatory BP index (Richey et al. 2008). Maggio et al. also reported that only 24-h ambulatory BP values and BMI associated with LV mass in univariate statistical analysis, while office BP values did not present any association with LV mass. In their obese population, increased LV mass was present even in the absence of hypertension (Maggio et al. 2008). LVH was present in 16.3% of subjects with obesity and ambulatory BP hypertension and 5.6% of subjects with obesity but without

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The Role of ABPM in Evaluation of Hypertensive Target-Organ Damage

hypertension (Dušan et al. 2015). In children and adolescents with primary hypertension, the levels of LVMI gradually increased as ambulatory BP progressed from below the 90th percentile, to between the 90th and 95th and ultimately to greater than 95th percentile, but a similar prevalence of LVH (LVMI >95th pediatric percentile) was found between the two latter groups (Stabouli et al. 2009). In another study, higher prevalence of LVH (LVMI >95th percentile for age and sex) was reported in children with ambulatory hypertension versus ambulatory prehypertension and normotension, but no difference in prevalence of LVH was observed between those with ambulatory hypertension (45%) and severe ambulatory hypertension (44%) (Obrycki et al. 2020). Using the criterion of LV mass > 51 g/m2.7, only two patients having severe ambulatory hypertension were identified to have LVH (Obrycki et al. 2020). One study provided evidence of LVH regression during antihypertensive treatment. After 1 year of treatment, 24-h BP values and LVMI were reduced; however, the effects of BP reduction on LVH were blunted by changes in body weight indices such as waist to hip ratio (Litwin et al. 2010). In this study, as in most studies on LVH in children with primary hypertension, the coexistence of obesity remains a significant challenge as weight loss could at least partly mediate any observed treatment effect. The thresholds used to define ambulatory hypertension impact the ability of ambulatory hypertension to predict LVH. Merchant et al. reported that using adult criteria from the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines to define ambulatory hypertension in a population of 306 adolescents resulted in better prediction of LVH (LVMI >95th age and sex-specific percentile) than when using pediatric ABPM criteria from the 2014 AHA guidelines to define ambulatory hypertension (Merchant et al. 2021). However, a further study in 124 adolescents did not find that youth with ambulatory hypertension defined according to the adult ACC/AHA 2017 criteria had significantly different odds of LVH than youth with ambulatory hypertension defined using 2014 AHA criteria, but it should be noted

811

that this smaller study used the adult threshold to define LVH (LVMI >51 g/m2.7), which may explain the difference in findings (Campbell et al. 2021). The parameters of ABPM that best predict LVH has been a subject of debate. Not all studies exploring how ABPM associates with TOD include BP load in their analyses and many that do include BP load have failed to show superiority over average ABP values in predicting TOD (Brady et al. 2008; Gupta et al. 2015). While Mitsnefes et al. found that 24-h, daytime and nighttime, systolic and diastolic BP load were significantly correlated with changes in LVMI during a 2-year follow-up study in patients with CKD (Mitsnefes et al. 2006), BP load was not found to provide significant benefit over mean BP on identifying youth with LVH in the Chronic Kidney Disease in Children (CKiD) cohort (Lee et al. 2020). Similarly, the Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP AHOY) study found that including BP load in the stratification of ambulatory BP status offered no significant benefit to the prediction of LVH among adolescents 13 years old than when using BP alone (Hamdani et al. 2021). Specifically, not only was mean daytime, night-time, and 24-h systolic blood pressure (SBP) superior in predicting LVH compared to SBP load but when both mean SBP and SBP load were included in the same statistical model, there was no improvement in prediction of LVH over models including mean BP alone. Further, neither CKiD nor SHIP AHOY found any significant association of mean diastolic blood pressure (DBP) or DBP load with LVH. Sharma et al. found in a population of 72 children and adolescents with primary hypertension that nighttime BP load was significantly associated with LVMI, but it was not associated with the presence LVH (Sharma et al. 2013). BP variability may explain how differences in BP load can be present among children with similar average BP levels (and thus, similar severity of BP elevation). Two studies assessed the association of BP variability with LVMI in children with primary hypertension showing conflicting results. The first study showed that nighttime systolic BP load and

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daytime systolic BP variability had significant associations with LVMI (Sharma et al. 2013) while the second reported an association of weighted 24-h BP variably with LVMI only in unadjusted analysis; this association disappeared after adjustment for BMI (Bjelakovic et al. 2013). Non-dipping status is highly prevalent in children with a solid organ transplant, as well as in children with CKD and obstructive sleep apnea, but found to be less reproducible than other ABPM parameters (Krmar and Berg 2005; Stabouli et al. 2007). Consistent associations between LVH and decreased dipping have not been reported in ambulatory BP studies in children and adolescents.

