Congenital Heart Defects: Etiology, Diagnosis and Treatment [1 ed.] 9781608764341, 9781606925591

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Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

Cardiology Research and Clinical Developments Series

CONGENITAL HEART DEFECTS: ETIOLOGY, DIAGNOSIS AND TREATMENT

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Practical Rapid ECG Interpretation (PREI) Abraham G. Kocheril and Ali A. Sovari 2009 ISBN: 978-1-60741-021-8 Congenital Heart Defects: Etiology, Diagnosis and Treatment Hiroto Nakamura 2009 ISBN: 978-1-60692-559-1

Cardiology Research and Clinical Developments Series

CONGENITAL HEART DEFECTS: ETIOLOGY, DIAGNOSIS AND TREATMENT

HIROTO NAKAMURA

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EDITOR

Nova Biomedical Books New York

Copyright © 2009 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication.

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Library of Congress Cataloging-in-Publication Data Congenital heart defects : etiology, diagnosis, and treatment / editor, Hiroto Nakamura. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60876-434-1 (E-Book) 1. Congenital heart disease. I. Nakamura, Hiroto. [DNLM: 1. Heart Defects, Congenital--diagnosis. 2. Heart Defects, Congenital--therapy. 3. Child. 4. Infant. WS 290 C7478 2009] RC687.C655 2009 616.1'2043--dc22 2008047035

Published by Nova Science Publishers, Inc.    New York

CONTENTS Preface Chapter I

Chapter II

Chapter III

Ventricular-Vascular Pathophysiology in Children with Cardiovascular Disease Hideaki Senzaki

1

Cardiopulmonary Exercise Testing in Children with Congenital Heart Disease A. Christian Blank and Tim Takken

39

Why the Diagnostic Algorithm in Children with CHD Should Include the Kidney? Ewa Król, Piotr Czarniak and Bolesław Rutkowski

61

Chapter IV

Prenatal Diagnosis of Fetal Congenital Heart Disease Shinro Matsuo and Nasima Akhter

Chapter V

Usefulness of Ultrasound Examination of Abdomen and Cranial in Neonates and Infants with New Recognized Congenital Heart Disease Piotr Czarniak and Wojciech Kosiak

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vii

Chapter VII

Coincidence of Congenital and Acquired Anomalies of Kidney and Upper Urinary Tract in Neonates and Infants with Congenital Heart Disease Piotr Czarniak Genetics of Congenital Heart Diseases: Where are we Now? Giuseppe Limongelli, Paolo Calabro’, Valeria Maddaloni, Raffaella D’Alessandro, Giuseppe Pacileo and Raffaele Calabro’

79

97

113 123

vi Chapter VIII

Sensitivity and Specificity of Three Different Methods for Diagnosis of Congenital Heart Diseases Martha A. Hernández-González, Sergio Solorio, Nilda Espínola-Zavaleta, Víctor M. Jarquín-Pérez, Blanca Murillo-Ortíz, Leonel Daza-Benítez, Luz Verónica Diaz de León, Leticia Rodríguez-Mariscal, Silvia Siu, Aloha Meave-González and Erick Alexanderson-Rosas

Chapter XIV

Single Ventricle Anatomy, Physiology, Repair and Outcome Galina Leyvi and John D. Wasnick

Chapter X

Multidetector-row Computed Tomography Evaluation in Congenital Heart Disease Patients - Additional Information to Echocardiography and Conventional Cardiac Catherterization Yasunobu Hayabuchi, Miki Inoue, Miho Sakata and Shoji Kagami

Chapter XI

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Contents

Three Dimensional Echocardiographic Imaging of Congenital Heart Disease: Initial Experience and Current Status with Real-Time Imaging Mohamed Seliem and Anysia Fedec

Chapter XII

Absence of Atrioventricular Connexion Luis Muñoz Castellanos, Magdalena Kuri Nivon and Nilda Espinola Zavaleta

Chapter XIII

Aneurysmal Formation in Adults After Correction of Aortic Coarctation Yskert von Kodolitsch, Alexander M. J. Bernhardt, and Muhammed A. Aydin

175

189

209

231 253

277

Chapter XIV

Surgical Palliative Options for Patients with Hypoplastic Left Heart Clifford L Cua, Christopher L Cua and Lillian S Lai

305

Chapter XV

Cardiac Tumors – A Review Kalgi Modi and Prasanna Venkatesh

319

Chapte XVI

Pulmonary Hypertension in the Down Syndrome Population Clifford L Cua Louis G Chicoine, Leif D Nelin, and Mary Mullen

327

Chapter XVII Atrioventricular Block during and after Trans-Catheter Closure of Ventricular Septal Defects Mechanisms: Prevention and Treatment Zhi-Yuan Song and Lei Zhang

335

Index

343

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PREFACE A congenital heart defect (CHD) is a defect in the structure of the heart and great vessels of a newborn. Most heart defects either obstruct blood flow in the heart or vessels near it or cause blood to flow through the heart in an abnormal pattern, although other defects affecting heart rhythm (such as long QT syndrome) can also occur. Heart defects are among the most common birth defects and are the leading cause of birth defect-related deaths. This new book presents the latest research in the field from around the world. Chapter I - Although recent advances in genetic, molecular and cellular biology and biochemistry have greatly contributed to uncovering the mystery of human living body, there is still a large gap in our understanding of the pathophysiology of several diseases due to the complex nature of the integrated physiology that is closely linked to the clinical manifestation of the diseases. In the field of cardiovascular disease, with an explosion of technological advances with a background theory on engineering, mathematics, and physics as well as physiology, our understanding of cardiovascular pathophysiology has accelerated since 1970’s. Vascular input impedance and time-varying elastance model in the ventricular pressure-volume framework have played dominant roles in such achievements. In this chapter, methodological and theoretical issues related to both impedance measurements and ventricular pressure-volume relationship will be discussed first, and then details of ventricular-vascular pathophysiology analyzed by these two methods in various cardiovascular diseases/conditions in children will be presented. Although recent advances in genetic, molecular and cellular biology and biochemistry have greatly contributed to uncovering the mystery of human living body, there is still a large gap in our understanding of the pathophysiology of several diseases due to the complex nature of the integrated physiology that is closely linked to the clinical manifestation of the diseases. In the field of cardiovascular disease, with an explosion of technological advances with a background theory on engineering, mathematics, and physics as well as physiology, our understanding of cardiovascular pathophysiology has accelerated since 1970’s. Vascular input impedance and time-varying elastance model in the ventricular pressure-volume framework have played dominant roles in such achievements. In this chapter, methodological and theoretical issues related to both impedance measurements and ventricular pressurevolume relationship will be discussed first, and then details of ventricular-vascular

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

viii

Hiroto Nakamura

pathophysiology analyzed by these two methods in various cardiovascular diseases/conditions in children will be presented. Chapter II - Cardiopulmonary exercise testing (CPET) in pediatric cardiology differs in many aspects from the tests performed in adult cardiology. Diseases that are associated with myocardial ischemia are very rare in children. Children’s cardiovascular responses to exercise present different characteristics, particularly oxygen uptake, heart rate and blood pressure response during exercise, which are essential in interpreting hemodynamic data. The main indications for CPET in children are evaluation of exercise capacity and identification of exercise-induced arrhythmias. In this chapter, we will review exercise equipment and protocols, the main indications for CPET in children with congenital heart disease, the contra-indications for exercise testing and the indications for terminating an exercise test. Moreover, we will address the interpretation of gas exchange data from CPET in children with congenital heart disease. Chapter III - Interaction between kidney and heart become more explore phenomenon on the field of patophysiology of both organs. Chronic kidney disease (CKD) is now a well established powerful risk factor for cardiovascular events. On the other hand cardiovascular disease (CVD) is a risk factor for progression of CKD. Among population of patients on renal replacement therapy, either adults or children, the mortality depends mostly on CVD. Moreover, CVD can deteriorate kidney function, e.g. like in cyanotic hearts defects. Increased incidence of congenital anomalies of urinary tract system accompanying congenital heart disease (CHD), prematurity, low birth weight, use of contrast media and nephrotoxic medications, surgical repairs with extracorporeal circulation, there are some of factors influencing kidney and heart function and can cause reciprocal injury to both organs. Early detection and proper treatment of CKD can delay progression of CKD towards most advanced stages and improve life prognosis in children with CHD. Diagnostic procedure (algorithm) for detection of CKD in children with CHD will be presented. Chapter IV - Congenital heart diseases (CHDs) are the most common congenital anomalies, with a prevalence of 4-13 per 1000 live births [1-6]. The fetal heart must be systematically checked in routine obstetric ultrasound examinations to detect any cardiac abnormality. If cardiac asymmetry is found, a more thorough examination of the fetal heart is indicated. A complete examination will study inflow tract on the four-chamber view, outflow tract by a static and dynamic study of the great arteries. Possible congenital heart disease or suspected heart defect noted on a screening obstetric sonogram is an important indication for fetal echocardiography [7-9]. An increasing number of patients are presenting at early gestational age as being at high risk for congenital heart disease, as a result of ultrasound screening by nuchal translucency (NT). The prevalence of major cardiac defects increases exponentially with fetal NT thickness and finding NT of 3.5 mm or more may lead to an earlier diagnosis of all major types of congenital heart defects. Euploid fetuses with increased NT thickness have a significantly increased risk of cardiac defects and constitute an additional indication for targeted fetal echocardiography [10-12]. Fetal CHDs can be identified reliably by prenatal echocardiography. In expert hands, fetal echocardiography is highly accurate [13,14]. Chapter V - Child with congenital heart disease (CHD) is a very particular patient. Its clinical status may vary from a good to life-threatening condition depending mostly on

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ix

hemodynamic abnormalities and concomitant diseases or anomalies of other systems. The incidence of other congenital defects accompanying CHD is defined as 11 to 45%. Coincidence of additional malformation aggravates prognosis and therefore early detection of them appears to be crucial to establish optimal therapeutic management. As a first-line diagnostic procedure the ultrasonography (US) can not be overestimated in evaluating other organs for potential pathology in newborn with CHD if performed by experienced ultrasonologist. In the chapter the technique of abdomen and cranial US examination was described. The most frequent anomalies accompanying CHD were reviewed, and interpretation of some changes seen on US was given. The abdomen and cranial ultrasound (US) examination should constitute the integral part of initial diagnostics of a child suffering from congenital heart disease (CHD). The technique of this examination does not differ significantly from examination carried out on patients with other diseases, except for the US examination is more often carried out at the patient’s bed or in an incubator. However, the interpretation of symptoms may cause problems as the procedure requires broad knowledge of heart defect pathophysiology during diagnostic process. It is important to search for focal lesions as well as to determine the topographical relations between organs and blood vessels. This is of significant importance in diagnostic of some heart and vessels defects, such as: a heterotaxy syndrome (situs ambiguous), situs inversus, total anomalous pulmonary venous connection (TAPVC), for instance. Chapter VI - Congenital heart diseases (CHD) are the most important reasons of mortality and morbidity in neonates and infants. Coincidence of additional malformation of other organs makes the prognosis worse. Diagnosis of additional abnormalities seems to be especially important in children with CHD in their first year of life. For many reasons ultrasonography (US) has become accepted as a valuable first-line diagnostic examination not only for the heart but also for other organs including kidney. The incidence of congenital and acquired kidney and upper urinary tract anomalies was estimated on the basis of US in 350 neonates and infants with CHD. In examined population congenital kidney anomalies were found in 4.9% of children from which 18% manifest as hypoplasia, and another 18% as dysplasia. Analyzing renal size there was found the kidney length in the longest dimension below 5th centyl in almost 9% of studied population. 15.3% of examined patients were diagnosed by dilatation of collecting system, whereof 3% mild, 7% moderate, and 5% severe degree. Acquired kidney anomalies concurrence with CHD included mainly increased renal cortical echoes above liver and spleen echo, and hyperechoic pyramids. The most frequent causes of cortical hyperechogenicity are infections, acute renal failure, cardiac related asphyxia, and thrombosis. Renal cortex higher in echogenicity than the liver or spleen occurred in 15% children with CHD. Hyperechoic pyramids are associated with abnormal function of renal tubules. This sonographic finding has been described in various diseases including transient renal insufficiency in neonates, or hypercalciuria induced by long-term furosemid therapy. In population with CHD hyperechoic pyramids were found in 7 % of cases. In conclusion the incidence of congenital kidney and upper urinary tract anomalies in the population of neonates and infants with CKD is high and accounts for 20%.

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Abdominal US screening with carefully examination of urinary tract should be performed in all neonates and infants with CKD. Chapter VII - Congenital heart disease is the most frequent form of major birth defects in newborns affecting close to 1% of newborn babies (8 per 1,000). The etiology is multifactorial, including a genetic basis (causative genes, or interactions between genes and environment) and the influence of non-inherited risk factors (such as multivitamins, maternal illness, drug administration, environmental agents exposure or also maternal and paternal sociodemographic factors). Heart is considered the first functional organ of the embryo. It develops from the mesodermal sheets through the formation of an early linear heart tube which begins to contract at the eight- to nine-somite stage before the formation of the chambers and the conduction system. Recently, several CHDs have been found to be caused by mutations of the genes involved in the heart embryogenesis (TFAP2B, Tbx1, NKX2-5, NKX2-6, ZFPM2/FOG2, GATA4). These genes are often investigated as candidate genes if their biological role could be associated to the cardiac defect. Genome wide linkage analysis, candidate gene association studies, RNA expression profiling and resequencing are commonly used techniques to identify genes responsible of a certain cardiovascular disorder. The method of analysis can be selected on the basis of the known information about the disease. As a consequence of the increasing number of congenital/genetic cardiovascular diseases discovered in recent years, the genetic counselling has become very useful to inform the family of the affected subject about the hereditary risk, and to suggest genetic testing for family members. In addition, due to the significant improvement of non invasive imaging techniques (ultrasound imaging) and molecular analysis, prenatal diagnosis is becoming available for many congenital disorders. Chromosomal karyotype with increased band number to identify large chromosome rearrangements, gene or region specific FISH analysis for detecting deletions/insertions or aneuploidies, indirect PCR assays to assess small gene specific mutations or deletions/insertions, or direct sequence analysis for the detection of specific point mutations represent some of the available techniques to detect the disease in an early phase. Examples of genetic proved congenital disorders for which a genetic test is available are DiGeorge syndrome (deletion 22q11, Tbx1 gene), Williams-Beuren syndrome (microdeletion 7q11.23, gene contiguous syndrome), Alagille syndrome (deletion 20p12, JAG1 gene), Noonan and LEOPARD syndrome (PTPN11, SOS1, KRAS, and RAF-1), Holt-Oram syndrome (mutations in TBX5 gene). Chapter VIII - Objective: To compare the accuracy of echocardiogram (ECHO), cardiac catheterization (CC) and cardiovascular magnetic resonance imaging (CMR) for anatomical and functional diagnosis of severe congenital heart diseases. Material, patients and methods: 36 patients younger than 18 years old with severe congenital heart disease were included; in those, the three methods of diagnosis were used. The findings of each method were corroborated with surgical description. We calculated the agreement for anatomical description, sensitivity and specificity of each method for

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hemodynamic variables and areas under curve ROC (AUC ROC) compared by Wilcoxon test (p< 0.05). Results: In 26 patients, the three methods reached the same conclusion; the CMR agreed better with the surgical findings (0.89 versus 0.83 CC and 0.80 ECHO). Hemodynamic analysis: the CC was the reference method. There were no differences between ECHO and CMR regarding systemic cardiac output (AUC ROC 0.95 CMR versus 0.84 ECHO, p=0.19), pulmonary cardiac output (AUC ROC 0.92 CMR versus 0.83 ECHO, p=0.26) and pulmonary artery systolic pressure (AUC ROC 0.78 CMR versus. 0.92 ECHO, p=0.06). The left ventricular ejection fraction AUC ROC by CMR is greater (AUC ROC 0.89 RMC versus 0.64 ECHO, p=0.01). The complications were displayed during the CC. There were no deaths attributable to the procedures. Conclusion: Cardiovascular magnetic resonance imaging has the best concordance with surgery or autopsy findings, and according to sensitivity and specificity it can quantify hemodynamic variables such as cardiac catheterization. Chapter XIV - There are many variant pathological conditions which give rise to the single ventricle. This can occur when one of the chambers is undeveloped, fails to make connection to any of the great vessels or when the two ventricular chambers are fused. . Survival of these patients has dramatically improved over the past few decades through modification in surgical correction techniques; however, late morbidity often presents and creates significant challenges for physicians taking care of this population. This chapter reviews the anatomical and the physiological characteristics of single ventricular pathology as well as approaches to surgical correction and long-term outcomes. Chapter X - Multidetector-row computed tomography (MDCT) scanners are a widely available, accurate, and noninvasive technique for the diagnosis of cardiovascular disorders. Recent adult studies report reliable detection and quantification of coronary artery calcification and stenosis using this method. However, there are few reports concerning the feasibility of MDCT in congenital heart disease patients. We demonstrated a close correlation between quantitative measurements of pulmonary artery diameters by MDCT and conventional invasive pulmonary angiography. This study also revealed the feasibility of MDCT in detecting and quantifying the degree of pulmonary stenoses. Precise noninvasive evaluation of pulmonary artery morphology is extremely important for the medical and surgical management of patients with cyanotic congenital heart disease. The results of this study have confirmed the feasibility of quantifying the pulmonary arteries using 16-slice MDCT. Next, we describe the clinical feasibility of MDCT for the evaluation of prosthetic polytetrafluoroethylene (PTFE) graft calcification. Calcification of PTFE has emerged as an important problem that affects its function and long-term durability. MDCT findings were consistent with the histologic analysis in the evaluation of calcification. Furthermore, the virtual endoscopy using MDCT enabled the evaluation of the inner space of the complex vascular malformations. Using this method, we observed the orifice of the ductus and performed a PDA fly-through that provided a virtual view of the catheter approach prior to coil occlusion. Visualization of the coil can also be established by viewing from inside. Virtual endoscopic imaging has potential applications before and after the coil occlusion of patent ductus arteriosus.

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With the technical development of MDCT, this technique has increasingly been used for noninvasive assessment of pre- and post-operative congenital heart disease. The results of our study show the feasibility of quantifying the pulmonary arteries, detection of PTFE calcification, and virtual endoscopy using MDCT. Chapter XI - Real Time 3-dimentional echocardiographic imaging (RT3DE) of congenital heart lesions has been introduced as a complementary echocardiographic imaging modality to our laboratory over the last three years. Although 2 dimensional ( 2 D)/Doppler echocardiography is currently the primary imaging modality of congenital heart disease; there are still same anatomic details that cannot be well delineated by that modality. Free-hand Real-time scanning adds instant morphologic details, which are not well delineated by conventional 2 D imaging. Matrix-array transducer imaging produces images with resolution, which is superior or equivalent to that obtained by 2 D imaging. Heart valves, septal defects and volumetric, valvular and vascular color flow morphologies are well delineated by RT3DE. Echocardiography is generally superior to other imaging modalities for delineating the anatomic details of the atrioventricular (AVV) and semilunar valves. Surgical repair of these valves, on the other hand, is more demanding especially in the pediatric age group where valve replacement has much more important long term clinical implications than in adults. Valve repair, when feasible, is therefore, the better option and gathering as many details as possible on these valves is of paramount importance for the surgeon in terms of both timing and choice of the reparative procedure. For cardiac septal imaging on the other hand, device occlusion of atrial or ventricular septal defects, is currently done under guidance with transesophageal echocardiography (TEE) which does not show the full 3-dimensional geometric appearance, size and location of these defects, all can be well delineated by RT3DE, including the recently developed RT3DTEE, which results in much better success rate of these procedures. Finally, volumetric and functional aspects of the heart, with special interest in the right ventricle in congenital cardiac lesions, are under intense research investigations using RT3DE/color Doppler for better and real assessment not based on any geometric assumptions. Chapter XII - This paper is focused on the morphologic analysis of the absence of atrioventricular connexion either right or left which permits to understand the pathophysiology of this congenital cardiac malformation and it is the framework for the correct interpretation of the diagnostic images as was shown in the anatomoechocardiographic correlation. The advance in surgical procedures which includes the cavopulmonary shunt necessitates more experience in morphological knowledge in order to comprehend surgical anatomy. The morphology of sixty five hearts with absence of atrioventricular connexion from the pathological heart collection of the Embryology Department at the Instituto Nacional de Cardiología “Ignacio Chávez” were studied. The segmental sequential system methodology was used for the diagnosis of congenital heart disease. Twenty four adult patients from the Out-Patient-Clinic of the same institution were assessed by echocardiography. The anatomo-echocardiographic correlation was done selecting the specimens which exhibited the key morphologic features in order to match them as closely as possible with the echocardiographic images obtained from the patients with the

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purpose of establishing the correspondence between the anatomy and the image. Sixty four hearts had atrial situs solitus and one situs inversus. Fifty eight hearts have right absence of atrioventricular connexion and seven the left one. In the right type fifty four had normally lateralized ventricles and the other four had ventricular inversion. In the left type six had ventricular inversion and one had normally lateralized ventricles. In all hearts there was a deep groove between the cardiac chambers involved in the absence of connexion, the atrial floor of the blind atrium was muscular with a depression in it projected to the main ventricle. There were two univentricular hearts one of the indeterminated type and the other was a solitary ventricle of right type. The ventriculoarterial connexion in the right absence of atrioventricular connexion was as follows: Concordant (43), discordant (10), one of them with aortic atresia and double outlet right ventricle (5). Twenty two patients had right absence of atrioventricular connexion and two of the left type. The anatomoechocardiographic correlation was precise and showed the key features both in morphology and in images. This study demostrates the morphological variability in terms of segmental connexion of cardiac chambers, the stenosis and/or atresia of the arterial valves and the fact that this type of congenital cardiac disease shares the basic morphology of the atrioventricular univentricular connexion. The anatomo-echocardiographic correlation clearly demonstrated that the comparison of the anatomic specimen with the corresponding echocardiographic images in the absence of atrioventricular connection types is potentially quite valuable in enhancing the echocardiographer´s understanding, and the value of this comparison lies in its contribution to a precise diagnosis, leading to early and appropriate treatment of patients with this type of complex congenital heart disease. Chapter XIII - Despite advanced techniques of surgical or percutaneous therapy coarctation of the aorta continues to carry a high risk of aneurysmal formation. The lethality of these aneurysms ranges between less than one percent and more than 90 percent. This remarkable disparity of outcomes reflects differences in the follow-up management after surgery or percutaneous intervention for aortic coarctation. This article reviews frequency, anatomical types, risk factors and mechanisms of aortic aneurysm forming late after surgical or percutaneous correction of aortic coarctation. We emphasize that aneurysms do not form exclusively at the site of previous intervention but also at remote locations such as the ascending aorta. Moreover, we emphasize that formation of aneurysm may only in part be attributed to a specific technique of coarctation therapy and we elucidate the role of a bicuspid aortic valve as a significant risk factor or aneurysmal formation in this scenario. Moreover, we report on presenting symptoms, diagnostic potentials and limitations of various imaging modalities, follow-up protocols, imaging criteria for local and proximal aneurysmal formation. Finally, we discuss criteria for prophylactic intervention at the site of such aneurysms and present options for treatment of different types of aneurysms. With this systematic review, we wish to provide some more uniform grounds for preventing, diagnosing and treating aneurysms associated with aortic coarctation. Chapter XIV - Hypoplastic left heart syndrome (HLHS) was once considered a lethal condition with the two treatment options consisting of hospice care or transplantation; however, with the advent of surgical palliation, first described by Norwood, morbidity and mortality has steadily improved for this patient population. In the current era, three surgical palliations are possible for the initial procedure. These options include: 1) Norwood

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procedure with pulmonary blood flow supplied via a modified Blalock-Taussig shunt, 2) modification of the Norwood procedure with pulmonary blood flow supplied with a right ventricle to pulmonary artery conduit, or 3) hybrid procedure consisting of bilateral pulmonary artery banding, ductus arteriosus stenting, and balloon atrial septostomy. Each method has certain advantages and disadvantages that make them unique. No method at this time has proven consistently superior and it may be that each procedure has certain advantages over the other depending on the clinical situation and HLHS anatomy. We review the current literature for the three surgical variations with the goal of obtaining a better understanding of the possible surgical options for this complex disease. Chapter XV - Primary cardiac tumors are extremely uncommon with reported rate between 0.001 and 0.28%. A risk of sudden cardiac death is extremely small (~0.0025%) from primary cardiac neoplasm [1]. The lethal potential of the myxoma can be attributed both to its location (usually in the left atrium) and its configuration. This pedunculated lesion, though tethered to the atrial septum, is capable of prolapsing through the mitral valve, creating a “ball valve” obstruction. Potentially lethal course and the possibility of cure with propitious excision make their diagnosis challenging and consequential. Therefore, to achieve diagnostic and therapeutic adequacy, clinicians should be knowledgeable of cardiac tumor pathology and their frequently atypical clinical presentations. Left ventricular metastatic tumors are particularly a rare finding with limited literature on its prevalence [2]. Chapter XVI - Down syndrome (DS) is a common genetic disorder with protean manifestations. Children with DS are at risk for multiple medical issues that are well described; however, a potentially underappreciated condition that appears to have a high prevalence in this patient population is pulmonary hypertension (PH). The increased prevalence of PH in this population may have serious short and long-term consequences. The causes of PH in the DS population are not precisely known, but may be due to multiple other associated medical conditions that these children have concurrently, or due to shared biological features. We review the literature that describes the possible etiologies of PH in DS children with the hope that further research is performed to better define this complicated population. Chapter XVII - The current commentary will discuss the anatomy in relation to the heart conduction system and VSD, the mechanisms of atrioventricular block during and after transcatheter closure procedure, and preventive methods. Subtitles include the relation between VSD and atrioventricular conduction pathway, incidence of cardiac conduction block during and after trans-catheter VSD closure, underlying mechanisms of atrioventricular block induced by trans-catheter VSD closure, and conduction block induced by trans-catheter VSD closure—features, prevention and treatment.

In: Congenital Heart Defects: Etiology, Diagnosis and Treatment ISBN 978-1-60692-559-1 Editor: Hiroto Nakamura © 2009 Nova Science Publishers, Inc.

Chapter I

VENTRICULAR-VASCULAR PATHOPHYSIOLOGY IN CHILDREN WITH CARDIOVASCULAR DISEASE Hideaki Senzaki∗ Department of Pediatric Cardiology and Cardiovascular Surgery, Saitama Medical University, Saitama, Japan.

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INTRODUCTION Although recent advances in genetic, molecular and cellular biology and biochemistry have greatly contributed to uncovering the mystery of human living body, there is still a large gap in our understanding of the pathophysiology of several diseases due to the complex nature of the integrated physiology that is closely linked to the clinical manifestation of the diseases. In the field of cardiovascular disease, with an explosion of technological advances with a background theory on engineering, mathematics, and physics as well as physiology, our understanding of cardiovascular pathophysiology has accelerated since 1970’s. Vascular input impedance and time-varying elastance model in the ventricular pressure-volume framework have played dominant roles in such achievements. In this chapter, methodological and theoretical issues related to both impedance measurements and ventricular pressurevolume relationship will be discussed first, and then details of ventricular-vascular pathophysiology analyzed by these two methods in various cardiovascular diseases/conditions in children will be presented.

∗

Correspondence concerning this article should be addressed to: Hideaki Senzaki, M.D. Staff Office Building 303 Department of Pediatric Cardiology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. Tel: +81-42-984-4569; Fax: +81-42-984-4569; E-mail: [email protected].

Hideaki Senzaki

2

PART 1: BASIC CONCEPTS OF VENTRICULAR AND VASCULAR PHYSIOLOGY 1.0 Vascular Input Impedance Measurement of Vascular Impedance Vascular resistance is the most commonly used index for assessment of the state of vascular bed. Resistance is a measure of the opposition to non-pulsatile flow, and is derived from the ratio between mean blood pressure and mean blood flow. However, blood pressure and flow in the human arterial system has pulsatility and travels along the finite arterial bed that can produce wave reflection. Therefore, measurement of resistance alone does not provide a complete picture of vascular physiology. Any comprehensive information about vascular physiology must include not only frequency-independent static (resistive) component but also frequency-dependent dynamic (elastic and reflective) components. Arterial input impedance, which is a measure of the opposition to the pulsatile flow, provides such information. Input impedance can be calculated using a mathematical technique of Fourier analysis for simultaneously measured instantaneous pressure and flow. Pressure (P(t)) and flow (F(t)) waveforms can be described as a sum of a trigonometric function with multiples of fundamental frequency (frequency at heart rate=HR/60) as below [1,2]: P(t) = Po+ ∑Pn sin(2πfn t + θn) F(t) = Fo+ ∑Fn sin(2πfn t + φn)

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where Pn, Fn = pressure and flow amplitude of nth harmonic, respectively fn=n HR/60 (frequency of nth harmonic), θn, φn = pressure and flow phase angle of nth harmonic t = time. In general, up to 10 to 12 harmonics are sufficient to precisely reproduce the original pressure and flow waveforms [3]. The ratio of pressure and flow amplitude for each harmonic (Pn/Fn) yields the input impedance of the nth harmonic. The ratio of the mean term (Po/Fo: impedance at 0 Hz) reflects the input impedance to mean flow, which corresponds to vascular resistance. The phase angle of the nth harmonic is estimated by subtracting the flow phase from the pressure phase (θn-φn), and its negative value indicates that flow harmonics lead pressure harmonics; a positive phase value indicates that flow harmonics lag pressure harmonics. Figure 1 shows typical impedance spectra. Impedance modulus values decline from a high value at 0 Hz (resistance) to a minimum around at 3-4 Hz in normal children, as in adults, and then oscillate thereafter. The impedance phase generally goes to negative values from 0 radians at 0 Hz, then crosses zero around at the frequency of impedance minimum.

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Figure 1. Typical impedance spectra recorded from an 8-year-old boy with a small ventricular septal defect. Both impedance modulus (upper panel) and phase angle (lower panel) are provided by Fourier analysis from measured pressure and flow waves.

