Encyclopedia of Cardiovascular Research and Medicine 1St Edition Douglas B Sawyer Full Chapter

Encyclopedia of Cardiovascular
Research and Medicine 1st Edition

Douglas B. Sawyer
Visit to download the full and correct content document:
https://ebookmass.com/product/encyclopedia-of-cardiovascular-research-and-medicin
e-1st-edition-douglas-b-sawyer/
ENCYCLOPEDIA OF
CARDIOVASCULAR RESEARCH
AND MEDICINE
This page intentionally left blank
ENCYCLOPEDIA OF
CARDIOVASCULAR RESEARCH
AND MEDICINE
EDITORS-IN-CHIEF
RAMACHANDRAN S. VASAN DOUGLAS B. SAWYER
Boston University School of Medicine, Boston, Maine Medical Center Research Institute,
MA, USA Scarborough, ME, USA
SECTION EDITORS
RAGAVENDRA R. BALIGA LUCY LIAW
The Ohio State University, Columbus, OH, USA Maine Medical Center Research Institute,
Scarborough, ME, USA
THOMAS DI SALVO
Medical University of South Carolina, AMY MAJOR
Charleston, SC, USA Vanderbilt University Medical Centre,
Nashville, TN, USA
CHRIS P. GALE
University of Leeds, Leeds, UK SATISH R. RAJ
Libin Cardiovascular Institute of Alberta,
THORSTEN KESSLER University of Calgary, Calgary, AB, Canada
German Heart Centre, Munich, Germany
HERIBERT SCHUNKERT
YOSHIHIRO KOKUBO German Heart Centre, Munich, Germany
National Cerebral and Cardiovascular Center,
Osaka, Japan
DANIEL LENIHAN
Washington University Medical Centre,
St. Louis, MO, USA
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA
Copyright © 2018 Elsevier Inc. All rights reserved
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on
how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as
the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted
herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in
research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods,
compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the
safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or
damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
ISBN 978-0-12-809657-4
For information on all publications

visit our website at http://store.elsevier.com
Printed and bound: YTC
Publisher: Oliver Walter

Acquisition Editor: Will Smaldon
Senior Content Project Manager: Richard Berryman
Designer: Christian Bilbow
Cover: Photomicrographs were provided by Laura

Pentassuglia, Sean Lenihan, Cristi Galindo, and
Christian Zuppinger
CONTENTS OF ALL VOLUMES
List of Contributors xvii

Preface xxxv
VOLUME 1
Adult Congenital Heart Disease 1
D Briston and E Bradley
Adverse Impact of Delayed Electrical Activation of the Heart and Benefits of Cardiac Resynchronization 10
A Guha and EG Daoud
AL Cardiac Amyloidosis: Classification, Diagnosis, and Treatment 34

OK Siddiqi and FL Ruberg
Alcohol 49
C Matsumoto
Alcoholic Cardiomyopathy 58
A Voiosu, S Wiese, JD Hove, T Voiosu, F Bendtsen, and S Møller
Amyloid Cardiomyopathy 66
T Sher and MA Gertz
Anemia in Heart Failure 80

A Patel and NL Altman
Angiogenesis 85
N Warmke, AMN Walker, and RM Cubbon
Animal Models of Ischemic Heart Disease: From Atherosclerosis and Thrombosis to Myocardial Infarction 97
R Covarrubias, AS Major, and RJ Gumina
Ankle-Brachial Pressure Index and Pulse Wave Velocity in Cardiovascular Risk Assessment 111
H Tomiyama and A Yamashina
Aortic Aneurysm 123

M Singh, BA Ziganshin, and JA Elefteriades
Aortic Valve Replacement in Patients With Congestive Heart Failure 143

VJ Nardy, JA Crestanello, and NP Jaik
Arrhythmias in Cancer and Cancer Treatment: A Review 162

D Haddad, A Guha, F Awan, EG Daoud, and R Baliga
Arrhythmogenic Right Ventricular Cardiomyopathy 182

MR Afzal, C Evanson, A Cardona, K Rusk, and R Weiss
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 192

GM Orgeron and H Calkins
v
vi Contents of All Volumes
Athlete's Heart 205

LM Safi and MJ Wood
Atrial Tachycardia—Mechanisms and Management 212

J Ahmed and P LeLorier
Atrioventricular Node Reentrant Tachycardia 224

AG Carrizo, B Ballantyne, and A Baranchuk
ATTR Cardiac Amyloidosis: Classification, Diagnosis, and Management 242

JA Cowgill and JN Wight Jr.
Behavior Modification and Cardiovascular Disease 257

V Ramirez, B Starobin, and J Monti
Bicuspid Aortic Valve and Sports Activity 263

L Stefani, G Galanti, and N Maffulli
Bioinformatics Principles for Deciphering Cardiovascular Diseases 273

L Shu, D Arneson, and X Yang
Biomarkers in Heart Failure, Use of 293

PU Gandhi
Biomarkers in Ischemic Heart Disease 303

JT Neumann and RB Schnabel
Biomarkers: Heart Failure 315

SS Gogia and JE Ho
Biomarkers: Population Screening and Risk-Stratification 323

I Ratjen, RS Vasan, and W Lieb
Biophysics of Ablation—Radiofrequency and Cryoablation 334

JG Andrade, MW Deyell, and L Macle
Blood Pressure Variability Versus Blood Pressure Level in Risk Stratification 350
F-F Wei, K Asayama, A Hara, TW Hansen, Y Li, and JA Staessen
Brugada Syndrome 356

C Antzelevitch
Cardiac Anatomy, Physiology, and Pathophysiology 373

KN Hor and AJ Trask
Cardiac and Induced Pluripotent Stem Cells 384

A Salerno, W Balkan, K Hatzistergos, and JM Hare
Cardiac Arrhythmia in Heart Failure 394

T Okabe and SJ Kalbfleisch
Cardiac Biomechanics in Normal Physiology and Disease 411

KM Broughton
Cardiac Fibroblast 420

J Park and MD Tallquist
Cardiac Hypertrophy: Signaling and Cellular Crosstalk 434

D Tirziu
Cardiac Magnetic Resonance Imaging in Heart Failure 451

A Reynolds and KM Zareba
Cardiac Pacing and Monitoring: Past, Present, and Future 463

F Chalhoub and T Mela
Cardiac Regeneration and Stem Cells as Therapy for Heart Disease 468
AJ Favreau-Lessard and DB Sawyer
Contents of All Volumes vii
Cardiac Resynchronization Therapy 475

G Voros
Cardiac Transplantation 489

A Hasan
Cardiohepatic Interactions 514

J Shah and E Shao
Cardiopulmonary Exercise Testing 523

V Franco
Cardiovascular Complications and Management in Sarcoidosis: A Review 527

DJ Roberts, S Francis, JA Rosenblatt, and ST Coffin
Cardiovascular Disease and Obesity 535

Y Matsushita
Catecholaminergic Polymorphic Ventricular Tachycardia 542

PJ Kannankeril
Catheter Ablation for Atrial Fibrillation (Methods) 553

JG Andrade, MW Deyell, and L Macle
Catheter Ablation for Ventricular Tachycardia 566

RM John and WG Stevenson
Cellular Sinoatrial Node and Atrioventricular Node Activity in the Heart 576
HJ Jansen, TA Quinn, and RA Rose
Chronic Infections of the Heart 593

M Edwards, C Withers, and K Thakarar
Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease 600

T Ninomiya
Clinical Assessment of the Cardiac Arrhythmia Patient 609

B Olshansky
Clinical Management of Inherited Arrhythmias 620

RL Jones and MV Perez
Clinical Trials for Atrial Fibrillation—What Do We Know? 630

DS Chew and SB Wilton
Complications of Pregnancy and Future Cardiovascular Risk 643

PH Andraweera, GA Dekker, M Arstall, T Bianco-Miotto, and CT Roberts
Comprehensive Lifestyle Modification for Hypertension and Lifestyle-Related Disease Under the New
Guidelines 651
Y Kokubo and C Matsumoto
Computational Systems Biology for the VEGF Family in Angiogenesis 659

JC Weddell and PI Imoukhuede
Congenital Heart Valve Disease in the Adult 677

A Luk, J Alvarez, and J Butany
Coronary Anatomy 691

M Sivananthan
Coronary Artery Bypass Grafting 700

RS Kramer, JR Morton, RC Groom, and DL Robaczewski
Cyanotic Congenital Heart Disease 730

MS Renno and JA Johns
viii Contents of All Volumes
VOLUME 2
Dairy Products and Cardiovascular Diseases 1
M Yanagi, N Amano, and T Nakamura
Diabetes Mellitus 9
H Sone
Diagnosis and Imaging of Congenital Heart Disease 17

SR Fuchs and JH Soslow
Diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) 47

M Vafaie and E Giannitsis
Diet in Heart Failure 54

M Rozmahel, E Colin-Ramirez, and JA Ezekowitz
Dietary Fat and Risk of Cardiovascular Disease 60

ES Eshak, K Yamagishi, and H Iso
Digital Data (mHealth and Social Media) 90

R Bhattacharjee and T Hussein
Diseases of the Mitral Valve 98

L Mc Carthy and P Collier
Diuretic Therapy 107

A Vazir, V Sundaram, and AR Harper
Driving and Syncope 117

D Sorajja and W-K Shen
Echocardiography in Heart Failure 126

T Chen and JN Kirkpatrick
Echocardiography: Assessment of Valve Structure and Function 142

S Vallurupalli, A Siraj, and S Kenchaiah
Economics of Heart Failure 187

S Stewart, C Mainland, and A David
Electrocardiographic Monitoring Strategies (Holter, Implantable Loop Recorder, in Between) 197

H Nazzari, L Halperin, and AD Krahn
Electrophysiology Approaches for Ventricular Tachycardia 211

RM John and W Stevenson
Emergency Medicine Approach and Management of Traumatic Injuries: An Overview 221

E Lavine and E Legome
Environmental Air Pollution: An Emerging Risk Factor for Stroke 231

B Delpont, AS Mariet, C Blanc, Y Bejot, M Giroud, and J Reis
Environmental Risk Factors for Stroke and Cardiovascular Disease 238

J Reis, M Giroud, and Y Kokubo
Epidemiology of Atherosclerotic Cardiovascular Disease 248

N Townsend
Epigenomics 258
TA Turunen, M-A Väänänen, and S Ylä-Herttuala
Exercise and Cardiac Rehabilitation in Heart Failure 266

SR Schubert
Exercise, Physical Activity, and Cardiovascular Disease 274

A Bauman, M Alharbi, N Lowres, R Gallagher, and E Stamatakis
Extracorporeal Membrane Oxygenation 281

A Kilic
Contents of All Volumes ix
Familial Hypercholesterolemia 285

A Pirillo and AL Catapano
Frailty in Heart Failure Patients 298

S Pedraza, TA Barrett, and CM Hritz
Genetic Atrial Fibrillation 303

R Chia, A Mehta, H Huang, and D Darbar
Genetic Disorders Involving Valve Function 313

M Afshar and G Thanassoulis
Genetic Disorders of the Vasculature 327

AJ Brownstein, BA Ziganshin, and JA Elefteriades
Genetics of Heart Failure 368

A Briasoulis, R Asleh, and N Pereira
Heart Development 380

E Dees and S Baldwin
Heart Failure in African Americans 399

M Jame, S Jame, and M Colvin
Heart Failure in Cancer Patients 406

A Vallakati, B Konda, and R Baliga
Heart Failure in Low- to Middle-Income Countries 417

S Stewart, F Taylor, and AK Keates
Heart Failure in Minorities 429

ER Fox, ME Hall, JD Pollard, SK Musani, CJ Rodriguez, and RS Vasan
Heart Failure in the Elderly 437

S Katsanos and J Parissis
Heart Failure Monitoring 453

ES Shao
Heart Failure With Preserved Ejection Fraction 464

S Day
Heart Regeneration with Stem Cell Therapies 469

M Natsumeda, BA Tompkins, V Florea, AC Rieger, M Banerjee, W Balkan, and JM Hare
Heart–Lung Transplantation 484

B LeNoir, M Malik, and BA Whitson
Hemodynamic Changes of Pregnancy 489

P Divanji and NI Parikh
Hemodynamics of the Right Heart in Health and Disease 497

DM Gopal and A Alsamarah
Hormonal Therapy in the Treatment of Chronic Heart Failure 508

R Napoli, A Salzano, E Bossone, and A Cittadini
Hypertensive Heart Disease 517

MU Moreno, A González, B López, S Ravassa, J Beaumont, G San José, R Querejeta, and J Díez
Hypertrophic Cardiomyopathy 527

LK Williams
VOLUME 3
Imaging of Mitral Regurgitation 1
JB Strom, KF Faridi, and CW Tsao
Imaging: CT Scanning of the Heart and Great Vessels 12

M Eid, MH Albrecht, CN De Cecco, D De Santis, A Varga-Szemes, D Caruso, VW Lesslie, and UJ Schoepf
x Contents of All Volumes
Imaging: Echocardiology—Assessment of Cardiac Structure and Function 35

D Bamira and MH Picard
Immune Mechanisms in Cardiac Physiology 55

SM Peterson, DJ Roberts, and S Ryzhov
Immune-Mediated Mechanisms of Atherosclerosis 68

M Bäck, DFJ Ketelhuth, S Malin, PS Olofsson, G Paulsson-Berne, Z-Q Yan, and GK Hansson
Implanted Pacemakers—Indications and Novel Programming 77

R Willems
Induced Pluripotent Stem Cell–Derived Cardiomyocytes in Advancing Cardiovascular Medicine 87

C Zhang, AG Cadar, and CC Hong
Infective Endocarditis in 21st Century 94

VV Kandasamy, S Pant, and JL Mehta
Inflammatory and Infectious Disorders of the Aorta 102

V Noori, B Nolan, and C Healey
Inotropes in Heart Failure 108

M Ginwalla and C Bianco
Interventions: Endomyocardial Biopsy 119

B Kherad, U Kühl, and C Tschöpe
Intra-aortic Balloon Pumps (IABP) and Percutaneous Ventricular Assist Devices (VADs) 126
NK Kapur and ML Esposito
Ion Channelopathy Genetics 132

