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J Wave Syndromes

Charles AntzelevitchGan-Xin Yan Editors

Brugada and Early Repolarization Syndromes

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J Wave Syndromes

Charles Antzelevitch • Gan-Xin Yan Editors

J Wave Syndromes Brugada and Early Repolarization Syndromes

ISBN 978-3-319-31576-8 ISBN 978-3-319-31578-2 (eBook) DOI 10.1007/978-3-319-31578-2

Library of Congress Control Number: 2016942096

© Springer International Publishing Switzerland 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland

Editors Charles Antzelevitch Cardiovascular Research Lankenau Institute for Medical Research Wynnewood Pennsylvania USA

Gan-Xin Yan Lankenau Institute for Medical Research Lankenau Medical Center Wynnewood Pennsylvania USA

We dedicate this book to the members of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asian-Pacifi c Heart Rhythm Society (APHRS) who met in Shanghai, China, in April 2015 to generate an expert consensus document and formulate this text focused on the J wave syndromes. We are also proud to dedicate this compendium to the many investigators whose collective works have advanced us to this exciting juncture in the history of cardiac electrophysiology and arrhythmias, on whose shoulders we stand, as well as to our mentors, collaborators, and fellows who have assisted us in advancing the fi eld. Last but certainly not least, we dedicate this book to our families, whose understanding and support permitted us to dedicate the time and effort needed to formulate this text.

Charles Antzelevitch Gan-Xin Yan

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Foreword

Sudden cardiac death remains the most important public health issue on the planet. Despite intense research efforts and remarkable progress in heart disease popula-tions, we have not been able to impact its overall incidence in the community where the vast majority of victims have not been previously identifi ed as being at risk. Particularly tragic is its continued occurrence in young and apparently healthy peo-ple. Although sudden death is far less common in this population, it is an unspeak-able calamity, truncating productive lives, widowing spouses, and orphaning children around the world.

It is now clear that a particularly important mechanism for sudden death in the young is some form of the newly defi ned J wave syndromes. Though knowledge regarding these entities has advanced rapidly, many challenges remain. Drs. Antzelevitch and Yan, outstanding leaders in this area of research, convened an expert panel to review the state of the art in order to identify those issues requiring better defi nition. These include ionic mechanisms, genetics, and, most importantly, methods of diagnosis, risk stratifi cation, and treatment that can be applied on a global basis. The aim of the exercise was to mark those areas in which research and educational methods can be most effi ciently and expeditiously directed.

It is fair to say that this elite group of scientists succeeded beyond expectations. Not only have they produced an extremely valuable consensus document, but they have also put forth this book that provides amplifi cation of the most complex issues. Most importantly, the information contained herein will help resolve confusion that exists in the clinical community and has led to inappropriate, ineffective, and fre-quently over-aggressive treatment.

As they have perennially, my colleagues Drs. Antzelevitch and Yan lead the way in helping us understand how we can translate learnings in the basic laboratory into the clinic, with the ultimate goal of mitigating, if not preventing, sudden cardiac death. For their stewardship of this Herculean effort, we are most grateful.

Wynnewood, PA, USA Peter R. Kowey , MD, FACC, FAHA, FHRS January 15, 2016

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Pref ace

The J wave syndromes, consisting of the Brugada (BrS) and early repolarization syn-dromes (ERS), have captured the interest of the cardiology community for over two decades, following the identifi cation of BrS as a new clinical entity in 1992. Although experimental evidence for a heightened risk for sudden cardiac death (SCD) associated with early repolarization was reported at the turn of the century, the clinical impact of ERS was not fully appreciated until 2008 with seminal reports on the subject from the groups of Haissaguerre, Viskin, and Nam. A book dedicated to the Brugada syndrome was published by us and the Brugada brothers in 2005, emanating from the expert consensus conference dedicated to BrS in 2004. A book specifi cally focused on ERS has not previously been published other than the expert consensus document dealing with terminology of early repolarization by MacFarlane and coworkers.

This book stemmed from an expert consensus conference forum organized in 2015 to evaluate new information and highlight emerging concepts with respect to differential diagnosis, prognosis, and cellular and ionic mechanisms and approaches to the therapy of the J wave syndromes. Leading experts, including members of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asian-Pacifi c Heart Rhythm Society (APHRS) met in Shanghai, China, in April 2015. The task force was charged with a review of emerging concepts and assessment of new evidence for or against particular diagnostic procedures and treatments.

Members of this Task Force were selected to represent professionals involved with the medical care of patients with the J wave syndromes as well as those involved in research into the mechanisms underlying these syndromes. Selected experts in the fi eld undertook a comprehensive review of the literature. Critical eval-uation of methods of diagnosis, risk stratifi cation, approaches to therapy, and mech-anistic insights was performed, including assessment of the risk–benefi t ratio.

This text is designed to supplement and complement the expert consensus docu-ment that will be simultaneously published dealing with the J wave Syndromes: Emerging Concepts and Gaps of Knowledge.

