Manual of Heart Failure [1 ed.] 9789352500703, 9789350906309

Citation preview

Manual of

Heart Failure

Manual of

Heart Failure

Editor Kanu Chatterjee Clinical Professor of Medicine The Carver College of Medicine University of Iowa United States of America Emeritus Professor of Medicine University of California, San Francisco United States of America

®

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • London • Philadelphia • Panama

®

Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Offices J.P. Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44-2031708910 Fax: +02-03-0086180 Email: [email protected]

Jaypee-Highlights Medical Publishers Inc City of Knowledge, Bld. 237, Clayton Panama City, Panama Phone: +1 507-301-0496 Fax: +1 507-301-0499 Email: [email protected]

Jaypee Medical Inc The Bourse 111 South Independence Mall East Suite 835, Philadelphia, PA 19106, USA Phone: +1 267-519-9789 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shaymali Mohammadpur, Dhaka-1207 Bangladesh Mobile: +08801912003485 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu, Nepal Phone: +977-9741283608 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2014, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. Inquiries for bulk sales may be solicited at: [email protected] Manual of Heart Failure First Edition:  2014 ISBN 978-93-5090-630-9 Printed at

Contributors Anne Mani  MD

Jefferson Medical College Philadelphia, USA

Ashrith Guha  MBBS MPH

Cardiology Division The Carver College of Medicine University of Iowa, USA

Barry M Massie  MD

Professor of Medicine University of California San Francisco, USA

David J Whellan  MD

Associate Professor of Medicine Director of Coordinating Center for Clinical Research Jefferson Medical College Philadelphia, USA

Frances Johnson  MD

Associate Professor of Medicine The Carver College of Medicine University of Iowa, USA

Ileana L Piña  MD

James Prempeh  MD

St Mary’s Good Samaritan Regional Health Center Mount Vernon, Illinois, USA

Kanu Chatterjee

Professor of Medicine The Carver College of Medicine University of Iowa Emeritus Professor of Medicine University of California San Francisco, USA

KellyAnn Light-McGroary  MD The Carver College of Medicine University of Iowa, USA

Michel Komajda  MD

Northwestern University School of Medicine Chicago, USA

Mihai Gheorghiade  MD Professor of Medicine North Western University Chicago, USA

Professor of Medicine and Epidemiology/Biostatistics Case Western Reserve University Cleveland, Ohio, USA

Nestor Mercado  MD

J Thomas Heywood  MD

North Western University Chicago, USA

Professor of Medicine Scripps Medical Center University of California San Diego, USA

Scripps Medical Center University of California San Diego, USA

Peter S Pang  MD

Preface Heart failure is pandemic amongst industrialized nations. It is a disease with stark implications, markedly reducing life-expectancy and diminishing the quality of life. The past few years have witnessed revolutionary changes in the understanding of the pathophysiologic mechanisms and management of heart failure. This book has been designed for the readers seeking a comprehensive overview of all aspects of the disease entity. This highly illustrated book covers heart failure in detail with the discussion focusing on our current understanding and the recent advancement that is happening at a fast pace in the field. The chapters have been organized in such a way that all the aspects of heart failure are covered. The initial chapters discuss the global burden of heart failure and the challenges involved in diagnosing it. A special emphasis on systolic and diastolic heart failure has been made highlighting its pathophysiology, diagnosis, and therapeutic options. Further chapters focus on conditions associated with heart failure, such as anemia, hyponatremia and cardiorenal syndromes and acute heart failure syndromes. The final chapters discuss the major challenges involved in treating people with end-stage heart failure with advanced cardiac therapies, including cardiac transplantation and mechanical circulatory support. With contributions from leading international experts, the text contains guidelines from reputed international bodies. I hope that this book will serve as a useful practical tool to all those responsible for managing patients with heart failure. Kanu Chatterjee

Contents 1. Heart Failure: Epidemiology Kanu Chatterjee ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

Introduction 1 Epidemiology 1 Prevalence 2 Incidence 5 Secular Trends  10

2. Heart Failure: Diagnosis Kanu Chatterjee ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

45

Introduction 45 Historical Perspective  45 Ventricular Remodeling  47 Functional Derangements and Hemodynamic Consequences 61 Initial Treatment of Systolic Heart Failure  62 Symptomatic Systolic Heart Failure  64 Follow-up Evaluation  83

4. Diastolic Heart Failure (Heart Failure with Preserved Ejection Fraction) Kanu Chatterjee ‰‰

15

Analysis of Symptoms  15 Physical Examination  16 Electrocardiogram 20 Chest Radiograph  22 Echocardiography 24 Radionuclide Ventriculography  27 Cardiac Magnetic Resonance  28 Cardiac Tomography  29 Routine Laboratory Tests  30 Biomarkers 30 Exercise Tests  36 Six-minute Walk Test  37 Coronary Arteriography  37 Myocardial Ischemia  37 Endomyocardial Biopsy  38 Genetic Studies  40

3. Systolic Heart Failure (Heart Failure with Reduced Ejection Fraction) Kanu Chatterjee ‰‰

1

Introduction 96 Definition 96 Epidemiology 97 Pathophysiology 98 Clinical Presentation  106 Diagnosis 107 Prognosis  109 Treatment Strategies  113 Future Directions  119

96

x

Manual of Heart Failure 5. Anemia in Patients with Chronic Heart Failure (Prevalence, Mechanism, Significance, and Treatment) James Prempeh, Barry M Massie ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

Overview of the Problem  126 Prevalence of Anemia in Heart Failure Patients  126 Mechanisms Underlying Anemia in Heart Failure Patients  127 Prognostic Significance of Anemia in Heart Failure Patients  128 Should Anemia Be Treated in Heart Failure Patients?  129 Safety Concerns Related to ESPs in a Variety of Anemic Patients 129 Treatment of Anemia in Heart Failure Patients  131

6. Hyponatremia and Congestive Heart Failure Anne Mani, David J Whellan ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

163

Introduction 163 Epidemiology of Chronic Kidney Disease in Patients with Heart Failure  163 Prognosis of Worsening Renal Function  164 Definition of the Cardiorenal Syndrome  172 Pathophysiology of the Cardiorenal Syndrome  175 Role of Decreased Cardiac Output  175 Role of Elevated Central Venous Pressure  178 Role of Evidence-based Therapies in Patients with Heart Failure and the Cardiorenal Syndrome  180 Role of Ultrafiltration on Diuretic Resistance and the Cardiorenal Syndrome  187 Treatment of the Cardiorenal Syndrome: An Approach to the Individual Patient  189

8. Acute Heart Failure Syndromes Peter S Pang, Michel Komajda, Mihai Gheorghiade ‰‰

142

Introduction 142 Mechanisms Causing Hyponatremia in Heart Failure  147 Treatment of Hyponatremia  151 Role of Diuretic Therapy in Hyponatremia  152 Role of Vasopressin Receptor Antagonists in Hyponatremia 153 Tolvaptan 154 Lixivaptan 157 Conivaptan 158

7. Cardiorenal Syndrome: The Interplay Between Cardiac and Renal Function in Patients with Congestive Heart Failure Nestor Mercado, J Thomas Heywood ‰‰

126

Introduction 200 Definition 200 Epidemiology 201 Patient’s Characteristics  201 Classification 203 Pathophysiology 204 Acute Heart Failure Syndromes Management  209 Clinical Trials in Acute Heart Failure Syndromes  219

200

Contents 9. Cardiopulmonary Exercise Testing and Training in Heart Failure Ileana L Piña ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

Introduction 230 Normal Response to Exercise  230 Exercise Response in Heart Failure  232 Cardiopulmonary Exercise Testing  234 Indications for CPX Testing in Heart Failure  240 Exercise Training in Heart Failure  243

10. Hibernating Myocardium Kanu Chatterjee ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

‰‰ ‰‰ ‰‰

‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰ ‰‰

281

Introduction 281 Identifying Candidates for Advanced Cardiac Therapies  283 Heart Transplantation  290 Mechanical Circulatory Support  305

12. Palliative Medicine and End-of-life Care in Heart Failure KellyAnn Light-McGroary ‰‰

255

Introduction 255 Historical Perspective  256 Definition 256 Pathophysiology 256 Hibernation and Stunning: Clinical Prevalence  260 Detection of Hibernating Myocardium  261 Revascularization of Hibernating Myocardium and Changes in Ventricular Function  266 Revascularization of Hibernating Myocardium and Changes in Prognosis  268

11. Advanced Cardiac Therapies for End-stage Heart Failure: Cardiac Transplantation and Mechanical Circulatory Support Ashrith Guha, Frances Johnson ‰‰

230

324

Introduction 324 Epidemiology of Heart Failure  325 Economic Impact of Heart Failure  325 History of Palliative Care/Definitions  328 Feasibility of the Use of Palliative Care in Heart Failure  329 Issues of Prognostication  331 Communication and Patient’s Understanding of their Disease 332 Suffering in End-stage Heart Failure  334 Symptom Management in Heart Failure  337 Management of Implantable Cardiac Devices  342

Index 357

xi

CHAPTER 1

Heart Failure: Epidemiology Kanu Chatterjee

Chapter Outline • Epidemiology • Prevalence • Incidence –– Racial Differences

–– Geographic Differences –– Gender Differences • Secular Trends

INTRODUCTION

The incidence, prevalence, and etiology of heart failure are variable and influenced by the definition of heart failure used and the relevant causes unique to the individual countries. For example, rheumatic heart disease as a cause of heart failure is more common in developing countries than in developed countries. However, irrespective of countries and the socio­ economic status, there are some common epidemiologic factors. Aging, hypertension, diabetes, obesity, and increased body mass index are the major risk factors of heart failure. Heart failure can result from primary valvular, pericardial, or myocardial diseases. It can be acute or chronic. Heart failure complicating acute coronary syndromes or myocarditis are examples of acute heart failure. Heart failure complicating acute coronary syndromes, valvular, pericardial, and myocardial diseases is discussed in different chapters. Decompensated heart failure is discussed in Chapter 8: Acute Heart Failure Syndromes. Presently chronic heart failure is classified into two major clinical subtypes: (i) heart failure with reduced ejection fraction (HFREF) [also termed systolic heart failure (SHF)] and (ii) heart failure with preserved ejection fraction (HFPEF) [also called diastolic heart failure (DHF)]. In this chapter, the epidemiology of HFREF and HFPEF has been discussed. In subsequent chapters, diagnosis, pathophysiology and management of HFREF and HFPEF have been discussed.

EPIDEMIOLOGY

The definition of HFREF is based on measurement of left ventricular ejection fraction. If the ejection fraction is 45% or less, HFREF is diagnosed. In HFPEF, left ventricular ejection fraction should be higher than 45%. For the diagnosis of heart failure based on signs and symptoms, a number of scoring

2

Manual of Heart Failure

systems have been proposed.1 However, in practice and also in clinical trials, the Framingham system is most frequently used.

PREVALENCE

Prevalence is calculated by determining the number of total cases occurring in the population at risk. The 2011 American Heart Association update has reported that the prevalence of heart failure is approximately 2.4% of the adult population of the United States of America. In 2011, it was estimated that in the United States of America there were about 5.7 million people had an established diagnosis of heart failure.2 By 2040, it is expected that approximately 10 million people will have heart failure (Tables 1 and 2).2a The worldwide prevalence of heart failure was estimated to be 23 millions. The prevalence of heart failure increases sharply with age. The Framingham heart study reported the prevalence in men of 8/1,000 at age of 50–59 years which increased to 66/1,000 at ages 80–89 years.3 In women, it was also 8/1,000 at age of 50–59 years and 79/1,000 at ages 80–89 years. In patients younger than 40 years, the prevalence is only 1%; in patients 80 years or older, it is 20%. The 2011 AHA update,2 reported that in the American males the prevalence was 3%, in females 2%. In non-Hispanic males, it was 2.7% and in non-Hispanic females 1.8%. The prevalence is much higher in non-Hispanic Black males, 4.5% and in females, 3.8%. In Mexican-American   TABLE 1  Epidemiology of heart failure in the United States of America • • • • •

Estimated 5,50,000 new cases occur/year Estimated to rise to 7,72,000/year by year 2040 More than 5 million Americans have heart failure Estimated to increase to 10 million by year 2040 Among medicare beneficiaries, heart failure is the leading cause of hospitalization • Cost of HF treatment is >35 billion $ in 2007   TABLE 2  Prevalence of heart failure in the United States of America • Heart failure is the third most prevalent cardiovascular disease • Prevalence and age: 20–39—less than 1% 80 or older—about 20% • Lifetime risk of developing heart failure 20% for both women and men • Lifetime risk of developing heart failure without coronary artery disease: Age 40—men—11.4%, women—15.4%

Heart Failure: Epidemiology

males the prevalence of heart failure is 2.3% and in females 1.3%.2 In Glasgow, Scotland, the estimated prevalence was 1.5% at ages 25–75 years.4 The Rotterdam study reported a prevalence of HFREF of 0.7% in people at ages 55–64 years, 2.7% at 65–74 years and 13% at 75–84 years.5 The similar rates of prevalence have been reported in other studies.6-8 Redfield and colleagues reported a prevalence of 2.2% in the population at the age of 45 years or older. In this study, patients with both SHFand DHF were included.9 The lifetime risk for developing heart failure has been estimated, and it is about 20% for both men and women. In absence of coronary artery disease at age 40 years, it is 11.4% in men and 15.4% in women.10 It is estimated that the prevalence of heart failure in the United States will increase during next three decades. Currently, approximately 570,000 patients are diagnosed with heart failure per year, and it is estimated that the number will increase to 770,000 per year by the year 2040.3 There appears to be several reasons for this increase in prevalence of heart failure. The aging of the population, improvement in longevity due to salvage of a greater proportion of patients with acute coronary syndrome with the modern therapy and the increase in diabetes and obesity in the population are likely causes for the epidemic of heart failure. Along with the increase in prevalence of heart failure, the hospital admission and readmission rates have increased (Fig. 1). The increased hospital admission rates are not only due to increased frequency of advanced heart failure but also due to comorbidities (such as renal failure), electrolyte abnormalities and multiorgan systems failure.

FIGURE 1: The increasing rates of hospital admission in women and men with discharge diagnosis of heart failure are illustrated (Source: Modified from American Heart Association)

3

4

Manual of Heart Failure   TABLE 3  Rate of hospitalizations, mortality, and morbidity of heart failure in the United States of America Prevalence • Increasing rate of hospitalizations: 1979—1,274,000 2004—3,860,000 • More than 80% of patients were among 65 years or older Prevalence and etiology • Mortality: Nearly 50,000 annually • Morbidity: 6.5 million days of hospital stay/year

FIGURE 2: The readmission rates in heart failure and the prognosis of patients requiring readmission are illustrated (Source: Modified from Jong P, et al. Arch Intern Med. 2002;162:1689-94)

Heart failure is the most common cause of hospital admissions in patients older than 65 years.10 Heart failure is also the most common discharge diagnosis and has increased by over 170% between 1979 and 2003 (Table 3).10 The 2011 AHA update reported that in 2007, there were 990,000 patients were discharged with a diagnosis of heart failure.2 In 1979, just over 1 million patients were admitted to hospital for heart failure; in 2004, it was close to 4 million. More than 80% of patients were 65 years of age or older.11,12 The hospital readmission rates are also high. Approximately 20% of patients are readmitted within 30 days, and 50% within 6 months. The readmissions are also associated with high mortality (Fig. 2). The mortality of patients requiring readmissions is about 12% at 30 days, 33% at 12 months and 50% at 5 years.13 The costs of management of heart failure also increase with number of hospitalizations. The total direct costs of heart failure are primarily related to number of hospitalizations and the length of hospital stay. In many developed countries, the cost of heart failure management is between 1% and 2% of the total health care budget.14 In the United States, the costs of care for heart failure exceeded 35 billion dollars in 2007. The prevalence of HFPEF (diastolic heart failure) appears to be similar to that of HFREF (systolic heart failure).

Heart Failure: Epidemiology

Approximately 50% of patients with overt heart failure have preserved left ventricular ejection fraction. However, there is a considerable variability in the reported prevalence of heart failure with preserved left ventricular ejection fraction, and it ranges between 13% and 74%.15 Similar to HFREF, the prevalence of HFPEF increases with age. It has been estimated that the prevalence in patients younger than 50 years of age is approximately 15%, between 50 and 70 years 33% and older than 70 years 50%.16 In Medicare-eligible patients hospitalized with the diagnosis of heart failure, 34% had preserved left ventricular ejection fraction.17 The HFPEF is more common in women than in men. A multivariate analysis has reported that the prevalence of HFPEF in women twofold higher than that in men (odds ratio 2.07, 95% Confidence Interval 1.93–2.34).

INCIDENCE

Incidence is calculated with the number of patients with new onset of heart failure divided by the number of people at risk of developing heart failure. The incidence of heart failure increases with increasing age. Over each successive decade of life the incidence almost doubles. In the Framingham study, the annual incidence of heart failure in men increased from 2/1,000 at the age 35–64 years to 12/1,000 at the age 65–94 years.3 The lifetime risk (incidence) of developing heart failure is about 20% at all ages older than 40 years.18 There is controversy regarding the incidence of heart failure in relation to time. The Framingham study reported that there has been no change in the age-adjusted incidence of heart failure in men between the time periods 1950–1969 and 1990–1999. In women, there was a decline in the incidence of heart failure.19 In another retrospective study, no change in the age-adjusted incidence of heart failure was found either in men or women between the time period of 1979 and 2000.20 In another study, however, an increase in the age-adjusted incidence of heart failure was reported between the periods 1970–1974 and 1990–1994.21 Among medicare beneficiaries, 65 years of age or older, the incidence of heart failure declined between 1994 and 2003. The decline was largest in people aged 80–84 years.22 The incidence of heart failure is lower in people of younger age. A five-year risk of developing heart failure in people 40 years of age is 0.1–0.2%.18 In another study, a similar lower incidence of heart failure was observed in people younger than 50 years of age.22 The 2011 AHA update reported that the incidence of heart failure in patients 45 years or older was 670,000, in males 350,000, and in females 320,000.2

5

6

Manual of Heart Failure

The risk factors for developing heart failure are summarized in Table 4 and Figure 3. The conventional risk factors are age, gender, hypertension, diabetes, obesity, and coronary artery disease. Insulin resistance, genetic factors and use of cardio­toxins are other risk factors that have been recognized. In patients with diabetes, the risk of developing heart failure in 10 years after the diagnosis is approximately 10% in men and 18% in women. In patients with hypertension, it is 12% in men and 8% in women. In patients having a myocardial infarction approximately of 30% of men and women develop heart failure in 10 years.23 Hypertension as a risk factor is now less common than coronary artery disease for developing heart failure (Table 5).24,25 In the studies of left ventricular dysfunction (SOLVD) registry, approximately 70% of patients had coronary artery disease and only 7% of patients had hypertension who developed SHF (Fig. 3).24 The population attributable risk has been assessed to determine the relative contribution of the various   TABLE 4  Risk factors for heart failure Heart failure in the United States of America: Epidemiology • Increasing age • Hypertension • Coronary artery disease • Diabetes • Obesity • Insulin resistance • Genetic factors • Use of cardiotoxins

FIGURE 3: The etiology of systolic heart failure in the SOLVD registry is illustrated. The most common cause was ischemic heart disease. (Source: Modified from Bourassa, et al. J Am Coll Cardiol. 1993;22: 14A-19A)

Heart Failure: Epidemiology   TABLE 5  Risk of heart failure due to diabetes, hypertension, or myocardial infarction Over 10 years, heart failure develops in • 10% of men • 18% of women with diabetes • 12% of men • 8% of women with hypertension • 30% of men • 30% of women with myocardial infarction   TABLE 6  Racial differences in the incidence of congestive heart failure Over all incidence African-American Hispanic White Chinese-American

3.1/1000 person-years 4.6/1000 person-years 3.5/1000 person-years 2.4/1000 person-years 1.0/1000 person-years

risk factors for developing heart failure.26 For coronary artery disease, the overall population attributable risk was 62%. It was 68% in men and 56% in women. For hypertension it was 10%, for cigarette smoking it was 17%, and for diabetes it was 3%. The overweight was associated with the population attributable risk for developing heart failure of 8%. It is of interest that in patients with established heart failure the traditional risk factors appear to be associated with reduced risk of mortality which is called reverse epidemiology.27 Newer risk factors for developing heart failure have been identified. Obesity and central adiposity,28 high-normal albuminuria,29 leukocytosis, parti­cularly granulocytosis and increased levels of C-reactive protein30 are associated with increased risk of heart failure. RACIAL DIFFERENCES Racial differences in the incidence of heart failure have been investigated (Table 6).31 In the multioethnic study of athero­ sclerosis, the overall incidence rate of developing heart failure during a median follow-up of 4.0 years was 3.1/1,000 personyears. The incidence rate among African Americans, Hispanic, White and Chinese Americans were 4.6, 3.5, 2.4 and 1.0/1,000 person-years respectively. However, when hypertension and/or diabetes were included, the incidence of congestive heart failure in African Americans were not statistically different compared to other ethnic population. The socioeconomic status also contributed to the higher incidence of congestive heart failure

7

8

Manual of Heart Failure

in the African Americans. The relative proportion of DHF was also higher in African Americans. GEOGRAPHIC DIFFERENCES The information about the prevalence or incidence of heart failure in the Asians or Southeast Asians is scarce. However as the incidence of coronary artery disease in these countries are increasing, it is very likely that the prevalence and incidence of heart failure resulting from coronary artery disease are also high. Furthermore, hypertension is very common in these countries and, therefore, hypertension-related heart failure is likely to be common as well. It has been reported that in Chinese in China, hypertension is the predominant risk factor for developing heart failure.32 In Japan, the characteristics and outcomes of HFPEF and HFREF were compared by using the national registry database. This was a prospective observational study and 2,675 patients were enrolled. The average duration of follow-up was 2.4 years. The patients with HFPEF were more likely to be older female with a higher frequency of hypertension than coronary artery disease. The patients with HFREF were more likely to be male, younger and with a higher frequency of coronary artery disease than hypertension. The risk of mortality and rehospitalization rates were similar in patients with HFPEF and HFREF.33 In Pakistan, the prognosis of new or recent onset of HFREF was evaluated in a relatively small number (196) of patients. These patients were younger and had higher frequency of prior ischemic heart disease. During a follow-up period of 379 days, 27.5% of patients died and 52% had combined event of death or rehospitalization.34 In Singapore, the prognosis of patients with HFREF was evaluated in 225 patients hospitalized for heart failure. Malay and Indian patients had higher incidence of heart failure compared to Chinese. Ischemic heart disease was the most common cause. During 5 years of follow-up, the mortality was 67.5% and female gender, older age, renal failure and severe heart failure were important risk factors.33 In Malaysia, the prevalence and the risk factors of heart failure were assessed from acute medical hospital admissions of 1,435 patients in a busy hospital in Kuala Lumpur. The prevalence of heart failure was 6.7%, and coronary artery disease was the major risk factor. In Malaysian Indians, diabetes was very prevalent.34 In Harrow, United Kingdom, the prevalence and the etiology of left ventricular systolic dysfunction among 1,392 patients who were 45 years of age or older were assessed. The incidence of probable and definite left ventricular systolic dysfunction was

Heart Failure: Epidemiology

5.5% and 3.5%, respectively. The prevalence was similar in white Caucasians and South Asians.35 In Leicester, United Kingdom, the prognosis and predictive factors were studied among 176 South Asians and 352 ageand sex-matched white Caucasians with new onset of heart failure. The South Asians and white Caucasians had similar rates of coronary heart disease, but the South Asians had more hypertension, diabetes and preserved left ventricular ejection fraction. During follow-up, the mortality in South Asians was 41.2% and in white Caucasians 47.4%. At the time of first hospital admission, heart failure was less severe in South Asians compared to that in white Caucasians.36 Geographic variation in heart failure hospitalization has been recognized.37 Number of primary care physicians per population, regional income level have been associated with rate of hospitalization for the treatment of heart failure.38 GENDER DIFFERENCES The gender differences in the incidence of heart failure have been studied.39 The age-adjusted incidence/1,000 person-years was highest in African Americans men, 9.1, followed by African women, 8.1 (Table 7). The incidence in Caucasian men was 6.0, and 3.4 in Caucasian women. Thus, the lowest incidence was in the Caucasian women in this study.40 In the Malmö preventive project study, 33,342 heart failure subjects were enrolled between 1974 and 1992 to assess the gender differences in the incidence of heart failure.41 In this community-based study, women had lower risk of developing heart failure than men. The incidence of all-cause mortality and heart failure-related death was also lower in women than in men during follow-up of over 20 years. In patients hospitalized with heart failure, in general women receive less appropriate hospital discharge instructions about follow-up management plans. The length of hospital stay is also longer in women than in men. Older patients, however, are less likely to receive guideline-recommended therapies irrespective of gender, and have higher risks of adverse outcomes.42   TABLE 7  Gender differences in the incidence of congestive heart failure Heart failure in the United States of America—Epidemiology Age adjusted incidence rate 1/1000 person-years: • Caucasian men: 6.0 • African-American men: 9.1 • Caucasian women: 3.4 • African women: 8.1 Lowest incidence is in Caucasian women

9

10

Manual of Heart Failure

In patients hospitalized with decompensated heart failure, the incidence of HFPEF and reduced ejection fraction are very similar. The patient with HFPEF is more common in elderly women, and hypertension is more common etiology. Coronary artery disease is more common in HFREF. The incidence of diabetes and atrial fibrillation was slightly higher in HFPEF (Table 8).43

SECULAR TRENDS

Very limited information is available regarding the secular trends in the incidence of heart failure. The mortality in men after the diagnosis of heart failure was approximately 70% between 1979 and 1984, 60% between 1985 and 1990 and 50% between 1991 and 1995, and 40% between 1996 and 2000 (Fig. 4).44 In women, it was 60% between 1979 and 1981, 55% between

  TABLE 8  Demographic differences between systolic (HFREF) and diastolic (HFPEF) from the ADHERE registry ADHERE—All enrolled discharges Profile EF Age Female CAD Diabetes AF

SHF (59,523) 40% 74.2* 62.2%* 54%* 46%* 33%*

*6 cm • Neck-vein distention • Rales • Cardiomegaly (circulation time >25 sec) • Hepatojugular reflux • Acute pulmonary edema • S3 gallop Minor criteria • Ankle edema • Night cough • Dyspnea on exertion • Pleural effusion • Decreased vital capacity • Sinus tachycardia (120 bpm or higher) Major or minor criteria • Weight loss >4.5 kg in five days in response to treatment • Two major or one major and two minor

16

Manual of Heart Failure

and specificity of paroxysmal nocturnal dyspnea were 39% and 80% and of orthopnea 22% and 74%.2 In another study of 1,306 patients with left ventricular ejection, a fraction of less than 40% undergoing cardiac catheterization, the sensitivity and specificity of symptoms of heart failure were determined.3 The sensitivity, specificity, and positive predictive value of exertional dyspnea were 66%, 52%, and 23%, respectively; of nocturnal dyspnea 33%, 76%, and 26%; and those of orthopnea were 21%, 81%, and 2%, respectively. In relatively elderly patients with documented left ventricular systolic dysfunction by echocardiography, exertional dyspnea and history of myocardial infarction or angina were associated with a higher independent predictive value for the diagnosis of left ventricular systolic dysfunction. However these symptoms were neither sensitive nor specific.4 Chest pain is an uncommon symptom of heart failure. However, typical angina and atypical chest pain are present in some patients with heart failure with or without coronary artery disease.5 Patients with chronic heart failure do not usually present with history of frank syncope. However, in patients with previously undiagnosed left ventricular systolic dysfunction, syncope resulting from ventricular tachyarrhythmias may occur as the initial manifestation of heart failure. Dizziness and light headedness however are quite common and usually result from hypotension, and most frequently due to the medicines that are used for treatment of heart failure. Palpitations are also common symptoms in patients with heart failure, but these symptoms are not of any diagnostic relevance. Exertional fatigue is a common presenting symptom of patients with heart failure. However, like exertional dyspnea, it has a relatively low positive predictive value. The other occasional symptoms of chronic heart failure are nocturnal cough, nocturia, right upper quadrant pain if hepatomegaly is present, and disordered sleep. Anorexia is uncommon except in patients with end-stage heart failure.

