Electrocardiography of Inherited Arrhythmias and Cardiomyopathies: From Basic Science to Clinical Practice [1st ed.] 9783030521721, 9783030521738

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Electrocardiography of Inherited Arrhythmias and Cardiomyopathies From Basic Science to Clinical Practice Martin Green Andrew Krahn Wael Alqarawi  Editors

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Electrocardiography of Inherited Arrhythmias and Cardiomyopathies

Martin Green  •  Andrew Krahn Wael Alqarawi Editors

Electrocardiography of Inherited Arrhythmias and Cardiomyopathies From Basic Science to Clinical Practice

Editors Martin Green Department of Medicine University of Ottawa Ottawa, ON Canada

Andrew Krahn Department of Medicine University of British Columbia Vancouver, BC Canada

Wael Alqarawi Department of Medicine University of Ottawa Ottawa, ON Canada

ISBN 978-3-030-52172-1    ISBN 978-3-030-52173-8 (eBook) https://doi.org/10.1007/978-3-030-52173-8 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

Arrhythmias associated with heritable heart diseases are important to understand, especially since they tend to strike young, and often previously asymptomatic individuals. The first test which may reveal abnormalities in these individuals is almost always the electrocardiogram. The ECG may be performed as part of screening or “case finding” in individuals with symptoms which may suggest arrhythmias. There are few comprehensive, detailed, and high-quality resources for practitioners to consult with respect to the range and nature of ECG abnormalities in inherited arrhythmia syndromes. This book fulfills an extremely important niche and brings together in a convenient and elegantly written and illustrated format the latest information regarding ECG abnormalities. Importantly, many of the syndromes discussed are only diagnosable from the ECG, which remains the essential test in clinical diagnosis. Drs. Green, Krahn, and Alqarawi have assembled the world experts in these various conditions to produce a practical and visually appealing compendium of ECGs in these various syndromes, which can lead to serious and potentially fatal arrhythmias. The explanatory text and background in each chapter is especially informative and useful. This book will be of great use to generalists and specialists alike, especially individuals that are called upon to evaluate individuals being screened or investigated for familial arrhythmia syndromes. If you are looking for the one definitive source of information on this topic, you have found it. Division of Cardiology University of Toronto Toronto, ON, Canada

Paul Dorian, MD, MSc, FRCPC, FHRS

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Acknowledgement

The editors share a common heritage of mentors poring over an ECG, seeking to better understand those fascinating signals from the hearts of patients they care for. Founders like Hein Wellens and George Klein instilled that interest and excitement about the ECG in us, and we have turned that focus to inherited arrhythmia related conditions, our clinical passion. Remarkably, the ECG is still teaching us many things about patients and heart. This can only happen with the support of the “village” in which we live, including teachers, trainees, peers and of course, patients and their families. Fellows ask us “why challenge accepted uncertainty?” and push us to answer questions. Thank you for insisting that we better understand the ECG and its implications for patients. We have made every effort to “pay it forward”, by becoming teachers and mentors to the students around us as we too continue to learn. Dr. Green taught Dr. Krahn in the 1980s, and he in turn taught Dr. Alqarawi not so long ago. Lastly, we are grateful to our partners who have shown unconditional support for our preoccupation with learning and teaching the world of ECGs. Thank you, Nancy, Susan and Arwa.

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Contents

Part I Inherited Arrhythmias 1 Long QT Syndrome ����������������������������������������������������������������������������������   3 Andrew Krahn, Wael Alqarawi, and Peter J. Schwatz 2 Brugada Syndrome������������������������������������������������������������������������������������  25 Chiara Scrocco and Elijah R. Behr 3 Short QT Syndrome����������������������������������������������������������������������������������  41 Jason Gencher, Bishoy Deif, and Jason D. Roberts 4 Early Repolarization Syndrome ��������������������������������������������������������������  51 Arnon Adler 5 Catecholaminergic Polymorphic Ventricular Tachycardia��������������������  67 John R. Giudicessi and Michael J. Ackerman 6 Idiopathic Ventricular Fibrillation ����������������������������������������������������������  79 Michael H. Gollob Part II Inherited Cardiomyopathies 7 Arrhythmogenic Cardiomyopathy ����������������������������������������������������������  85 V. M. Proost and Arthur A. Wilde 8 Hypertrophic Cardiomyopathy���������������������������������������������������������������� 117 Charles A. S. Miller, Ethan J. Rowin, and Martin J. Maron 9 The PRKAG2 Cardiac Syndrome������������������������������������������������������������ 125 Wael Alqarawi, Michael H. Gollob, and Martin Green Part III ECG in Athletes 10 ECG in Athletes������������������������������������������������������������������������������������������ 137 Mark Abela and Sanjay Sharma Index�������������������������������������������������������������������������������������������������������������������� 159