Wynnewood, PA, USA Charles Antzelevitch Wynnewood, PA, USA Gan-Xin Yan

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Contents

1 History of the J Wave and J Wave Syndromes. . . . . . . . . . . . . . . . . . . . . 1 Ihor Gussak and Georg Gussak

2 J Wave Syndromes: From Bench to Bedside . . . . . . . . . . . . . . . . . . . . . 15 Gan-Xin Yan , Jian-Zeng Dong , and Chang-Cong Cui

3 Ionic and Cellular Mechanisms Underlying J Wave Syndromes . . . . . 33 Charles Antzelevitch and Bence Patocskai

4 Genetic Basis of Early Repolarization Syndrome . . . . . . . . . . . . . . . . . 77 Minoru Horie , Keiko Sonoda , and Seiko Ohno

5 J Wave Syndrome-Susceptibility Mutations Versus Benign Rare Variants: How Do We Decide? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Jamie D. Kapplinger , David J. Tester , and Michael J. Ackerman

6 Prevalence and Clinical Characteristics of Brugada Syndrome . . . . 121 Arthur A. M. Wilde and Pieter G. Postema

7 Update on the Differential Diagnosis and Treatment of Brugada Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Elena Arbelo and Josep Brugada Terradellas

8 Risk Stratification in Brugada Syndrome: Clinical Characteristics, Electrocardiographic Parameters and Auxiliary Testing . . . . . . . . . . 173 Arnon Adler and Sami Viskin

9 Prevalence and Risk Stratification of Patients with Electrocardiographic Pattern of Early Repolarization. . . . . . . . 193 Heikki V. Huikuri

10 Prognostic Value of Early Repolarization Pattern in Development of VT/VF in Ischemic Heart Disease, Hypothermia, Etc. . . . . . . . . . . 207 Hiroshi Morita and Hiroki Sugiyama

xii

11 Similarities and Differences in the Electrocardiographic and Clinical Features Between Early Repolarization Syndrome and Brugada Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Wataru Shimizu

12 Atrial Arrhythmias Associated with J Wave Syndromes . . . . . . . . . . 245 Can Hasdemir

13 Phenotypic Expression and Genetics of J Wave Syndrome in the Early Stage of Arrhythmogenic Right Ventricular Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Domenico Corrado , Marina Cerrone , Alessandro Zorzi , and Mario Delmar

14 Clinical Features of Electrical Storms Associated with J Wave Syndromes and Acquired Forms of J Wave Syndrome . . . . . . . . . . . . 281 Gi-Byoung Nam

15 Therapy for J Wave Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Antonio Frontera , Michael E. Field , Arnaud Denis , Nicolas Derval , Caroline Thambo , Pierre Jais , Meleze Hocini , Michel Haissaguerre , and Frédéric Sacher

16 J Wave Syndromes in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 Jihong Guo and Changsheng Ma

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

Contents

xiii

Contributors

Michael J. Ackerman , MD, PhD Divisions of Cardiovascular Diseases and Pediatric Cardiology, Departments of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics , Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic , Rochester , MN , USA

Arnon Adler , MD Department of Cardiology , Tel-Aviv Sourasky Medical Center , Tel Aviv , Israel

Charles Antzelevitch , PhD Cardiovascular Research , Lankenau Institute for Medical Research , Wynnewood , PA , USA

Elena Arbelo , MD, PhD Arrhythmia Unit, Department of Cardiology , Thorax Institute, Hospital Clinic , Barcelona , Spain

Josep Brugada Terradellas , MD, PhD Cardiology Department , Hospital Clinic Barcelona , Barcelona , Spain

Marina Cerrone , MD, PhD The Leon H. Charney Division of Cardiology , New York University School of Medicine , New York , NY , USA

Domenico Corrado , MD, PhD Inherited Arrhythmogenic Cardiomyopathy Unit, Department of Cardiac, Thoracic, and Vascular Sciences , University of Padova , Padova , Italy

Chang-Cong Cui , MD Cardiology , The First Affi liated Hospital of Xi’an Jiaotong University , Xi’An , Shanxi , China

Mario Delmar , MD, PhD The Leon H. Charney Division of Cardiology , New York University School of Medicine , New York , NY , USA

Arnaud Denis , MD Cardiology Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Nicolas Derval , MD Cardiology Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

xiv

Jian-Zeng Dong , MD, PhD Cardiology , Anzhen Hospital, Capital Medical University , Beijing , China

Michael E. Field , MD Cardiology Department , University of Wisconsin , Madison , WI , USA

Antonio Frontera , MD Cardiology Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Jihong Guo , PhD Electrophysiological Center , Peking University of People’s Hospital , Beijing , China

Georg Gussak , BA Experimental Cardiac Electrophysiology , Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine , Chicago , IL , USA

Ihor Gussak , MD, PhD, FACC Rutgers University, UMDNJ-RWJ Medical School , New Brunswick , NJ , USA