PHYSICAL EXAMINATION

Adequate physical examination is essential for the diagnosis of heart failure. The presence of abnormal physical findings not only establishes the diagnosis but also provides clues regarding the etiology of heart failure. Elevated jugular venous pressure has a specificity of 97%, sensitivity of 10% and a positive predictive value of 2% (Fig. 1). Lower extremity edema has a specificity of 99%, sensitivity of 13% and the positive predictive value of 6%. The S3 gallop sound in patients older than 45 years has a specificity

Heart Failure: Diagnosis

FIGURE 1: Distended right external and internal jugular veins in a patient with heart failure are illustrated

of 95%, sensitivity of 31% and a positive predictive value of 61%.3 Thus the presence of an S3 gallop sound has a significant diagnostic relevance. An S3 gallop sound is associated with increased left ventricular end diastolic pressure, and increased levels of B-type Natriuretic Peptide (BNP).6 An S3 gallop sound has been reported to indicate left atrial pressure exceeding 20 mm Hg and left ventricular end diastolic pressure greater than 15 mm Hg. However, considerable interobserver variability was observed in detection of S3 gallop sound.7,8 In a phonocardiographic study9 the hemodynamic correlation between gallop sounds and directly measured left ventricular end-diastolic pressure were determined. The sensitivity of an S3 was 40–50% but specificity was 90%. It was also highly specific (90%) for elevated serum BNP.10 A gallop rhythm almost always indicates heart failure with reduced ejection fraction (HFREF) due to dilated cardiomyopathy with increased end systolic and end diastolic volumes and end diastolic pressure. Presence of pulsus alternans is diagnostic of systolic heart failure (HFREF) (Fig. 2). Similarly a positive hepatojugular reflux is also very suggestive of systolic heart failure (HFREF) (Fig. 3).7

FIGURE 2: Direct arterial pressure record­ing showing pulsus alternans in a patient with systolic heart failure (HFREF) is illustrated

17

18

Manual of Heart Failure

FIGURE 3: Schematic illustration of positive hepatojugular reflux which usually indicates systolic heart failure (HFREF) (Source: Published with permission from Ewy GA. Ann Intern Med. 1998;109:456)

FIGURES 4A TO C: Schematic illustrations of a normal (A), hyperdynamic (B) and sustained (C) left ventricular apical impulse (Abbreviations: OM: Outward movement; A2: Aortic component of the second heart sound; P2: Pulmonic component of the second heart sound; O: Opening of the mitral valve; RFW: Rapid filling wave; A: A wave; S1: First heart sound; S4: Fourth heart sound; E: E point). The illustrations represent apex cardiogram

In patients with suspected or established heart failure, assessment of the character of the left ventricular apical impulse is useful to determine whether it is normal or sustained. A normal apical impulse is almost always associated with normal left ventricular ejection fraction, whereas a sustained impulse indicates reduced ejection fraction or severe left ventricular hypertrophy (Figs 4A to C). The hyperdynamic apical impulse is also associated with normal ejection fraction. Cardiac enlargement should be suspected if the apical impulse is

Heart Failure: Diagnosis

displaced laterally past the left midclavicular line. A palpable right ventricular heave (left parasternal lift) usually indicates right ventricular failure and may be present in patients with advanced heart failure. The presence of pulmonary crackles during auscultation may indicate pulmonary venous congestion; however, in absence of other findings of heart failure pulmonary crackles have very little diagnostic value. The sensitivity, specificity and positive predictive value were reported to be 13%, 99%, and 6%, respectively.3 The signs of pulmonary arterial hypertension, such as an increased intensity of the pulmonic component of the second heart sound (P2), may be detected during auscultation. It can be present both in patients with systolic or diastolic heart failure. Auscultatory signs of mitral regurgitation, when detected, usually indicate systolic heart failure. Tricuspid regurgitation is usually secondary to pulmonary hypertension and may be present both in systolic and diastolic heart failure. Marked loss of weight (cardiac cachexia), if present, indicates end stage heart failure. Similarly a marked elevation of systemic venous pressures, ascites and peripheral edema despite diuretic treatments usually indicates end stage refractory heart failure. In patients with advanced heart failure, signs of low cardiac output often can be detected. Sinus tachycardia, narrow pulse pressure, and cool, clammy and pale skin indicate low cardiac output. The cool, clammy and pale skin results from reflex adrenergic stimulation and peripheral vasoconstriction in response to low cardiac output. Peripheral cyanosis also suggests low cardiac output and impaired tissue perfusion. During clinical evaluation, it is highly desirable to assess the severity of symptoms and the stages of heart failure. To assess the functional class, the New York Heart Association (NYHA) classification is used (Table 2). NYHA functional class I indicates asymptomatic patients; class II when symptoms develop during more than usual activity. In NYHA class III patients, the symptoms develop during less than usual physical activity; in patients in NYHA IIIb, the symptoms develop with   TABLE 2  New York Heart Association functional classification 1. No limitations on physical activity, no symptoms with ordinary activities 2. Slight limitation, symptoms with ordinary activities 3. Marked limitation, symptoms with less than ordinary activities 4. Severe limitation, symptoms of heart failure at rest Symptoms: Fatigue, dyspnea, palpitations, or angina

19

20

Manual of Heart Failure   TABLE 3  Heart failure: new classification not based on the severity of symptoms Stage A: At high risk for HF but without structural heart disease or symptoms of HF Stage B: Structural heart disease but without symptoms of HF Stage C: Structural heart disease with prior or current symptoms of HF Stage D: Refractory HF requiring specialized interventions

minimal activity. NYHA class IV patients are symptomatic at rest. Determination of functional class is important to assess prognosis. For the diagnosis of the potential etiology and the stages of heart failure the recommendations in the ACC/AHA guidelines are employed (Table 3).5 In patients in stage A, there are risk factors for developing heart failure without structural heart disease. In stage B patients, there is asymptomatic left ventricular systolic dysfunction. Stage C patients are sympto­ matic heart failure and on recommended treatments for heart failure. Stage D patients have refractory heart failure who are candidates for heart transplantation and/or assist devices. The noninvasive as well as invasive tests, if required, should also be considered during the diagnostic work up of patients with suspected heart failure.

ELECTROCARDIOGRAM

An electrocardiogram should be obtained in all patients. It may reveal arrhythmias, evidence of previous myocardial infarction, and left ventricular hypertrophy. The electrocardiographic evidence of old myocardial infarction with or without changes of chronic left ventricular aneurysm usually indicates systolic heart failure (Fig. 5). The evidence of left ventricular hyper­trophy may be present in both systolic and diastolic heart failure (Figs 6 and 7). In elderly patients, however, electrocardiographic abnormalities of left ventricular hypertrophy are frequently present and their positive predictive value is low.11 A completely normal electrocardiogram is very uncommon in patients with chronic heart failure.11 A normal electrocardiogram has been reported to have a negative predictive value of 98%.2 The electrocardiogram may reveal atrial fibrillation with rapid ventricular response which may be the etiology of heart failure (tachycardic cardiomyopathy) or the case of worsening heart failure. The electrocardiogram is useful for the diagnosis of myocardial ischemia which may cause dyspnea similar to heart failure. In patients with systolic heart failure electro­ cardiogram should be performed to detect the presence of left bundle branch block to decide whether chronic resynchroniza­ tion treatment is necessary.

Heart Failure: Diagnosis

FIGURE 5: Electrocardiographic features of chronic left ventricular aneurysm are illustrated. Anterolateral myocardial infarction with Q waves in leads V2–V6 with persistent ST segments elevations are present. Localized slurring of ORS in V5 lead suggests peri-infarction block of “GRANT”

FIGURE 6: Electrocardiographic features of concentric left ventricular hypertrophy are illustrated. Left ventricular hypertrophy with repolarization abnormalities and normal frontal plane QRS axis are evident

Electrocardiograms may reveal uncommon causes of heart failure, such as apical hypertrophic cardiomyopathy (Fig. 8). The characteristic electrocardiographic features in this condi­ tion are large QRS voltage in the lateral precordial leads with deep T Wave inversions (giant T wave inversions). It should be appreciated that heart failure is much less common in apical hypertrophic cardiomyopathy than in hypertrophic obstructive

21

22

Manual of Heart Failure

FIGURE 7: Electrocardiographic features of eccentric left ventricular hypertrophy are illustrated. Left ventricular hypertrophy with repolarization changes and left axis deviation of QRS complex are evident

FIGURE 8: Electrocardiographic features of apical hypertrophic cardiomyopathy showing increased QRS voltage in lateral precordial leads with giant T wave inversions

cardiomyopathy. Giant T wave inversions may also be observed in hypertrophic obstructive cardiomyopathy. The causes of giant T wave inversions are summarized in Table 4.

CHEST RADIOGRAPH

In patients with suspected heart failure a plain chest radiograph should be obtained. The diagnosis of heart failure can be established if the radiologic findings of hemodynamic pulmo­ nary edema are present. However, even in patients with decompensated chronic heart failure, the chest radiograph may

Heart Failure: Diagnosis   TABLE 4  Sumary of causes of “giant T wave” inversions • • • • • • • • •

Intermittent left bundle branch block Post-pacing T wave changes (cardiac memory, Chatterjee syndrome) Post ablation of accessory pathway Subarracnoid hemorrhage Apical hypertrophic cardiomyopathy Hypertrophic obstructive cardiomyopathy Markedly prolonged QT Post Stokes-Adams-Morganni syndrome Post-right coronary artery contrast injection

FIGURE 9: Chest radiograph of a patient with chronic systolic heart failure is illustrated. Cardiomegaly, left atrial enlargement and redistribution of pulmonary vascular distributions are evident. It is to be noted that despite a marked increase in pulmonary capillary wedge pressure there was no radiologic evince of florid pulmonary edema

be normal. The radiologic findings of hemodynamic pulmonary edema, such as prominent upper lobe vessels, perihilar haziness and Kerley’s B lines, may be absent. Cardiomegaly (cardiothoracic ratio of >50%), left atrial enlargement, pleural effusions and right ventricular enlargement in patients with ejection fraction of 40% or lower identified patients with pulmonary capillary wedge pressure of less than 15 mm Hg from those patients with pulmonary capillary wedge pressure between 15 mm Hg and 24 mm Hg, but failed to identify patients with higher than 24 mm Hg (Fig. 9).12 The usefulness of the chest radiograph for the diagnosis of increased pulmonary venous pressure and reduced left ventricular ejection fraction has been performed.13,14 The pulmonary vascular redistribution and cardiomegaly were the best predictors of increased left ventricular diastolic pressure and reduced ejection fraction respectively. In a multicenter

23

24

Manual of Heart Failure

FIGURE 10: In a patient with chronic systolic heart failure frank pulmonary edema can occur which indicates pulmonary venous pressures are higher than 25 mm Hg

study of 880 patients, alveolar edema, interstitial edema and pulmonary vascular redistribution had a specificity of greater than 90% for the diagnosis of heart failure and cardiomegaly had a sensitivity of greater than 50%. However, even in patients with decompen­sated chronic heart failure, the chest radiograph may be negative and may not show evidence of heart failure.15 In patients with chronic systolic heart failure, frank pulmonary edema can also occur which indicates hydrostatic pressure is considerably higher than the oncotic pressure (Fig. 10). Evaluation of the character of the left ventricular apical impulse may be helpful to assess left ventricular ejection fraction. A sustained left ventricular apical impulse usually indicates reduced left ventricular ejection fraction provided the causes of severe left ventricular hypertrophy can be excluded. A displaced left ventricular apical impulse has a high sensitivity, specificity and positive and negative predictive values for the diagnosis of systolic heart failure.2

ECHOCARDIOGRAPHY

In all patients with suspected or established heart failure a transthoracic echocardiogram should be obtained. Echocardio­ graphy is the preferred method for assessment of cardiac dysfunction.16 The guidelines recommend that echocardiography is appropriate for evaluation of cardiac dyspnea and other symptoms of heart failure.16 Echocardiography is less expensive, less time consuming and can easily be obtained. It is indeed should be considered as the initial noninvasive imaging test of choice. Echocardiography is useful to distinguish between systolic and diastolic heart failure. In systolic heart failure left ventricle is dilated, end-diastolic and

Heart Failure: Diagnosis

end systolic volumes are increased and the ejection fraction is reduced (Fig. 11). An ejection fraction of less than 45% by echocardiography is used for the diagnosis of systolic heart failure. Left ventricular ejection fraction of 45% or greater is used for the diagnosis of diastolic heart failure. In diastolic heart failure left ventricular size is normal and its wall thickness is increased (Fig. 12). Atrial enlargements can be present in both systolic and diastolic heart failure. Doppler echocardiography is essential to assess left ventricular diastolic function. An early left ventricular diastolic dysfunction is characterized by a decrease in peak transmitral E-velocity, an increase in atrial-induced A-velocity and a decrease in E/A ratio. The early abnormal filling pattern is related to impaired left ventricular relaxation. In patients

FIGURE 11: Transthoracic echocardiogram of a patient with systolic heart failure due to dilated cardiomyopathy is illustrated (Panel A and B). The left ventricle is dilated and its wall appears thinner than normal

25

26

Manual of Heart Failure

FIGURE 12: Transthoracic echocardiogram of a patient with diastolic heart failure is illustrated. The left ventricular cavity size is normal and its wall thickness is increased. Doppler echocardiographs show dominant “A” wave. Panel B shows normal transmitral flow pattern

with advanced heart failure, the “restrictive filling pattern” is observed. A marked increase in E/A ratio with a short E-deceleration time is the major Doppler echocardiographic features of “restrictive filling pattern” (Fig. 13). The abbreviated duration of E wave velocity is related to elevated left ventricular end-systolic pressure and a rapid decrease in the transmitral pressure gradient during left ventricular filling.17 The moderate left ventricular diastolic dysfunction is characterized by normal E/A ratio—“the pseudo-normalized filling pattern.” This pattern can be distinguished from normal filling pattern by demons­ trating the reduced E-velocity by Tissue Doppler Imaging.18 It should be appreciated that the abnormal left ventricular transmitral filling patterns can be present in both systolic and diastolic heart failure.

Heart Failure: Diagnosis

FIGURE 13: Doppler echocardiography of a patient with systolic heart failure is illustrated. It shows pseudonormalization of transmitral flow pattern

Echocardiography is also essential noninvasive test for evaluation of heart failure due to valvular heart disease. The signs and symptoms of heart failure in valvular heart disease may be similar to those of primary systolic or diastolic heart failure (Figs 14 and 15). The echocardiography is also essential for diagnosis of heart failure due to hypertrophic cardio­myopathy.

RADIONUCLIDE VENTRICULOGRAPHY

Radionuclide ventriculography can be used to assess left ventricular volumes and end ejection fraction. The advantage of this technique is its independence of geometric assumption for calculation of ventricular volumes. This technique can also be used to assess diastolic function by determining time to filling rate.19 Radionuclide ventriculography, however, is infrequently

27

28

Manual of Heart Failure

FIGURE 14: Doppler echocardiography in a patient with severe aortic valve stenosis

FIGURE 15: Transthoracic echocardiography in a patient with severe mitral stenosis showing markedly reduced mitral valve orifice (with permission)

employed in clinical practice for evaluation of patients with heart failure.

CARDIAC MAGNETIC RESONANCE

Cardiac magnetic resonance (CMR) imaging can also be used to assess left ventricular volumes and ejection fraction (Fig. 16).20,21 In patients with systolic and diastolic heart failure the left ventricular volumes, size and ejection fraction can be determined by CMR. With the use of contrast agents such as gadolinium the other morphologic changes, such as left ventricular mass and magnitude of fibrosis can be more

Heart Failure: Diagnosis

FIGURE 16: Cardiac magnetic resonance image of a patient with systolic heart failure is illustrated. The left ventricle is dilated and its wall is thin

FIGURE 17: Cardiac magnetic resonance image of a patient with constrictive pericarditis is illustrated (spin-echo; horizontal long axis). The fibrous calcified nature of the pericardium is evident. (Source: Klein AL, Scalia GN)23

accurately assessed by this technique. The CMR angiography is being also used for the detection of obstructive coronary artery disease. In presence of heavily calcified coronary artery segments, CMR imaging is a better noninvasive technique than computed tomography, as the images are not interfered by the presence of calcium.22 It can be used to assess pericardial thickness to distinguish between constrictive pericarditis and the restrictive cardiomyopathy (Fig. 17).

CARDIAC TOMOGRAPHY

The electron beam computed tomography (EBCT) is useful for the diagnosis of presence of coronary artery calcium. A high coronary calcium score is associated with a greater likelihood of atherosclerotic coronary artery disease. Coronary artery calcium detected by multidetector computed tomography

29

30

Manual of Heart Failure

FIGURE 18: Computed tomographic image of a patient with constrictive pericarditis is illustrated. Calcium in the pericardium is an evident

(MDCT) also suggests coronary artery disease. However, in presence of coronary artery calcium, the specificity is reduced. The specificity is reduced from 86 to 53% for detection of 50% or greater degree of coronary artery stenosis with calcium scores of 400 or less versus greater than 400 Agatston units. 24-26 The contrast enhanced multislice computed tomo­g raphic coronary angiography is being increasingly used not only for detection of presence of coronary artery disease but also for diagnosis of ischemic and nonischemic dilated cardio­m yo­p athy. 27 The contrast CT can be used for distinguishing between restrictive cardiomyopathy and constrictive pericarditis (Fig. 18).

ROUTINE LABORATORY TESTS

During initial workup of patients with suspected or established heart failure, blood tests should include a complete blood count, serum electrolytes, blood urea nitrogen and creatinine. Presently the creatinine clearance to assess glomerular filtration rate is automatically provided by the laboratory. It provides an estimation of renal function. Routine blood count is done to exclude significant anemia which can exacerbate heart failure. Renal failure can also exacerbate heart failure. Liver function or thyroid function tests do not need to be routinely performed. However, in special circumstances such as in patients taking amiodarone, liver function and thyroid functions should be performed to exclude its toxicity. Lipid profiles and blood sugar levels should also be determined in the appropriate patients.

BIOMARKERS

A number of biomarkers can be elevated in heart failure (Table 5). Neurohormones including natriuretic peptides,

Heart Failure: Diagnosis   TABLE 5  Biomarkers in heart failure Neurohormones • Natriuretic peptides (ANP, BNP, CNP) • Plasma renins and angiotensins • Catecholamines • Endothelins • Arginine vasopressins • Adrenomedullin Cardiac injury biomarkers • Troponins • Heart-type fatty acid binding protein • Apoptotic protein • Growth differentiating factor-15 Inflammatory markers • Tumor necrosis factor-alpha • C-reactive protein Matrix remodeling markers • Matrix metalloproteinases • Tissue inhibitors of metalloproteinases • Telopeptides and propeptides of collagen type I and III • Galectin Oxidative stress markers • Oxidized low-density lipoproteins • Myeloperoxidase • Plasma malondialdehyde • Serum uric acid

biomarkers resulting from cardiac injury, biomarkers related to cardiac remodeling and oxidative stress and inflammatory markers can be increased in heart failure. Natriuretic peptide serum levels, particularly of BNP or its counterpart aminoterminal pro-B-type natriuretic peptide (NT-proBNP), should be determined in all patients with suspected or established heart failure. The BNP was initially identified in the porcine brain, and thus it is also called brain natruretic peptide. The BNP hormone is physiologically active and is formed from the cleavage from its prohormone, proBNP. The N-terminal fragment, NT-proBNP is concurrently released into circulation. The NT-proBNP is not physiologically active, but it has a longer half-life of elimination; thus, it can be measured for a longer period than BNP. The measurement of serum BNP and NT-proBNP is most useful in distinguishing between cardiac and noncardiac dyspnea. In patients with noncardiac dyspnea, the BNP levels are considerably lower than in patients with cardiac dyspnea.28 In patients with cardiac dyspnea, the BNP levels are usually higher than 400 pg/mL. When the BNP concentrations are between 100 pg/mL and 400 pg/mL, the specificity and sensitivity for diagnosis of heart failure are not high. In patients presenting in the emergency care unit, the accuracy of measurement of

31

32

Manual of Heart Failure

BNP was superior to that of clinical judgment (Fig. 19). The combination of clinical judgment and measurement of BNP did not improve the diagnostic accuracy.29 In patients with overt heart failure, the BNP levels are higher than those with asymptomatic left ventricular dysfunction (Fig. 20). The levels of serum concentration of BNP are directly related to the severity of congestive heart failure. Both in males and females, the BNP levels progressively increase with the increasing severity of NYHA functional class (Fig. 21). It should be appreciated that the level of natriuretic peptides can be elevated in absence of overt heart failure. In patients with acute coronary syndromes, stable angina due to coronary artery disease, valvular heart disease, paroxysmal atrial fibrillation, isolated atrial enlargements and left ventricular hypertrophy (Table 5). Furthermore, the levels of BNP and NT-proBNP are also related to the age and genders. It is higher in elderly females than in younger males.30 In patients with obesity and increased body mass index BNP and NT-proBNP levels are lower than in nonobese patients.31-33 Thus, in these patients with normal levels of these natriuretic peptides do not exclude heart failure. Furthermore, despite lower plasma levels of BNP in obese patients, worse prognosis is observed with higher plasma BNP levels within any body mass index category.34 The mechanisms for decreased levels of natriuretic peptides in obese subjects have not been elucidated. Increased clearance and decreased production are possible mechanisms.

FIGURE 19: The B-type natriuretic peptide (BNP) levels in patients presenting to the emergency department with dyspnea are illustrated. The measurement of BNP levels was superior to clinical judgment. (Source: McCullough PA, Nowak RM, McCord J, et al. B-Type Natriuretic Peptide and Clinical Judgment in Emergency Diagnosis of Heart Failure: Analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002;106:416, with permission)

Heart Failure: Diagnosis

FIGURE 20: The BNP levels in patients presenting with dyspnea are illustrated. The BNP levels were higher in patients with overt systolic heart failure compared to those with asymptomatic left ventricular dysfunction and controls (Source: Modified from Maisel AS et al. N Engl J Med. 2002;347:161)

FIGURE 21: The relations between BNP levels and the severity of heart failure. Both in men and women, BNP levels increase with increasing NYHA class (Source: Modified from Maisel AS et al. N Engl J Med. 2002;347:161-7)

In renal failure the levels of BNP and NT-proBNP are higher than those of patients without renal failure.35 The BNP is cleared by the receptor mediated binding and removal, by enzymatic degradation by neutral endopeptidase and also by passive renal excretion.36,37 Thus, the glomerular filtration rate is inversely related to BNP concentrations. The NT-proBNP is entirely cleared by kidney and its plasma concentrations are elevated with renal failure alone. In a review

33

34

Manual of Heart Failure

of 599 patients with a serum creatinine 2.5 mg/dL or less, the levels of NT-proBNP were correlated with estimated glomerular filtration rate. The sensitivity and specificity for diagnosis of heart failure were 85% and 88% for those with glomerular filtration rate 60 mL/min/1.73 m2 and 89% and 72% in those with less than 60 mL/min/1.73 m2.35 Troponins I and T are cardiac specific regulatory proteins.38 After myocardial damage they are released into circulation and their levels can be detected within 3–12 hours of myocardial injury. The levels of troponins reflect the extent of myocardial injury. The troponins can be detected for 5–14 days after the initial insult. The elimination time is substantially prolonged in presence of renal failure.39 Troponins are released in patients with chronic heart failure even in absence of coronary artery disease.40 Troponins are also elevated in patients with acute decompensated heart failure.41 Myocyte damage is the principal mechanism for the elevated troponins in heart failure.42 Stretching of cardiac myocytes may cause transient elevation of troponins43 due to loss of cell membrane integrity. This mechanism may explain transient increase in troponins in marathon runners and it can occur in absence of myocyte loss. There are noncardiac causes of elevation of troponins.44 In patients with renal failure, the cardiac troponins levels are increased. In patients with heart failure and renal dysfunction, decreased renal clearance and increased production contribute to increased levels of troponins. There are methodological causes of elevated troponins. For example, in patients with rheumatoid arthritis or history of mononucleosis the presence of antibodies may interfere with the assay.43 The cardiac troponins levels may be increased in patients with myocarditis, nonischemic dilated cardiomyopathy, and isolated chronic right heart failure. It can also be elevated in patients with sepsis, and pulmonary embolism, and following coronary angioplasty (procedural myocardial infarction). It should be appreciated that irrespective of the cause of elevated troponins, the long-term prognosis is worse in these patients compared to those with normal troponins levels.45 In clinical conditions in which cardiac specific troponins levels may be increased are summarized in Table 6. Cystatin C is an endogenous biomarker which is being used to assess renal function and it has been reported to be a more sensitive marker for detection of renal dysfunction than glome­ rular filtration rate.46 The prognosis of patients with elevated cystatin C is worse than those with normal cystatin C levels.47 It is also a risk factor for developing heart failure.48

Heart Failure: Diagnosis   TABLE 6  Elevated B-type natriuretic peptide (BNP) without clinical heart failure • Acute coronary syndromes • Chronic stable angina • Left ventricular hypertrophy • Asymptomatic LV dysfunction • Isolated left atrial enlargement • Paroxysmal atrial fibrillation • Renal failure • Valvular heart disease • Very elderly, particularly females   TABLE 7  Clinical conditions in which cardiac troponins may be elevated • Heart failure • Acute coronary syndromes • Chronic ischemic heart disease • Isolated right ventricular failure • Acute pulmonary embolism • Chronic—precapillary pulmonary arterial hypertension • Myopericarditis • Periprocedural (angioplasty) • Renal failure

Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to be a predictor of increased risk of development of worsening heart failure.49 However its diagnostic and prognostic values compared to other biomarkers have not been clearly established. Although a large number of biomarkers are elevated in heart failure, for its diagnosis, only measurement of BNP or NT-proBNP is necessary. The ACC/AHA guidelines for indi­ cations of measurement of natriuretic peptides are summarized in Table 7. Myeloperoxidase, a leukocyte derived enzyme, has been reported to play a mechanistic role for development of heart failure. Increased plasma levels of myeloperoxidase was associated with more severe symptoms diastolic dysfunction and higher clinical events.50 Inflammatory and oxidative biomarkers have been investigated in patients with heart failure.51 The C-reactive protein has been used to distinguish between valve disease and heart failure.51 In the Val-Heft trial, the higher levels of C-reactive protein were associated with more severe symptoms and worse prognosis.