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Contributors

Mark  Abela  Cardiology Clinical Academic Group, St. George’s, University of London, St. George’s University Hospitals NHS Foundation Trust, London, UK Faculty of Medicine & Surgery, University of Malta, Mater Dei Hospital, Msida, Malta Michael  J.  Ackerman  Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN, USA Arnon  Adler  Department of Cardiology, Toronto General Hospital and the University of Toronto, Toronto, ON, Canada Wael  Alqarawi  Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada Elijah  R.  Behr  Cardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George’s University of London, London, UK St George’s University Hospitals’ NHS Foundation Trust, London, UK Bishoy  Deif  Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada Jason  Gencher  Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada John  R.  Giudicessi  Department of Cardiovascular Medicine (Clinician-­ Investigator Training Program), Mayo Clinic, Rochester, MN, USA Michael H. Gollob  Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada Martin Green  Department of Medicine, University of Ottawa, Ottawa, ON, Canada Andrew  Krahn  Department of Medicine, University of British Columbia, Vancouver, BC, Canada xi

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Contributors

Martin J. Maron  Tufts Medical Center, Boston, MA, USA Charles A. S. Miller  Tufts Medical Center, Boston, MA, USA V.  M.  Proost  Amsterdam UMC, Location AMC, Heart Centre, Amsterdam, Netherlands Jason D. Roberts  Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada Ethan J. Rowin  Tufts Medical Center, Boston, MA, USA Peter  J.  Schwatz  Istituto Auxologico Italiano, IRCCS  – Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy Chiara  Scrocco  Cardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George’s University of London, London, UK St George’s University Hospitals’ NHS Foundation Trust, London, UK Sanjay Sharma  Cardiology Clinical Academic Group, St. George’s, University of London, St. George’s University Hospitals NHS Foundation Trust, London, UK Arthur  A.  Wilde  Amsterdam UMC, location AMC, Heart Centre, Amsterdam, Netherlands

Part I Inherited Arrhythmias

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Long QT Syndrome Andrew Krahn, Wael Alqarawi, and Peter J. Schwatz

Introduction The long QT syndrome (LQTS) is a life-threatening disease that represents a leading cause of sudden cardiac death in the young [1]. The ECG features of this disease are QTc prolongation and T-wave abnormalities at rest and failure of the QTc to shorten with exercise [2]. Approximately one in 2500 healthy live births will have an abnormally long QT interval and a genetically mediated LQTS, transmitted via an autosomal dominance inheritance pattern [3]. One of the characteristic features of LQTS is the marked heterogeneity of patients, ranging from sudden death in infancy to lifelong asymptomatic disease carriers [4]. Only one third of patients will ever be symptomatic. As many as 40% of LQTS patients will have normal or non-­ diagnostic QT intervals at rest [5–7]. With improved screening and therapy, the mortality rate in LQTS has dropped dramatically [1]. Lifestyle modifications such as avoidance of strenuous exercise, unsupervised swimming and QT-prolonging medications are advocated for all patients. Beta-blocker therapy is the primary treatment, offering substantial protection from fatal cardiac events [8]. Patients who have cardiac events while on beta-­blockers, have suffered a cardiac arrest, or are deemed sufficiently high risk can be offered left cardiac sympathetic denervation or an implantable

A. Krahn Department of Medicine, University of British Columbia, Vancouver, BC, Canada W. Alqarawi Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada P. J. Schwatz (*) Istituto Auxologico Italiano, IRCCS – Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. Green et al. (eds.), Electrocardiography of Inherited Arrhythmias and Cardiomyopathies, https://doi.org/10.1007/978-3-030-52173-8_1

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cardioverter-­defibrillator (ICD) [9–11]. ICD therapy, however, has lifelong implications, and complications are common and even expected when the recipient has had the device for decades. ECG remains the cornerstone of phenotype recognition, with incremental value in provoking diagnostic QT changes with exercise testing [14, 15]. At the molecular level, there are three major LQTS genes (KCNQ1, KCNH2 and SCN5A) that account for approximately 80% of the disorder [12, 16]. Fifteen other genes have been associated with LQTS, the majority of which account for 1–2% of all cases [12, 16, 17]. Genetic testing can inform the diagnosis, prognosis and family screening of patients with suspected LQTS [12, 13, 17]. Genotype-phenotype correlations have shown distinct gene-specific triggers, response to medical therapies and ECG patterns [18]. Insufficient distinct phenotype data exist for the rare forms of LQTS, so the three major LQTS genes and Andersen-Tawil syndrome (ATS) with clear ECG patterns will be discussed in this chapter. ECG Findings 1 . Prolonged QT interval (a) QT measurement (Fig. 1.1a, b) (b) Corrected QT interval (QTc) (Fig. 1.2) 2. Specific T-wave morphologies (a) LQT1 (Fig. 1.3) (b) LQT2 (Figs. 1.4a, b; and 1.6) (c) LQT3 (Fig. 1.5) a