Michel Haissaguerre , MD Cardiology Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Can Hasdemir , MD Department of Cardiology , Ege University School of Medicine , Bornova, Izmir , Turkey

Meleze Hocini , MD Cardiology Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Minoru Horie , MD, PhD Department of Cardiovascular Medicine , Shiga University of Medical Science , Otsu City , Japan

Heikki V. Huikuri , MD, PhD Cardiology, Research Unit of Internal Medicine , Medical Research Center, University Hospital of Oulu, and University of Oulu , Oulu , Finland

Pierre Jais , MD Cardiology Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Jamie D. Kapplinger , BA Department of Molecular Pharmacology and Experimental Therapeutics , Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic , Rochester , MN , USA

Peter R. Kowey , MD Cardiology , Main Line Health, Lankenau Heart Institute, Jefferson Medical College , Wynnewood , PA , USA

Changsheng Ma , MD Cardiology Center , Beijing Anzhen Hospital, Capital Medical University , Beijing , China

Hiroshi Morita , MD, PhD Cardiovascular Therapeutics , Okayama University Graduate School of Medicine , Kita-ku, Okayama , Japan

Gi-Byoung Nam , MD, PhD Division of Cardiology, Department of Internal Medicine , Asan Medical Center, University of Ulsan College of Medicine , Songpa-gu, Seoul , South Korea

Contributors

xv

Seiko Ohno , MD, PhD Department of Cardiovascular Medicine , Shiga University of Medical Science , Otsu City , Japan

Bence Patocskai , MD Department of Pharmacology & Pharmacotherapy , University of Szeged , Szeged , Hungary

Pieter G. Postema , MD, PhD Heart Centre, Department of Clinical and Experimental Cardiology , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands

Frédéric Sacher , MD, PhD Cardiology Department, Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Wataru Shimizu , MD, PhD Department of Cardiovascular Medicine , Graduate School of Medicine, Nippon Medical School , Tokyo , Japan

Keiko Sonoda , MD Department of Cardiovascular Medicine , Shiga University of Medical Science , Otsu City , Japan

Hiroki Sugiyama , MD, PhD Cardiovascular Therapeutics , Okayama University Graduate School of Medicine , Kita-ku, Okayama , Japan

David J. Tester , BS Division of Cardiovascular Diseases, Department of Medicine , Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic , Rochester , MN , USA

Caroline Thambo , MD, PhD Genetic Department , Bordeaux University Hospital, LIRYC Institute, INSERM , Bordeaux , France

Sami Viskin , MD Department of Cardiology , Tel Aviv Medical Center , Tel Aviv , Israel

Arthur A. M. Wilde , MD, PhD Heart Centre, Department of Clinical and Experimental Cardiology , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands

Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders , Jeddah , Saudi Arabia

Gan-Xin Yan , MD, PhD Cardiology , Lankenau Medical Center, Lankenau Institute for Medical Research , Wynnewood , PA , USA

Alessandro Zorzi , MD Department of Cardiac, Thoracic, and Vascular Sciences , University of Padua , Padua , Italy

Contributors

1© Springer International Publishing Switzerland 2016 C. Antzelevitch, G.-X. Yan (eds.), J Wave Syndromes, DOI 10.1007/978-3-319-31578-2_1

Chapter 1 History of the J Wave and J Wave Syndromes

Ihor Gussak and Georg Gussak

Abstract Since discovery of the Brugada syndrome, ECG phenomena of late ven-tricular depolarization and early ventricular repolarization has rapidly gained recog-nition as a major cause of life-threatening arrhythmias, and dramatically accelerated a series of remarkably insightful discoveries in experimental, genetic, and clinical cardiac electrophysiology. Theme of “J-wave Syndromes” occupies a prominent portion of the time devoted to cardiac arrhythmias at national and international meetings, and continuing to appear in publications on the subject continue to appear at a brisk rate. More questions than answers still remain with regard to etiology, pathogenesis, arrhythmogenesis, risk stratifi cation, epidemiology, prevention, and treatment of the JWS. These and other ambiguities concerning diagnosis and arrhythmogenic potential of the JWS have prompted an “Expert Consensus Conference on J-wave Syndromes. Mechanisms, Diagnosis, Prognosis, Risk Stratifi cation and Treatment of Brugada and Early Repolarization Syndromes” to be held in Shanghai, China on April 21–23, 2015.

This chapter is focused on a brief history of names, terms, some important dis-coveries in experimental and clinical cardiac electrophysiology related to hypother-mic, acquired, idiopathic J-waves, early repolarization and Brugada syndromes, and their proarrhythmic potential.