A Adler and MH Gollob
Ischemic Cardiomyopathy 145

S Airhart and S Murali
Kidney in Heart Failure 155

DN Pratt and A Diez
Lead-Related Complications 166

B Mondesert and R Parkash
Left and Right Ventricular Remodeling 171

D Pinkhas and X Gao
Left Ventricular Assist Device (LVAD) and Circulatory Devices in Heart Failure 186
P Lee
Left-Sided Obstructive Congenital Heart Lesions: Including Hypoplastic Left Heart 200
CJ Prendergast and GT Nicholson
Lipid-Mediated Mechanisms in Atherosclerosis 214

Q Liu, J Martinez, J Hodge, and D Fan
Lipids and Cardiovascular Diseases: Epidemiologic Perspectives 221

T Okamura, D Sugiyama, T Hirata, K Kuwabara, and A Hirata
Long QT Syndrome and Torsade de Pointes 230

N El-Sherif, G Turitto, and M Boutjdir
Management and Care of Older Cardiac Patients 245

AA Damluji, A Ramireddy, and DE Forman
Management of Cardiac Sarcoidosis 266

L Alghothani and ED Crouser
Management of Patients With Implantable Cardiac Devices Referred for Magnetic Resonance Imaging: A
Rapidly Changing Landscape 274
I Roifman and JA White
Contents of All Volumes xi
Management of Pregnancy With Underlying Congenital and Acquired Cardiac Disease 282
AM Moran
Management of Ventricular Tachycardia in Ischemic and Nonischemic Cardiomyopathy 292

A AbdelWahab, VP Kuriachan, GL Sumner, LB Mitchell, and J Sapp
Managing Cardiovascular Disease in Sport and Athletes 302

AB Shah and AL Baggish
Mechanisms of Cardiac Arrhythmias: Molecular and Cellular Perspective 316

P Zhabyeyev and GY Oudit
Medical Management of Left Ventricular Assist Devices 328

S Emani
Metabolomics in Cardiovascular Research 331

V Salomaa and M Inouye
MicroRNAs in Cardiac Development and Function 340

Y Tian
Microvasculature in Health and Disease 349

JE Beare, L Curtis-Whitchurch, AJ LeBlanc, and JB Hoying
Mitochondrial Bioenergetics in the Heart 365

EJ Lesnefsky, Q Chen, B Tandler, and CL Hoppel
Modern Considerations in ICD Therapy 381

TD Richardson and CR Ellis
MR Imaging of the Heart and the Great Vessels 388

U Neisius and C Tsao
Myocardial Perfusion Imaging 404

RB Morgan
Myocardial Repair 425

K Breckwoldt and T Eschenhagen
Myocarditis 440
ALP Caforio, G Malipiero, R Marcolongo, and S Iliceto
Myocarditis in Heart Failure 452

G Sinagra, J Artico, P Gentile, E Fabris, R Bussani, A Cannatà, and M Merlo
Neurohormonal Blockade 459

L Cunningham, W Kayani, and A Deswal
Neurological Regulation of the Circulation 477

DN Jackson, NM Novielli, and J Twynstra
Noninfective Inflammatory Disorders of the Pericardium 492

B Ravaee and BD Hoit
Non-ST-Elevation Acute Coronary Syndrome Prognosis 502

H Haghbayan, CP Gale, and AT Yan
Non-ST-Elevation Myocardial Infarction: Management 522

M Cimci, B Gencer, and M Roffi
Nutrition—Macronutrients 531
T Nakamura and S Kuranuki
Nutrition: Soy and Fish 538

Y Yamori, M Sagara, H Mori, and M Mori
Obesity and the Obesity Paradox in Heart Failure 546

AA Oktay, CJ Lavie, and HO Ventura
xii Contents of All Volumes
Oral Health and Cardiovascular Disease: Recent Findings and Future View With a Novel Aspect 565
T Ono, M Kida, T Kosaka, and M Kikui
Orthostatic Hypotension and Vasovagal Syncope 573

BH Shaw, Jessica Ng, and SR Raj
VOLUME 4
Palliative Care in Advanced Heart Failure 1
M Ginwalla and BP Dhakal
Pediatric Catheter Ablation 8

AE Radbill, FA Fish, and TP Graham Jr.
Perioperative Management in Heart Failure 37

C Mayeur and A Mebazaa
Peripartum Cardiomyopathy 42
LJ Hassen and S Roble
Peripheral Arterial Disease 49

K Matsushita, A Barleben, and M Allison
Pharmacogenomics of Antiarrhythmic Drug Therapy for Atrial Fibrillation 60

D Darbar
Pharmacology of Medications Used in the Treatment of Atherosclerotic Cardiovascular Disease 68

R Khatib and F Wilson
Physical Examination: Heritable Cardiovascular Syndromes 89

K Puri and JP Zachariah
Physical Examination: Normal Examination in Adult Acquired and Congenital Heart Disease 106
TR Schlingmann and JP Zachariah
Physiological Adaptations of the Heart in Elite Athletes 116

A D’Andrea, J Radmilovich, L Riegler, R Scarafile, B Liccardo, T Formisano, A Carbone, R America, F Martone,
M Scherillo, M Galderisi, and R Calabrò
Practical Guide to Evidence-Based Management of Heart Failure in the Outpatient Setting 125
AM Maw, RL Page II, and RS Boxer
Preclinical Cardiovascular Imaging 143

I Pinz
Preeclampsia and Hypertension in Pregnancy 154

N Jafar, N Hippalgaonkar, and NI Parikh
Pregnancy and Cardiovascular Disease 160

R Neki
Proteomics 166
G Suna and M Mayr
Pulmonary Arterial Hypertension 181

R El Yafawi, ME Knauft, K Stokem, JM Palminteri, and JA Wirth
Pulmonary Embolism 195

SC Berngard and J Mandel
Pulmonary Hypertension 204

DR Fraidenburg and JX-J Yuan
Pulmonary Hypertension Associated With Left-Sided Heart Disease 223

DN Tukaye and V Franco
Quality Indicators for the Management of Acute Myocardial Infarction 230

O Bebb, M Hall, and C Gale
Contents of All Volumes xiii
Recreational Drugs: Effects on the Heart and Cardiovascular System 240

B Starobin, S Jablonski, AM Andrle, and JB Powers
Relationship Between Vegetables and Fruits (Antioxidant Vitamins, Minerals, and Fiber)
Intake and Risk of Cardiovascular Disease 249
J Ishihara, M Umesawa, C Okada, Y Kokubo, and H Iso
Remission and Recovery in Heart Failure 284

JS Guseh and JE Ho
Remote Monitoring of Cardiovascular Implantable Electronic Devices 292

B Plourde and R Parkash
Right Heart Catheterization 298

BC Lampert
Risk Factors for Cardiovascular Disease 307

EJ Teufel
Risk Prediction 315

H Yatsuya
Role of Coronary Artery Revascularization in Heart Failure 319

B Shukrallah, A Kilic, and T Lescouflair
Role of Digoxin in Heart Failure 323

A Bucca
Role of Echocardiography in Selection, Implantation, and Management of Left Ventricular

Assist Device Therapy 327
M Dandel and R Hetzer
Salt and Blood Pressure 345

Y Yano
Sex and Gender Differences in Cardiovascular Disease 351

L Mathews, P Chandrashekar, M Prasad, VM Miller, K Sharma, T Sedlak, CN Bairey Merz, and P Ouyang
Sex Differences in the Physiology and Pathology of the Aging Heart 368
A Ghimire, AE Kane, and SE Howlett
Signaling in Cardiac Physiology and Disease 377

S Mukherjee, S Srikanthan, and SV Naga Prasad
Sinus Tachycardias: Inappropriate Sinus Tachycardia and Postural Tachycardia Syndrome 388
BH Shaw, J Ng, and SR Raj
Skeletal Muscle in Heart Failure 404

S Scheetz and R Baliga
Sleep and Circadian Cardiovascular Medicine 424

K Kario
Sleep-Disordered Breathing and Heart Failure Interactions and Controversies 438

WJ Healy and R Khayat
Socioeconomic Factors and CVD 442

M Kabayama and K Kamide
Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors 446
KM Alexander and M Nayor
Stage B Heart Failure 456

J Aljabban, R Baliga, and I Aljabban
STEMI: Diagnosis 465

PE Puddu, E Cenko, B Ricci, and R Bugiardini
xiv Contents of All Volumes
STEMI: Management 474

R Beatrice, M Olivia, E Cenko, and R Bugiardini
STEMI: Prognosis 489

E Cenko, B Ricci, and R Bugiardini
Structure and Function of the Adult Vertebrate Cardiovascular System 499

JD Schultz and DM Bader
Sudden Cardiac Death 511

GL Sumner, VP Kuriachan, and LB Mitchell
Surgical Management of Atrial Fibrillation 521

G Shanmugam, D Exner, and R Damiano
Takotsubo Syndrome 533

MH Tranter and AR Lyon
Tobacco and Cardiovascular Diseases 537

H Kanda and T Hisamatsu
Total Artificial Heart 545

T Lee and G Torregrossa
Transcriptomics in Cardiovascular Medicine 558

D Börnigen and T Zeller
Transcriptome and Epigenome Applications for Coronary Heart Disease Research 572
R Joehanes
Transplant Arteriosclerosis 582

JC Choy
Trends in the Incidence and Mortality of Cardiovascular Disease 593

J Hata
Ultrafiltration for the Treatment of Acute Decompensated Heart Failure 600

S Emani
Unstable Angina: Presentation, Diagnosis, and Management 606

P Manning and EH Awtry
Vascular Guidance Cues 616

D Valdembri, G Serini, and N Gioelli
Vascular Repair at the Interface of the Endothelium: The Roles of Protease-Activated

Receptors and Neuregulin-1 627
CL Galindo, O Odiete, and JH Cleator
Vasculogenesis in Development 640

SC Chetty, K Choi, and S Sumanas
Ventricular Arrhythmias and Sudden Cardiac Death in Hypertrophic Cardiomyopathy 654

MA Cain and MS Link
Ventricular Assist Devices and Heart Transplantation 664

A Kinsella, Y Moayedi, V Rao, HJ Ross, and J Butany
Ventricular Fibrillation and Defibrillation 674

H Kawata and U Birgersdotter-Green
Ventricular Remodeling in Heart Failure 683

I Aquila and AM Shah
Ventricular Tachycardia in Ischemic and Dilated Cardiomyopathy: Mechanisms and Diagnosis 690
VP Kuriachan, GL Sumner, AA Wahab, J Sapp, and LB Mitchell
Ventricular Tachycardia in Structurally Normal Hearts 700

AG Bhatt and S Mittal
Contents of All Volumes xv
Wide QRS Complex Tachycardia: What is the Diagnosis? 725

S Wang and FR Quinn
Wolff–Parkinson–White and Preexcitation Syndromes 747

B Brembilla-Perrot
Zebrafish 759
X-XI Zeng and TP Zhong
Zebrafish as a Tool to Study Congenital Heart Diseases 771

AM Shafik and D Cifuentes
Index 779
LIST OF CONTRIBUTORS
A AbdelWahab A Alsamarah
QEII Health Sciences Centre, Halifax, NS, Canada Boston University School of Medicine, Boston, MA, United
States
A Adler
University of Toronto, Toronto, ON, Canada NL Altman
University of Colorado, Denver, United States
M Afshar
University of Toronto, Toronto, ON, Canada J Alvarez
Peter Munk Cardiac Center, Toronto, ON, Canada
MR Afzal
Ohio State University Medical Center, Columbus, OH, N Amano
United States Konan Women's University, Kobe, Japan
J Ahmed R America
LSU Health Sciences New Orleans, New Orleans, LA, Luigi Vanvitelli University, Naples, Italy
United States
JG Andrade
S Airhart Université de Montréal, Montreal, QC, Canada; The
Cardiovascular Institute, Allegheny Health Network, University of British Columbia, Vancouver, BC, Canada
Pittsburgh, PA, United States
PH Andraweera
MH Albrecht The University of Adelaide, Adelaide, SA, Australia
Medical University of South Carolina, Charleston, SC,
AM Andrle
United States; University Hospital Frankfurt, Frankfurt,
Maine Medical Center, Portland, ME, United States
Germany
C Antzelevitch
KM Alexander
Lankenau Heart Institute, Wynnewood, PA, United States
Brigham and Women's Hospital, Boston, MA, United
States I Aquila
Brigham and Women's Hospital, Boston, MA, United
L Alghothani
States; Magna Graecia University, Catanzaro, Italy
The Ohio State University Wexner Medical Center,
Columbus, OH, United States D Arneson
University of California, Los Angeles, CA, United States
M Alharbi
Sydney University, Sydney, NSW, Australia M Arstall
Lyell McEwin Hospital, Elizabeth Vale, SA, Australia; The
I Aljabban
University of Adelaide, Adelaide, Australia
The Pennsylvania State University College of Medicine,
Hershey, PA, United States J Artico
Azienda Sanitaria Universitaria Integrata and University
J Aljabban
of Trieste, Trieste, Italy
The Ohio State University College of Medicine, Columbus,
OH, United States K Asayama
Tohoku University Graduate School of Pharmaceutical
M Allison
Sciences, Sendai, Japan; Teikyo University School of
University of California, San Diego, CA, United
Medicine, Tokyo, Japan
States
xvii
xviii List of Contributors
R Asleh JE Beare
Mayo Clinic, Rochester, MN, United States University of Louisville, Louisville, KY, United
States
F Awan
Ohio State University, Columbus, OH, United States R Beatrice
University of Bologna, Bologna, Italy
EH Awtry
Boston Medical Center, Boston, MA, United States J Beaumont
University of Navarra, Pamplona, Spain; CIMA,
M Bäck
Pamplona, Spain; Navarra Institute for Health
Karolinska Institutet, Stockholm, Sweden
Research, Pamplona, Spain; CIBERCV,
DM Bader Spain
Vanderbilt University School of Medicine, Nashville, TN,
O Bebb
United States
University of Leeds, Leeds, United Kingdom; York
AL Baggish Teaching Hospital NHS Foundation Trust, York, United
Massachusetts General Hospital, Boston, MA, United Kingdom
States
Y Bejot
CN Bairey Merz University Hospital François Mitterrand, Dijon, France;
Cedars Sinai Medicine Center, Los Angeles, CA, United University of Burgundy, Dijon, France
States
F Bendtsen
S Baldwin University of Copenhagen, Copenhagen, Denmark
Pediatric Heart Institute, Monroe Carell Jr. Children's
SC Berngard
Hospital at Vanderbilt, Vanderbilt University Medical
University of California, San Diego, La Jolla, CA, United
Center, Nashville, TN, USA
States
R Baliga
AG Bhatt
Valley Health System, Paramus, NJ, United States
OH, United States; The Ohio State University Wexner
Medical Center, Columbus, OH, United States; Davis R Bhattacharjee
Heart and Lung Research Institute (HLRI), Columbus, National Institute for Stroke and Applied Neurosciences,
OH, United States Auckland, New Zealand
W Balkan C Bianco
University of Miami Miller School of Medicine, Miami, FL, Case Western Reserve University, Cleveland, OH, United
United States States
B Ballantyne T Bianco-Miotto
Western University, London, ON, Canada The University of Adelaide, Adelaide, SA, Australia
D Bamira U Birgersdotter-Green
Massachusetts General Hospital, Boston, MA, United UCSD Medical Center, Sulpizio Cardiovascular Center,
States La Jolla, CA, United States
M Banerjee C Blanc
University of Miami Miller School of MedicineMiami, FL, University Hospital François Mitterrand, Dijon, France;
United States University of Burgundy, Dijon, France
A Baranchuk D Börnigen
Queen's University, Kingston, ON, Canada Clinic for General and Interventional Cardiology,
University Heart Center Hamburg, Hamburg,
A Barleben
Germany; German Center for Cardiovascular Research
University of California, San Diego, CA, United States
(DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel,
TA Barrett Hamburg, Germany
The Ohio State University, Columbus, OH, United States
E Bossone
A Bauman University Hospital “Scuola Medica Salernitana”, Salerno,
Sydney University, Sydney, NSW, Australia Italy
List of Contributors xix
M Boutjdir ALP Caforio