b

Fig. 1.1 (a) Tangent method: the end of the T wave is defined as the point where the tangent on the steepest point of the terminal limb of the T wave intersects with the isoelectric baseline, which is obtained by connecting the T wave of the preceding complex to the P wave. Note that the QT here is 580  ms. (b) Tangent method: note the notched T wave and the different slopes of the descending limb of the T wave. It is important to differentiate the notching noted here from a U wave. U waves are virtually never larger than T waves, so instances where notched T waves have a second component of the T wave that is greater in amplitude than the first (T’) should include the second component of the T wave in the QT interval calculation. In this instance, it is possible that the tangent method underestimates the end of repolarization (i.e. QT duration); it is most commonly used and reproducible. The QT here is 460 ms

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Fig. 1.2  The corrected QT interval (QTc) by Bazett’s method is obtained by dividing the QT intervals in milliseconds (ms) by the square root of the preceding RR interval measured in seconds (sec) (QTms/√RRsec). The QT interval in this example is 440 ms by the tangent method. The RR interval is 0.84 sec. As such, the QTc is 471 ms. Note the long isoelectric line followed by a relatively normal morphology T wave, typical in this patient with LQT3

Fig. 1.3  The classic T-wave morphology in a patient with LQT1. The T wave is broad-based with normal voltages. Note the prolonged upslope of the T wave with a relatively normal terminal portion

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a

b

Fig. 1.4 (a) The classic T-wave morphology in LQT2 is notched (+/− low amplitude). Note the eccentric shape of the T wave, with notching which is most obvious in V4 (magnified in Fig. 1.5). T-wave amplitude is normal in this patient (T-wave amplitude >10% of QRS). (b) Magnified T-wave morphology in LQT2

Fig. 1.5  The classic T-wave morphology in LQT3 is a long isoelectric ST segment, followed by a relatively normal T wave. The poor R-wave progression is an incidental finding that was not related to LQT3 in this patient. The patient had no other evidence of heart disease

1  Long QT Syndrome Fig. 1.6  Different T-wave morphologies in affected members of the same family. The proband, with cardiac arrest as first manifestation of LQTS, has deep negative T waves in the precordial leads and a very prolonged QTc. His asymptomatic sister has biphasic T waves. His father, with notched T waves and a QTc 584 ms, had two episodes of syncope. The arrows point to examples of notched T wave. (From: Schwartz et al. [38])

7 Proband G.T. 7 years QTc: 630 ms

Sister S.T. 10 years QTc: 605 ms

Father V.T. 37 years QTc: 584 ms

3. Andersen-Tawil syndrome (LQT7) (a) Prominent U wave (Fig. 1.7) (b) Polymorphic ventricular tachycardia (PMVT) at rest (Fig. 1.8) (c) Exercise treadmill test (ETT) (Figs. 1.9a, b) 4. Dynamic QT interval changes (a) LQT1 with ETT (Fig. 1.10a–c) (b) LQT2 with ETT (Fig. 1.11a–c) (c) LQT2 with standing test (Fig. 1.12a, b) 5. T wave alternans (Figs. 1.13, 1.14 and 1.15) 6. LQTS mimics (a) Hypocalcaemia (Fig. 1.16) (b) Structural heart disease (Fig. 1.17) (c) Ischaemia (Figs. 1.18 and 1.19)

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Fig. 1.7  This ECG was obtained from a patient with ATS. Note the prominent U wave in V2 and V3. It should be mentioned that the U wave should be excluded in the measurement of the QT interval, historically termed pseudo-QT prolongation in ATS.  In this case, for example, the QT interval by the tangent method is 420 ms. Including the U wave would result in an extreme QT interval value (QT = 600 ms)

Fig. 1.8  This ECG shows frequent polymorphic (bidirectional) PVCs in a bigeminal pattern at rest in a patient with ATS

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a

b

Fig. 1.9 (a) Exercise ECG in a patient with ATS taken at peak exercise. It shows frequent PVCs in a bigeminal pattern, with late-coupled PVCs with variable fusion with intrinsic conduction. Note two different morphologies in lead III. (b) This is the same patient at 11 min in recovery. The persistence of PVCs in recovery is an important feature to differentiate ATS from CPVT

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Prolonged QT Interval ECG Description The QT interval is defined as the interval from the onset of the QRS complex to the end of the T wave [19]. In leads with no Q or R wave, the earliest ventricular activation should be defined as the onset of the QT interval. Defining where the T wave

a

b

Fig. 1.10 (a) This is a resting ECG from a patient with LQT1 and a borderline prolonged QT at rest. The QT is 420  ms (QTc  =  463  ms). (b) Same patient at 4-min recovery. QT is 420  ms (QTc  =  509  ms). Values ≥445  ms at 4-min recovery is suggestive of LQTS.  Note that at rest (Fig. 1.10a), the QT is normal, which highlights the important role of exercise in the provocation of abnormal QT dynamics. (c) Same patient at 1-min recovery. The QT is 320 ms (QTc = 482 ms). Values ≥460 ms are suggestive of LQTS1 (confirmed in this case)