Myocardial Function Indices LV function, in addition to LV mass, has been examined in limited studies of children and adolescents. In a cohort of 66 children with primary hypertension, myocardial performance index, defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the left ventricular ejection time, increased by 0.14 units for every 10 unit increase in 24-h systolic BP (Gupta-Malhotra et al. 2016). In the Effects of Strict Blood Pressure Control and AngiotensinConverting Enzyme Inhibition (ACEi) on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial, ambulatory BP control reduced LVMI in patients with LVH (LVMI >95th percentile) and improved myocardial function (Matteucci et al. 2013). After 1 year of ACEi treatment, LVH prevalence decreased overall from 38% to 25%. Comparing patients according to randomization arm, the increase in LV systolic function parameters was greater in the presence of intensified BP targets compared with standard BP targets, but there was no difference in LVMI reduction between groups. In the CKiD cohort, diastolic dysfunction defined as early mitral inflow velocityto-early mitral annular peak velocity (E/e’) ratio > 8.0 was demonstrated in children with sustained ambulatory hypertension. A higher E/e’ ratio was independently associated with ambulatory hypertension but not with office BP, highlighting the role of ABPM in identifying children at risk for abnormal subclinical cardiac function (Mitsnefes et al. 2021b).

S. Stabouli and V. Kotsis

Arteries Carotid Intima-Media Thickness Carotid intima-media thickness (cIMT) has emerged as an early indicator of subclinical CVD in children and adolescents in research settings and has been shown to be increased in children with traditional CVD risk factors, such as obesity, hypertension, diabetes mellitus, and CKD (Giannopoulou et al. 2019; Doyon et al. 2013). Several studies identified independent positive associations between standardized BMI and brachial pulse pressure with cIMT suggesting that cIMT values should be normalized to age, sex, and height to take into account maturational changes occurring during childhood and adolescence (Jourdan et al. 2005). A large cohort study of healthy children and adolescents provided extensive novel information about sex-specific L, M, and S values calculated for height at 5 cm intervals and age at 6-month intervals and provided respective percentile curves (Doyon et al. 2013). Obesity-related ambulatory hypertension in youth has been shown to associate with increased cIMT. Stabouli et al. found significantly higher cIMT in obese hypertensive than in nonobese normotensive children and adolescents (Stabouli et al. 2005a). Systolic ambulatory BP parameters including 24-h, daytime and nighttime SBP, daytime and nighttime pulse pressures, and BP indices are all associated with cIMT. However, obesity and age also correlated with mean cIMT independent of sex, office, and ambulatory BP levels (Stabouli et al. 2012). Litwin et al. found higher cIMT and decreased distensibility and elasticity of the common carotid artery in a population of 49 children with newly diagnosed ambulatory BP hypertension. Only distensibility coefficient values, but not cIMT measurements, correlated negatively with daytime pulse pressure (Litwin et al. 2004). In a further study including 72 hypertensive children they found significant associations between cIMT and 24-h systolic BP, daytime systolic BP, systolic BP loads, and pulse pressure (Litwin et al. 2006). They also reported greater cIMT in hypertensive than in normotensive children. However, when they examined cIMT values in subgroups of their population