State University of New York, Brooklyn, NY, United States; University of Padua, Padua, Italy
VA NY Harbor Healthcare System, New York, NY,
MA Cain
United States; NYU School of Medicine, New York, NY,
University of Texas Southwestern, Dallas, TX, United
United States
States
RS Boxer
R Calabrò
University of Colorado, Aurora CO, United States
Second University of Naples, Caserta, Italy
E Bradley
H Calkins
Johns Hopkins University, Baltimore, MD,
Columbus, OH, United States; Nationwide Children's
United States
Hospital, Columbus, OH, United States
A Cannatà
K Breckwoldt
University Medical Center Hamburg-Eppendorf, Hamburg,
Germany; DZHK (German Centre for Cardiovascular
Research), Berlin, Germany A Carbone
Luigi Vanvitelli University, Naples, Italy
B Brembilla-Perrot
Department of Cardiology, Nancy University Hospital, A Cardona
Vandoeuvre-les-Nancy, France Ohio State University Medical Center, Columbus, OH,
United States
A Briasoulis
Mayo Clinic, Rochester, MN, United States AG Carrizo
McMaster University, Hamilton, ON, Canada
D Briston
The Ohio State University Wexner Medical Center, D Caruso
Columbus, OH, United States; Nationwide Children’s Medical University of South Carolina, Charleston, SC,
Hospital, Columbus, OH, United States United States; University of Rome “Sapienza",
Latina, Italy
KM Broughton
San Diego State University Heart Institute and the AL Catapano
Integrated Regenerative Research Institute, San Diego, CA, IRCCS Multimedica, Milan, Italy; University of Milan,
United States Milan, Italy
AJ Brownstein E Cenko
Yale University School of Medicine, New Haven, CT, University of Bologna, Bologna, Italy
United States
F Chalhoub
A Bucca Harvard Medical School, Boston, MA, United
Ohio State University College of Medicine, Columbus, OH, States
USA
P Chandrashekar
R Bugiardini Mayo Clinic, Rochester, MN, United States
Q Chen
R Bussani Virginia Commonwealth University, Richmond, VA,
Azienda Sanitaria Universitaria Integrata and University United States
T Chen
J Butany University of Washington School of Medicine, Seattle, WA,
Peter Munk Cardiac Center, Toronto, ON, Canada; United States
University of Toronto, Toronto, ON, Canada;
SC Chetty
Toronto General Hospital, Toronto, ON,
Cincinnati Children's Hospital Medical Center,
Canada
Cincinnati, OH, United States
AG Cadar
DS Chew
University of Calgary, Calgary, AB, Canada
United States
xx List of Contributors
R Chia L Curtis-Whitchurch
University of Illinois at Chicago, Chicago, IL, United University of Louisville, Louisville, KY, United States
States
R Damiano
K Choi Washington University, Saint Louis, MO, United
Washington University School of Medicine, St. Louis, MO, States
United States
AA Damluji
JC Choy LifeBridge Health Cardiovascular Institute, Baltimore,
Simon Fraser University, Burnaby, BC, Canada MD, United States; Johns Hopkins University, Baltimore,
MD, United States
D Cifuentes
Boston University School of Medicine, Boston, MA, United M Dandel
States German Centre for Heart and Circulatory Research
(DZHK), Berlin, Germany; Deutsches Herzzentrum
M Cimci
Berlin, Berlin, Germany
Geneva University Hospitals, Geneva, Switzerland
EG Daoud
A Cittadini
The Ohio State University, Columbus, OH, United
Federico II University School of Medicine, Naples, Italy
States
JH Cleator
D Darbar
Vanderbilt University Medical Center, Nashville, TN,
University of Illinois at Chicago, Chicago, IL,
United States
United States
ST Coffin
A David
Australian Catholic University, Melbourne, VIC,
E Colin-Ramirez Australia
National Institute of Cardiology ‘Ignacio Chavez’, Mexico
S Day
City, Mexico
P Collier Columbus, OH, United States
Cleveland Clinic Lerner College of Medicine, Case Western
CN De Cecco
Reserve University, Cleveland, OH, United States; Sydell
and Arnold Miller Family Heart and Vascular Institute,
United States
The Cleveland Clinic Foundation, Cleveland, OH, United
States D De Santis
M Colvin
United States; University of Rome “Sapienza", Latina, Italy
University of Michigan, Ann Arbor, MI, United States
E Dees
R Covarrubias
Pediatric Heart Institute, Monroe Carell Jr. Children's
Hospital at Vanderbilt, Vanderbilt University Medical
United States
Center, Nashville, TN, USA
JA Cowgill
GA Dekker
The University of Adelaide, Adelaide, SA, Australia; Lyell
JA Crestanello McEwin Hospital, Elizabeth Vale, SA, Australia
B Delpont
Columbus, OH, United States
University Hospital François Mitterrand, Dijon, France;
ED Crouser University of Burgundy, Dijon, France
A Deswal
Michael E. DeBakey Veterans Affairs Medical Center,
RM Cubbon Houston, TX, United States; Baylor College of Medicine,
The University of Leeds, Leeds, United Kingdom Houston, TX, United States
L Cunningham MW Deyell
Baylor College of Medicine, Houston, TX, United The University of British Columbia, Vancouver, BC,
States Canada
List of Contributors xxi
BP Dhakal ML Esposito
University Hospitals Cleveland Medical Center, Cleveland, Tufts Medical Center, Boston, MA, United States
OH, United States
C Evanson
A Diez Ohio State University Medical Center, Columbus, OH,
United States
D Exner
J Díez University of Calgary, Calgary, AB, Canada; Cumming
University of Navarra, Pamplona, Spain; CIMA, School of Medicine, Calgary, AB, Canada
Pamplona, Spain; Navarra Institute for Health
JA Ezekowitz
Research, Pamplona, Spain; University of
University of Alberta, Edmonton, AB, Canada
Navarra Clinic, Pamplona, Spain; CIBERCV,
Spain E Fabris
P Divanji
University of California San Francisco, San Francisco, CA,
United States D Fan
University of South Carolina School of Medicine,
A D’Andrea
Columbia, SC, United States
KF Faridi
M Edwards
Harvard Medical School, Boston, MA, United States
AJ Favreau-Lessard
M Eid
Maine Medical Center Research Institute, Scarborough,
ME, United States
United States
FA Fish
R El Yafawi
Vanderbilt University, Nashville, TN, United States
V Florea
JA Elefteriades
University of Miami Miller School of MedicineMiami, FL,
Yale University School of Medicine, New Haven, CT,
United States
United States
DE Forman
ME Knauft
University of Pittsburgh, Pittsburgh, PA, United States; VA
Tufts University School of Medicine, Boston, MA, United
Pittsburgh Healthcare System, Pittsburgh, PA, United
States; Maine Medical Center, Portland, ME, United
States
States
T Formisano
CR Ellis
Vanderbilt Heart and Vascular Institute, Nashville, TN,
United States ER Fox
University of Mississippi Medical Center, Jackson, MS,
N El-Sherif
United States; University of Mississippi School of Medicine,
State University of New York, Brooklyn, NY, United States;
Jackson, MS, United States
VA NY Harbor Healthcare System, New York, NY, United
States DR Fraidenburg
University of Illinois at Chicago, Chicago, IL,
S Emani
United States
Columbus, OH, United States S Francis
T Eschenhagen
University Medical Center Hamburg-Eppendorf, Hamburg, V Franco
Germany; DZHK (German Centre for Cardiovascular The Ohio State University, Columbus, OH, United
Research), Berlin, Germany States
ES Eshak SR Fuchs
Osaka University Graduate School of Medicine, Suita-shi, Vanderbilt University Medical Center, Nashville, TN,
Japan; Minia University, Minia, Egypt United States
xxii List of Contributors
G Galanti MH Gollob
University of Florence, Florence, Italy University of Toronto, Toronto, ON, Canada
M Galderisi A González
Federico II University of Naples, Napoli, Italy University of Navarra, Pamplona, Spain; CIMA,
Pamplona, Spain; Navarra Institute for Health Research,
CP Gale
Pamplona, Spain; CIBERCV, Spain
Professor of Cardiovascular Medicine, School of Medicine,
University of Leeds, Leeds, UK DM Gopal
Boston University School of Medicine, Boston, MA, United
CL Galindo
States
United States TP Graham Jr.
R Gallagher
Sydney University, Sydney, NSW, Australia RC Groom
Maine Medical Center, Portland, ME, United
PU Gandhi
States
United States A Guha
X Gao
States
Columbus, OH, United States RJ Gumina
B Gencer
United States; Veterans Administration, Nashville, TN,
United States
P Gentile
JS Guseh
Division of Cardiology, Department of Medicine,
Massachusetts General Hospital, Boston, MA, United
MA Gertz States
Mayo Clinic, Rochester, MN, United States
D Haddad
A Ghimire Ohio State University, Columbus, OH, United
Dalhousie University, Halifax, NS, Canada States
E Giannitsis H Haghbayan
University Hospital of Heidelberg, Heidelberg, Department of Medicine, University of Toronto, Toronto,
Germany Ontario, Canada
M Ginwalla M Hall
Case Western Reserve University, Cleveland, OH, United University of Leeds, Leeds, United Kingdom
States; University Hospitals Cleveland Medical Center,
ME Hall
Cleveland, OH, United States
University of Mississippi School of Medicine, Jackson, MS,
N Gioelli United States
Candiolo Cancer Institute – Fondazione del Piemonte
L Halperin
per l’Oncologia (FPO) Istituto di Ricovero e Cura a
University of British Columbia, Vancouver, BC,
Carattere Scientifico (IRCCS), Candiolo, Torino,
Canada
Italy
TW Hansen
M Giroud
Gentofte and Research Center for Prevention and Health,
University Hospital François Mitterrand, Dijon, France;
Copenhagen, Denmark
University of Burgundy, Dijon, France
GK Hansson
SS Gogia
Karolinska Institutet, Stockholm, Sweden
Cardiology Division, Department of Medicine,
Massachusetts General Hospital, Boston, MA, United A Hara
States Showa Pharmaceutical University, Tokyo, Japan
List of Contributors xxiii
JM Hare CC Hong
University of Miami Miller School of Medicine, Miami, FL, Vanderbilt University School of Medicine, Nashville, TN,
United States United States; Veterans Affairs Tennessee Valley
Healthcare System, Nashville, TN, United States
AR Harper
Royal Brompton and Harefield NHS Foundation Trust, CL Hoppel
London, United Kingdom; University of Oxford, Oxford, Case Western Reserve University School of Medicine,
United Kingdom Cleveland, OH, United States
A Hasan KN Hor
Advanced Heart Failure and Cardiac Transplantation Nationwide Children's Hospital, Columbus, OH, United
Fellowship Program, Columbus, OH, United States; The Ohio State University College of Medicine,
States Columbus, OH, United States
LJ Hassen JD Hove
The Ohio State University & Nationwide Children's University of Copenhagen, Copenhagen, Denmark
SE Howlett
J Hata Dalhousie University, Halifax, NS, Canada
Kyushu University, Fukuoka, Japan
JB Hoying
K Hatzistergos University of Louisville, Louisville, KY, United States
University of Miami Miller School of Medicine, Miami, FL,
CM Hritz
United States
C Healey States
H Huang
WJ Healy University of Illinois at Chicago, Chicago, IL, United States
The Ohio State University Sleep Heart Program, Columbus,
T Hussein
OH, United States
AUT ICT Development, Auckland, New Zealand
R Hetzer
S Iliceto
Deutsches Herzzentrum Berlin, Berlin, Germany; Cardio
University of Padua, Padua, Italy
Centrum Berlin, Berlin, Germany
PI Imoukhuede
N Hippalgaonkar
University of Illinois at Urbana-Champaign, Urbana, IL,
Florida Atlantic University, Boca Raton, FL,
United States
United States
M Inouye
A Hirata
University of Melbourne, Parkville, VIC, Australia; Systems
Keio University School of Medicine, Tokyo, Japan
Genomics Lab, Baker Heart and Diabetes Institute,
T Hirata Melbourne, Victoria, Australia
Keio University School of Medicine, Tokyo, Japan
Junko Ishihara
T Hisamatsu Sagami Women's University, Sagamihara, Japan
Shimane University, Izumo, Japan
H Iso
JE Ho Osaka University Graduate School of Medicine, Suita-shi,
Massachusetts General Hospital, Boston, MA, United Japan
States
S Jablonski
J Hodge Maine Medical Center, Portland, ME, United States
DN Jackson
The University of Western Ontario, London, ON, Canada
BD Hoit
N Jafar
University Hospitals Cleveland Medical Center,
University of California San Francisco, San Francisco, CA,
Cleveland, OH, United States; Case Western Reserve
United States
University, Cleveland, OH, United States
xxiv List of Contributors
NP Jaik K Kario
Pinnacle Health Cardiovascular Institute, Harrisburg, PA, Jichi Medical University School of Medicine, Shimotsuke,
United States Tochigi, Japan
M Jame S Katsanos
University of Michigan, Ann Arbor, MI, United States Attikon University Hospital, Athens, Greece
S Jame H Kawata
University of Michigan, Ann Arbor, MI, United States UC Irvine School of Medicine, Orange, CA, United States
HJ Jansen W Kayani
Dalhousie University, Halifax, NS, Canada Baylor College of Medicine, Houston, TX, United States
R Joehanes AK Keates
Hebrew SeniorLife, Boston, MA, United States; Beth Israel Mary MacKillop Institute for Health Research, Australian
Deaconess Medical Center, Boston, MA, United States; Catholic University, Melbourne, VIC, Australia
S Kenchaiah
RM John University of Arkansas for Medical Sciences, Little Rock,
Harvard Medical School, Boston, MA, United States; AR, United States; Central Arkansas Veterans Healthcare
Vanderbilt University Medical Center, Nashville, TN, System, Little Rock, AR, United States
United States
DFJ Ketelhuth
JA Johns Karolinska Institutet, Stockholm, Sweden
R Khatib
United States
Leeds Teaching Hospitals NHS Trust, Leeds, United
RL Jones Kingdom; University of Leeds, Leeds, United Kingdom;
The Stanford University Medical Center, Stanford, CA, University of Bradford, Bradford, United Kingdom
United States
R Khayat
UJ Schoepf The Ohio State University Sleep Heart Program, Columbus,
Medical University of South Carolina, Charleston, SC, OH, United States
United States
B Kherad
M Kabayama Department of Cardiology, Charité–University Medicine
Osaka University Graduate School of Medicine, Osaka, Berlin - Campus Virchow, Berlin, Germany
Japan
M Kida
SJ Kalbfleisch Osaka University Graduate School of Dentistry, Osaka,
The Ohio State University Wexner Medical Center, Japan
M Kikui
K Kamide Osaka University Graduate School of Dentistry, Osaka,
Osaka University Graduate School of Medicine, Osaka, Japan
Japan
A Kilic
H Kanda The Ohio State University Wexner Medical Center,
Shimane University, Izumo, Japan Columbus, OH, United States
VV Kandasamy A Kinsella
University of Louisville School of Medicine, Louisville, KY, Peter Munk Cardiac Center, Toronto, ON, Canada
United States
JN Kirkpatrick
AE Kane University of Washington School of Medicine, Seattle, WA,
Dalhousie University, Halifax, NS, Canada United States
PJ Kannankeril Y Kokubo
Vanderbilt University Medical Center, Nashville, TN, National Cerebral and Cardiovascular Center,
United States Suita, Japan
NK Kapur B Konda
Tufts Medical Center, Boston, MA, United States The Ohio State University, Columbus, OH, United States
List of Contributors xxv
T Kosaka EJ Lesnefsky
Osaka University Graduate School of Dentistry, Osaka, Virginia Commonwealth University, Richmond, VA,
Japan United States; McGuire Veterans Affairs Medical Center,
Richmond, VA, United States
AD Krahn
University of British Columbia, Vancouver, BC, Canada VW Lesslie
RS Kramer
United States
Y Li
U Kühl
Shanghai Jiao Tong University School of Medicine,
Department of Cardiology, Charité–University Medicine
Shanghai, China
Berlin - Campus Virchow, Berlin, Germany
B Liccardo
S Kuranuki
Kanagawa University of Human Services,
Yokosuka, Japan W Lieb
Christian-Albrechts-University Kiel, Kiel, Germany
VP Kuriachan
Libin Cardiovascular Institute of Alberta, Calgary, AB, MS Link