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c

Fig. 1.10 (continued)

ends can be challenging. The “tangent method” is an easily applied method that has been used to standardize the QT interval measurement (described in Fig. 1.1a) [20]. There is diversity of opinion on the merits of the tangent method and the basis thereof, with proponents arguing the simplicity and reproducibility of the method. On the other hand, the pathophysiology of the repolarization currents suggests this technique is misleading because IKr and IKs reductions are often (though not always) associated with a delayed return of the T wave to baseline despite a fast initial downslope. This then argues that the tail of the T wave represents important late repolarization that should not be ignored with a technique such as the tangent method. Both perspectives make valid points, with a mixture of loyalty within the vested community. With the tangent method, the end of the T wave is defined as the point where the tangent on the steepest point of the terminal limb of the T wave intersects with the isoelectric baseline, which is obtained by connecting the T wave of the preceding complex to the P wave. While the “tangent method” is widely used in clinical practice and is the basis of QT measurement in many studies in the LQTS literature, it is important to note that it likely underestimates the true length of the QT interval, and as such, care should be taken when applying this method in patients with two different slopes of the descending limb of the T wave. Additional important technique recommendations are to avoid attempts to measure the QT interval when the T-wave complex is very small, which leads to spurious errors in measurement. It is also important to exclude the U wave. U waves are virtually never larger than T waves, so instances where notched T waves have a second component of the T wave that is greater in amplitude than the first (so-called T’) should include the second component of the T wave in the QT interval calculation (Fig. 1.1b). The QT interval should be measured in the lead with the longest QT interval and should be adjusted for gender, heart rate and QRS duration. In general, women have

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longer QT intervals than men, which is reflected in the cut-off values proposed to suspect LQTS (470 ms for men and 480 ms for women) and in the weighted points assigned by the Schwartz risk score for the QT interval [6, 8, 14, 19, 21]. Many formulas have been proposed for QT correction for heart rate. The most widely used is the formula derived by Bazett in 1920 that is endorsed by guidelines [11, 22]. Although reasonable arguments suggest that the Framingham, Hodges and Fridericia formulas are mathematically more robust, the Bazett correction is the basis of virtually all diagnostic and prognostic information in LQTS, and it reflects a reasonably linear relationship correction at physiologic resting heart rates and is useful also in infants [23]. The QRS duration in LQTS is almost always normal, and as such QT correction for QRS duration is not discussed in this chapter [24].

Pathophysiologic Explanation The QT interval is a measure of ventricular depolarization and repolarization. LQTS is caused by ion channels’ dysfunction resulting in prolonged repolarization, which manifests on ECG with a prolonged QT interval. A critical feature of normal cardiac repolarization is its ability to adapt to heart rate, which ensures that the myocardium remains constantly excitable. This necessitates the need to correct for heart rate when measuring the QT interval.

Fig. 1.11 (a) This is a resting ECG from a first-degree relative of a confirmed patient with LQT2. Note the normal QT interval at rest. QT is 460 ms (QTc = 428 ms). (b) Same patient at 4-min recovery. QT is 440  ms (QTc  =  468  ms). Values ≥445  ms at 4-min recovery are suggestive of LQTS.  Note that at rest (Fig.  1.11a), the QT is normal, which highlights the important role of exercise in the provocation of abnormal QT dynamics. Also note the somewhat flattened T-wave morphology with an eccentric T wave with subtle notching or humps, suggestive of LQT2. (c) Same patient at 1-min recovery. QT is 360 ms (QTc = 420 ms). Note the normal QTc, which is classic for LQT2, with a normal T-wave morphology

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b

c

Fig. 1.11 (continued)

Specific T-Wave Morphologies ECG Description At present, T-wave morphology is a largely visual-pattern-related description. Active signal processing analytics and artificial intelligence promise to bring greater structure, sophistication and accuracy of analysis in the near future. Genotype-­specific T-wave morphologies have been described for the main LQTS types (LQT1, LQT2 and LQT3), but many exceptions exist. Even members of the same family, all carrying the same mutation, may have very different repolarization patterns (Fig. 1.6). It is important to remember that T-wave morphology is not a substitute for genetic testing. Each morphology is discussed with an example provided.