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The Role of ABPM in Evaluation of Hypertensive Target-Organ Damage

they found no differences between normotensive and hypertensive children with obesity suggesting that the coexistence of hypertension and obesity is what led to increased cIMT. Yet, in another study, hypertensive children had increased cIMT levels compared to age, sex and BMI matched controls (Lande et al. 2006). cIMT correlated with ambulatory BP parameters with the strongest correlation found with daytime systolic BP index (Lande et al. 2006). Sleep disordered breathing and primary snoring diagnosed by polysomnography have also been associated with high ambulatory BP and cIMT (Tagetti et al. 2017). Greater cIMT has been reported in pediatric patients with systemic lupus erythematosus or type 1 diabetes mellitus who presented with non-dipping status (Chang et al. 2020). In children and adolescents with repaired coarctation of the aorta, a higher mean 24-h systolic BP SDS and greater systolic BP load were each independent predictors of increased cIMT in stepwise linear regression, while BMI z score, age, sex, office systolic and diastolic BP SDS, and mean 24-h diastolic BP SDS or load were not significant predictors of cIMT (Dempsey et al. 2019). Finally, in non-dialysis children with CKD participating in the 4C study only office systolic BP associated with cIMT (Schaefer et al. 2017). A further study from the same cohort showed that independent predictors of elevated cIMT were nocturnal hypertension along with low birth weight, BMI, and low physical activity, but not office hypertension or biochemical parameters (Düzova et al. 2019). In youth referred to a hypertension center, carotid femoral pulse wave velocity (PWV) was reported to be higher in children with ambulatory hypertension compared to those with normal ambulatory BP. Significant correlations were found between carotid femoral PWV and multiple ambulatory BP parameters including 24-h systolic and diastolic BP, BP loads, MAP, daytime and nighttime systolic BP, weighted 24-h systolic BP variability, daytime and nighttime systolic BP variability. In analysis of covariance, only weighted 24-h systolic BP variability and daytime SBP variability were the independent determinants of carotid femoral PWV after adjustment for mean ambulatory BP levels, age, and BMI

813

(Stabouli et al. 2015). Interestingly, ambulatory BP parameters, 24-h pulse pressure, and ambulatory arterial stiffness index, which have been proposed as surrogate markers of arterial stiffness, did not correlate with PWV. Although BP variability is frequently underlined as significant predictor of cardiovascular events in adults, data in children and adolescents are scarce. Increased 24-h systolic BP variability may result in repetitive fluctuations of shear stress on arterial wall that results in morphological changes and arterial stiffening. The independent association between systolic BP variability and carotid femoral PWV could also imply a common pathogenetic mechanism in early stages of hypertension in youth. PWV z scores were also reported to be increased in pediatric patients with ambulatory prehypertension defined as office BP 90th percentile, 24-h BP 2 mg/mg) were least likely to achieve control of BP over time (Wilson and Flynn 2020). In another report from the CKiD cohort, daytime and office systolic BP taken in a protocol-driven setting were found to be similar in discriminating risk of end-stage kidney disease. The authors concluded that office BPs are not consistently inferior to ambulatory BP in the discrimination of BP-related adverse outcomes in children with CKD (Ku et al. 2018). Nevertheless, there is increasing evidence to support the importance of ABPM in pediatric and adult patients with CKD, as ambulatory BP values have closer associations with TOD and treatment targeting ABPM levels improves patient prognosis and delays adverse outcomes. ABPM is particularly important for children with CKD; masked hypertension is found among 37% of children with CKD, which is a far greater prevalence than described in non-CKD pediatric populations (Wilson and Flynn 2020). ABPM data among non-treated children with CKD and hypertension reported increased systolic and diastolic BP variability during sleep and decreased heart rate variability, suggesting that sympathetic nervous system activity may play a role in future cardiorenal outcomes in this population (Barletta et al. 2014). Pediatric patients after kidney transplantation frequently have isolated nocturnal hypertension (Alstrup et al. 2010; Paripovic et al. 2010). A reduced nocturnal dip detected beyond the first year after transplantation has been strongly associated with underlying kidney pathology.