35

36

Manual of Heart Failure

EXERCISE TESTS

Reduced exercise tolerance is one of the major symptoms of heart failure. Although exercise tests are not necessary for the diagnosis of heart failure, they are useful to assess the functional class and prognosis. The NYHA classification is most frequently used to determine the functional class (Table 8). The prognosis is worse in class IV patients than in patients in classes II and III. Several methods can be used to assess exercise capacity. One method is cardiopulmonary exercise test.50 During cardio­ pulmonary exercise test, peak exercise capacity is determined which is defined as the maximal ability of the cardiovascular system to deliver oxygen to the exercising muscles. Measure­ ment of oxygen uptake (VO2), carbon dioxide production (VCO2) and minute ventilation during cardiopulmonary test allow quantitative measurement of exercise capacity (see the Chapter 9: Cardiopulmonary Exercise Testing and Training in Heart Failure). The ventilatory threshold formally called anaerobic threshold can be used to distinguish between noncardiac and cardiac   TABLE 8  ACC/AHA and HFSA guidelines on the use of natriuretic peptide measurement in patients with heart failure ACC/AHA 2009 Heart Failure Guideline Update

HFSA 2006 Practice Guideline: Acute Heart Failure Diagnosis

Measurement of natriuretic peptides [B-type natriuretic peptide (BNP) and NT-proBNP] can be useful in the evaluation of patients presenting the urgent care setting in whom the clinical diagnosis of heart failure is uncertain. Measurement of natriuretic peptides (BNP and NT-proBNP) can be helpful in risk stratification (Level of evidence: A)

The diagnosis of decompensated heart failure should be based primarily on signs and symptoms (Level of evidence: C)

The value of serial measurements of BNP to guide therapy for patients with heart failure is not well established

When the diagnosis is uncertain, determination of plasma BNP or NT-proBNIP concentration should be considered in patients being evaluated for dyspnea who have signs and symptoms compatible with HF (Level of evidence: A) The natriuretic peptide concentration should not be interpreted in isolation, but in the context of all available clinical data bearing on the diagnosis of HF

Heart Failure: Diagnosis

dyspnea. In patients with noncardiac dyspnea, fatigue occurs before the ventilatory threshold is reached.50 Maximal exercise testing with measurement of maximal oxygen consumption (VO2 max) is frequently used to identify patients referred for cardiac transplantation or other treatments for advanced heart failure.5

SIX-MINUTE WALK TEST

The six-minute walk test measures the total distance that a patient can walk on the level surface with their maximal capacity, in six minutes. It is being increasingly used in clinical trials as well as in clinical practice to assess the functional capacity of a patient with heart failure.51-55 This test is most applicable to distinguish between patients with NYHA classes III and IV heart failure. It correlates well with the NYHA functional class for the assessment of prognosis but correlates less well, with VO2 particularly in patients in the NYHA functional classes I and II. It should be appreciated that exercise test is not essential for the diagnosis of heart failure but it is useful to assess the exercise capacity and prognosis. During follow-up evaluation, a six-minute walk test along with measurements of natriuretic peptides is commonly employed to assess efficacy of interventions particularly in clinical trials. For routine follow-up of patients, however, exercise tests or measurements of natriuretic peptides are not necessary and only clinical evaluations appear to be adequate.

CORONARY ARTERIOGRAPHY

In patients with heart failure who present with chest pain, coronary arteriography may be considered if the etiology of chest pain remains uncertain and evaluation for obstructive coronary artery disease has not been done previously.5 It should be also considered in patients who present with symptoms of heart failure without chest pain and have known or suspected coronary artery disease.5 Presently in many institutions, multi-slice contrast computed tomographic coronary angiography (CTA) is being performed instead of invasive coronary arteriography in patients with heart failure with similar clinical presentations. However the reliability of the contrast CTA has not been firmly established.

MYOCARDIAL ISCHEMIA

In patients with heart failure, with known or suspected coronary artery disease presence of myocardial ischemia should be assessed. The many noninvasive imaging techniques are available for the detection of myocardial ischemia. Pharma­

37

38

Manual of Heart Failure

cologic or exercise stress thallium or Tc-99m sestamibi tomographic perfusion imaging can demonstrate reversible perfusion defects which indicate myocardial ischemia (Fig. 22). Positron emission tomography with the use of fluoro­ deoxyglucose to assess myocardial metabolism and a blood flow agent, such as rubidium, can also demonstrate myocardial ischemia and viability (Fig. 23). Cardiac magnetic resonance imaging (CMRI) with the use of contrast agent, such as gadolinium, can demonstrate myocardial fibrosis (Fig. 24). Dobutamine stress echocardiography can be used for the diagnosis of myocardial ischemia (Fig. 25). With low dose dobutamine, thickening of the myocardium along with enhanced wall motion occurs. With a larger dose, wall motion abnor­ malities and thinning of the myocardial segments occur.

ENDOMYOCARDIAL BIOPSY Endomyocardial biopsy should not routinely be performed for the diagnosis of the etiology of heart failure. However, when a specific cause such as giant cell myocarditis or

FIGURE 22: Gated perfusion single photon emission computed tomography dual isotope imaging using thallium-201 (rest, even rows) technetium-99m sestamibi (stress-related, odd rows) to detect the presence and extent of ischemic myocardium. The first four rows from the top show short axis slices from apex (left) to base (right). Rows 5 and 6 show vertical long axis slices from septum (left) to lateral wall (right) and rows 7 and 8 show horizontal long axis slices from inferior wall (left) to anterior wall (right). A large reversible perfusion defect in the anterolateral wall of the left ventricle (left anterior descending coronary artery territory) is evident, indicating the presence of ischemic myocardium (Source: Dr Eli Botvinick, University of California/San Francisco)

Heart Failure: Diagnosis

cardiac amyloidosis is suspected, endomyocardial biopsy is indicated. It is also indicated for the diagnosis of fulminant myocarditis. Endomyocardial biopsy can be used to assess presence and degree of myocardial fibrosis (Fig. 26).5 Endomyocardial

FIGURE 23: Radionuclide (scintigraphic) evaluation of the presence of ischemic but viable myocardium by positron emission tomography (PET) is illustrated. Short axis slices (rows 1–4), vertical long axis slices (rows 5 and 6), and horizontal long axis slices (rows 7 and 8) are shown. The resting perfusion images with rubidium-82 (rows 1, 3, 5, and 7) demonstrate a large lateral perfusion defect, but other areas take up rudium-82 indicating that these myocardial segments are perfused and viable. The fluor-deoxyglucose images (rows 2, 4, 6 and 8) show complementary uptake which indicates active myocardial metabolism and thus viability. (Source: Dr Eli Botvinick, University of California/San Francisco)

FIGURE 24: Cardiac magnetic resonance imaging with the use of the contrast gadolinium in a patient with heart failure is illustrated. The delayed enhancement image shows area of myocardial fibrosis (arrows)

39

40

Manual of Heart Failure

FIGURE 25: Dobutamine stress echocardiogram in a patient with systolic heart failure is illustrated. With the low dose of dobutamine there was thickening of the anteroapical segment of left ventricle. With larger doses, there was thinning of the same segments

FIGURE 26: Endomyocardial biopsy in a patient with restrictive cardiomyopathy is illustrated. The extensive fibrosis with intact myocytes is evident (Source: JD Hosenpud. 1989)

biopsy is also useful to distinguish between restrictive cardiomyopathy and constrictive pericarditis.55,56

GENETIC STUDIES

Nonischemic dilated cardiomyopathy can be familial, and its frequency has been estimated to be about 11%.57 It should be appreciated that the true incidence of familial dilated cardiomyopathy has not been firmly established. A prospective cohort study reported a genetic abnormality to be present in approximately 2.7% of patients with familial dilated cardiomyopathy.57 Endomyocardial biopsy usually shows myocyte hypertrophy and death with replacement fibrosis.57 The guidelines recom­ mend genetic evaluation in patients with suspected nonischemic dilated cardiomyopathy.57 It should include obtaining careful family history of the patient, screening family members, genetic counseling and genetic testing.58 Approximately mutations of 30 genes have been identified in patients with familial dilated cardiomyopathy.59-62 However,

Heart Failure: Diagnosis

it remains unclear whether genetic studies provide any benefit in the management of these patients. In clinical practice routine genetic studies are not necessary.

REFERENCES

1. McKee PA, Castelli WP, McNamara PM, et al. The natural history 2. 3. 4.

5.

6. 7. 8. 9. 10. 11.

12. 13. 14.

of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441-6. Davie AP, Francis CM, Caruana L, et al. Assessing diagnosis in heart failure: which features are of any use? QJM. 1997;90:335-9. Harlan WR, Oberman A, Grimm R, et al. Chronic congestive heart failure in coronary artery disease: clinical criteria. Ann Intern Med. 1977;86:133-8. Morgan S, Smith H, Simpson I, et al. Prevalence and clinical characteristics of left ventricular dysfunction among elderly patients in general practice setting: cross sectional survey. Brit Med J. 1999;318:368-72. Hunt SA, Abraham WT, Chin MH, et al. Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Developed in collaboration with the International society for heart and lung transplantation. Circulation. 2009;119:e391-479. Marcus GM, Michaels AD, De Marco T, et al. Usefulness of the third heart sound in predicting an elevated level of B-type natriuretic peptide. Am J Cardiol. 2004;3:1312-3. Ewy GA. The abdominojugular test: technique and hemodynamic correlates. Ann Intern Med. 1998;109:456-60. Ishmail AA, Wing S, Ferguson J, et al. Interobserver agreement by auscultation in the presence of a third heart sound in patients with congestive heart failure. Chest. 1987;91:870-3. Lok CE, Morgan CD, Ranganathan N. The accuracy and interobserver agreement in detecting the gallop sounds by cardiac auscultation. Chest. 1998;114:1283-8. Marcus GM, Gerber IL, McKeown BH, et al. Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function. JAMA. 2005;293:2238-44. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the European society of cardiology. Eur Heart J. 2005;26:1115-40. Dash H, Lipton MJ, Parmley WW, et al. Estimation of pulmonary capillary wedge pressure from chest radiograph in patients with congestive cardiomyopathy. Br Heart J. 1980;44:322-39. Badgett RG, Mulrow CD, Otto PM, et al. How well can the chest radiograph diagnose left ventricular dysfunction? J Gen Intern Med. 1996;11:625-34. Knudsen CW, Omland T, Clopton P, et al. Diagnostic value of B-type natriuretic peptide and chest radiographic findings in patients with acute dyspnea. Am J Med. 2004;116:363-8.

41

42

Manual of Heart Failure 15. Collins SP, Lindsell CJ, Storrow AB, et al. Prevalence of negative chest radiography in the emergency department patient with decompensated heart failure. Ann Emerg Med. 2006;47:13-8. 16. Douglas PS, Khandheria B, Stainback RF, et al. ACCF/ASE/ASNC/ SCAI/SCCT/SCMR 2007 appropriateness criteria for transthoracic and transesophageal echocardiography: a report of the American college of cardiology foundation quality strategic directions commit­ tee criteria working group, American society of echocardiography, American college of emergency physicians, American society of nuclear cardiology, society of cardiovascular computed tomography and the society for cardiovascular magnetic resonance endorsed by the American college of chest physicians and the society of critical care medicine. J Am Coll Cardiol. 2007;50:187-204. 17. Thomas JD, Choong CY, Flachskampf FA, et al. Analysis of the early transmitral Doppler velocity curve: effect of primary physiologic changes and compensatory preload adjustment. J Am Coll Cardiol. 1990;16:644-55. 18. Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997;30:474-80. 19. Bonow RO, Bacharach SL, Green MV, et al. Impaired left ventricular diastolic filling in patients with coronary artery disease: assessment with radionuclide angiography. Circulation. 1981;64:315-23. 20. Bellenger NG, Davies LC, Francis JM, et al. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2000;2:271-8. 21. Semelka RC, Tomei E, Wagner S, et al. Interstudy reproducibility of dimensional and functional measurements between cine magnetic resonance studies in the morphologically abnormal left ventricle. Am Heart J. 1990;119:1367-73. 22. Langer C, Wiemer M, Peterschroder A, et al. Images in cardiovascular medicine. Multislice computed tomography and magnetic resonance imaging: complementary use in noninvasive coronary angiography. Circulation. 2005;112:e343-4. 23. Klein AL, Scalia GN. Constrictive pericarditis. In: Eric Topol (Ed). Textbook of Cardiovascular Medicine. Philadelphia/New York: Lippincott-Raven Publishers; 1998. pp. 639-705. 24. Leber AW, Knez A, von Ziegler F, et al. Quantification of obstructive and nonobstructive coronary lesions by 64-slice computed tomography: a comparative study with quantitative coronary angiography and intravascular ultrasound. J Am Coll Cardiol. 2005;46:147-54. 25. Raff GL, Gallagher MJ, O’Neill WW, et al. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol. 2005;46:552-7. 26. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (assessment by coronary computed tomographic angiography of individuals undergoing invasive coronary angiography) trial. J Am Coll Cardiol. 2008;52:1724-32. 27. Andreini D, Pontone G, Pepi M, et al. Diagnostic accuracy of multi­ detector computed tomography coronary angiography in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2007;49:2044-50.

Heart Failure: Diagnosis 28. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Eng J Med. 2002;347:161-7. 29. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from breathing not properly (BNP) multicenter study. Circulation. 2002;106:416-22. 30. Raymond I, Groenning BA, Hildebrandt PR, et al. The influence of age, sex, and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of general population. Heart. 2003;89:745-51. 31. Das SR, Drazner MH, Dries DL, et al. Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas heart study. Circulation. 2005;112:2163-8. 32. Mehra MR, Uber PA, Park MH, et al. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol. 2004;43:1590-5. 33. Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004;109:594-600. 34. Horwich TB, Hamilton MA, Fonarow GC. B-type natriuretic peptide levels in obese patients with advanced heart failure. J Am Coll Cardiol. 2006;47:85-90. 35. Anwaruddin S, Lloyd-Jones DM, Baggish A, et al. Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP investigation of dyspnea in the emergency department (PRIDE) study. J Am Coll Cardiol. 2006;47:91-7. 36. Cataliotti A, Malatino LS, Jougasaki M, et al. Circulating natriuretic peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling. Mayo Clin Proc. 2001;76:1111-9. 37. McCullough PA, Duc P, Omland T, et al. B-type natriuretic peptide and renal function in the diagnosis of heart failure: an analysis from the breathing not properly multinational study. Am J Kidney Dis. 2003;41:571-9. 38. Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: the present and the future. J Am Coll Cardiol. 2006;48:1-11. 39. Abbas NA, John RI, Webb MC, et al. Cardiac troponins and renal function in non-dialysis patients with chronic kidney disease. Clin Chem. 2005;51:2059-66. 40. Missov E, Calzolari C, Pau B. Circulating. Troponin I in severe congestive heart failure. Circulation. 1997;96:2953-8. 41. Peacock WF 4th, De Marco T, Fonarow GC, et al. ADHERE investigators. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008;358:2117-26. 42. Masson S, Latini R, Anand IS. An update on cardiac troponins as circulating biomarkers in heart failure. Curr Heart Fail Rep. 2010;7:15-21. 43. Jerimias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005;142:786-91. 44. Tsutamoto T, Kawahara C, Yamaji M, et al. Relationship between renal function and serum cardiac troponin T in patients with chronic heart failure. Eur J Heart Fail. 2009;11:653-8.

43

44

Manual of Heart Failure 45. Latini R, Masson S, Anand IS, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation. 2007;116:1242-9. 46. Kato K, Sato N, Yamamoto T, et al. Valuable markers for contrastinduced nephropathy in patients undergoing cardiac catheterization. Circ J. 2008;72:1499-505. 47. Manzano-Fernández S, Boronat-Garcia M, Albaladejo-Otón MD, et  al. Complementary prognostic value of cystatin C, N-terminal pro-B type natriuretic peptide and cardiac troponin T in patients with acute heart failure. Am J Cardiol. 2009;103:1753-9. 48. Taglieri N, Koenig W, Kaski JC. Cystatin C and cardiovascular risk. Clin Chem. 2009;55:1932-43. 49. Aghel A, Shrestha K, Mullens W, et al. Serum neutrophil gelatinaseassociated lipocalin (NGAL) in predicting worsening renal function in acute decompensated heart failure. J Card Fail. 2010;16:49-54. 50. Tang WH, Brenan ML, Phillip K, et al. Plasma myeloperoxidase levels in patients with heart failure. Am J Cardiol. 2006;98:796-9. 51. Nagarajan V, Tang WH. Biomarkers in advanced heart failure: diagnosis and therapeutic insights. Congestive Heart Failure. 2011;17:169-74. 52. Anand IS, Latini R, Florea VG, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005;112:1428-34. 53. McElroy PA, Janicki JS, Weber KT. Cardiopulmonary exercise testing in congestive heart failure. Am J Cardiol. 1988;62:35A-40A. 54. Roul G, Germain P, Bareiss P. Does the 6-minute walk test predict the prognosis in patients with NYHA class II or III chronic heart failure? Am Heart J. 1998;136:449-57. 55. Zugck C, Krüger C, Dürr S, et al. Is the 6-minute walk test a reliable substitute for peak oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J. 2000;21:540-9. 56. Shah MR, Hasselblad V, Gheorghiade M, et al. Prognostic usefulness of the six-minute walk in patients with advanced congestive heart failure secondary to ischemic or nonischemic cardiomyopathy. Am J Cardiol. 2001;88:987-93. 57. Elhendy A, Schinkel AF, van Domburg RT, et al. Incidence and predictors of heart failure during long-term follow-up after stress Tc-99m sestamibi tomography in patients with suspected coronary artery disease. J Nucl Cardiol. 2004;11:527-33. 58. Hosenpud JD. Restrictive cardiomyopathy. In: Zipes DP, Rowlands DJ (Eds). Progress in Cardiology. Philadelphia: Lea and Febiger; 1989. p. 91. 59. Grünig E, Tasman JA, Kücherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998;31:186-94. 60. Bharati S, Surawicz B, Vidaillet HJ Jr, et al. Familial congenital sinus rhytm anomalies: clinical and pathological correlations. Pacing Clin Electrophysiol. 1992;15:1720-9. 61. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy: a Heart Failure Society of America practice guideline. J Card Fail. 2009;15:83-97. 62. Hershberger RE, Cowan J, Morales A, et al. Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/ cardiomyopathy. Circ Heart Fail. 2009;2:253-61.

CHAPTER 3

Systolic Heart Failure

(Heart Failure with Reduced Ejection Fraction) Kanu Chatterjee

Chapter Outline • Historical Perspective –– Definitions –– Risk Factors • Ventricular Remodeling • Functional Derangements and Hemodynamic Consequences

• Initial Treatment of Systolic Heart Failure • Symptomatic Systolic Heart Failure –– Pharmacologic Treatments –– Nonpharmacologic Treatments • Follow-up Evaluation

INTRODUCTION

Heart failure is a common clinical syndrome, and its clinical presentations and etiology are protean. For example, it can be acute which is often defined when the symptoms of heart failure develop rapidly within hours or a few days. Frequently acute heart failure develops as complications of acute coronary syndromes or of valvular heart diseases. Chronic heart failure is defined when the symptoms of heart failure develop slowly in days and months, and it may be caused by myocardial, pericardial, or valvular heart diseases. Heart failures due to primary cardiomyopathies, such as hypertrophic, dilated and restrictive cardiomyopathies, are discussed in the chapters of cardiomyopathies. Systolic (Heart Failure with Reduced Ejection Fraction— HFREF) and diastolic heart failures (Heart Failure with Preserved Ejection Fraction—HFPEF) are two common clinical subsets of chronic heart failure. In this chapter systolic heart failure has been discussed.

HISTORICAL PERSPECTIVE

Existence of heart failure was known in the ancient Egyptian and Greek civilization.1-3 In India, cardiac glycosides were used several centuries BC. In the Roman literature, benefits of the plant fox gloves have been mentioned.4 Digitalis purpura was introduced by Withering in 1785.5 Nitrates were introduced for the treatment of angina in 1853. For the treatments of various types of edema, a number of pharmacologic and nonpharmacologic treatments were used before the presently available treatment modalities for heart failure were introduced in clinical practice. Bloodletting and Southey’s tubes were used for centuries. The only pharmacologic treatments for heart failure that were available in early 20th century were

46

Manual of Heart Failure   TABLE 1  Heart failure: Historical perspectives • Heart failure was known in the ancient Egyptian and early Greek civilizations • Cardiac glycosides were probably used in India several centuries BC • Reports of the benefits of foxglove exist in the Roman literature • Blood letting, the use of leeches and Southey’s tubes for treatment of edema have been used for centuries • Digitalis purpura was introduced for treatment of dropsy by Withering in 1785 • Nitrates were introduced by Hering in 1853 • Diuretics (sulfonamides) were introduced in 1920 • Mercurial diuretics were introduced in 1949 • Thiazide diuretics were introduced in 1958 • Intravenous hydralazine for the treatment of hypertensive heart failure was introduced by Judson in 1956 • Oral hydralazine for the treatment of chronic heart failure was introduced by Chatterjee, Drew and Parmley in 1976

digitalis, nitrates, sulfonamides, and mercurial diuretics. In 1956, intravenous hydralazine was introduced for the treatment of hypertensive congestive heart failure.6 Oral hydralazine therapy for chronic heart failure was first introduced in 1976.7 The few historical aspects of heart failure are summarized in Table 1. Functional differences between systolic and diastolic heart failure ware recognized by Dr Fishberg and he wrote in 1937 that diastolic heart failure results from inadequate filling of the ventricle (hypodiastolic failure) and systolic heart failure from inadequate emptying (hyposystolic failure) of the heart. DEFINITIONS Sir Thomas Lewis, in 1933, defined systolic heart failure as a condition in which heart fails to discharge its content. Professor Eugene Braunwald, in 1980, defined systolic heart failure as a pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metaboliz­ing tissues. Although these definitions provide precise pathophysiologic mechanisms, they are difficult to use in clinical practice. The clinical definition of systolic heart failure is a “syndrome which results from reduced left ventricular ejection fraction”. It should be appreciated that ejection fraction is not independent of loading conditions. A markedly reduced preload and increased

Systolic Heart Failure   TABLE 2  Risk factors for developing systolic heart failure • • • • • • •

Hypertension Coronary artery disease Diabetes Insulin resistance Smoking Cardiotoxins Family history of cardiomyopathy

afterload is associated with reduced ejection fraction without any changes in contractile function. RISK FACTORS A number of risk factors for developing systolic heart failure have been identified (Table 2). Coronary artery disease particularly a previous myocardial infarction is a major risk factor. Hypertension, obesity and diabetes are also important risk factors for developing systolic heart failure. Insulin resistance cardiomyopathy has also been identified. In these patients heart failure occurs in absence of frank diabetes and in presence of insulin resistance. The potential mechanisms are impaired phosphorylation of Akt-I, decreased inhibition of apoptosis, decreased production of nitric oxide and decreased hypertrophy and fibrosis. Use of cardiotoxins, such as chemotherapeutic agents, is a risk factor for developing systolic heart failure. The incidence of systolic heart failure in patients with a family history of dilated cardiomyopathy is higher. Smoking is also a risk factor for systolic heart failure.

VENTRICULAR REMODELING

In systolic heart failure the left ventricle is dilated and becomes more spherical. This altered shape and geometry is the principal mechanism for secondary mitral regurgitation. The increase in transverse diameter is greater than that of longitudinal axis. The distance between the anteromedial and posterolateral papillary muscles increases causing misalignment of the papillary muscles, chordae tendineae and mitral valve leaflets. Thus, the secondary or functional mitral regurgitation occurs without any structural changes of the mitral valve leaflets. The left ventricular wall thickness either remains unchanged or decrease compared to normal controls (Fig. 1).8,9 The left ventricular cavity size is substantially increased. As a result, left ventricular wall stress is increased which contributes to reduced ejection fraction. There is an inverse relation between wall stress and ejection fraction.

47

48

Manual of Heart Failure

FIGURE 1: The left hand panel illustrates the transverse sections of the heart in a heart and in severe systolic heart failure, with diastolic heart failure. In the right hand panel two-dimensional echocardio­graphic cross-sectional views of the heart are shown. Compared to normal, in systolic heart failure, the left ventricle is dilated and spherical. The wall thickness is not increased. In diastolic heart failure, the left ventricular cavity is smaller than normal, and the left ventricular wall thick­ness is markedly increased (Source: MA Konstam. JCF. 2003;9:1-3)

Both end-diastolic and end-systolic volumes are increased, but there is a greater increase in end-systolic than in end-diastolic volumes which is contributory to reduced ejection fraction. In systolic heart failure left ventricular hypertrophy is eccentric. The calculated left ventricular mass is increased, but as the cavity size is also increased, the cavity/mass ratio is increased. The echocardiographic left ventricular volumes, ejection fraction and mass in patients with systolic heart failure compared to normal controls are summarized in Table 3.10 In systolic heart failure synchronous contraction and relaxation of left ventricular walls are absent or impaired in a substantial number of patients.11,12 This mechanical dyssyn­ chrony occurs most frequently when the QRS duration is prolonged such as in left bundle branch block or in intra­ ventricular conduction defect of left bundle branch block type. It should be appreciated that mechanical dyssynchrony can occur in presence of narrow QRS complex. Some of the features of left ventricular remodeling in systolic heart failure are summarized in Table 4.