Low Frequency Impedance Impedance moduli at low frequency ranges are predominantly influenced by wave reflection and peripheral arterial compliance in a way that increased wave reflection and decreased compliance increase low frequency impedance [4-6]. Several studies highlighted the importance of low frequency impedance as a determinant of cardiac output by serving as a pulsatile load on the ventricle, regardless of the resistance value [7-9]. Peripheral arterial compliance incorporated in the low frequency impedance can be estimated from the aortic pressure trajectory. The majority of previously proposed methods calculated compliance by assuming monoexponential decay of diastolic aortic pressure [6,10-12]. In reality, however, this decay is often not a true monoexponential function, being subject to estimation errors. In contrast, the method proposed by Liu et al. [13] uses the area under the diastolic pressure waveform rather than the waveform shape, and thus has the advantage that the value of compliance is not critically dependent on strict monoexponential pressure decay. The summarized equation for calculating compliance (CA) by Liu’s method is as follows: CA = SVI/K(Ps-Pd) where Ps = aortic pressure at incisura, Pd = aortic diastolic pressure K = an area index obtained by dividing the total area under the aortic pressure curve by the area under the diastolic pressure waveform. More recently, Stergiopulos et al. [14] have proposed another approach to estimate compliance; the pulse pressure method. The method requires the measurements of pressure and flow, and is based on fitting the pulse pressure predicted by the two-element windkessel

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model to the measured pulse pressure. They demonstrated that whereas the area method by Liu et al. appeared very sensitive to the wave reflection intensity, the pulse pressure method was relatively independent of the wave reflection intensity [15], inferring that the pulse pressure method is the most consistent method for estimating total arterial compliance. The applicability and validity of this method in the field of pediatric cardiovascular disease have yet to be determined, however. Issues related to wave reflection, another important determinant of low frequency impedance, will be discussed later in details. Characteristic Impedance At higher frequencies, input impedance approaches characteristic impedance, which represents impedance where there is no wave reflection [16]. The characteristic impedance is therefore approximated by the average of high frequency impedances (usually above 2 Hz) [16,17]. Because characteristic impedance is predominantly determined by the stiffness of proximal arteries [16,18], it has been extensively used as an index of proximal arterial stiffness and has provided important findings in both experimental and clinical settings. Pressure and flow waves are transmitted in the arterial system, and their transmission velocities (pulse wave velocity: PWV) increase when arterial wall stiffness increases, and thus, PWV and characteristic impedance are closely related [19]: Characteristic impedance = ρPWV/πr2

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where ρ = blood density r = arterial lumen radius Because PWV is much easier to measure compared to characteristic impedance [20,21], PWV has often been used as a useful index of arterial wall stiffness and found to provide important information in several clinical settings [20-23]. Although these two measures denote arterial wall stiffness, they have markedly differing degrees of inverse sensitivity to vessel diameter: PWV is relatively insensitive to diameter, whereas characteristic impedance is highly dependent on diameter. Consequently, these “stiffness” measures change divergently with changes in vessel diameter [19,24]. By measuring both stiffness indexes and looking for disparate change, one can estimate the relative contribution to arterial stiffening of changes in the material properties of the arterial wall versus changes in lumen diameter [19,25]. Wave Reflection Oscillation of impedance moduli at high frequencies around characteristic impedance occurs due to wave reflection, and increases with increased wave reflection. An impedance minimum, approximately at which the frequency phase crosses zero, provides information about the major reflection site. Because wavelength (λ) of the first impedance minima is determined as: λ = PWV/f

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where PWV = pulse wave velocity f = frequency at first impedance minima and because the reflection site of this wave is a quarter of the wavelength as a rule of physics, the distance (d) from the site of measurement to the major reflection site is given by: d = PWV/4f Therefore, at a constant PWV, a shift in the frequency at impedance minima and phase crossing zero to the right (higher frequency) indicate a shift in the major reflection site to a more proximal part of the arterial bed. Conversely, without any change in the reflection site, increased PWV also induces a shift in the frequency at impedance minima and phase crossing zero to the right. Both conditions induce earlier return of reflected wave and thereby impose pulsatile load on the ejecting ventricle [16,18,26]. Reflected pressure and flow waveform can also be directly obtained from impedance analysis [27]. The measured pressure wave (Pm) is equal to the sum of forward (Pf) and reflected (Pr) pressure waves (Pm = Pf + Pr). The measured flow wave (Fm) is also equal to the sum of forward (Ff) and reflected (Fr) flow waves (Fm = Ff + Fr). The forward and reflected pressure and flow are related by the characteristic impedance of the aorta as follows: Pf = Zo Ff Pr =-Zo Fr where Zo = characteristic impedance These equations can be solved to yield the forward and reflected pressure and flow waves [27]:

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Pf = (Pm + Zo Fm) / 2 Pr = (Pm – Zo Fm) / 2 Thus, measured waves can be dissected into their forward and reflected components, using Pm, Fm, and Zo. An example of such analysis is shown in Figure 2. The reflected pressure wave is added to the forward pressure wave, yielding the archetypical ascending aortic pressure waveform with a late systolic wave. With this approach, the timing and magnitude of wave reflections can be identified more clearly, and the relative contribution of wave reflection as a pulsatile load on the ventricle can be understood easily.

2. Ventricular Pressure-Volume Relationship Although impedance analysis provides comprehensive measures of arterial hemodynamics, hemodynamic parameters that define the net circulatory status, such as blood pressure, stroke volume or stroke work, are determined not only by the state of arterial bed but also by the properties of the ventricle to which the artery is coupled. Therefore, it is extremely important to consider heart-arterial interaction whenever one tries to assess overall

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cardiovascular hemodynamics. The ventricular pressure-volume relationship provides a powerful tool for understanding and quantifying cardiac function and the heart-vascular system interaction. The concept of pressure-volume diagram appeared more than a century ago by a legacy experiment by Frank Otto using the frog ventricle [28]. The concept was revisited in 1973 by Suga’s historical finding of the load-independent index of ventricular contractility (termed Emax) derived from the pressure-volume diagram [29]. Because traditional evaluation of cardiac function is too often limited by reliance on measurements with complex interdependence between cardiac properties and loading factors [30], the discovery of loadindependent measure of cardiac function had long been awaited. Thus, the Emax has gained the greatest interest of many researchers and clinicians, has provided fertile area of research, and has significantly helped broaden our understanding of cardiac mechanics and hemodynamics. 120

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Figure 2. Example of pressure tracings in which the measured pressure is dissected into forward and reflected components. Note that reflected waveform is the main contributor to the late systolic augmentation of the measured pressure.

Emax and Ees Figure 3A demonstrates the instantaneous changes in ventricular pressure and volume as a function of time during one cardiac cycle. Simply plotting the simultaneously measured volume and pressure generates pressure-volume diagram corresponding to the curves of Figure 3A, with volume on the abscissa and pressure on the ordinate (Figure 3B). As shown, the plot of pressure versus volume for one cardiac cycle forms a loop, called the pressurevolume loop. As time proceeds, the pressure-volume points go around the loop in a counter clockwise direction from the onset of systole (A; end-diastole). During the first part of the cycle, pressure rises but volume stays the same (isovolume contraction). Ultimately, left ventricular (LV) pressure rises above aortic pressure, the aortic valve opens (B), ejection begins and volume starts to go down. After the ventricle reaches its maximum activated state

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(C, upper left corner of pressure-volume loop), LV pressure falls below aortic pressure, the aortic valve closes and isovolumic relaxation commences. Finally, filling begins with mitral valve opening (D, bottom left corner). If the ventricular loading condition is acutely altered such as by transient inferior vena caval occlusion, one can construct a series of pressurevolume loops as illustrated in the left panel of Figure 4.

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Figure 3. A: Instantaneous changes in left ventricular pressure (LVP) and volume (LVV) as a function of time during one cardiac cycle. Aortic (AOP) and left atrial (LAP) pressures are also shown. B: Pressure-volume loop constructed by plotting the simultaneously measured LVP and LVV shown in panel A. See text for more details.

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Figure 4. A: Pressure-volume relationships during preload reduction by inferior vena cava obstruction. The E(t) relations at four different time points (10, 40, 60, 240 ms) from the onset of contraction are shown by dashed lines. The E(t) at 240 ms is the maximal value of E(t) or Emax. B: E(t) curve as a function of time corresponding to panel A.

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In the time-varying elastance model of ventricular contraction proposed by Suga et al. [31], the maximal value of ventricular elastance [E(t): P(t)/(V(t) - Vo(t))] using differently loaded beats synchronized in time defines the Emax, as illustrated in Figure 4. Suga et al. demonstrated in isolated canine heart preparation that the Emax was nearly identical between isovolumic and auxobaric contraction over a wide range of intraventricular volume, while it significantly increased when the inotropic background was enhanced by catecholamine infusion [31], indicating that Emax is a load-independent measure of ventricular contractility. On the other hand, the set of points for maximal P/(V - Vo) chosen from differently loaded beats regardless of timing (end-systolic points) constitutes the end-systolic pressure volume relationship (ESPVR). The slope of this relationship is called end-systolic elastance (Ees). Originally, Emax and Ees were thought to be the same measure. However, subsequent studies revealed that when afterload is significantly altered among the cardiac cycles used for Ees or Emax determination, the two can be very different due to resistive and inertial influences on end-systolic pressures [32,33], as well as changes in the time to reach end-systole as a function of load [34]. These influences can often lead to an Emax that is significantly steeper, and in contrast to Ees, does not fall at the corners of the pressure-volume loops (Figure 5). Because Ees is easier to define and can be coupled with arterial load, the majority of clinical studies have utilized Ees rather than Emax to assess ventricular contractility, although the term “Emax” is frequently misused probably due in part to the great impact of Suga’s cornerstone work of 1973.

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Figure 5. An example of pressure-volume diagram demonstrating that end-systolic elastance (Ees; solid line) is shallower than Emax (dashed line).

Ventricular Systolic Property in Pressure-Volume Diagram The earlier studies emphasized the linearity of ESPVR over a reasonably wide range of loading conditions and often stressed the importance of ESPVR linearity, because the linearity does represent load-independence. However, subsequent studies revealed that ESPVR shows non-linearity under various conditions, such as regional ischemia [35] or substantial changes in contractility [36,37]. Nonlinearity of ESPVR may be accentuated in

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puppy hearts [38]. ESPVR can also be afterload-dependent [5,39] due to ventricular internal resistance [32,33], shortening deactivation [40,41], or length-dependent Ca2+ activation [34]. The potential load-dependence and curve linearity of ESPVR would be a disappointment for those who wish to use the Ees as an ultimate index of ventricular contractility of loadindependence. However, linearity is just a convenience that allows the description of the relationship in a single term. The ESPVR represents to what extent the ventricle can produce systolic pressure at a given systolic volume. This can be viewed as another expression of the classic Frank-Starling law of the heart. A ventricle with higher systolic performance would produce higher systolic pressure at a given systolic volume, and this notion is never to be undermined by whether the relationship is linear or not. It is, therefore, important to recognize that the strength of ESPVR is it separately provides ventricular systolic property in its relation to diastolic and loading properties within the single plane, as further discussed below. In addition, the nonlinearity and load-dependence of ESPVR in humans is minimal compared with substantial changes in inotropic state [34,42,43]. Therefore, ESPVR and its slope Ees are still useful and powerful measures of systolic properties when assessing pump function, if the investigators use them with the understanding that the model they choose to fit to the relationship adequately describes the data in the pressure-volume range of interest.

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Figure 6. Relatively load-insensitive measures of ventricular contractility obtained from a pressurevolume relationship. A: pressure-volume relationship during inferior vena cava occlusion. B: classic Frank-Staring relationship derived from the pressure-volume diagram show in panel A. C: plots of endsystolic pressure-volume relationship presented in panel A, yielding the end-systolic elastance (Ees). D: relationship between the maximal rate of ventricular pressure rise (dp/dtmax) and end-diastolic volume (EDV). E: relationship between the maximal ventricular power (PWRmax) and EDV. F: the stroke work (SW)-EDV relationship, yielding the preload-recruitable stroke work (PRSW). The most important notion with the use of these indexes is that the underlying physiology common to these relationships is the Frank-Starling framework described in panel B.

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Hideaki Senzaki

In addition to the Ees, the pressure-volume diagram provides several other indices of relatively load-independent index of ventricular contractility. Such example is demonstrated in Figure 6. Panel C shows a plot of the ESPVR presented in panel A, yielding the Ees. The other indices presented (panels D, E, F) are derived from the same set of pressure-volume relations presented in panel A. The slope of the relationship between the maximal rate of ventricular pressure rise (dp/dtmax) and end-diastolic volume (EDV) (panel D) was first proposed by Little et al. [44] The linearity of this relationship is mathematically linked to the linearity of ESPVR [44], and the dp/dtmax measured in vivo has the physiologic feature of apparent afterload independence because dp/dtmax generally occurs before the opening of the aortic valve. Compared to the Ees, the dp/dtmax-EDV relationship is more sensitive but also more variable measure of the contractile state [45]. In addition, while the Ees represents the force of contraction, the dp/dtmax –EDV relation represents the rate of contraction [46]. Therefore, this index should provide additional information about ventricular contractility when used with the Ees. Maximal ventricular power (Panel E), defined as the maximal value of the product of instantaneous pressure and flow generated by the ventricle, also changes linearly with preload alteration, but may be little sensitive to afterload alteration because any pressure rise caused by an increase in afterload can be cancelled out by flow reduction induced by the increased afterload. Kass et al. [47] first demonstrated in open-chest dogs that preload-adjusted maximal ventricular power is sensitive to contractile changes but is little affected by loading conditions. They subsequently showed similar results in humans with wide range of myocardial diseases including normal hearts [48,49]. The advantage of this index is the potential for a simple noninvasive application, because aortic pressure and flow, and EDV at steady state rather than during loading intervention can be measured noninvasively. The linearity of the preload-recruitable stroke work (PRSW), or the slope of the stroke work-EDV relationship (Panel F) was first suggested by Sarnoff et al. [50] More than 3 decades after the report of Sarnoff, Glower et al. [51] re-examined the nature of this relation in closed-chest dogs, and proposed the PRSW to be a load-insensitive measure of ventricular contractility. The PRSW is attractive because it is quite linear over a wide range of physiologic conditions [30,45]. In addition, despite the clear potential for afterload sensitivity (stroke work declines to zero at both no load and infinite load), PRSW is quite stable over a range of physiologic afterloads [30,45,51]. Furthermore, PRSW has a unit of pressure alone (without a unit of volume), providing chamber size independent measure and thus enable us to compare the contractility even among different species with different ventricular size. On the other hand, there is a limitation in using PRSW as a pure systolic index, particularly in cases with a significant abnormality in diastolic properties. For example, PRSW could be different even if the ESPVR is identical when diastolic pressure-volume relationship is different. Each of the above four indices has strengths and limitations, different levels of sensitivity and stability in the assessment of inotropic changes, and should provide more accurate information about chamber contractile states in a compensatory manner [34,52]. However, again, it is important to understand that the underlying common physiology to these relationships is the Frank-Starling framework described in panel B. Regardless of whether the

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relationships are linear or not, left and upperward shift of relationships indicates increased systolic performance. B A Ea

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Figure 7. A: Definition of effective arterial elastance (Ea) in the pressure-volume diagram. B: hemodynamic consequences of changes in afterload represented by Ea can be easily understood in association with, and separately from ventricular properties and preload condition. A decrease in Ea (upper panel) induces an increase in stroke volume and a decrease in systolic pressure, and vice versa (lower panel).

Ventricular Afterload in Pressure-Volume Diagram The slope of the line connecting end-systolic point and the point at end-diastolic volume on the volume-axis (Figure 7A) is termed effective arterial elastance (Ea), which is defined as the ratio between end-systolic pressure and stroke volume [53]. Ea is a lumped measure of vascular property serving as a ventricular afterload that incorporates both the mean and pulsatile components represented by impedance spectra [54]. Although the aortic input impedance spectra defined in the frequency domain provide information about both the mean and pulsatile components of ventricular afterload as mentioned earlier, it is very difficult to link such data with time-domain or pressure-volume measurements of ventricular function. In contrast, Ea shares common units with elastance measures of ventricular function and thus enables ventricular-arterial interactions to be easily evaluated. Changes in afterload alone without changes in other properties (preload, systolic and diastolic properties) clearly define the net hemodynamic consequence as illustrated in Figure 7B. Ventricular Diastolic Properties in Pressure-Volume Diagram The pressure-volume diagram also provides important information about ventricular diastolic properties. The set of end-diastolic points at various loads constitutes the enddiastolic pressure-volume relationship (EDPVR) that reflects diastolic passive chamber stiffness [55]. The pressure-volume relationship during the filling phase of diastole obtained from a single pressure-volume loop at rest also defines the diastolic chamber stiffness (active diastolic stiffness), but this stiffness is influenced by several factors other than chamber specific diastolic stiffness, including the effects of pericardial constraint, preceding relaxation, ongoing filling (viscosity), and atrial contraction [46,52,55]. On the other hand,

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EDPVR, particularly that derived from the pressure-volume points just before the atrial contraction eliminates such effects, and thus is thought to represent chamber-specific diastolic property [55,56]. The steeper EDPVR indicates increased ventricular diastolic chamber stiffness (left in Figure 8A), while a parallel shift without altering its steepness reflects the influence of external constraint (right in Figure 8A); two conditions that affect end-diastolic pressure (EDP) can be clearly distinguished by examining the EDPVR. Furthermore, active stiffness derived from a steady state beat and passive stiffness defined by EDPVR can often show considerable disparity as shown in Figure 8B. The steady state pressure-volume relationship is flat, but EDPVR is rather steep, reflecting the contribution of increased stiffness to the elevated EDP in this particular patient. Similar finding has been reported in HCM patients [57], further highlighting the notion that caution should be used in the interpretation of stiffness results derived from steady-state data. A

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Figure 8. A: changes in end-diastolic pressure-volume relationships (see text for more details). B: an example plot of end-diastolic pressure-volume relationship showing marked disparity from a singleloop-based diastolic pressure-volume relationship, which is much flatter than end-diastolic pressurevolume relationship.

Introducing the Concept of Pressure-Volume Diagram in the Field of Pediatric Cardiology Because ventricular preload can be clearly defined as EDV on the pressure-volume diagram, one can determine the ventricular systolic (ESPVR) and diastolic (EDPVR) properties with both ventricular preload (EDV) and afterload (Ea) conditions taken into account, and can derive net cardiac performance (stroke volume and blood pressure) as a consequence of interaction between cardiac and loading properties. Anatomical abnormalities in congenital heart disease (CHD) are generally associated with volume and/or pressure overloading of the pulmonary, systemic, or both ventricles [58]. Under some conditions, overloading of one ventricle causes underloading of the opposite ventricular chamber. Such loading abnormalities can profoundly affect ventricular chamber mechanics [59,60]. Hypoxemia superimposed on various loading conditions may further influence myocardial performance. In addition to these baseline hemodynamic characteristics in CHD, pharmacological, surgical or catheter intervention often dramatically alter chamber

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loading, which may simultaneously accompany changes in chamber contractile function [61,62]. Thus, to better understand cardiovascular dynamics in CHD, chamber contractility and ventricular loading conditions must be quantified separately. The pressure-volume diagram is best suited for this purpose. In 1980’s, the development of the conductance catheter that allows on-line continuous recording of left ventricular volume [63], coupled with the development of method that permits rapid, reversible load alteration by inferior vena caval (IVC) balloon obstruction [64], made it feasible to construct pressure-volume loop in the clinical setting in adult population [64]. However, to date, application of these methodologies to pediatric patients remains problematic, particularly to patients with congenital cardiac anomalies. For example, LV volume measured by the conductance catheter in patients with inter-ventricular communications such as in ventricular septal defect (VSD) can include right ventricular (RV) volume through the defect, making volume measurement inaccurate [65]. Conversely, it is impossible to measure total ventricular volume by this catheter when both RV and LV act as a functional single ventricle as in Fontan circulation of double outlet of the right ventricle or Type I/IIc of tricuspid atresia. In addition, atrioventricular valve regurgitation or significant RV volume overload, often observed in CHD, could potentially induce signal errors in conductance catheter measurements [65]. Technically, there is also the added problem of lack of availability of small-size balloon catheters appropriate for IVC occlusion in pediatric patients. This is due to the technical difficulty in construction of a large balloon with a small shaft catheter, since currently available materials for balloon fabrication have limited expandability [66]. The alternative approach to change ventricular loading conditions is to use vasoactive agents, such as angiotensin II or nitroglycerine. However, the pharmacological approach has a limitation in that vasoactive drugs themselves may affect the ventricular contractile state [67]. Furthermore, one has to wait for a significantly long time to re-establish the initial baseline condition after the first use of such drugs. This obviously limits the capacity to conduct several measurements in a single subject under different conditions, e.g., pacing or drug intervention. To circumvent these problems, we measured instantaneous ventricular cavity area rather than ventricular volume, and thus constructed ventricular pressure-area relationships [42]. We also developed a new balloon catheter of a reasonable size to fit all pediatric patients, by arranging the shape and wall thickness of the balloon and by changing the method of attaching the balloon to the catheter shaft (Figure 9) [66]. Furthermore, we were able to monitor in real-time changes in ventricular cavity area using an automated border detection echocardiographic system [68,69] (Sonos 2500, Hewlett-Packard) with a 3.5- or 5-MHz phased-array transducer. Transthoracic 2-dimensional images were recorded from the midventricular short-axis plane using the midpapillary muscle level as an anatomical landmark. Ventricular pressure was measured with a high-fidelity pressure transducer mounted on a 0.014Fr guidewire (RADI Medical Systems AB), placed within a 4- or 5-Fr pigtail catheter. Ventricular area measured by this method was highly reproducible, as shown in Figure 10A. The most important issue regarding validation of the applicability of ventricular pressure-area relationship as a surrogate of ventricular pressure-volume relationship is that area changes measured by this method adequately reflect volume changes, although several previous studies [46,70,71] have indicated that even pressure-dimension

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relations correlate well with pressure-volume relations both in normal and failing hearts. We indeed confirmed a significant correlation between changes in stroke area measured by automated border detection and stroke volume measured by electromagnetic flow probe (Millar Ins, TX) during IVC occlusion in various types of CHD (Figure 10B).

Figure 9. Newly designed balloon catheter for inferior vena caval occlusion in children. Three different sizes are available for recommended sheath sizes of 5, 6 and 7 Fr.

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Figure 10. A: the area measured by automated border detection algorithm at different time points is highly reproducible (y = 0.98x+0.28, r = 0.99, SEE = 0.69 for end-diastolic area index (EDAI); and y = 1.0x+0.1, r = 0.99, SEE = 0.44 for end-systolic area index (ESAI), both p 40 mm at the site of previous coarctation repair [23] New geometric changes at the site of coarctation repair [106]

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Proximal Aneurysms Postsurgical aneurysm of the aortic root or the ascending aorta is diagnosed with standard criteria. Aortic root dimensions should be measured in the parasternal long-axis view at all four standard levels by cross-sectional echocardiography and measurements should be plotted against body surface area using a nomogram provided by Roman and coworkers [107]. Such nomograms are useful to identify aortic root diameters outside the upper confidence interval for the normal population. With enlarged diameters on these nomograms, aortic ratios should be assessed to further quantify aortic root enlargement. These ratios can be calculated as the observed maximum diameter of the aortic root divided by the predicted diameter based on age and body surface area (BSA) of normal individuals. For children of less than 18 years of age, the predicted sinus diameter (cm) is 1.02 + (0.98 x BSA (m²)). For adults aged 18 through 40 years, the predicted sinus diameter is 0.97 + (1.12 x BSA (m²)), and for adults of above 40 years of age 1.92 + (0.74 x BSA (m²)) [107]. An aortic ratio of 1.18 is the upper confidence limit for a ratio of 1.0, a ratio of 1.3 indicates a 30 percent enlargement of the aortic root above the mean of normal individuals reflective of aortic root dilatation, and a ratio of 1.5 corresponds to aortic root aneurysm [95, 108].

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Nondissecting aneurysm requires a fusiform or saccular dilatation of at least 50 mm; aortic dissection is present with an intimal flap and false lumen flow and intramural hemorrhage is diagnosed with a circular or crescent-shaped regional wall thickening of at least 7 mm but no dissecting membrane [92, 108-110].

INDICATIONS FOR REINTERVENTION Local Aneurysm Controversy Exists About Optimal Timing Of Elective Surgery For Local Aneurysms. Some Authors Recommend To Delay Resection Of Local Aneurysm Presuming That They “Involute” With Time [111]. However, Mendelsohn And Colleagues Do Not Observe Spontaneous Resolution Of Local Aneurysm But, In Contrast Find That Children With An Aortic Ratio ≥ 1.5 At The Repair Site Develop Significant Progression Of Their Ratios From 1.64 ± 0.06 At Baseline To 2.04 ± 0.2 Within Three To Five Years Of Follow-Up [89]. Parikh And Colleagues Find An Aortic Ratio ≥ 1.68 A Better Criterion For Progression Since They Observe That In Children Aortic Ratios < 1.68 Usually Decrease With Growth [106]. Kron And Coworkers Recommend To Resect Aneurysms Related To Patch Grafts With A Diameter ≥ 60 Mm [17]. Aebert And Colleges Perform Reoperation Of The Descending Aorta When The Diameter Of A Fusiform Dilatation Exceeds 45 Mm Or When A Saccular Aneurysm Is Noted [23]. Some Authors Suggest Yearly Tomographic Imaging In Patients With Local Aneurysm And Recommend Surgical Intervention Only In Cases With Progressive Aneurysmal Dilatation [10, 19, 78]. However, Since A Critical Ratio For Rupture Is Unknown And The Mortality Of Ruptured Aneurysms Is High Many Surgeons Tend To Operate Soon After Local Aneurysm Is Diagnosed [9, 11, 12, 15, 89]. The Presence Of A Pseudoaneurysm At A Previous Suture Line Is Also Considered An Indication For Reintervention [27] (Table 2).

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Table 2. Reported indications for intervention for aneurysmal formation at the site of previous coarctation repair Aortic ratio at the repair site ≥ 1.5 [89], or ≥ 1.68 [106] Aneurysms related to patch grafts with a diameter ≥ 60 mm [17] Diameter of a fusiform dilatation of the descending aorta ≥ 45 mm [23]. Saccular aneurysm of the descending aorta [23] Pseudoaneurysm at a previous suture line [27] Surgical intervention only with progressive aneurysmal dilatation on annual tomographic images [10, 19, 78] Surgical intervention as soon after local aneurysm is diagnosed [9, 11, 12, 15, 89]

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Proximal Aneurysm Surgeons usually recommend to monitor the aortic root diameter for timing of elective replacement of the aortic root. In patients with coarctation repair and a bicuspid aortic valve data are not available to establish specific guidelines for prophylactic intervention. Most authors, however, adopt guidelines for prophylactic aortic root replacement from Marfan patients, who are at a risk for aortic dissection and rupture that is considered similar to patients with concurrent bicuspid aortic valve and coarctation [83, 84]. Thus, prophylactic intervention is classically recommended with maximum aortic root diameters ≥ 55 mm [112]. Intervention may be carried out earlier in high risk patients; these comprise patients with an annual increase of the aortic ratio exceeding 5 percent, with dilatation of the aortic sinuses involving the ascending aorta, with severe aortic or mitral valve regurgitation, with a family history of aortic dissection, with other major surgery required in the near future, or, in women planning pregnancy [113-115]. However, some surgeons already replace the ascending aorta with diameters ≥ 40 mm [116, 117].

TECHNIQUES OF INTERVENTION

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Local Aneurysms Surgeons remove the aneurysmal sac, the patch or other grafts and resect the diseased aortic wall segments. Some surgeons repair small aortic aneurysms by aortorrhaphy [15] , by external support with wrapping of the aneurysm [9], patch plasty [15] or end-to-end anastomosis [11]. In cases with concomitant cardiovascular malformations and technically demanding aneurysms, a palliative surgical approach may be used by implanting a prosthetic graft that bypasses the isthmic region [27, 72, 118]. However, these techniques may be appropriate only in selected patients. The surgical gold standard is to insert a tube graft after the aneurym is resected [9, 11, 12, 15-17, 23, 119]. Usually, the aorta is cross-clamped and various types of artificial circulation are used to maintain adequate circulation [15]. Cardiopulmonary bypass with hypothermic circulatory arrest avoids aortic clamping and sacrifice of intercostal arteries and provides adequate protection of the spinal cord and other vital organs. This technique is particularly useful in extended surgery for postsurgical complications of complex coarctation with extensive aortic aneurysm, persistent hypoplastic aortic arch or aneurysm of aberrant left subclavian arteries [30, 120]. Patients may require both, resection of local aneurysm and repair of concomitant aortic or mitral valve disease. In this setting both strategies, a one-stage repair through a median sternotomy and a two-stage repair through median sternotomy and thoracotomy have been advocated [121, 122]; there are no definitive guidelines and most surgeons agree that surgical strategies should be individualized [27, 123].

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Proximal Aneurysms Severe regurgitation of a bicuspid valve combined with aneurysm of the ascending aorta is treated optimally with a composite root replacement. However, surgeons also perform separate replacement of the aortic valve and the supracoronary ascending aorta. In Marfan patients this procedure is not appropriate, since aneurysms develop in the diseased aortic tissue that is left between the valve graft and the aortic tube graft [124]. Unfortunately, there are no long-term studies on the postoperative course after surgery of bicuspid aortic valves comparing both surgical techniques. However, in a series of 27 procedures with bicuspid aortic valve replacement and separate tube graft implantation in the ascending aorta no patient required reintervention for recurrent aneurysm of the aortic root [116]. Thus, this strategy may be appropriate particularly in older patients with valvular stenosis requiring extensive concomitant surgical procedures [116]. Surgeons also use the remodelling and reimplantation techniques for valve-sparing operations in patients with aortic root aneurysms associated with a bicuspid aortic valve [125-129]. However, long-term results are not available, and at least from a theoretical point of view, this procedure does not eliminate the inherent susceptibility of a bicuspid aortic valve for endocarditis or valve dysfunction [130].

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PROGNOSIS Patients suffering acute symptoms from a previously unknown aortic aneurysm may die suddenly, or if referred to a hospital, have a poor prognosis because of severe complications. In hospitalised patients without immediate surgical intervention, reported lethality averages 56 percent in a total of 55 cases with a range between 20 and 100 percent across different series [4, 8, 11, 14, 15, 18, 20]. However, even when surgery is carried out immediately, the average lethality remains high with an average of 42 percent in 19 cases reported in the literature [4, 5, 12, 14-17]. Conversely, elective interventions are survived without complications in the majority of patients; a total of 92 elective interventions for postsurgical aneurysmal formation yields only two deaths within thirty days after the surgical procedure (2.2 percent) [4, 5, 9, 12, 14-17]. Thus, survival of aneurysmal formation depends on the quality of medical management and surveillance of the entire thoracic aorta is a cornerstone for preventing highly lethal complications after surgical or interventional therapy of aortic coarctation.

ACKNOWLEDGEMENT We wish to express our cordial gratitude to Mrs. Sabine Wuttke for her valuable assistance in generating the graphical artwork of this article. We furthermore want to thank doctor Christian R. Habermann for providing us with the imaging material presented in this article.

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Yskert von Kodolitsch, Alexander M. J. Bernhardt, and Muhammed A. Aydin von Kodolitsch Y, Nienaber C, Dieckmann C, Schwartz AG, Hofmann T, Brekenfeld C, Nicolas V, Berger J, Meinertz T. Chest radiography for the diagnosis of acute aortic syndrome. Am J Med. 2003;116:73-7. von Kodolitsch Y, Koschyk DH, Krause N, Nienaber CA, Dieckmann C. Transthoracic ultrasound and x-rax computed tomography in combination for the diagnosis of acute aortic syndrome. Cardiovascular Reviews & Reports. 2002;23:4751. Erbel R, Bednarczyk I, Pop T, Todt M, Henrichs KJ, Brunier A, Thelen M, Meyer J. Detection of dissection of the aortic intima and media after angioplasty of coarctation of the aorta. Circulation. 1990;81:805-14. Erbel R, Alfonso F, Boileau C, et al. Diagnosis and management of aortic dissection. Recommendations of the task force on aortic dissection, European Society of Cardiology. Eur Heart J. 2001;22:1642-81. Emmrich KM, Herbst M, Trenckmann H, et al. Severe late complications after operative correction of aortic coarctation by interposition of prosthethis. J Cardiovasc Surg. 1982;23:205-8. Muhler EG, Neuerburg JM, Ruben A, et al. Evaluation of aortic coarctation after surgical repair: role of magnetic resonance imaging and Doppler ultrasound. Br Heart J. 1993;70:285-90. Simpson IA, Chung KJ, Glass RF, Sahn DJ, Sherman FS, Hesselink J. Cine magnetic resonance imaging for evaluation of anatomy and flow relations in infants and children with coarctation of the aorta. Circulation. 1988;78:142-8. Stern H, Locker D, Wallnöfer K, et al. Noninvasive assessment fo coarctation of the aorta: comparative measurements by two-dimensional echocardiography, magnetic resonance, and angiography. Pediatr Cardiol. 1991;12:1-5. Mendelsohn AM, Banerjee A, Donnelly LF, Schwartz DC. Is echocardiography or magnetic resonance imaging superior for precoarctation angioplasty evaluation? Cathet Cardiovasc Diagn. 1997;42:26-30. Engvall J, Sjöqvist L, Nylander E, Thomas KA, Wranne B. Biplane transesophageal echocardiography, transthoracic Doppler, and magnetic resonance imaging in the assessment of coarctation of the aorta. Eur Heart J. 1995;16:1399-409. Mohiaddin RH, Kilner PJ, Rees SS, Langmore DB. Magnetic resonance volume flow and jet velocity mapping in aortic coarctation. J Am Coll Cardiol. 1993;22:1515-21. Deanfield JTE, Warnes C, Webb G, Kolbel F, Hoffmann A, Sorensen K, Kaemmerer H, Thilen U, Bink-Boelkens M, Iserin L, Daliento L, Silove E, Redington A, Vouhe P. Management of grow up congenital heart disease. Eur Heart J. 2003;24:1035-84. Swan L, Wilson N, Houston AB, Doig W, Pollock JCS, Hissis WS. The long-term management of the patient with an aortic coarctation repair. Eur Heart J. 1998;19:382-6. Jagannath AS, Sos TA, Lockhart SH, Saddekni S, Sniderman KW. Aortic dissection: a statistical analysis of the usefulness of plain chest radiographic findings. Am J Roentgenol. 1986;147:1123-6.