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The Role of ABPM in Evaluation of Hypertensive Target-Organ Damage

The European ESCAPE trial provided evidence that intensified BP control targeting 24-h BP levels in the low range of normal confers a substantial benefit for renal function among children with CKD. Specifically, this trial demonstrated that aggressive BP treatment to 24-h MAP 110 mmHg in both sexes (Lauer et al. 1992) during peak activity. Normal SBP increase from rest to peak exercise approximates 50–60 mmHg and 40–50 mmHg in young adult males and females (age 20–29), respectively (Daida et al. 1996). In children and adolescents, the 95th percentile for SBP during exercise is an increase in SBP >53 to 89 mmHg above baseline depending on a child’s age (Clarke et al. 2021) VO2 increases proportionately with the intensity of exercise until it plateaus. VO2 is higher in treadmill versus cycle ergometer use (Hermansen and Saltin 1969). VO2 is significantly higher in males than in females (Fomin et al. 2012) Once the VAT is reached, tissue oxygen delivery reaches the maximum and additional energy sources are provided by glycolysis. This switch from aerobic to anaerobic metabolism at the VAT leads to a rise in muscle and plasma lactic acid. VAT 3 consecutive premature ventricular complexes) (Paridon et al. 2006); or if the child develops symptoms of inadequate cardiac output, such as extreme fatigue or dizziness (Paridon et al. 2006; Longmuir et al. 2013).

Indications and Contraindications for Exercise Testing In 2006, the American Heart Association Council on Cardiovascular Disease in the Young, Committee on Atherosclerosis, Hypertension and

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Obesity in Youth (AHOY) published an updated report describing appropriate performance of exercise testing in children (Paridon et al. 2006). In this report, the committee members noted that the role for pediatric exercise testing had expanded. Common reasons to perform pediatric exercise stress testing include: (1) evaluation of specific signs and symptoms induced or aggravated by exercise; (2) assessment and/or identification of abnormal responses to exercise in children with cardiac (e.g., arrhythmias), pulmonary, or other organ disorders; (3) assessment of the efficacy of specific medical and/or surgical treatments; (4) assessment of functional capacity in preparation for participation in recreational, athletic, or vocational activities; (5) evaluation and prognosis in children with known heart disease (or risk factor for heart disease); and (6) establishing baseline data prior to the initiation of cardiac, pulmonary, or musculoskeletal rehabilitation. There are few absolute contraindications to exercise testing (e.g., acute myocardial injury, pericardial inflammation, and severe outflow tract obstruction). However, many conditions require caution on the part of the performing providers and careful monitoring during testing (Paridon et al. 2006). Individuals with high risk conditions, such as children with pulmonary hypertension, documented congenital ion channelopathies (e.g., long QT syndrome, catecholaminergic polymorphic ventricular tachycardia), dilated cardiomyopathy, restrictive cardiomyopathy, hypertrophic cardiomyopathy with symptoms, mild left ventricular outflow tract obstruction (LVOTO), documented arrhythmia, and unexplained syncope, are among the highest risk patients for whom the physician should remain present and on alert during stress testing (Paridon et al. 2006). Recognition of exercise-induced hypertension may indicate specific pathological significance in otherwise normotensive individuals at rest. Exercise-induced hypertension can unmask normotensive adults for future hypertension and increased LV mass, and can be associated with cardiovascular complications (Sharman et al. 2011; Berger et al. 2015; Allison et al. 1999).

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Exercise-induced hypertension has been demonstrated to be a predictor of chronic hypertension in adults after successful surgical repair of coarctation of aorta in childhood (Luijendijk et al. 2011).

Normal Blood Pressure Response to Exercise In general, exercise is a structured activity that involves repetitive motions of the body. The purpose of exercise is to maintain or improve one or more levels of physical fitness. There are various types of exercise: dynamic/aerobic, static/isometric, isotonic, and isokinetic. Dynamic activity involves “joint movement through relatively small forces within the muscle” (Mitchell et al. 1994) while static activity is exercise that involves large intramuscular forces but little to no joint movement (Mitchell et al. 1994). Isotonic exercise refers to activities where the muscle shortens through a constant external load (i.e., equal tone). Isokinetic exercise involves lengthening (or shortening) of the muscle at a constant velocity. Normal blood pressure response during dynamic exercise (e.g., swimming, running, cycling) is an increase in SBP due to a disproportionate increase in cardiac output versus decline in peripheral vascular resistance (Paridon et al. 2006). In contrast, the blood pressure response to static/isometric exercise (e.g., weight lifting, etc.) is a smaller increase in CO but a greater increase in mean arterial pressure (MAP). In static/isometric activity, the degree of increase in MAP is proportional to the muscle mass involved, the duration of the contraction, and the percentage of maximal muscle tension (Braden and Strong 1990; Buck et al. 1980; Mitchell et al. 1980, 1981; Seals et al. 1983). For example, extreme elevation in both systolic and diastolic blood pressure up to 300 and 250 mmHg, respectively, was reported in response to heavyweight lifting in young male bodybuilders (MacDougall et al. 1985). In general, most exercises are not solely dynamic or static (see Fig. 1: taken from ACC Task Force), but include a combination of dynamic and static activity.