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a

b

Fig. 1.12 (a) This is a resting ECG from a patient with LQT2 and a normal QTc interval. QT is 520 ms (QTc = 450 ms). Note the low T-wave amplitude in the inferior leads. (b) Same patient after standing with minimal increase in heart rate (47 bpm at rest to 63 bpm after standing). QT is 520 ms (QTc = 533 ms). Again, note that the QT remained the same (i.e. failed to shorten), and as a result of the increase in heart rate, the QTc is prolonged

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Fig. 1.13  This ECG shows T-wave alternans with beat-to-beat alternating variation in the amplitude and polarity of the T wave at peak exercise. Note the dramatically prolonged QTc at high heart rates in conjunction with the alternans, consistent with the underlying diagnosis of LQT1

Fig. 1.14  This ECG shows much more subtle evidence of T-wave alternans with beat-to-beat alternating amplitude in leads V1 to V3. Note two late-coupled PVCs likely due to early after depolarization (EAD)

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Fig. 1.15  Example of T-wave alternans from a 2-year-old long QT syndrome patient carrying the CALM1-D1306 mutation and who had multiple episodes of cardiac arrest. Tracings are from a 24-hour Holter recording. (From: Schwartz et al. [1])

Fig. 1.16  This is obtained from a patient with severe hypocalcaemia (Ca 1.8 mmol/L). Note the prolonged QT with long isoelectric ST segment similar to LQT3 (Fig. 1.5). This is due to prolonged phase 2 of the AP. Hypocalcaemia generally does not cause T-wave inversions as it does not affect phase 3 of the AP, which makes it undistinguishable from LQT3 on ECG [36]

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Fig. 1.17  This ECG is obtained from a patient with hypertrophic cardiomyopathy. Note the prolonged QT interval (QT = 400 ms, QTc = 484 ms). However, there is also LVH by Sokolow-Lyon criteria and diffuse T-wave inversions. ECG abnormalities in LQTS are usually confined to QT prolongation, bradycardia and/or anterior T-wave inversion (in LQT2) [24]. Other ECG abnormalities should raise the suspicion for structural heart disease. Remodelling of the ion channels in patients with LVH is thought to be the cause of the prolongation in AP, which manifests as a long QT interval on ECG, along with prolonged depolarization secondary to hypertrophy [37]

Fig. 1.18  This was obtained from a patient with inferior ST-segment elevation myocardial infarction (STEMI). It shows the initiation of PMVT.  Note the normal QT interval (QT = 360  ms, QTc = 451 ms), marked ST elevation, normal to elevated resting heart rate and the short coupling interval of the first PVC

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Fig. 1.19  This was obtained from a patient with LQTS and shows TdP. Note the long QT interval and the long coupling interval of the initiating PVC

Pathophysiologic Explanation The T wave represents ventricular repolarization, which generally proceeds from epicardium to endocardium due to the shorter action potential (AP) of the cardiac myocytes in the sub-epicardial region [25]. This results in a concordant T wave with QRS as polarity is reversed between depolarization and repolarization and explains the normal T-wave polarity in the vast majority of patients with LQTS as depolarization is rarely affected. In LQT1, reduced IKs current prolongs the AP of all cell types, resulting in QT prolongation with less significant change in T-wave morphology, whereas reduced IKr current in LQT2 might produce disproportional prolongation of the AP, resulting in increased transmural dispersion and notched T waves as described in an animal model [26, 27]. The T wave in LQT3 is characterized by a long ST segment due to a prolonged phase 2 of the AP as a result of persistent sodium current (failed inactivation) resulting in a gain of function [26].

Andersen-Tawil Syndrome (ATS) ECG Description The classic ECG features of ATS are pseudo-QT prolongation with a prominent U wave and frequent premature ventricular contractions (PVCs), including polymorphic ventricular tachycardia (PMVT) at rest. Some patients have exercise worsening

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of PVCs, but ambient PVCs are a hallmark. The U wave is best seen in V2 to V4 and does not disappear at fast heart rate. The QT interval is often normal when the U wave is excluded [28]. Exercise provokes PVCs, but a distinguishing feature between ATS and catecholaminergic polymorphic ventricular tachycardia (CPVT) is the presence of PVCs at rest and during recovery.

Pathophysiologic Explanation The origin of the U wave in ATS is controversial; however, due to the important role of Ik1  in the final repolarization of the AP, one potential explanation is that the reduced Ik1 generates the U wave by delaying late repolarization of APs. This also creates delayed after depolarizations (DADs), which promotes polymorphic VT by triggering DADs at multiple shifting sites, which explains the PMVT seen in the resting ECG of ATS patients [29].