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[106] Parikh SR, Hurwitz RA, Hubbard JE, Brown JW, King H, Girod DA. Preoperative and postoperative "aneurysm" associated with coarctation of the aorta. J Am Coll Cardiol. 1991;17:1367-72. [107] Roman MJ, Devereux RB, Kramer-Fox R, O´Ranghlin J. Two dimensional aortic root dimensions in normal children and adults. Am J Cardiol. 1989;64:507-12. [108] von Kodolitsch Y, Rybczinsky M. Cardiovascular aspects of the Marfan syndrome A systematic review. In: Marfan syndrome: a primer for clinicians and Scientists; Robinson PN, Godfrey M, editors. 2004;Eurekah.com and Kluwer Academic / Plenum Publishers:45-69. [109] Ergin MA, Spielvogel D, Apaydin A, Lansmann SL, McCullough JN, Galla JD, Griepp RB. Surgical treatment of the dilated ascending aorta: when and how? Ann Thorac Surg. 1999;67:1834-9. [110] von Kodolitsch Y, Csösz SK, Koschyk DH, Schalwat I, Loose R, Karck M, Dieckmann C, Fattori R, Haverich A, Berger J, Meinertz T, Nienaber CA. Intramural hematoma of the aorta: predictors of progression to dissection and rupture. Circulation. 2003;107:1158-63. [111] Morriss MJH, McNamara DG. Coarctation of the aorta and interrupted aortic arch. In: Garson A Jr, McNamara DG, eds. 1990;The science and practice of pediatric cardiology. Philadelphia: Lea & Febinger.:1353-81. [112] Gott VL, Greene PS, Alejo DE, et al. Replacement of the aortic root in patients with Marfan syndrome. N Engl J Med. 1999;340:1307-13. [113] Roman MJ, Rosen SE, Kramer-Fox R, Devereux RB. Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. J Am Coll Cardiol. 1993;22:1470-6. [114] Pyeritz RE. Predictors of dissection of the ascending aorta in Marfan syndrome. Circulation. 1991;84(suppl II):II-351. [115] Treasure T. Elective replacement of the aortic root in Marfan´s syndrome. Br Heart J. 1993;69:101-3. [116] Sundt TM, Mora BN, Moon MR, Bailey MS, Pasque MK, Gay Jr WA. Options for repair of a bicuspid aortic valve and ascending aortic anerysm. Ann Thorac Surg. 2000;69:1333-7. [117] von Kodolitsch Y, Rybczynski M, Detter C, Robinson PN. Diagnosis and management of Marfan syndrome. Future Cardiology.2008(4):85-96. [118] Caspi J, Ilbawi MN, Milo S, Bar-El Y, Roberson DA, Thilenius OG, et al. Alternative techniques for surgical management of recoarctation. Eur J Cardio-thorac Surg. 1997;12:116-9. [119] Ala-Kulju K, Järvinen A, Maamies T, Mattila S, Merkikallio E. Late aneurysms after patch aortoplasty for coarctation of the aorta in adults. Thorac Cardiovasc Surg. 1983;31:301-5. [120] Lange R, Thielmann M, Schmidt KG, Bauernschmitt R, Jakob H, Hasper B, et al. Spinal cord protection using hypothermic cardiopulmonary arrest in extended repair of recoarctation and persistent hypoplastic aortic arch. Eur J Cardio-thorac Surg. 1997;11:697-702.

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[121] Mullen JC, Bentley MJ, Talwar MK. Coarctation of the aorta: tailoring the surgical approach. Can J Cardiol. 1997;13:931-5. [122] Vijayanagar R, Natarajan P, Eckstein PF, Bognolo DA, Toole JC. Aortic valvular insufficiency and psotductal aortic coarctation in the adult: combined surgical management through median sternotomy: a new surgical approach. J Thorac Cardiovasc Surg. 1980;79:266-8. [123] Musumeci F, Penny WJ. Aortic coarctation associated with aortic or mitral valve disease: which lesion to correct first? (letter). Ann Thorac Surg. 1998;66:603-4. [124] Lawrie GM, Earle N, DeBakey ME. Long-term fate of the aortic root and aortic valve after ascending aneurysm surgery. Ann Surgery. 1993;217:711-20. [125] de Oliveira NC, David TE, Ivanov J, Armstrong S, Eriksson MJ, Rakowski H, et al. Results of surgery for aortic root aneurysm in patients with the Marfan syndrome. J Thorac Cardiovasc Surg. 2003;125:789-96. [126] Kallenbach K, Karck M, Leyh RG, Hagel C, Walles T, Harringer W, Haverich A. Valve-sparing aortic root reconstruction in patients with significant aortic insufficiency. Ann Thorac Surg. 2002;74:S1765-8. [127] Schäfers HJ, Langer F, Aicher D, Graeter TP, Wendler O. Remodeling of the aortic root and reconstruction of the bicuspid aortic valve. Ann Thorac Surg. 2000;70:542-6. [128] Suematsu Y, Morota T, Kubota H, Ninomiya M, Takamoto S. Valve-sparing operation for aortic root aneurysm in patients with bicuspid aortic valves. Ann Thorac Surg. 2002;74:907-8. [129] Yacoub MH, Gehle P, Chandrasekaran V, Birks EJ, Child A, Radley-Smith R. Late results of a valve-preserving operation in patients with aneurysms of the ascending aorta and root. J Thorac Cardiovasc Surg. 1998;115:1080-90. [130] Miller DC. Valve sparing aortic root replacement in patients with the Marfan syndrome. J Thorac Cardiovasc Surg. 2003;125:773-8. [131] Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol. 2004 Jul 7;44(1):138-43.

In: Congenital Heart Defects: Etiology, Diagnosis and Treatment ISBN 978-1-60692-559-1 Editor: Hiroto Nakamura © 2009 Nova Science Publishers, Inc.

Chapter XIV

SURGICAL PALLIATIVE OPTIONS FOR PATIENTS WITH HYPOPLASTIC LEFT HEART Clifford L Cua1,∗, Christopher L Cua2 and Lillian S Lai3 1

Heart Center, Columbus Children’s Hospital; Section of Thoracic Surgery, Faulkner Hospital; 3 Section of Cardiology, Children’s Hospital of Eastern Ontario. 2

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ABSTRACT Hypoplastic left heart syndrome (HLHS) was once considered a lethal condition with the two treatment options consisting of hospice care or transplantation; however, with the advent of surgical palliation, first described by Norwood, morbidity and mortality has steadily improved for this patient population. In the current era, three surgical palliations are possible for the initial procedure. These options include: 1) Norwood procedure with pulmonary blood flow supplied via a modified Blalock-Taussig shunt, 2) modification of the Norwood procedure with pulmonary blood flow supplied with a right ventricle to pulmonary artery conduit, or 3) hybrid procedure consisting of bilateral pulmonary artery banding, ductus arteriosus stenting, and balloon atrial septostomy. Each method has certain advantages and disadvantages that make them unique. No method at this time has proven consistently superior and it may be that each procedure has certain advantages over the other depending on the clinical situation and HLHS anatomy. We review the current literature for the three surgical variations with the goal of obtaining a better understanding of the possible surgical options for this complex disease.

∗

Correspondence concerning this article should be addressed to: Clifford Cua, MD, Heart Center, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205-2696. Phone: 614-722-2530; Fax: 614-7222549; [email protected].

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Clifford L Cua, Christopher L Cua and Lillian S Lai

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INTRODUCTION Hypoplastic left heart syndrome (HLHS) is estimated to occur in approximately 0.162 to 0.267 per 1000 live-births [1]. In the past, it was essentially a lethal congenital heart defect with survival in one natural history study of only 39% within the first week of life [2]. The only two options available for these children were either cardiac transplantation or hospice care. Though transplantation allowed for normal physiology, issues with transplantation included scarcity of pediatric organs, mortality awaiting transplantation, infectious issues, systemic hypertension, chronic immunosuppression, and graft rejection [(3-9]. Results from transplantation have steadily improved [10,11], but this option is still impractical for all children with HLHS secondary to organ availability. A surgical palliative procedure was therefore needed and was first described by Norwood [12]. Norwood’s first cohort consisted of sixteen patients with nine of the patients undergoing what has become known as the Norwood procedure consisting of anastomosis of the main pulmonary artery to the ascending aorta, aortic arch augmentation, atrial septectomy, and pulmonary blood flow supplied via a central shunt from the newly constructed ascending aorta to the confluence of the pulmonary arteries. This procedure allowed an alternative palliation that theoretically could be performed at any institution; however, there was a 55% (5/9) hospital mortality and a 25% (1/4) late mortality rate [12]. The other seven patients in the original cohort underwent different surgical palliative procedures that were less successful. One theoretical reason for the high mortality rate in those nine patients included decreased systemic and coronary perfusion due to diastolic run-off of blood flow into the pulmonary arteries through the central shunt. Due to lack of control of pulmonary blood flow with the central shunt, modification of this procedure continued in the ensuring years that eventually resulted in the use of a modified Blalock-Taussig shunt (NW-BT) instead of a central shunt. Since the NW-BT procedure was first described, initial surgical [13-19], inter-stage [2022], and second and third stage surgical palliative procedure mortalities [6,19,23-29] have improved. This is likely due to multiple reasons including more experience with dealing with this complex patient population and advances in pre-operative [30], operative [31], and postoperative care [32-36] and technology. Certain risk factors have been implicated that increase morbidity and mortality for the NW-BT procedure and include prematurity, low birthweight, poor ventricular function, diminutive ascending aorta, extracardiac abnormalities, aortic atresia, tricuspid valve insufficiency, coronary artery anatomy abnormalities, cardiopulmonary bypass length, circulatory arrest length, and restrictive atrial septum [15,17,18,37-43]. Again, as more experience has been gained, these risk factors have become less significant [44-46] except for possibly the presence of an intact or highly restrictive atrial septum [47-51]. With all the advances made, initial surgical mortality has decreased significantly in some centers to the high single or mid-teen percentages in the current era [36,45,52]; however, not all centers have been able to duplicate this success with the NW-BT procedure [53-55]. Due to this variability in outcomes and high mortality for certain groups of patients, alternative palliative procedures were thus explored.

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One alternative procedure was a modification of the Norwood procedure with pulmonary blood flow being supplied via a right ventricle to pulmonary artery conduit (NW-RVPA) [5658] which eliminated any diastolic run-off in the systemic circulation. Interestingly, this procedure was also originally described by Norwood in three of his patients, but all three had hospital deaths and thus the procedure was abandoned [12]. The first large cohort to undergo the NW-RVPA procedure in the current era had an initial surgical survival rate of 89% (2/19) compared to a historical NW-BT reference group who had a survival rate of 53% [57]. Since then, other institutions have reported improved surgical survival using the NW-RVPA procedure versus the NW-BT [59-63]; however, other institutions have noted no difference in surgical mortality [45,52,64-66]. The improvement in results by some institutions may be due to the fact that most of these studies used historical NW-BT patients as a comparison group rather than a contemporary one. These studies thus could not account for improvement due to “learning experience” or technical advances. The studies that showed no difference in mortality came from institutions that had relatively low mortality rates with the NW-BT procedure and consequently it would be unlikely that the NW-RVPA procedure would improve mortality significantly. The main reason given for the improved survival using the NW-RVPA procedure is improved coronary perfusion secondary to higher diastolic blood pressures. All the studies so far comparing hemodynamic variables between the NW-BT and NW-RVPA have documented significantly higher diastolic blood pressures in the NW-RVPA patients [52,6062,64,67]. The higher diastolic blood pressures are not surprising considering the fact the NW-BT has to and fro flow thru the modified Blalock-Taussig shunt whereas the NW-RVPA has no diastolic run-off because of the neo-aortic valve. Previous studies have shown that one of the reasons for death in these patients may be abnormal coronary anatomy [42,68]; furthermore, children with HLHS have been shown to have abnormal coronary perfusion [69]. One study has documented decreased intensive care and hospital stay and improved enteral feeding [52] but the majority of studies have shown no significant difference in hospital stay [45,60,66]. The improved enteral feeding in the NW-RVPA patients may be another important factor to study considering the high incidence of necrotizing enterocolitis reported for patients undergoing the NW-BT and HLHS patients in general [70,71]. The higher diastolic blood pressures in the NW-RVPA patients would hypothetically improve systemic perfusion [72] and thus the patients would tolerate stressors better in the immediate post-operative period and accordingly have better morbidity and mortality. The inter-stage time period has also shown significant mortality differences between the two procedures. Multiple studies have shown decreased mortality with the NW-RVPA versus the NW-BT procedure [45,73-78]. Multiple etiologies hypothesized for death during this time period include decreased coronary perfusion, residual arch lesions, shunt/conduit obstruction, arrhythmias, right ventricular failure, and acute intercurrent illness [22,67,68]. Assuming most of the variables would be similar between the two groups, the possible reasons for decreased mortality include improved perfusion and decrease risk for shunt obstruction in the NW-RVPA patients. One study however has shown that inter-stage mortality can be significantly decreased from their original incidence of 15.8% (9/57) to 0% (0/24) in NW-BT patients if a strict home monitoring protocol is instituted [21].

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There is conflicting data on the differences in morbidity between these two groups during this time period as well. Some studies have documented no difference in weight at time of the second surgery, age at second stage surgery, need for rehospitalization, or shunt interventions, [45,64,76,79,80] whereas other studies have shown improved weight gain, increased catheterization/surgical interventions, earlier need for second surgery secondary to increase cyanosis, and decreased need for gastrostomy tubes in the NW-RVPA group [45,78,80]. There have also been reports of pseudoaneurysms arising from the site of the RVPA conduit as well as right ventricular outflow obstruction [66,81-83]. The principal question for the NW-RVPA procedure is what effect an incision has on the right ventricular function long-term. Again, the data from echocardiographic and catheterization studies are contradictory. From a qualitative standpoint, most studies that have compared echocardiographic data between the two procedures have not shown any significant difference in right ventricular function or tricuspid regurgitation [64,78,80,84]. One study did show a trend for worse function and tricuspid regurgitation in the NW-RVPA group long-term, but again this did not reach significance [85]. Another study using strain Doppler echocardiography documented improved longitudinal function in the NW-RVPA group while another study showed similar ventricular efficiency, but decreased contractility in the NW-RVPA patients [83]. Most of the catheterization data obtained before the second stage surgery show increased diastolic blood pressure, decreased systemic saturation, and decreased pulmonary to systemic blood flow ration in the NW-RVPA group [64,79,80,85]. One study showed higher dp/dt (mmHg/s2) in the NW-RVPA group [61]. No study has shown worse right ventricular end diastolic pressure, pulmonary artery pressure, or cardiac index in the NW-RVPA patients [61,78,80]. The McGoon ratio and Nakata index has been noted to be higher in the NW-RVPA patients with more uniform flow to the left and right pulmonary arteries [78,86] though assorted pulmonary artery distortions, especially at the insertion site of the shunt/conduit, have been seen for both procedures [85-88]. The studies comparing stage two results for the two different groups have not shown any significant differences in morbidity or mortality [45,78,80]. Some studies have shown increased incidence of pulmonary artery stenosis in the NW-RVPA group that required pulmonary arterioplasty [59,87], but with modification of the initial NW-RVPA procedure, the incidence of central pulmonary artery stenosis significantly decreased [87]. The length of ventilation, intensive care stay, and hospital stay were equivalent [78,80] and the postoperative hemodynamics for the two groups were essentially the same as well [80]. The three year survival rate for the NW-BT and the NW-RVPA group were similar [45,85]. When stratifying for risk factors, there was no significant difference in type of procedure performed and outcomes; however, there was a trend toward to improved survival in patients with aortic atresia who underwent the NW-RVPA procedure [45]. The only study so far systematically comparing stage three results for the two procedures demonstrated larger pulmonary arteries, more systemic collaterals, higher systemic saturation, and lower systemic pressure and resistance in the NW-RVPA patients. There was no difference in right ventricular end diastolic pressures or qualitative echocardiographic function. There was no difference in length of ventilation, intensive care stay, or hospital stay. There was 100% operative survival [89]. The only other data available comparing post stage three data showed worse echocardiographic function in the NW-RVPA patients [85].

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Due to the lack of consistent improvement in morbidity and mortality with the NWRVPA procedure, the search for an alternative procedure led to the third option for palliation of HLHS patients. Known commonly as the “hybrid” procedure, this procedure consists of bilateral pulmonary artery banding, ductus arteriosus stenting, and balloon atrial septostomy. As early as 1993, stenting of the ductus arteriosus had been described in patients as a bridge to transplantation secondary to the long waiting period [90-92]. This procedure has since evolved into another possibility for HLHS palliation [93-95]. As with the NW-RVPA and NW-BT, advances in technology and experience with this procedure have improved results over time [94,96,97]. The theoretical advantage of this procedure is the ability to avoid a cardiopulmonary bypass run during the neonatal period. Abnormal head size [98], cranial MRI [99,100], cranial ultrasound [101], and fetal cranial blood flow studies [102] have been documented in patients with HLHS before any intervention has been performed and increased cranial ischemic lesions after HLHS surgery have been seen [99,100]. By avoiding bypass during the neonatal period when the cranial vasculature is immature, the hope is that this will improve neurocognitive outcome. This must be weighed against the significantly longer bypass time that is required during the second procedure, which consists of removal of the pulmonary artery bands and ductal stent, anastomosis of the main pulmonary artery to the ascending aorta, aortic arch augmentation, atrial septectomy, and superior vena cavopulmonary connection [94,96,103]. The question of long-term outcome remains unanswered when comparing two bypass runs for the NW pathway during infancy, with one being in the neonatal time period, versus one long bypass run for the hybrid pathway during infancy. The other advantage is that no incision is made into the right ventricle compared to the NWRVPA procedure and so concerns about long term ventricular function are mitigated. However, the hybrid still has diastolic run-off through the stented ductus similar to the NWBT, so coronary perfusion could still be theoretically impaired compared to the NW-RVPA. This procedure was initially performed on high risk patients, as described above, that continued to have significant mortality even in the current era with the NW-RVPA or NWBT surgery. Mortality or unexpected need for transplantation after hybrid procedure for this high risk group has been reported to be 20% (1 transplantation/5) [104], 21% (3 deaths/14) [103,105], and 60% (9 deaths/15) [106]. When evaluating results from non-high risk patients undergoing this procedure, the mortality rate is significantly lower and has been reported as low as 2.5% (1 death/40) [97] to 18% (2 deaths/11) [107]. The need for postoperative manipulation appears to be less intensive than the NW-RVPA or NW-BT procedure [93,94,108], though one study suggests that this may not necessarily be beneficial for those undergoing the hybrid procedure [108]. This study showed larger fluctuations in systemic and pulmonary vasculature resistance and blood flow, cardiac output, oxygen extraction, and oxygen delivery pre- and post-hybrid compared to the NW-BT. This study also showed no difference in diastolic blood pressures between the two groups. Though the hemodynamics eventually became equal or better than the NW-BT, the authors concluded that some support may be warranted immediately after the hybrid procedure [108]. This institution however routinely placed a 3.5 mm shunt from the innominate artery to the pulmonary artery to prevent loss of flow in the aortic arch and so their results may not be applicable to the hybrid procedure that does not use the “reverse” Blalock-Taussig shunt.

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There also continues to be morbidity and mortality during the inter-stage period for this procedure. For the high risk patients, inter-stage mortality has been reported to be 17% (1 death/6) [106], 18% (2 deaths/11) [105], 27% (2 deaths and 1 stage two not pursued secondary to renal dysfunction/11) [103], and 50% (2 deaths/4) [104]. For the non-high risk patients, mortality during this time period ranged from 0% (0/9) [107] to 8% (2 deaths and 1 transplantation/39) [97]. The rate of interventions for this procedure, either surgical or catheter based, range from approximately 30% to 80% [94,97,103,104,106,107,109]. Most of the interventions deal with progressive stenosis of the atrial wall, ductus arteriosus, or isthmus area. Narrowing of the isthmus area, cranially located above the ductus stent, has come to be known as a “retrocoarctation”. Interventions described include stenting the atrial septum, placing another stent in the ductus arteriosus, stenting the retro-aortic arch, ballooning the atrial septum, ductus or arch [93,94,96,103,105]. Surgical procedures described include retrieving stents, tightening pulmonary bands, and placing “reverse” Blalock-Taussig shunts [93,94,96,97,103,105,107,109]. Close surveillance is hence required during this time period to monitor for any of these complications so prompt therapy can be initiated. Retro-coarctation appears to be the most troublesome issue, especially for patients with aortic atresia since coronary blood flow is entirely dependent on patency of the isthmus area. There is a significant incidence of coarctation previously reported in HLHS patients [110113[ and interventions to relieve this obstruction in the context of the hybrid procedure have met with mixed results [94,97,104,105,109]. If ventricular function is affected by a retrocoarctation and the obstruction is not relieved satisfactorily via catheterization interventions, then the only options available are an early stage two procedure, conversion to a NW, or transplantation. Previous reports have attempted to predict occurrence of coarctation in HLHS patients [114,115] and this should be further investigated because those patients may not be good candidates for the hybrid procedure. Stage two mortality post hybrid procedure for high risk patients have ranged from 25% (2 deaths/8) [103,105] to 75% (3 deaths/4) [106]. Non-high risk patient mortality ranged from 8% (3 deaths/36) (97) to 11% (1 death/9) [107]. Various interventions consisting of pulmonary arterioplasty as well as extensive arch reconstruction have been reported for this procedure [87,97,103,106]. Timing of this surgery ranged from 3 to 6 months and was institution dependent. The median bypass times reported were 124 [103] to 291 minutes. In general, length of hospital stay did not appear significantly different compared to reported times for the NW-BT or NW-RVPA procedure. Limited data exist for the stage three procedure, but at this time, the available data report no surgical mortality (0/15) [97], (0/4) [103], and (0/11) [96]. Since Norwood first described a surgical palliative treatment for patients with HLHS, significant strides have been made. No comment was even made about current fetal intervention procedures for this patient population. These fetal procedures will no doubt also change future treatment avenues. Multiple options are now available where before there were none. The aspiration continues to be to decrease the morbidity and mortality for this complicated patient population. No option so far as demonstrated superior results. It may be that patients with various anatomical subtypes of HLHS or clinical scenarios would benefit with one procedure over another, but this must be risked assessed. The future objective

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should be to better delineate this possibility. We look forward to upcoming studies that may answer this question and improve the outcome in this challenging population.

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[17] Bando K, Turrentine MW, Sun K, et al. Surgical management of hypoplastic left heart syndrome. Ann Thorac Surg 1996;62:70-6; discussion 76-7. [18] Azakie T, Merklinger SL, McCrindle BW, et al. Evolving strategies and improving outcomes of the modified norwood procedure: a 10-year single-institution experience. Ann Thorac Surg 2001;72:1349-53. [19] Thies WR, Breymann T, Boethig D, Blanz U, Meyer H, Koerfer R. Results of staged reconstruction for hypoplasia of the left heart: an experience of 12 years from one institution. Cardiol Young 2003;13:509-18. [20] Ghanayem NS, Cava JR, Jaquiss RD, Tweddell JS. Home monitoring of infants after stage one palliation for hypoplastic left heart syndrome. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2004;7:32-8. [21] Ghanayem NS, Hoffman GM, Mussatto KA, et al. Home surveillance program prevents interstage mortality after the Norwood procedure. J Thorac Cardiovasc Surg 2003;126:1367-77. [22] Mahle WT, Spray TL, Gaynor JW, Clark BJ, 3rd. Unexpected death after reconstructive surgery for hypoplastic left heart syndrome. Ann Thorac Surg 2001;71:61-5. [23] Breymann T, Kirchner G, Blanz U, et al. Results after Norwood procedure and subsequent cavopulmonary anastomoses for typical hypoplastic left heart syndrome and similar complex cardiovascular malformations. Eur J Cardiothorac Surg 1999;16:11724. [24] Weldner PW, Myers JL, Gleason MM, et al. The Norwood operation and subsequent Fontan operation in infants with complex congenital heart disease. J Thorac Cardiovasc Surg 1995;109:654-62. [25] Forbess JM, Cook N, Serraf A, Burke RP, Mayer JE, Jr., Jonas RA. An institutional experience with second- and third-stage palliative procedures for hypoplastic left heart syndrome: the impact of the bidirectional cavopulmonary shunt. J Am Coll Cardiol 1997;29:665-70. [26] Bove EL. Current status of staged reconstruction for hypoplastic left heart syndrome. Pediatr Cardiol 1998;19:308-15. [27] Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark BJ, 3rd. Survival after reconstructive surgery for hypoplastic left heart syndrome: A 15-year experience from a single institution. Circulation 2000;102:III136-41. [28] Andrews R, Tulloh R, Sharland G, et al. Outcome of staged reconstructive surgery for hypoplastic left heart syndrome following antenatal diagnosis. Arch Dis Child 2001;85:474-7. [29] Farrell PE, Jr., Chang AC, Murdison KA, Baffa JM, Norwood WI, Murphy JD. Outcome and assessment after the modified Fontan procedure for hypoplastic left heart syndrome. Circulation 1992;85:116-22. [30] Atz AM, Feinstein JA, Jonas RA, Perry SB, Wessel DL. Preoperative management of pulmonary venous hypertension in hypoplastic left heart syndrome with restrictive atrial septal defect. Am J Cardiol 1999;83:1224-8.

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[31] Gaynor JW, Kuypers M, van Rossem M, et al. Haemodynamic changes during modified ultrafiltration immediately following the first stage of the Norwood reconstruction. Cardiol Young 2005;15:4-7. [32] Bradley SM, Simsic JM, Atz AM. Hemodynamic effects of inspired carbon dioxide after the Norwood procedure. Ann Thorac Surg 2001;72:2088-93; discussion 2093-4. [33] Rossi AF, Sommer RJ, Lotvin A, et al. Usefulness of intermittent monitoring of mixed venous oxygen saturation after stage I palliation for hypoplastic left heart syndrome. Am J Cardiol 1994;73:1118-23. [34] Barnea O, Austin EH, Richman B, Santamore WP. Balancing the circulation: theoretic optimization of pulmonary/systemic flow ratio in hypoplastic left heart syndrome. J Am Coll Cardiol 1994;24:1376-81. [35] Bradley SM, Atz AM, Simsic JM. Redefining the impact of oxygen and hyperventilation after the Norwood procedure. J Thorac Cardiovasc Surg 2004;127:473-80. [36] Tweddell JS, Ghanayem NS, Mussatto KA, et al. Mixed venous oxygen saturation monitoring after stage 1 palliation for hypoplastic left heart syndrome. Ann Thorac Surg 2007;84:1301-10; discussion 1310-1. [37] Barber G, Helton JG, Aglira BA, et al. The significance of tricuspid regurgitation in hypoplastic left-heart syndrome. Am Heart J 1988;116:1563-7. [38] Sauer U, Gittenberger-de Groot AC, Geishauser M, Babic R, Buhlmeyer K. Coronary arteries in the hypoplastic left heart syndrome. Histopathologic and histometrical studies and implications for surgery. Circulation 1989;80:I168-76. [39] Lloyd TR, Marvin WJ, Jr. Age at death in the hypoplastic left heart syndrome: multivariate analysis and importance of the coronary arteries. Am Heart J 1989;117:1337-43. [40] Jonas RA, Hansen DD, Cook N, Wessel D. Anatomic subtype and survival after reconstructive operation for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 1994;107:1121-7; discussion 1127-8. [41] Kern JH, Hayes CJ, Michler RE, Gersony WM, Quaegebeur JM. Survival and risk factor analysis for the Norwood procedure for hypoplastic left heart syndrome. Am J Cardiol 1997;80:170-4. [42] Vida VL, Bacha EA, Larrazabal A, et al. Surgical outcome for patients with the mitral stenosis-aortic atresia variant of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2008;135:339-46. [43] Nilsson B, Mellander M, Sudow G, Berggren H. Results of staged palliation for hypoplastic left heart syndrome: a complete population-based series. Acta Paediatr 2006;95:1594-600. [44] Weinstein S, Gaynor JW, Bridges ND, et al. Early survival of infants weighing 2.5 kilograms or less undergoing first-stage reconstruction for hypoplastic left heart syndrome. Circulation 1999;100:II167-70. [45] Tabbutt S, Dominguez TE, Ravishankar C, et al. Outcomes after the stage I reconstruction comparing the right ventricular to pulmonary artery conduit with the modified Blalock Taussig shunt. Ann Thorac Surg 2005;80:1582-90; discussion 15901.