Keywords Brugada syndrome • J-waves • Early repolarization • ECG phenomena • History

I. Gussak , MD, PhD, FACC (*) Rutgers University, UMDNJ-RWJ Medical School , New Brunswick , NJ , USA e-mail: [email protected]

G. Gussak , BA Experimental Cardiac Electrophysiology , Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine , Chicago , IL , USA

mailto:[email protected]

2

Introduction

For many decades, cardiology community had continuously expressed its fascina-tion regarding the electrophysiological processes associated with the transition of cardiac ventricular excitability to its recovery phase and their refl ection on the sur-face ECG, such as J-points, J-defl ections, notch or slur of the downsloping limb of the QRS complex, and J-waves. ECG phenomena of early ventricular repolarization (VR) have in the past often been misdiagnosed or misinterpreted mainly because of prevailing opinion of the unequivocally “benign”, “innocent”, or “misleading” nature of these ECG abnormalities [ 1 , 2 ]. As a result, some of them were over-looked for decades [ 3 , 4 ].

The interest in ECG phenomena and syndromes of the early VR has been rekin-dled from 1991 to 1992 when Pedro and Josep Brugada described what is now known as Brugada syndrome (BrS) [ 5 , 6 ]. As result, the BrS has rapidly gained recognition as a major cause of sudden cardiac death (SCD) and also dramatically accelerated a series of remarkably insightful discoveries in experimental and genetic cardiac electrophysiology that have revolutionized our understanding of the ionic, cellular and molecular mechanisms that underlie life-threatening arrhythmias, par-ticularly these related to the early VR.

The main objective of this chapter is to present a historical review of clinical and experimental data concerning electrocardiographic J-waves and J-wave Syndromes (JWS). The authors would like to apologize for possible and unintentional omis-sions of proper acknowledgements and credit to all historic milestones and contri-butions by individuals and institutions to the history of the J-wave and JWS.

History of ECG Phenomena of Early Ventricular Repolarization

Terminology and Defi nitions

The end of ventricular depolarization (VD) and onset of VR coincides on the sur-face ECG with the end of QRS complex and onset of ST-segment at so-called “J” or “junction point”. In the normal heart, the evolution of VD into VR on the surface ECG is not an abrupt yet a relatively short process and there is certain normal “physiological” overlap (~10 ms [ 7 ]) between the end of the QRS complex and beginning of the ST-segment. The prominence (duration and magnitude) of this “overlapping” time-interval is greatly modulated by an early VR transient potas-sium outward current (I to ) that is responsible for the prominent “notch and dome” pattern of action potential (AP) in epicardium (but not in endocardium) resulting in both transmural ventricular gradient and dispersion of the early VR [ 8 – 12 ]. Of note, resulting AP “notch” of mid-myocardium is normally buried inside of the

I. Gussak and G. Gussak

3

QRS. Furthermore, any abnormal conditions or genetic mutations that affect either early VR, delayed VD, and/or transmural or intraventricular conductions can mod-ify the pattern of this timing interval on the surface ECG. Noteworthy, when the right ventricle is paced or left bundle branch block is present, an I to -mediated J-wave is obscured and rarely seen because the activation sequence and timing are signifi -cantly changed.

Debates about whether the J-waves are part of the ST-segment (early repolariza-tion), the QRS complex (delayed depolarization or conduction), both, or neither has been going on for decades. A clear distinction between delayed VD and early VR cannot always be made on the basis of an ECG alone. The distinction of these pro-cesses is important since abnormal early VR is commonly associated with electrical instability, whereas the arrhythmogenic potential of delayed VD due to intraven-tricular conduction defects is much less electrically “malignant”. Nevertheless, ECG phenomena of delayed VD and early VR can be differentiated (to some extent) based on their responses to the changes in (a) heart rate or cardiac cycle length (deceleration-dependence), (b) various drugs, and (c) neuromodulators. Furthermore, ECG phenomena of early VR, unlike intraventricular conduction defects, are dynamic (“wax-and-wane” pattern), share similar clinical (strong male predomi-nance and relatively young age) and various electrophysiological peculiarities, including a common arrhythmic platform related to amplifi cation of the J-wave and its arrhythmogenic potential. Therefore, introduction of the term “J-Wave Syndromes (JWS)” by Yan et al. in 2004–2005 [ 13 , 14 ] was an appropriate evolu-tionary step to outline a new clinical syndrome and now widely accepted by cardiol-ogy community [ 15 ].

The electrocardiographic J-point is defi ned as a point near isoelectric line at which there is abrupt transition from the QRS complex and ST-segment. Deviation of the J-point from isoelectric line leads to the presence of a J-defl ection, which is (together with followed ST-elevation and positive T-waves in the same leads) a common ECG feature of early repolarization syndrome (ERS) and BrS, but also seen in acute myocardial ischemia, hypercalemia, pericarditis, arrhythmogenic right ventricular dysplasia/cardiomyopathy, and various intraventricular conduc-tion defects. If a J-defl ection (due to increased amplitude, duration, and size) takes the shape of a dome or a hump, it is usually referred to as a J-wave (Fig. 1.1 ). Often, the J-wave appears as a J-point elevation, with part of the J-wave buried inside the QRS. Occasionally, “slurring or notching” of the downsloping (termi-nal) portion of the QRS complex is considered as an atypical J-wave [ 16 ]. The prominent J-waves followed by downsloping ST-segment elevation in the right precordial leads is a pathognomonic ECG sign of BrS. In contrast, J-defl ections (followed by upsloping or horizontal ST-segment elevation), particularly in mid-precordial (V3–V5) leads “classical” signature of an early repolarization pattern (ERP) [ 16 ]. The term “ early repolarization syndrome (ERS) ” is best preserved to identify otherwise healthy individuals with such ECG fi ndings who may be at increased risk of ventricular electrical instability leading to SCD [ 3 , 4 ].