C. M. Baker-Smith and T. Tsuda

Blood Pressure Response to Exercise in Pediatric Subpopulations Exercise testing can play an important role in our understanding of how the body responds to stress. Age and BMI have been shown to be predictors of exaggerated blood pressure response to exercise stress testing (de Lima et al. 2012). With regard to the diagnosis of hypertension, stress testing can also be used to determine a person’s likelihood of developing hypertension (Matthews et al. 1998; Lima et al. 2013; Özdemir et al. 2020). Exercise testing elicits responses of the body not present at rest (Washington et al. 1994). For instance, it has been well established that adults with risk factors for premature cardiovascular disease have abnormal blood pressure response to exercise, even when resting blood pressures are normal. In particular, adults with risk factors for premature cardiovascular disease such as obesity, dyslipidemia, and diabetes who have a normal or near normal resting blood pressure have been found to have marked elevation in BP during peak activity (Miyai et al. 2002; Matthews et al. 1998). In a case-control study of 151 men later diagnosed with hypertension versus 200 controls, the presence of an exaggerated response to exercise, defined as an increase in SBP >60 mmHg after 5 min of exercise or increase in SBP >70 mmHg after 10 min of exercise, was associated with a 2.4 times greater odds of developing systemic hypertension (Matthews et al. 1998). Similarly, in a study of 1033 Japanese men without preidentified cardiovascular disease undergoing routine exercise stress testing as a part of a biannual physical examination, men with exaggerated exerciserelated BP response within the highest quartile were 3 to 4 times more likely to develop hypertension (Miyai et al. 2002). Children with risk factors for premature cardiovascular disease also display abnormal BP response during peak activity. In fact, it has been argued that exercise BP may be a more reliable parameter of one’s true blood pressure given the opportunity for a lesser impact of psychological stress on measured blood pressure (i.e., white coat hypertension). Details regarding the relationship between risk factors for premature cardiovascular

Exercise Testing in Hypertension and Hypertension in Athletes

II. Moderate (10-20%) I. Low (30%)

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Bobsledding/Luge Field events (throwing) Gymnastics*† Martial arts Rock climbing Sailing Water skiing*† Weight lifting*† Windsurfing*†

Body building*† Downhill skiing Skateboarding*† Snow boarding*† Wrestling*

Boxing Canoeing Kayaking Cycling*† Decathlon Rowing Speed skating Triathlon*†

Archery Auto racing*† Diving*† Equestrian*† Motorcycling*†

American football* Field events (jumping) Figure skating Rodeoing*† Rugby Running (sprint) Surfing Synchronized swimming† “Ultra” racing

Basketball* Ice hockey* Cross-country skiing (skating technique) Lacrosse* Running (middle distance) Swimming Team handball Tennis

Bowling Cricket Curling Golf Riflery Yoga

Baseball/Softball Fencing Table tennis Volleyball

Badminton Cross-country skiing (classic technique) Field hockey* Orienteering Race walking Racquetball/Squash Running (long distance) Soccer*

A. Low (75%)

Increasing Dynamic Component

Fig. 1 Classification of sports activities by degree of peak dynamic and static components (Ref: Levine et al. 2015)

disease and changes in peripheral vascular resistance have also been previously described (Kavey et al. 1997; Treiber et al. 1991). In particular, children with severely increased LDL cholesterol have a significantly higher postexercise systolic and diastolic blood pressure (Kavey et al. 1997). Similarly, children with a family history of coronary artery disease exhibit higher increases in systolic blood pressure during peak activity (Treiber et al. 1991).