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[46] Pizarro C, Davis DA, Galantowicz ME, Munro H, Gidding SS, Norwood WI. Stage I palliation for hypoplastic left heart syndrome in low birth weight neonates: can we justify it? Eur J Cardiothorac Surg 2002;21:716-20. [47] Vlahos AP, Lock JE, McElhinney DB, van der Velde ME. Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: outcome after neonatal transcatheter atrial septostomy. Circulation 2004;109:2326-30. [48] Vida VL, Bacha EA, Larrazabal A, et al. Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: surgical experience from a single center. Ann Thorac Surg 2007;84:581-5; discussion 586. [49] Glatz JA, Tabbutt S, Gaynor JW, et al. Hypoplastic left heart syndrome with atrial level restriction in the era of prenatal diagnosis. Ann Thorac Surg 2007;84:1633-8. [50] Photiadis J, Urban AE, Sinzobahamvya N, et al. Restrictive left atrial outflow adversely affects outcome after the modified Norwood procedure. Eur J Cardiothorac Surg 2005;27:962-7. [51] Rychik J, Rome JJ, Collins MH, DeCampli WM, Spray TL. The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 1999;34:554-60. [52] Cua CL, Thiagarajan RR, Gauvreau K, et al. Early postoperative outcomes in a series of infants with hypoplastic left heart syndrome undergoing stage I palliation operation with either modified Blalock-Taussig shunt or right ventricle to pulmonary artery conduit. Pediatr Crit Care Med 2006;7:238-44. [53] Jacobs ML, Blackstone EH, Bailey LL. Intermediate survival in neonates with aortic atresia: a multi-institutional study. The Congenital Heart Surgeons Society. J Thorac Cardiovasc Surg 1998;116:417-31. [54] Gutgesell HP, Gibson J. Management of hypoplastic left heart syndrome in the 1990s. Am J Cardiol 2002;89:842-6. [55] Lofland GK, McCrindle BW, Williams WG, et al. Critical aortic stenosis in the neonate: a multi-institutional study of management, outcomes, and risk factors. Congenital Heart Surgeons Society. J Thorac Cardiovasc Surg 2001;121:10-27. [56] Kishimoto H, Kawahira Y, Kawata H, Miura T, Iwai S, Mori T. The modified Norwood palliation on a beating heart. J Thorac Cardiovasc Surg 1999;118:1130-2. [57] Sano S, Ishino K, Kawada M, et al. Right ventricle-pulmonary artery shunt in firststage palliation of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2003;126:504-9; discussion 509-10. [58] Imoto Y, Kado H, Shiokawa Y, Fukae K, Yasui H. Norwood procedure without circulatory arrest. Ann Thorac Surg 1999;68:559-61. [59] Griselli M, McGuirk SP, Stumper O, et al. Influence of surgical strategies on outcome after the Norwood procedure. J Thorac Cardiovasc Surg 2006;131:418-26. [60] Mair R, Tulzer G, Sames E, et al. Right ventricular to pulmonary artery conduit instead of modified Blalock-Taussig shunt improves postoperative hemodynamics in newborns after the Norwood operation. J Thorac Cardiovasc Surg 2003;126:1378-84. [61] Malec E, Januszewska K, Kolcz J, Mroczek T. Right ventricle-to-pulmonary artery shunt versus modified Blalock-Taussig shunt in the Norwood procedure for hypoplastic

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left heart syndrome - influence on early and late haemodynamic status. Eur J Cardiothorac Surg 2003;23:728-33; discussion 733-4. Pizarro C, Malec E, Maher KO, et al. Right ventricle to pulmonary artery conduit improves outcome after stage I Norwood for hypoplastic left heart syndrome. Circulation 2003;108 Suppl 1:II155-60. Tibballs J, Kawahira Y, Carter BG, Donath S, Brizard C, Wilkinson J. Outcomes of surgical treatment of infants with hypoplastic left heart syndrome: an institutional experience 1983-2004. J Paediatr Child Health 2007;43:746-51. Azakie A, Martinez D, Sapru A, Fineman J, Teitel D, Karl TR. Impact of right ventricle to pulmonary artery conduit on outcome of the modified Norwood procedure. Ann Thorac Surg 2004;77:1727-33. Bradley SM, Simsic JM, McQuinn TC, Habib DM, Shirali GS, Atz AM. Hemodynamic status after the Norwood procedure: a comparison of right ventricle-to-pulmonary artery connection versus modified Blalock-Taussig shunt. Ann Thorac Surg 2004;78:933-41; discussion 933-41. Mahle WT, Cuadrado AR, Tam VK. Early experience with a modified Norwood procedure using right ventricle to pulmonary artery conduit. Ann Thorac Surg 2003;76:1084-8; discussion 1089. Ghanayem NS, Jaquiss RD, Cava JR, et al. Right ventricle-to-pulmonary artery conduit versus Blalock-Taussig shunt: a hemodynamic comparison. Ann Thorac Surg 2006;82:1603-9; discussion 1609-10. Bartram U, Grunenfelder J, Van Praagh R. Causes of death after the modified Norwood procedure: a study of 122 postmortem cases. Ann Thorac Surg 1997;64:1795-802. Donnelly JP, Raffel DM, Shulkin BL, et al. Resting coronary flow and coronary flow reserve in human infants after repair or palliation of congenital heart defects as measured by positron emission tomography. J Thorac Cardiovasc Surg 1998;115:10310. Jeffries HE, Wells WJ, Starnes VA, Wetzel RC, Moromisato DY. Gastrointestinal morbidity after Norwood palliation for hypoplastic left heart syndrome. Ann Thorac Surg 2006;81:982-7. McElhinney DB, Hedrick HL, Bush DM, et al. Necrotizing enterocolitis in neonates with congenital heart disease: risk factors and outcomes. Pediatrics 2000;106:1080-7. Harrison AM, Davis S, Reid JR, et al. Neonates with hypoplastic left heart syndrome have ultrasound evidence of abnormal superior mesenteric artery perfusion before and after modified Norwood procedure. Pediatr Crit Care Med 2005;6:445-7. Cua CL, Thiagarajan RR, Taeed R, et al. Improved interstage mortality with the modified Norwood procedure: a meta-analysis. Ann Thorac Surg 2005;80:44-9. da Silva JP, da Fonseca L, Baumgratz JF, et al. Hypoplastic left heart syndrome: the report of a surgical strategy and comparative results of Norwood x Norwood-Sano approach. Rev Bras Cir Cardiovasc 2007;22:160-8. Pigula FA, Vida V, Del Nido P, Bacha E. Contemporary results and current strategies in the management of hypoplastic left heart syndrome. Semin Thorac Cardiovasc Surg 2007;19:238-44.

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[76] Pizarro C, Mroczek T, Malec E, Norwood WI. Right ventricle to pulmonary artery conduit reduces interim mortality after stage 1 Norwood for hypoplastic left heart syndrome. Ann Thorac Surg 2004;78:1959-63; discussion 1963-4. [77] Silva JP, Fonseca L, Baumgratz JF, et al. Hypoplastic left heart syndrome: the influence of surgical strategy on outcomes. Arq Bras Cardiol 2007;88:354-60. [78] Graham EM, Atz AM, Bradley SM, et al. Does a ventriculotomy have deleterious effects following palliation in the Norwood procedure using a shunt placed from the right ventricle to the pulmonary arteries? Cardiol Young 2007;17:145-50. [79] Malec E, Januszewska K, Kolz J, Pajak J. Factors influencing early outcome of Norwood procedure for hypoplastic left heart syndrome. Eur J Cardiothorac Surg 2000;18:202-6. [80] Lai L, Laussen PC, Cua CL, et al. Outcomes after bidirectional Glenn operation: Blalock-Taussig shunt versus right ventricle-to-pulmonary artery conduit. Ann Thorac Surg 2007;83:1768-73. [81] Cua CL, Sanghavi D, Voss S, et al. Right ventricular pseudoaneurysm after modified Norwood procedure. Ann Thorac Surg 2004;78:e72-3. [82] Sano S, Ishino K, Kado H, et al. Outcome of right ventricle-to-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome: a multi-institutional study. Ann Thorac Surg 2004;78:1951-7; discussion 1957-8. [83] Tanoue Y, Kado H, Shiokawa Y, Fusazaki N, Ishikawa S. Midterm ventricular performance after Norwood procedure with right ventricular-pulmonary artery conduit. Ann Thorac Surg 2004;78:1965-71; discussion 1971. [84] Frommelt PC, Sheridan DC, Mussatto KA, et al. Effect of shunt type on echocardiographic indices after initial palliations for hypoplastic left heart syndrome: Blalock-Taussig shunt versus right ventricle-pulmonary artery conduit. J Am Soc Echocardiogr 2007;20:1364-73. [85] Ballweg JA, Dominguez TE, Ravishankar C, et al. A contemporary comparison of the effect of shunt type in hypoplastic left heart syndrome on the hemodynamics and outcome at stage 2 reconstruction. J Thorac Cardiovasc Surg 2007;134:297-303. [86] Rumball EM, McGuirk SP, Stumper O, et al. The RV-PA conduit stimulates better growth of the pulmonary arteries in hypoplastic left heart syndrome. Eur J Cardiothorac Surg 2005;27:801-6. [87] Nakano T, Fukae K, Sonoda H, et al. Follow-up study of pulmonary artery configuration in hypoplastic left heart syndrome. Gen Thorac Cardiovasc Surg 2008;56:54-62. [88] Griselli M, McGuirk SP, Ofoe V, et al. Fate of pulmonary arteries following Norwood Procedure. Eur J Cardiothorac Surg 2006;30:930-5. [89] Januszewska K, Stebel A, Malec E. Consequences of right ventricle-to-pulmonary artery shunt at the first stage for the Fontan operation. Ann Thorac Surg 2007;84:16117. [90] Ruiz CE, Gamra H, Zhang HP, Garcia EJ, Boucek MM. Brief report: stenting of the ductus arteriosus as a bridge to cardiac transplantation in infants with the hypoplastic left-heart syndrome. N Engl J Med 1993;328:1605-8.

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[91] Boucek MM, Mashburn C, Chan KC. Catheter-based interventional palliation for hypoplastic left heart syndrome. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2005:72-7. [92] Slack MC, Kirby WC, Towbin JA, et al. Stenting of the ductus arteriosus in hypoplastic left heart syndrome as an ambulatory bridge to cardiac transplantation. Am J Cardiol 1994;74:636-7. [93] Akintuerk H, Michel-Behnke I, Valeske K, et al. Stenting of the arterial duct and banding of the pulmonary arteries: basis for combined Norwood stage I and II repair in hypoplastic left heart. Circulation 2002;105:1099-103. [94] Galantowicz M, Cheatham JP. Lessons learned from the development of a new hybrid strategy for the management of hypoplastic left heart syndrome. Pediatr Cardiol 2005;26:190-9. [95] Michel-Behnke I, Akintuerk H, Marquardt I, et al. Stenting of the ductus arteriosus and banding of the pulmonary arteries: basis for various surgical strategies in newborns with multiple left heart obstructive lesions. Heart 2003;89:645-50. [96] Akinturk H, Michel-Behnke I, Valeske K, et al. Hybrid transcatheter-surgical palliation: basis for univentricular or biventricular repair: the Giessen experience. Pediatr Cardiol 2007;28:79-87. [97] Galantowicz M, Cheatham JP, Phillips A, et al. Hybrid approach for hypoplastic left heart syndrome: intermediate results after the learning curve. Ann Thorac Surg 2008;85:2063-71. [98] Manzar S, Nair AK, Pai MG, Al-Khusaiby SM. Head size at birth in neonates with transposition of great arteries and hypoplastic left heart syndrome. Saudi Med J 2005;26:453-6. [99] Dent CL, Spaeth JP, Jones BV, et al. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2006;131:190-7. [100] Dent CL, Spaeth JP, Jones BV, et al. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2005;130:1523-30. [101] Te Pas AB, van Wezel-Meijler G, Bokenkamp-Gramann R, Walther FJ. Preoperative cranial ultrasound findings in infants with major congenital heart disease. Acta Paediatr 2005;94:1597-603. [102] Kaltman JR, Di H, Tian Z, Rychik J. Impact of congenital heart disease on cerebrovascular blood flow dynamics in the fetus. Ultrasound Obstet Gynecol 2005;25:32-6. [103] Pizarro C, Murdison KA, Derby CD, Radtke W. Stage II reconstruction after hybrid palliation for high-risk patients with a single ventricle. Ann Thorac Surg 2008;85:13828. [104] Lim DS, Peeler BB, Matherne GP, Kron IL, Gutgesell HP. Risk-stratified approach to hybrid transcatheter-surgical palliation of hypoplastic left heart syndrome. Pediatr Cardiol 2006;27:91-5.

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[105] Bacha EA, Daves S, Hardin J, et al. Single-ventricle palliation for high-risk neonates: the emergence of an alternative hybrid stage I strategy. J Thorac Cardiovasc Surg 2006;131:163-171 e2. [106] Pilla CB, Pedra CA, Nogueira AJ, et al. Hybrid Management for Hypoplastic Left Heart Syndrome : An Experience from Brazil. Pediatr Cardiol 2007. [107] Caldarone CA, Benson L, Holtby H, Li J, Redington AN, Van Arsdell GS. Initial experience with hybrid palliation for neonates with single-ventricle physiology. Ann Thorac Surg 2007;84:1294-300. [108] Li J, Zhang G, Benson L, et al. Comparison of the profiles of postoperative systemic hemodynamics and oxygen transport in neonates after the hybrid or the Norwood procedure: a pilot study. Circulation 2007;116:I179-87. [109] Caldarone CA, Benson LN, Holtby H, Van Arsdell GS. Main pulmonary artery to innominate artery shunt during hybrid palliation of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2005;130:e1-2. [110] Hawkins JA, Doty DB. Aortic atresia: morphologic characteristics affecting survival and operative palliation. J Thorac Cardiovasc Surg 1984;88:620-6. [111] Jonas RA, Lang P, Hansen D, Hickey P, Castaneda AR. First-stage palliation of hypoplastic left heart syndrome. The importance of coarctation and shunt size. J Thorac Cardiovasc Surg 1986;92:6-13. [112] Zellers TM. Balloon angioplasty for recurrent coarctation of the aorta in patients following staged palliation for hypoplastic left heart syndrome. Am J Cardiol 1999;84:231-3, A9. [113] Zeltser I, Menteer J, Gaynor JW, et al. Impact of re-coarctation following the Norwood operation on survival in the balloon angioplasty era. J Am Coll Cardiol 2005;45:18448. [114] Boucek MM, Mashburn C, Kunz E, Chan KC. Ductal anatomy: a determinant of successful stenting in hypoplastic left heart syndrome. Pediatr Cardiol 2005;26:200-5. [115] Lemler MS, Zellers TM, Harris KA, Ramaciotti C. Coarctation index: identification of recurrent coarctation in infants with hypoplastic left heart syndrome after the Norwood procedure. Am J Cardiol 2000;86:697-9, A9.

In: Congenital Heart Defects: Etiology, Diagnosis and Treatment ISBN 978-1-60692-559-1 Editor: Hiroto Nakamura © 2009 Nova Science Publishers, Inc.

Chapter XV

CARDIAC TUMORS – A REVIEW Kalgi Modi and Prasanna Venkatesh Division of Cardiology, Louisiana State University Health Science Center, Shreveport, Louisiana, USA.

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Primary cardiac tumors are extremely uncommon with reported rate between 0.001 and 0.28%. A risk of sudden cardiac death is extremely small (~0.0025%) from primary cardiac neoplasm [1]. The lethal potential of the myxoma can be attributed both to its location (usually in the left atrium) and its configuration. This pedunculated lesion, though tethered to the atrial septum, is capable of prolapsing through the mitral valve, creating a “ball valve” obstruction. Potentially lethal course and the possibility of cure with propitious excision make their diagnosis challenging and consequential. Therefore, to achieve diagnostic and therapeutic adequacy, clinicians should be knowledgeable of cardiac tumor pathology and their frequently atypical clinical presentations. Left ventricular metastatic tumors are particularly a rare finding with limited literature on its prevalence [2]. Cardiac tumors may involve the right atrium, right ventricle, left atrium or the left ventricle. They may be benign or malignant. The relative frequencies of the various cardiac tumors are shown in Table 1. The symptoms may be secondary to: A. Mechanical obstruction – causing obstruction of the heart or heart valves, producing symptoms of heart failure, and reduced cardiac output, which may prove fatal. B. Myocardial and pericardial invasion – causing impaired contractility, arrhythmias, heart block, or pericardial effusion with or without tamponade C. Embolization – which can be systemic or pulmonary D. Constitutional or systemic symptoms Right atrial tumors – myxomas are more common in the right atrium. However, sarcomas (particularly angiosarcomas) have been reported. These tumors grow into the right atrial lumen and may cause hemodynamic changes simulating tricuspid stenosis and present as

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right heart failure such as fatigue, peripheral edema, hepatomegaly, ascites, large a waves in the jugular veins. Physical exam may reveal a diastolic murmur and the characteristic “tumor plop”. Distal embolization of the tumor fragments may present as pulmonary embolization. Right ventricular tumors – Tumors arising in the right ventricular cavity interfere with the right ventricular filling or outflow, presenting with signs and symptoms of right heart failure. Left atrial tumors – myxomas are the most common tumors in the left atrium. Tumors arising in the left atrium grow into the left atrial lumen causing obstruction of the the mitral valve orifice or mitral regurgitation, thus simulating mitral valve disease and produce heart failure and / or pulmonary hypertension. Commonly observed symptoms include dyspnoea, orthopnea, paroxysmal nocturnal dyspnoea, pulmonary edema, cough, hemoptysis, edema and fatigue. Symptoms may be postural. Physical exam may reveal the characteristic “tumor plop” heard in early diastole. The tumor embolization may present with neurologic deficits or other signs of systemic embolization. Left ventricular tumors – Left ventricular tumors may be intramural or intracavitary. Intra mural tumors may present with arrhythmias or conduction defects. Intracavitary tumors may present with mechanical outflow obstruction, left ventricular failure, syncope or systemic embolization. Table 1. Relative frequency of primary cardiac tumors

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Benign Myxoma – 30% Lipoma – 10% Papillary fibroelastoma – 8% Rhabdomyoma – 6% Fibroma – 3% Hemangioma – 2% Teratoma – 1% Malignant Angiosarcoma – 8% Rhabdomyosarcoma – 5% Fibrosarcoma – 3% Mesothelioma – 3% Lymphoma – 2% Leiomyosarcoma – 1%

DIAGNOSTIC WORK UP OF CARDIAC TUMORS The diagnostic evaluation is to ascertain the presence of the cardiac tumor, its location, extent, characteristics (benign vs. malignant) and surgical resectability. Echocardiography, cardiac MRI and ultrafast CT provide complementary information in the diagnostic evaluation.

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Echocardiography Echocardiography is an accurate technique to detect and characterize the masses. The echocardiographic evaluation of cardiac tumors is critically dependant on the ability to distinguish normal and abnormal findings. As shown in table 3, a variety of normal variants and benign conditions are often misinterpreted as pathologic. Table 2. Metastatic Tumors to the Heart Original Source Lung Breast Lymphoma GI Melanoma Renal cell carcinoma Carcinoid

Cardiac effect Direct extension, often via pulmonary veins, effusion common Hematogenous or lymphatic spread; effusion common Lymphatic spread, varied manifestations Variable manifestations Intracardiac or myocardial involvement IVC to RA to RV; confused with thrombus Tricuspid and pulmonic valve thickening

Cardiac MRI and Ultrafast CT Although both cardiac MRI and ultrafast CT provide non-invasive, high resolution images of the heart, MRI is generally preferred. In addition to the anatomic details, the T1and T2- weighted sequences provide clues to the type of tumor, depiction of contour and the relationship with surrounding cardiac structures [3]. Gadolinium enhancement has been shown to add useful information in cases with myxoma, rhabdomyoma, angiosarcoma, and mesothelioma [3]. Indicators of malignancy in MR imaging are invasive behavior, involvement of the right side of the heart or the pericardium, tissue inhomogeneity, diameter greater than 5 cm, and enhancement after administration of gadolinium contrast material [4].

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SPECIFIC TUMORS Atrial Myxomas They are the most common benign primary cardiac tumor accounting for 30% of all primary cardiac tumors. Although considered benign tumors, sarcomatous presentation (myxosarcoma) with rapid progression of symptoms has been reported [5]. Malignant sarcomas with myxoid degeneration can masquerade as atrial myxomas [6,7]. Myxomas are usually single and occur in the left atrium in 75% of cases where they most often arise from the area of fossa ovalis. They may however involve the right atrium (15%) or the left or right ventricles (5% each). The clinical manifestations are as summarized under left atrial tumors. Carney complex is an inherited, autosomal dominant disorder characterized by multiple tumors, including atrial and extra cardiac myxomas, shwannomas, and various endocrine

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tumors. The cardiac myxomas are generally diagnosed at an earlier age than sporadic myxomas and have a higher tendency to recur [8]. In addition, patients may have pigmentation abnormalities. The size, shape and texture of the myxomas can be quite varied. They can be smooth or irregular with filamentous fronds or have appearance of “cluster of grapes” in echocardiography. They are typically non-homogenous in texture with lucent centers or areas of calcification. Bilobulated [9] or multicavitary [10] presentations of left atrial myxomas have also been reported. The most important clue to diagnosis is their location in the left atrium and the origin from the midportion of the atrial septum. Transthoracic echo is usually sufficient for diagnosis, although small tumors that involve the right heart may require a transesophageal echo.

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Table 3. Normal variants and benign conditions often misinterpreted as pathologic Right Atrium ¾ Chiari network ¾ Eustachian valve ¾ Crista terminalis ¾ Catheters/pacemaker leads ¾ Lipomatous hypertrophy of the interatrial septum ¾ Pectinate muscles ¾ Fatty material (surrounding the tricuspid annulus) Left Atrium ¾ Suture line following transplant ¾ Fossa ovalis ¾ Calcified mitral annulus ¾ Coronary sinus ¾ Ridge between LUPV and LAA ¾ Lipomatous hypertrophy of interatrial septum ¾ Pectinate muscles ¾ Transverse sinus Right Ventricle ¾ Moderator Band ¾ Muscle bundles/trabeculations ¾ Catheters / pacemaker leads Left Ventricle ¾ False chords ¾ Papillary muscles ¾ LV trabeculations

Once the diagnosis of myxoma is made, prompt resection is indicated due to the risk of embolic and cardiovascular complications, including sudden death. Complications of myxomas also include bleeding due to the high vascularity, which can cause sudden clinical deterioration. The results of surgical resection are generally very good with most series reporting an operative morality rate under 5% [11-13]. Myxomas can recur following surgical excision. In one large series, recurrence rates of myxomas following resection was about 5%

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[11]. Development of a second primary myxoma may be more common in patients with a family history of myxoma [14]. Therefore, surveillance echocardiograms should be obtained annually for several years to guard against this possibility.

Papillary Fibroelastomas They account for 10% of all primary tumors. They are usually found in older patients, arise from either aortic or mitral valves and are the most common valve associated tumors. They are small – 0.5 to 2.0 cm in diameter. These tumors usually attached to the downstream side of the valve by a small pedicle and are irregularly shaped with delicate frond like surfaces. Mobility is common and generally considered risk factor for embolization. Differential diagnoses include vegetations, lambl’s excrescences, and blood cysts. Surgery is indicated for patients with embolic complications that are related to tumor mobility. Asymptomatic patients with small, non-mobile papillary fibroelastomas may be observed clinically. Other benign tumors include rhabdomyomas, fibromas, teratomas, lipomas and hamartomas most of which are predominantly seen in the pediatric population. Paragangliomas are neuroendocrine tumors, which may be benign or malignant. Mesotheliomas may arise as benign tumors in the pericardium, however can present as malignant mesotheliomas causing pericardial constriction, tamponade or conduction abnormalities.

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MALIGNANT PRIMARY CARDIAC TUMORS Malignant primary tumors involving the heart are rare and include angiosarcoma, rhabdomyosarcoma, and fibrosarcoma. Rarer varieties include osteosarcoma, synovial sarcoma, undifferentiated sarcoma, reticulum cell sarcoma, neurofibrosarcoma, and malignant fibrous histiocytoma. There is invasion or replacement of myocardial tissue with disruption of the anatomic planes and obliteration of contiguous structures with tethering and relative immobility. Because primary cardiac malignancy is so much less common than metastatic involvement, echocardiographic demonstration of invasive cardiac tumor should suggest possibility of metastatic disease. Angiosarcomas usually affect the right atrium, rhabdomyosarcoma can occur anywhere, and fibrosarcomas may infiltrate into the myocardium. Leiomyosarcomas most frequently arise in the left atrium. Associated pericardial effusion is common leading to tamponade. The prognosis of sarcomas is poor with a median survival of 6-12 months [15], although long term survival has been reported with complete resection [15-17]. Primary lymphomas arising in the myocardium have been reported and generally have a poor prognosis [18].

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METASTATIC CARDIAC TUMORS Metastasis to the heart can spread by direct invasion from adjacent sources, venous propagation or hematogenous spread. The common metastatic tumors to the heart are shown in Table 2. Among the listed tumors, melanoma has a high propensity for metastasizing to the pericardium and/or myocardium, involving the heart in more than 50% of cases. Lymphoma is relatively uncommon to metastasize to the heart, so it poorly differentiated carcinoma, which is extremely rare to metastasize to the heart. In very carefully selected patients, resection of the cardiac metastases has been used to provide symptom palliation and prolong life [19,20].

CONCLUSION Although uncommon, cardiac tumors are encountered clinically, with metastatic tumors being more common than primary cardiac tumors. Early diagnosis and appropriate management is crucial in preventing complications.

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[3]

[4]

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[5] [6]

[7]

[8]

[9]

Reynen, K. Frequency of primary tumors of the heart. Am J Cardiol 1996; 77:107 Yelamanchili P, Wanat FE, Knezevic D, Nanda NC, Patel V. Two-dimensional transthoracic contrast echocardiographic assessment of metastatic left ventricular tumors. Echocardiography. 2006 Mar;23(3):248-50. Kaminaga T, Takeshita T, Kimura I. Role of magnetic resonance imaging for evaluation of tumors in the cardiac region. Eur Radiol. 2003 Dec;13 Suppl 6:L1-L10. Epub 2003 Jan 18. Sparrow PJ, Kurian JB, Jones TR, Sivananthan MU. MR imaging of cardiac tumors. Radiographics. 2005 Sep-Oct; 25(5):1255-76. Awamleh P, Alberca MT, Gamallo C, Enrech S, Sarraj A. Left atrium myxosarcoma: an exceptional cardiac malignant primary tumor. Clin Cardiol. 2007 Jun; 30(6):306-8. Morin JE, Rahal DP, Hüttner I. Myxoid leiomyosarcoma of the left atrium: a rare malignancy of the heart and its comparison with atrial myxoma. Can J Cardiol. 2001 Mar; 17(3):331-6. Kim JT, Baek WK, Kim KH, Yoon YH, Kim DH, Lim HK. A primary cardiac sarcoma preoperatively presented as a benign left atrial myxoma. Yonsei Med J. 2003 Jun 30; 44(3):530-3. Vidaillet, HJ Jr, Seward, JB, Fyke FE, 3rd et al. ‘Syndrome myxoma’ : a subset of patients with cardiac myxoma associated with pigmented skin lesions and peripheral and endocrine neoplasm’s. Br Heart J 1987; 57:247 Mundo-Sagardía JA, Calderón R, Defendini E. Bilobulated atrial myxoma originating from low interatrial septum. Bol Asoc Med P R. 2005 Oct-Dec;97(4):323-7.

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[10] Ibanez B, Marcos-Alberca P, Rey M, de Rabago R, Orejas M, Renedo G, Farre J. Multicavitated left atrial myxoma mimicking a hydatid cyst. Eur J Echocardiogr. 2005 Jun;6(3):231-3. [11] Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma. A series of 122 consecutive cases. Medicine (Baltimore) 2001; 80:159 [12] Keeling IM, Oberwalder P, Anelli-Monti M, et al. Cardiac myxomas: 24 years of experience in 49 patients. Eur J Cardiothorac Surg 2002; 22:971 [13] Bakaeen FG, Reardon MJ, Coselli JS, et al. Surgical outcome in 85 patients with primary cardiac tumors. Am J Surg 2003:186:641. [14] Bhan A, Mehrotra R, Choudhary K, et al. Surgical experience with intracardiac myxomas: Long term follow up. Ann Thorac Surg1998; 66:810. [15] Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart. Cancer 1992; 69:387. [16] Raaf, HN, Raaf JH. Sarcomas related to the heart and vasculature. Semin Surg Oncol 1994; 10:374. [17] Putnam JB Jr, Sweeney MS, Colon R, et al. Primary cardiac sarcomas. Ann Thorac Surg 1991; 51:906. [18] Ikeda H, Nakamura S, Nishimaki H, et al. Primary lymphoma of the heart: case report and literature review. Pathol Int 2004; 54:187. [19] Manner G, Harting MT, Russo P, et al. Surgical management of metastatic melanoma to the ventricle. Tex Heart Inst J 2003; 30:218. [20] Labib SB, Schick EC Jr, Isner JM. Obstruction of right ventricular outflow tract caused by intracavitary metastatic disease: analysis of 14 cases. J Am Coll Cardiol 1992; 19:1664.

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In: Congenital Heart Defects: Etiology, Diagnosis and Treatment ISBN:978-1-60692-559-1 Editor: Hiroto Nakamura © 2009 Nova Science Publishers, Inc.

Chapte XVI

PULMONARY HYPERTENSION IN THE DOWN SYNDROME POPULATION Clifford L Cua 1a Louis G Chicoine b, Leif D Nelinb, and Mary Mullenc a

Heart Center, bSection of Neonatology, Department of Pediatrics, a, ,b Nationwide Children’s Hospital and the Department of Cardiology, cChildren’s Hospital Boston

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ABSTRACT Down syndrome (DS) is a common genetic disorder with protean manifestations. Children with DS are at risk for multiple medical issues that are well described; however, a potentially underappreciated condition that appears to have a high prevalence in this patient population is pulmonary hypertension (PH). The increased prevalence of PH in this population may have serious short and long-term consequences. The causes of PH in the DS population are not precisely known, but may be due to multiple other associated medical conditions that these children have concurrently, or due to shared biological features. We review the literature that describes the possible etiologies of PH in DS children with the hope that further research is performed to better define this complicated population.