Canada; Foothills Hospital, Calgary, AB, Canada University of Texas Southwestern, Dallas, TX, United
States
K Kuwabara
Keio University School of Medicine, Tokyo, Japan Q Liu
BC Lampert
Columbus, OH, United States B López
CJ Lavie
John Ochsner Heart and Vascular Institute, Ochsner
Clinical School, The University of Queensland School of
Medicine, New Orleans, LA, United States N Lowres
Sydney University, Sydney, NSW, Australia
E Lavine
Icahn School of Medicine at Mount Sinai, New York, NY, A Luk
United States Peter Munk Cardiac Center, Toronto, ON, Canada
AJ LeBlanc AR Lyon
University of Louisville, Louisville, KY, United States Imperial Centre for Translational and Biomedical
Medicine, Hammersmith Hospital, London, United
P Lee
Kingdom; NIHR Cardiovascular Biomedical Research
Unit, Royal Brompton Hospital, London,
T Lee United Kingdom
Mount Sinai St. Luke's Hospital, Amsterdam, NY, United
L Macle
States
Université de Montréal, Montreal, QC, Canada
E Legome
N Maffulli
Icahn School of Medicine at Mount Sinai, New York, NY,
University of Salerno, Salerno, Italy; Queen Mary
United States
University of London, London, United Kingdom
P LeLorier
C Mainland
LSU Health Sciences New Orleans, New Orleans, LA,
Australian Catholic University, Melbourne, VIC, Australia
United States
AS Major
B LeNoir
Veterans Administration, Nashville, TN, United States;
United States
United States
T Lescouflair
M Malik
University of Washington, Seattle, WA, United States
xxvi List of Contributors
S Malin T Mela
Karolinska Institutet, Stockholm, Sweden Harvard Medical School, Boston, MA, United States
G Malipiero M Merlo
University of Padua, Padua, Italy Azienda Sanitaria Universitaria Integrata and University
J Mandel
UC San Diego School of Medicine, La Jolla, CA, United VM Miller
States Mayo Clinic, Rochester, MN, United States
P Manning LB Mitchell
Boston Medical Center, Boston, MA, United States Libin Cardiovascular Institute of Alberta, Calgary, AB,
Canada; Foothills Hospital, Calgary, AB,
R Marcolongo
Canada
University of Padua, Padua, Italy
S Mittal
AS Mariet
Valley Health System, Paramus, NJ, United States
University Hospital François Mitterrand, Dijon, France
Y Moayedi
J Martinez
Peter Munk Cardiac Center, Toronto, ON, Canada
Columbia, SC, United States S Møller
University of Copenhagen, Copenhagen, Denmark
F Martone
Luigi Vanvitelli University, Naples, Italy B Mondesert
Montreal Heart Institute, Montreal, QC, Canada
L Mathews
Johns Hopkins Medicine, Baltimore, MD, United States J Monti
Maine Medical Center, Portland Maine, ME, United
C Matsumoto
States; Tufts University School of Medicine, Boston, MA,
Hyogo College of Medicine, Nishinomiya, Japan
United States
K Matsushita
AM Moran
John Hopkins University, Baltimore, MD, United
Congenital Heart, Scarborough, ME, United States
States
MU Moreno
Y Matsushita
National Center for Global Health and Medicine, Toyama,
Japan
AM Maw
RB Morgan
MMP MaineHealth Augusta Cardiology, Augusta, ME,
C Mayeur United States
Lariboisière University Hospital, Paris, France
H Mori
M Mayr Mukogawa Women's University, Nishinomiya, Hyogo,
King's British Heart Foundation Centre, King's College Japan
London, London, United Kingdom
M Mori
L Mc Carthy Mukogawa Women's University, Nishinomiya, Hyogo,
University College Cork, Cork, Ireland Japan
A Mebazaa JR Morton
Lariboisière University Hospital, Paris, France Maine Medical Center, Portland, ME, United
States
A Mehta
University of Illinois at Chicago, Chicago, IL, United S Mukherjee
States Cleveland Clinic, Cleveland, OH, United States
JL Mehta S Murali
University of Arkansas for Medical Sciences, Little Rock, Cardiovascular Institute, Allegheny Health Network,
AR, United States Pittsburgh, PA, United States
List of Contributors xxvii
SK Musani T Okabe
University of Mississippi School of Medicine, Jackson, MS, The Ohio State University Wexner Medical Center,
United States Columbus, OH, United States
SV Naga Prasad C Okada
Cleveland Clinic, Cleveland, OH, United States Osaka University Graduate School of Medicine, Osaka,
Japan
T Nakamura
Kanagawa University of Human Services, T Okamura
Yokosuka, Japan; Ryukoku University, Otsu, Japan Keio University School of Medicine, Tokyo, Japan
R Napoli AA Oktay
Federico II University School of Medicine, Naples, Italy John Ochsner Heart and Vascular Institute, Ochsner
Clinical School, The University of Queensland School of
VJ Nardy
Medicine, New Orleans, LA, United States
Columbus, OH, United States M Olivia
M Natsumeda
University of Miami Miller School of MedicineMiami, FL, PS Olofsson
United States Karolinska Institutet, Stockholm, Sweden
M Nayor B Olshansky
Brigham and Women's Hospital, Boston, MA, United University of Iowa, Iowa City, IA, United States;
States Mercy Hospital – North Iowa, Mason City, IA, United
States
H Nazzari
University of British Columbia, Vancouver, BC, Canada T Ono
Niigata University Graduate School of Medical and Dental
U Neisius
Sciences, Niigata, Japan; Osaka University Graduate
School of Dentistry, Osaka, Japan
R Neki
GM Orgeron
National Cerebral and Cardiovascular Center, Suita,
Johns Hopkins University, Baltimore, MD, United
Osaka, Japan
States
JT Neumann
GY Oudit
University Heart Center, Hamburg, Germany
J Ng
P Ouyang
Johns Hopkins University School of Medicine, Baltimore,
GT Nicholson MD, United States
RL Page II
United States
T Ninomiya
JM Palminteri
Kyushu University, Fukuoka, Japan
Tufts University School of Medicine, Boston, MA, United
B Nolan States; Maine Medical Center, Portland, ME, United
Maine Medical Center, Portland, ME, United States States
V Noori S Pant
Maine Medical Center, Portland, ME, United States University of Louisville School of Medicine, Louisville, KY,
United States
NM Novielli
The University of Western Ontario, London, ON, NI Parikh
Canada University of California San Francisco, San Francisco, CA,
United States
O Odiete
Vanderbilt University Medical Center, Nashville, TN, J Parissis
United States Attikon University Hospital, Athens, Greece
xxviii List of Contributors
J Park CJ Prendergast
University of Hawaii, Honolulu, HI, United States Vanderbilt University School of Medicine, Nashville, TN,
United States
R Parkash
QEII Health Sciences Centre, Halifax, NS, Canada PE Puddu
Sapienza University of Rome, Rome, Italy
A Patel
St. Vincent Hospital, Indianapolis, IN, United K Puri
States Baylor College of Medicine, Houston, TX, United
States
G Paulsson-Berne
Karolinska Institutet, Stockholm, Sweden R Querejeta
University of the Basque Country, San Sebastian, Spain;
S Pedraza
Biodonostia Research Institute, San Sebastian, Spain;
Donostia University Hospital, San Sebastian,
States
Spain
N Pereira
FR Quinn
Libin Cardiovascular Institute of Alberta, Calgary, AB,
MV Perez Canada
The Stanford University Medical Center, Stanford, CA,
TA Quinn
United States
Dalhousie University, Halifax, NS, Canada
SM Peterson
AE Radbill
ME, USA
J Radmilovich
MH Picard
States SR Raj
University of Calgary, Calgary, AB, Canada; Vanderbilt
D Pinkhas
University, Nashville, TN, United States
Columbus, OH, United States A Ramireddy
University of Miami Miller School of Medicine, Miami, FL,
I Pinz
United States
ME, United States; Tufts University, Sackler School of V Ramirez
Graduate Biomedical Sciences, Boston, MA, United Maine Medical Center, Portland Maine, ME, United
States States; Tufts University School of Medicine, Boston, MA,
United States
A Pirillo
Center for the Study of Atherosclerosis, Bassini Hospital, V Rao
Cinisello Balsamo, Italy; IRCCS Multimedica, Milan, Peter Munk Cardiac Center, Toronto, ON, Canada;
Italy University of Toronto, Toronto, ON, Canada
B Plourde I Ratjen
IUCPQ affiliated to University Laval, Quebec, Canada Christian-Albrechts-University Kiel, Kiel, Germany
JD Pollard B Ravaee
University of Mississippi School of Medicine, Jackson, MS, University Hospitals Cleveland Medical Center, Cleveland,
United States OH, United States; Case Western Reserve University,
Cleveland, OH, United States
JB Powers
Maine Medical Center, Portland, ME, United States S Ravassa
M Prasad
DN Pratt
J Reis
University Hospital of Strasbourg, Strasbourg, France
States
List of Contributors xxix
MS Renno K Rusk
Vanderbilt University Medical Center, Nashville, TN, Ohio State University Medical Center, Columbus, OH,
United States United States
A Reynolds S Ryzhov
The Ohio State University, Columbus, OH, United Maine Medical Center Research Institute, Scarborough,
States ME, USA
B Ricci LM Safi
University of Bologna, Bologna, Italy Harvard Medical School, Boston, MA, United States
TD Richardson M Sagara
Vanderbilt Heart and Vascular Institute, Nashville, TN, Disease Model Cooperative Research Association, Kyoto,
United States Japan
AC Rieger A Salerno
University of Miami Miller School of MedicineMiami, FL, University of Miami Miller School of Medicine, Miami, FL,
United States United States
L Riegler V Salomaa
Luigi Vanvitelli University, Naples, Italy National Institute for Health and Welfare, Helsinki,
Finland
DL Robaczewski
Maine Medical Center, Portland, ME, United States A Salzano
Federico II University School of Medicine, Naples,
CT Roberts
Italy
The University of Adelaide, Adelaide, SA, Australia
G San José
DJ Roberts
S Roble Pamplona, Spain; CIBERCV, Spain
The Ohio State University & Nationwide Children's
J Sapp
QEII Health Sciences Centre, Halifax, NS, Canada
CJ Rodriguez
DB Sawyer
Wake Forest University School of Medicine,
Winston-Salem, NC, United States
ME, United States
M Roffi
R Scarafile
I Roifman
S Scheetz
University of Toronto, Toronto, ON, Canada
RA Rose OH, United States
Dalhousie University, Halifax, NS, Canada; University of
M Scherillo
Calgary, Calgary, AB, Canada
Rummo Hospital, Benevento, Italy
JA Rosenblatt
TR Schlingmann
Maine Medical Center, Portland, ME,
Baylor College of Medicine – Texas Children's Hospital,
United States
Houston, TX, United States
HJ Ross
RB Schnabel
Peter Munk Cardiac Center, Toronto, ON, Canada;
University Heart Center, Hamburg, Germany
University of Toronto, Toronto, ON, Canada
SR Schubert
M Rozmahel
FL Ruberg
JD Schultz
States
United States
xxx List of Contributors
T Sedlak G Sinagra
University of British Columbia, Vancouver, BC, United Azienda Sanitaria Universitaria Integrata and University
States of Trieste, Trieste, Italy
G Serini M Singh
University of Torino School of Medicine, Candiolo, Torino, Yale University School of Medicine, New Haven, CT,
Italy; Candiolo Cancer Institute – Fondazione del Piemonte United States
A Siraj
Carattere Scientifico (IRCCS), Candiolo, Torino,
University of Arkansas for Medical Sciences, Little Rock,
Italy
AR, United States; Central Arkansas Veterans Healthcare
AM Shafik System, Little Rock, AR, United States
M Sivananthan
States
Leeds Teaching Hospitals NHS Trust, Leeds, United
AB Shah Kingdom
H Sone
States
Niigata University, Niigata, Japan
AM Shah
D Sorajja
Brigham and Women's Hospital, Boston, MA,
Mayo Clinic Arizona, Phoenix, AZ, United States
United States; Magna Graecia University, Catanzaro,
Italy JH Soslow
J Shah
United States
Maine Medical Center, Portland, ME, United
States S Srikanthan
Cleveland Clinic, Cleveland, OH, United States
G Shanmugam
Libin Cardiovascular Institute, Calgary, AB, Canada; JA Staessen
Foothills Medical Centre, Calgary, AB, Canada University of Leuven, Leuven, Belgium; Maastricht
University, Maastricht, The Netherlands
ES Shao
Maine Medical Center, Scarborough, ME, E Stamatakis
United States; Maine Medical Center, Portland, ME, Sydney University, Sydney, NSW, Australia
United States
B Starobin
K Sharma Maine Medical Center, Portland, ME, United States; Tufts
Johns Hopkins Medicine, Baltimore, MD, United University School of Medicine, Boston, MA, United
States States
BH Shaw L Stefani
University of Calgary, Calgary, AB, Canada University of Florence, Florence, Italy
W-K Shen WG Stevenson
Mayo Clinic Arizona, Phoenix, AZ, United Harvard Medical School, Boston, MA, United
States States
T Sher S Stewart
Mayo Clinic, Jacksonville, FL, United States Australian Catholic University, Melbourne, VIC,
Australia
L Shu
University of California, Los Angeles, CA, United K Stokem
States Maine Medical Center, Portland, ME, United
States
B Shukrallah
The Ohio State University Wexner Medical Center, JB Strom
Columbus, OH, United States Harvard Medical School, Boston, MA, United
States
OK Siddiqi
Boston University School of Medicine, Boston, MA, United D Sugiyama
States Keio University School of Medicine, Tokyo, Japan
List of Contributors xxxi
S Sumanas AJ Trask
Cincinnati Children's Hospital Medical Center, Nationwide Children's Hospital, Columbus, OH, United
Cincinnati, OH, United States States; The Ohio State University College of Medicine,
GL Sumner
Libin Cardiovascular Institute of Alberta, Calgary, AB, C Tsao
Canada; Foothills Hospital, Calgary, AB, Canada Harvard Medical School, Boston, MA, United States
G Suna CW Tsao
King's British Heart Foundation Centre, King's College Harvard Medical School, Boston, MA, United States
London, London, United Kingdom
C Tschöpe
V Sundaram Department of Cardiology, Charité–University Medicine
Imperial College London, London, United Kingdom; Case Berlin - Campus Virchow, Berlin, Germany; Berlin-
Western Reserve University, Cleveland, OH, United States Brandenburg Center for Regenerative Therapies (BCRT),
Berlin, Germany; German Centre for Cardiovascular
MD Tallquist
Research (DZHK), Berlin, Germany
University of Hawaii, Honolulu, HI, United States
DN Tukaye
B Tandler
Emory University, Atlanta, GA, United States
CWRU School of Dental Medicine, Cleveland, OH, United
States G Turitto
New York Presbyterian-Brooklyn Methodist Hospital,
F Taylor
Brooklyn, NY, United States
Mary MacKillop Institute for Health Research, Australian
Catholic University, Melbourne, VIC, Australia TA Turunen
A.I. Virtanen Institute, University of Eastern Finland,
EJ Teufel
Kuopio, Finland
MaineHealth Cardiology, Scarborough, ME,
United States J Twynstra
The University of Western Ontario, London,
K Thakarar
ON, Canada
M Umesawa
G Thanassoulis
Dokkyo Medical University, Mibu, Japan
McGill University, Montreal, QC, Canada
M-A Väänänen
Y Tian
A.I. Virtanen Institute, University of Eastern Finland,
Temple University School of Medicine, Philadelphia, PA,
Kuopio, Finland
United States
M Vafaie
D Tirziu
University Hospital of Heidelberg, Heidelberg, Germany
United States D Valdembri
University of Torino School of Medicine, Candiolo, Torino,
H Tomiyama
Italy; Candiolo Cancer Institute – Fondazione del Piemonte
Tokyo Medical University, Tokyo, Japan
BA Tompkins Carattere Scientifico (IRCCS), Candiolo, Torino,
University of Miami Miller School of MedicineMiami, FL, Italy
United States
A Vallakati
G Torregrossa The Ohio State University, Columbus, OH,
Mount Sinai St. Luke's Hospital, Amsterdam, NY, United United States
States
S Vallurupalli
N Townsend University of Arkansas for Medical Sciences, Little Rock,
University of Oxford, Oxford, United Kingdom AR, United States; Central Arkansas Veterans Healthcare
System, Little Rock, AR, United States
MH Tranter
Imperial Centre for Translational and Biomedical A Varga-Szemes
Medicine, Hammersmith Hospital, London, United Medical University of South Carolina, Charleston, SC,
Kingdom United States
xxxii List of Contributors
RS Vasan JN Wight Jr.