1 History of the J Wave and J Wave Syndromes

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Different names have been used at different time for the J-wave. They include “camel hump sign”, “hathook junction’, “K wave”, “H wave”, “late delta wave”, “current of injury”, “J point wave”, “hypothermic wave”, “hypothermic hump”, and “Osborn wave” [ 17 ]. J-waves can be classifi ed as:

(a) Hypothermic, (b) Acquired (Non-hypothermic), and (c) Idiopathic [ 3 ].

History of Hypothermic J-Wave

• The hypothermic J-waves was fi rst reported in 1938 when Tomashewski described as extra slowly inscribed defl ection between the QRS complex and the earliest part of the ST-segment on the ECG obtained from an accidentally frozen man (“ à côté de l ’ onge R on en voit en voit une autre , ressemblant au T en dome ”) [ 18 ].

• In 1940, Kossmann [ 19 ] noted an ECG “alteration in the form of the fi nal ven-tricular defl ections” accompanied by a lowering of body temperature.

• In 1943, Grosse-Brockhoff and Schoedel [ 20 ] produced “a specifi c ventricular conduction disorder (“ oufsteigenden S - Schenkel eine deutliche Nachzacke ”) identical to J-waves in experiments with dogs. This was the fi rst experimental work dedicated to the infl uence of hypothermia on different organ-systems of the body, including a widening of the “secondary defl ection” on the descending limb of the QRS complex and associated arrhythmia.

I aVR V1 V4

V5

V6

V2

V3

aVL

aVF

II

III

Fig. 1.1 Twelve-lead ECG obtained from an accidentally frozen person. Please note a prominent J (Osborn) – wave present in majority of leads


5

• Similar ECG changes induced by hypothermia were described by Bigelow et al. in 1950 [ 21 ] and Juvenelle et al. in 1952 [ 22 ].

• In 1953, Osborn brought attention to the possible the link between the degree of hypothermia, prominence of the J-wave, which he called “current of injury” (later named “Osborn wave”) and ventricular fi brillation [ 23 ].

• In 1959, Emslie-Smith et al. found differences in the endocardial and epicardial responses of ventricular myocardium to hypothermia; J-waves were more promi-nent in epicardial than in endocardial leads [ 24 ].

• In 1959, West et al. demonstrated that “spike and dome” in the epicardial AP in dogs appeared markedly accentuated under hypothermic conditions and the “resulting notch” in the AP was heart rate sensitive; disappearing at increased heart rate [ 25 ].

• Systematic and thorough investigation of the cellular, ionic, and molecular mecha-nisms of J-waves, ST-segment elevation, and their arrhythmogenic potentials under various abnormal conditions (including hypothermia and ischemia), its modulation by rate, drugs, temperature, and neurotransmitters have been initiated by Antzelevitch and his associates from Masonic Research Laboratory (Utica, NY) since 1980s [ 11 , 26 – 29 ]. They fi rst proposed that transmural differences in early phases of the action potential (phases 1 and 2) mediated by a prominent I to current in ventricular epicardium but not endocardium are responsible for inscription of the electrocardiographic J-wave. Direct evidence in support of this hypothesis was obtained in arterially-perfused canine ventricular wedge preparations in 1996 [ 9 ] and open-chest experiments with hypothermia in dogs [ 30 ] pointed out:

(a) Appearance of the J-wave on a surface ECG during hypothermia is modu-lated primarily by changes of the AP shape in epicardial tissue and involved increase in 4-aminopyridine sensitive I to

(b) Phase 2 re-entry (i.e., re-entry within different myocardial layers) is the arrhythmogenic mechanism for I to -mediated ventricular fi brillation

(c) Quinidine via blockade of I to can abolish J-wave and ventricular fi brillation (d) Sodium channels blockers can be used to unmask latent early VR abnormali-

ties and might induce life-threatening ventricular tachyarrhytmias (e) Possible similarities in the pathophysiologic mechanisms between hypother-

mic J wave and ECG marker of Brugada syndrome.