Children with Obesity Obesity is very common among children and adolescents. Among children 2–17 years of age, the prevalence of obesity has remained fairly stable at 17% (https://www.cdc.gov/obesity/data/child hood.html). Greater time spent in moderate to vigorous physical activity has been associated with lower levels of obesity (Katzmarzyk and

Staiano 2017) and with lower blood pressure in youth (Ekelund et al. 2012). Recommendations for reducing the prevalence of childhood obesity, and thus the risk of hypertension, include dietary modifications, but also a greater reliance on physical activity (The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure 1997; García-Hermoso et al. 2013; Fife-Schaw et al. 2014). In fact, current data confirms the benefit of regular physical activity on body mass in children. A systematic review of randomized controlled trials conducted between 1 January 1990, and 31 December 2012, evaluated the impact of exercise on BMI among 971 children with obesity, 2–18 years of age participating in structured physical activity programs (e.g., aerobic training, strength training, both) for at least 4 weeks. The primary outcome measure was a change in BMI (kg/m2) following exercise participation. Secondary outcome measures of

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change in body weight, percent body fat, fat mass and fat-free mass, maximum oxygen consumption in ml/kg/min (VO2max), upper and lower body strength, and kilocalorie intake were also assessed. A significant reduction in BMI (3.6%; mean of 1.08 kg/m2) was observed among participants pre- and postexercise participation (Kelley et al. 2015). Thus, participation in structured physical activity programs has the potential to reduce the BMI of nearly 13 million children with obesity living in the United States. Additional meta-analyses conducted during earlier periods have also supported these findings (Maziekas et al. 2003). Similar to children without obesity, stress testing may be carried out in children with obesity for a variety of reasons including for the evaluation of exercise-related chest pain, fatigue, and shortness of breath. Studies suggest that children with obesity have significantly lower exercise capacity compared to lean children (de Sousa et al. 2009). Youth with obesity exhibit adaptive changes in cardiac structure, output, and VO2 in proportion to the degree of obesity. In a study of 35 boys, 10–12 years of age, progressive and maximal exercise testing was conducted on a bicycle ergometer in a semi-supine position, after a 3 min warm-up period at 30 W, followed by incremental increases of 15 W every 3 min. Children with the highest degrees of obesity had higher baseline BMI, SBP, and DBP. During exercise, children with obesity achieved similar maximum heart rate but had greater stroke volume and thus generated greater CO than those without obesity. However, cardiac index (CI), defined as CO indexed for BSA, was no different. Similarly, although VO2 is highly correlated with fat-free body mass and is highest in children with obesity (Sorof et al. 2004), VO2 indexed by body weight was similar in those with lean versus obese body habitus (Schuster et al. 2009). This study also found that significant cardiac remodeling occurred in children with obesity versus those without (e.g., increased left atrial dimension, increased left ventricular end-diastolic diameter, and increased LV mass). In general, children with obesity experience significant alterations in cardiac response to exercise. While these responses

C. M. Baker-Smith and T. Tsuda

are initially adaptive, compensatory changes become maladaptive and contribute to cardiac damage as the degree of obesity increases. What begins as a hyperkinetic, adaptive response to exercise evolves to deterioration in systolic and diastolic myocardial function, as indicated by a decline in shortening fraction (SF) and an increase in diastolic and systolic ventricular diameter in children with the most extreme obesity (Schuster et al. 2009).

Elevated Blood Pressure and Hypertensive Children Early data from the Muscatine study demonstrated that similar to normotensive youth, blood pressure also increases during exercise among youth with elevated blood pressure and youth with hypertension. Blood pressure increases in proportion to the degree of resting blood pressure, such that children with elevated blood pressure and hypertension demonstrate more marked increases in systolic blood pressure response during peak activity than children with normal resting blood pressure (Schieken et al. 1983). Intensive cardiopulmonary training, however, may reduce the degree of exercise-induced elevation in blood pressure even among persons with a family history of hypertension (Shook et al. 2012).