The Framingham Heart Study, Framingham, MA, United Tufts University School of Medicine, Maine Medical
States; Boston University School of Medicine, Boston, MA, Center, Portland, ME, United States
United States; Boston University School of Public Health,
R Willems
Boston, MA, United States
University Leuven, Leuven, Belgium
A Vazir
LK Williams
Royal Brompton and Harefield NHS Foundation Trust,
Papworth Hospital NHS Foundation Trust, Cambridge,
Imperial College London, London, United
United Kingdom
Kingdom
F Wilson
HO Ventura
Leeds General Infirmary, Leeds, United Kingdom
John Ochsner Heart and Vascular Institute, Ochsner
Clinical School, The University of Queensland SB Wilton
School of Medicine, New Orleans, LA, United University of Calgary, Calgary, AB, Canada
States
JA Wirth
A Voiosu Tufts University School of Medicine, Boston, MA, United
University of Copenhagen, Copenhagen, Denmark; “Carol States; Maine Medical Center, Portland, ME, United
Davila” University of Medicine and Pharmacy, Bucureşti, States
Romania
C Withers
T Voiosu Maine Medical Center, Portland, ME, United States
“Carol Davila” University of Medicine and Pharmacy,
MJ Wood
Bucureşti, Romania
Harvard Medical School, Boston, MA, United
G Voros States
University Hospitals Leuven, Leuven, Belgium
K Yamagishi
AMN Walker University of Tsukuba, Tsukuba, Japan
The University of Leeds, Leeds, United
A Yamashina
Kingdom
Tokyo Medical University, Tokyo, Japan
S Wang
Y Yamori
Libin Cardiovascular Institute of Alberta, Calgary, AB,
Mukogawa Women's University, Nishinomiya, Hyogo,
Canada
Japan; Disease Model Cooperative Research Association,
N Warmke Kyoto, Japan; Hyogo Prefecture Health Promotion
The University of Leeds, Leeds, United Association, Hyogo, Japan
Kingdom
AT Yan
JC Weddell Division of Cardiology, St. Michael's Hospital, University of
University of Illinois at Urbana-Champaign, Urbana, IL, Toronto, Toronto, Ontario, Canada
United States
Z-Q Yan
F-F Wei Karolinska Institutet, Stockholm, Sweden
University of Leuven, Leuven, Belgium
M Yanagi
R Weiss Tezukayama University, Nara, Japan
Ohio State University Medical Center, Columbus, OH,
X Yang
United States
University of California, Los Angeles, CA, United
JA White States
Y Yano
BA Whitson Northwestern University Feinberg School of Medicine,
The Ohio State University Wexner Medical Center, Chicago, IL, United States
H Yatsuya
S Wiese Fujita Health University School of Medicine, Aichi,
University of Copenhagen, Copenhagen, Denmark Japan
List of Contributors xxxiii
S Ylä-Herttuala X-XI Zeng