History of Non-hypothermic (Acquired and Idiopathic) J-Waves

Acquired (Non-hypothermic) J-Waves

ECG changes resembling those in hypothermia-induced J-waves have been observed in various abnormal conditions in clinical and experimental settings with normal body temperature, such as myocardial ischemia, acute pulmonary


6

thromboembolism, right ventricular infarction, electrolyte or metabolic disorders, pulmonary or infl ammatory diseases, abnormalities of central or peripheral nervous system, and intoxication by heterocyclic antidepressant or cocaine. Levine et al. [ 31 ] observed ST-segment elevation in the right chest leads with some degree of conduction block in the right ventricle in patients with severe hyperkalemia [ 32 ]. The authors named such RS-T segment shift as “dialyzable current of injury” and postulated that the “wax-and-wane” pattern of this ECG abnormality was dependent on the level of plasma potassium, and not related to the conduction block in the right ventricle. Prominent J-waves most frequently are observed in acute myocar-dial ischemia. A link between the acquired (non-hypothermic) J-waves and elec-trical instability has not been established yet, although experimental studies have demonstrated that, similar to BrS, phase 2 re-entry is the underlying mechanism of ventricular fi brillation in ST-segment elevation acute myocardial infarction [ 31 ]. At present, it is the prevailing opinion that in most clinical settings, the propensity to malignant ventricular arrhythmias associated with this ECG phenomenon is chiefl y dependent upon the underlying disease.

Idiopathic J-Waves

In the absence of any structural cardiac abnormalities or extracardiac diseases, changes of early VR can be classifi ed as primary or “ idiopathic ”. Idiopathic J-waves have been described in the ECG of many species, including human.

In animals . Both the shape and the duration of VR in small rodents, including rats and mice (but not guinea pig), are very striking [ 33 ]. The characteristic features in ECG recordings from these rodents, have been described as “rapid” (accelerated) VR that manifests on the surface ECG as an absence of a distinct isoelectric interval between the QRS complex and the next ECG waveform. The latter wave could be arguably classifi ed as a prominent J-wave.

History and terminology . Confusion and inconsistency have surrounded the ECG interpretation of such unusual manifestation of the ventricular repolarization in small mammals since 1929 , when the fi rst murine ECG was recorded. Agduhr and Stenström reported that they were unable to fi nd “ discernible T waves ” in ECG recordings from mice obtained using a string galvanometer. Although O ’ Bryant and colleagues identifi ed R and T waves in mice 20 years later , a report by Lombard in 1952 described the putative “ R and T waves ” as a “ notch at the end of the QRS complex ,” and again suggested that T waves are absent in mice. Similarly , Richards and coworkers reported in 1953 that a distinct T wave could not be detected in murine ECGs , whereas the T wave was clearly visible in ECGs from guinea pigs. They also mentioned that the “ notch ” between the two peaks of the QRS complex was deepened and the amplitudes of the separated waves were increased in ECG recordings from hypothermic mice. Subsequently , Goldbarg and colleagues sug-gested that this refl ected “ erroneously ascribed T wave .” This recurring confusion led subsequent investigators to use such terms as “ no measurable ST segment ,” “ merging QRS with the T wave ,” or “ lack of distinct ST segment ” to describe the presence of a prominent J - wave ( see more details in the Reference [ 33 ]).


7

Although, the unique features of these rodent ECGs, particularly the prominent J-wave, are not typically seen in larger animals or in humans, they do bear some resem-blance to ECG abnormalities seen in patients with BrS and in other pathophysiologic conditions, including hypothermia and myocardial ischemia. A considerable experi-mental body of evidence suggests that in some murine, including rats and mice, such an ECG morphology is apparently attributable to the presence of large-amplitude rapidly activating and inactivating 4-aminopyridine-sensitive I to that dominates the early phase of VR in these rodents. Importantly, the density of I to in rats and mice is high, whereas this current is minimal or not evident in the ventricular myocytes of guinea pigs.

In humans . Several forms of idiopathic appearance of a J-wave with or without accompanying ST-segment elevation have been described. Prominent J-waves fol-lowed by downsloping ST-segments elevation with inverted T-waves in the right chest leads is an ECG hallmark of the BrS. The ECG prominence of J-waves in both BrS and ERS are dynamic and often referred “wax-and-wane” pattern, likely due to variations of autonomic activity. Of interest, clinical and experimental studies point to high spinal cord injury as a cause of ERS-like changes in the ECG. High cervical spinal cord injury can lead to signifi cant deterioration or even complete disruption of the cardiac sympathetic activity, leaving parasympathetic activity unopposed [ 34 ]. Parasympathetic activation has an opposite effect in both syndromes, causing ST-segment elevation due to depression or loss of the AP plateau [ 11 ].