Children with Dyslipidemia Exaggerated blood pressure response to exercise has also been demonstrated in children with increased LDL cholesterol (Kavey et al. 1997). In a two-part, retrospective case-control study of 15 boys >10 years of age with LDL cholesterol 160 mg/dL versus 32 normolipidemic children and a prospective case-control study of ten hypercholesterolemic boys with LDL cholesterol >160 mg/dL and ten normolipidemic age-matched boys, at the end of a 10-min recovery period, SBP remained significantly higher in the high LDL group (mean SBP of 120 mmHg versus 112 mmHg, p 140 mmHg or DBP >90 mmHg) in the absence of target organ damage, blood pressure should be controlled before initiation or resumption of participation in high static competitive sports such as field track events (e.g., throwing), gymnastics, sailing, weight lifting, bodybuilding, wrestling, and boxing (see Table below) (McCambridge et al. 2010). Among persons with Stage 1 hypertension at rest, in the absence of target organ injury, there are no recommended limitations to competitive sports participation. Among children and adolescents with elevated blood pressure or Stage 1 hypertension, nonpharmacologic therapy (diet changes, weight loss, and lifestyle changes) should be prescribed and considered the first line of therapy. Pharmacological treatment may be considered if the nonpharmacological management is not effective or if there is Stage 2 hypertension without a clearly identified modifying risk factor. Overall, noncompetitive sports (e.g., recreational) as well as low-intensity dynamic and low intensity static activity (such as billiards, bowling, golf, and cricket) is always recommended regardless of BP control (Niedfeldt 2002). The American Academy of Pediatrics recommends avoiding heavy weight lifting, power lifting, bodybuilding, and high-static component sports among youth with uncontrolled hypertension (Rice 2008). A recent AHA/ACC Scientific Statement provides guidance for exercise recommendations for hypertensive athletes (see Table 2). Cardiovascular screening of athletes and nonathletes is complex and evolving (Maron et al. 1998, 2016). The risk of sudden death among an athlete with hypertension does not appear to be any greater than that of a nonhypertensive athlete, such that treatment of the hypertension does not result in a decline in the rate of sudden death

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Exercise Testing in Hypertension and Hypertension in Athletes

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Table 2 AHA/ACC scientific statement exercise recommendations for hypertensive youth (Black et al. 2015) Modified to Reflect 2017 Pediatric Hypertension Guideline Definitions 1

2

3

4

5

6

Recommendation It is reasonable that the presence of stage 1 hypertension in the absence of target-organ damage should not limit the eligibility for any competitive sport. Once having begun a training program, the hypertensive athlete should have BP measured every 2 to 4 months (or more frequently, if indicated) to monitor the impact of exercise (Class I; level of evidence B) Before adolescents begin training for competitive athletics, it is reasonable that they undergo careful assessment of BP, and those with initially high levels (SBP and/or DBP  95th percentile for children if 90), the prevalence rate in the same age group increased to 5.6% (Roberts and Maurer 1977). Around this time, pharmacologic treatment of childhood hypertension was generally restricted to those with an established underlying cause and/or symptomatic disease. Given the rarity with which antihypertensive drugs were used in children, it is not surprising that young patients were largely ignored in early studies evaluating the safety and efficacy of these agents. Over the last four decades, childhood BP has been studied more rigorously, resulting in clearer definitions of pediatric BP values and consensus recommendations pertaining to appropriate BP measurement and monitoring. This has resulted in a broader understanding of the prevalence of childhood hypertension as well as the implications of hypertension for overall short-term and long-term health. In addition, indications for the initiation of drug therapy have been further clarified. Since the National Heart, Lung, and Blood Institute (NHLBI) commissioned the First Task Force on Blood Pressure Control in Children in 1977, normative BP values have been adopted as the standard for assessment of BP in children (Blumenthal et al. 1977). Hypertension has been defined as BP consistently above the 95th percentile for age, sex, and height. Normative BP values have been refined over time, with the most recent update in the United States published in the 2017 American Academy of Pediatrics Clinical Practice Guideline for the Screening and Management of High Blood Pressure in Children and Adolescents (Flynn et al. 2017). Table 1 summarizes the current BP classification scheme in the United States and in Europe (Lurbe et al. 2016).

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Pharmacologic Treatment of Pediatric Hypertension

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Table 1 BP categories and stages United States guidelines

European guidelines

Classification Normal

Children aged 1–13y SBP and DBP