Systolic Heart Failure   TABLE 3  Systolic heart failure

Controls

SHF

• • • • •

102 46 54 125 1.49

192 137 31 230 1.22



LVEDV LVESV LVEF LVM LVM/V

(Abbreviations: LVEDV: Left ventricular diastolic volume; LVESV: Left ventricular end systolic volume; LVEF: Left ventricular ejection fraction; LVM: Left ventricular mass; LVM/V: Left ventricular mass/volume ratio)   TABLE 4  Systolic heart failure remodeling • • • • • • • • •

Usually eccentric hypertrophy Disproportionate increase in ventricular cavity size Increased ventricular mass Cavity/mass ratio increased Wall thickness—decreased or unchanged Increased wall stress Reduced ejection fraction Altered ventricular shape and geometry Frequent mechanical dyssynchrony with or without electrical dyssynchrony

The changes in the myocytes and myocardial architecture are illustrated in Figure 2.9 In systolic heart failure the myocyte length is increased without any change in the thickness of the myocytes and the myocyte length/width ratio is increased. The sarcomeres are replicated in series. The myocardial architecture is also abnormal. There is an increase in collagen volume and fibrosis. The collagen bundles surrounding the myocytes are thinner than normal, and there is degradation and disruption of fibrillar collagen.9 The total collagen content, however, is normal and not different from that in diastolic heart failure.13 The collagen cross links are decreased in systolic heart failure. In general the matrix metalloproteinases are increased and the endogenous tissue inhibitors of metalloproteinase are decreased.14,15 These changes in metalloproteinases metabolism may be contributory to the collagen disruption in systolic heart failure. Increased circulating levels of amino-terminal propeptide of type III procollagen have been observed in systolic heart failure which is another evidence of abnormal collagen metabolism.16 In human left ventricular myocardial biopsy samples, titin isoforms were measured.13 The N2BA isoform is more compliant collagen molecule than the N2B isoform. The

49

50

Manual of Heart Failure

FIGURE 2: Changes in myocytes (left) and in extracellular matrix (right) in systolic heart failure resulting from dilated cardiomyopathy and diastolic heart failure resulting from pressure overload compared with normals in the animal models are illustrated. The myocyte length is increased in DCM-Systolic heart failure. In POH-Diastolic heart failure, the myocyte is thicker. In systolic heart failure, there is collagen disruption. In diastolic heart failure, the collagen bundles are thicker (Source: GP Aurigema, et al. Circulation. 2006;113:296-304, with permission)

N2BA/N2B ratio of collagen isoforms is increased in systolic heart failure.13,17 The mechanical and electrical functions of the myocytes of patients with severe systolic heart have been studied.17 The tissue was obtained from the explanted heart. The developed force of the myocytes was decreased along with impaired relaxation. The action potential duration was prolonged. There was a blunted rise in intracellular calcium transient following depolarization suggesting slower delivery of calcium to the contractile proteins. During repolarization, the fall of intracellular calcium was also slower indicating slower reuptake of calcium by sarcoplasmic reticulum.18 It is generally agreed that myofibrillar function is depressed in heart failure. Upregulation of beta-myosin heavy chain and downregulation of alpha-myosin heavy chain have been observed.19 In systolic heart failure there is loss of myocytes by necrosis and apoptosis. Necrosis results from myocyte injury when cell membrane is disintegrated. Following cell membrane rupture, the intracellular organelles and intracellular proteins are exposed which also promote inflammatory response. There is also leakage of intracellular calcium causing calcium overload, which is associated with enhanced ischemia, worsening heart failure and propensity for developing arrhythmias. Necrotic myocyte death occurs in acute coronary syndrome, and in ischemic and nonischemic dilated cardiomyopathy.

Systolic Heart Failure   TABLE 5  Systolic heart failure Myocyte Hypertrophy Apoptosis Necrosis Fibrosis Ca regulation MMPs/TIMPs Collagen Cross-links Titin isoforms N2BA/N2B

+ + + + – + – +

+: Increased; –: Decreased (Abbreviations: Ca: Calcium; MMPs: Matrix metalloproteinases; TIMPs: Tissue inhibitors of metalloproteinases)

The “troponin leaks” provide evidence for myocyte injury irrespective of clinical circumstances when it occurs. Apoptosis also called programmed cell death is observed in systolic heart failure. The apoptotic cells are preprogrammed to be selectively eliminated. There is no cell swelling in apoptosis and the cell membrane remains intact. The nuclei are dense and fragmented. There is no pericellular inflammatory response. Both in ischemic and non-ischemic dilated cardiomyopathy, apoptopic cell death occurs. There is activation of cell death pathway and suppression of cell survival pathway.20 The cellular and molecular changes in systolic heart failure are summarized in Table 5. It has been suggested that in systolic heart failure oxidative stress contributes to the progression of heart failure. In oxidative stress, the free radicals, such as superoxide anion and hydrogen peroxide, are present in relative excess. These highly reactive molecules are referred as reactive oxygen species. The oxidative stress can promote atherosclerosis, myocyte necrosis and apoptosis.21 Superoxide anion has been reported to reduce calcium-activated myocardial force development.22 In animal studies, oxidative stress have been shown to contribute to development of heart failure both due to increased production of free radicals and decreased availability of free radical scavengers.23,24 In rabbits with pacing induced heart failure, increased oxidative stress and myocyte apoptosis has been reported.25 In patients with chronic systolic heart failure an increase in oxidative stress has been observed. Both in patients with ischemic and non-ischemic dilated cardiomyopathy, increased plasma levels of malondialdehyde, a marker of lipid peroxi­ dation, have been reported.26,27 Another marker of oxidative

51

52

Manual of Heart Failure   TABLE 6  Neurohormonal activation in systolic heart failure •

Vasoconstrictive, antinatriuretic and mitogenic neurohormones: — Norepinephrine, epinephrine, dopamine — Renin and angiotensins — Aldosterone — Endothelin — Arginine vasopressin — Insulin — Cortisol — Growth hormone — Tumor necrosis factor-alpha — Interleukin-6 — Cardiotropin-I

•

Vasodilatory, natriuretic and antimitogenic neurohormones: — Atrial and B-type natriuretic peptides — Bradykinins — Prostaglandins — Neuropeptide Y — Adrenomedullin — Urodilantin — Endothelium derived relaxing factors — Nitric oxide

stress, oxidized low density lipoprotein is elevated in patients with chronic heart failure and it is associated with worse prognosis.28 Serum uric acid levels which reflects the degree of xanthine oxidase activation is elevated in patients with chronic heart failure and its level is directly proportional to the severity of symptoms.29 It should be appreciated that the treatments designed to decrease oxidative stress have not been found effective in prospective randomized clinical trials.30 In systolic heart failure plasma levels of many neuro­ hormones are elevated (Table 6). Neurohormonal activation has been shown to be a major contributing mechanism for progression of heart failure. The activation of vasoconstrictive, antinatriuretic and antimitogenic neurohormones, such as catecholamines, angiotensins, aldo­ sterone, vasopressin, endothelins and cytokines, is associated with adverse ventricular remodeling. The compensatory vasodilatory, natriuretic and antimitogenic neurohormones, such as natriuretic peptides, prostacyclins and endothelium derived relaxing factors and nitric oxide, are also increased. If a balance of these two systems is maintained, the progression of heart failure can be prevented. However, if there is more activation of neurohormones with the potential to produce adverse remodeling, progression of heart failure occurs (Fig. 3) (Table 7). Angiotensin II is a potent vasoconstrictive, proinflammatory, mitogenic and prothrombotic hormone. It promotes athero­ sclerosis, and causes vascular smooth muscle cell proliferation

Systolic Heart Failure

FIGURE 3: Neurohormonal activation in systolic heart failure is illustrated. The changes in plasma norepinephrine, rennin activity, atrial natriuretic factor and vasopressin in patients with asymptomatic left ventricular systolic dysfunction (prevention) and with overt clinical heart failure (treatment) compared with normal controls are illustrated. There is increasing levels of these neurohormones in patients with systolic dysfunction (Source: GS Francis, et al. Circulation. 1990;82:1724-9, with permission)   TABLE 7  Adverse effects of neurohormonal activation • • • • • • • •

Adverse hemodynamic effects Vascular remodeling Ventricular remodeling — Myocyte hypertrophy — Extracellular matrix changes Promotes atherothrombosis Increased oxidative stress Endothelial dysfunction Myocardial necrosis Apoptosis

and increases vascular intimal thickening. Angiotensin also promotes release of aldosterone which is associated with abnormal collagen synthesis and fibrosis. Angiotensins contri­bute to myocyte necrosis and apoptosis. Existence of tissue renin-angiotensin system in the myocardium has been

53

54

Manual of Heart Failure

documented and its activation is associated with myocardial hypertrophy and failure.31 The adverse vascular and cardiac effects of angiotensin are mediated by activation of angiotensin subtype 1 (AT1) receptors. Activation of angiotensin subtype 2 (AT2) receptors produce counter regulatory effects such as vasodilatation, decreased vascular smooth muscle cell proliferation and decreased myocardial hypertrophy. Both angiotensin I and angiotensin II can generate angiotensin-(I-VII) which also cause vasodilatation and decrease growth.32 It also promotes formation and release of vasodilator prostaglandins and nitric oxide. Endothelins are potent vasoconstrictors and are produced by vascular smooth muscle cells.33a,b Although its blood levels are increased in chronic systolic heart failure, the significance of increased endothelin remains uncertain.34 Endothelin is produced by conversion of big endothelin-1 by an endothelinconverting enzyme. Endothelin synthesis and release are promoted by angiotensin II, norepinephrine, growth factors and oxidized low density lipoproteins.35 Endothelin produces its pathophysiologic effects by stimulating endothelin A and B receptors. The activation of endothelin A receptors is associated with increased development of vascular smooth muscle cells tension, cell proliferation and hypertrophy. The endothelin-B receptor stimulation is associated with vasodilatation probably due to increased production of nitric oxide.36 It should be appreciated that endothelin antagonists are not effective for the treatment of left heart failure but they are approved for the treatment of precapillary pulmonary hypertension. The plasma arginine vasopressin levels are increased in patients with heart failure and the levels are higher in patients with symptomatic than in patients with asymptomatic left ventricular systolic dysfunction (Fig. 3).36 Arginine vasopressin is a nonapeptide and it is secreted from the posterior pituitary gland. The stimuli for the secretion are a fall in blood pressure, a reduction in plasma volume, arterial underfilling and a rise in plasma osmolality. It should be appreciated that in heart failure release of arginine vasopressin is not mediated by changes in plasma osmolality (Fig. 4).37 In congestive heart failure, release of arginine vasopressin appears to be due to activation of baroreceptors.38 Whether the patients are on diuretic therapy or not, the plasma levels of arginine vasopressin remain unchanged with changes in plasma osmolality. The arginine vasopressin exerts its pathophysiologic effects by activation of vasopressin 1 and 2 receptors. The activation of V1a receptors which are present in the vascular bed is associated with increased tension of the vascular smooth muscle cells and vasoconstriction. Systemic vascular resistance is increased which is associated with increased left ventricular afterload

Systolic Heart Failure

FIGURE 4: The changes in plasma arginine vasopressin in relation to changes in plasma osmolality in congestive heart failure are illustrated. Irrespective of diuretic therapy lack of correlation between arginine vasopressin levels and plasma osmolality is evident (Source: Modified from Szatalowics, et al. N Engl J Med. 1981;305:263-6)

which impairs left ventricular pump function.39 Systemic venoconstriction is associated with increased left ventricular preload. Coronary arterial vasoconstriction can induce myocardial ischemia. The V1a receptors are also present in the myocardium and the activation of myocardial V1a receptors is associated with myocardial hypertrophy. The V1b receptors are present in the anterior pituitary gland and its stimulation results in increased release of adreno­ corticotrophic hormone and aldosterone. Increased aldosterone results in adverse vascular remodeling, myocardial hypertrophy and fibrosis. There is also impaired renal sodium and water clearance. Vasopressin-2 receptors are located in renal distal tubule and collecting ducts. Its stimulation is associated with activation of water channel aquaporin-2.40 There is decreased water permeability in the collecting duct resulting in water retention, volume overload and hyponatremia. The pathophysiologic effects of arginine vasopressin in heart failure are summarized in Table 8. In systolic heart failure, sympathoadrenergic activity is increased. The plasma levels of norepinephrine are substantially elevated (Table 9) (Fig. 3).36,41,42 The level of norepinephrine is higher in patients with more severe heart failure. There is not only increased synthesis and release of norepinephrine, but there is also decreased norepinephrine reuptake by the presynaptic neuronal nerve endings. Increased

55

56

Manual of Heart Failure   TABLE 8  Arginine vasopressin (AVP) in heart failure AVP* is a nonapeptide secreted from the posterior pituitary gland •

Stimuli for secretion: – A decrease in blood pressure – A reduction in circulating blood volume – Arterial underfilling – A rise in plasma osmolality

•

Activation of V1a receptors – Vascular bed Systemic arterial vasoconstriction Increased SVR, increased LV afterload Systemic venoconstriction—increased preload Coronary vasoconstriction—myocardial ischemia – Myocardium Myocyte hypertrophy

•

Activation of V1b receptors (anterior pituitary) – Increased release of ACTH – Increased release of aldosterone Adverse vascular remodeling Myocardial hypertrophy and fibrosis Impaired renal water and sodium excretion

•

Activation of V2 receptors in renal collecting ducts and distal tubule – Activation of water channel aquaporin-2 – Decreased water permeability in collecting duct – Increased water retention – Volume overload – Hyponatremia

*Also known as antidiuretic hormone (ADH)   TABLE 9  Circulating catecholamines and hemodynamics in patients with and without heart failure (HF) Norepinephrine (pg/mL) Dopamine (pg/mL) Epinephrine (pg/mL) SWI (gm/m2) PCWP (mm Hg)

Patients with HF (n = 63)

Patients without HF (n = 26)

665 + 510* 407 + 405† 73 + 98NS 21 + 9* 27 + 8*

184 + 135 197 + 259 55 + 73 53 + 13 11 + 3

*p < 0.01 †p < 0.05

plasma norepinephrine levels are associated with increased systemic vascular resistance which enhances left ventricular afterload which, may cause impairment of left ventricular pump function. Increased sympathetic activity also causes systemic venoconstriction which increase left ventricular preload which may be initially beneficial to maintain stroke volume. However, increased ventricular volumes are associated with increased wall

Systolic Heart Failure

stress, which decreases forward stroke volume. Furthermore, due to its direct toxic effects, there is myocyte necrosis. It may also cause myocyte hypertrophy and contribute to adverse ventricular remodeling. In congestive heart failure, increased centrally mediated muscle sympathetic nerve activity has been demonstrated by intraneural recordings which also indicates increased systemic adrenergic activity.43 That in systolic heart failure cardiac adrenergic activity is increased has been documented by studies measuring cardiac norepinephrine balance.44,45 The concentration of norepi­ nephrine in the coronary sinus venous blood is higher than its concentration in the coronary arterial blood. The calculated cardiac norepinephrine balance is approximately 40-fold higher in patients with heart failure than that in patients without heart failure. Myocardial oxygen demand is increased with increased cardiac adrenergic activity which may induce myocardial ischemia and may be contributory to myocyte necrosis and adverse ventricular remodeling. There is also an increase in renal sympathetic activity which is associated with efferent renal arterial vasoconstriction which initially maintain glomerular filtration rate. However, when compensatory mechanisms fail, glomerular filtration rate declines. Activation of sympathetic adrenergic system is an independent prognostic factor in patients with congestive heart failure. The higher the plasma norepinephrine level, the worse is the prognosis.46 The analysis of approximately 4,000 patients, reported that the plasma norepinephrine levels, equal to or higher than 572 pg/mL was associated with a significantly higher mortality at 2 years compared to patients with normal plasma norepinephrine levels.46,47 Aldosterone is a mineralocorticoid synthesized in zona glomerulosa of adrenal cortex. It is a trophic hormone for renin-angiotensin. It binds with the nuclear receptors in the renal tubular cells and myocardium. Aldosterone level is elevated in systolic heart failure (Fig. 5). It promotes inflammation and increases oxidative stress. It also increases collagen synthesis and fibrosis. Aldosterone decrease arterial compliance which is associated with increased left ventricular afterload. Aldosterone impairs endothelial function and promotes atherosclerosis. It also promotes thrombosis by increasing plasminogen activator inhibitor-1 and inhibiting tissue plasminogen activator. Increased levels of aldosterone are associated with water and salt retention and worsening heart failure. There is increased loss of potassium and magnesium which is associated with increased risks of arrhythmia. The potential adverse effects of aldosterone are summarized in Table 7 (Fig. 6).

57

58

Manual of Heart Failure

FIGURE 5: The changes in plasma rennin activity and aldosterone levels in patients with systolic heart failure are illustrated

FIGURE 6: The effects of aldosterone on ventricular remodeling (Source: Modified from Tsutamoto, et al. J Am Coll Cardiol. 2001;37:1228-33)

Activation of cytokines, such as tumor necrosis factor-alpha and interleukin-1, may be contributory to the progression of heart failure. These cytokines have the proinflammatory and prothrombotic properties and they are also produced in the myocardium. These cytokines may cause direct toxic effects on the myocytes and cause myocyte necrosis and apoptosis. They also exert adverse effects on extracellular matrix and promote adverse ventricular remodeling.48 Increased levels of these cytokines may cause impairment of left ventricular function. It should be appreciated, however, that any beneficial effect of pharmacologic interventions to counteract the adverse effects of these inflammatory cytokines has not been documented. The counter regulatory neurohormones are activated as a compensatory mechanism to reduce the risks of adverse left ventricular remodeling. The brain natriuretic peptides (B-type)

Systolic Heart Failure

and atrial natriuretic peptides are activated to counteract the deleterious effects of renin-angiotensin and adrenergic systems on ventricular and atrial remodeling. The natriuretic peptides decrease myocyte hypertrophy, fibrosis and collagen synthesis. Atrial natriuretic peptides decrease atrial remodeling and B-type natriuretic peptides reduce adverse ventricular remodel­ ing. In physiologic conditions, the natruretic peptides promote diuresis and improve renal function. However, in heart failure, effects of natriuretic peptides on renal function is markedly blunted. The vasodilator prostacyclins, nitric oxide and endogenous antioxidants are increased in heart failure, and they have the potential for decreasing adverse ventricular remodel­ing. The other neurohormones, such as adreno­medullin, which also has the potential to reduce progression of heart failure, have not been adequately investigated. The impaired left ventricular systolic function can establish a vicious cycle of adverse remodeling (Fig. 7). Decreased stroke volume and cardiac output activates the vasoconstrictive neurohormones, which increase left ventricular afterload. Increased afterload is associated with a further decrease in stroke volume and cardiac output and thus a vicious cycle is established. The reduced cardiac output compromises renal perfusion, which causes increased sodium and water retention, increased blood volume and increased left ventricular preload. Increased left ventricular volume without an increase in its wall thickness is associated with increased afterload which further impairs left ventricular pump function. Furthermore, these hemodynamic changes are associated with activation of sympathetic, renin-angiotensin and aldosterone systems which may cause a disproportionate increase in left ventricular afterload and preload which may cause further impairment of left

FIGURE 7: The vicious cycle of adverse left ventricular remodeling in systolic heart failure initiated by impaired systolic function is illustrated

59

60

Manual of Heart Failure

ventricular function. The vasopressin is a potent vaso­constrictor and its plasma level is increased in heart failure. There is an increase in systemic vascular resistance which decreases left ventricular systolic function. These neuro­hormonal changes also contribute to establish the vicious cycle. The ischemic heart disease is the most common cause of systolic heart failure. In acute coronary syndromes, ventricular remodeling is initiated soon after the onset of myocardial infarction. The infracted segments expand due to stretching and thinning. There is myocyte necrosis and disruption of the extracellular matrix with disorganization of the collagen fibrils in the infracted segment. There is also accumulation of inflammatory cells which release cytokines and increase oxidative stress and promotes myocyte necrosis. There is also myocyte thinning and slippage. In the remote noninfarcted segments, there is myocyte hypertrophy, which can be eccentric and concentric. There is continued myocyte loss due to necrosis and apoptosis. The disruption of the collagen matrix in the noninfarcted segments occurs allowing these segments to stretch. The net effect of these morphologic changes in infarcted and noninfarcted segments is a dilated left ventricle with an increase in ventricular volumes and altered geometry. The features of the postinfarction left ventricular remodeling are illustrated in Figure 8. It should be appreciated that the adverse left ventricular remodeling can occur despite adequate recanalization of the infarct related artery but a threshold magnitude of myocardium needs to be damaged. It is uncommon for the adverse remodeling to occur if the left ventricular ejection fraction is greater than 40% and the infarct size is relatively small.49,50

FIGURE 8: Schematic illustrations of left ventricular remodeling soon after acute myocardial infarction (stage 1) and late after myocardial infarction (stage 2) are shown

Systolic Heart Failure

FUNCTIONAL DERANGEMENTS AND HEMODYNAMIC CONSEQUENCES

The principal myocardial dysfunction in systolic heart failure is impaired left ventricular contractility. The analysis of left ventricular pressure volume loop demonstrates a rightward and downward shift of the left ventricular end-systolic pressure volume line indicating reduced contractile function (Figs 9A and B). The stroke volume declines and there is an increase in end-systolic and end-diastolic volumes. Initially, stroke volume is maintained by Frank–Starling mechanism due to increased preload. With a further deterioration of ventricular function; however, stroke volume declines and there is an increase in residual volumes. The increase in left ventricular volume is associated with increased wall stress (afterload) which causes further impairment of left ventricular systolic function. The hemodynamic consequences of impaired pump function in systolic heart failure are characterized by decreased stroke volume and cardiac output and increased left ventricular diastolic pressure. There is a passive increase in left atrial and pulmonary venous pressures which is associated with increased pulmonary artery pressure. The pulmonary arterial hypertension is predominantly post capillary. However, in chronic severe systolic heart failure, there is also an increase in pulmonary vascular resistance. This mixed type of pulmonary arterial

FIGURES 9A AND B: Schematic illustrations of left ventricular pressurevolume loops in normal individuals (A) and patients with systolic dysfunction (B) are shown. The straight dotted line is the end systolic pressure-volume line, and the curve dotted line represents the normal pressure volume relation in diastole. The area within the loop represents left ventricular stroke work. In patients with systolic heart failure, the end systolic pressure-volume line shifts downward and to the right due to reduced contractile function. There is a reduction in stroke volume and an increase in end systolic and end diastolic volumes. Initially, stroke volume is maintained by Frank–Starling mechanism due to the increased to end diastolic volume (preload). With further progression of heart failure, there is reduction in stroke volume and cardiac output

61

62

Manual of Heart Failure

hypertension increases right ventricular afterload and induce right ventricular failure. Thus there is an increase in systemic venous pressure with its hemodynamic consequences such as lower extremity edema.

INITIAL TREATMENT OF SYSTOLIC HEART FAILURE

The risk factors for developing heart failure (Stage A) are hypertension, diabetes, obesity, coronary artery disease, insulin resistance, male gender and age. Except age and gender, the other risk factors are modifiable and every effort should be made to treat these risk factors (Table 10). The patients in stage B have structural heart disease and have asymptomatic left ventricular systolic dysfunction. In time, these asymptomatic patients develop overt heart failure. The rate of development of symptomatic heart failure in untreated patients is approxi­mately 10% per year.51 Furthermore the mortality in the untreated patients is much higher. In the studies of left ventricular dysfunction (SOLVD) trial, the yearly mortality rate was about 5% per year in patients with asymptomatic left ventricular systolic dysfunction.51 Large clinical trials have demonstrated that treatment with angiotensinconverting enzyme inhibitors in these patients is associated with decreased cardiovascular mortality and morbidity.51 In post-infarction patients there is a substantial reduction in total mortality, cardiovascular mortality and the risk of developing heart failure with treatment with angiotensin-converting enzyme inhibitors compared to placebo.52 The beta-blocker therapy also decreases morbidity and mortality in patients with acute coronary syndromes irrespective of the symptomatic and functional status.53 In the carvedilol post-infarction survival controlled evaluation (CAPRICORN) trial, a large number of patients with left ventricular ejection fraction of 40% or less   TABLE 10  Systolic heart failure: Management • • • •

Stage A—treat hypertension   Encourage smoking cessation   Treat lipid disorders   Encourage regular exercise   Discourage alcohol abuse   Discourage illicit drug use   Angiotensin inhibition in appropriate patients Stage B—treatment for stage A Angiotensin inhibition in appropriate patients Beta-blockers in appropriate patients

Systolic Heart Failure

were randomized to receive carvedilol or placebo. The patients were already being treated with angiotensin-converting enzyme inhibitors and received appropriate reperfusion therapy. There was a significant reduction in all cause mortality, cardiovascular mortality and nonfatal myocardial infarction during follow-up of about 15 months. The majority of patients were asymptomatic in this trial.54 The treatment with aldosterone antagonist in post-infarction patients is also associated with decreased risks of developing heart failure, cardiovascular mortality, sudden cardiac death and ventricular remodeling. In the eplerenone postacute myocardial infarction heart failure efficacy and survival study (EPHESUS) trial patients following myocardial infarction with ejection fraction of 40% or less was randomized to receive placebo or eplerenone, a selective aldosterone antagonist. Treatment with eplerenone was associated with a reduction in all cause mortality, cardiovascular mortality, sudden cardiac death and adverse ventricular remodeling.55,56 The treatment of the risk factors for developing heart failure such as management of hypertension, diabetes and obesity are similar to those in patients in stage A heart failure (Table 11).57 Increased systolic and diastolic blood pressures are major risk factors for developing heart failure.58 The controlled studies have reported that adequate treatment of hypertension is associated with approximately 50% reduction of the risks of developing new heart failure.59 For the treatment of hypertension, the use of angiotensinconverting enzyme inhibitors or angiotensin receptor blocking agents are preferable to alpha adrenergic blocking agents for reduction of the risk of development of heart failure.60,61 Alpha-adrenergic blocking agents have the potential to increase the risk of heart failure. Obesity, insulin resistance and type 2 diabetes increase the risk of development of heart failure.62,63 In the type 2 diabetes hypertension, cardiovascular events and ramipril (DIABHYCAR) study, in patients with type 2 diabetes and albuminuria about 5% of patients developed heart failure, but over 30% of these patients died during follow-up period.64 The risk of developing heart failure is approximately threefold higher in women than in men with type 2 diabetes.65 In patients   TABLE 11  Systolic heart failure stage C • • • • • • •

Angiotensin inhibition therapy Adrenergic blocking agents Aldosterone antagonists in severe heart failure Hydralazine-isosorbide dinitrate, in self reported blacks Diuretics to relieve congestive symptoms Digitalis in selected patients Treatments for stage A

63

64

Manual of Heart Failure

with diabetes with or without hypertension, treatments with angiotensin-converting enzyme inhibitors or angiotensin receptor blocking agents should be considered not only to reduce the risk of end organ damage but also to reduce the risk of development of heart failure.66-68 The metabolic syndrome is defined when there is clustering of risk factors for coronary artery disease and it is diagnosed when any three of the following criteria are present: abdominal adiposity, hypertriglyceridemia, low high density lipoprotein, hypertension and fasting hyperglycemia. The metabolic syndrome is associated with increased risk of developing heart failure.69 Hyperlipidemia is one of the major risk factors of atherosclerotic vascular disease. In patients with history of myocardial infarction, adequate control of lipids particularly with the use of “statins” has the potential to decrease the risk of death and development of heart failure.70 There is controversy regarding the use of aspirin concurrently with angiotensin-converting enzyme inhibitors. Angiotensinconverting enzyme inhibitors reduce degradation of bradykinin, and bradykinin mediated vasodilatation has been postulated as one of the mechanisms of their beneficial effects. Aspirin inhibits synthesis of vasodilator prostaglandins and can interfere with the efficacy of angiotensin-converting enzyme inhibitors. It has been reported that the survival benefit of the angiotensin-converting enzyme inhibitors is reduced with concurrent treatment with aspirin.71,72 However, in the meta-analysis involving 12,763 patients, the survival benefit of the angiotensin-converting enzyme inhibitors was not significantly reduced with aspirin treatment.73 Thus, in patients with coro­nary artery disease, aspirin treatment is indicated. In absence of coronary artery disease, aspirin should be avoided.