In addition to the ECG manifestation of BrS, reviewed below J-wave-like ECG abnormalities have been described as case reports in otherwise healthy individuals prone to paroxysmal ventricular tachycardia/fi brillation (Fig. 1.2 ):

• Aizawa and his colleagues [ 35 ] described a several patients with idiopathic ven-tricular fi brillation in whom they found “bradycardia-dependent intraventricular block ”. The common ECG features of these patients included:

(a) Incomplete right bundle branch block (b) Prominent “notch” on downsloping limb of the QRS complex in leads V 3 -

V 5 , II, III, and aVF (c) Elevated ST-segment with positive T-waves leads V 2 –V 3 (d) Rate (bradycardia) – dependent accentuation of the prominence of the “notch” (e) Garg and his associates [ 36 ] reported a case of “familial sudden cardiac

death associated with a terminal QRS abnormality on surface 12-lead elec-trocardiogram”. The abnormal low-amplitude defl ections on the downslop-ing limp of the QRS complex (J-wave-like) in leads II, III, aVF and I, aVL and V6 were coincident with recording of late potentials on signal-averaged electrocardiography. Noteworthy:

(a) Administration of quinidine but not by beta-blockers normalized both surface ECG and signal-averaged ECG

(b) J-waves appeared to be more prominent after procainamide compared to baseline

(c) Sustained polymorphic ventricular tachycardia, which degenerated into ventricular fi brillation was easily inducible during programmed stimulation from the right ventricular apex, despite administration of procainamide or atenolol.


8

History of Idiopathic J-Waves in Brugada Syndrome

To our knowledge, the fi rst clinical report of the unusual electrocardiographic pat-tern consistent with the ECG signature of the BrS was published in:

(a) 1953 by Osher and Wolff [ 37 ]. They described right bundle branch block (RBBB) with persistent elevation of the ST-segment and T-wave inversion in the right precordial leads with minor variations in three healthy males.

05:39

05:34

IaV

RV1

V4

V5

V6

V2

V3

aVL

aVF

IIIII IaV

RV1

V4

V5

V6

V2

V3

aVL

aVF

II

II

III

Fig. 1.2 Development of polymorphic ventricular tachycardia/fi brillation (VT/VF) ( middle trac-ing) in a patient with Brugada syndrome (upper tracing). Please note: (a) appearance of atrial fi brillation and occasional premature ventricular complex (lower tracing) 5 min after termination of VT/VF and (b) deceleration-dependent prominence of J-waves in the right precordial leads


9

(b) One year later (1954), Edeiken identifi ed persistent and apparent RS-T segment elevation without RBBB in another ten asymptomatic males [ 38 ].

(c) In 1960, Roesler observed unusually “high take-off of the R(R’)S-T segment” in the right precordial leads in four patients with hump-shaped elevation of the ST-segment. In each case, the repolarization abnormality was more prominent in the high right chest leads, and neither RBBB nor reciprocal changes in the opposite leads were present [ 39 ].

(d) Similarly, Calo (1975) noted that “the triad of secondary R waves, RS-T seg-ment elevation and T wave inversion in the right precordial leads” was more prominent at higher levels of the electrode position than in routine right precor-dial leads. He noted a benign course in one patient during a 14-year follow-up period. This author also questioned the primary role of RBBB in the genesis of the elevated ST-segment elevation [ 40 ].

(e) Variations in the degree of plateau elevation of the right precordial ST-segment dependent upon displacement of the exploring chest electrodes in an asymp-tomatic individual were included in the textbook on ECG by Marriott [ 41 ].

(f) Apparently, this striking ECG phenomenon had been largely ignored until Martini et al. [ 42 ] and Aihara and et al. [ 43 ] called attention to a possible link between this VR abnormality and SCD in one and four of their patients, respectively.

(g) In 1991 Pedro and Josep Brugada described an additional four patients with sudden and aborted SCD, in whom they found “right bundle branch block and persistent ST segment elevation in leads V1–V3” and in some – additional left anterior hemiblock, PR and/or H-V interval prolongation [ 5 ]. In 1992, based on eight clinical cases, they outlined a new “distinct clinical and electrocardio-graphic syndrome” [ 6 ].

(h) In 1994, prior to introducing BrS as a primary electrical diseases of the heart in 1999 [ 44 ], ECG manifestation of the BrS on 12-lead ECG was coined as a “prominent J-wave” in right chest leads [ 45 ].

The term “Brugada syndrome” was introduced during a cardiology confer-ence on SCD organized by the brothers Brugada in July 1995 and held in the Cardiovascular Center OLV Hospital in Aalst, Belgium. Use of the term Brugada syndrome (known in Belgium at this time also as “Brugi-Brugi syndrome”) was proposed in lieu of the original lengthy description. The fi rst literature reference to the newly named Brugada syndrome was documented in 1996; Yan and Antzelevitch [ 9 ] highlighted the importance of the ST-segment elevation described by Brugada and Brugada as the basis for a substrate capable of giving rise to malignant arrhythmias. Kobayashi et al. [ 46 ] and Miyazaki et al. [ 47 ] fol-lowed suit the same year.

At the same conference in Aalst (1995), Nademanee pointed out similarities in both the electrocardiographic and the clinical presentations between patients with Brugada syndrome and victims of sudden unexplained death syndrome, a disorder most prevalent in Southeast Asia, which had been highlighted in the US govern-ments Morbidity and Mortality Weekly Reports since, 1981 [ 48 ].