A.I. Virtanen Institute, University of Eastern Finland, East China Normal University, School of Life Sciences,
Kuopio, Finland; Heart Center, Kuopio University Shanghai, China; Sanford Burnham Prebys Medical
Hospital, Kuopio, Finland Discovery Institute, La Jolla, CA, United States
JX-J Yuan Pavel Zhabyeyev
University of Arizona, Tucson, AZ, United States University of Alberta, Edmonton, AB, Canada
JP Zachariah C Zhang
Baylor College of Medicine, Houston, TX, United States; Vanderbilt University School of Medicine, Nashville, TN,
Texas Children's Hospital, Houston, TX, United States United States
KM Zareba TP Zhong
The Ohio State University, Columbus, OH, United States East China Normal University, School of Life Sciences,
Shanghai, China; Fudan University School of Life Sciences,
T Zeller
Shanghai, China
Clinic for General and Interventional Cardiology,
University Heart Center Hamburg, Hamburg, Germany; BA Ziganshin
German Center for Cardiovascular Research (DZHK e.V.), Yale University School of Medicine, New Haven, CT,
Partner Site Hamburg/Lübeck/Kiel, Hamburg, United States
Germany
PREFACE
The burden of cardiovascular disease is growing across the globe as the leading noncommunicable cause of
morbidity and mortality. This is despite outstanding research that has improved our understanding of cardio-
vascular biology, the determinants of disease, and development of new therapies. We are optimistic that the
next generation of scientists and clinicians will further these efforts and ultimately bring about changes that will
reduce risk and improve outcomes for patients worldwide. We have assembled this encyclopedia with the
explicit intent to provide this generation with easy access to past and current wisdom, with the hope that this
helps to accelerate innovation in cardiovascular medicine.
This encyclopedia represents both a dream and a labor of love. The dream is to create a scientific compen-
dium that recognizes that the methods and tools used to access and study the scientific literature have changed,
with a burgeoning impact of digital technology—the so-called pocket book encyclopedia that is accessible on a
smart phone fitting into medical overalls, and that can also be read as a textbook at a desk! These changes in the
access of publications have been accompanied by the evolving need for studying different aspects of biology and
disease as stand-alone chapters not necessarily read sequentially. Furthermore, as editors we recognize the
fundamental importance of conveying knowledge through brilliantly illustrated texts that are profusely embed-
ded with links to key references. The critical importance to use multimedia tools and to provide downloadable
slides for educational purposes is reflected in this encyclopedia. Additionally, we want to ensure the feasibility
of updating text, figures, and other reading material iteratively even after a publication date, recognizing the
rapid advent of information and huge strides made in cardiovascular medicine every day. Thus, this work
represents the end of the beginning of a live text that will metamorphose over time, being guided by the rapid
strides and advances in both cardiovascular medicine and publication science.
Overall, we conceptualized this work as providing broad coverage of science and also serving the expansive
needs of a readership that is quite diverse, that is, encompassing medical students, residents, fellows, and
postdoctoral scientists interested in cardiovascular medicine. We hope the labor of love of an outstanding team
of editors and a stellar group of authors is readily evident to the broad readership we have targeted.
Assembling this compendium had many challenges. Early on we made the choice to cover the broad range of
cardiovascular biology, pathophysiology, epidemiology, and treatment of disease. We sought to assure equal
coverage to foundational cardiovascular cellular and molecular biology as well as state-of-the-art treatments.
Covering the breadth inevitably led to some overlap between some chapters, and yet we certainly have some
residual gaps. We hope to have the opportunity to fill these gaps in future editions. There is also inevitable
variation in the style and scope of articles in this multiauthor publication. We and the section editors felt it was
more important to allow our expert authors freedom in how they chose to present their topic.
We invite feedback on how this encyclopedia can be improved as a resource for trainees worldwide.
Undoubtedly, as noted above, there are gaps in content areas that need to be bridged in future iterations of
this encyclopedia. We look forward to hearing from and listening to our readership about how the text can be
better organized or better compiled to serve their scholarship better in future years.
This project was made possible through the hard work of many people from across the globe. We were
pleased to have section editors and authors from around the world. Drs. Kessler and Schunkert, renowned
cardiologists with an outstanding record of accomplishment in genetic research, have compiled a series of
chapters on genetics and genomics. Dr. Baliga, a distinguished cardiologist and educator, has conceptualized a
tour de force of chapters that capture all aspects of the heart failure syndrome, whereas Dr. DiSalvo, a master
clinician and educator, has synthesized a fine tapestry of chapters focusing on diagnostic testing with key
sections on cardiac imaging, interventions, and device therapy. Dr. Raj, an outstanding clinical investigator and
xxxv
xxxvi Preface
electrophysiologist, brought together an exemplary collection of chapters that offer coverage of a broad
spectrum of topics in cardiac electrophysiology. Drs. Major and Liaw, both highly accomplished basic scientists
and educators, were instrumental in identifying topics of fundamental importance to the field of cardiovascular
biology and medicine. Dr. Lenihan, a pioneering clinical scientist and outstanding cardiologist, brought
together a special set of articles that represent interactions between cardiovascular and other fields of medicine.
Dr. Gale, a celebrated cardiologist with expertise in comparative effectiveness research and clinical cardiology,
offers a series of stellar chapters underscoring various aspects of the pathogenesis and management of athero-
sclerotic cardiovascular disease. Dr. Kokubo, a leading preventive cardiologist with specialization in cardiovas-
cular epidemiology, has orchestrated state-of-the-art chapters on cardiovascular epidemiology.
We would like to thank our colleagues at Elsevier who provided steadfast support of an exemplary nature
throughout this long journey. Last but not the least, the editors would like to thank their families, their mentors,
and their respective institutions for the constant encouragement, advice, and support over the years.
Ramachandran S. Vasan, MBBS, MD, DM
Douglas B. Sawyer, MD PhD
A
Adult Congenital Heart Disease
D Briston and E Bradley, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Nationwide Children's Hospital,
© 2018 Elsevier Inc. All rights reserved.
Introduction 1
Etiology 2
Embryology 2
Nomenclature 3
Acyanotic Lesions 3
Obstructive lesions 3
Left-to-right shunts 4
Cyanotic Lesions 6
Treatment 8
Cardiac Manifestations in ACHD 8
Extracardiac Manifestations of ACHD 8
Conclusions 9
References 9
Glossary
ACHD Adult congenital heart disease: Field of medicine dealing with adult survivors of cardiovascular birth defects relating to
their prior pathology as well as consequences of prior interventions.
ASD Atrial septal defect: A communication between the atria resulting from incomplete formation of the interatrial septum.
CHD Congenital heart disease: Field of medicine dealing with cardiology resulting from embryologic errors and structural
problems present since birth.
CoA Coarctation of the aorta: A narrowing of the aorta, which may be defined or focal, commonly near to the juxtaductal region.
ES Eisenmenger syndrome: Disease state in which a previously left-to-right shunting lesions reverses and becomes right-to-left.
FALD Fontan-associated liver disease: Unique state of liver dysfunction found in the majority of patients who undergo single-
ventricle palliation.
PAH Pulmonary arterial hypertension: Elevated blood pressure in the pulmonary vasculature.
PDA Patent ductus arteriosus: A fetal blood vessel connecting the pulmonary artery to the descending aorta.
VSD Ventricular septal defect: A communication between the atria resulting from incomplete formation of the interventricular
septum.
Introduction
Congenital heart disease (CHD) is a term used to describe structural malformations of the heart and/or great vessels present since
birth. CHD is the most common major birth defect present in approximately 8/1000 live births (Bernier et al., 2010; Marelli et al.,
2014; Shuler et al., 2013). The term CHD has been used for decades and is generally accepted in reference to children, as prior to the
past few decades, few palliative/surgical options were available that permitted survival into adulthood. In the past 50 years
significant advances in medical, surgical, and interventional treatments have changed the face of CHD. There are now more adults
living with CHD than children, making the field of adult congenital heart disease (ACHD) a relatively new subspecialty that focuses
on the unique care needs of the adult patient who has survived with CHD. Adults with CHD vary in their presentation to the
healthcare system, with many asymptomatic to those with significant cardiovascular disease including late sequelae from the
original CHD anatomy and/or repair. Commonly, these patients may experience heart failure, arrhythmia including malignant
variants, and extracardiac involvement. Each ACHD patient has unique needs reflective of underlying anatomy, prior surgical
Encyclopedia of Cardiovascular Research and Medicine https://doi.org/10.1016/B978-0-12-809657-4.99641-8 1