SYMPTOMATIC SYSTOLIC HEART FAILURE PHARMACOLOGIC TREATMENTS

In patients in stage C heart failure, angiotensin-converting enzyme inhibitors or angiotensin receptor blocking agents and beta-blocking agents are indicated. These therapies have been documented not only to ameliorate symptoms but also to improve morbidity and mortality (Figs 10 and 11) (Table 7). The angiotensin-converting enzyme inhibitors reduce the formation of angiotensin by blocking the angiotensin-converting enzymes. The use of angiotensin-converting enzyme inhibitors is associated with reverse ventricular remodeling, improved ventricular function and decrease in morbidity and mortality. To assess the effects of angiotensin-converting enzyme inhibitors on mortality and morbidity of patients with chronic systolic heart failure, the different types of angiotensin-converting enzyme inhibitors have been used in the randomized clinical trials.74

Systolic Heart Failure

FIGURE 10: The effects of angiotensin-converting enzyme inhibitors on the mortality and morbidity of patients with systolic heart failure are illustrated. Compared to placebo there is a reduction in total mortality, death or hospitalizations for heart failure, death due to heart failure and fatal myocardial infarction (Abbreviations: ACEI: Angiotensin-converting enzyme inhibitor; MI: Myocardial infarction). (Source: Modified from Garg, et al. JAMA. 1995;273:1450-6)

FIGURE 11: The mortality benefit of beta-blocker treatment in the United States. Carvedilol, MERIT-HF, CIBIS-II and COPERNICUS trials are illustrated (Abbreviations: CIBIS: Cardiac insufficiency bisoprolol study; MERIT-HF: Metoprolol CR/XL rendomized intervention trial in congestive heart failure; COPERNICUS: Carvedilol prospective randomized cumulative survival trial).

The first placebo controlled randomized trial was with the use of enalapril. In the cooperative north scandinavian enalapril survival study (CONSENSUS), patients with severe heart failure, in NYHA class III B or IV, were randomized. There was a substantial survival benefit with enalapril compared to placebo.75 Subsequently, a large number of randomized trials have been performed in patients with less severe heart failure and in patients with asymptomatic left ventricular systolic dysfunction. The results of 32 randomized clinical trials are summarized in the Figure 10. There was a substantial and statistically significant reduction in total mortality (23%), death or hospitalization for heart failure (35%), death due to

65

66

Manual of Heart Failure   TABLE 12  Angiotensin inhibitors used in the treatment of heart failure Agent

Total daily dose (mg)

Frequency

ACEI Captopril Enalapril Fosinopril Lisinopril Quinapril Ramipril Trandolapril

75–150 10–40 10–40 10–40 10–40 2.5–20 1–4

Thrice daily Twice daily Once daily Once daily Once or twice daily Once or twice daily Once daily

ARB Losartan Valsartan Candesartan

25–50 150–300 4–16

Twice daily Once daily Once daily

(Abbreviations: ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocking agent)

heart failure (31%) and fatal myocardial infarction (20%). The magnitude of benefit in mortality and morbidity were similar with the various types of angiotensin-converting inhibitors that were used in these studies. 76-78 There was also amelioration of symptoms and improvement in exercise tolerance.76 The commonly used angiotensin inhibitors and their doses are summarized in Table 12. The serious adverse effects of angiotensin-converting enzyme inhibitor therapy are uncommon. The most common complication is nonproductive irritating cough which most patients tolerate. However, some patients get intolerant to cough and discontinue the therapy. The cough is mediated by bradykinin and is unrelated to the type of angiotensin-converting enzyme inhibitors used. Angioedema, which is also related to bradykinin is a rare complication of angiotensin-converting enzyme inhibitors. But it is a life threatening complication. The incidence of angioedema is about 1%. In patients with history of angioedema angiotensin-converting enzyme inhibitors should not be used. A significant hyperkalemia is another contraindication for treatment with angiotensin-converting enzyme inhibitors. It should be appreciated that even severe renal dysfunction is not a contraindication for use of angiotensin-converting enzyme inhibitors. Another contraindication of angiotensin-inhibition therapy is during pregnancy as their use can be associated with fetal renal failure. The starting dose of angiotensin-converting enzyme inhibitors should be low, particularly in hypotensive patients and the dose should be titrated slowly. If there is a rapid deterioration of renal function or marked increase in serum

Systolic Heart Failure

potassium, the angiotensin-converting enzyme inhibitors should be discontinued. In patients intolerant to angiotensin-converting enzyme inhibitors or with contraindications for their use, angiotensin receptor blocking agents should be considered. The angiotensin receptor blocking agents exert their beneficial effects by blockade of the angiotensin II receptor subtype I and the angiotensin-converting enzyme pathway is not involved. The blockade of angiotensin receptors is associated with increased levels of angiotensin-converting enzyme due to activation of the negative feedback loop. Thus there is increased production of bradykinin which may be associated with increased incidence of both of its side effects and beneficial effects. The three angiotensin receptor blocking agents that are used for the treatment of chronic heart failure are losartan, valsartan and candesartan. In the valsartan heart failure trial (Val-Heft), 5,010 patients were randomized to receive either valsartan or placebo. The patients were in NYHA Class II or III. The results showed that there was a slight but statistically significant reduction in a clinically composite endpoint consisting of all-cause mortality and hospitalizations for heart failure.79 In the losartan heart failure survival study (ELITE II), the patients with left ventricular ejection fraction of less than 40% were randomized to receive losartan or enalapril. There was no difference between the angiotensin receptor blocking agents and the angiotensin-converting enzyme inhibitors.80 In the candesartan in heart failure assessment of reduction in mortality and morbidity (CHARM) trial, the effects of candesartan was compared to those of angiotensinconverting enzyme inhi­bitors.81,82 This study reported a small but statistically significant benefit of candesartan.83 That heart failure is a hyperadrenergic state has been documented by many studies. The increased systemic and regional adrenergic activity is associated with deleterious hemodynamics and adverse vascular and ventricular remodeling. In addition, there is downregulation of myocardial betaadrenergic-1 receptors with little or no change of the betaadrenergic-2 receptors. The clinical implication of these changes in myocardial adrenergic receptors subtypes density is that the myocardial contractile response to adrenergic stimulation is blunted in patients with heart failure. The increased cardiac adrenergic activity is associated with increased myocardial oxygen demand, calcium overload, energy wastage, and myocardial ischemia. Myocyte hypertrophy occurs as well as disorganization of myocardial architecture. There is a direct toxic effect of catecholamines on the cardiac myocytes which may cause myocyte necrosis. This is similar to that of pheochromocytoma cardiomyopathy.84

67

68

Manual of Heart Failure

The rational of beta-blocker therapy in systolic heart failure is to decrease the adverse effects of increased adrenergic activity. There are several potential mechanisms for the beneficial effects of beta-blocker therapy. There is a decrease in systemic vascular resistance which reduces left ventricular afterload and can improve left ventricular ejection fraction.85-87 A decrease in heart rate is associated with a reduction in the reversed force frequency relation which enhances contractile function. Furthermore, there is improvement in ventricular filling and relaxation. During chronic beta-blocker therapy, left ventricular reverse remodeling occurs. There is reduction in left ventricular end-diastolic and end-systolic volume, and an increase in ejection fraction. There is also enhanced contractile response of the left ventricle. Reverse remodeling is also associated with improved survival. An adequate reduction in heart rate is necessary for the beneficial effects including survival benefit of beta-blocker therapy. The magnitude of decrease in heart rate but not the dose of beta blockers used is associated with the magnitude of decrease in mortality.88 It should be appreciated that initially with introduction of beta-blocker therapy there may be deterioration of hemodynamics, and left ventricular function due to decrease in the contractile function. However, usually in 6–8 weeks, there is improvement in symptoms and left ventricular function. Several prospective randomized trials have documented symptomatic improvement and prognosis with beta-blocker therapy (Fig. 11). In an earlier, the metoprolol in dilated cardiomyopathy (MDC) trial, 383 patients with nonischemic dilated cardiomyopathy were randomized to receive metoprolol tartrate (50–75 mg) or placebo. During a follow-up period of approximately 12 months there was a significant improvement in hemodynamics and there was a trend for reduction in mortality and need for cardiac transplantation.89 In another earlier, the cardiac insufficiency bisoprolol survival (CIBIS I) trial, 641 patients with either ischemic or non-ischemic dilated cardiomyopathy were randomized to receive bisoprolol (target dose, 5 mg), or placebo. During a follow-up of approximately 1.9 years, there was a trend to lower mortality and decreased rate of hospital admissions for worsening heart failure.90 A number of large prospective randomized clinical trials have been performed and all have demonstrated survival benefit of long-term beta-blocker treatment in patients with chronic systolic heart failure. In the US Carvedilol trial, 1,094 patients with left ventricular ejection fraction of 35% or less were randomized to receive either carvedilol or placebo. The patients were receiving angiotensinconverting enzyme inhibitors and diuretics before randomization. This trial reported a 65% reduction in all-cause mortality during

Systolic Heart Failure

the follow-up period.91 In the carvedilol prospective randomized cumulative survival (COPERNICUS) trial, 2,289 patients in NYHA class III or IV, being treated with standard heart failure therapy, were randomized to receive carvedilol (target dose 25 mg twice daily) or placebo. During a follow-up of about 24 months, there was a 35% reduction in risk of death with carvedilol treatment.92 In the metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF), 3,991 patients with systolic heart failure, in NYHA class II and III with a mean ejection fraction of 28%, were randomized to receive either placebo or metoprolol succinate (target dose 200 mg a day). Patients in both groups received standard background treatment with angiotensin-converting enzyme inhibitor or angiotensin receptor blocking agent, diuretics and digoxin. During only about a follow-up period of 1 year, there was a 34% reduction in the risk of total mortality. There was also reduction in the risk of sudden cardiac death, heart failure hospitalization and functional class.93 In the cardiac insufficiency bisoprolol survival (CIBIS II) trial, 2,647 patients with systolic heart failure with either ischemic or nonischemic cardiomyopathy were randomized to receive either placebo or bisoprolol (target dose of 10 mg). During the follow-up period, there was 34% reduction in total mortality, 44% reduction in sudden cardiac death and 20% reduction in hospitalization with bisoprolol treatment.94 In the Carvedilol Or Metoprolol European trial (COMET), more than 3,000 patients with moderately severe heart failure were randomized to receive metoprolol tartrate (target dose of 50 mg twice daily) or carvedilol (target dose of 25 mg twice daily). With carvedilol there was a 17% greater reduction in mortality.95 It needs to be appreciated that all beta-adrenergic antagonists do not provide benefit. In the beta-blocker evaluation survival trial (BEST), 2,708 patients in NYHA class III or IV were randomized to receive bucindolol or placebo.96 After about 2 years of follow-up, the trial was terminated as there was no probability of survival benefit with bucindolol. There was a trend towards improved survival in patients in NYHA class III and with left ventricular ejection fraction of greater than 20%. There was no benefit in patients with an ejection fraction of 20% or less. There was also no benefit in blacks. It has been postulated that the differences in the pharma­ cologic properties may explain lack of benefit with bucindolol compared to that of bisoprolol, metoprolol and carvedilol. Bisoprolol is a selective beta-1 adrenergic receptor antagonist with a vasodilating property. Metoprolol is also a selective beta blocker but, unlike bisoprolol, it does not possess a vasodilating effect. Carvedilol is a nonselective beta-blocking agent and has weak alpha-1 blocking property. It also appears to have antioxidant effects and decrease oxidative stress. Bucindolol, although is similar to carvedilol, it has inverse agonist and intrinsic sympathomimetic activity.97,98

69

70

Manual of Heart Failure

Nebivolol, a selective beta-1 adrenergic antagonist with nitric oxide-mediated vasodilating property, was used in the study of effects of nebivolol intervention on outcomes and rehospitalization in seniors with heart failure (SENIORS) trial. During the follow-up period of approximately 12 months, there was a significant reduction in the composite endpoint of death, or cardiovascular hospitalization in the elderly patients with left ventricular ejection fraction of less than 35%.99 That complete adrenergic inhibition may not be beneficial in patients with heart failure has also been documented.100 Moxonidine, a centrally acting sympatholytic agent which decreases adrenergic activity substantially, was investigated in the moxonidine in heart failure (MOXCON) trial. The trial was prematurely terminated as there was a higher mortality in the patients treated with moxonidine. In clinical practice, presently bisoprolol, metoprolol succinate or carvedilol are recommended for the treatment of systolic heart failure. The optimal dose of bisoprolol is 10 mg once daily, of metoprolol succinate 200 mg once daily and of carvedilol 25 mg twice daily. During initiation of beta-blocker therapy, the dose of the beta blocker should be low and the dose should be increased slowly to the maximum tolerated dose. If the patients are admitted for the treatment of decompensated heart failure, the beta blockers should not be discontinued. The discontinuation of beta blockers is associated with worse prognosis.101 It should be appreciated that the beta-blocker therapy is not contraindicated in patients with chronic obstructive pulmonary disease, renal failure or diabetes. It can also be used in combination with angiotensinconverting enzyme inhibitors or angiotensin receptor blocking agents and aldosterone antagonists. The beta-blocker therapy appears to be equally effective in men and women, in Whites and Blacks, and in younger and older patients.102 The aldosterone receptor antagonists spironolactone and eplerenone are effective in producing left ventricular reverse remodeling and improving prognosis of patients with systolic heart failure. The efficacy of spironolactone was assessed in the Randomized Aldactone Evaluation Study (RALES) trial.103a In this study, 1,663 patients with systolic heart failure in NYHA III or IV were randomized to receive aldactone (target dose of 25–50 mg) or placebo. The left ventricular ejection fraction before randomization required to be 35% or less. The mean ejection fraction was 25% in the randomized patients. The patients with plasma concentration of creatinine of greater than 2.5 mg/dL or a plasma concentration of serum potassium greater than 5.0 mEq/L were excluded. After an average duration of follow-up of 24 months, the trial was prematurely discontinued because there was a 30% reduction in all-cause mortality, which was due to reduction in risk of sudden cardiac death and death

Systolic Heart Failure

FIGURE 12: The effects of spironolactone on mortality of patients with severe chronic heart failure in randomized aldactone evaluation study (RALES). (Source: B Pitt, et al. N Engl J Med. 1999;341:709, with permission)

from heart failure (Fig. 12). There was also a 35% reduction in the rate of hospitalization for worsening heart failure. These benefits were observed in patients with ischemic or nonischemic dilated cardiomyopathy. The selective aldosterone antagonist eplerenone was also demonstrated to produce beneficial effects on survival and development of congestive heart failure in the postinfarction patients.55 In the eplerenone post-acute myocardial infarction heart failure efficacy and survival study, 3–14 days after acute myocardial infarction with left ventricular ejection fraction of 40% or less, 6,642 patients were randomized to receive eplerenone (target dose of 50 mg daily) or placebo. The patients were adequately treated with reperfusion therapy and angio­tensin inhibition and beta-blocker therapy before randomization. There was a 15% reduction in all-cause mortality, sudden cardiac death, and hospitalizations for heart failure (Fig. 13). Both spironolactone and eplerenone have been shown to exert beneficial effects on left ventricular remodeling. There is a reduction in left ventricular end-diastolic and end-systolic volumes and an increase in ejection fraction. There is also a reduction in the collagen turnover marker procollagen type I N-terminal propeptide, indicating reduced fibrosis.103b,c Spironolactone and eplerenone are competitive antagonists of mineralocorticoid nuclear receptor aldosterone. Aldosterone receptors are present not only in the zona glomerulosa of the adrenal cortex but also in the myocytes and in the coronary vascular bed. The cardiac aldosterone synthesis by the aldosterone receptors is increased in heart failure and is mediated by enhanced activity of aldosterone synthase which

71

72

Manual of Heart Failure

FIGURE 13: The effects of eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction (Source: B Pitt, et al. N Engl J Med. 2003;348:1309, with permission)

is stimulated by angiotensin II.104 The angiotensin II is the major stimulus for the aldosterone release. Thus theoretically inhibition of the formation of angiotensin may be associated with decreased level of aldosterone. However, the effects of aldosterone antagonists are not diminished with the concurrent use of angiotensin-converting enzyme inhibitors or angiotensin receptor blocking agents. Aldosterone antagonists decrease myocyte and vascular smooth muscle cell hypertrophy and decrease myocardial fibrosis, the principal mechanisms of their beneficial effects on ventricular remodeling. Gynecomastia, painful breast enlargements in females, menstrual irregularities, impotence and decreased libido are the endocrine side effects specific to spironolactone. These side effects result from binding to androgen and progesterone receptors. Eplerenone is a selective aldosterone antagonist and is not associated with these side effects.105 The serious and potentially life-threatening complication of aldosterone antagonism is hyperkalemia. A number of risk factors contribute to hyperkalemia: increasing age, diabetes mellitus, preexisting renal dysfunction, hypovolumia, and concurrent use of both an angiotensin-converting enzyme inhibitor and angiotensin receptor-blocking agent. Uses of potassium supplements or potassium containing salt substitutes are also contributory. Hyponatremia is also a side effect of aldosterone antagonism. Lack of monitoring of renal function and electrolytes may be associated with severe unexpected hyperkalemia and increased mortality.106 It is suggested that the starting dose of aldosterone antagonists should be low and the electrolytes and renal function

Systolic Heart Failure

should be evaluated at 1 week and then at 2 weeks before increasing the dose. After increasing the dose, the electrolytes and renal function should be repeated again after 1 and 2 weeks. It is advisable to monitor renal function and electrolytes more frequently in patients with relative hypotension and more severe heart failure. It is also important not to use aldosterone antagonists in patients with serum creatinine greater than 2.5 mg/dL or serum potassium greater than 5.0 mEq/L. Aldosterone antagonists are usually used for the treatment of severely symptomatic patients (NYHA III) with systolic heart failure. However, it has been reported that eplerenone is effective in mildly symptomatic patients (NYHA II) in reducing mortality and morbidity. In the eplerenone in patients with systolic heart failure and mild symptoms (EMPHASIS–HF) trial, 2,737 patients with ejection fraction of not higher than 35% were randomized either to receive eplerenone (up to 50 mg daily) or placebo. The primary endpoint was a composite of death from cardiovascular causes or hospitalizations for heart failure. After a median follow-up period of 21 months, the primary outcome occurred in 25.9% in the placebo group and in 18.3% in the eplerenone treated group. The mortality was 12.5% in the eplerenone treated patients and 15.5% in the placebo group. These findings suggest that eplerenone decrease mortality and morbidity in mildly symptomatic patients with systolic heart failure.107 Omega-3 fatty acids have the potential to improve left ventricular ejection fraction and promote reverse remodeling in patients with nonischemic systolic heart failure.108 In the GISSI-HF trial, 133 clinically stable patients with non-ischemic dilated cardiomyopathy with an ejection fraction of 45 % or less were randomized to receive omega-3 (2 capsules/day) or placebo. After follow-up of approximately 11 months, there was a statistically significant increase in left ventricular ejection fraction. There was also an increase in peak maximal oxygen consumption (VO2). There was no beneficial effect of statin rosuvastatin. Hydralazine and nitrates are effective in improving symp­ toms and prognosis of patients with severe heart failure. Hydralazine is predominantly an arteriolar dilator and decrease systemic vascular resistance, increases stroke volume and cardiac output. Although it is a vasodilator antihypertensive agent, hydralazine does not decrease systolic arterial pressure in patients with heart failure. The systolic blood pressure may actually increase when there is increase in stroke volume. In patients with heart failure there is also no reflex increase in heart rate.109 This is partly due to impaired baroreceptor sensitivity in heart failure. Furthermore, increased stroke volume is associated with loading of the baroreceptors. The

73

74

Manual of Heart Failure

FIGURE 14: Hemodynamic effects of hydralizine alone, nitrates alone, and of combination of hydralazine and nitrates are illustrated. The combination therapy decreased pulmonary capillary wedge pressure and increased cardiac output (Abbreviations: C: Control; H: Hydralazine; N: Nitrates; H+N: Hydralazine and nitrate combination). (Source: B Massie, et al. Am J Cardiol. 1977;40:794-801, with permission)

nitrates are predominantly venodilators and decrease systemic and pulmonary venous pressures. The hemodynamic effects of combination of hydralazine and nitrate are characterized by a decrease in right atrial, pulmonary capillary wedge and mean pulmonary heart pressure. There is a reduction in systemic vascular resistance, increase in stroke volume and cardiac output without a significant change in heart rate and blood pressure (Fig. 14)110 A number of randomized clinical trials have been performed to assess effects of combination of hydralazine and isosorbide dinitrate on survival of patients with systolic heart failure. In the veteran administration heart failure I, 642 men in NYHA class II or III were randomized to receive placebo, prazosin or hydralazine and isosorbide dinitrate. 111 With hydralazine and isosorbide dinitrate there was a reduction in allcause mortality compared to placebo. The survival benefit was found in blacks. There was no difference in mortality between prazosin and placebo. In the veterans administration heart failure trial II, hydralazine and isosorbide dinitrate combination treatment was compared to angiotensin-converting enzyme inhibitor.112 The mortality rate was lower with angiotensinconverting enzyme inhibitors compared to hydralazine and nitrate. In the African-American heart failure trial (A-HeFT), 1,050 self-reported Blacks in NYHA III or IV receiving standard heart failure treatment including angiotensin-inhibition therapy (87%), beta blockers (74%), and spironolactone (39%) were randomi­zed to fixed doses of hydralazine (37.5–75 mg three times daily) and isosorbide dinitrate (20–40 mg three times daily).

Systolic Heart Failure   TABLE 13  Results A-HeFT study Endpoint

Composite score

Hydralazine nitrate (95% CI)

Hazard

– 0.16 – 0.47 +/– 1.93 +/-2.04 All-cause mortality 6.2% 10.2% First hospitalization 16.4% 24.4% For heart failure (Abbreviation: NA: Not available)

Placebo Risk ratio

p value reduction

N/A

N/A

< 0.021

0.57 0.61

43% 39%

0.012 < 0.001

The trial was terminated prematurely due to substantial survival benefit with hydralazine and isosorbide dinitrate (Table 13).113 It has been postulated that the increased nitric oxide availability may be contributory to the beneficial effects of hydralazine and nitrates-combination therapy. Nitrates are nitric oxide donor and improve endothelial function. Hydralazine may also be an antioxidant and it decreases nitrate tolerance.114 The guidelines recommend the use of hydralazine and nitrate combination therapy for all patients, irrespective of race or gender, with severe systolic heart failure who remain sympto­matic despite standard therapy.57 The complications of hydralazine and nitrate therapy are uncommon. With the dose of hydralazine used for the treatment of heart failure, the lupus-like syndrome does not occur. Amlodipine is a dihydropyridine calcium-channel blocker which has vasodilating property, and it has been tested in randomized clinical trials to assess its potential beneficial effects in patients with systolic heart failure due to ischemic or nonischemic dilated cardiomyopathy. It is a long acting arteriolar dilator and decreases systemic vascular resistance. Like all calcium-channel blockers it also exerts a negative inotropic effect although its negative inotropic effect appears to be less compared to that of other calcium-channel blockers. The effects of amlodipine were assessed in the two pros­ pective randomized amlodipine survival evaluation (PRAISE) studies.115 Although there was a trend for benefit in patients with non-ischemic dilated cardiomyopathy, the overall results were neutral. Thus there is no indication for its use in patients with systolic heart failure except for the treatment of associated hypertension or angina. Diuretics are essential to relieve congestive symptoms. In patients with signs and symptoms of pulmonary and systemic venous congestion, initially loop diuretics are used. The loop diuretics that are used in clinical practice are furosemide, ethacrynic acid, bumetanide and torsemide. Although furosemide

75

76

Manual of Heart Failure

is the most frequently used diuretic, it should be appreciated that when it is administered orally its bioavailability is only 50%. The absorptions of torsemide and bumetanide are greater and more predictable. Thus, in patients poorly responsive to furosemide, torsemide or bumetanide should be considered. The relative efficacy of furosemide and torsemide were compared in an open label randomized clinical trial. In this trial, 234 patients with heart failure were randomized.116 The primary endpoint was the hospital admissions for heart failure. During a follow-up period of 1 year, the hospital admission rates with furosemide was 32%, and with torsemide 17%. There was also reduced incidence of fatigue with torsemide. The dose of the loop diuretics are increased according to the diuretic response. The daily dose of furosemide in heart failure is between 20 mg and 240 mg, of bumetanide 0.5 mg and 10 mg, of ethacrynic acid 50 mg and 200 mg and of torsemide 10 mg and 200 mg. However, the usual doses that are used initially for patients with normal glomerular filtration rate with mild to moderately severe heart failure are lower. In these patients the usual daily dose of furosemide is 40–80 mg, of bumetanide 2–3 mg and of torsemide 20–50 mg. In patients with renal failure larger doses of diuretics are required. For individual patients the diuretic doses should be determined based on clinical response. During chronic diuretic therapy, there is potential for improvement in hemodynamics and left ventricular function. Left ventricular end diastolic volumes may decrease which is associated with decreased wall stress. Thus, there is reduction in afterload which is associated with an increase in stroke volume and cardiac output.117 Chronic diuretic treatments may also improve exercise tolerance.118 Patients with severe heart failure may respond poorly to intermittent intravenous administration of furosemide. In these patients, a continuous infusion of furosemide is frequently employed. However, it appears that there is no difference in urine output between intermittent administration and continuous infusion of furosemide The more severe the heart failure is, the more likely that it will be necessary to use combination of diuretics with different sites of action on the nephrons. The loop diuretics are combined with thiazide diuretics and then with potassium sparing diuretics. The most frequently used oral thiazide diuretic is metolazone. The dose of metolazone is between 2.5 mg and 20 mg daily. Initially, a smaller dose, such as 2.5–5 mg twice or thrice per week, is employed. The dose and frequency can then be increased based on diuretic response. Intravenous thiazide diuretics are also used when oral therapy becomes ineffective. Acetazolamide is a proximal tubular diuretic, but it is less potent than the loop diuretics.