10

• Sudden and unexpected death of young adults during sleep, known in the Philippines as bangungut (“to rise and moan in sleep”), was fi rst described in the Philippine medical literature in 1917.

• In 1997, Nademanee et al. [ 49 ] reported that a majority of Thai men referred for aborted cases of what was known in Thailand as Lai Tai (“death during sleep”) displayed ECG patterns typical of Brugada syndrome.

• Alings and Wilde reviewed the literature in 1999, and reported that of 163 patients who met the criteria for Brugada syndrome, 58 % were of Asian origin [ 50 ].

The terms “transient, latent, and manifested” and “symptomatic and asymptom-atic” forms of the syndrome were also introduced by Brugada brothers.

History of J-Waves in Early Repolarization Pattern and Syndrome

The term “early repolarizations syndrome” was introduced more than half a century ago and, similarly to BrS, had been regarded as typically benign, “innocent” or “mis-leading” [ 1 , 2 ] ECG pattern of VR, often found in young, thin, athletic males (Fig. 1.3 ). The ERS has been ascribed a number of names, including “early repolarization”, “early ventricular repolarization”, “benign early repolarization”, “benign J-wave”, “aspecifi c changes of ventricular repolarization”, “repolarization variant”, “normal variant RS-T segment elevation”, and “juvenile or unconventional ST-T pattern” [ 4 ].

• An early repolarization (ER) pattern on the ECG was fi rst described in 1936 by Shipley and Hallaran, who studied four-lead ECGs of 200 healthy young men and women and described J-defl ection as slurring or notching of the terminal part of QRS complex and considered it as a normal variant [ 51 ].

Fig. 1.3 Twelve-lead ECG obtained from a young male athlete. Please note: (a) prominent J-wave defl ection (particularly in leads V5 and II), (b) diffuse upward ST-segment concavity concordant with the QRS complex, and (c) positive T-waves in the same leads


11

• Subsequently, ST-segment elevation was added by Grant (1951) to these ECG manifestations and the complex was designated “early repolarization” based on the presumption that early repolarization was responsible [ 52 ] although no data was available to support this assertion.

• Experimental data in support of the hypothesis was fi rst advanced with the iden-tifi cation of the cellular basis for the J-wave in 1996 by Yan and Antzelevitch [ 9 ].

• In 2000, the “benign” nature of ERS was challenged [ 4 ] on the basis of available experimental data suggesting that:

(a) Early repolarization pattern should not be considered as either normal or benign a priori and

(b) Under certain conditions known to predispose ST-segment elevation, sub-jects with early repolarization pattern may be at greater arrhythmogenic risk.

In 2008, validation of this hypothesis was provided by Haïssaguerre et al. [ 53 ], and a letter to the editor by Nam et al. [ 54 ] in the New England Journal of Medicine . These reports together with numerous additional case control and pop-ulation based studies provided clinical evidence that there is an increased preva-lence of early repolarization, particularly in the inferior and inferior-lateral leads, among patients with a history of idiopathic ventricular fi brillation, thus confi rm-ing a link between early repolarization pattern and life-threatening cardiac arrhythmias [ 55 ]. The recently published “Expert Consensus on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes” has noted that an “ER pattern can be diagnosed in the presence of J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG”. If such an individual has suffered SCD or been resuscitated from idiopathic ven-tricular fi brillation and has such ECG fi ndings, the entity is referred to as the “Early Repolarization Syndrome” [ 15 ].

Epilogue

Since discovery of the BrS, abnormal early VR has rapidly gained recognition as a major cause of SCD and also dramatically accelerated a series of remarkably insightful discoveries in experimental and genetic cardiac electrophysiology that have revolutionized our understanding of the ionic, cellular and molecular mecha-nisms that underlie life-threatening arrhythmias, particularly those related to early VR. Combined efforts of researchers and clinicians have culminated in:

(a) Delineating of a new set of cardiac diseases called “primary electrical diseases and syndromes”

(b) Dramatically improved identifi cation and stratifi cation of patients at risk of SCD,

(c) Prevention of SCD in many otherwise healthy individuals, and (d) Prevention of iatrogenic arrhythmogenic complications (e.g., use of sodium

channels blockers in BrS) in patients.


12

JWS occupies a prominent portion of the time devoted to cardiac arrhythmias at national and international meetings, and continuing to appear in publications on the subject continue to appear at a brisk rate. More questions than answers still remain with regard to etiology, pathogenesis, arrhythmogenesis, risk stratifi cation, epide-miology, prevention, and treatment of the JWS. These and other ambiguities con-cerning diagnosis and arrhythmogenic potential of the JWS have prompted an “Expert Consensus Conference on J-wave Syndromes. Mechanisms, Diagnosis, Prognosis, Risk Stratifi cation and Treatment of Brugada and Early Repolarization Syndromes” to be held in Shanghai, China on April 21–23, 2015.

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