Keywords: Down syndrome, pulmonary hypertension

1

Corresponding author, Assistant Professor of Pediatrics, Heart Center, Department of Pediatrics, Nationwide Children’s Hospital. 700 Children’s Drive, Columbus, OH 43205, Bus: 614-722-2530, Fax: 614-722-2549, Email: [email protected]

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INTRODUCTION Down syndrome (DS) is a common genetic disorder and the most viable trisomy(1). Multiple medical problems including neurologic(2), orthopedic(3), endocrinologic(4,5), cardiac(6), gastrointestinal(7,8), oncologic(9,10), and immunologic(11,12) have been associated with this syndrome. One medical condition that has also been associated with DS, but may be underappreciated, is pulmonary hypertension (PH). PH may have serious detrimental consequences in these individuals and should be recognized and treated as soon as diagnosed to improve short and long-term outcomes. Neither the contributors to PH in DS patients, nor the precise incidence or prevalence over time are well established. This review will describe some of the possibilities that may place DS patients at risk for PH. Several of the medical issues associated with DS may contribute to the development of PH, such as cardiac lesions and respiratory problems. There may also be specific intrinsic biological links between DS and PH that account for the severity in this population. The etiology for PH in DS is almost certainly multi-factorial and may be classified according to the recent WHO/Evian classification for PH(13). This classification scheme identifies etiologies to PH as associated with disorders of the respiratory system or hypoxemia: 3.1: chronic obstructive pulmonary disease, 3.3: sleep disordered breathing, 3.4: alveolar hypoventilation, 3.6: neonatal lung disease, 3.7: alveolar capillary dysplasia; PH related to 1.2(b): congenital systemic-to-pulmonary shunts, or PH that is 1.1(a) sporadic. Anatomical upper airway obstruction (UAO) is common in DS. Well described abnormalities that contribute to UAO include macroglossia, tonsillar and adenoidal enlargement, subglottic stenosis, laryngomalacia, and tracheomalacia(14). These abnormalities may contribute to chronic hypoventilation and hypoxemia and thus put the DS patient at risk factor for developing PH(15). In one study, 53 pediatric (7.4 + 1.2 years) DS patients had nap polysomnograms performed and 77% of the patients studied subsequently had abnormal findings. Findings included obstructive and central apnea, hypoventilation, and oxygen saturations less than 90%. Sixteen of these DS patients additionally had overnight sleep polysomnograms and 100% of them had abnormal findings. Age, obesity, or presence of congenital heart disease (CHD) did not predict abnormal polysomnography studies. The polysomnograms improved in the patients that subsequently underwent tonsillectomy and adenoidectomy, but did not totally normalize in any of the patients(16). A smaller study with seven DS patients also showed improvement in their polymsomnograms and clinical symptoms after UAO surgery(17). These observations are consistent with multiple case reports and case series of PH in DS with UAO that either improved or normalized after the obstruction was relieved with removal of the tissue or with placement of a tracheostomy(1825). One group reported on a large cohort of patients with UAO and found that premature infants or DS patients with CHD had the highest risk for developing PAH(26). They also reported on 71 DS patients with UAO, 34 of which had PH, who underwent surgical palliation for UAO. Symptoms and PH frequently improved after surgery, but similar to other studies, did not completely normalize. Nonetheless, 39% still had significant residual symptoms and there were five deaths(27). In addition to UAO, DS can be associated with abnormalities in the lung parenchyma or vasculature that may predispose to PH, though the data are conflicting. One of the earliest

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studies examined lung specimens in 82 DS patients. These specimens were matched for age, sex, and CHD in non-DS patients. This study found no significant differences in the pulmonary vasculature from lung specimens from DS versus non-DS patients(28). However, recent studies have shown abnormalities in DS versus non-DS patients in lung architecture. Lung hypoplasia with decreased number of alveoli in relation to acini as well as enlarged alveolar ducts have been reported in DS versus non-DS patients with lung biopsies(29). Other investigators have noted differences in the number of type II alveolar cells between DS versus non-DS patients(30). Case reports have identified alveolar capillary dysplasia in DS patients that lead to intractable PH(31,32), though the low incidence of such dysplasia, in general, makes comparisons between DS and non-DS populations challenging(33). Collectively, these recent findings point toward substantial differences in lung parenchymal and vasculature changes that may be risk factors for DS patients developing PH. Another common medical issue in DS is the presence of CHD. DS patients have approximately a 50% incidence of CHD with atrioventricular septal defects (AVSD) and ventricular septal defects (VSD) comprising the vast majority of lesions(6,34). These lesions allow left-to-right intra-cardiac blood flow resulting in increased pulmonary blood flow, which over time damages the pulmonary vasculature and leads to PH(35). A specific anatomical lesion seen with AVSD has also been implicated in increasing the risk for PH(36). Regardless of the mechanism, there is no question that unrepaired CHD associated with a left-to-right shunt is a substantial risk factor for the development of PH(37,38). While CHD increases the risk of PH, DS patients appear to have a higher incidence of developing PH compared to non-DS patients with CHD(34,37,39-41). DS patients also appear to have a more significant degree of pre-operative PH compared to non-DS patients with similar CHD lesions. DS has been associated with significantly lower pulmonary blood flow and higher pulmonary vasculature resistance compared to non-DS patients before cardiac surgery and to a higher risk of developing fixed PH at less than one year of age compared to non-DS patients(42). Moreover, pathological lung specimens have increased pulmonary vasculature intimal changes, pulmonary arterial lumen narrowing, thinning of the arterial media, and fibrotic intimal proliferation in DS patients versus non-DS patients with similar CHD lesions(43,44). Surgical repair of CHD achieves improvement in pulmonary artery pressures(45-47), but DS patients still appear to have a higher incidence and less resolution of PH post-repair. In a study with 1349 patients less than 18 years of age, the incidence of PH episodes was 9.9% in DS patients versus 1.2% in non-DS patients(48). An additional study documented a larger decrease in pulmonary vasculature resistance in non-DS patients than in DS patients after VSD repair(49). Even accounting for multiple risk factors that predispose to developing PH such as UAO or CHD, DS patients also appear to have an increased incidence with greater severity of PH compared to non-DS patients. This observation has led to speculation that DS may directly contribute the risk for PH irrespective of related cardiopulmonary conditions. Examples of this include the demonstration of an increased risk of persistent pulmonary hypertension of the newborn (PPHN) compared non-DS patients regardless of baseline demographics(50). Another study examined the ELSO database which contained 15,946 patients placed on extracorporeal membrane oxygenation (ECMO) in the neonatal period, of which 91 had DS. This study found that the primary reason for ECMO support was significantly different for

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DS patients versus non-DS patients with PPHN being the primary reason in 47.3% of the DS patients and only 13% in the non-DS patients. The DS patients also had a greater risk for being placed on ECMO with worse survival than did patients without DS(51). Both studies suggest that the transition from intra- to extra-uterine life in DS patients may not be normal in regards to the pulmonary vasculature. Catheterization data suggests that DS patients do not exhibit the same level of pulmonary vasodilatation to nitric oxide (NO) or oxygen as do non-DS patients(52,53). In the systemic circulation, DS can also be associated with decreased brachial blood flow and a decreased vascular resistance response to acetylcholine administration versus non-DS patients, though the response to nitroglycerin was similar between the two groups of patients. This study implied that NO production is impaired in the DS patient since acetylcholine vasodilation is mediated by NO production in the endothelium whereas nitroglycerin is a direct NO donor(54). In addition to these differences in physiology, cellular differences may also exist in the lung vasculature. Endothelial progenitor cells, which are central to the maintenance of vascular homeostasis, were shown to be lowest in DS patients with Eisenmenger physiology (i.e. PH associated with CHD) versus non-DS patients with Eisenmenger physiology, idiopathic PH, or controls without PH(55). Levels of endothelin, a potent endogenously produced vasoconstrictor, were shown to be significantly elevated in DS patients versus nonDS patients pre- and post-CHD surgery. There was a direct correlation between endothelin levels and pulmonary artery pressures(56). Finally, there have been differences noted in alkaline phosphatase activity, which has a role in pulmonary surfactant secretion, between lung tissue of DS versus non-DS patients(30). These diverse findings suggest that simply having the diagnosis of DS increases the risk and severity of PH compared to the non-DS population. Genetic variations that predispose to PH have been studied in DS patients, but at this time, there has been no definitive genetic variations identified in DS patients that predispose them to PH(57,58). There is a growing recognition of the problem of PH in DS patients. Factors important to causing PH in DS include well known congenital abnormalities, but also may reflect intrinsic differences between DS and non-DS individuals. These preliminary clinical and laboratory observations warrant for more extensive evaluation of pulmonary vasculature function in DS patients so as to understand the precise incidence and etiology for this condition. PH significantly increases morbidity and mortality and if not identified and treated appropriately may have added detrimental effects on this population already at risk. Further studies examining the mechanism, possible genetic variations, and treatment for PH in this complicated population are needed to improve outcomes.

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Matsuda Y, Sano N, Watanabe S, Oki S, Shibata T. Atlanto-occipital hypermobility in subjects with Down's syndrome. Spine 1995;20:2283-6. Unachak K, Tanpaiboon P, Pongprot Y, et al. Thyroid functions in children with Down's syndrome. J Med Assoc Thai 2008;91:56-61. Fonseca CT, Amaral DM, Ribeiro MG, Beserra IC, Guimaraes MM. Insulin resistance in adolescents with Down syndrome: a cross-sectional study. BMC Endocr Disord 2005;5:6. Freeman SB, Bean LH, Allen EG, et al. Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genet Med 2008;10:173-80. Aquino A, Domini M, Rossi C, Sardella L, Palka G, Chiesa PL. Correlation between Down's syndrome and malformations of pediatric surgical interest. J Pediatr Surg 1998;33:1380-2. Kallen B, Mastroiacovo P, Robert E. Major congenital malformations in Down syndrome. Am J Med Genet 1996;65:160-6. Vyas P, Roberts I. Down myeloid disorders: a paradigm for childhood preleukaemia and leukaemia and insights into normal megakaryopoiesis. Early Hum Dev 2006;82:767-73. Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 2006;135:595-602. Rodriguez de al Nuez AL, Sanchez Dominguez T, Villa-Elizaga I, Subira ML. Down's syndrome and immune function. Am J Dis Child 1982;136:81. Ugazio AG, Maccario R, Notarangelo LD, Burgio GR. Immunology of Down syndrome: a review. Am J Med Genet Suppl 1990;7:204-12. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S. Rohde M, Banner J. Respiratory tract malacia: possible cause of sudden death in infancy and early childhood. Acta Paediatr 2006;95:867-70. Levine OR, Simpser M. Alveolar hypoventilation and cor pulmonale associated with chronic airway obstruction in infants with Down syndrome. Clin Pediatr (Phila) 1982;21:25-9. Marcus CL, Keens TG, Bautista DB, von Pechmann WS, Ward SL. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991;88:132-9. Lefaivre JF, Cohen SR, Burstein FD, et al. Down syndrome: identification and surgical management of obstructive sleep apnea. Plast Reconstr Surg 1997;99:629-37. Kasian GF, Duncan WJ, Tyrrell MJ, Oman-Ganes LA. Elective oro-tracheal intubation to diagnose sleep apnea syndrome in children with Down's syndrome and ventricular septal defect. Can J Cardiol 1987;3:2-5. Ayeni TI, Roper HP. Pulmonary hypertension resulting from upper airways obstruction in Down's syndrome. J R Soc Med 1998;91:321-2. Bloch K, Witztum A, Wieser HG, Schmid S, Russi E. [Obstructive sleep apnea syndrome in a child with trisomy 21]. Monatsschr Kinderheilkd 1990;138:817-22.

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[21] Fernandez Pastor FJ, Paez Gonzalez R, Mateos Perez G, Benito Bernal AI, Gil Sanchez A. [Pulmonary hypertension in a patient with Down syndrome and chronic upper airway obstruction]. An Pediatr (Barc) 2005;62:178-9. [22] Hoch B, Barth H. Cheyne-Stokes respiration as an additional risk factor for pulmonary hypertension in a boy with trisomy 21 and atrioventricular septal defect. Pediatr Pulmonol 2001;31:261-4. [23] Rowland TW, Nordstrom LG, Bean MS, Burkhardt H. Chronic upper airway obstruction and pulmonary hypertension in Down's syndrome. Am J Dis Child 1981;135:1050-2. [24] Hultcrantz E, Svanholm H. Down syndrome and sleep apnea--a therapeutic challenge. Int J Pediatr Otorhinolaryngol 1991;21:263-8. [25] Clark RW, Schmidt HS, Schuller DE. Sleep-induced ventilatory dysfunction in Down's syndrome. Arch Intern Med 1980;140:45-50. [26] Jacobs IN, Teague WG, Bland JW, Jr. Pulmonary vascular complications of chronic airway obstruction in children. Arch Otolaryngol Head Neck Surg 1997;123:700-4. [27] Jacobs IN, Gray RF, Todd NW. Upper airway obstruction in children with Down syndrome. Arch Otolaryngol Head Neck Surg 1996;122:945-50. [28] Wilson SK, Hutchins GM, Neill CA. Hypertensive pulmonary vascular disease in Down syndrome. J Pediatr 1979;95:722-6. [29] Cooney TP, Thurlbeck WM. Pulmonary hypoplasia in Down's syndrome. N Engl J Med 1982;307:1170-3. [30] Hasegawa N, Oshima M, Kawakami H, Hirano H. Changes in pulmonary tissue of patients with congenital heart disease and Down syndrome: a morphological and histochemical study. Acta Paediatr Jpn 1990;32:60-6. [31] Galambos C. Alveolar Capillary Dysplasia in a Patient with Down's Syndrome. Pediatr Dev Pathol 2006;9:254-5; author reply 256. [32] Shehata BM, Abramowsky CR. Alveolar capillary dysplasia in an infant with trisomy 21. Pediatr Dev Pathol 2005;8:696-700. [33] Tibballs J, Chow CW. Incidence of alveolar capillary dysplasia in severe idiopathic persistent pulmonary hypertension of the newborn. J Paediatr Child Health 2002;38:397-400. [34] Greenwood RD, Nadas AS. The clinical course of cardiac disease in Down's syndrome. Pediatrics 1976;58:893-7. [35] Cantor WJ, Harrison DA, Moussadji JS, et al. Determinants of survival and length of survival in adults with Eisenmenger syndrome. Am J Cardiol 1999;84:677-81. [36] Suzuki K, Yamaki S, Mimori S, et al. Pulmonary vascular disease in Down's syndrome with complete atrioventricular septal defect. Am J Cardiol 2000;86:434-7. [37] Borowski A, Zeuchner M, Schickendantz S, Korb H. Efficacy of pulmonary artery banding in the prevention of pulmonary vascular obstructive disease. Cardiology 1994;85:207-15. [38] Thieren M, Stijns-Cailteux M, Tremouroux-Wattiez M, et al. [Congenital heart diseases and obstructive pulmonary vascular diseases in Down's syndrome. Apropos of 142 children with trisomy 21]. Arch Mal Coeur Vaiss 1988;81:655-61.

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[39] Calderon-Colmenero J, Flores A, Ramirez S, et al. [Surgical treatment results of congenital heart defects in children with Down's syndrome.]. Arch Cardiol Mex 2004;74:39-44. [40] Kwiatkowska J, Tomaszewski M, Bielinska B, Potaz P, Erecinski J. Atrioventricular septal defect: clinical and diagnostic problems in children hospitalised in 1993-1998. Med Sci Monit 2000;6:1148-54. [41] Chi TPLKJ. The pulmonary vascular bed in children with Down syndrome. J Pediatr 1975;86:533-8. [42] Clapp S, Perry BL, Farooki ZQ, et al. Down's syndrome, complete atrioventricular canal, and pulmonary vascular obstructive disease. J Thorac Cardiovasc Surg 1990;100:115-21. [43] Yamaki S, Horiuchi T, Sekino Y. Quantitative analysis of pulmonary vascular disease in simple cardiac anomalies with the Down syndrome. Am J Cardiol 1983;51:1502-6. [44] Yamaki S, Yasui H, Kado H, et al. Pulmonary vascular disease and operative indications in complete atrioventricular canal defect in early infancy. J Thorac Cardiovasc Surg 1993;106:398-405. [45] Ando H, Yasui H, Kado H, et al. [Total repair of complete atrioventricular canal: relationship between age at operation and late results]. Nippon Kyobu Geka Gakkai Zasshi 1989;37:265-73. [46] Frid C, Thoren C, Book K, Bjork VO. Repair of complete atrioventricular canal. 15 year's experience. Scand J Thorac Cardiovasc Surg 1991;25:101-5. [47] Okada H, Tsuboi H, Nishi K, et al. [Surgical treatment of ventricular septal defect associated with Down syndrome]. Kyobu Geka 1993;46:396-8. [48] Lindberg L, Olsson AK, Jogi P, Jonmarker C. How common is severe pulmonary hypertension after pediatric cardiac surgery? J Thorac Cardiovasc Surg 2002;123:1155-63. [49] Kawai T, Wada Y, Enmoto T, et al. Comparison of hemodynamic data before and after corrective surgery for Down's syndrome and ventricular septal defect. Heart Vessels 1995;10:154-7. [50] Cua CL, Blankenship A, North AL, Hayes J, Nelin LD. Increased incidence of idiopathic persistent pulmonary hypertension in Down syndrome neonates. Pediatr Cardiol 2007;28:250-4. [51] Southgate WM, Annibale DJ, Hulsey TC, Purohit DM. International experience with trisomy 21 infants placed on extracorporeal membrane oxygenation. Pediatrics 2001;107:549-52. [52] Cannon BC, Feltes TF, Fraley JK, Grifka RG, Riddle EM, Kovalchin JP. Nitric oxide in the evaluation of congenital heart disease with pulmonary hypertension: factors related to nitric oxide response. Pediatr Cardiol 2005;26:565-9. [53] Vazquez-Antona CA, Lomeli C, Buendia A, Vargas-Barron J. [Pulmonary hypertension in children with Down's syndrome and congenital heart disease. Is it really more severe?]. Arch Cardiol Mex 2006;76:16-27. [54] Cappelli-Bigazzi M, Santoro G, Battaglia C, et al. Endothelial cell function in patients with Down's syndrome. Am J Cardiol 2004;94:392-5.

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[55] Diller GP, van Eijl S, Okonko DO, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 2008;117:3020-30. [56] Kageyama K, Hashimoto S, Nakajima Y, Shime N, Hashimoto S. The change of plasma endothelin-1 levels before and after surgery with or without Down syndrome. Paediatr Anaesth 2007;17:1071-7. [57] Canter JA, Summar ML, Smith HB, et al. Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: a validated genetic association study. Mitochondrion 2007;7:204-10. [58] Cua CL, Cooke G, Taylor M, et al. Endothelial nitric oxide synthase polymorphisms associated with abnormal nitric oxide production are not over-represented in children with Down syndrome. Congenit Heart Dis 2006;1:169-74.

In: Congenital Heart Defects: Etiology, Diagnosis and Treatment ISBN 978-1-60692-559-1 Editor: Hiroto Nakamura © 2009 Nova Science Publishers, Inc.

Chapter XVII

ATRIOVENTRICULAR BLOCK DURING AND AFTER TRANS-CATHETER CLOSURE OF VENTRICULAR SEPTAL DEFECTS MECHANISMS: PREVENTION AND TREATMENT Zhi-Yuan Song∗ and Lei Zhang Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.

ABSTRACT

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The current commentary will discuss the anatomy in relation to the heart conduction system and VSD, the mechanisms of atrioventricular block during and after transcatheter closure procedure, and preventive methods. Subtitles include the relation between VSD and atrioventricular conduction pathway, incidence of cardiac conduction block during and after trans-catheter VSD closure, underlying mechanisms of atrioventricular block induced by trans-catheter VSD closure, and conduction block induced by trans-catheter VSD closure—features, prevention and treatment.

Keywords: congenital heart defects, interventional therapy, cardiac conduction block

With the improvement of the devices and development of some new interventional treatment strategies, in recent years the safety and the efficacy of trans-catheter closure of ventricular septal defects (VSD) has gained approval. On the other hand, the increase in cases draws more attention to atrioventricular-block during the catheter closure procedure. The ∗

Correspondence concerning this article should be addressed to: Dr. Song Zhiyuan, Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. Tel: 011-86-2368765168; E-mail: [email protected].

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current paper will discuss anatomy in relation to the heart conduction system and VSD, the mechanisms of atrioventricular block during and after trans-catheter closure procedure, and preventive methods.

THE RELATION BETWEEN VSD AND ATRIOVENTRICULAR CONDUCTION PATHWAY The ventricular septum is divided into two sections: the muscular septum (inferior) and the membranous septum (superior). The muscular septum, forming the main part of the ventricular septum, can be divided into the inlet septum, the trabecular septum, and the outlet septum. (The outlet septum is also called the conal or infundibular septum.) VSD can be found at any part of septum. There are three type of VSD: •

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• •

The defects occuring in the region of the membranous septum also are known as pure-membranous, peri-membranous defects and defects under the septal leaflet. The second type of defect is one with an entirely muscular rim. The third type of defect occurs when the infundibular septum is deficient. This is commonly referred to as subaortic and infracristal defects.

The relationship between the margin of VSD and the AV conduction pathway varies according to the type of VSD. Generally, perimembranous defects and inlet defects show a close relation with the AV conduction pathway. The AV conduction pathway is originated at the apex of the triangle of Koch, penetrates into the part of ventricular septum between noncoronary sinus and right-coronary sinus, through the posterior part of ventricular septum, runs from the inferior part of the membranous septum into the supracristal part of the muscular septum, and divides into left and right branches. It is found that the AV conduction pathway always locates posteriorly to perimembranous defects. The distance between VSD and AV conduction is commonly 2–4mm. Meanwhile, secondary endocardial myocardial fibrosis can usually be found at the edge of perimembranous defect. Both branches are often encapsulated in the fibrous tissue at the edge of defect. The frangibility of the conduction fiber is strongly correlated with the thickness of the wrapping fibrous tissue. For a patient with a thicker fibrous tissue, pre-procedure AV block is commonly seen; on the other hand, for thinner ones, damage-related AV block is commonly seen after trans-catheter VSD closure.

INCIDENCE OF CARDIAC CONDUCTION BLOCK DURING AND AFTER TRANS-CATHETER VSD CLOSURE Cardiac conduction block is a common type of complication in surgical revision. The incidence rate ranges from 20 to 81%. The block type includes: complete left bundle branch block (CLBBB), complete right bundle branch block (CRBBB), incomplete right bundle

Atrioventricular Block during and after Trans-Catheter Closure…

337

branch block (IRBBB), and III° AVB. The most common type is CRBBB, while the least common type is III° AVB (less than 1%). Theoretically, the incidence of trans-catheter closure is lower compared with surgical revision due to the fact that an interventional method avoids an open-heart incision, thus causing less damage to the conduction pathway. But in the real world, with the increase in cases with cardiac conduction block induced by transcatheter closure procedure, clinical practitioners have focused more and more attention on this issue. Until now, accurate incidence data based on a large-scale population study has not been reported. Here, as shown in Table 1, is a recent clinical trial data collection. Table 1. The incidence of catheter related cardiac conduction block Author

Qin YW Carminati Masura Zhang YS Xie YM Fu Djer Yuan PL Liu TL Tong SF

Year of publication

Sample size(n)

2004 2005 2005 2005 2005 2006 2006 2006 2006 2007

286 122 186 262 182 35 17 102 94 232

LBBB/ Ⅱ° AVB (%) 8(2.8%) 6(4.9%) 2(1.1%) 9(3.4%) 8(4.4%) 3(8.6%) 2(11.8%)

19§(8.2%)

Ⅲ° AVB

Time of occurrence (day)

Time to recovery (day)

THP※/PHP

2(0.7%) 5(4.1%) 2(1.1%) 5(1.9%) 3(1.6%) 3(8.6%) 2(11.8%) 2(2.0%) 3(3.2%) 5(2.2%)

3,5 0-360 0-1

10,19 7-30

2/0 1/1 0/0

4-7

2-3

3/0 1/3

2-7 0-6

2-20 1-30

2/0 0/0

※ THP: temporary heart pacing; PHP: permanent heart pacing; § CLBBB 5cases, CRBBB 6 cases, IRBBB 8 cases.

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As shown in Table 1, the incidence of cardiac conduction block varies considerably according to different centers. We suppose the possible reasons for this variation are difference in sample size, the type of VSD (closure of peri-membranous defects show a trend toward a higher conduction block incidence), and the type of occluder. Based on our clinical data of 232 patients, the incidence of cardiac conduction block during and after procedure is 11.6% (27/232), including eight patients with III° AVB (three of them occurred during procedure). All of these eight patients were cured with high-dosage adrenocorticoid treatment.

UNDERLYING MECHANISMS OF ATRIOVENTRICULAR BLOCK INDUCED BY TRANS-CATHETER VSD CLOSURE Up till now, there is no established method for us to predict the incidence of conduction block. To our knowledge, the underlying mechanisms of cardiac conduction block during and after VSD closure procedure include the location and size of defect, the type and size of occluder, and operative damage.

Zhi-Yuan Song and Lei Zhang

338 Anatomy of VSD

It is generally believed that there is a strong correlation between the defects located at the trabecular septum/the inlet septum with the conduction pathway. The distance between the edges of these two types of VSD and the trunk or bifurcation point of conduction pathway is only 2–4mm. Trans-caster closure-induced conduction block is liable to occur in these types of VSD. Meanwhile, distance between VSD located at the outlet septum with the conduction pathway is generally 5mm and over. For defects posterior to septal leaflet, though being far from the aortic valve but closer to the bundle of His and proximal part of the AV node, procedure-induced conduction block is also liable to occur.

Size of VSD The pathological change of myocardium in a large VSD is more obvious due to a higher shunt flow volume and a more serious hemodynamic disturbance. At the edge of VSD, endocardial myocardial fibrosis and scar tissue formation is commonly seen. Consequently, that would facilitate the incidence of conduction block during and after VSD closure.

Shape and Size of Occluder

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An oversized occluder may induce a high stress at the margin of the target defect. A consequent tissue edema may compresses on the conduction system, and then, causes conduction block. The shape of Amplatzer occluder for peri-membranous VSD is eccentric with an inferior margin of 3 to 5.5mm in length. Oversized occluder is likely to compress His-bundle, the bifurcation part and right bundle, and then, causes a block. It has been reported that the incidence of post-operative arrhythmia is higher in patients with the occluder diameter 10mm and over. We found that, as shown in Table 2, the difference value of the VSD diameter and the occluder diameter is higher in patients with newly developed conduction block. We propose that oversized occluder might be one of the important reasons for the occurrence of post-operative conduction block. Table 2 .The diameter of VSD, the distance between VSD and aortic valve , the size of occluder: conduction block group vs. control ( x ±S, mm) Group

Conduction block Control

Case (n)

VSD

27 27

Size of occluder

Difference value of VSD and occluder diameter

5.91±1.92

Distance between VSD and Aorta 3.30±1.65

8.81±2.62

2.94±0.92△

6.01±1.88

3.52±1.58

7.93±2.38

1.94±0.69

diameter

※

※: VSD diameter is detained by ventriculography; △: p＜0.01.

Atrioventricular Block during and after Trans-Catheter Closure…

339

Operative Tips The relation between VSD and the conduction system is considerably complicated. Common damaging operations include an oversized long-sheath and an inadequate sendingin process, an inadequate high-pressure on artery-vein steel wire track that may enlarge the ventricular defects or tear the VSD marginal tissue, damages and consequent inflammation caused by repeated detecting the opening of defects on the left side of septum. In our catheter lab, two patients developed complete AVB when the right coronary artery catheter irritated the inter-ventricular septum; another AVB was caused by using an oversized long-sheath. All three AVBs disappeared after the process was stopped. These three procedures were finally successful after we replaced and adjusted the positions of these occluders.

CONDUCTION BLOCK INDUCED BY TRANS-CATHETER VSD CLOSURE: FEATURES, PREVENTION AND TREATMENT Conduction Block during Trans-Catheter VSD Closure Procedure

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Conduction block during trans-catheter VSD closure procedure is correlated mostly with the operative manipulation. The common type includes complete left bundle brunch block (CLBBB), complete right bundle brunch block (CRBBB) and all three-degree types of AVB. A new CLBBB, CRBBB or first-degree AVB, is usually reversible, with a limited adverse effects on operation results. For a newly-developed second-degree AVB or a complete one, the operator should be more cautious. High-degree AVB can be induced by the stimulation of catheters on the ventricular wall, especially on the left side of the ventricular septum. A certain amount of high-degree AVB found during operation will disappear when the operation is suspended or when the tip of the catheter passes though the defect. On the occurrence of a repeated high-degree AVB on operative stimulation, or a long-lasting highdegree AVB (up to five minutes) after the pause of operation, closure procedure should be given up. When an AVB occurs on the releasing of occluder and disappearing after pulling it back, it is reasonable to choose a smaller occluder. For an AVB occurring on the release of a proper-size occluder, closure procedure should also be given up.

Conduction Block after Trans-Catheter VSD Closure Procedure Post-operative conduction block often occurs from several hours to one week after each procedure. The most frequent and most severe type is CAVB. Syncope is commonly seen among these patients, even sudden death. More caution should be paid to patients with intermittent CAVB. Post-operative CAVB can be completely cured on high-dosage adrenocorticoid treatment. Permanent CAVB is rarely seen. All five cases with post-operative conduction block in our catheter lab were cured by the application of adrenocorticoids without heart pacing.

340

Zhi-Yuan Song and Lei Zhang

To prevent late AV block after VSD closure procedure, we highlight the following points. Firstly, the size of each occluder should be chosen individually. The inclination of using an oversized occluder should be avoided. The size of each occluder should be decided based on left ventriculography. In our catheter center, we divide the diameter of VSD into three groups: 5mm or less, 6–9mm and 10 mm and over. The size of occluder should be 0– 1mm, 1–2mm and 2–3mm larger than the VSD diameter for each group separately. Secondly, patients should stay in hospital for at least one week after VSD closure procedure. Dynamic electrocardiogram is useful for the early detection of intermittent complete atrioventricular block. Thirdly, for a new CLBBB or CRBBB after closure procedure, with or without symptoms, adrenocorticoids should be applied to prevent complete AVB. In general, although the short-term treatment effect of trans-catheter VSD closure has been well approved, the long-term result is still unclear. The incidence of severe AV block is comparatively low; clinical data based on a single center can hardly deduce an objective evaluation. For this reason, it is crucially important to establish a standardized treatment protocol and to launch a systematic, multi-center clinical trail. We suppose that these efforts might facilitate an accurate evaluation for the long-term effects on trans-catheter closure of VSD.