Systolic Heart Failure

It is seldom used except for severe diuretic induced metabolic alkalosis. It should be appreciated that several complications may occur during aggressive diuretic therapy. Deterioration of renal function occurs in approximately 30% of patients with decompensated heart failure receiving diuretics.119 An electrolyte imbalance, such as hypokalemia and hypomagnesemia, can occur which may induce life-threatening ventricular arrhy­ thmias.120 Impaired renal function is also associated with poor prognosis.121,122 Thus, the careful monitoring of renal function and electrolytes are advisable during diuretic therapy. In patients with chronic heart failure, rapid intravenous administration of a loop diuretic is associated with adverse hemodynamic and neurohormonal effects.123 There is a transient decrease in cardiac output and an increase in plasma norepinephrine, renin, aldosterone and vasopressin levels. In patients with chronic heart failure, however, the magnitude of reduction in stroke volume is small, as these patients are on the flat portion of the Frank–Starling curve. The other complications of diuretic therapy are hyponatremia, hyperuricemia and hyperglycemia. Deafness is a rare but reversible complication when large doses of furosemide or ethacrynic acid are used rapidly (please see the chapter on Diuretics). The inadequate response to diuretics in heart failure is often called diuretic resistance or cardiorenal syndrome.124 A number of factors appear to be contributory to the development of cardiorenal syndrome. Decreased renal perfusion due to low cardiac output, renal vasoconstriction and redistribution of cardiac output has been postulated. Inappropriate systemic and renal neuroendocrine activation are important mechanisms. The vasodilatation of the afferent renal arterioles is partly mediated by prostaglandins and nonsteroidal anti-inflammatory agents (NSAIDS) which block the prostaglandins reduce the efficacy of the diuretics. The efferent arteriolar vasoregulation is mediated by the renin–angiotensin system. Diuretic therapy is associated with increased renin and angiotensin which may maintain renal blood flow and glomerular filtration rate. The use of angiotensin inhibitors which are indicated for the treatment of heart failure may contribute to deteriorating renal function in heart failure (please see Chapter 7: Cardiorenal Syndrome). Another potential mechanism for inadequate response to diuretics in heart failure is decreased sodium load to the tubules due to low cardiac output and a marked reabsorp­tion of sodium. In patients with obvious volume overload and resistance to diuretic therapy, mechanical means for fluid removal may be employed. Ultrafiltration is effective in removing sodium and water. In the relief for acutely fluid-overload patients with decompensated congestive heart failure (RAPID-CHF) trial,

77

78

Manual of Heart Failure

40 patients were randomized to receive diuretic treatment or ultrafiltration. The removal of fluid after 24 hours was about twofold greater with ultrafiltration.124 In the ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated congestive heart failure (UNLOAD) study, ultrafiltration was compared with intravenous diuretics. In this study, 200 patients were randomized to receive diuretic therapy or ultrafiltration. There was no difference in the dyspnea score, but ultrafiltration was associated with greater fluid loss at 48 hours125 (please see Chapter 7: Cardiorenal Syndrome). In patients with refractory heart failure, intravenous vasodilators are often used to improve hemodynamics and cardiac function. The intravenous vasodilators that are used in clinical practice are sodium nitroprusside, nitroglycerine and nesiritide. Sodium nitroprusside is a balanced vasodilator and causes arterial and venodilatation. The hemodynamic effects are characterized by a reduction in systemic vascular resistance, systemic and pulmonary venous pressures and an increase in cardiac output. Sodium nitroprusside is particularly useful in patients with mitral regurgitation. Thiocyanate toxicity is a rare complication of nitroprusside treatment. However, thiocyanate levels should be monitored when pronged and large doses of sodium nitroprusside are used. There is some evidence to indicate that in patients hospitalized with advanced heart failure stabilization with sodium nitroprusside may be associated with a better long-term prognosis.126 The dose of nitroprusside for the treatment of advanced heart failure is much lower than for the treatment of hypertensive crisis. The usual dose is between 10 µg/min and 30 µg/min. Nitroglycerin is predominantly a venodilator and decreases systemic and pulmonary venous pressures with little or no change in cardiac output. The major disadvantage of nitroglycerin is the development of tolerance. The tolerance develops when large doses are used for more than 48 hours. The starting dose of nitroglycerin should be low, such as 10–20 µg/min, and gradually increased to the maximum dose of 200 µg/min. However, the dose does not need to be increased if the hemodynamic goals are achieved at a lower dose. Both sodium nitroprusside and nitroglycerin are used for improve­ment of hemodynamics in patients being considered for cardiac transplantation. Nesiritide is a synthesized brain natriuretic peptide (BNP) that has been used for the treatment of refractory heart failure. In the vasodilation in the management of acute congestive heart failure (CHF) (VMAC) study, intravenous nesiritide was compared to intravenous nitroglycerin. In this study, nesiritide was reported to be better than intravenous nitroglycerin in improving symptoms and hemodynamics.127 Nesiritide improves

Systolic Heart Failure

renal function and enhances diuresis in patients without heart failure. In patients with heart failure, however, there is usually little or no improvement in renal function or diuresis. Also, concerns have been expressed about safety of nesiritide as there were reports that nesiritide may be associated with increased risk of mortality.128 However, a large randomized clinical trial has demonstrated that intravenous nesiritide does not cause increased mortality or deterioration of renal function. Its efficacy was similar to the placebo treatment. In a large multicenter, multinational prospective randomized clinical trial, the effect of nesiritide in patients with acute decompensated heart failure was evaluated.128a In the nesiritide group there were 3,496 patients and in the placebo group, 3,511 patients. Approximately 80% of patients had left ventricular ejection fraction less than 40% and 20%, greater than 40%. Nesiritide was not associated with any significant effect on dyspnea. Compared to placebo, it did not decrease or increase rate of death or rehospitalization. Use of nesiritide was not associated with worsening renal function but there were significantly higher number of patients who developed hypotension. Thus routine use of nesiritide cannot be recommended. To determine whether BNP-guided therapy is beneficial in the management of patients with advanced systolic heart failure, in the TIME-CHF trial, 251 patients were randomized to receive intensified BNPguided therapy and 248 patients to receive standard therapy. There was no benefit in survival or quality of life with BNPguided therapy.128b In patients with advanced heart failure, the positive inotropic agents are used when there is poor response to standard pharmacologic treatments. Oral digoxin has been employed to improve hemodynamics and left ventricular function in patients with systolic heart failure.129 In the digitalis investigation (DIG) trial, long-term oral digoxin therapy did not provide any survival benefit. In patients with digoxin blood level of 1.2 ng/mL or higher, there was an increased risk of arrhythmic death. Thus, if digoxin is used it is advisable to keep its blood level less than 1.2 ng/mL.130 Intravenous catecholamines and vasopressors are used as supportive treatments in patients with severe refractory heart failure (stage D). Dobutamine is predominantly a beta-1 adrenoreceptor agonist. It also stimulates beta-2 adrenergic receptors. The hemodynamic effects of dobutamine are characterized by an increase in stroke volume and cardiac output and a modest decrease in mean arterial pressure. Thus, if the main objective is to increase arterial pressure, dobutamine is not the drug of choice. The pulmonary capillary wedge and pulmonary artery pressures may not decrease significantly. The

79

80

Manual of Heart Failure

heart rate increases modestly.131 It should be appreciated that as there is downregulation of the myocardial beta-1 receptors, contractile response to dobutamine is blunted. Dopamine stimulates dopaminergic receptors (DA1 and DA2), and adrenergic receptors (beta-1, beta-2 and alpha). Neuronal release of norepinephrine and its reduced neuronal reuptake occur with dopamine. Thus, circulating norepinephrine levels are substantially increased.132 The hemodynamic effects of dopamine are related to its dose. The lower dose (1–2 µg/kg/ min) is associated with activation of DA1 and DA2 receptors. The stimulation of DA1 receptors causes dilatation of renal and mesenteric vascular system. With this dose, arterial pressure and cardiac output remain unchanged. With the dose 4–10 µg/kg/ min, beta receptors are activated and there is an increase in stroke volume, cardiac output and heart rate. With a further increase in the dose exceeding 10 µg/kg/min, the alpha receptors are stimulated which is associated with systemic vasoconstriction. The hemodynamic effects with higher doses are characterized by increased, systemic vascular resistance, arterial pressure and no further increase in cardiac output. Pulmonary capillary wedge and pulmonary artery pressures may also increase.133 To increase arterial pressure with dopamine it is necessary to use the alpha receptors stimulating doses. Norepinephrine and phenylephrine are also used in hypotensive patients to maintain arterial pressures. Norepi­ nephrine is predominantly an alpha receptor agonist, and it does possess mild beta receptor agonist property. Phenylephrine is an alpha-receptor agonist. Both norepinephrine and phenylephrine increase systemic vascular resistance and arterial pressure without inducing tachycardia. Stroke volume and cardiac output may decrease due to increased left ventricular afterload. The relatively cardiospecific phosphodiesterase inhibitors (phosphodiesterase III and IV) milrinone and amrinone exert positive inotropic effect and increase stroke volume and cardiac output. Systemic vascular resistance and mean arterial pressure may decrease. There is also a substantial reduction of systemic and pulmonary venous pressures. However, these agents increase ventricular arrhythmias and may increase mortality. 134 The long-term effects of oral milrinone and other phospho­diesterase inhibitors have been evaluated in a few studies.135,136 In one clinical trial, 1,088 patients in NYHA class III or IV systolic heart failure were randomized to receive either 40 mg of oral milrinone or placebo. There was a significant increase in the incidence of mortality and morbidity in patients treated with milrinone. Results of a meta analysis of the randomized clinical

Systolic Heart Failure

trials also reported a significant increase in the risk of mortality with the use of oral phosphodiesterase inhibitors. The phosphodiesterase type V inhibitors are systemic and pulmonary vasodilators and are widely used for the treatment of precapillary pulmonary arterial hypertension and for erectile dysfunction. Preliminary studies indicate that these agents may be beneficial in patients with pulmonary hypertension due to left ventricular dysfunction.137 The clinical effects of the calcium sensitizing agents that increase myocardial response to a given concentration of calcium have been tested for the management of refractory heart failure. Levosimendan is an intravenous calcium sensitizing agent, and has been shown to produce beneficial hemodynamic effects which consist of increase in cardiac output and decrease in pulmonary capillary wedge pressure.138 However, in a rando­ mized clinical trial comparing levosimendan and dobutamine, there was no survival benefit with levosimendan.139 To assess the effects of reduction of heart rate alone without affecting the beta-adrenergic system in patients with systolic heart failure with left ventricular ejection fraction of less than 40%, a randomized clinical trial was performed with the use of ivabradine.140 All patients had stable chronic coronary artery disease. Ivabradine inhibits I(f) currents in the sinoatrial node and lowers the sinus rate. It does not possess any beta-adrenergic antagonist effect. In the BEAUTIFUL trial, 5,479 patients received ivabradine (5–7.5 mg) and 5,438 patients received placebo during the median follow-up period of 19 months. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. Ivabradine did not affect primary endpoint (hazard ratio 1.00; 95% confidence interval 0.91–1.1; p = 0.94). In the ivabradine group, all-cause mortality was 10.4% and in the placebo group 10.1%. The results of this study did not demonstrate any benefit of ivabradine in the treatment of systolic heart failure. In patients with dilated cardiomyopathy with heart failure a beneficial effect of trimetazidine, a metabolic modulator, has been observed.140a Trimetazidine increased cardiac and extracardiac metabolic effects. Cardiac free fatty acid oxidation decreased modestly and myocardial oxidative rate was unchanged. Trimetazidine also increased left ventricular ejection fraction. There was also a greater myocardial B1-adrenoreceptor occupancy suggesting a synergistic mechanism of improved metabolic and mechanical functions.

81

82

Manual of Heart Failure   TABLE 14  Nonpharmacologic interventions • • • • • • • •

LV volume reduction surgery   Batista, Dore, Saver procedures Mitral valve repairs DDD-pacing with short P-R interval Ventricular assist devices Passive ventricular constraint devices – Myosplints – Mesh jacket Cardiac transplantation Revascularization in ischemic cardiomyopathy Resynchronization with or without ICD

NONPHARMACOLOGIC TREATMENTS A number of nonpharmacologic treatments have been attempted for the treatment of refractory systolic heart failure (Table 14). The chronic resynchronization treatment (CRT) with or without implantable cardioverter-defibrillator (ICD) has been tested in patients with moderately severe and severe systolic heart failure. The CRT with or without ICD has the potential to improve symptoms, hemodynamics and prognosis of these patients. The CRT treatment is indicated in patients with QRS complex duration of 120 milliseconds or greater.140b The ICD treatment has been shown to decrease the risk of sudden cardiac death.141a Atrioventricular sequential dual chamber pacing with short P-R intervals have also been used in patients with dilated cardiomyopathy without success. Left ventricular constrain devices, such as myosplints and mesh jackets, have been used to decrease left ventricular remodeling Effectiveness of these procedures however has not been proven and is still experimental. Left ventricular volume reduction surgery, such as the “Batista”, “Dore” and “Saver” procedures, has been employed to decrease left ventricular volume and adverse remodeling. The long-term results of these surgical procedures have not been encouraging. Left ventricular remodeling is not prevented and outcomes are not improved. Surgical mitral valve repair in patients with significant secondary mitral regurgitation improves hemodynamics and has the potential to decrease progressive left ventricular dilatation. Whether long-term prognosis also improves or not has not been established. The catheter-based mitral valve repair is being performed, which is associated with less risk of mortality and morbidity than with surgical repair.

Systolic Heart Failure

Left ventricular assist devices are primarily used to support patients waiting for cardiac transplantation. However, left ventricular assist devices are also being used as a destination therapy. A regular exercise program should be implemented as part of the management strategy of patients with systolic heart failure. The moderate level of exercise is well tolerated, even by patients with severe heart failure. The regular exercise improves sense of well-being and also hemodynamics (please see Chapter 9: “Cardiopulmonary Exercise Testing and Training in Heart Failure”). In a preliminary multicenter non-randomized clinical trial, chronic vagus nerve stimulation in patients with stage C systolic heart failure has been shown to decrease left ventricular end systolic volume and to increase left ventricular ejection fraction. There was also clinical improvement.141b However, without a large randomized clinical trial, the role of this new nonpharmacologic treatment remains unproven.

FOLLOW-UP EVALUATION

Heart failure is a chronic disease and is associated with a high mortality and morbidity rates. The unplanned hospital readmission rates for the treatment of heart failure and the visits to the emergency department are high.142 The length of stay of the patients who require unplanned admissions to the hospital for the treatment of heart failure are usually longer.143 In the United States of America, over 6.5 million hospital days are required for the treatment of patients with heart failure. Thus, the cost of care markedly increases, and in 2007, more than 35 billion dollars were spent for management of patients with heart failure.142 The quality of life of patients with chronic heart failure is also poor, particularly when adequate follow-up management is not provided. Many therapeutic advances, as outlined in this chapter, have been made for the treatment of systolic heart failure. However, these life saving therapies continue to be underused, even in the developed countries. Thus, a mechanism needs to be established for a greater use of these therapeutic agents. It has been suggested that patient education, evidence-based, guideline-recommended treatments should be initiated in the hospitals prior to discharge of the patients.144 Heart failure disease management programs should be established and the team should include pharmacists.145 Medicine management for heart failure is

83

84

Manual of Heart Failure

complex. Physicians are frequently unaware of drug–drug interactions, and inappropriate medicines and doses may be prescribed. Inappropriate medications have the potential to increase morbidity such as frequency of hospital readmissions. Multidisciplinary chronic heart failure management programs should be established which allow implementation of appropriate therapy.146-149 The team should consist of nurses trained in management of heart failure, heart failure specialists and pharmacists.150 Some programs also include exercise and rehabilitation specialists. The nurse specialists play the pivotal roles in these programs. Randomized clinical trials have reported that nurseled, clinic- and home-based intervention programs reduce the rate of recurrent admissions to the hospitals.147 The specialists can alter the dose of the diuretics, beta-blockers and angio­ tensin inhibitors. The patients are advised to weigh themselves every day and the diuretic doses are adjusted accordingly. The patients are seen in the clinic by the physicians and the nurse practitioners as needed. After the clinic visits, follow-up tests are performed if necessary. Nurse-led management program is also cost effective.151 In this multicenter clinical trial, 1,163 patients were randomized to control group who received standard care and to specialist nurse-led management program. The nurse-led disease management program was associated with an increase in the economic evaluation of quality-adjusted life years. The prospective trial has reported that specialized heart failure programs can improve recovery and good health in the hospitalized veterans. The disease management programs can improve quality of life of patients with heart failure. It has been observed that patients younger than 65 years of age with chronic heart failure and poor quality of life are at a higher risk of adverse outcomes.148 However, nurse-supported hospital discharge programs have been reported to decrease unplanned admissions to the hospitals, even in the relatively older popula­tions with heart failure. It has been observed that the multi­disciplinary home-based intervention programs can detect deterioration of heart failure earlier, and thus can facilitate earlier institution of appropriate treatments.152 It has also been observed that specialist nurse management programs can substantially decrease the cost of the treatment of patients with heart failure.153 In a randomized clinical trial the efficacy of telemonitoringguided heart failure care was assessed. There were 826 patients in the treatment group and 827 patients in the usual care group. The all-cause readmission/death was 52.3% in the treatment group and 51.5% in the usual care group. Thus, this study

Systolic Heart Failure   TABLE 15  Potential mechanisms of benefits of exercise training in heart failure • Reduction in sympathetic activity, increase in parasympathetic activity • Decrease in circulating deleterious neurohormones • Decrease generation of reactive oxygen species (ROS) • Restore endothelial function • Generation of more nitric oxide (NO) • Exerts anti-inflammatory effect by reducing inflammatory cytokines, platelet-related inflammatory mediators and peripheral markers of endothelial dysfunction

  TABLE 16  Potential mechanisms of benefits of exercise training in heart failure • Improves oxygen consumption, and lactate threshold, delays onset of anaerobic metabolism in skeletal muscle • Decreases systemic vascular resistance • Decreases end-diastolic and end-systolic volumes and increases left ventricular ejection fraction

demonstrated no benefit with telemonitoring-guided heart failure management program.154 In the telemedicine interventional monitoring in heart failure (TIM-HF) trial, the hazard ratio of all cause mortality was 0.97 (p 0.87) and of cardiovascular death/heart failure hospitalization was 0.89 (p 44). Thus this study also demonstrated that telemonitoring-guided heart failure treatment does not provide any benefit.155 That physical activity may be associated with beneficial effects in patients with chronic heart failure has been documented.156 In this study, 28,334 Finish men and 29,874 women, aged 25–75 years, were followed for 18.4 years. During the followup period,1,868 men and 1,640 women developed heart failure. The multivariate adjusted hazard ratios for development of heart failure were determined. The results of this study showed that both men and women, moderate and high levels of occupational and leisure-time physical activity reduce risk of developing heart failure. Exercise training is recommended in NYHA class II and III patients with chronic heart failure. Regular exercise can improve symptoms, exercise capacity, and quality of life. It can be associated with reduced hospitalization rates. The potential mechanisms of the benefits of exercise training in heart failure are summarized in Tables 15 and 16.

85

86

Manual of Heart Failure

REFERENCES

1. Dalla-Volte S. A short historical survey of heart failure. Clin Invest. 1993;71:S167-76. 2. Sharma JN. Cardiovascular system and its diseases in the ancient indian literature. Indian J Chest Dis. 1967;9:32-40. 3. Moore DA, Wilkins MR, Kendall MJ, et al. William Withering and digitalis, 1785-1985. Br Med J. 1985;290:7-8. 4. Withering W. An account of the foxglove, and some of its medical uses: with practical remarks on dropsy, and other diseases. London: Robinson; 1785. 5. Brunton TL. On the use of nitrate of amyl in angina pectoris. Lancet. 1867;2:97-8. 6. Judson WE, Hollander W, Wilkins RW. The effects of intravenous apresoline (hydralazine) on cardiovascular and renal function in patients with and without congestive heart failure. Circulation. 1956;13:644-74. 7. Chatterjee K, Parmley WW, Massie B, et al. Oral hydralazine therapy for chronic refractory heart failure. Circulation. 1976;54:879-83. 8. Konstam MA. Systolic and diastolic dysfunction in heart failure? Time for a new paradigm. J Cardiac Fail. 2003;9:1-3. 9. Aurigema GP, Zile MR, Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure with emphasis on regional systolic function. Circulation. 2006;113:296-304. 10. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288:2144-50. 11. Wang J, Kurrelmeyer KM, Torre-Amione N, et al. Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy. J Am Coll Cardiol. 2007;49:88-96. 12. Chatterjee K, Massie B. Systolic and diastolic heart failure: differences and similarities. J Cardiac Fail. 2007;13:569-76. 13. Van Heerebeek L, Borbély A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113:1966-73. 14. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res. 2002;90:520-30. 15. Ahmed SH, Clark LL, Pennington WR, et al. Matrix metallo­ proteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006;113:2089-96. 16. Rossi A, Cicoira M, Golia G, et al. Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis. Heart. 2004;90:650-4. 17. Katz AM, Zile MR. New molecular mechanism in diastolic heart failure. Circulation. 2006;113:1922-5. 18. Houser SR, Margulies KB. Is depressed myocyte contractility centrally involved in heart failure? Circ Res. 2003;92:350-8. 19. Lowes BD, Minobe W, Abraham WT, et al. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied failing ventricular myocardium. J Clin Invest. 1997;100:2315-24.

Systolic Heart Failure 20. Chatterjee K, Zhang J, Honbo N, et al. Doxorubicin cardiomyopathy. Cardiology. 2010;115:155-62. 21. Lopez BL, Liu GL, Christopher TA, et al. Peroxynitrite, the product of nitric oxide and superoxide, causes myocardial injury in the isolated perfused rat heart. Coronary Artery Dis. 1997;8:149-53. 22. Gao WD, Liu Y, Marban E. Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation. 1996;94: 2597-604. 23. Dhalla AK, Hill MF, Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol. 1996;28:506-14. 24. Dhalla AK, Singal PK. Antioxidant changes in hypertrophied and failing guinea pig hearts. Am J Physiol. 1994;266:H1280-5. 25. Qin F, Shite J, Liang CS. Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways. Am J Physiol Heart Circ Physiol. 2003;285:H82232. 26. McMurray J, McLay, Chopra M, et al. Evidence for enhanced free radical in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1990;65:1261-2. 27. McMurray J, Chopra M, Abdullah I, et al. Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J. 1993;14:1493-8. 28. Tsutsui T, Tsutamoto T, Wada A, et al. Plasma oxidized lowdensity lipoprotein as a prognostic predictor in patients with chronic congestive heart failure. J Am Coll Cardiol. 2002;39:957-62. 29. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, func­tional, and hemodynamic staging. Circulation. 2003;107:1991-7. 30. Wijeysundera HC, Hansen MS, Stanton E, et al. Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine. Am Heart J. 2003;146:291-7. 31. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med. 1993;153:937-42. 32. Grobe JL, Mecca AP, Lingis M, et al. Prevention of angiotensin II-induced cardiac remodeling by angiotensin (1-7). Am J Physiol Heart Circ Physiol. 2007;292:H736-42. 33a. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-5. 33b. McMurray JJ, Ray SG, Abdullah I, et al. Plasma endothelin in chronic heart failure. Circulation. 1992;85:1374-9. 34. Levine ER. Endothelins. N Engl J Med. 1995;333:356-63. 35. Chatterjee K, De Marco T, McGlothlin D. Remodeling in systolic heart failure effects of neurohormonal modulators: basis for current pharmacotherapy. Cardiol Today. 2005;9:270-7. 36. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990;82: 1724-9. 37. Szatalowicz VL, Arnold PE, Chaimovitz C, et al. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med. 1981;305:263-6.