2 Adult Congenital Heart Disease
procedures, catheter interventions, and other comorbid disease. Heterogeneity in any of these factors contributes to the complex
care that this special population requires.
Etiology
There is no readily identifiable precise cause of CHD. However, there are some important associations with CHD. For instance,
maternal infections such as rubella are associated with increased risk of CHD in the fetus. Pregnant women with diabetes mellitus,
whether gestational or pregestational, are known to have fetuses with higher rates of CHD (Simeone et al., 2015). Some medications
are associated with increased risk of CHD: isotretinoin, lithium, anticonvulsant medications, folic acid antagonists, and thalido-
mide among others (Ruedy, 1984). Genetics, and more specifically cardiogenetics, is an evolving field. While there are no universal
known genetic associations with CHD, research has shown that CHD can result from: single-nucleotide polymorphisms, micro-
deletions, duplications, single-gene mutations, and aneuploidy (Fahed et al., 2015; Emer et al., 2015; Su et al., 2016). Trisomy
syndromes are relatively common; for instance, Trisomy 21 (Down's syndrome) is associated with midline defects involving the
endocardial cushions such as partial and complete atrioventricular septal defects. Meanwhile, specific genetic mutations in TBX5,
NKX2-5, TLL1, and others have been associated with other CHD lesions. Regardless of the cause, once the alteration in normal
embryologic development is sustained, CHD can result.
Embryology
To understand CHD, one must have a brief understanding of the embryologic basis of cardiac development. Errors at any of the
steps in normal cardiovascular development may lead to CHD or even fetal demise. Cardiogenesis is dependent on multiple
transcription factors and proteins interacting at specific times and locations throughout gestation and still is not completely
understood. Cells destined to become cardiac structures are identified as early as 15 days and form a cardiac tube at approximately
21 days gestation. It develops into a sinus venosus structure, which ultimately forms atria, which receive venous structures as well as
multiple primitive structures (Fig. 1). Over the following week, the bulboventricular region separates from the primitive atrium and
ventricle, and the endocardial cushion forms and fuses dividing the atrioventricular canal into two segments. Around the same time,
a septum forms in the primitive atrium both from the endocardial cushions and also from the ventral wall of the ostium primum.
Also, the primitive ventricle undergoes septation via a distinct series of events, which lead to left and right ventricles forming side-by-
side. The interventricular septum has contributions from neural crest cells of the endocardial cushion, the bulboventricular flange,
and the inferior edge of the spiral septum of the conotruncus, which is the outflow chamber for the primitive ventricles. The
conotruncus undergoes spiral septation allowing the aortic valve to move posteriorly to the left ventricle and the pulmonary valve to
align with the anterior right ventricle. This series of developmental folds and morphologic relationships form the structurally
recognizable normal anatomic heart and great vessels.
Fig. 1 Schematic of cardiac morphogenesis. Illustrations depict cardiac development with color coding of morphologically related regions, seen from a ventral
view. Cardiogenic precursors form a crescent (left-most panel) that is specified to form specific segments of the linear heart tube, which is patterned along the
anterior–posterior axis to form the various regions and chambers of the looped and mature heart. Each cardiac chamber balloons out from the outer curvature of the
looped heart tube in a segmental fashion. Neural crest cells populate the bilaterally symmetrical aortic arch arteries (III, IV, and VI) and aortic sac (AS) that together
contribute to specific segments of the mature aortic arch, also color coded. Mesenchymal cells form the cardiac valves from the conotruncal (CT) and atrioventricular
valve (AW) segments. Corresponding days of human embryonic development are indicated. A, atrium; Ao, aorta; DA, ductus arteriosus; LA, left atrium; LCC, left
common carotid; LSCA, left subclavian artery; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RCC, right common carotid; RSCA, right subclavian artery; RV,
right ventricle; V, ventricle.
Nomenclature
There are multiple systems of nomenclature to describe CHD, and none of them is universally accepted. Herein we will use the
presence of cyanosis at birth (saturation 85%) as the initial delineation (cyanotic vs acyanotic lesions). An acyanotic lesion is
typically the result of an obstructive lesion or a left-to-right shunt. Among cyanotic lesions, a right-to-left shunt must be present. For
the interested reader, complex nomenclature practices can be reviewed (Anderson et al., 1984; Van Praagh, 1972).
Acyanotic Lesions
Obstructive lesions
Obstructive lesions include those affecting the right ventricular outflow tract such as pulmonary stenosis, and those affecting the left
ventricular outflow tract, such as aortic stenosis (subvalvular, valvular, and supravalvular) and coarctation of the aorta (CoA).
By definition, obstructive lesions restrict forward flow of blood. Symptoms are largely dependent on the location and severity of
obstruction. Pulmonary stenosis is among one of the most common types of CHD, and it is variable in its pathology, occurring
below, at, or above the valve level. Pathology varies and can include valvular dysplasia and/or doming of the pulmonary valve
leaflet due to abnormal coaptation and valve function. Depending on the extent of obstruction, atrial level shunting may occur if an
interatrial communication persists. If this is the case, oxygen saturation may be affected until the obstruction is palliated.
Commonly, even after palliation, poststenotic dilation of the main pulmonary artery is seen.
In left ventricular outflow tract obstruction pathology is similar and can occur below, at, or above the valve level. Valvular
pathology can include unicupsid, bicuspid, tricuspid, and quadricuspid aortic cusp variants with or without valvar dysplasia. Like
pulmonary stenosis, poststenotic dilation commonly is seen (here of the aorta). Discrete and long-segment CoA subtypes may
influence the type of intervention timing as well as age of presentation (including whether or not there is a well-developed spinal
arterial system and dependent upon the presence of collateral blood vessels) (Fig. 2). Blood flow inferior to the diaphragm is
Fig. 2 Coarctation of the aorta is demonstrated here and represents an obstructive lesion of the aorta, which affects distal blood flow.
compromised by this lesion when the patent ductus arteriosus (PDA) closes, and collateralization occurs to supply blood distal to
the level of obstruction. The proximal segment is sometimes dilated and is exposed to increased blood pressure while the distal
segment is often diminutive because of decreased flow and with subsystemic pressure. It is not uncommon for adults to present with
CoA undiagnosed. They typically have few if any symptoms, and the only finding may be hypertension.
Left-to-right shunts
Atrial septal defects (ASDs) constitute the most common ACHD lesion and occur when there is a defect in the septum between the
atria. There are four major types, and all of them lead to varying degrees of the same shunting physiology (Fig. 3). ASDs typically
lead to volume overload of the right atrium and ventricle. Over decades this volume-loading lesion may lead to elevated right-sided
pressure and resistance, and in a minority of patients pulmonary arterial hypertension (PAH) may occur.
Ventricular septal defects (VSDs) are another common type of intracardiac shunt. Given the embryologic origin of the ventricular
septum, a VSD can form in several locations. Commonly VSDs are seen in the membranous septum, which lies beneath the aortic
valve. Other defect locations include: conal septum, adjacent to the tricuspid valve and within the muscular septum, and muscular
septum (Fig. 4). Defects vary in size, number, and shape, making their physiology and anatomy strikingly disparate. Lesions can
coalesce and atrioventricular canal defects occur when the endocardial cushions fail to fuse properly. This leads to failure of the
mitral valve to form correctly, and a cleft in the left-sided atrioventricular valve is always present.
PDA is the persistence of a fetal vessel called the ductus arteriosus, which normally involutes in the first few days after birth. It is
an artery connecting the aorta to the pulmonary artery (Fig. 5). Its persistence is more commonly seen in premature infants but may
be seen in full term infants as well. The muscular artery's persistence leads to variable outcomes. If tortuous and narrow, then it acts
as a resistor and protects the pulmonary vascular bed; however, it may be broad and straight, which may lead to pulmonary
overcirculation and/or PAH early in life.
Fig. 3 Atrial septal defect is demonstrated here and represents a deficiency in the atrial septum that permits shunting of blood at this level.
Fig. 4 Ventricular septal defect (VSD) is demonstrated here and represents a deficiency in any area of the ventricular septum that permits shunting of blood at this
level. Levels of shunting include subarterial VSD (1), membranous VSD (2), inlet VSD (3), and muscular VSD (4).
Fig. 5 Patent ductus arteriosus is demonstrated here and represents the continued existence of a fetal structure, which connects the aorta to the pulmonary artery.
Cyanotic Lesions
Cyanotic CHD requires the presence of right-to-left or deoxygenated-oxygenated blood shunting. This scenario may exist in the
form of parallel circulations when two usually interdependent circulations do not distribute and receive blood from one another
appropriately. Instead, they work in isolation and recirculate their own blood that each pumps out redundantly. Cyanotic CHD
occurs in the presence of such parallel circulations, obstruction leading to decreased pulmonary blood flow, or mixture of arterial or
venous blood.
In the unrepaired state (typically infants), Tetralogy of Fallot is the most common scenario where right-to-left shunting of blood
occurs. This pathology occurs because of anterior–superior deviation of the conal septum leading to the presence of a VSD,
pulmonary stenosis, right ventricular hypertrophy, and overriding aorta (Fig. 6). Coronary artery anomalies are sometimes seen,
which may complicate surgical repair. ASDs are often present, which may lead to further shunting depending on the degree of right
ventricular diastolic dysfunction. Lesions associated with pulmonary valve atresia also lead to right-to-left shunting whether at the
atrial or ventricular level. Another cause of cyanotic CHD is complete transposition of the great arteries, where the aorta and
pulmonary artery insert into the right and left ventricles, respectively. This ventriculoarterial discordance leads to a complicated
physiologic state in which oxygenated blood is recirculated to the lungs and deoxygenated blood recirculates within the body. ASDs
and VSDs as well as the PDA serve as shunts to allow for oxygenation of deoxygenated blood and circulation of oxygenated blood.
This serious condition is incompatible with prolonged survival without surgical intervention. Any adult seen with this condition in
the unrepaired state has survived strictly from mixing of oxygenated and deoxygenated blood at any the level of remaining shunt.
Finally, mixture of arterial and venous blood may lead to net deoxygenated blood. Some examples of this are: atrioventricular valve
atresia concurrent with an unrepaired shunt, total anomalous pulmonary venous return, in some cases partial anomalous
pulmonary venous return, arteriovenous malformations, and truncus arteriosus. In truncus arteriosus for instance, cardiac output
from the left and right ventricles join in a common outflow artery, termed the truncus. The lung gets blood via pulmonary arteries
that emanate from the truncus arteriosus and sometimes also by PDA. The lungs are exposed to high pressure and volume overload,
making early surgical repair important for normal cardiopulmonary development and competence.
Fig. 6 Tetralogy of Fallot (TOF) is demonstrated here and is characterized by a series of findings, which occurs secondary to anterior deviation of the conal septum.
It is exemplified by ventricular septal defect (1), pulmonary stenosis (2), aortic override (3) and right ventricular hypertrophy (4).
Single-ventricle patients represent a unique subpopulation of those with ACHD. These patients can have a diverse array of
underlying CHD but ultimately have a similar palliative plan. Whether the systemic or pulmonary output is compromised, the first
stage of surgical palliation ensures adequate cardiac output for both systems, adequate venous blood admixture at the atrial level
and the integrity of the aortic arch (Fig. 7A). The second stage, commonly called a Bidirectional Glenn procedure or Bidirectional
cavopulmonary anastomosis, redirects some of the systemic venous blood directly to the pulmonary arteries while permitting
deoxygenated infradiaphragmatic blood flow to return to the heart (Fig. 7B). Finally, in the third stage which is commonly referred
to as the Fontan completion, the deoxygenated venous blood that had been returning to the heart is redirected to the pulmonary
artery leading to a circuit with only one pump and passive pulmonary blood flow as is required without a subpulmonary ventricle
(Fig. 7C). Late findings in the Fontan-palliated patient are similar despite underlying native anatomy. The current standard
modification performed is the extracardiac Fontan procedure (Fig. 8). We are just beginning to learn of both the late-cardiac and
Fig. 7 The traditional three step palliation is demonstrated here. In A, the modified Blalock-Taussig-Thomas shunt is shown connecting the right subclavian
artery to the right pulmonary artery along with an aortic arch reconstruction. In B, the superior vena cava is redirected to the pulmonary arteries and the Blalock-
Taussig-Thomas shunt is taken down. In C, the sub-diaphragmatic blood is redirected to passively drain into the pulmonary artery.
Fig. 8 Iterations of the third palliative surgery step are demonstrated here. The Classic Fontan was initially utilized with sub-diaphragmatic blood flowing
only to the left lung and using the right atrium as a conduit. In the Atriopulmonary Fontan, the right atrial appendage is anastomosed directly to the main pulmonary
artery. In the Lateral Tunnel Fontan, sub-diaphragmatic blood utilizes native right atrial tissue within the baffle as it ascends to the pulmonary artery. In the
Extracardiac Fontan, a conduit is placed outside of the heart, which connects sub-diaphragmatic blood to the pulmonary artery.
extracardiac manifestations that result from this surgical procedure, as the first patients surviving this operation typically had the
procedure in the early 1970s (Van Praagh, 1972).
Treatment
Prior to the 1950s, surgical interventions were not possible, and CHD was a harbinger of early death. However, with the advent of
cardiopulmonary bypass, surgical interventions have become increasingly more complex and common. Since the 1960s, however,
catheter interventions have been utilized and changed diagnosis and treatment of CHD (Rashkind and Miller, 1966). Since the
1970s, such procedures have eliminated the need for some open surgical procedures (King and Mills, 1974).
Transcatheter interventions are multiple and the details of them are beyond the scope of this article. They may be used to relieve
valvar obstruction, dilate blood vessels, place stents, insert devices to occlude septal defects, coil anomalous vessels, and insert new
valves, among other procedures. The benefits of transcatheter interventions are several: avoidance of thoracotomy/sternotomy
including effects on respiratory mechanics, no requirement for cardiopulmonary bypass and therefore offer neurologic protection
and potentially avert late neurocognitive abnormalities and shorter hospitalization, among others. The ability to place valve
homografts in the pulmonary and aortic positions has revolutionized the treatment of CHD specifically as it relates to transcatheter
pulmonary valve utilization particularly in Tetralogy of Fallot. It would be expected that these types of interventions will continue to
develop and improve, offering more patients procedural success for treatment of CHD.
Surgical interventions for CHD are widespread and specific to the underlying type of CHD. Similar to transcatheter interventions,
valvular interventions and septal defects may be intervened upon but in this case with direct visualization. Although percutaneous
options are increasing, there are times where surgical intervention is preferred for precise repair, for example, when defect repair is in
a location that intimately interfaces with the conduction system. Creation of shunts and placement of conduits largely remain
procedures that require surgical intervention; however, newer percutaneous options are in study and may be on the horizon in the
near future. Interventions on arteries and veins to ensure patency or redirect flow are also routinely preferentially performed
surgically. Staged repairs over weeks to years are commonly utilized alone or in concert with transcatheter interventions, particularly
in complex CHD such as the single-ventricle population. In the setting of dire circumstances, heart transplantation may be
performed by congenital heart surgeons when other options are deemed too risky.
Cardiac Manifestations in ACHD
ACHD patients face several cardiovascular problems as they age. This may be the result of residual congenital lesions, or a result of
the surgical palliation performed in childhood. Congestive heart failure is not uncommon, and although tolerable in youth, over
time the same pressure–volume relationships may not be as well tolerated (Engelings et al., 2016). There remains a paucity of data
about use of traditional heart failure medications in the CHD population, and it remains an important area of research (Book and
Shaddy, 2014; Gurvitz et al., 2016). Medications may slow down this progression but reversal may not be possible (Stout et al.,
2016). CHD patients with valvular heart disease typically progress independent of CHD and can compound existing hemodynamic
derangements. Arrhythmia is another late common cardiac problem for many CHD patients (Moore, 2014). These issues can arise
from scar tissue secondary to the original repair, for instance, the ventriculotomy scar in Tetralogy of Fallot, or from the abnormal
hemodynamic milieu. PAH is a dreaded complication of CHD and is known to affect overall survival (Manes et al., 2014;
Dimopoulos et al., 2014). This occurs when the mean pulmonary artery pressure is 25 mmHg, pulmonary capillary wedge
pressure is 15 mmHg, and pulmonary vascular resistance is >3 Wood units. One common way that PAH develops is from an
unrepaired nonrestrictive shunt. In this condition, such as is the case with an unrepaired VSD, a shunt that once went left-to-right
reverses to right-to-left secondary to the increased pulmonary vascular resistance. This condition is known as Eisenmenger's
syndrome (ES) and is associated with increased mortality and several extracardiac manifestations of CHD (Dimopoulos et al., 2014).
Extracardiac Manifestations of ACHD
ACHD patients have pathology extending beyond the cardiopulmonary system. For those who have single-ventricle physiology, the
ingenious palliative Fontan operation has permitted survival into adulthood for those who otherwise might have died young;
however, late problems in adulthood are commonplace (Hsu, 2015; Cohen et al., 2013). These patients typically remain at least
mildly cyanotic and secondary erythrocytosis is common, as is coagulopathy. Peripheral skin and soft tissue changes, particularly in
the legs, are frequent due to passive and often congestive systemic venous return via the Fontan circuit. Liver involvement is
common, and in fact has its own unique term: Fontan-associated liver disease (FALD), because it is unlike other liver disease due to
common mechanisms such as hepatitis or alcohol abuse. Nearly all adults with a prior Fontan will have histopathology consistent
with liver fibrosis, if not cirrhosis (Pundi et al., 2016). Hyperenhancing liver nodules are not uncommon in the Fontan population,
and there is an increased incidence of hepatocellular carcinoma compared to other types of CHD (Wells et al., 2016). Protein losing
enteropathy may also occur in adulthood and is characterized by fluid retention, low albumin, and is generally poorly tolerated
with no good treatment strategies available (Hsu, 2015).
Another random document with
no related content on Scribd:
You may laugh, children, but it is true. The dolphin had a servant,
who was also a dolphin, but of the family of the Globiceps. These are
so called because of their round heads, which look like the globes
used in the electric lighting of streets.
The young dolphin was playing in the water. He tried to attract
Pinocchio’s attention in many ways. He spouted water through the
hole which every dolphin has at the top of his head. He called to the
marionette. He smiled at the youngster. It was of no use. Pinocchio,
with his wooden nose in the air and his dough cap on one ear, would
not even turn his head.
“I wonder if he is deaf or blind?” the dolphin finally said, loudly
enough to be heard.
Pinocchio turned with a start.
“For your own benefit, I just wish to say that I am not now and never
have been deaf,” he said as haughtily as he could.
“Then why do you look at me in that fashion? And why don’t you
answer me?” was the reply.
“I am acting just as a gentleman should toward those who are
beneath him,” said Pinocchio.
“I don’t know which of us is the better of the two. All I do know is, that
my father was the richest inhabitant of the sea and that the other
dolphins considered him their king.”
“King?” mumbled Pinocchio, who knew himself to be the son of a
poor carpenter, earning so little that he never had a penny in his
pocket.
“But king or not, what does it matter? In this world we are all equal,
for we have all been created by God. Listen, my dear marionette.
Come here. As we are to travel such a long distance together, we
should be friends. Are you willing to be my friend?”
These pleasing words made Pinocchio see how stupid and how rude
he had been.
“Think of it! A fish (oh, no, I mean a sea animal) giving me lessons in
politeness!” Then turning to the dolphin, he said, “Yes, we shall be
friends. What is your name?”
“Marsovino. And yours?”
“Pinocchio.”
“A beautiful name. Come, shake hands.”
“Very willingly,” replied Pinocchio.
The good little animal stuck one of his fore fins out of the water for
Pinocchio to shake.
“And what is the tutor’s name?” said the boy of wood to the boy of
the sea.
“The tutor is a dolphin of the Tursio family, but I call him father. Is it
true that you are coming with us on our travels?”
“Yes,” said the marionette, proudly. “And I am able to teach you.”
“Teach me! That’s strange. How do you expect to teach me?”
“You will soon find out. You talk rather disrespectfully to me. I have
been in all the schools of the kingdom. And you? You probably have
never been on land for twenty-four hours.”
Marsovino looked at the marionette smilingly, but made no reply.
Pinocchio walked up and down with his hands in his pockets and his
hat at an angle of forty-five degrees, ruffling his feathers at the
brilliant remark he had made.
As soon as Tursio came near, Marsovino asked him if he were ready.
“Yes. Everything is finished,” was the reply. “Are you ready,
Pinocchio?”
“Yes. I am ready. Let us start.”
“Start? How? Do you mean to say that you are coming under the sea
with that suit?”
“Of course. It’s the only one I have.”
“A suit of paper! The very idea! Luckily I have prepared for this.
Here, Globicephalous,” he said to his servant, “give me that little suit
of ray leather,—the one I had you make this morning.”
“Splendid,” cried Pinocchio, clapping his hands. “Now I have a new
suit.”
Putting it on, he looked at himself in the water. Seeing how dark and
unbecoming it appeared, he turned to Tursio and said excitedly:
“I don’t want this. It is too ugly. I like my pretty flowered-paper one
better.”
“Your paper one Globicephalous will carry in his satchel for you.
Should you wear it in the water, it would be spoiled.”
“I want my pretty suit,” insisted Pinocchio. “If any one saw me in this
thing, he would ask me if I had been through the coal-hole.”
“But yours will be ruined if you wear it in the water, I tell you.”
“I want mine. I want mine,” wailed Pinocchio.
“Very well. Globicephalous, take the paper suit out of the traveling
bag and give it to the boy.”
The marionette turned, expecting to see an ordinary traveling bag.
Instead, he saw Globicephalous take an enormous oyster out of the
water.
“Isn’t that strange! Oyster shells for a traveling bag!”
“Strange? Why, what is strange about that?” asked Tursio.
“What is its name?” asked Pinocchio.
“That is the giant Tridacna. They are the largest oyster shells
known.”
“How large the animal inside must be,” observed Pinocchio, with a
yawn.
“Yes. It is very large, and also very beautiful. The center of the body
is a violet color dotted with black. Around this is a green border. At
the extreme edge the colors change from deepest to lightest blue.
Yes, indeed. It is very beautiful.”
“What a good meal it would make,” thought Pinocchio. His only wish
was for a good dinner, but in order to be polite he said, “Who would
ever think that there are such things under the sea!”
“Why, you have been in every school in the kingdom and don’t know
that?”
“Books on the subject you can find everywhere.”
Pinocchio bit his lips, but did not say a word. Quickly he dressed
himself again in his paper suit and declared himself ready to start.
“All right! Come along!” said the dolphin, stretching a fin out to help
Pinocchio along.
The marionette started to walk into the water. He had not gone far,
however, before his paper suit began to leave him. Hastening back
to the shore, he very meekly put on the ray-leather suit which
Globicephalous handed to him.
“Remember, my boy,” said Tursio, “that in this world of ours we must
think not only of the beauty but also of the usefulness of things. Also,
do not forget that a boy who never learns anything will never be
anything.”
“But I have learned much,” answered Pinocchio. “To prove this to
you, I can now tell you of what material this suit is made.”
“I have told you already. It is of ray leather. Do you know what a ray
is?”
“Surely I know. You may give it another name. Still, it must be that
white animal on four legs. You know. The one the shepherds shear
during some month or other.”
“Mercy!” cried Tursio. “You are talking about sheep. They give wool
to man.”
Pinocchio, without moving an eyelid, went on:
“Yes, that’s true. I have made a mistake. I should have said it is that
plant that bears round fruit, that when it opens....”
“Worse and worse,” interrupted the old dolphin. “What are you
talking of, anyway? That is the cotton plant. Marsovino, please
explain to this boy, who has read all the books in the world, what a
ray is.”
So Marsovino went on: “A ray is a fish, in shape like a large fan. It
has a very long tail, which it uses as a weapon.”
“To what class of fishes does it belong?” asked Pinocchio.
“It belongs to the same class as the lampreys, which look like
snakes, the torpedo,—”
“Be careful never to touch that fellow,” here interrupted Tursio.
“—the sawfish and the squaloids,—that is, the common shark and
the hammerhead.”
“The saw? The hammer?” observed Pinocchio. “If I find them, I must
keep them for my father. He is a carpenter, but so poor that he
seldom has money with which to buy tools.”
“Let us hope that you will never meet the saw, the terrible
hammerhead, or even the common shark,” said Tursio.
Pinocchio made no answer, but in his heart he kept thinking, “I am
very much afraid that the dolphins are teaching me, not I the
dolphins.”
Tursio then handed Pinocchio a small shell of very strange shape. It
looked like a helmet.
“Wear this, Pinocchio,” he said. “It will make a pretty cap for you.”
“It is very pretty. What is it?”
“It is a very rare shell.”
“But it is only one shell. Where is its mate?”
“It has none. It is a univalve. That means it has only one shell. The
tellines have two shells, and are therefore called bivalve. Another
kind looks like a box with a cover.”
“But does an animal live in there?”
“Of course. Every shell has its mollusk.”
“Mollusk?” repeated Pinocchio.
“Yes. The small animals that live in shells are called by that name.”
“They have a very soft body. By means of a member, called a foot,
they get such a strong hold on rocks that it is very hard to tear them
off.”
“Some mollusks have a strong golden-colored thread by which they
also hang to rocks. Why, people have even made cloth out of these
threads.”
Pinocchio cared little for all this explanation. He looked at himself in
the water, and was, after all, very much pleased with himself.
“This cap seems made for me,” he said. “Too bad I have no feather
for it.”
“Perhaps we shall find one on our journey,” laughed Tursio.
“Where will you get it? In the sea?”
“Yes, in the sea,” answered Tursio, in a tone which made the
impudent marionette almost believe him.
CHAPTER IV
“Well, children, let us hasten. If we talk so much,
the sun will rise and find us here. Come, Pinocchio!
Jump on my back and let us start.”
There was no need for Tursio to repeat his
command. In the twinkling of an eye, Pinocchio was
riding on the dolphin’s back, holding on tightly to the
dorsal fin.
“Gallop and gallop, my pretty horse,