REFERENCES [1]

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Zhang Yu-shun, Zhu Xian-Yang, Zhang Jun. Application of echocardiogram in the treatment of trans-catheter closure for congenital heart disease. World Publishing Corporation, 2005. Chinese Ho SY, Path FC, Mccarthy KP , et al . Morphology of perimembranous Ventricular Septal Defects: implications for trans-catheter device closure. J Interven Cardill, 2004, 17:99-108 Qin Yong-Wen, Zhao Xian-Xian, Wu Hong. Transcatheter closure of perimembranous ventricular septal defects using the china-made VSD occluder. Journal of Interventional Radiology, 2004,12(s):141-3. Chinese Carminati M, Butera G, Chessa M, et al. Trans-catheter closure of congenital ventricular septal defect with Amplatzer septal occluders. Am J Cardiol ,2005 ,96 :52L58L Masura J, Gao W, Gavora P, et al. Percutaneous closure of perimembranous ventricular septal defects with the eccentric Amplatzer device: multicenter follow-up study. Pediatr Cardiol, 2005, 26:216-219 Zhang YS, Li H, Liu JP, Dai ZX, Wang L, Zhang J, Li J, Wang XY. Complications of trans-catheter interventional occlusion of ventricular septal defects. Zhonghua Er Ke Za Zhi 2005; 43 :35-8. Chinese Xie YM, Zhang ZW, Li YF, Qian MY, Wang HS. Management of the arrhythmia around the procedure of trans-catheter closure of ventricular septal defects in pediatric patients. Zhonghua Xin Xue Guan Bing Za Zhi, 2005; 33:1092-4. Chinese

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Fu YC, Bass J, Amin Z, et al. T Trans-catheter Closure of Perimem2branous Ventricular Septal Defects Using the New Amplatzer Membra2nous VSD Occluder: Results of the U. S. Phase I Trial. J Am CollCardiol, 2006; 47:319-325 Djer MM, Latiff HA, Alwi M, et al. Transcatheter closure of muscular ventricular septal defect using the Amplatzer devices. Heart Lung Circ, 2006; 15:12-17 Yuan PL. Clinical Study on Domestic-made Two-disc-like Occluder Device to Treat Perimembrane Ventricular Septal Defect. Journal of Interventional Radiology, 2006; 15(s):31-3 Chinese Liu TL, Wang YL, Zhang JJ. Preventive and therapy of cardiac block after intervention occlusion in the patients with ventricular septal defect. Journal of Interventional Radiology, 2006; 15(s):43-5 Chinese Song ZY, Zhang ZH, He GX. Atrioventricular block during and after trans-catheter closure of ventricular septal defects. Zhonghua Xin Xue Guan Bing Za Zhi, 2006;34: 497-9. Chinese Tong SF, Zhang ZH, Chen L. The prevention and treatment of arrhythmia during the trans-catheter closure of ventricular septal defect. Chinese Journal of Cardiac Pacing and Electrophysiology，2007, 21:212-214. Chinese

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INDEX

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A abdomen, ix, 85, 97, 98, 100, 176 abnormalities, ix, 12, 18, 21, 23, 25, 37, 47, 63, 65, 80, 81, 83, 90, 91, 92, 95, 97, 107, 110, 111, 113, 114, 116, 118, 120, 138, 142, 143, 154, 156, 172, 197, 198, 199, 204, 209, 211, 226, 280, 304, 315, 320, 321, 326, 328 aboriginal, 64, 75 ACC, 175, 184 acceptor, 152 accounting, 319, 327 accuracy, x, 84, 85, 87, 90, 93, 109, 173, 209, 243 ACE, 67, 70, 78, 137 ACE inhibitors, 67, 137 ACEI, 78 acetylcholine, 328 acid, 57, 59, 61, 67, 83, 101, 136, 154 acidosis, 68, 107, 118 acoustic, 208, 245 acrocentric chromosome, 141 actin, 283 activation, 8, 41, 71, 73, 119, 127, 134, 140, 154, 157, 195, 204 active site, 157 activity level, 56 acute, ix, 23, 28, 47, 51, 58, 59, 63, 65, 67, 68, 78, 99, 103, 113, 117, 209, 283, 288, 293, 300, 305, 329 acute aortic dissection, 288 acute kidney failure, 67 acute kidney injury, 63, 117 acute renal failure, ix, 68, 113 adaptation, 19, 20, 162 adenoidectomy, 326

adhesion, 154 adjustment, 31, 68, 162 administration, x, 15, 67, 99, 118, 120, 123, 176, 180, 199, 208, 319, 328 adolescence, 108 adolescents, 18, 36, 40, 43, 46, 56, 60, 66, 67, 75, 76, 119, 273, 283, 285, 329 adrenal gland, 101 adrenal glands, 101 adult, viii, xi, xii, 13, 22, 37, 39, 42, 49, 50, 56, 57, 62, 73, 80, 99, 142, 143, 148, 163, 168, 185, 198, 200, 207, 209, 210, 225, 226, 231, 233, 251, 255, 284, 289, 296, 302 adult population, 13, 42, 62, 99 adulthood, 19, 63 adults, viii, xii, 2, 16, 23, 33, 36, 37, 40, 46, 47, 49, 51, 52, 55, 59, 61, 70, 74, 76, 98, 99, 116, 117, 138, 143, 153, 184, 204, 208, 209, 224, 227, 229, 276, 283, 284, 289, 290, 294, 297, 298, 299, 300, 301, 330 adverse event, 157 aerobic, 45, 48, 49, 53, 57, 58, 59, 60 aerobic exercise, 49, 59 aetiology, 124, 127 age, viii, xii, 19, 23, 25, 35, 46, 47, 50, 51, 55, 56, 57, 59, 64, 66, 68, 79, 85, 90, 104, 115, 116, 117, 124, 137, 157, 163, 164, 175, 176, 192, 194, 210, 214, 217, 229, 231, 276, 283, 288, 290, 306, 320, 327, 331 agent, 15 agents, x, 13, 32, 68, 123, 137, 199 aggregation, 166, 280 aging, 23, 35, 36 agonist, 35 aid, 255 air, 50, 57, 137

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344

Index

Air Force, 44, 57 air quality, 137 albumin, 62, 65, 73, 199 albuminuria, 62, 64, 65, 68, 74 alcohol, 42, 137 aldosterone, 78, 166, 199 algorithm, viii, 14, 54, 55, 60, 61, 65, 101, 117 alkaline, 328 alkaline phosphatase, 328 allele, 130, 152 alleles, 130 Aloha, 173 alpha, 165, 270 alternative, 13, 66, 181, 192, 205, 227, 304, 305, 307, 315 alternatives, 162 alveoli, 327 American Academy of Pediatrics, 167, 169 American Heart Association, 56, 57, 58, 71, 167, 169, 175, 184 amino, 107, 154 amino acid, 107, 154 amino acids, 107 amniocentesis, 142, 153, 158, 162 amniotic, 138, 156, 158 amniotic fluid, 138, 156, 158 amplitude, 2, 176 ampulla, 221, 222, 224 amputation, 66 Amsterdam, 57 amyloidosis, 64 anaerobic, 53, 54, 60 anal atresia, 142 anastomoses, 200, 284, 310 anastomosis, 185, 190, 192, 194, 196, 203, 205, 278, 284, 292, 304, 307 anatomy, xii, xiv, 80, 84, 109, 142, 174, 175, 176, 182, 188, 208, 209, 224, 243, 245, 246, 249, 251, 254, 255, 272, 300, 303, 304, 305, 315, 333, 334 anemia, 51, 62, 68, 69, 72, 76, 77, 99, 174 aneuploidy, 81, 92, 160 aneurysm, xiii, 23, 156, 227, 275, 276, 277, 278, 280, 283, 284, 285, 287, 288, 289, 290, 291, 292, 293, 294, 295, 298, 299, 301, 302 angiogram, 211, 213, 244 angiography, xi, 176, 183, 190, 207, 208, 209, 210, 211, 212, 219, 222, 224, 225, 226, 230, 286, 289, 290, 294, 300 angioplasty, 183, 294, 295, 299, 300, 315 angiosarcoma, 319, 321

angiotensin, 299 angiotensin converting enzyme, 48, 285 angiotensin II, 13, 31, 67, 70, 78, 166, 204, 299 angiotensin-converting enzyme (ACE), 78, 199 angulation, 85, 283 animal studies, 21 animals, 31 aniridia, 150 anomalous, ix, 33, 80, 97, 142, 197, 236 antagonism, 71 antagonists, 71, 136 antecedents, 182 antibacterial, 117 antibiotic, 100 antibiotics, 99 anticoagulant, 195 antidiuretic, 62, 199 antidiuretic hormone, 62, 199 anxiety, 80, 162 aorta, xiii, 5, 15, 17, 18, 19, 23, 24, 28, 33, 37, 41, 52, 80, 83, 85, 86, 88, 90, 125, 132, 137, 150, 151, 155, 161, 176, 188, 191, 192, 194, 200, 208, 209, 212, 219, 221, 222, 224, 226, 227, 232, 235, 256, 258, 260, 262, 264, 265, 269, 270, 275, 276, 277, 278, 280, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 304, 307, 315 aortic aneurysm, xiii, 227, 275, 276, 278, 284, 287, 288, 289, 292, 293, 299 aortic dilatation, 27, 28, 37, 296, 299 aortic insufficiency, 302 aortic stenosis, 42, 47, 80, 137, 143, 145, 312 aortic valve, xiii, 6, 10, 24, 63, 85, 137, 139, 161, 188, 192, 260, 261, 265, 270, 275, 278, 280, 281, 282, 285, 286, 292, 293, 296, 297, 299, 301, 302, 305, 336 apnea, 326 apoptosis, 280, 285, 299 apoptotic, 280 application, 10, 13, 16, 30, 183, 184, 194, 214, 219, 245, 337 ARB, 70, 78 ARBs, 67 ARIC, 76 Arizona, 215 armed forces, 57 arrest, 192, 201, 292, 296, 301, 304, 312 arrhythmia, 37, 41, 47, 48, 63, 174, 175, 195, 197, 200, 202, 227, 336, 338, 339

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Index arrhythmias, viii, 39, 83, 156, 195, 198, 200, 305, 317, 318 arterial hypertension, 178, 181, 184, 186, 283, 332 arteries, viii, 4, 18, 24, 28, 41, 79, 80, 85, 90, 98, 133, 137, 150, 178, 185, 192, 209, 211, 220, 223, 235, 240, 241, 255, 261, 263, 265, 268, 269, 270, 272, 273, 274, 280, 292, 311, 314 arteriovenous malformation, 190, 196 artery, xi, xiv, 5, 17, 23, 27, 34, 36, 37, 41, 44, 47, 85, 86, 90, 95, 114, 132, 137, 150, 155, 164, 174, 175, 176, 178, 179, 180, 183, 185, 188, 189, 190, 191, 192, 194, 196, 197, 198, 201, 207, 209, 210, 211, 212, 213, 219, 220, 221, 222, 223, 224, 225, 226, 227, 256, 260, 261, 262, 263, 264, 269, 270, 283, 289, 298, 303, 304, 305, 306, 307, 311, 312, 313, 314, 315, 327, 328, 330, 332, 337 ascites, 193, 194, 195, 317 ASD, 15, 17, 19, 20, 52, 100, 101, 136, 139, 155, 158, 159, 161, 178, 231, 253 asphyxia, ix, 113 aspiration, 308 aspirin, 199 assessment, xii, 2, 10, 30, 32, 34, 35, 36, 41, 49, 51, 57, 66, 82, 83, 84, 87, 89, 90, 94, 98, 99, 100, 102, 105, 106, 114, 116, 117, 118, 119, 127, 140, 158, 160, 162, 184, 203, 208, 209, 210, 219, 223, 224, 226, 227, 230, 244, 249, 294, 295, 300, 310, 322 assignment, 128, 149 assumptions, xii, 230, 244, 268 asthma, 40, 41 asymmetry, viii, 79, 90, 91 asymptomatic, 17, 19, 142 asymptotic, 49 atherosclerosis, 36, 284 Atherosclerosis Risk in Communities, 76 athletes, 50, 51, 58 ATP, 164 atresia, xiii, 13, 33, 34, 35, 37, 80, 83, 87, 101, 107, 109, 114, 142, 178, 181, 188, 190, 201, 202, 209, 210, 211, 212, 217, 226, 252, 253, 257, 260, 261, 262, 263, 264, 267, 268, 269, 270, 272, 273, 274, 298, 304, 306, 308, 311, 312, 315 atria, 84, 125, 127, 196, 252 atrial fibrillation, 195 atrial flutter, 195 atrial myxoma, 319, 320, 322, 323 atrial septal defect, 15, 17, 33, 136, 149, 154, 161, 178, 185, 188, 192, 231, 232, 252, 253, 256, 257, 258, 260, 269, 310

345

atrio-ventricular, 84, 192, 233 atrioventricular block, xiv, 333, 334, 335, 338 atrium, xiii, 27, 125, 191, 199, 252, 254, 257, 259, 260, 261, 262, 263, 264, 266, 269, 318, 322 attachment, 235 Australia, 74 autonomic nervous system, 51 autonomy, 163 autopsy, xi, 37, 95, 110, 174, 177, 178, 180, 181, 182, 269, 285 autosomal dominant, 136, 139, 142, 143, 148, 149, 153, 154, 156, 158, 160, 166, 282, 319 autosomal recessive, 165, 166 autosomes, 139 availability, 13, 200, 304 avoidance, 195

B B cells, 144 babies, x, 82, 98, 123 bacteria, 100 bacterial, 144 balloon angioplasty, 276, 284, 297, 315 baroreceptor, 33 barriers, 92 basal ganglia, 102, 104, 105, 111 base pair, 140, 170 basement membrane, 141 Bayesian, 177, 182 Bayesian analysis, 177, 182 beating, 201, 230, 243, 245, 246, 249, 312 behavior, 16, 182, 319 beneficial effect, 27, 70, 202 benefits, 78, 90 benign, 99, 156, 317, 318, 319, 320, 321, 322 benign tumors, 99, 319, 321 beta-blockers, 299 bias, 212, 213 bicarbonate, 166 bicuspid, xiii, 137, 139, 161, 257, 275, 278, 280, 281, 282, 285, 292, 293, 296, 297, 299, 301, 302 bifurcation, 220, 224, 336 bifurcation point, 336 bile, 149 bile duct, 149 biliary atresia, 101, 114 biliary tract, 108 binding, 66, 131, 134, 135, 141, 144, 146, 164, 165, 170

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346

Index

biochemistry, vii, 1 biomaterials, 214 biometry, 108 biophysics, 28 biopsies, 43, 327 biopsy, 36, 204 birth, vii, viii, x, 23, 36, 61, 63, 67, 75, 81, 85, 105, 107, 116, 120, 123, 124, 132, 167, 186, 188, 311, 314, 328 birth weight, viii, 61, 63, 67, 75, 116, 120, 186, 311 births, viii, 79, 81, 114, 143, 154, 158, 269, 273, 304 bleeding, 47, 99, 101, 103, 106, 320 blocks, 70 blood, vii, viii, ix, xiv, 2, 4, 5, 12, 17, 18, 20, 28, 33, 39, 42, 43, 45, 46, 50, 51, 52, 53, 61, 65, 67, 69, 70, 72, 87, 88, 89, 95, 97, 110, 117, 118, 132, 138, 152, 156, 165, 166, 174, 176, 184, 188, 189, 190, 191, 192, 193, 196, 197, 198, 199, 200, 202, 205, 209, 210, 214, 220, 227, 245, 252, 269, 270, 282, 283, 284, 298, 303, 304, 305, 306, 307, 308, 315, 321, 327, 328 blood flow, vii, xiv, 2, 17, 20, 28, 51, 87, 89, 95, 117, 118, 165, 184, 188, 189, 190, 191, 192, 193, 196, 198, 200, 202, 205, 209, 210, 220, 227, 252, 269, 270, 282, 284, 298, 303, 304, 305, 306, 307, 308, 315, 327, 328 blood pressure, viii, 2, 5, 12, 18, 33, 39, 41, 42, 43, 45, 46, 50, 52, 61, 65, 67, 70, 166, 176, 197, 305 blood shunting, 88 blood vessels, ix, 18, 89, 97, 199, 245, 283 body fat, 51 body mass index (BMI), 51, 108 body size, 26, 27, 59, 66, 175 body weight, 41, 49, 50, 231, 245 bonds, 151, 152 borderline, 62 Boston, 194, 325 boys, 50, 175 brain, 102, 103, 104, 105, 106, 107, 110, 114, 135 brain aneurysm, 114 brain natriuretic peptide (BNP), 135 brain structure, 103, 106 branching, 211 Brazil, 315 breathing, 76, 193, 326 bronchospasm, 41 bundle branch block, 334 bypass, 20, 32, 34, 45, 190, 191, 192, 194, 238, 249, 284, 292, 296, 298, 304, 307, 308 bypass graft, 284, 298

C Ca2+, 8 cables, 42 caffeine, 137 calcification, xi, xii, 63, 207, 208, 214, 215, 216, 217, 218, 219, 223, 224, 225, 227, 282, 288, 320 calcium, 30, 106, 118, 167, 199, 205, 214, 215, 224 calculus, 99 caliber, 208 calyx, 116 canals, 267 candidates, 63, 192, 308 capacitance, 36 capillary, 326, 327, 330 carbon dioxide, 42, 53, 176, 310 carbon monoxide, 137 carcinoma, 116, 319, 322 cardiac arrhythmia, 174, 175 cardiac catheterization, x, xi, 23, 24, 173, 174, 178, 180, 183, 186, 189, 196, 198, 200, 210, 220, 231 cardiac dysrhythmia, 84 cardiac function, 5, 20, 50, 63, 81, 175, 193, 197 cardiac output, xi, 3, 22, 23, 25, 46, 50, 51, 52, 174, 176, 179, 180, 184, 190, 191, 193, 198, 199, 202, 307, 317 cardiac pacemaker, 175 cardiac reserve, 21 cardiac rhabdomyoma, 95 cardiac surgery, 214, 244, 249, 327, 331 cardiac valves, 87 cardiogenesis, 136, 284, 298 cardiogenic shock, 63, 285 cardiologist, 40, 47, 72, 233 cardiology, viii, 12, 32, 33, 35, 37, 39, 56, 72, 76, 85, 90, 109, 127, 226, 244, 301 cardiomyopathy, 42, 48, 55, 136 cardiopulmonary, 32, 42, 49, 51, 56, 57, 58, 60, 191, 192, 194, 238, 296, 301, 304, 307, 327 cardiopulmonary bypass, 32, 191, 192, 194, 238, 296, 304, 307 cardiovascular disease, vii, viii, x, 1, 4, 15, 23, 27, 51, 58, 61, 62, 63, 64, 68, 72, 73, 75, 123, 124, 125, 127, 128, 154, 163, 165, 170, 209, 295 cardiovascular risk, 29, 36, 62, 64, 70, 72, 73, 74, 75, 78 carotid arteries, 24 carrier, 153, 155, 163, 166 CAT, 80 catecholamine, 7

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Index catecholamines, 101 categorization, 270 catheter, vi, xi, xiv, 12, 13, 14, 31, 32, 184, 195, 200, 202, 208, 210, 211, 221, 225, 227, 308, 333, 334, 335, 337, 338, 339 catheterization, x, xi, 23, 24, 48, 173, 174, 176, 178, 179, 180, 183, 186, 189, 196, 198, 199, 200, 210, 220, 231, 243, 306, 308 catheters, 13, 176, 183, 208, 337 cell, 66, 116, 140, 141, 144, 150, 151, 154, 156, 280, 299, 319, 321, 332 cell adhesion, 154 cell cycle, 141 cell differentiation, 150, 154 cell fate, 150 cell surface, 151 central nervous system, 111, 137 centromeric, 144 cerebellum, 102 cerebral arteries, 104 cerebral hemorrhage, 103 cerebral palsy, 110 cerebrovascular, 63, 315 c-fos, 144 channels, 166 chest radiograph, 285, 288, 289, 290, 301 chest radiography, 285, 288, 289, 290 Cheyne-Stokes respiration, 330 CHF, 240, 241 chickens, 132 child mortality, 184 childhood, 33, 36, 76, 77, 80, 108, 117, 119, 120, 274, 276, 295, 329 China, 35, 333 chloral, 210 chloride, 166 cholecystitis, 98, 99, 107 cholelithiasis, 99, 108 cholestasis, 149 cholesterol, 165 chorionic villi, 138, 153, 156, 158 choroid, 102 chromatin, 134, 140, 145, 146, 147 chromosomal abnormalities, 81, 90, 92, 138 chromosome, x, 107, 124, 130, 136, 138, 139, 140, 141, 142, 143, 145, 149, 151, 159, 160, 161, 165 chromosome 20, 149 chromosomes, 141, 144, 146, 150, 165 chronic disease, 77

347

chronic kidney disease (CKD), 62, 63, 64, 67, 68, 72, 73, 75, 76, 78 chronic kidney failure, 115 chronic obstructive pulmonary disease, 326 chronic renal failure, 71, 75, 77, 114, 116, 117, 119, 120 cigarette smoking, 124 circulation, viii, 13, 20, 21, 28, 31, 34, 49, 52, 60, 61, 104, 105, 181, 188, 189, 190, 191, 193, 195, 196, 197, 199, 201, 202, 215, 270, 292, 305, 311, 328 cirrhosis, 71 cis, 134, 140 CK, 58, 249, 296 CKD, viii, ix, x, 61, 62, 63, 64, 65, 67, 68, 69, 114 classical, 140, 190, 196, 268, 269, 270, 276, 278, 284, 286 classification, 63, 71, 72, 76, 103, 182, 194, 270, 272, 273, 274, 281, 297, 326, 329 claustrophobia, 175 cleaning, 42 cleft palate, 137, 140, 142, 159 clients, 162 clinical assessment, 98 clinical diagnosis, 148, 153, 172, 175, 255 clinical examination, 160, 174, 286 clinical presentation, xiv, 76, 317 clinical symptoms, 99, 142, 326 clinical trial, 185, 335 clinically significant, 52, 195, 224 cloning, 127, 128 closure, vi, xiv, 48, 132, 196, 203, 214, 219, 220, 224, 226, 227, 232, 238, 240, 241, 243, 273, 333, 334, 335, 336, 337, 338, 339 clustering, 280 CMV, 105 CNS, 102, 103, 104, 105, 106, 107 Co, 94, 317 CO2, 50, 53, 54 coarctation, xiii, 15, 17, 19, 28, 33, 42, 52, 60, 83, 90, 107, 115, 137, 155, 161, 169, 200, 226, 235, 275, 276, 277, 278, 279, 280, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 308, 315 cocaine, 137 coding, 130, 134, 136, 138, 145, 152, 153, 155, 157, 159, 160 codon, 130 codons, 151 cofactors, 152

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348

Index

cohort, 76, 93, 304, 305, 326 coil, xi, 176, 208, 219, 220, 221, 223, 224, 225, 227 colic, 100 collagen, 218, 219, 283 collateral, 190, 196, 199, 289 colleges, 283 colors, 87 communication, 31, 125, 162, 252, 270, 272 community, 35, 72, 74, 75, 77, 182 compensation, 135 competitive sport, 48, 58 complex interactions, 63 complexity, 105 compliance, 3, 23, 24, 25, 26, 28, 35 complications, xi, 17, 23, 48, 65, 67, 68, 70, 75, 99, 105, 110, 118, 174, 180, 181, 182, 183, 198, 201, 205, 209, 210, 219, 276, 285, 286, 288, 292, 293, 294, 296, 300, 308, 320, 321, 322, 330 components, 2, 5, 6, 11, 140, 233 composition, 127, 222 compounds, 27, 214 comprehension, 131, 140 computed tomography, vi, xi, 189, 207, 208, 216, 225, 226, 227, 300 computing, 89 concentration, 50, 66, 69, 76 concordance, xi, 174, 175, 177, 179 conductance, 13, 31, 32 conduction, x, xiv, 31, 123, 125, 127, 134, 158, 159, 161, 197, 198, 200, 318, 321, 333, 334, 335, 336, 337 conduction block, xiv, 134, 333, 334, 335, 336, 337 conductive, 195 confidence, 48, 49, 58, 177, 179, 290 confidence interval, 177, 179, 290 confidence intervals, 177 confidentiality, 163 configuration, xiv, 185, 215, 286, 314, 317 confusion, 270 congestive heart failure, 22, 28, 53, 62, 66, 77, 108, 189, 191, 195, 198, 200, 238, 241 consensus, 58, 71, 199, 284 consent, 131, 175 constant load, 46 constraints, 43 construction, 13, 127, 214 consumption, 40, 41, 42, 49, 50, 53 continuity, 196, 252, 269 contractions, 46 contracture, 282

control, 17, 19, 21, 22, 23, 24, 25, 26, 27, 60, 67, 70, 99, 117, 130, 134, 136, 166, 210, 285, 336 control group, 24, 25, 26, 27, 130 conversion, 166, 195, 199, 200, 202, 203, 308 Copenhagen, 59 cor pulmonale, 329 coronary arteries, 23, 208, 225, 227, 245, 280, 311 coronary artery aneurysms, 36 coronary artery disease, 44, 47, 164, 209, 225, 289 coronary heart disease, 64, 76, 124 corpus callosum, 106, 111 correlation, xi, xii, 14, 59, 80, 87, 92, 94, 109, 110, 119, 134, 140, 159, 170, 171, 182, 207, 212, 222, 225, 243, 251, 254, 255, 264, 271, 328, 336 correlations, 184 cortex, ix, 107, 113, 117 corticospinal, 101 corticosteroids, 137 cortisol, 166 cost-effective, 289, 300 costs, 44, 45, 62 cough, 318 counseling, 80, 90, 142, 148, 153, 158, 160, 162 coupling, 16, 18, 19, 32, 35, 52, 127, 167, 197 craniofacial, 132, 133 creatinine, 65, 66, 76 critically ill, 33 crossing over, 128, 141, 143, 144, 147 cross-sectional, 74, 87, 92, 271, 290, 329 cross-sectional study, 329 CRS, 63, 64, 65, 67, 69, 70, 71 CRT, 244 CT scan, 210, 214, 216, 218, 288 C-terminal, 151 CVD, viii, 61, 124, 164, 165 cyanosis, 21, 189, 190, 196, 199, 306 cyanotic, viii, xi, 59, 61, 63, 66, 76, 98, 99, 100, 101, 103, 116, 117, 118, 189, 190, 207, 209, 210, 227 cycles, 8 cycling, 41, 42, 45, 48, 50 cyclists, 59 cyst, 98, 107, 108, 323 cysteine, 151, 152 cysteine residues, 151 cysts, 99, 101, 106, 110, 115, 321 cytochrome, 166 cytokines, 154 cytomegalovirus, 110, 111 cytoplasm, 144, 151

Index

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D dacron, 294 data collection, 335 data set, 219, 220, 227, 231 database, 327 de novo, 73, 134, 141, 142, 143, 148, 152, 153, 154, 155, 158, 160 deafness, 156 death, xiv, 34, 37, 47, 62, 67, 69, 72, 73, 74, 76, 77, 100, 114, 134, 137, 143, 180, 276, 295, 305, 307, 308, 309, 310, 311, 313, 317, 320, 329, 337 death rate, 62 deaths, vii, xi, 139, 174, 209, 293, 307, 308, 326 decay, 3, 151, 152 decision making, 40, 241 decisions, 40 defibrillator, 40 deficiency, 104, 144 deficits, 318 definition, 19, 56, 62, 63, 93, 145, 161, 224 deformation, 159 deformities, 158 degradation, 151, 211, 214 dehydrogenase, 166 delivery, 52, 200, 307 demographic characteristics, 137 demographics, 327 density, 4, 127, 216, 217, 220, 224 density values, 217, 224 deposition, 214, 215, 224 depressed, 18, 21 depression, xiii, 46, 252, 257 deregulation, 140 destruction, 105, 234 detection, viii, ix, x, xi, xii, 13, 14, 16, 32, 33, 41, 61, 65, 74, 82, 83, 87, 89, 90, 91, 92, 93, 94, 95, 97, 110, 118, 120, 124, 125, 130, 131, 138, 142, 148, 157, 160, 174, 181, 207, 208, 209, 214, 218, 338 developmental disorder, 169 deviation, 270 diabetes, 62, 64, 67, 69, 81, 83, 136 diabetic nephropathy, 64 diagnostic criteria, 116, 289 dialysis, 67, 77 diaphragm, 84, 290 diarrhea, 67, 195 diastole, 6, 11, 239, 240, 243, 318 diastolic blood pressure, 46, 305, 306, 307

349

diastolic pressure, 3, 10, 11, 12, 19, 22, 31, 191, 198, 306 diet, 66, 68, 136, 199 dietary, 67 differential diagnosis, 98, 106 differentiation, 98, 110, 127, 150, 154, 172 diffusion, 55 DiGeorge Syndrome, 139, 169 digestive tract, 101 dilated cardiomyopathy, 15, 30, 35, 137 dilation, 19, 23, 24, 26, 37, 107, 115, 116, 117, 161, 280, 297, 301 disappointment, 8 discharges, 181 disclosure, 104 discomfort, 195 discontinuity, 265 discordance, 31 discovery, 127 diseases, vii, viii, ix, x, 1, 10, 27, 62, 63, 79, 81, 97, 100, 105, 106, 113, 123, 124, 125, 127, 131, 140, 141, 142, 150, 155, 158, 159, 161, 162, 163, 164, 165, 167, 174, 175, 181, 182, 189, 297, 331 disequilibrium, 125, 130 disorder, x, xiv, 31, 48, 63, 123, 129, 139, 144, 155, 162, 165, 166, 319, 325, 326 displacement, 182 dissociation, 154 distortions, 306 distress, 162, 195 distribution, 217 disulfide, 151, 152 disulfide bonds, 151, 152 diuretic, 69, 199 diuretics, 118, 199 divergence, 178 diversity, 182 divorce, 137, 162 dizziness, 46 DNA, 131, 135, 138, 144, 145, 148, 156, 158, 163, 170 DNA testing, 156, 158 dogs, 10, 16, 28, 30, 32, 36 donor, 200, 328 doppler, xii, 80, 87, 88, 89, 90, 92, 93, 94, 95, 109, 110, 111, 174, 175, 183, 184, 201, 202, 220, 221, 229, 230, 231, 232, 233, 238, 245, 247, 249, 255, 262, 300, 306 dosage, 144, 148, 159, 335, 337

Index

350

Down syndrome, xiv, 92, 137, 161, 325, 326, 328, 329, 330, 331, 332 down-regulation, 35 Drosophila, 132, 143 drug exposure, 137 drug therapy, 125, 165 drugs, 13, 70, 125, 137, 165, 285 DSL, 150 ductus arteriosus, xiv, 87, 132, 133, 150, 178, 189, 192, 211, 219, 221, 222, 224, 232, 260, 282, 283, 298, 303, 307, 308, 314 duplication, 101, 132, 142, 153, 155, 159, 160, 172 DuPont, 249 durability, xi, 208, 214 duration, 43, 45, 127, 194, 195, 197, 223 dysplasia, ix, 63, 67, 113, 114, 115, 326, 327, 330 dyspnea, 46

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E ears, 139, 156 Eastern Europe, 73 echocardiogram, x, 84, 158, 173, 178, 179, 180, 338 edema, 160, 195, 317, 318, 336 education, 72 effusion, 204, 319 elastin, 143, 144, 145, 169, 170 elective surgery, 289 electrocardiogram, 338 electrodes, 42 electrolyte, 61, 71, 99 electromagnetic, 14 electron, 37, 227 electron beam, 227 emboli, 196, 198, 199, 204, 209, 243, 318, 321 embolization, 196, 199, 243, 318, 321 embryo, x, 123, 125, 297 embryogenesis, x, 123, 126, 268 embryology, 187 embryos, 127, 138, 141, 150, 170, 283 emission, 313 encapsulated, 334 encephalopathy, 110 encoding, 140, 144, 150, 151, 154, 157, 158, 164, 165 encouragement, 40 endocarditis, 63, 234, 293, 295 endocardium, 182 endocrine, 142, 166, 319, 322 endoderm, 133, 134, 135

endoplasmic reticulum, 151 endoscopy, xi, xii, 208, 219, 220, 221, 222, 223, 224, 225, 227 endothelial progenitor cells, 332 endothelin-1, 332 endothelium, 22, 24, 197, 204, 214, 282, 328 endotoxemia, 108 end-stage kidney disease, 62 end-stage renal disease, 29, 62, 63, 67, 73, 74 end-to-end, 278, 284, 292 endurance, 44, 51 energy, 22, 53, 195, 197, 199 energy consumption, 53 enlargement, 98, 100, 101, 102, 194, 199, 200, 290, 326 enterocolitis, 305, 313 environment, x, 123, 124, 141, 146, 147 environmental factors, 124, 165 environmental influences, 124 enzyme inhibitors, 78, 299 enzymes, 125, 157 ependymal, 103 epicardium, 16 epidemic, 74 epidemiology, 72, 73, 114, 119 epigastrium, 98 epigenetic, 283, 284, 298 epilepsy, 137 epinephrine, 29 epithelium, 150 equilibrium, 67 erythropoietin, 69, 72, 77 esophageal atresia, 101, 114 esophagus, 178, 180 estimating, 4, 28 ethnicity, 137 etiology, x, 123, 198, 326, 328 eukaryotic cell, 141 Euro, 185, 202 Europe, 45, 185 evolution, 36 examinations, viii, 79, 82, 89, 102, 104, 105, 107, 114, 117, 210, 214, 232, 234, 235, 289 excision, xiv, 317, 320 excitation, 167 exclusion, 155, 160 excretion, 62, 66, 73, 118, 166 exercise, viii, 18, 22, 23, 33, 34, 35, 36, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 72, 195, 289

Index exertion, 49, 51 exons, 153, 155, 156, 157, 160 expertise, 230 exposure, x, 83, 123, 137, 210 expressivity, 152 expulsion, 181 extracellular matrix, 141, 285 extraction, 49, 51, 307

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F fabrication, 13 facies, 140, 143, 149, 154 factor analysis, 74, 311 factor VII, 198 factorial, 195, 326 failure, 17, 18, 20, 22, 23, 31, 52, 56, 62, 63, 66, 68, 69, 71, 72, 74, 99, 116, 125, 132, 165, 181, 182, 191, 192, 194, 195, 196, 197, 198, 199, 200, 214, 223, 238, 305, 318 failure to thrive, 238 familial, 124, 134, 139, 141, 155, 162, 164, 165, 166, 168, 169, 280 familial aggregation, 166, 280 familial hypercholesterolemia, 165 family, x, 81, 83, 124, 128, 129, 131, 138, 142, 144, 148, 149, 150, 155, 158, 159, 160, 161, 162, 163, 166, 167, 170, 280, 282, 292, 296, 321 family history, 81, 83, 142, 160, 163, 292, 321 family members, x, 124, 129, 138, 142, 148, 149, 158, 162 fatalities, 276 fatigue, 45, 46, 48, 57, 195, 214, 317, 318 feedback, 83, 230, 231 feeding, 141, 305 feet, 161 females, 50, 214, 276 fetal, viii, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 111, 120, 188, 249, 298, 307, 308 fetal abnormalities, 95 fetus, 80, 81, 82, 83, 85, 93, 95, 114, 315 fetuses, viii, 79, 81, 84, 89, 90, 91, 93, 95 fever, 174, 285 fiber, 334 fibers, 24, 218, 219 fibrillation, 195 fibrils, 128 fibrin, 214 fibroblast, 133, 218