87

88

Manual of Heart Failure 38. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341:577-85. 39. Goldsmith SR, Francis GS, Cowley AW, et al. Hemodynamic effects of infused arginine vasopressin in congestive heart failure. J Am Coll Cardiol. 1986;8:779-83. 40. Goldsmith SR, Francis GS, Cowley AW, et al. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol. 1983;1:1385-90. 41. Levine TB, Francis GS, Goldsmith SR, et al. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnor­ malities in congestive heart failure. Am J Cardiol. 1982;49:1659-66. 42. Viquerat CE, Daly P, Swedberg K, et al. Endogenous catecholamine levels in chronic heart failure: relation to the severity of hemodynamic abnormalities. Am J Med. 1985;78:455-60. 43. Leimbach WN, Wallin BG, Victor RG, et al. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986;73:913-9. 44. Swedberg K, Viquerat C, Rouleau JL, et al. Comparison of myocardial catecholamine balance in chronic congestive heart failure and in angina pectoris without heart failure. Am J Cardiol. 1984;54:783-6. 45. Hasking GL, Esler MD, Jennings GL, et al. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986;73:615-21. 46. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic heart failure. N Engl J Med. 1984;311:819-23. 47. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107:1278-83. 48. Mann DL. Inflammatory mediators and the failing heart: past, present and the foreseeable future. Circ Res. 2002;91:988-98. 49. Bolognese L, Neskovic AN, Parodi G, et al. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilatation and long term prognostic implications. Circulation. 2002;106:2351-7. 50. Pfeffer MA, Janice M. Pfeffer memorial lecture. J Card Fail. 2002;8: S248-52. 51. The SOLVD investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-91. 52. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327: 669-77. 53. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction. Lancet. 2001;357:138590. 54. Vantrimpont P, Rouleau JL, Wun CC, et al. Additive beneficial effects of beta blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) study. J Am Coll Cardiol. 1997;29:229-36.

Systolic Heart Failure 55. Pitt B, Remme W, Zanand F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-21. 56. Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005;46:425-31. 57. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;53:e1-90. 58. Wilhelmsen L, Rosengren A, Eriksson H, et al. Heart failure in the general population of men morbidity, risk factors and prognosis. J Intern Med. 2001;249:253-61. 59. Baker DW. Prevention of heart failure. J Card Fail. 2002;8:333-46. 60. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-52. 61. ALLHAT Investigators. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-97. 62. Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation. 2002;105:1727-33. 63. He J, Odgen LG, Bazzano LA, et al. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996-1002. 64. Vaur L, Gueret P, Lievre M, et al. Development of congestive heart failure in type 2 diabetic patients with microalbuminuria or proteinuria; observations from the DIABHYCAR (type 2 DIABetes, Hypertension, Cardiovascular Events and Ramipril) study. Diabetes Care. 2003;26:855-60. 65. Levy D, Larson MG, Vasan RS, et al. The progression from hyper­ tension to congestive heart failure. JAMA. 1996;275:1557-62. 66. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. 67. Bert T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003;138:542-9. 68. Zanella MT, Ribeiro AB. The role of angiotensin II antagonism in type diabetes mellitus: a review of reno-protection studies. Clin Ther. 2002;24:1019-34. 69. Wilson PW, Grundy SM. The metabolic syndrome: practical guide to origins and treatment: Part I. Circulation. 2003;108:1422-4. 70. Kjekshus J, Pedersen TR, Olsson AG, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. 1997;3:249-54. 71. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet agents and survival: a cohort analysis from the Studies of Left

89

90

Manual of Heart Failure

72.

73.

74.

75.

76. 77. 78. 79. 80.

81.

82.

83.

84. 85.

Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol. 1998;31:419-25. Guazzi M, Brambilla R, Reina G, et al. Aspirin-angiotensin-converting enzyme inhibitor coadministration and mortality in patients with heart failure: a dose related adverse effect of aspirin. Arch Intern Med. 2003;163:1574-9. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355:157581. Grag R, Yusuf S. Overview of randomized trials of angiotensinconverting inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450-6. The Concensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-35. Sharpe DN, Murphy J, Coxon R, et al. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circulation. 1984;70:271-8. Captopril Multicenter Research Group. A placebo controlled trial of captopril in refractory chronic heart failure. J Am Coll Cardiol. 1983;2:755-63. Chalmers JP, West MJ, Cyran J, et al. Placebo-controlled study of lisinopril in congestive heart failure: a multi-centre study. J Cardiovasc Pharmacol. 1987;9:S89-97. Cohn JN, Tognoni G, Valsartan Heart Failure Investigators. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-75. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582-7. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM–Alternative trial. Lancet. 2003;362:772-6. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-71. Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation. 2004;110: 2618-26. Dalby MC, Burke M, Radley-Smith R, et al. Pheochromocytoma presenting after cardiac transplantation for dilated cardiomyopathy. J Heart Lung Transplant. 2001;20:773-5. Gilbert EM, Anderson JL, Deitchman D. Chronic b-blockervasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990;88:223-9.

Systolic Heart Failure 86. RESOLVD Investigators. Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy. The Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot study. Circulation. 2000;101:378-84. 87. Groenning BA, Nilsson JC, Sondergaard L, et al. Anti-remodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol. 2000;36:207280. 88. McAlister FA, Wiebe N, Ezekowitz JA, et al. Meta-analysis: betablocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-94. 89. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) trial study group. Lancet. 1993;342:1441-6. 90. CIBIS Investigators and Committees. A randomized trail of betablockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;90:1765-73. 91. Packer M, Bristow MR, Cohn J, et al. The effects of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:134955. 92. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure: results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. N Engl J Med. 2001;344:1651-8. 93. Effect of metoprolol CR/XL in chronic heart failure: Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-7. 94. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. Lancet. 1999;353:913. 95. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomized controlled trial. Lancet. 2003;362:7-13. 96. A trial of the beta-blocker bucindolol in patients with advanced heart failure. N Engl J Med. 2001;344:1659-67. 97. Maack C, Cremers B, Flesch M, et al. Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium. Br J Pharmacol. 2000;130:1131-9. 98. Andreka P, Aiyar N, Olson LC, et al. Bucindolol displays intrinsic sympathomimetic activity in human myocardium. Circulation. 2002;105:2429-34. 99. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-25. 100. Cohn JN, Pfeffer MA, Rouleau J, et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003;5:65967. 101. Fonarow GC, Abraham WT, Albert NM, et al. Influence of beta-blocker continuation or withdrawal on outcomes in patients

91

92

Manual of Heart Failure hospitalized with heart failure: findings from the OPTIMIZE-HF program. J Am Coll Cardiol. 2008;52:190-9. 102. Salpeter SR, Ormiston TM, Salpeter EE. Cardio-selective betablockers in patients with reactive airway disease: a meta-analysis. Ann Intern Med. 2002;137:715-25. 103a. Pitt B, Zannad F, Remme WJ, et al. For the Randomized Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-17. 103b. Tsutamoto T, Wada A, Maeda K, et al. The effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001;37:1228-33. 103c. Udelson JE, Feldman AM, Greenberg B, et al. Randomized, doubleblind multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular dysfunction. Circ Heart Fail. 2010;3:347-53. 104. Silverstre JS, Heymes C, Oubénaïssa A, et al. Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation. 1999;99:2694-701. 105. de Gasparo M, Joss U, Ramjoué HP, et al. Three new epoxyspirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther. 1987;240:650-6. 106. Shah KB, Rao K, Sawyer R, et al. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46:845-9. 107. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med. 2011;364;11-21. 108. Nodari S, Triggiani M, Campus U, et al. Effects of n-3 polyunsatu­ rated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2011; DOI:10.1016. 109. Chatterjee K, Parmley WW, Massie B, et al. Oral hydralazine therapy for chronic refractory heart failure. Circulation. 1976;54:879-83. 110. Massie B, Chatterjee K, Werner J, et al. Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. Am J Cardiol. 1977;40:794-801. 111. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547-52. 112. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril wit hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303-10. 113. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-57. 114. Elkayam U. Nitrates in the treatment of congestive heart failure. Am J Cardiol. 1996;77:41C-51. 115. Packer M, O’Conner CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107-14.

Systolic Heart Failure 116. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-20. 117. Wilson JR, Reichek N, Dunkman WB, et al. Effect of diuresis on the performance of the failing left ventricle in man. Am J Med. 1981;70:234-9. 118. Bayliss J, Norell M, Canepa-Anson R, et al. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J. 1987;57:17-22. 119. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147:331-8. 120. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671-8. 121. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006;47:1987-96. 122. Francis GS, Siegel RM, Goldsmith SR, et al. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohormonal axis. Ann Intern Med. 1985;103:1-6. 123. Cooper HA, Dries DL, Davis CE, et al. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation. 1999;100:1311-5. 124. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care for hospitalized patients with heart failure: The Relief for Acutely Fluid-Overloaded Patients with Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol. 2005;46:2043-6. 125. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for acute decompensated heart failure. J Am Coll Cardiol. 2007;49:675-83. 126. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitroprusside for advanced low-out put heart failure. J Am Coll Cardiol. 2008;52:200-7. 127. VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-40. 128. Sackner-Bernstein JD, Skopick HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111:1487-91. 128a. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32-43. 128b. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy, the Trial of intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIMECHF) randomized trial. JAMA. 2009;301:383-92. 129. Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med. 1980;303:1443-8. 130. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-33. 131. Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe heart failure. Circulation. 1977;56:468-72.

93

94

Manual of Heart Failure 132. Goldberg LI, Rajfer SI. Dopamine receptors: application in clinical cardiology. Circulation. 1985;72:245-8. 133. Leier CV, Heban PF, Huss P, et al. Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation. 1978;58:466-75. 134. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-7. 135. Amsallem E, Kasparian C, Haddour G, et al. Phosphodiesterase III inhibitors for heart failure. Cochrane Database Syst Rev. 2005;25: CD002230. 136. Simonton CA, Chatterjee K, Cody RJ, et al. Milrinone in congestive heart failure: acute and chronic hemodynamic and clinical evaluation. J Am Coll Cardiol. 1985;6:453-9. 137. Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol. 2007;50:2136-44. 138. Kivikko M, Lehtonen L, Collucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107:81-6. 139. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297:1883-91. 140. Fox K, Ford I, Steg PG, et al. BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL) a randomized double-blind placebo-controlled trial. Lancet. 2008;372:807-16. 140a. Tuunanen H, Engblom E, Naum A, et al. Trimetazidine, a metabolic modulator has cardiac and extracardiac beifits in idiopathic dilated cardiomayopathy. Circulation. 2008;118:1250-8. 140b. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure (COMPANION). N Engl J Med. 2004;350: 2140-50. 141a. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an Implantable Cardioverter-Defibrillator for Congestive Heart Failure (SCD-HeFT). N Engl J Med. 2005;352:225-37. 141b. De Ferrari GM, Crijns HGM, Borggrefe M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2010; DOI:1093/eurheartj/ehq391. 142. Muus KJ, Knudson A, Klug MG, et al. Effect of post-discharge follow-up care on re-admissions among US veterans with congestive heart failure: a rural-urban comparison. Rural Remote Health. 2010;10:1447. 143. Wright SP, Verouhis D, Gamble G, et al. Factors influencing the length of hospital stay of patients with heart failure. Eur J Heart Fail. 2003;5:201-9. 144. Fonarow GC, Abraham WT, Albert NM, et al. Organized Program To Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design. Am Heart J. 2004;148:43-51. 145. Ponniah A, Anderson B, Shakib S, et al. Pharmacists’ role in the post-discharge management of patients with heart failure: a literature review. J Clin Pharm Ther. 2007;32:343-52.

Systolic Heart Failure 146. Thompson DR, Roebuck A, Stewart S. Effects of a nurse-led, clinic and home-based intervention on recurrent hospital use in chronic heart failure. Eur J Heart Fail. 2004;7:377-84. 147. Kwok T, Lee J, Woo J, et al. A randomized controlled trial of community nurse-supported hospital discharge program in older patients with chronic heart failure. J Clin Nurs. 2008;17:109-17. 148. O’Loughlin C, Murphy NF, Conlon C, et al. Quality of life predicts outcome in a heart failure disease management program. Int J Cardiol. 2010;139:60-7. 149. Driscoll A, Worrall-Carter L, Hare DL, et al. Evidence-based chronic heart failure management programs: reality or myth? Qual Saf Health Care. 2009;18:450-5. 150. Stewart S, Horwitz JD. Specialist nurse management programs: economic benefits in the management of heart failure. Pharmaco­ economics. 2003;21:225-40. 151. Stewart S, Horwitz JD. Detecting early clinical deterioration in chronic heart failure patients post-acute hospitalization a critical component of multidisciplinary, home based intervention? Eur J Heart Fail. 2001;4:345-51. 152. Stewart S, Blue L, Walker A, et al. An economic analysis of specialist heart failure nurse management in the UK: can we afford not to implement it? Eur Heart J. 2002;23:1323-5. 153. Chaudhry SI, Mattera JA, Curtis JP, et al. Telemonitoring in patients with heart failure. N Eng J Med. 2010;363:2301-9. 154. Koehler F, Winkler S, Schieber M, et al. Telemedical interventional monitoring in heart failure (TIM-HF), a randomized, controlled, intervention trial investigating the impact of telemedicine on mortality in ambulatory patients with chronic heart failure study design. Eur J Heart Fail. 2010;12:1354-62. 155. Turner DA, et al. Heart. 2008;94:1601-6. 156. Wang Y, et al. Occupational, Commuting, and Leisure-Time Physical Activity in Relation to Heart Failure Among Finish Men and Women. JACC. 2010;56:1140-8.

95

CHAPTER 4

Diastolic Heart Failure

(Heart Failure with Preserved Ejection Fraction) Kanu Chatterjee

Chapter Outline • Definition • Epidemiology • Pathophysiology –– Ventricular Remodeling –– Neurohormonal Changes –– Functional Derangements –– Hemodynamic Consequences

• • • • •

Clinical Presentation Diagnosis Prognosis Treatment Strategies Future Directions

INTRODUCTION

Diastolic heart failure as a clinical entity was recognized over 70 years ago by Dr. Fishberg, who wrote in 1937 that “this form of cardiac insufficiency results from inadequate filling of the heart” and he termed this form of heart failure as “hypodiastolic failure”.1 However the syndrome of diastolic heart failure was not appreciated until about two decades ago when the cardiologists and the heart failure specialists recognized that diastolic heart failure is as common as systolic heart failure. The prevalence of diastolic heart failure appears to have also increased in recent years. In one community-based study, the prevalence of diastolic heart failure was approximately 35% in 1986, and it increased to over 50% in 2002.2 It should also be appreciated that the recognition of this clinical subset of chronic heart failure by the physicians has also increased in recent years.

DEFINITION

There are not only confusions regarding the definition of diastolic heart failure but also for the timing of onset and duration of diastole. In the Webster Dictionary, diastole is defined as “the dilatation of the heart with blood: opposed to systole, or contraction”. The onset of diastole coincides with the closure of the aortic valve as it has been conventionally recognized as the onset of left ventricular relaxation.3 However, as the left ventricular ejection influences its relaxation, it has been proposed that these phases should be regarded as part of systole and not of diastole.4 In clinical practice the opening of the mitral valve is used as the beginning of diastole and the closure of the mitral valve as the end of diastole.5 This phase is also called auxotonic relaxation phase.

Diastolic Heart Failure

One of the pathophysiologic definitions, as proposed by Brutsaert et al.4 is that it is “a condition resulting from an increased resistance to filling of one or both ventricles leading to symptoms of congestion due to an inappropriate upward shift of the diastolic-pressure-volume relation (i.e. during the terminal phase of the cardiac cycle). Another proposed pathophysiologic definition is that it is a condition in which the “ventricular chamber is unable to accept an adequate volume of blood during diastole at normal diastolic pressures and at volumes sufficient to maintain an appropriate stroke volume”.6 Although these definitions describe the pathophysiologic characteristics of diastolic heart failure, they cannot be used in clinical practice. A number of clinical definitions have also been proposed. One definition is that the diastolic heart failure is a “clinical syndrome characterized by the symptoms and signs of heart failure, a preserved ejection fraction (EF), and abnormal diastolic function”.6 Other definitions, such as “heart failure with normal or near normal ejection fraction”, have also been used. In clinical practice most commonly used definition of diastolic heart failure (HFNEF) is when “the symptoms and signs of heart failure are present and the ejection fraction is greater than 45%”. It should be appreciated that EF is load dependent. A lower preload and a higher after load are associated with a lower EF. Thus, at the time of measurement of EF, it is desirable to consider the determinants of preload (e.g. end-diastolic volume) and of afterload (e.g. blood pressure).

EPIDEMIOLOGY

The incidence and prevalence of diastolic heart failure have been studied in a number of epidemiologic studies.2,7-12 These studies estimated the prevalence of diastolic heart failure between 50% and 55%. The prevalence increases with age, and it is more common in women than in men. In the cardiovascular health study,11a,12 the risk of developing heart failure was higher in elderly women. In women at age between 65 and 69 years, the incidence was 6.6%, and it increased to 14% in women older than 85 years.7,11a,12 That diastolic heart failure is more common in women than in men has been recognized in many studies.13,14 In the cardiovascular health study, the prevalence of diastolic heart failure in women was 67% and that in men 42%.11a,12 Similar findings were observed in the Framingham study.13,14 In the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity-Preserved (CHARM-Preserved) trial, the incidence of diastolic heart failure was higher in women than in men.15 In this study, left ventricular EF needed to be greater than 40% to be included in the trial. The prevalence of women was 40% in the CHARM-Preserved study. In the

97

98

Manual of Heart Failure   TABLE 1  Systolic vs diastolic heart failure ADHERE—All enrolled discharges Profile

SHF

DHF

EF (59,523) (50,497) EF 40% Age 69.9 74.2* Female 39% 62.2%* CAD 63% 54%* Diabetes 42% 46%* AF 29% 33%* BNP 1486 925* * 65 years of age. Am J Cardiol. 2001;87:413-9. 13. Vasan RS, Larson MG, Benjamin Ej, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction. J Am Coll Cardiol. 1999;33:1948-55. 14. Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham study. J AM Coll Cardiol. 1993;22:6A-13A. 15. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left ventricular ejection fraction: the CHARM–Preserved trial. Lancet. 2003;362: 777-81. 16. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-67. 17. Sweitzer NK, Lopatin M, Yancy CW, et al. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or = 55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (< 40%) fractions. Am J Cardiol. 2008,101:1151-6. 18. Quinones MA, Zile MR, Massie BM, et al. Chronic heart failure: a report from the Dartmouth Diastolic Discourses. Congest Heart Fail. 2006;12:162-5. 19. Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior in the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation. 2006;113:296-304. 20. Aurigemma GP, Gaasch WH. Diastolic heart failure. N Engl J Med. 2004;351:1097-105. 21. Baicu CF, Zile MR, Aurigemma GP, et al. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation. 2005;111:2306-12. 22. Borbély A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111:774-81. 23. van Heerebeek L, Borbély A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113:1966-73.

121

122

Manual of Heart Failure 24. Wang J, Kurrelmeyer KM, Torre-Aminone N, et al. Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy. J Am Coll Cardiol. 2007;49:88-96. 25. Yu CM, Zhang Q, Yip GW, et al. Diastolic and systolic asynchrony in patients with diastolic heart failure: a common but ignored condition. J Am Coll Cardiol. 2007;49:97-105. 26. Chatterjee K, Massie B. Systolic and diastolic heart failure: differences and similarities. J Card Fail. 2007;13:569-76. 27. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288:2144-50. 28. Konstam MA. Systolic and diastolic dysfunction in heart failure? Time for a new paradigm. J Cardiac Failure. 2003;9:1-3. 29. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res. 2002;90:520-30. 30. Ahmed SH, Clark LL, Pennington WR, et al. Matrix metallopro­ teinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006;113:2089-96. 31. Morgan JP. Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med. 1991;325: 625-32. 32. Weinberg EO, Apstein CS, Vogel WM. Impaired myocardial relaxation is improved by combined beta-adrenergic stimulation and calcium channel blockade. J Mol Cell Cardiol. 1991;23:S68. 33. Katz AM, Zile MR. New molecular mechanism in diastolic heart failure. Circulation. 2006;113:1922-5. 34. Mak GJ, Ledwidge MT, Watson CJ, et al. Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol. 2009;54:1674-82. 35. Kihara Y, Grossman W, Morgan JR. Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res. 1989;65:102944. 36. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure-abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350:1953-9. 37. Handoko ML, van Heerebeek L, Bronzwaer JG, et al. Does diastolic heart failure evolve to systolic heart failure? Abstract. Circulation. 2006;114:II-816. 38. Lam CS, Roger VL, Rodeheffer RJ, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009;53:1119-26. 39. Grewal J, McCully RB, Kane GC, et al. Left ventricular function and exercise capacity. JAMA. 2009;301:286-94. 40a. Bitter T, Faber L, Hering D, et al. Sleep-disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail. 2009;11:602-8. 40b. Daneshvar D, Wei J, Tolstrup K, et al. Diastolic dysfunction: improved understanding using emerging imaging techniques. Am Heart J. 2010;160:394-404. 41a. Bella JN, Palmieri V, Roman MJ, et al. Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in

Diastolic Heart Failure

41b. 42. 43.

44.

45. 46. 47.

48.

49. 50. 51. 52. 53. 54. 55. 56.

middle-aged and elderly adults: the strong heart study. Circulation. 2002;105:1928-33. Zhang Y, Safer ME, Iaria P, et al. Prevalence and prognosis of left ventricular diastolic dysfunction in the elderly: the PROTEGER study. Am Heart J. 2010;160:471-8. Ren X, Ristow B, Na B, et al. Prevalence and prognosis of asympto­ matic left ventricular diastolic dysfunction in ambulatory patients with coronary heart disease. Am J Cardiol. 2007;99:1643-7. Gottdiener JS, McClelland RL, Marshal R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The cardiovascular health study. Ann Intern Med. 2002;137:631-9. Pulignano G, Del Sindaco D,Tavazzi L, et al. Clinical features and outcomes of elderly outpatients with heart failure followed up in hospital cardiology units: data from a large nationwide cardiology database (IN-CHF Registry). Am Heart J. 2002;143:45-55. Smith GL, Masoudi FA, Vaccarino V, et al. Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline. J Am Coll Cardiol. 2003;41:1510-8. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260-9. Yancy CW, Lopatin M, Stevenson LW, et al. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure Registry (ADHERE) Database. J Am Coll Cardiol. 2006;47:76-84. Danciu SC, Gonzalez J, Gandhi N, et al. Comparison of six-month outcomes and hospitalization rates in heart failure patients with and without preserved left ventricular ejection fraction and with and without intraventricular conduction defect. Am J Cardiol. 2006;97: 256-9. O’Connor CM, Gattis WA, Shaw L, et al. Clinical characteristics and long-term outcomes of patients with heart failure and preserved systolic function. Am J Cardiol. 2000;86:863-7. Jones RC, Francis GS, Lauer MS. Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial. J Am Coll Cardiol. 2004;44:1025-9. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671-8. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-7. Al-Khatib SM, Shaw LK, O’Connor C, et al. Incidence and predictors of sudden cardiac death in patients with diastolic heart failure. J Cardiovasc Electrophysiol. 2007;18:1231-5. Hsia J, Jablonski KA, Rice MM, et al. Sudden cardiac death in patients with stable coronary artery disease and preserved left ventricular systolic function. Am J Cardiol. 2008;101:457-61. Paulus WJ, Ballegoij JJ. Treatment of heart failure with normal ejection fraction. An inconvenient truth! J Am Coll Cardiol. 2010;55: 526-37. Yip GW, Wang M, Wang T, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan

123

124

Manual of Heart Failure

57. 58.

59.

60. 61.

62. 63.

64.

65.

66.

67.

68.

69. 70.

and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008;94:573-80. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension 80 years of age or older. N Engl J Med. 2008;358:1887-98. Klapholz M, Maurer M, Lowe AM, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York heart failure registry. J Am Coll Cardiol. 2004;43:1432-8. Fonarow GC, Stough WC, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768-77. McMurray JW, Carson PE, Komajda M, et al. Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail. 2008;10:149-56. Friedrich SP, Lorell BH, Rousseau MF, et al. Intracardiac angiotensinconverting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation. 1994;90:2761-71. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338-45. Wachtell K, Belle JN, Rokkedal J, et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation. 2002;105:1071-6. Díez J, Querejeta R, López B, et al. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002;105: 2512-7. Solomon SD, Janardhanan R, Verma A, et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomized trial. Lancet. 2007;369:2079-87. Bergstörm A, Andersson B, Edner M, et al. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail. 2004;6:453-61. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-25. van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (Study of Effects of Nevibolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure). J Am Coll Cardiol. 2009;53:2150-8. Mak GJ, Ledwidge MT, Watson CJ, et al. Natural history of markers of turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol. 2009;54:1674-82. Mottram PM, Haluska B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004;110:558-65.

Diastolic Heart Failure 71. Ramasubbu K, Estrep J, White DL, et al. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol. 2008;51:415-26. 72. Fukuta H, Sane DC, Brucks S, et al. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation. 2005;112:357-63. 73. Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension in heart failure with preserved ejection fraction. A target of phospho­ diesterase -5 inhibition in 1-year study. Circulation. 2011;124:164-74. 74. Piña IL, Apstein CS, Balady GJ, et al. Exercise and heart failure: a statement from the American Heart Association Committee on Exer­ cise, Rehabilitation and Prevention. Circulation. 2003;107:1210-25. 75. Nagayama T, Hsu S, Zhang M, et al. Sildenafil stops progressive chamber, cellular and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol. 2009;53:207-15. 76. Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling and disease. Circ Res. 2004;94:28495. 77. Linke WA. Sense and stretchability: the role of titin and titin associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res. 2008;77:637-48. 78. Kass DA, Bronzwaer JG, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res. 2004;94:1533-42. 79. Shapiro BP, Owan TE, Mohammed SF, et al. Advanced glycation end products accumulate in vascular smooth muscle and modify vascular but not ventricular properties in elderly hypertensive canines. Circulation. 2008;118:1002-10. 80. Little WC, Zile MR, Kitzman DW, et al. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treat­ ment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191-5. 81. Bronzwaer JG, Paulus WJ. Nitric-oxide: the missing lusitrope in failing myocardium. Eur Heart J. 2008;29:2453-5.

125

CHAPTER 5

Anemia in Patients with Chronic Heart Failure (Prevalence, Mechanism, Significance, and Treatment) James Prempeh, Barry M Massie

Chapter Outline • Overview of the Problem • Prevalence of Anemia in Heart Failure Patients • Mechanisms Underlying Anemia in Heart Failure Patients • Prognostic Significance of Anemia in Heart Failure Patients • Should Anemia Be Treated in Heart Failure Patients?