Swiftly over the boundless sea.
Straight through the water take thy course,
Till my dear father again I see.”
“Gallop and gallop, my pretty horse,

Gallop away under the sea.
Swim to the south, and swim to the north,
Till my dear father again I see.”
So sang Pinocchio gleefully.

Tursio and his swimming companions, with a few shakes of their
strong tails, were soon far away from shore. This is not to be
wondered at, for dolphins are known to be very swift. Very soon
Pinocchio saw nothing but sea and sky. Always holding on tightly to
Tursio’s fin, he looked to the right and to the left; but nothing could
he see of his dear father.
“Hold fast, Pinocchio,” suddenly cried Tursio.
“All right, Mr. Tursio,” replied Pinocchio, but he could say no more.
For suddenly, with a great jump, the dolphin was under water.
What a moment for our poor wooden hero!
“Now I understand it all,” he thought. “This dolphin wants to get me
into the sea that he may eat me at his leisure. Oh, poor me! I shall
never again see the light of day.”
But marvel of marvels! He suddenly awoke to the fact that, instead of
drowning, he was breathing easily. Not only that, but he could
actually talk!
“This is strange,” said he. “I have always thought that people would
drown in the water.”
“And it is true,” answered the dolphin, “that men usually drown in the
sea. But I have given you the power to live under water. You see,
then, you have become a real amphibian.”
“A real what? What am I now?”
“An amphibian. That is, you have the power to live both in the air and
in the water.”
“But are there such animals?”
“Why, of course, child. Frogs, for example, which belong to the
Batrachia family. In the water they breathe with branchiæ, or gills,
and in the air with lungs. Usually, however, the name is given only to
those mammals that live in the water and move only with great
difficulty on the earth. To this class belong the seals and the sea
lions.”
“Well, then, I shall never drown.”
“No; and you will have a wonderful journey under the sea. Just hold
on to me, and I will carry you. Do not be afraid.”
“Afraid? Of course not. But I don’t like the darkness very much.”
“That is too bad. But the darkness will not last very long. You know, I
promised that we should make our journey by the light of the sun.
Wait awhile.”
Through the water Tursio went like an arrow, followed by Marsovino
and the servant.
Pinocchio, to gain courage, shut his eyes. When he opened them
again, wonder of wonders! Very near to him a large sun was moving
back and forth. It looked as if it were alive.
“The sun at the bottom of the sea!” yelled Pinocchio, frightened
almost to death. “Do you want me to believe that? You must be a
wizard playing tricks on me.”
“I am not a wizard, Pinocchio, and the sun is not a trick. It is nothing
more nor less than a fish.”
“I never heard of such a thing.”
“And you have been in all the schools of the kingdom! Marsovino,
please explain to this boy what a sunfish is.”
“The sunfish is so called because of the bright light that comes from
its body. When several of these fish are together, the sea looks as if
it were full of little, shining suns.”
As usual, Pinocchio was silent. He was beginning to think that even
dolphins knew more than he did.
Stretching out his hand, he touched a small fish that was passing by.
Another surprise! As soon as he touched it, it began to swell and
swell, until it was as round as a ball. And from this ball, countless
points began to stick out.
“Suddenly, with a Great Jump, the Dolphin was under the
Water.”
“Oh!” yelled Pinocchio again. “What is it this time?”
“It is only a globefish, my marionette. It is harmless, if you don’t
touch it.”
“But why should it turn into a balloon?”
“It does that to protect itself,” answered Tursio. “It is possible for the
globefish to do that, because it can take in a large quantity of air.
With bristles ready, it can then meet the attacks of other fish, as each
point is as sharp as a needle.”
“I never knew that before,” exclaimed Pinocchio, forgetting his
previous boast.
Tursio and Marsovino looked at each other and laughed.
CHAPTER V
The night passed without further adventure.
As soon as morning dawned, the four friends rose
to the surface. Our marionette was delighted to see
the sun again. The pure morning air, though,
reminded him that he was hungry. The day before,
if you remember, he had eaten very little.
“I should like something to eat,” he said in a weak
voice.
“Let us go to breakfast,” answered the dolphin. Gayly he dove into
the water, and led the party deep into the sea. After a short swim, he
stopped. But, unfortunately, the four friends found themselves in a
place where there were very few herring and salmon. These, you
know, are the dolphin’s favorite food.
The salmon is a fish that lives both in rivers and in seas. Like the
swallow, he looks for warm places in which to pass the winter. So, in
large numbers he migrates to the sea at that time of the year, and in
the spring he returns to the rivers.
“This morning our breakfast will be light,” observed Tursio,
swallowing three herring at once.
“I shall not eat anything. I don’t feel very well. Besides, salmon is the
only thing I can eat,” said Marsovino.
Tursio, wishing to please his pupil, started to swim toward two very
high rocks. They were so high that their tops stuck out of the water.
Very probably they were the base of an island in the middle of the
sea. But although he looked here, there, and everywhere, he could
find no salmon.
Globicephalous satisfied his hunger with three dozen herring and
half a bushel of smelts.
And Pinocchio? Pinocchio this time certainly did not suffer from lack
of food.
Tursio had shown him a large rock, attached to which were hundreds
of oysters. Some were of the size of a pinhead. Others were as large
as a boy’s cap, and these were two years old.
“Go and have your breakfast,” said Tursio.
“Must I eat those horrible-looking things?” asked Pinocchio.
“Open them and see what is inside,” was the reply.
“Pinocchio this Time certainly did not suffer from Lack of
Food.”
After Pinocchio had opened and eaten one, he no longer thought of
the looks of the oyster shells. He opened and ate so many, that it
was a wonder to Marsovino that so small a person could hold so
much.
Suddenly Pinocchio noticed numberless tiny, tiny white specks
coming out of some oysters. To him they looked like grains of sand.
But when he saw the specks moving and trying hard to attach
themselves to rocks, he could not help crying out, “O look at the live
sand, Tursio.”
“Who told you it is live sand?” asked Tursio. “Those are the newborn
oysters, looking for a place on which to spend their lives. Where
those small grains hang, there the oysters will live, grow, and die.”
“If no one gets them before that,” added Globicephalous.
“And are all those little dots oysters?”
“Yes. All of them. And many of them come from a single oyster, for
an oyster gives forth almost two millions of eggs at a time. These
little things have so many enemies, however, that very seldom do
more than ten of the millions grow old.”
“Two millions! Then I may eat all I want to,” continued Pinocchio,
unmercifully tearing away the poor oysters, young and old.
“Look, Pinocchio,” here called Tursio, pointing to a small fish, colored
with brilliant blues and reds. “That is the stickleback. You may have
heard that this fish makes a nest, as do birds. Also that the male, not
the female, takes care of the eggs.”
“Surely I have,” answered Pinocchio, seriously.
The stickleback seemed to be very much excited. He moved around
the nest he had made and watched it anxiously. The cause for this
was soon evident. A second stickleback made its appearance from
behind the rocks. At once the two engaged in a terrific struggle. They
bit each other, used their tails as weapons, and charged each other
viciously. During the battle they changed color—to a beautiful blue
mottled with silver.
Pinocchio was struck with wonder. “Look! Look! One is wounded....
He falls.... He dies!” he cried. “And look at the other. How quickly he
returns to the nest to guard the eggs!”
“But how is it,” here asked Marsovino, “that once I saw a stickleback
swallow one of his little ones?”
“If you had followed him, you would later have seen the small fish
come safely out of the large one’s mouth,” answered Tursio.
“‘Look! Look! One is Wounded.’”
“But why did the large one swallow the small one?” asked Pinocchio.
“Because the little one probably wanted to run away from the nest. It
was too soon, the little one was too young to take care of himself; so
the father took the only means he had to save the youngster from an
enemy,” patiently explained Tursio.
Just then a small fish attracted the dolphin’s attention.
“Boys,” he said, “do you see that tiny fish? It is called the pilot fish. It
is the shark’s most faithful friend. Wherever goes the shark, there
goes the pilot fish.”
“Now, Pinocchio,” he continued after a pause, “I shall leave you with
Globicephalous. Marsovino and I are going to pay a visit to the
dolphin Beluga, who is a great friend of mine. He usually lives in the
polar seas, but on account of his health, he has come to warmer
waters. We shall return this evening, if all be well. Meet us near
those two mountains which are so close together that they form a
gorge. You may take a walk with Globicephalous, but be sure to be
at that spot to-night.”
“I am ashamed to be seen with a servant,” began Pinocchio.
“You are a fine fellow,” answered Tursio, with sarcasm. “Do you
know what you should do? Buy a cloak of ignorance and a throne of
stupidity, and proclaim yourself King of False Pride of the Old and
the New World!”
With this remark Tursio turned to his pupil, and the two swam away.

Encyclopedia of Cardiovascular Research and Medicine 1St Edition Douglas B Sawyer Full Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Encyclopedia of Cardiovascular Research and Medicine 1St Edition Douglas B Sawyer Full Chapter

Uploaded by

Copyright:

Available Formats

Encyclopedia of Cardiovascular

Research and Medicine 1st Edition

Copyright © 2018 Elsevier Inc. All rights reserved

Library of Congress Cataloging-in-Publication Data

British Library Cataloguing-in-Publication Data

For information on all publications

Printed and bound: YTC

Publisher: Oliver Walter

Cover: Photomicrographs were provided by Laura

List of Contributors xvii

AL Cardiac Amyloidosis: Classification, Diagnosis, and Treatment 34

Anemia in Heart Failure 80

Aortic Aneurysm 123

Aortic Valve Replacement in Patients With Congestive Heart Failure 143

Arrhythmias in Cancer and Cancer Treatment: A Review 162

Arrhythmogenic Right Ventricular Cardiomyopathy 182

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 192

Athlete's Heart 205

Atrial Tachycardia—Mechanisms and Management 212

Atrioventricular Node Reentrant Tachycardia 224

ATTR Cardiac Amyloidosis: Classification, Diagnosis, and Management 242

Behavior Modification and Cardiovascular Disease 257

Bicuspid Aortic Valve and Sports Activity 263

Bioinformatics Principles for Deciphering Cardiovascular Diseases 273

Biomarkers in Heart Failure, Use of 293

Biomarkers in Ischemic Heart Disease 303

Biomarkers: Heart Failure 315

Biomarkers: Population Screening and Risk-Stratification 323

Biophysics of Ablation—Radiofrequency and Cryoablation 334

Brugada Syndrome 356

Cardiac Anatomy, Physiology, and Pathophysiology 373

Cardiac and Induced Pluripotent Stem Cells 384

Cardiac Arrhythmia in Heart Failure 394

Cardiac Biomechanics in Normal Physiology and Disease 411

Cardiac Fibroblast 420

Cardiac Hypertrophy: Signaling and Cellular Crosstalk 434

Cardiac Magnetic Resonance Imaging in Heart Failure 451

Cardiac Pacing and Monitoring: Past, Present, and Future 463

Cardiac Resynchronization Therapy 475

Cardiac Transplantation 489

Cardiohepatic Interactions 514

Cardiopulmonary Exercise Testing 523

Cardiovascular Complications and Management in Sarcoidosis: A Review 527

Cardiovascular Disease and Obesity 535

Catecholaminergic Polymorphic Ventricular Tachycardia 542

Catheter Ablation for Atrial Fibrillation (Methods) 553

Catheter Ablation for Ventricular Tachycardia 566

Chronic Infections of the Heart 593

Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease 600

Clinical Assessment of the Cardiac Arrhythmia Patient 609

Clinical Management of Inherited Arrhythmias 620

Clinical Trials for Atrial Fibrillation—What Do We Know? 630

Complications of Pregnancy and Future Cardiovascular Risk 643

Computational Systems Biology for the VEGF Family in Angiogenesis 659

Congenital Heart Valve Disease in the Adult 677

Coronary Anatomy 691

Coronary Artery Bypass Grafting 700

Cyanotic Congenital Heart Disease 730

Diagnosis and Imaging of Congenital Heart Disease 17

Diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) 47

Diet in Heart Failure 54

Dietary Fat and Risk of Cardiovascular Disease 60

Digital Data (mHealth and Social Media) 90