351

fibroblast growth factor, 133 fibroblasts, 219 fibrogenesis, 66 fibrosarcoma, 321 fibrosis, 24, 334, 336 fibrous tissue, 334 fidelity, 13 filtration, 62, 66, 67, 74, 76, 117, 194 FISH, x, 124, 138, 142, 148, 150, 153, 155, 157, 160 fitness, 46, 49, 50, 57, 59, 60 flexibility, 214 flow rate, 249 fluctuations, 307 fluid, 69, 71, 77, 81, 89, 93, 102, 105, 106, 110, 138, 155, 158, 199, 204, 298 focusing, 162 folate, 137 folding, 106, 136, 151, 152 folic acid, 67, 136 foramen, 17, 87, 125, 188, 260, 262, 265, 269 foramen ovale, 17, 87, 260, 262, 265, 269 fornix, 102, 105, 106 Fourier, 2, 3, 176 Fourier analysis, 2, 3 fragmentation, 24 frog, 5 functional analysis, 174 functional aspects, xii, 230 fundus, 102 fusiform, 291 fusion, 280, 281

G gadolinium, 319 gallbladder, 99, 108 gallstones, 108 ganglia, 102, 104, 105, 111 ganglioneuroblastoma, 109 ganglioneuroma, 109 gas, viii, 39, 40, 42, 43, 55, 56 gas exchange, viii, 39, 42, 43, 55, 56 gases, 176 gastrointestinal, 101, 193, 278, 326 gastrointestinal bleeding, 278 gastrointestinal tract, 101 gauge, 208, 210 gender, 50, 66 gene, x, 123, 124, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143,

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352

Index

144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 155, 156, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 170, 171, 187, 280, 282, 285, 296 gene expression, 126, 134, 135, 145, 148, 170 gene silencing, 170 general anesthesia, 210, 211, 238 General Electric, 176 generation, 27, 158 genes, x, 123, 124, 125, 127, 128, 129, 130, 131, 133, 134, 140, 141, 143, 144, 148, 150, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 164, 165, 166, 168, 170 genetic alteration, 138, 187 genetic counselling, x, 123, 124, 155, 161, 162, 163 genetic disease, 150, 161, 170 genetic disorders, 81, 114, 162 genetic endowment, 161 genetic factors, 135 genetic information, 128, 162 genetic marker, 127, 128 genetic mutations, 158, 159, 161 genetic syndromes, 141 genetic testing, x, 124, 138, 142, 148, 149, 153, 155, 158, 163 genetics, 124, 148, 157, 160, 161, 167 genome, 127, 128, 131, 148, 168 genomic, 127, 128, 129, 133, 146, 147, 148, 161, 162, 166 genomic regions, 128, 146 genotype, 124, 156, 171 genotypes, 129 Germany, 176, 231, 275 gestation, 80, 81, 82, 84, 89, 90, 91, 93, 95, 125, 142, 155, 158 gestational age, viii, 79, 85, 90, 104 girls, 50, 175 gland, 101, 109 glomerulonephritis, 63, 64 glucose, 141 glucose metabolism, 141 glycine, 136 goals, 162, 192 gold, 50, 208, 209, 210, 241, 289, 292 gold standard, 50, 208, 209, 210, 241, 289, 292 gonad, 115 gonadal dysgenesis, 161 G-protein, 145 grading, 103, 120 grafting, 284, 295, 298, 299 grafts, 214, 215, 216, 217, 218, 284, 291, 292, 294

grapes, 320 grey matter, 104 groups, 17, 41, 70, 81, 100, 103, 125, 216, 224, 230, 276, 304, 305, 306, 307, 328, 338 growth, 59, 66, 68, 115, 119, 133, 154, 156, 158, 168, 192, 226, 227, 269, 283, 284, 297, 298, 299, 314 growth factor, 66, 133, 154, 168 growth factors, 154 guidance, xii, 192, 229, 238, 243 guidelines, 59, 67, 76, 93, 117, 163, 172, 289, 292, 293 gut, 194

H hamartomas, 321 hands, viii, 80, 132, 160, 174 haploinsufficiency, 133, 140, 141, 144, 151, 159 haplotype, 130 haplotypes, 130 harm, 163 harmonics, 2 HDL, 165 headache, 46 health, 62, 124, 125 health problems, 124 healthcare, 57 heart block, 83, 134, 317 heart disease, vi, viii, ix, x, xi, xiii, 12, 17, 28, 32, 35, 39, 40, 47, 51, 55, 56, 61, 62, 63, 64, 65, 66, 67, 70, 76, 77, 79, 81, 82, 87, 91, 92, 93, 94, 97, 113, 123, 124, 131, 168, 173, 175, 181, 182, 184, 185, 189, 190, 207, 209, 210, 211, 214, 222, 223, 225, 226, 227, 230, 233, 247, 252, 255, 270, 271, 273, 315, 326, 330, 331 heart failure, 17, 18, 22, 25, 31, 32, 48, 54, 62, 63, 66, 68, 69, 70, 72, 73, 76, 77, 78, 119, 132, 317, 318 heart rate, viii, 2, 22, 29, 39, 43, 46, 48, 49, 50, 51, 52, 54, 60, 176, 210 heart transplantation, 196 heart valves, 150, 280, 317 heartbeat, 51 heat, 180, 185 height, 43, 46, 66, 116, 182 helix, 148 hemangioma, 99 hematocrit, 74, 78 hematologic, 99

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Index hematologic disorders, 99 hematoma, 180, 285, 288, 301 hematopoietic, 100, 154, 156 hematopoietic system, 100 hematoxylin-eosin, 218 hematuria, 64 hemisphere, 102 hemodialysis, 78 hemodynamic, viii, ix, xi, 5, 11, 12, 25, 39, 43, 61, 87, 97, 98, 99, 117, 118, 174, 175, 179, 180, 181, 182, 198, 200, 205, 269, 283, 305, 313, 317, 331, 336 hemodynamics, 5, 6, 20, 23, 24, 27, 29, 34, 202, 209, 224, 284, 306, 307, 312, 314, 315 hemoglobin, 50, 69, 77 hemolytic anemia, 100 hemoptysis, 278, 285, 318 hemorrhage, 101, 102, 103, 110, 111, 291 hemorrhages, 103, 104, 105 hemostasis, 99 Heparin, 204 hepatic failure, 108 hepatitis, 47, 99 hepatomegaly, 98, 317 herbicides, 137 heredity, 162 heritability, 166, 296 heterochromatin, 147 heterogeneity, 125, 143, 152, 154, 155, 156, 157, 159, 160, 171, 182, 271 heterogeneous, 150, 154 heterozygote, 165 heterozygotes, 165 high resolution, 140, 319 high risk, viii, xiii, 24, 62, 63, 64, 79, 80, 102, 200, 225, 275, 284, 289, 292, 307, 308 high-performance liquid chromatography, 138 high-risk, 81, 82, 83, 84, 142, 160, 315 histochemical, 330 histological, 24, 37, 218 histopathology, 312 HIV, 136 homeostasis, 104, 199, 328 homogenous, 320 homolog, 143 homology, 148, 154 homozygote, 165 hormone, 62, 166, 199 hormones, 137, 154 hospice, xiii, 303, 304

353

hospital, 40, 192, 197, 230, 293, 304, 305, 306, 308, 338 hospital death, 305 hospitalization, 76 hospitals, 77 House, 71, 119 human, vii, 1, 2, 16, 33, 35, 61, 119, 124, 125, 127, 132, 135, 150, 159, 161, 170, 282, 313 human genome, 127 humans, 9, 10, 28, 30, 31, 132 humidity, 40 hybrid, xiv, 192, 303, 307, 308, 314, 315 hybridization, 138 hydatid, 323 hydrate, 210 hydration, 116 hydrocephalus, 107, 110 hydrogen, 157 hydrogen bonds, 157 hydronephrosis, 114, 117, 120 hydrops, 83, 93 hypercalcemia, 118, 143 hypercalciuria, ix, 113, 118 hypercarbia, 189 hypercholesterolemia, 124, 164, 165 hypercoagulable, 195 hyperhomocysteinemia, 67 hyperkalemia, 78 hyperlipidemia, 68 hyperparathyroidism, 118 hyperplasia, 216, 217, 224 hypertelorism, 139, 142 hypertension, vi, 18, 28, 29, 33, 35, 36, 47, 57, 62, 63, 64, 65, 68, 71, 75, 109, 116, 143, 166, 285, 289, 298, 304, 310, 325, 329, 330, 332 hypertensive, 18, 29, 33, 64, 72, 74, 166, 181 hyperthyroidism, 174 hypertrophic cardiomyopathy, 31, 128, 154, 155, 156 hypertrophy, 18, 62, 64, 69, 72, 74, 137, 143, 156, 157, 196, 200, 280, 286, 320 hyperventilation, 311 hypoplasia, ix, 63, 113, 114, 115, 149, 209, 278, 283, 284, 294, 298, 310, 327, 330 hypotension, 70 hypotensive, 70 hypothesis, 129, 148, 149, 150, 151, 152, 273, 282 hypoventilation, 326, 329 hypoxemia, 51, 190, 326 hypoxia, 101, 104, 105, 118, 182

Index

354 hypoxic, 102, 104, 105, 106, 107, 110, 111 hypoxic-ischemic, 102, 104, 105, 106, 107

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I ibuprofen, 137 id, 194 identical twins, 164 identification, viii, 39, 89, 90, 94, 127, 128, 130, 135, 140, 142, 247, 315, 329 identity, 135, 141, 143, 145, 170 idiopathic, 31, 35, 328, 330, 331, 332 IFT, 125, 127 image analysis, 177 images, xii, 13, 84, 87, 88, 89, 174, 176, 182, 183, 185, 208, 211, 212, 214, 215, 216, 218, 219, 220, 221, 224, 225, 229, 230, 231, 232, 233, 236, 239, 241, 243, 245, 251, 254, 255, 261, 262, 271, 289, 292, 319 imaging, vi, x, xi, xii, xiii, 32, 48, 84, 87, 88, 89, 91, 93, 94, 95, 98, 108, 109, 110, 111, 124, 173, 174, 176, 178, 179, 180, 183, 184, 185, 208, 209, 210, 219, 225, 226, 229, 230, 231, 232, 233, 236, 237, 238, 241, 243, 244, 245, 246, 247, 248, 249, 275, 276, 285, 288, 289, 290, 294, 300, 315, 319, 322 imaging modalities, xii, xiii, 89, 229, 238, 275 imaging techniques, x, 93, 124 immune function, 329 immunodeficiency, 140, 195 immunoglobulin, 78 immunoglobulins, 195 immunosuppression, 304 imperforate anus, 114 implementation, 92, 107, 116 in situ, 30, 138, 256, 258 in situ hybridization, 138 in utero, 108 in vitro, 151, 184 in vivo, 10, 30, 32, 184, 248, 283 incidence, viii, ix, xiv, 23, 61, 62, 74, 91, 97, 98, 113, 114, 115, 116, 118, 143, 154, 155, 191, 193, 194, 195, 199, 269, 276, 278, 282, 295, 305, 306, 308, 326, 327, 328, 329, 331, 333, 334, 335, 336, 338 inclusion, 141 independence, 8, 10, 29 independent variable, 25 Indian, 93 Indians, 64 indication, viii, 48, 49, 79, 81, 90, 174, 175, 200

indicators, 66, 120 indices, 9, 10, 15, 24, 314 infancy, 99, 120, 143, 156, 157, 185, 274, 284, 295, 297, 307, 329, 331 infants, ix, x, 18, 33, 75, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 113, 114, 116, 117, 118, 119, 120, 121, 124, 137, 186, 208, 231, 245, 273, 283, 297, 300, 309, 310, 311, 312, 313, 314, 315, 329, 331 infection, 65, 98, 100, 105, 106, 108, 110, 111, 117, 285 infections, ix, 67, 68, 83, 99, 100, 105, 113, 117, 195 infectious, 304 infectious disease, 105 inferences, 268 inferior vena cava, 6, 7, 9, 13, 14, 32, 190, 191, 253 infinite, 10, 87 inflammation, 24, 117, 337 inflammatory, 23, 47, 99, 105, 106 informed consent, 175 infundibulum, 256, 257, 258, 259, 265, 272 ingestion, 137 inheritance, 124, 128, 130, 131, 161, 163, 280 inherited, x, 47, 48, 123, 124, 128, 139, 142, 143, 148, 152, 153, 154, 156, 158, 160, 319 inhibition, 70, 78 inhibitor, 78 inhibitors, 48, 70, 78, 199, 285, 299 inhomogeneity, 319 initiation, 130, 174, 175 injection, 15, 190, 208 injuries, 102, 105 injury, viii, 47, 61, 65, 66, 99, 104, 105, 106, 210, 284 innominate, 307, 315 insertion, 151, 194, 195, 306 inspection, 230 inspiration, 193 institutions, 305 instruments, 87 intensive care unit, 231, 236 interaction, 5, 12, 17, 19, 20, 27, 28, 31, 127, 133, 134, 135, 145, 150, 151, 154, 157 interactions, x, 11, 27, 63, 123, 133, 135, 141, 152, 202, 204 interdependence, 6, 21 interdisciplinary, 63, 118 interphase, 142 interstitial, 140, 141

Index interval, 41, 42, 143, 176, 177, 197, 214, 215, 216, 218, 223, 246, 276 intervention, xiii, 10, 12, 13, 27, 30, 104, 148, 188, 195, 235, 240, 241, 275, 276, 278, 291, 292, 293, 307, 308, 339 intestine, 195 intima, 36, 300 intracerebral, 103, 104, 107 intracerebral bleed, 104 intracerebral hemorrhage, 103, 107 intracranial, 103, 106, 110, 175 intraoperative, 284 intravascular, 192 intravenous, 15, 77, 176, 210 intrinsic, 20, 326, 328 intron, 145 invasive, xi, 43, 48, 89, 182, 192, 207, 208, 210, 211, 212, 219, 222, 225, 289, 319, 321 inversion, xiii, 88, 147, 148, 170, 251, 256, 257, 264, 270 inversions, 138, 153 invertebrates, 132 iodinated contrast, 208 ionizing radiation, 175, 211 iris, 142 iron, 69, 77 ischemia, 8, 30, 42, 63, 104, 105, 189 ischemic, 47, 63, 104, 105, 111, 248, 284, 307 ischemic heart disease, 47, 63 isoforms, 144, 156 isolation, 116 Italy, 123 IVC, 13, 14, 190, 193, 196, 197, 253, 319

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J JAMA, 72, 74, 76 Japan, 1, 79, 207, 210, 220 Japanese, 28, 64, 74 job loss, 137 Jordan, 119 judgment, 219 Jun, 28, 29, 30, 31, 32, 33, 34, 35, 172, 298, 322, 323, 338 junior high, 75

K kappa, 177

355

karyotype, x, 83, 91, 93, 124, 138, 142, 155, 158, 160 karyotyping, 81, 90 Kawasaki disease, 15, 17, 23, 24, 25, 29, 36, 37 ketamine, 176 kidney, viii, ix, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 75, 76, 78, 108, 113, 114, 115, 116, 117, 119, 120, 151, 166 kidney failure, 62 kidneys, 63, 114, 115, 116, 117, 118, 119, 143 kinase, 141, 143, 154, 156, 157, 166 kinase activity, 157 kinases, 141, 144, 166 Korea, 64, 65

L L1, 322 LA, 94, 253, 329 LAA, 258, 320 laceration, 284 lack of control, 304 lactate level, 53 lactic acid, 57, 59, 107 lambda, 101 lamina, 197 laminar, 197 LAN, 141 large-scale, 335 laterality, 136 law, 9 LDL, 164, 165 lean body mass, 51 learning, 140, 141, 142, 148, 158, 162, 201, 305, 314 learning difficulties, 158 learning disabilities, 140, 141, 142 left atrium, xiv, 84, 88, 188, 190, 253, 254, 256, 257, 258, 264, 266, 269, 317, 318, 319, 320, 321, 322 left ventricle, 25, 29, 30, 85, 88, 125, 156, 177, 179, 185, 187, 188, 200, 241, 253, 254, 256, 257, 258, 260, 263, 264, 265, 266, 267, 269, 270, 273, 317 left ventricular, xi, 6, 7, 13, 28, 30, 31, 32, 33, 35, 47, 52, 62, 69, 72, 74, 85, 88, 137, 156, 174, 176, 177, 181, 182, 185, 203, 205, 238, 247, 249, 256, 280, 283, 286, 296, 299, 318, 322 Leopard syndrome, 157, 158 lesions, ix, xii, 23, 36, 83, 97, 98, 103, 104, 105, 107, 110, 115, 156, 183, 209, 229, 230, 231, 232, 241, 284, 305, 307, 314, 322, 326, 327 leukaemia, 329

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356

Index

leukemia, 100, 154 LIFE, 64, 72, 74 life span, 200 lifestyle, 74 life-threatening, viii, 47, 97 ligand, 141, 150, 280, 296 ligands, 140 likelihood, 41, 129 limitation, 10, 13, 55 limitations, xiii, 10, 22, 54, 87, 101, 159, 160, 183, 245, 246, 275 linear, x, 9, 10, 14, 15, 45, 52, 101, 110, 111, 123, 125, 126 linear regression, 15 linkage, x, 123, 125, 128, 129, 130, 153, 155, 156, 168 links, 148, 326 lipid, 141 lipid metabolism, 141 lipids, 68 lipoprotein, 164, 165 lipoxygenase, 165 liquid chromatography, 74, 138 Lithium, 83 liver, ix, 71, 98, 99, 100, 108, 113, 117, 119, 120, 151, 193, 195, 196 liver disease, 71 localization, 127, 144, 272 location, xii, xiv, 80, 88, 104, 116, 221, 223, 224, 230, 232, 238, 241, 243, 276, 285, 317, 318, 320, 335 locus, 129, 134, 136, 147, 168, 169 LOD, 129 London, 29, 57, 272, 273 losses, 199 Louisiana State University, 317 low birthweight, 304 low risk, 82, 284 low-density lipoprotein, 141, 164 low-density lipoprotein receptor, 141 LTA, 165 lumen, 4, 99, 102, 103, 194, 209, 220, 224, 252, 267, 269, 283, 291, 317, 318, 327 lung, 151, 190, 196, 208, 227, 326, 327, 328 lung disease, 326 lungs, 40, 49, 132, 195, 196, 200, 202 lupus erythematosus, 64 lymph, 194 lymphatic, 194, 198, 319 lymphedema, 160

lymphocytes, 138 lymphoma, 323 lymphomas, 321 lysine, 166

M machinery, 145 macroglossia, 326 magnet, 285 magnetic resonance, x, xi, 89, 94, 95, 106, 110, 173, 174, 176, 178, 179, 180, 183, 184, 185, 186, 202, 226, 247, 249, 294, 300, 315, 322 magnetic resonance image, 176 magnetic resonance imaging, x, xi, 89, 94, 95, 173, 174, 176, 178, 179, 180, 183, 184, 185, 247, 249, 289, 300, 315, 322 maintenance, 328 males, 67, 214, 276 malignancy, 319, 321, 322 malignant, 317, 318, 321, 322 malignant mesothelioma, 321 malnutrition, 66, 68, 174 mammalian, 167 management, ix, xi, xiii, 40, 56, 65, 67, 68, 69, 71, 77, 80, 81, 90, 91, 97, 111, 155, 158, 162, 189, 195, 198, 199, 200, 204, 207, 209, 238, 241, 275, 293, 294, 296, 300, 301, 302, 309, 310, 312, 313, 314, 322, 323, 329 manipulation, 191, 195, 307, 337 manpower, 230 manufacturer, 42 mapping, 85, 87, 88, 93, 94, 140, 175, 177, 183, 184, 185, 231, 300 Marfan syndrome, 282, 285, 299, 301, 302 maternal, x, 81, 82, 85, 123, 136, 169, 172 mathematical biology, 28 mathematics, vii, 1 matrix, 36, 110, 141, 165, 176, 230, 238, 243, 282, 285, 299 matrix metalloproteinase, 36, 165, 282, 285 Mb, 143 measurement, 2, 5, 13, 28, 31, 40, 41, 42, 43, 50, 52, 57, 65, 81, 82, 89, 98, 100, 101, 102, 110, 119, 174, 175, 179, 182, 183, 184, 222, 249 measures, 4, 5, 9, 11, 20, 30, 285 mechanical properties, 24, 26, 30, 214 mechanical ventilation, 191, 193 media, viii, 24, 36, 61, 208, 278, 280, 284, 285, 300, 327

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Index median, 102, 105, 190, 192, 217, 231, 238, 293, 302, 308, 321 medical care, 165 medical student, 45 medication, 40, 48, 210 medications, viii, 61, 68, 136 medicine, 28, 31, 37, 58, 71, 162 meiosis, 141 melanoma, 322, 323 men, 29, 51, 57, 60, 64, 137 mental retardation, 142 mesoderm, 125 mesothelioma, 319 meta-analysis, 313 metabolic, 42, 50, 52, 59, 100, 107, 118 metabolic disorder, 100, 107, 118 metabolic rate, 59 metabolism, 53, 59, 60, 71, 76, 107, 125, 141, 162 metabolizing, 53 metalloproteinases, 36, 285 metaphase, 138, 142, 148, 153, 155, 160 metastases, 322 metastasize, 322 metastatic, xiv, 317, 321, 322, 323 metastatic disease, 321, 323 MHC, 127, 128 mice, 132, 133, 135, 187, 282, 296 microarray, 148 microscope, 269 middle-aged, 29 migration, 105, 106, 141, 283 mimicking, 193, 323 minority, 149, 156, 159, 190 minors, 163, 172 MIP, 211, 212, 215, 216 mirror, 256 misfolded, 151 mitochondria, 49 mitochondrial, 141, 332 mitochondrial membrane, 141 mitogen, 154 mitral, xiv, 6, 15, 18, 33, 47, 63, 83, 154, 156, 177, 232, 233, 234, 235, 236, 237, 247, 248, 249, 252, 253, 258, 259, 261, 263, 264, 265, 268, 269, 270, 273, 280, 286, 292, 293, 302, 311, 317, 318, 320, 321 mitral regurgitation, 33, 248, 318 mitral stenosis, 47, 311 mitral valve, xiv, 6, 15, 18, 154, 156, 232, 234, 236, 237, 247, 248, 249, 252, 253, 258, 259, 261, 263,

357

264, 265, 269, 280, 286, 292, 293, 302, 317, 318, 321 mitral valve prolapse, 236, 280 mixing, 52, 191 mobility, 321 modalities, xii, xiii, 88, 94, 198, 229, 238, 255, 275, 285 modality, xii, 88, 198, 229, 230, 232, 241, 245, 246, 288 models, 29 modifier gene, 124, 152 modulus, 2, 3, 25 molecules, 154 monogenic, 127, 165 monosomy, 139, 141 monozygotic, 171 Montenegro, 95 morality, 320 morbidity, ix, xi, xiii, 23, 34, 62, 63, 71, 77, 99, 113, 185, 187, 195, 200, 202, 203, 223, 296, 303, 304, 305, 306, 307, 308, 313, 328 morphological, xii, 210, 251, 254, 257, 263, 330 morphology, xi, xii, 89, 102, 190, 194, 196, 198, 203, 207, 208, 209, 210, 220, 221, 225, 231, 232, 233, 235, 241, 243, 248, 251, 254, 255, 294, 297, 312 mortality, viii, ix, xiii, 20, 23, 29, 34, 61, 62, 63, 69, 71, 72, 73, 75, 76, 77, 80, 90, 113, 114, 139, 174, 181, 184, 185, 192, 194, 195, 197, 203, 223, 283, 296, 303, 304, 305, 306, 307, 308, 309, 310, 313, 328 mortality rate, 62, 192, 304, 305, 307 mortality risk, 62 mosaic, 147, 152 mothers, 82, 93, 137 motion, 41, 42, 44, 45, 184, 203, 208, 210, 215, 221, 222, 226, 236, 237, 245, 247 mouse, 133, 135, 141, 187 mouth, 139 movement, 187 MRI, 48, 89, 95, 101, 176, 177, 178, 180, 185, 189, 209, 230, 285, 287, 289, 290, 307, 318, 319 mRNA, 130, 144, 151 MTHFR, 164 mucocutaneous lymph node syndrome, 36 multidisciplinary, 71, 90 multiples, 2 multivariate, 16, 311 murmur, 189, 318

Index

358

muscle, 13, 24, 40, 41, 42, 43, 47, 49, 50, 52, 53, 59, 66, 71, 148, 151, 170, 273, 280, 283, 285, 299 muscle cells, 24, 280, 285 muscle mass, 50, 66 muscles, 41, 50, 237, 320 musculoskeletal, 54 mutant, 135, 141, 151 mutation, 130, 132, 133, 134, 135, 136, 138, 140, 141, 142, 143, 145, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 163, 165, 166, 168, 296 mutation rate, 143 mutations, x, 123, 124, 128, 130, 131, 132, 133, 134, 135, 136, 138, 141, 142, 143, 145, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 164, 165, 166, 171, 296 myeloid, 329 myocardial infarction, 47, 49, 58, 78, 168 myocardial ischemia, viii, 39 myocardial tissue, 321 myocardium, 89, 125, 127, 128, 252, 321, 322, 336 myocyte, 134 myosin, 128, 135

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N narcotics, 137 nation, 64 natural, 273, 304, 309 nausea, 46 neck, 81, 154, 160 necrosis, 24, 284 neighbourhoods, 170 neonatal, 81, 90, 99, 109, 120, 307, 311, 326, 327 neonate, 114, 201, 274, 312 neonates, ix, x, 75, 99, 100, 102, 103, 106, 110, 113, 114, 115, 116, 117, 118, 119, 120, 121, 138, 189, 208, 311, 312, 313, 314, 315, 331 neoplasia, 71 neoplasm, xiv, 115, 116, 317, 322 nephrocalcinosis, 120 nephrolithiasis, 108 nephrologist, 67, 68 nephropathy, 63, 78 nephrotic syndrome, 71 nephrotoxic, viii, 61, 68 nephrotoxic medications, viii, 61 nerve, 71, 105 nerves, 71 nervous system, 114

Netherlands, 39, 211 network, 320 neural crest, 125, 131, 141, 280, 296, 297 neuroblastoma, 98, 101, 109 neuroectoderm, 131 neuroendocrine, 321 neurogenic, 71 neurohormonal, 62, 73, 119 neurologic symptom, 107 neuronal migration, 106 neurons, 105 neutrophils, 219 New England, 28, 57 New York, 58, 108, 274 Newton, 168 next generation, 141, 142 Ni, 331 Nielsen, 59 nitric oxide (NO), 22, 35, 197, 204, 282, 296, 328, 331, 332 nitric oxide synthase, 282, 296, 332 non invasive, x, 124 nondisclosure, 162, 172 nongenetic, 152 non-infectious, 105 non-invasive, 52, 65, 174, 175, 176, 177, 180, 209, 246, 319 non-linearity, 8 nonsense mutation, 151, 159 norepinephrine, 33 normal, 2, 10, 13, 17, 18, 19, 20, 21, 28, 29, 31, 36, 44, 50, 51, 52, 53, 54, 56, 57, 58, 60, 62, 63, 66, 67, 78, 80, 83, 84, 85, 89, 91, 93, 94, 95, 108, 109, 110, 115, 119, 130, 132, 142, 144, 147, 152, 155, 158, 159, 161, 179, 188, 192, 193, 197, 214, 249, 267, 268, 269, 280, 281, 283, 290, 296, 301, 304, 319, 328, 329 normal children, 2, 51, 53, 58, 119, 301 normal development, 267, 268 normalization, 67 norms, 98, 116 North America, 45, 108 North Carolina, 42 Norway, 74 NOS, 282 N-terminal, 151 nuclear, 48, 144, 152 nucleotides, 138 nucleus, 102 nutrition, 99, 108

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Index

359

O

P

obese, 50 obesity, 49, 59, 74, 326 observations, 36, 105, 110, 118, 223, 241, 283, 326, 328 obstruction, xiv, 7, 13, 47, 80, 119, 174, 177, 180, 188, 189, 191, 196, 198, 199, 200, 223, 232, 235, 270, 272, 282, 283, 296, 305, 306, 308, 317, 318, 326, 329, 330 obstructive sleep apnea, 329 obstructive uropathy, 114, 116, 117 occluding, 227, 269 occlusion, xi, xii, 6, 9, 13, 14, 32, 137, 208, 219, 220, 221, 223, 224, 225, 227, 229, 238, 240, 241, 243, 338, 339 occupational, 43, 48 ocular coloboma, 142 ocular hypertelorism, 156 odds ratio, 69 oedema, 155 Oman, 329 oncology, 109 online, 231 on-line, 13, 32 operator, 85, 87, 88, 90, 181, 246, 337 opposition, 2 optimization, 87, 311 oral, 204, 210 organ, x, 47, 63, 87, 107, 109, 123, 125, 252, 304 organic, 107 orientation, 143, 146, 235, 245 orthopnea, 318 osteosarcoma, 321 ostium, 136, 158, 274 outpatient, 239 overload, 13, 17, 21, 33, 62, 190, 191, 195, 196 overweight, 49, 50, 51 oxide, 22, 35, 197, 204, 282, 296, 331, 332 oxygen, viii, 39, 40, 41, 42, 43, 44, 45, 47, 49, 50, 51, 52, 53, 57, 59, 60, 191, 192, 208, 307, 310, 311, 315, 326, 328 oxygen consumption, 40, 41, 42, 49, 50, 53 oxygen saturation, 42, 47, 52, 191, 192, 208, 310, 311, 326 oxygenation, 61, 189, 327, 331 ozone, 137

PAA, 133 pacemaker, 48, 194, 195, 200, 320 pacemakers, 41, 44, 175 pacing, 13, 22, 35, 200, 205, 249, 335, 337 pain, 41, 46, 148, 285 palliative, 190, 191, 200, 210, 292, 304, 308, 309, 310 pallor, 46 palpebral, 139, 142, 156 pancreas, 109 pancreatitis, 99 paracentric inversion, 147 parameter, 52 parasympathetic, 52 parathyroid, 133, 139 parathyroid glands, 139 parenchyma, 66, 326 parenchymal, 103, 115, 327 parenteral, 99, 108 parents, 48, 80, 137, 141, 143, 148, 152, 153, 155, 156, 158, 160, 163, 175 Parkinson, 273 passive, 11, 31, 190 patella, 159 patent ductus arteriosus, xi, 15, 33, 124, 132, 136, 149, 161, 168, 188, 208, 219, 221, 222, 223, 224, 227 paternal, x, 123, 137, 155 paternity, 158 pathogenesis, 71, 103, 116, 125, 157, 282, 295 pathogenic, 69 pathologists, 245 pathology, ix, xi, xiv, 37, 70, 97, 98, 99, 101, 117, 174, 182, 187, 188, 273, 278, 286, 289, 296, 317 pathophysiological, 299 patho-physiological, 56, 190 pathophysiology, vii, ix, xii, 1, 20, 27, 33, 36, 97, 251, 254 pathways, 154, 168, 191, 192, 198 patterning, 154 PCR, x, 124, 138, 148 pediatric, viii, xii, 4, 12, 13, 15, 30, 32, 39, 40, 42, 47, 56, 57, 76, 78, 85, 90, 91, 101, 108, 109, 118, 161, 183, 185, 186, 208, 209, 210, 214, 225, 226, 229, 230, 231, 233, 245, 246, 249, 301, 304, 321, 326, 329, 331, 338 pediatric patients, 13, 15, 30, 32, 42, 56, 78, 183, 233, 245, 249, 338