Dynamic QT Interval Changes ECG Description Given the QT adaptation to heart rate changes seen in healthy states, heart rate acceleration and deceleration provide an opportunity to evaluate for the presence of failed shortening of the QT interval and provoke morphology changes to unmask evidence of long QT syndrome. A simple algorithm based on exercise testing has been widely adopted which uses a QTc ≥445 ms at 4-min recovery to distinguish LQTS versus controls and a QTc 140 ms) duration after sodium channel provocation test, and HV interval ≥60 ms at invasive electrophysiological study can predict the presence of an SCN5A mutation [28]. In a study on 325 BrS patients, first-degree AV block was independently associated with SCD or implantable cardioverter-defibrillator appropriated therapies (OR 2.41) [29]. Right ventricular delay had been recognized as pathognomonic of the Brugada ECG since its original description in 1992. Although clear identification of the J point in the leads showing a “coved” type 1 ECG pattern is not always possible, a clear mismatch in QRS duration between the right and left precordial leads is evident in most cases, suggesting a localized right ventricular delay with no reciprocal changes in the left leads (Fig. 2.2). In the absence of a typical RBBB morphology, broad and deep S waves in the left-sided limb leads represent conduction delay in the RVOT, and the presence of a deep, broad S wave (amplitude >0.1  mV and/or duration >40 ms) in lead I has been associated with increased risk of VF/SCD [30].  RS Fragmentation (fQRS) Q QRS fragmentation (fQRS) has been defined as the presence of an additional R wave (R’) or notching in the nadir of the R wave or the S wave or the presence of >1 R’ (fragmentation) in two contiguous leads (Figs. 2.1 and 2.2). In the presence of

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a

b

Fig. 2.6  Right ventricular delay and “coved” type 1 Brugada ECG. Panel A: resting 12-lead ECG with V1 and V2 recorded in the fourth, third (E1−E2), and second (E3−V3) intercostal spaces in an index patient. Panel B: resting 12-lead ECG of index patient’s father. A 40-year-old man was admitted after a pre-syncope while driving. During his inpatient stay, an episode of sinus arrest with an 18-second pause was recorded. His ECG (Panel A) shows a spontaneous “coved” type 1 Brugada ECG with complete RBBB and fQRS in the right precordial leads. Screening of his family members revealed similar changes in his 66-year-old father (Panel B). Note the first-degree AV block and the broad QRS complex (170 ms) with a spontaneous “coved” type 1 V1 to V2. Cardiac MRI in the father showed normal RV size with mildly impaired systolic function but no obvious regional thinning or wall motion abnormalities. Coronary angiogram revealed noncritical multivessel coronary artery disease managed with medical therapy. Both patients were found to carry a pathogenic SCN5A variant, and the son underwent transvenous dual chamber ICD implantation. The father also elected to undergo ICD implantation following counselling

QRS complexes >120 ms, at least two notches in the R or the S wave must be present (Fig. 2.6). First described in patients with coronary artery disease and myocardial scar, fQRS can also be seen in other conditions such as cardiomyopathies and congenital heart disease. fQRS indicates changes in the direction of ventricular activation caused by scar tissue that can be a substrate for reentrant arrhythmias in heart disease [31], including BrS [32]. In a study on 456 BrS patients, the presence of fQRS in the inferior, lateral, or right precordial leads was associated with VF events, with worse prognosis in those with diffuse localization, suggesting a more extensive disease [33].

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 eripheral Leads Showing the BrS Pattern P The heterogeneity of the Brugada ECG phenotypic expression can lead to “atypical” localization of the “coved” type 1 pattern at baseline or during sodium channel blocker provocation test. Batchvarov et al. found that a diagnostic type 1 pattern in the peripheral leads could be observed in 4.2% of patients during ajmaline test (10.3% of positive tests) and was associated with longer QRS and greater QTc prolongation [34]. In a more recent study of 327 BrS patients, the simultaneous presence of a spontaneous or drug-induced “coved” type 1 in the right precordial and inferior/lateral leads was detected in 9% of the cases and was independently associated with malignant arrhythmic events. This was more frequent in subjects carrying a pathogenic SCN5A variant and has been speculated to be a sign of a more extensive underlying abnormal myocardial substrate [35].  arly Repolarization and BrS Pattern E The presence of an end-QRS slur or notch ≥0.1 mV in the infero-lateral leads, with or without concomitant ST-segment elevation, is known as early repolarization pattern (ERP). ERP is a common ECG finding (estimated incidence 1–13%) and is usually considered innocent among healthy asymptomatic young, although in the last decade it has been associated with idiopathic VF (early repolarization syndrome (ERS)) [4] and the occurrence of arrhythmias in both structural and nonstructural heart disease. In a study of 280 BrS patients, ERP was present in 11% of subjects at baseline ECG and in 8% after sodium channel blocker provocation test. It was associated with a higher likelihood of both spontaneous and drug-induced diagnostic “coved” type 1 pattern (Fig. 2.5) and the incidence of symptoms [36]. In a Japanese cohort, the prevalence of ERP was as high as 63% and persistent ERP invariably associated with VF recurrence [37]. An emerging concept that BrS and ERS could be part of the same spectrum of diseases named “J wave syndromes” offers interesting speculations on the interplay between repolarization and depolarization abnormalities in these two conditions [1].  peak-Tend Interval and Dispersion of Repolarization T Increased transmural dispersion of the repolarization within the ventricular myocardium has been suggested to underlie arrhythmogenesis in both structural and nonstructural cardiac conditions, including hypertrophic cardiomyopathy, congenital and acquired long QT syndrome, and congenital short QT syndrome. Prolonged QTc (≥460 ms in V2) and Tpeak-Tend intervals (≥100 ms) in the precordial leads, together with increased Tpeak-Tend dispersion at baseline ECG, have been associated with higher risk of arrhythmias in BrS patients [38, 39].