• Safety Concerns Related to ESPs in a Variety of Anemic Patients • Treatment of Anemia in Heart Failure Patients –– Erythropoietin-stimulating Proteins (ESPs) –– Iron Deficiency and Iron Replacement in Heart Failure

OVERVIEW OF THE PROBLEM

In recent years, it has been recognized that anemia is common in heart failure patients and is associated with a poor prognosis compared to patients with normal hemoglobin levels. Anemia itself can cause heart failure, although it is uncommon for it to be the sole mechanism. In part this not only reflects the impact of comorbid conditions, such as chronic kidney disease, but also processes, such as cytokine activation, other inflammatory processes and aging. Conversely, heart failure may itself cause anemia or increase plasma volume which may present as anemia due to low hemoglobin levels. Importantly, heart failure patients with anemia have a poor prognosis. As a result, there has been considerable interest in the correction of anemia with erythropoietin-stimulating proteins (ESPs) or iron replacement. This chapter has reviewed the current information on the prevalence, mechanisms and prognostic significance of anemia in heart failure patients. It has also discussed the potential benefits and risks of anemia correction and reviewed the data from clinical trials that have evaluated the effects of anemia correction.

PREVALENCE OF ANEMIA IN HEART FAILURE PATIENTS

Anemia is common in older population, and particularly so in patients with cardiovascular and renal disease. Using the World Health Organization definition of anemia (hemoglobin 25% increase furosemide, NYHA class, low hospitalization LVEF Mullens et al. 145 >0.3 mg/dL 40 High admission and post-treatment Not reported CVP, baseline renal insufficiency Damman et al. 1,023 >0.3 mg/dL and 11 Baseline GFR, age, DM and Increased HF hospitalization and (COACH) >25% Anemia all-cause mortality

Authors

Contd...

170 Manual of Heart Failure

Cardiorenal Syndrome

FIGURE 3: Relationship of blood urea nitrogen (BUN) to survival in 680 outpatients with left ventricular systolic dysfunction followed for five years. By multivariate analysis BUN was a better predictor of survival than serum creatinine (Source: Modified from Heywood JT, et al. J Cardiovasc Pharmacol Ther. 2005;10:173-80)

FIGURE 4: Worsening renal function is a strong predictor of increased length of stay and mortality in patients admitted with acute decompensated heart failure. A serum creatinine rise of >0.3 mg/dL provided the best sensitivity and specificity in predicting both mortality and increased length of stay (Source: Modified from Gottlieb SS, et al. Journal of Cardiac Failure. 2002;8:136-41)

using data from over 60,000 admissions created a mortality model based of classification and regression tree (CART) analysis and found that a BUN greater than 43 mg/dL was the most powerful predictor of inpatient mortality, followed by low systolic blood pressure and serum creatinine (Flowchart 1).

171

172

Manual of Heart Failure FLOWCHART 1: Data from the Acute Decompensated Heart Failure National Registry (ADHERE) was used to create a risk classification system for patients admitted with heart failure. Using CART analysis, 39 variables were evaluated to create a model to predict inpatient mortality. This was done first for a derivation group of 33,046 patients and then applied to a 32,229 patient validation group with very similar results. In this model a BUN of 43 mg/dL was the most powerful predictor of mortality followed by low systolic blood pressure and then serum creatinine. In the validation group shown 32,229 patients were evaluated but only 31,635 had all 3 parameters for evaluation

(Source: Modified from Fonarow GC, et al. JAMA. 2005;293:572-80)

DEFINITION OF THE CARDIORENAL SYNDROME

The definition of the cardiorenal syndrome (CRS) is described as concomitant dysfunction of the heart and kidneys in which an acute or chronic dysfunction in one organ may result in an acute or chronic dysfunction in the other organ, WRF during acute HF treatment or diuretic resistance.6,7 Ronco et al. have suggested that the CRS should be characterized according to whether the impairment of each organ is primary, secondary or whether abnormal heart and kidney functions occur simultaneously as a result of a systemic disease.6 For example, acute HF decompensation can cause both acute renal failure (ARF) and CKD: a decreased cardiac output (CO) is associated with renal arterial underfilling and increased venous pressure which, in turn, result in a reduced GFR.8 The direct and indirect effects of each dysfunctional organ can initiate and perpetuate the combined disorder of the two organs through complex neurohormonal feedback mechanisms.

Cardiorenal Syndrome   TABLE 5  Cardiorenal syndrome Type Name

Description

Type 1 Acute cardiorenal

Abrupt worsening of cardiac function



(e.g. acute cardiogenic shock, or

syndrome



acutely decompensated heart failure)



leading to acute kidney injury

Type 2 Chronic cardiorenal

Chronic abnormalities in cardiac



function (e.g. chronic heart failure)

syndrome



causing progressive and potentially



permanent chronic kidney disease

Type 3 Acute renocardiac

Abrupt worsening of renal function



(e.g. acute kidney ischemia or

syndrome



glomerulonephritis) causing acute



cardiac disorders (e.g. heart failure,



arrhythmia, ischemia)

Type 4 Chronic renocardiac

Chronic kidney disease (e.g. chronic



glomerular or interstitial disease)

syndrome



contributing to decreased cardiac



function, cardiac hypertrophy and/or



increased risk of adverse



cardiovascular events

Type 5 Secondary cardiorenal Systemic conditions (e.g. diabetes syndrome mellitus, sepsis) causing both cardiac and renal dysfunction (Source: Reference 6)

Consequently the subdivision of CRS into five different subtypes may facilitate care of individual patients (Table 5). Type 1 CRS (acute CRS) defines a rapid deterioration in cardiac function, which produces ARF. Preexistent CKD is frequent and increases the risk of ARF. The severity of ARF is greater in patients with impaired than in those with preserved LV systolic function, and it occurs in more than 70% of patients with cardiogenic shock.9 Renal dysfunction independently predicts one-year mortality in patients with ADHF, possibly due to an acute decline in renal function accelerates progression of cardiovascular (CV) disease through activation of inflammatory pathways.10 Fundamental concerns regarding ARF are whether it represents inadequate renal perfusion due to either a low CO and/or marked increase in central venous pressure (CVP), or intravascular volume depletion from overdiuresis. Accurate diagnosis and appropriate treatment of type 1 CRS may require measurement of CO and CVP. Renal function should also be closely monitored in patients with acute myocardial infarction (AMI), and in those undergoing cardiac surgery, percutaneous

173

174

Manual of Heart Failure

coronary intervention (PCI) or radiocontrast imaging because in these settings an increase in creatinine signals the onset of ARF which, in turn, may accelerate CV injury through activation of neurohormonal, immunological and inflammatory pathways. Even a modest increase in creatinine (>0.3 mg/dL) is an independent predictor of unfavorable CV outcomes.4 Type 2 CRS (chronic CRS) refers to progressive CKD occurring in approximately 25% of HF patients.11 The presence and worsening of renal function in HF patients is associated with adverse outcomes. Chronic HF may be associated with longstanding renal hypoperfusion often aggravated by coexisting microvascular and macrovascular disease.12 Other causes of the onset and progression of renal dysfunction in chronic HF include neurohormonal activation, resistance to natriuretic peptides, iatrogenic hypovolemia and hypotension. Type 3 CRS (acute renocardiac syndrome) consists of a rapid worsening of kidney function due to ARF, ischemia or glomerulo­nephritis, which leads to acute cardiac abnormalities, including ischemia, arrhythmias and HF. According to the Risk, Injury, and Failure; Loss; and End-stage kidney disease (RIFLE) consensus definition, ARF can be identified in approximately 9% of ADHF patients and in more than 35% of those requiring ICU care.13 In patients with an acute renocardiac syndrome, fluid overload can result in pulmonary edema, and hyperkalemia can cause arrhythmias and even cardiac arrest. Untreated uremia causes accumulation of myocardial depressant factors and pericarditis.14 Patients with bilateral renal artery stenosis (or unilateral stenosis in a solitary kidney) are prone to decompen­sated diastolic HF due to neurohormonally mediated arterial hypertension, sodium, and water retention from renal dysfunction, and acute myocardial ischemia caused by an increased myocardial oxygen demand resulting from intense peripheral vasoconstriction.10 Markers of myocardial ischemia (troponin), or of myocyte stress (BNP), may permit earlier diagnosis and treatment of type 3 CRS.15 Detection of ARF can trigger reduction or even discontinuation of both diuretics and ACE-I, which exposes patients to a greater risk of ADHF and kidney injury due to hyperfiltration. If ARF is severe enough to require renal replacement therapy (RRT), continuous techniques are safer than conventional dialysis because the avoidance of rapid fluid and electrolyte shifts minimizes the risk of hypotension, arrhythmias, and myocardial ischemia. Type 4 CRS (chronic renocardiac syndrome) develops when primary CKD contributes to the aggravation of systolic and diastolic LV dysfunction, left ventricular hypertrophy (LVH) and increased risk of adverse CV events. In CRS type 4, increased levels of biomarkers, such as BNP and troponin, have also been correlated to unfavorable CV outcomes. These

Cardiorenal Syndrome

findings suggest a possible link between chronic inflammation, subclinical infections, accelerated atherosclerosis and adverse cardiorenal outcomes. Unfortunately, because of concerns about WRF, less than 50% of CKD patients are treated with therapies aimed at minimizing CV risk factors, including aspirin, betablockers, ACE-I and statins.16 Type 5 CRS (secondary CRS) is characterized by concomi­tant cardiac and renal dysfunction due to acute or chronic systemic disorders such as sepsis, hypertension, diabetes, amyloidosis and autoimmune diseases. Severe sepsis can produce AKF and myocardial depression through the upregu­lation of tumor necrosis factor (TNF)-α and other proinflammatory mediators.17 While decreased CO can further impair renal function, ARF can negatively affect cardiac performance. Hypotension-induced renal ischemia can further worsen myocardial injury in a vicious cycle harmful to both organs. Therefore, early detection and interruption of this circle is important to improve cardiorenal outcomes.

PATHOPHYSIOLOGY OF THE CARDIORENAL SYNDROME

The kidney receives 20% of CO; thus the function of the heart and kidney are closely intertwined. Changes in volume and pressure in the cardiac atria initiate atrial–renal reflexes, which alter renal function. An increase in left atrial pressure is associated with diuresis through suppression of the antidiuretic hormone, arginine vasopressin (AVP) via vagus nerve stimulation and a decrease in renal sympathetic activity, attenuating neurally mediated vasoconstriction of the kidney18 (Flowchart 2).

ROLE OF DECREASED CARDIAC OUTPUT

The heart can also affect the kidney by activating high-pressure arterial stretch baroreceptors19 located in the carotid sinus, aortic arch and afferent arteriole of the glomerulus. The vagal and glossopharyngeal afferent pathways from these high-pressure receptors would normally inhibit sympathetic outflow from the central nervous system (CNS), but with a decrease in stroke volume or a decline in arterial pressure, CNS inhibition is removed and an increase in sympathetic efferent outflow as well as nonosmotic AVP release occurs with multiple effects on the kidney. When stimulated, the adrenergic and angiotensin receptors on the proximal tubule epithelium enhance proximal tubule sodium reabsorption. In addition to these direct effects on sodium balance, the resultant decreased fluid and sodium delivery to the distal nephron also has an effect on urinary

175

176

Manual of Heart Failure FLOWCHART 2: The development of the cardiorenal syndrome is complex and still poorly understood. Intrinsic renal disease and impaired renal perfusion are important physiologic components of the syndrome. Renal blood flow is not only dependent on CO, but is affected by high venous pressures as well. Patients may have worsening renal function due to multiple intrinsic and extrinsic renal factors

sodium excretion. The sodium retaining effect of aldosterone is only temporary due to the “escape phenomenon”. Normally, the expansion of extracellular fluid volume (ECVF) secondary to aldosterone increases GFR, decreases proximal tubule reabsorption and enhances sodium delivery to the distal nephron, the site of aldosterone activity. This effect, along with the rise in plasma ANP, which occurs with ECVF expansion, overrides the effect of aldosterone to enhance tubular sodium reabsorption and accounts for aldosterone escape. In contrast, the diminished distal sodium delivery, which occurs with neurohumoral activation, abolishes the normal aldosterone escape. This leads to continued aldosterone-mediated renal sodium retention. As with aldosterone, the site of action of natriuretic peptides is also in the distal nephron, namely the collecting duct. The natriuretic response of these peptides is also dependent on distal sodium delivery. Therefore, the resistance to the natriuretic response of ANP and BNP in HF appears to be secondary to the neuro­ humoral-mediated diminished sodium delivery to the collecting duct site of their action. The role of decreased CO in the pathogenesis of the cardiorenal syndrome is more complex than it would first appear. A seminal study by Ljungman20 clearly demonstrates the powerful autoregulatory ability of the kidney to maintain renal perfusion even with significant reductions in CO. However, the same study found that when the cardiac index fell below 1.5 L/min/m2 renal perfusion was reduced with a significant fall in GFR (Fig. 5). Finally, marked cardiorenal dysfunction can be reversed in some patients when CO is restored using a left ventricular assist device.21

Cardiorenal Syndrome

FIGURE 5: Data from Ljungman et al. evaluating the effect of CO on renal function. There was a stepwise decrease in renal blood flow as cardiac index declined with worsening heart failure. Of note, however, GFR is relatively maintained until cardiac index falls below a critical level of 1.5 L/min/m2. (Source: Modified from Ljungman S, et al. Drugs. 1990;39:10-21)

The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial did not find a significant relation between CO and WRF.22 Similarly, Mullens23 reported that reduced CO was not associated with declining renal function. The average entry creatinine in the ESCAPE trial was only 1.5 mg/dL 24 and investigators may not have enrolled patients who had already improved with inotrope infusions. In general, the data suggest that very low CO may impair renal function in selected patients but other factors clearly play a role.

177

178

Manual of Heart Failure

ROLE OF ELEVATED CENTRAL VENOUS PRESSURE

Renal perfusion, as in all organs is influenced by the pressure gradient across its vascular bed. Thus maintenance of a threshold arterial pressure is required for normal renal function. Blood pressure varies from individual to individual and surprisingly low arterial pressures may be well tolerated although rarely below 70–80 mm Hg systolic. Sensitivity to low arterial pressure may also be influenced by coexisting vascular disease. Less well appreciated has been the influence of renal venous pressures on renal perfusion. This is not a new concept since it was formulated by Winton in 1931.25 However, despite convincing animal data, this concept has been largely ignored (Fig. 6). Firth and his colleagues found that GFR declined significantly in a rodent model when venous pressure was raised above 18 mm Hg and was reversible when pressure was normalized.26 The fact that the kidney is an encapsulated organ may augment the effects of venous hypertension. In an elegant model in the rhesus monkey, Stone27 produced acute tubular necrosis and instrumented each kidney. The renal capsule was stripped from one organ and left in place in the other. Creatinine and urea clearance fell to a much greater extent in the encapsulated kidney (Fig. 7). Until recently data supporting the role of elevated venous pressure in the development of renal dysfunction in HF has been lacking, but recent studies have lent support to this concept. Mullens in a study of severely ill HF patients found that CVP was the best predictor of the percentage who would go on to develop renal insufficiency.23 The same group has advanced the concept of a related parameter, namely increased

FIGURE 6: Effect of elevated renal vein pressure on renal blood flow (RBF) and glomerular filtration rate (GFR). In this swine experiment, the central venous pressure was increased to 30 mm Hg. The RBF decreased from 2.7 to 1.5 mL/min/gr and GFR was reduced to less than 30% of the baseline value (Source: Modified from Doty JM, et al. J Trauma. 1999;47:1000-3)

Cardiorenal Syndrome

FIGURE 7: In this elegantly simple experiment, the authors induced acute tubular necrosis in rhesus monkeys via aortic clamping above the renal arteries for one hour. In each animal the renal capsule was removed prior to unclamping the aorta from one kidney and left in place in the other. Clearances of creatinine, urea and free water were calculated for each kidney (Source: Modified from Stone HH, et al. Ann Surg. 1977;186:343-55)

FIGURE 8: Technique for measuring intra-abdominal pressure at the bedside using a modified urinary catheter. When filled with fluid the bladder pressure is at equilibrium with the intra-abominal pressure and can be measured using a standard transducer leveled at the midaxillary (midabdominal) line (Source: Modified from Mullens W, et al. J Am Coll Cardiol. 2008;51:300-6)

intra-abdominal pressure as risk factor for renal insufficiency28 (Figs 8 and 9). In the Figure 8, the technique for measuring intra-abdominal pressure at the bedside with the use of a

179

180

Manual of Heart Failure

FIGURE 9: Levels of intra-abdominal pressure greater than 8 mm Hg were associated with significantly higher serum creatinine levels in patients admitted with severe decompensated heart failure (Source: Modified from Mullens W, et al. J Am Coll Cardiol. 2008;51:300-6)

modified urinary catheter is illustrated. They also have reported that in patients admitted with decompensated HF serum creatinine levels are significantly higher when intra-abdominal pressure was greater than 8 mm Hg (Fig. 9). They also have shown that reduction of intra-abdominal pressure either by paracentesis when ascites is present or by ultrafiltration may at times result in improved renal function.29

ROLE OF EVIDENCE-BASED THERAPIES IN PATIENTS WITH HEART FAILURE AND THE CARDIORENAL SYNDROME DIURETICS Diuretics form the cornerstone of therapy for patients with HF who are hospitalized for symptoms of volume overload and are also important for maintenance of euvolemia in the outpatient setting. Renal dysfunction is common in patients with HF. Since impaired clearance of sodium and water occur in both HF and CKD, patients with these comorbidities have a tendency for volume overload and effective diuretic management is essential. The basic physiology of diuretic agents when renal dysfunction is present can be categorized according to the different types of diuretics as loop, distal convoluted tube, and potassiumsparing diuretics.

Cardiorenal Syndrome

Loop Diuretics Furosemide, torsemide, bumetanide and ethacrynic are amongst the most potent agents for stimulating diuresis and natriuresis through inhibition of the Na+/K+/2Cl– cotransporter on the luminal side of the thick ascending limb of the loop of Henle. Since 25% of the filtered load of sodium chloride is normally reabsorbed here, loop diuretics can cause profound diuresis and natriuresis. Nevertheless, loop diuretics often lower GFR via adenosine release and stimulation of the renin angiotensin aldosterone system (RAAS). Loop diuretics decrease pulmonary congestion and lower left ventricular filling pressures prior to the onset of their diuretic effects. This is probably related to increased synthesis and release of prostaglandins by the kidney in response to these agents.30 In this way, loop diuretics can be effective in the treatment of acute pulmonary congestion and edema even in cases of advanced or end-stage renal disease. Distal Convoluted Tubule Diuretics Thiazide diuretics and metolazone (a thiazide-like agent) inhibit an electrically neutral sodium and chloride cotransporter in the early distal convoluted tubule. These drugs are rarely used as sole diuretic agents in HF as they are significantly less potent compared to loop diuretics. Renal clearance of thiazides is affected in CHF or other disorders with impaired renal blood flow (RBF). Compared to loop diuretics, thiazides also carry a greater risk for hyponatremia and hypokalemia.31 Thiazide and thiazide-like agents have greatest utility in CHF when used concomitantly with loop diuretics.32 In advanced HF the combination of decreased RBF, progressive renal dysfunction and RAAS activation may render maximal doses of loop diuretic therapy ineffective. In the setting of acute and chronic loop diuretic therapy, functional adaptation of the distal tubule with compensatory increases in sodium reabsorption (or diuretic resistance) and the effects of extracellular fluid volume depletion have also been well described. Simultaneous use of high-dose loop diuretics and a thiazide or metolazone inhibits sodium transport in the ascending thick limb of the loop of Henle as well as the compensatory sodium reabsorption in the early distal convoluted tubule. Most thiazide drugs also directly inhibit carbonic anhydrase, which minimizes compensatory sodium reabsorption in the proximal tubule. Diuresis and natriuresis can be greatly enhanced by combination diuretic therapy, though the risk of severe hyponatremia and hypokalemia can be significant. Thus the combination may aid in diuresis when there is significant diuretic resistance in the cardiorenal syndrome with impaired natiuretic response to loop diuretics alone.

181

182

Manual of Heart Failure

Potassium-sparing Diuretics Spironolactone, eplerenone, triamterene, and amiloride inhibit sodium reabsorption at the cortical collecting tubule. Spironolactone and eplerenone are competitive inhibitors of the intracellular mineralocorticoid receptor, decreasing translocation of active sodium transporters to the luminal membrane. Triamterene and amiloride directly inhibit these extracellular sodium channels. Since only 1–2% of the filtered load of sodium chloride is absorbed at this location, the potassium sparing diuretics have relatively low potency as diuretic and natriuretic agents. Their diuretic utility in HF is to counteract potassium wasting and hypokalemic metabolic alkalosis associated with loop and thiazide diuretic use. High doses of potassium-sparing diuretics should be avoided or used with caution in patients with CHF and renal dysfunction as development of dosedependent hyperkalemia is common in this setting. However, in some instances of marked diuretic resistance; high dose spironolactone when used with careful monitoring has been found to augment diuresis.33 Effect of Diuretic Use on Morbidity and Mortality According to the ADHERE registry, 70% of patients took a diuretic as part of their outpatient medication regimen.34 Among patients hospitalized for HF, loop diuretic use is associated with further deterioration of renal function, and this is observed more frequently among patients receiving combination loop diuretic and metolazone therapy.35 Furthermore, higher doses of loop diuretics are associated with higher serum creatinine and reduced survival.36 Patients taking loop diuretics also have an increased risk of hospitalization and death related to CHF compared to those not taking these medications.37 The observations regarding progression of CKD and HF associated with diuretic use are derived from nonrandomized or retrospective studies and should be interpreted with caution. Even though multivariate analyses of retrospective studies that have adjusted for possible confounders have observed disease progression associated with diuretics, such studies cannot control for all the differences among patients, and individuals with more CKD and HF are the most likely to be on diuretics. Thus the severity of baseline disease, rather than the diuretic therapy, may be the cause of the disease progression and death. While the use of diuretics is essential for most patients with CHF, there are adverse outcomes associated with worsening renal and left ventricular function. Spironolactone and eplerenone are currently the only diuretics which have been shown to reduce mortality in HF, and this is probably not related to the agents’ diuretic effect.38,39 The largest diuretic trial to date, the diuretic optimization strategies

Cardiorenal Syndrome

evaluation (DOSE) in acute heart failure trial40 brings a new perspective to the debate on dose and route of administration of diuretics in HF. In this trial, patients were randomized into four groups who received substantially different diuretic regimens. Group 1 received 2.5 times their daily furosemide dose give continuously over the next 48 hours. Group 2 was given the same dose as Group 1 but in divided doses on every 12 hours. Group 3 continued the same daily dose of furosemide but via a continuous intravenous infusion while Group 4 received the same daily dose as Group 3 but in two increments at 12 hours, similarly to Group 2. The high doses of furosemide were associated with slightly higher serum creatinine levels at 48 hours, but these were not statistically significant. This change was greatest at day 4 and resolved by day 60. There was a greater total urine output at 48 hours in the high dose groups. There was no statistically significant difference in the combined endpoint of death, rehospitalization or emergency department visit at 60 days between the groups. The DOSE study is perhaps our best look at different diuretic regimens and their outcomes, but it has important limitations in that it was underpowered to evaluate mortality differences and perhaps the low dose regimen was too low to be effective. Nonetheless, it demonstrated that mild WRF that was seen early in hospitalization usually resolved after discharge without long-term consequences. ACE-I AND ARB In patients with both symptomatic and asymptomatic myocardial dysfunction, long-term administration of ACE-I reduces symptoms, morbidity and mortality from HF associated with reduced ejection fraction.41 The beneficial effects of ACE-I and ARB treatment in patients with CKD (with or without HF) are related to their hemodynamic actions and a wide range of neurohumoral, cellular and vascular actions. The frequency with which renal function changes in HF patients treated chronically with ACE-I was reported in the studies of left ventricular dysfunction (SOLVD). Decreased renal function was defined as a rise in serum creatinine of greater than 0.5 mg/dL above baseline. More patients randomly assigned to enalapril had a decrease in renal function compared with controls (16% vs 12%). Older age, diuretic therapy and diabetes were associated with a greater likelihood of a negative renal function change, whereas beta-blocker treatment and a higher ejection fraction were renoprotective in all patients irrespective of therapy.42 Renal function can also deteriorate suddenly when ACE-I or ARB therapy is first begun or it can acutely change in patients receiving chronic therapy. In most patients who experience ARF with ACE-I or ARB therapy, one or more of four mechanisms

183

184

Manual of Heart Failure

are typically implicated. First, ACE-I or ARB related hypotension is more common with long-acting agents, and if the mean arterial pressure falls to levels that cannot maintain renal perfusion, renal function can be expected to decline.43 Second, ACE-I or ARBs are more likely to cause ARF in the patient with HF who becomes volume depleted from overly aggressive diuresis or intercurrent volume-depleting illness.44 Third, ACE-I or ARB may induce ARF in patients with high-grade bilateral renal artery stenosis or stenosis of a dominant or a single kidney renal artery, or in patients with extensive atherosclerotic disease in smaller preglomerular vessels.45 Finally, ACE-I or ARB may precipitate ARF in patients who are taking nonsteroidal antiinflammatory agents (NSAIDs) or cyclooxygenase-2-specific inhibitors46 (Table 6). Nonetheless, RAAS blockade should be continued when at all possible as mortality is very high when ACE-I/ARBs are stopped for renal reasons and the inability to maintain the use of these agents is a marker for very poor prognosis47 (Fig. 10).   TABLE 6  Principles of ACE-I or ARB therapy: renal considerations • ACE inhibitors and ARBs improve RBF and stabilize glomerular filtration rate in most patients with HF unless they adversely affect cardiac hemodynamics • ACE inhibitor and ARB therapy are indicated in patients with diabetic nephropathy and in patients with nondiabetic nephropathies when protein excretion exceeds 1 g/d. Concurrent primary renal diseases are not uncommon in the HF patient • A rise in serum creatinine may occur after initiation of RAAS inhibitor therapy in patients with HF. This rise usually occurs shortly after initiation of therapy, is in the 10–20% range, is not progressive and is of renal hemodynamic origin. Renal function often stabilizes and may decline thereafter • Although there is no serum creatinine level per se that contraindicates ACE inhibitor therapy, greater increases in serum creatinine occur more frequently when ACE inhibitors are used in patients with underlying chronic kidney disease • The occurrence of AKI should prompt a search for systemic hypotension (MAP