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360

Index

pedigree, 129 pelvic, 116, 120 pelvis, 115, 116, 117 penetrance, 133, 149, 159 peptide, 66, 76, 150, 199 peptides, 62 percentile, 116, 156 perception, 66 perforation, 234, 236 perfusion, 52, 53, 61, 77, 87, 117, 188, 189, 190, 191, 199, 209, 227, 304, 305, 307, 313, 315 pericardial, 11, 215, 285, 317, 321 pericardial effusion, 317, 321 pericardial tamponade, 285 pericardium, 234, 319, 321, 322 perinatal, 80, 90, 101, 104, 105, 118 periodic, 99, 116, 117 peripheral, 3 peripheral blood, 138, 152 peripheral blood lymphocytes, 138 peripheral vascular disease, 55 peritoneal, 194 peritoneal cavity, 194 periventricular, 104, 105, 106, 110 permit, 289 persistent pulmonary hypertension of the newborn (PPHN), 327, 330 pharmacological, 12, 13, 124, 125, 199 pharmacological treatment, 124 phenotype, 124, 128, 129, 130, 133, 140, 143, 147, 150, 151, 152, 157, 159, 160, 170, 171, 187 phenotypes, 124, 125, 132, 147, 151, 283 phenotypic, 125, 128, 132, 133, 140, 147, 152, 154, 157, 158, 160, 165, 166, 171, 282, 297 phenylketonuria, 136 Philadelphia, 57, 71, 119, 201, 225, 229, 230, 301 philtrum, 139 phone, 123 phosphate, 106, 118, 332 phosphodiesterase, 32 phosphoenolpyruvate, 141 phosphorylation, 136, 144, 170 physical exercise, 48 physical fitness, 57 physicians, xi, 40, 58, 71, 181, 187 physics, vii, 1, 5 physiological, xi, 35, 44, 46, 52, 58, 187, 192, 199 physiologists, 43, 49 physiology, vii, 1, 2, 9, 10, 20, 21, 28, 29, 30, 31, 32, 34, 43, 58, 191, 192, 193, 195, 304, 315, 328

pilot study, 74, 78, 315 planning, 90, 158, 223, 292 plaque, 288 plasma, 76, 332 plasminogen, 198 plastic, 214 play, 28, 141, 151, 199, 219, 284 pleural, 155, 195, 197 pleural effusion, 155, 195, 197 plexus, 102 pneumonia, 47 point mutation, x, 124, 141 Poland, 61, 74, 109 polarity, 127, 141 polycystic kidney disease, 67, 114 polymer, 214 polymerase, 138 polymerase chain reaction, 138 polymorphism, 130, 138, 148, 170 polymorphisms, 127, 152, 165, 168, 332 polypeptide, 164, 165, 166 polysomnography, 326 polytetrafluoroethylene, xi, 208, 214, 226, 285, 299 pons, 102 poor, 20, 55, 62, 77, 82, 87, 127, 182, 189, 193, 209, 230, 234, 237, 245, 293, 304, 321 population, viii, ix, xi, xiii, xiv, 13, 36, 47, 61, 62, 63, 64, 65, 67, 70, 71, 73, 74, 76, 77, 84, 91, 92, 93, 98, 99, 100, 101, 103, 105, 106, 113, 114, 115, 116, 117, 118, 125, 156, 157, 159, 187, 195, 290, 303, 304, 308, 311, 321, 325, 326, 328, 335 population group, 125 portal hypertension, 99, 100 portal vein, 150 portal venous system, 193 positron, 313 positron emission tomography, 313 postmortem, 95, 110, 313 postoperative, 27, 28, 48, 185, 193, 197, 204, 205, 209, 214, 215, 216, 223, 224, 239, 241, 283, 285, 286, 289, 290, 293, 294, 296, 301, 306, 307, 312, 315 postoperative outcome, 312 potassium, 70, 164, 166 power, 9, 10, 21, 30, 31, 45, 50, 109, 197 power relations, 50 PPHN, 327 PPS, 143 prediction, 33, 62, 66, 110, 294 predictive accuracy, 157

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Index predictors, 34, 76, 181, 197, 301 prednisone, 204 pre-existing, 21 pregnancy, 71, 80, 81, 83, 89, 95, 102, 103, 125, 136, 142, 153, 158, 292 pregnant, 82 pregnant women, 82 premature babies, 98 premature death, 114 premature infant, 33, 67, 103, 108, 326 prematurity, viii, 61, 63, 103, 111, 304 prenatal care, 82 president, 161 pressure, vii, viii, xi, 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 27, 28, 29, 30, 31, 32, 33, 39, 41, 42, 43, 45, 46, 50, 52, 53, 61, 65, 67, 69, 70, 104, 166, 174, 175, 176, 179, 180, 183, 184, 185, 189, 190, 191, 192, 193, 194, 195, 197, 198, 199, 202, 205, 208, 306, 332, 337 preterm infants, 106 prevention, vi, xiv, 72, 74, 75, 162, 224, 330, 333, 337, 339 preventive, xiv, 100, 333, 334 primary tumor, 321, 322 privacy, 163 probability, 128, 129, 153, 158, 194, 309 proband, 134, 148, 153, 158, 160 probands, 135, 158 probe, 14, 256, 265 production, 42, 53, 54, 77, 108, 130, 141, 165, 197, 328, 332 progenitor cells, 328 progenitors, 143 prognosis, viii, ix, 19, 25, 61, 80, 81, 97, 104, 107, 113, 114, 115, 156, 174, 181, 182, 293, 294, 321 prognostic value, 76 program, 58, 81, 82, 127, 310 prolapse, 247 proliferation, 105, 327 promoter, 132, 133, 136, 138, 144, 145, 146 promoter region, 132, 138, 145 propagation, 322 property, 8, 9, 11, 12 prophylactic, xiii, 275, 285, 292 prophylaxis, 100, 117, 199 propositus, 158 prostaglandin, 189 prostheses, 174, 214, 216, 219 prosthesis, 214, 215, 224, 226 protection, 70, 195, 292, 301

361

protein, 66, 68, 128, 130, 132, 134, 135, 138, 140, 141, 144, 145, 148, 150, 151, 152, 154, 155, 156, 157, 159, 164, 165, 166, 170, 193, 194, 198, 199, 202, 204, 205, 285 protein folding, 151, 152 protein function, 151 protein kinases, 141 protein structure, 128, 157 protein synthesis, 130 protein tyrosine phosphatases, 154 protein-protein interactions, 152 proteins, 132, 134, 141, 146, 148, 151, 165, 168, 193, 195 proteinuria, 64, 65, 74, 75 protocol, 42, 43, 44, 45, 46, 57, 58, 117, 175, 210, 305, 338 protocols, viii, xiii, 39, 43, 44, 45, 56, 57, 198, 225, 275, 289 pseudogene, 144 psychological distress, 162 psychologist, 162 PTFE, xi, xii, 208, 214, 215, 216, 217, 218, 219, 223, 224, 225, 227, 285 ptosis, 156 PTPs, 154 public, 62, 73, 74, 125, 333 public health, 62, 73, 74 publishers, 91 pulmonary angiogram, 211, 212 pulmonary arteries, xi, xii, 125, 190, 192, 207, 208, 209, 211, 212, 221, 223, 226, 232, 304, 306, 313, 314 pulmonary artery pressure, 175, 179, 180, 185, 194, 197, 198, 306, 327, 328, 332 pulmonary circulation, 22, 188, 189, 190, 191, 192, 193, 196, 197, 198 pulmonary edema, 318 pulmonary hypertension, xiv, 28, 47, 132, 175, 178, 184, 185, 318, 325, 326, 327, 329, 330, 331 pulmonary stenosis, 15, 17, 47, 137, 143, 148, 177, 178, 181, 212, 261, 262, 263 pulmonary vascular resistance, 22, 35, 189, 191, 192, 197, 198, 199 pulmonic stenosis, 154, 155, 156 pulmonic valve, 319 pulse, 3, 4, 24, 25, 26, 28, 29, 42, 51, 176 pumping, 197 PVS, 156 pyloric stenosis, 101, 107, 109, 114 pyramidal, 107, 118, 231

Index

362

Q QRS complex, 200 quality assurance, 81 quality of life, 40 quartile, 194

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R race, 66, 75 radiation, 175, 208, 210, 211, 289 radiofrequency, 202 radiography, 286, 287, 300 radiological, 192 radiologists, 177, 224 radius, 4 Raman, 248 range, 7, 8, 10, 41, 42, 53, 103, 116, 144, 145, 174, 210, 214, 217, 245, 276, 288, 293, 308 RAS, 156, 157 rat, 141 reactivity, 24, 33 real time, 109, 230, 236, 246, 247, 249 reality, 3 receptors, 125, 145, 151, 166 recognition, 101, 328 recombination, 143, 144, 151 reconstruction, 87, 88, 192, 214, 216, 220, 221, 222, 223, 224, 225, 226, 227, 233, 238, 241, 243, 248, 302, 308, 309, 310, 311, 314, 315 reconstructive surgery, 310 recovery, 51, 60, 335 recreational, 48 recurrence, 124, 148, 155, 158, 162, 320 redundancy, 232 reflection, 2, 3, 4, 5, 24, 25, 26, 28, 29, 49 reflexes, 52 reflux nephropathy, 63, 68 regional, 8, 30, 291, 315 registries, 119 registry, 75, 119 regression, 14, 15, 16, 25, 26 regression analysis, 16, 25, 26 regular, 24, 50 regulation, 31, 35, 61, 71, 130, 134, 138, 148 regulators, 53 rehabilitation, 48, 49, 51, 60, 105 rehabilitation program, 51 rejection, 304

relationship, vii, 1, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 19, 21, 29, 30, 31, 33, 52, 60, 85, 93, 108, 118, 120, 162, 182, 218, 221, 224, 234, 298, 319, 331, 334 relationships, 7, 9, 10, 12, 13, 16, 19, 20, 27, 29, 32, 50 relative size, 235 relatives, 62, 64, 135, 162 relaxation, 6, 11 relevance, 125 reliability, 210 remodeling, 62, 132, 299 remodelling, 133, 293 renal, viii, ix, 29, 36, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 99, 107, 113, 114, 115, 116, 117, 118, 119, 120, 121, 141, 161, 166, 308 renal artery stenosis, 36, 114 renal disease, 29, 62, 63, 67, 73, 74, 75, 77, 78 renal dysfunction, 64, 76, 308 renal failure, 63, 71, 73, 77, 114, 115, 116 renal function, 62, 63, 65, 70, 73, 76, 77, 78 renal medulla, 120 renal replacement therapy, viii, 61, 62, 66, 68, 73 renin, 33, 62, 70, 78, 199 repair, xii, 18, 19, 24, 28, 33, 34, 35, 37, 60, 76, 81, 181, 188, 190, 193, 199, 210, 214, 216, 218, 223, 229, 234, 235, 236, 237, 239, 240, 241, 274, 276, 277, 278, 279, 283, 284, 285, 288, 289, 290, 291, 292, 294, 295, 296, 297, 298, 299, 300, 301, 309, 313, 314, 327, 331, 332 replication, 143, 165 repression, 136 reproduction, 158, 162 resection, 284, 289, 293, 295, 320, 321, 322 residues, 151, 152 resistance, 2, 3, 8, 22, 29, 35, 87, 174, 175, 189, 191, 192, 193, 194, 197, 198, 199, 214, 306, 307, 327, 328, 329 resistive, 2, 8 resolution, xii, 23, 85, 89, 90, 127, 129, 138, 140, 174, 215, 229, 246, 319, 327 resources, 162 respiration, 58, 193 respiratory, 53, 114, 193, 326 respiratory problems, 326 responsiveness, 21, 35 restriction fragment length polymorphis, 127 resuscitation, 40, 189 retardation, 156

Index retention, 62, 69, 71, 77, 166, 204 reticulum, 151, 167, 321 retina, 142 retinol, 66 retinol-binding protein, 66 RFLP, 127 rheumatoid arthritis, 56 rhythm, vii, 42 right atrium, 88, 125, 188, 190, 191, 199, 253, 254, 256, 257, 258, 259, 264, 265, 266, 269, 317, 319, 321 right ventricle, xii, xiii, xiv, 13, 15, 31, 35, 80, 88, 90, 125, 139, 178, 181, 188, 191, 192, 197, 201, 210, 212, 230, 241, 252, 253, 254, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 269, 270, 303, 305, 307, 312, 313, 314, 317, 319 right-to-left shunt, 198 rings, 226 risk assessment, 152 risk factors, x, xiii, 36, 62, 67, 69, 70, 72, 74, 75, 77, 82, 83, 101, 123, 124, 194, 275, 284, 304, 306, 309, 312, 313, 327 risks, 76, 124, 162, 192, 294 Rita, 172 RNA, x, 123, 130, 140 Robertsonian translocation, 161 Rome, 248, 312 Royal Society, 57 rubella, 105, 110, 111 runoff, 191 rural, 35 rural communities, 35

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S safety, 95, 333 SAI, 19 saline, 190 salt, 67 sample, 138, 142, 182, 335 sampling, 158, 183 sarcomas, 317, 319, 321, 323 saturation, 42, 47, 52, 191, 192, 208, 306, 310, 311 scar tissue, 336 scarcity, 304 scavenger, 165 school, 64, 65, 75 sclerosis, 63 screening programs, 64, 81, 82 search, ix, 97, 131, 198, 307

363

secretin, 145 secretion, 328 sedation, 175, 176, 183, 230 sedative, 183 segmentation, 133 segregation, 128, 164 seizures, 328 selecting, xii, 251, 255 semilunar valve, xii, 154, 176, 178, 229, 232, 233, 237, 244, 296 sensitivity, x, xi, 4, 10, 28, 71, 83, 84, 138, 173, 174, 175, 177, 181, 182, 286, 288 sensors, 41 separation, 125, 137, 162, 189, 259, 261, 266 sepsis, 64, 99, 101 septum, xiv, 48, 87, 88, 158, 174, 181, 233, 236, 237, 240, 241, 243, 252, 257, 259, 261, 262, 265, 267, 269, 270, 280, 304, 308, 311, 312, 317, 320, 322, 334, 336, 337 sequelae, 180, 215 sequencing, 127, 128, 153, 155, 160 series, 6, 84, 125, 169, 193, 195, 196, 210, 232, 235, 269, 278, 284, 293, 311, 312, 320, 323, 326 serine, 141, 156, 166 serum, 66, 70, 101, 148, 165, 170 services, iv severity, 153, 156, 181, 189, 209, 222, 232, 255, 326, 327, 328 sex, 51, 59, 327, 329 shape, 3, 13, 101, 102, 103, 221, 224, 239, 240, 241, 280, 297, 320, 336 shares, xiii, 11, 252 shear, 278, 284 shock, 63, 285 short-term, 31, 338 shoulder, 85 shunts, 28, 33, 132, 174, 184, 190, 195, 232, 308, 326 siblings, 148, 153, 158, 160 sick sinus syndrome, 249 side effects, 117 Siemens, 176, 177 sign, 62, 90, 98, 105, 286 signal peptide, 150 signaling, 32, 296 signalling, 134, 141, 144, 150, 152, 157, 168, 280, 282 signals, 141, 144 signs, 103, 108, 117, 142, 144, 145, 149, 153, 156, 158, 160, 175, 289, 318

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364 sildenafil, 199 silencers, 147 similarity, 129, 141, 144, 148, 270 simulation, 20, 21, 219 Singapore, 64, 65, 74, 75 single-nucleotide polymorphism, 165 sinus, 51, 125, 193, 195, 197, 199, 203, 205, 263, 290, 320, 334 sinuses, 280, 292 sites, 143, 146, 208, 212, 214, 215, 218, 225, 277, 284 situs inversus, ix, xiii, 97, 98, 251, 256, 257, 258, 263 skeletal muscle, 148, 151, 170 skeleton, 114, 143 skills, 40, 85, 90, 241 skin, 36, 42, 46, 81, 142, 157, 158, 160, 322 skin tags, 142 sleep, 326, 329, 330 sleep apnea, 329, 330 sludge, 99 smoking, 68, 124 smoking cessation, 68 smooth muscle, 24, 280, 283, 285, 299 smooth muscle cells, 24, 280, 285 social work, 161 socioeconomic, 75, 309 socioeconomic status, 309 sodium, 62, 66, 71, 164, 166 software, 129, 177, 221, 231, 236 solvent, 157 Sonic hedgehog, 134, 168 spatial, 216, 224, 230, 235, 238, 241, 245 spatiotemporal, 80, 87, 92, 94 species, 10 specificity, x, xi, 83, 84, 135, 173, 174, 175, 177, 179, 182, 286 spectrum, 141, 171, 185, 194, 231, 273, 282 speculation, 327 speech, 141, 142 speed, 44, 45, 87, 208, 210, 226 spin, 176 spinal cord, 106, 292, 301 spine, 81, 85, 86 spleen, ix, 98, 100, 108, 113, 119, 120, 151, 181 splenomegaly, 100 sporadic, 134, 143, 156, 158, 168, 320, 326 sports, 48, 58 spouse, 49 SPSS, 177

Index stability, 10, 130, 151, 157 stabilization, 141, 154, 189 stages, viii, 43, 44, 61, 62, 66, 67, 69, 71, 189, 192, 197, 267, 268 standard deviation, 67, 115 standards, 56, 57, 59, 89, 162, 185 statins, 68 statistical analysis, 129, 301 steady state, 10, 12, 43 steel, 337 stenosis, xi, xiii, 20, 41, 101, 109, 115, 136, 139, 143, 149, 155, 156, 181, 189, 196, 200, 207, 209, 211, 212, 213, 214, 215, 219, 222, 224, 226, 232, 245, 249, 252, 255, 264, 269, 270, 280, 293, 297, 298, 306, 308, 317, 326 stent, 19, 192, 284, 307, 308 steroids, 118, 199 stiffness, 4, 11, 19, 21, 23, 24, 25, 26, 29, 31, 33, 36, 37, 197, 283 stimulus, 269 stochastic, 145 stomach, 83, 100 storage, 245 strain, 306 strategies, 67, 70, 71, 127, 168, 293, 310, 312, 313, 314, 333 stratification, 72, 76 strength, 9 stress, 48, 56, 57, 137, 197, 278, 284, 290, 336 stressors, 305 stroke, 5, 9, 10, 11, 12, 14, 15, 18, 31, 49, 50, 51, 165, 195, 198 stroke volume, 5, 11, 12, 14, 18, 49, 50, 51 structural defect, 87, 90 structural defects, 87 subaortic stenosis, 188, 273 subgroups, 270 subjective, 198, 241 substances, 125 substitution, 151, 159 substrates, 48 subtilisin, 165 success rate, xii, 230 suffering, ix, 97, 117, 293 superior vena cava, 85, 86, 190, 191, 253, 263 superiority, 181 supplements, 53, 66 supply, 53, 57, 59, 69, 77, 209 supramaximal, 59 surface area, 17, 27, 43, 59, 290

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Index surfactant, 328 surgeons, 20, 187, 191, 245, 284, 289, 291, 292, 293, 312 surgery, xi, xiii, 1, 15, 19, 30, 31, 33, 34, 37, 48, 80, 110, 174, 177, 180, 181, 182, 183, 191, 192, 195, 198, 200, 201, 202, 205, 209, 214, 215, 234, 235, 244, 245, 249, 275, 276, 280, 282, 291, 292, 293, 295, 298, 302, 303, 306, 307, 308, 309, 311, 321, 326, 327, 328, 331, 332 surgical, viii, x, xi, xii, xiii, 12, 33, 37, 61, 76, 81, 173, 174, 175, 176, 178, 179, 181, 182, 187, 189, 192, 194, 196, 199, 205, 207, 209, 210, 214, 215, 223, 230, 232, 234, 235, 236, 237, 238, 239, 240, 241, 248, 251, 254, 273, 274, 275, 276, 277, 278, 279, 284, 292, 293, 294, 295, 297, 300, 301, 302, 303, 304, 305, 306, 308, 311, 312, 313, 314, 318, 320, 326, 329, 332, 334 surgical intervention, 235, 240, 293, 306 surgical resection, 320 surveillance, 293, 308, 310, 321 survival, 29, 34, 73, 80, 81, 115, 119, 191, 192, 194, 197, 200, 293, 304, 305, 306, 309, 311, 312, 315, 321, 328, 330 survival rate, 305, 306 survivors, 20, 76, 195 susceptibility, 293 suture, 195, 240, 241, 284, 291 symbiosis, 61 sympathetic, 62, 71, 199 sympathetic nervous system, 62, 71, 199 symptom, 104, 105, 106, 117, 118, 322 symptoms, ix, xiii, 17, 18, 41, 46, 97, 98, 99, 104, 105, 106, 107, 140, 142, 145, 148, 156, 158, 159, 160, 175, 189, 275, 285, 293, 317, 318, 319, 326, 338 syndrome, vii, ix, x, xiii, 23, 41, 42, 63, 64, 69, 75, 77, 80, 92, 97, 98, 100, 107, 108, 109, 111, 114, 115, 118, 121, 124, 131, 133, 134, 136, 139, 140, 141, 142, 143, 145, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 164, 166, 168, 169, 170, 171, 172, 175, 178, 185, 188, 189, 194, 195, 197, 200, 201, 203, 231, 235, 236, 280, 296, 299, 300, 301, 303, 304, 309, 310, 311, 312, 313, 314, 315, 326, 329, 330, 331, 332 synergistic, 69 synergistic effect, 69 synthesis, 130 system analysis, 50 systemic circulation, 188, 189, 190, 191, 192, 196, 197, 305, 328

365

systemic lupus erythematosus, 64 systems, ix, 18, 42, 62, 87, 97, 98, 143, 214, 230, 269 systolic blood pressure, 46, 69, 192 systolic pressure, xi, 8, 9, 11, 15, 18, 19, 22, 23, 28, 30, 32, 52, 174

T tachycardia, 31, 46, 47, 202, 240 task force, 300 T-cell, 140 teaching, 83 technicians, 40 technology, 87, 94, 138, 230, 238, 243, 245, 247, 276, 304, 307 teenagers, 36 telomere, 143 temperature, 40 temporal, 92, 94, 117 teratogen, 137 teratogenic, 105, 137 teratogens, 83 teratology, 272 teratoma, 318 teratomas, 321 termination codon, 151, 152 Tesla, 176, 226, 249 testis, 141 tetralogy, 24, 26, 27, 28, 37, 41, 52, 99, 115, 134, 135, 136, 139, 142, 149, 154, 178, 181, 209, 210, 212, 241, 262, 268, 270, 272, 280, 283 Tetralogy of Fallot, 24, 80, 139, 168, 178, 240, 272 TGA, 80, 83, 90, 98, 99, 100, 101, 178, 181, 182, 200, 234, 235, 240, 241 TGF, 66 Thai, 329 thalamus, 102, 104, 111 therapeutic approaches, 205 therapy, ix, xiii, 31, 48, 62, 63, 67, 68, 70, 71, 73, 77, 78, 81, 113, 118, 125, 162, 198, 199, 204, 205, 219, 275, 285, 293, 308, 333, 339 thiazide, 199 thiazide diuretics, 199 thoracic, 30, 31, 34, 37, 176, 194, 198, 208, 209, 225, 276, 277, 288, 293 thoracotomy, 293 thorax, 81, 84, 85, 225 three-dimensional, 94, 130, 152, 182, 183, 216, 226, 227, 247, 248, 249, 289, 294

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366

Index

three-dimensional reconstruction, 226 threonine, 141, 154, 156, 166 threshold, 40, 42, 43, 45, 49, 52, 53, 54, 224 thrombocytopenia, 99 thromboembolic, 198 thromboembolism, 199, 209, 223, 227 thrombosis, ix, 113, 117, 223, 224 thrombotic, 199 thrombus, 103, 204, 224, 319 thymus, 133, 139 time constraints, 43 timing, xii, 5, 8, 229, 292 tissue, 53, 61, 81, 89, 104, 105, 125, 131, 133, 152, 168, 183, 208, 215, 218, 219, 221, 227, 252, 264, 270, 278, 282, 283, 293, 298, 319, 321, 326, 328, 330, 334, 336, 337 tissue perfusion, 61 Tokyo, 108, 210, 220 tolerance, 22, 34, 58 tonsillectomy, 326 Toshiba, 210 total parenteral nutrition, 108 toxoplasmosis, 105 trachea, 85, 178, 180 tracheoesophageal fistula, 101 tracheostomy, 326 tracking, 42 training, 57, 58, 83, 85 traits, 101, 103, 167 trajectory, 3 trans, vi, xiv, 134, 198, 333, 334, 335, 337, 338, 339 transcatheter, 219, 220, 221, 223, 224, 311, 314, 315 transcript, 141, 152 transcription, 130, 131, 133, 134, 135, 136, 140, 144, 145, 146, 148, 158, 159, 164, 167, 168, 169, 170 transcription factor, 131, 133, 134, 135, 136, 144, 146, 148, 158, 159, 167, 168, 170 transcription factors, 135, 146, 148 transcriptional, 135, 146, 282 transcripts, 140, 141, 151 transducer, xii, 13, 16, 85, 87, 101, 175, 229, 230, 231, 245, 246, 255 transection, 209 transesophageal echocardiography, xii, 16, 229, 285, 300 transition, 328 translation, 130, 151, 271 translocation, 139, 144, 147, 149, 150, 170 translocations, 138, 141, 153, 172 transmembrane, 150

transmembrane region, 150 transmission, 4, 124, 139, 141, 142, 153, 160, 163, 165 transpiration, 42 transplant, 192, 200, 309, 320 transplantation, xiii, 196, 200, 201, 303, 304, 307, 308, 309, 314 transport, 140, 141, 151, 315 transportation, 45 transposases, 144 transthoracic echocardiography, 208, 221 transverse section, 85, 102 treatment methods, 195 trial, 159, 185, 335 tricuspid valve, 15, 87, 188, 194, 253, 256, 267, 272, 304 trisomy, 82, 141, 142, 161, 326, 329, 330, 331 trisomy 21, 82, 329, 330, 331 tubular, 66, 118, 127, 278, 298 tumor, xiv, 101, 115, 116, 317, 318, 319, 321, 322 tumors, xiv, 99, 317, 318, 319, 320, 321, 322, 323 turbulence, 284 turbulent, 191 twinning, 152 twins, 61, 71, 152, 164 two-dimensional (2D), 84, 183, 185, 189, 300 type 1 diabetes, 69 tyrosine, 144, 152, 154, 156, 157, 171

U ultrasonography, ix, 65, 81, 89, 92, 94, 97, 101, 107, 110, 113, 118, 223 ultrasound, viii, ix, x, 65, 75, 79, 80, 82, 83, 85, 87, 88, 89, 91, 93, 94, 95, 97, 98, 99, 101, 104, 105, 109, 110, 116, 117, 120, 121, 124, 142, 155, 158, 160, 174, 184, 300, 307, 313, 315 umbilical artery, 90, 95 underlying mechanisms, xiv, 22, 27, 333, 335 uniform, xiii, 83, 140, 275, 284, 306 United Kingdom (UK), 81 , 227 United States, 45, 56, 57, 62, 73, 75, 120, 184, 328 updating, 124 upper airways, 329 urethra, 114 urinalysis, 75 urinary, viii, ix, x, 61, 62, 65, 67, 68, 73, 75, 113, 114, 117, 118, 119, 120 urinary tract, viii, ix, x, 61, 62, 65, 67, 68, 75, 113, 114, 117, 119, 120

Index urinary tract infection, 65, 67, 68 urine, 65, 66, 101, 107, 115 uterus, 137

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V vaccinations, 100 validation, 13, 184, 185, 235, 248, 249 validity, 4 values, 2, 14, 17, 18, 44, 50, 51, 53, 55, 56, 66, 69, 78, 84, 98, 100, 102, 109, 110, 116, 177, 179, 182, 216, 217, 224, 249 variability, xiii, 149, 152, 154, 160, 169, 174, 177, 182, 185, 241, 252, 270, 283, 304 variable expressivity, 160 variables, xi, 14, 25, 51, 174, 180, 181, 182, 194, 210, 295, 305 variation, 130, 135, 142, 145, 149, 152, 160, 166, 271, 332, 335 variegation, 144, 147, 170 vascular disease, 55, 197, 330, 331 vascular diseases, 197, 331 vascular grafts, 214, 278 vascular inflammation, 24 vascular system, 5, 166 vascular wall, 19 vasculature, 190, 191, 197, 204, 209, 307, 323, 326, 327, 328 vasculitis, 23, 36 vasoconstrictor, 328 vasodilatation, 328 vasodilation, 328 vasodilator, 199 vasopressin, 71, 204 vein, 176, 190, 210, 226, 337 velo-cardio-facial syndrome, 140, 169 velocity, 4, 18, 24, 25, 26, 28, 29, 36, 87, 175, 176, 177, 183, 184, 185, 197, 221, 231, 300 venous pressure, 20, 191, 192, 193, 195, 198, 199 ventilation, 53, 189, 193, 202, 209, 306 ventricle, xi, xiii, 3, 5, 6, 9, 10, 12, 13, 15, 20, 21, 22, 27, 28, 31, 34, 35, 41, 102, 103, 104, 105, 106, 125, 136, 177, 181, 187, 188, 189, 190, 192, 193, 195, 196, 198, 200, 201, 217, 252, 254, 256, 257, 258, 259, 260, 262, 264, 266, 269, 270, 272, 274, 312, 313, 315, 323 ventricles, xiii, 12, 18, 27, 31, 84, 102, 103, 104, 105, 110, 125, 127, 181, 188, 197, 210, 214, 234, 251, 252, 254, 255, 256, 257, 261, 262, 270, 271, 319

367

ventricular arrhythmia, 47 ventricular arrhythmias, 47 ventricular septal defect, vi, xii, 3, 13, 15, 17, 32, 37, 80, 87, 88, 94, 134, 136, 169, 175, 178, 181, 188, 194, 210, 211, 212, 214, 226, 229, 231, 237, 238, 241, 243, 248, 252, 256, 258, 259, 260, 261, 262, 264, 265, 266, 269, 270, 273, 298, 327, 329, 331, 333, 338, 339 ventricular septum, 48, 80, 85, 178, 181, 236, 260, 263, 264, 266, 269, 334, 337 ventricular tachycardia, 47, 240 vertebrates, 132 vessels, vii, ix, xi, 85, 87, 89, 90, 94, 97, 105, 136, 150, 187, 192, 196, 208, 224, 255, 274 viral hepatitis, 99 virus, 105 viscera, 176 viscoelastic properties, 35 viscosity, 11 visible, 104, 118, 215, 216, 219, 222 visualization, 80, 82, 84, 85, 88, 209, 220, 224 vitamin A, 137 vitamin D, 118, 195, 199 vitamin D deficiency, 195, 199 vitamin K, 104 voids, 292 VSD, xiv, 13, 15, 17, 19, 52, 88, 99, 100, 115, 139, 155, 158, 159, 161, 178, 188, 191, 200, 210, 214, 215, 216, 217, 224, 231, 232, 234, 235, 237, 238, 239, 240, 241, 243, 327, 333, 334, 335, 336, 337, 338

W walking, 44, 45, 58 water, 62, 71, 99, 117 weakness, 278 weeping, 85 weight gain, 306 weight loss, 48 white matter, 104, 105, 110 wild type, 151, 159, 161 Williams-Beuren Syndrome, 143 windows, 208, 237, 242, 245 Wisconsin, 176 withdrawal, 52 wives, 58 women, 29, 50, 82, 136, 292 workload, 42, 43, 44, 45, 46, 58 World Health Organization (WHO), 49, 326

Index

368

X X chromosome, 160 X-linked, 159

Y yield, 5, 181, 245, 289 young adults, 33, 36, 184

Z

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zebrafish, 283 zinc, 135