Pathophysiology of the Brugada ECG The cellular mechanisms underlying the Brugada ECG and the occurrence of polymorphic VT/VF are still debated; two main hypotheses have been advanced that propose either underlying repolarization or depolarization abnormalities [19, 40].

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Under normal conditions, the J wave is relatively small or absent in the anterior precordial leads and the ST segment is isoelectric. The J point and ST elevation as well as T-wave inversion seen in the type 1 Brugada pattern arise due to transmural voltage gradients between the epicardium and the endocardium at the RVOT. The repolarization theory asserts that a net outward shift of cellular current is created by increased transient outward potassium currents (It)o or by decreased inward currents, either L-type calcium current and/or peak INa. This leads to dispersion of transmural repolarization due to prolonged endocardial action potential duration relative to the epicardium, causing J point and ST elevation on the surface ECG. This is heterogeneous and leads to local epicardial reexcitation, T-wave inversion on the ECG, and the potential for phase 2 reentry arrhythmias [1, 41]. The depolarization hypothesis asserts that dramatically slowed conduction in the RVOT epicardium versus the endocardium is responsible for transmural voltage gradients and hence J point and ST elevation, followed by the inverted T wave. This gives rise to prolonged and delayed abnormal late potentials at the RVOT epicardium that may act as the substrate for reentrant arrhythmias. Slowed conduction is secondary to subtle fibrosis and reduced gap junction expression at the RVOT epicardium and a net reduction of inward cellular currents impairing the safety of conduction at high-resistance junctions such as regions of extensive fibrosis and Purkinje fiber ventricular myocyte junctions [42, 43]. The balance of data in the human seems to support the latter hypothesis, but it is possible that both mechanisms may coexist to varying extents in different patients.

 rugada Syndrome and ECG Diagnostic Criteria (Consensus B Conferences and Expert Recommendations) The first appearance of a “coved” ST-segment elevation resembling a typical Brugada type 1 pattern dates back to 1989, when Martini presented a case series of six subjects with resuscitated VF and a structurally normal heart [44]. Later, in 1992, the “Right bundle branch block and persistent ST segment elevation Syndrome” was described in eight cardiac arrest survivors by Pedro and Josep Brugada [6]. In 2002, a consensus report first defined the diagnostic Brugada ECG as a coved-type ST elevation in the presence of at least a 2-mm  J/ST elevation (“coved” or type 1 pattern) in the right precordial leads (V1 to V3), either occurring spontaneously or after a sodium channel blocker provocation test (i.e., type 2 or 3 conversion into type 1). The diagnosis of BrS encompassed this pattern and at least one of the following: documented VF, self-terminating polymorphic VT, a family history of SCD 40 years [40].

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ECG Features Due to the broad spectrum of phenotypes in FLNC-related cardiomyopathy, ECG findings vary considerably. In contrast to ARVC associated with desmosomal variants, ECG abnormalities do not appear to be an early marker of disease in FLNC [1]. Ortiz-Genga et al. [40] studied ECG features in a cohort of 82 mutation carriers (58% symptomatic, 34% probands). Most patients were in sinus rhythm, and cardiac conduction defects were mild and uncommon. Negative T waves were seen in left precordial (12%), inferior (6%), left and inferior (9%) or left and right precordial (4%) leads. Low QRS voltages in the limb leads were found in 25% of mutation carriers. Terminal QRS duration >55 ms in leads V1 to V3 was recorded in 18% of the carriers evaluated. No subjects showed epsilon waves. Probands (N = 28) represented a group of highly symptomatic patients (89%) and revealed higher percentages of negative T waves and low voltages, 62% and 36% respectively. Unfortunately, the ECG findings were not specified per cardiomyopathy phenotype. Regarding ECG parameters in FLNC carriers with an HCM phenotype, Ader et al. [44] showed that 3/13 patients had atrial fibrillation (AF) and 2/13 presented with a complete bundle branch block. Patients with a DCM phenotype predominantly suffered from ventricular arrhythmias [1, 39, 40, 46]. The 24-h Holter monitoring illustrated in Fig. 7.17a shows an asymptomatic FLNC carrier with frequent ventricular triplets. Figure 7.17b demonstrates the 12-lead ECG of the same patient (using beta blockade). The relatively low voltages in the limb leads are the only abnormal finding and could point towards a cardiomyopathy, especially with the frequent ventricular ectopy during the Holter monitoring.

Ventricular Arrhythmias and Sudden Cardiac Death Ventricular arrhythmias (VA) and sudden cardiac death (SCD) are frequent among carriers [1, 39, 40, 44, 46]. In the cohort of Ader et  al. [44], NSVT occurred in 17.8% of the patients, including two DCM patients who died from SCD. In seven cases (25%), the family history revealed SCD before 50 years. Nine patients (32%) have been implanted with an ICD (primary prevention). The prevalence of VAs is higher in the study population of Ortiz-Genga et al. [40] Ventricular arrhythmias occurred in 82% of the cases, most likely related to left ventricular myocardial fibrosis (even in the absence of severe LV dilation and dysfunction). A smaller study by Begay et al. [47] included 13 FLNC mutation carriers. Eleven (85%) had either ventricular arrhythmias or sudden cardiac death. Figure  7.18a shows a typical example of a first medical encounter of an FLNC mutation carrier. Figure 7.18b is the same patient in sinus rhythm, with typical features on his ECG for the diagnosis of an arrhythmogenic cardiomyopathy (in combination with family history and echocardiographic and MRI findings).

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a

b

Fig. 7.17 (a) A 38-year-old asymptomatic patient with a familial FLNC mutation. A routine 24-h Holter monitoring revealed frequent polymorphic ventricular triplets. Ventricular ectopy was therapy refractory, and also due to the progressive nature of this specific cardiomyopathy, a subcutaneous ICD was implanted as primary prevention for SCD. (b) Sinus bradycardia (and AV junctional escape beats), T-wave inversion in lead III, with low-voltage complexes in the limb leads

Cardiac Sarcoidosis Sarcoidosis is a granulomatous disease of unknown etiology. Non-caseating granulomas are the pathological hallmark and are most often associated with pulmonary involvement but may also involve the heart, liver, peripheral lymph node, spleen, skin, eyes, phalangeal bones, parotid gland, or other organs and tissues [48]. Most diseases (70%) occur in patients aged 25–45  years. Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. Cardiac sarcoidosis (CS) predisposes patients to conduction abnormalities, ventricular arrhythmias,

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a

b

Fig. 7.18 (a) A 43-year-old patient presents with a ventricular tachycardia as a first manifestation of arrhythmogenic dilated cardiomyopathy. The MRI shows a reduced ejection fraction with extensive mid-myocardial and epicardial fibrosis. Predominantly anterior-lateral and inferior, with involvement of the whole septum and the RV free wall. Family history was positive for SCD. Procainamide failed to restore SR, which was ultimately reached with electric cardioversion. The ECG shows a ventricular tachycardia with a ventricular heart rate of 200 bpm; the QRS is RBBB shaped with a superior axis. The exit site of the VT appears apical (left ventricle). (b) ECG in sinus rhythm. Low voltages in the limb leads. The QRS complex is fractioned, as seen in the infero-lateral leads, accompanied by inverted T waves. Premature ventricular beat with an LBTB morphology and negative concordance over the precordial leads, suggesting that the premature ventricular beat originates from the apical septum. Notice that the last complex is an atrial paced complex as the patient received an ICD and metoprolol in an attempt to reduce the ventricular ectopy burden

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sudden cardiac death and heart failure. These manifestations of CS are dependent on the location, extent and activity of the disease. In addition, many patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement. Autopsy studies estimated the prevalence of cardiac involvement in at least 25% of patients, These autopsy findings are consistent with recent data using late gadolinium-­ enhanced (LGE) cardiovascular magnetic resonance (CMR) technology with sarcoidosis. CS can be the first manifestation of sarcoidosis in any organ. Between 16% and 35% of patients presenting with complete atrioventricular (AV) block (age 1 R’ (fragmentation) in two anatomically contiguous leads, and wide complex QRS fragmentation was defined as >2 R waves (R’), >2 notches within the R wave or >2 notches within the S wave (Fig. 7.19). A right bundle branch block was seen in 23% of the patients with CS (Fig.  7.20). When fQRS and bundle branch block were combined, 90.4% of CS patients’ ECGs contained at least one of the features. Other studies confirmed these ECG abnormalities, including various degrees of conduction block, due to involvement of the basal interventricular septum, such as isolated bundle branch block and fascicular block. Right bundle branch block is consistently more common than left bundle branch block [48, 49]. There are numerous disease states that may affect the cardiac conduction system [51]. A recent study from Finland reported on 72 patients younger than 55 years with unexplained, new onset, significant conduction system disease. Biopsy-proven CS was found in 14 of 72 patients (19%) [52]. Nery et al. [53] presented with similar data from a tertiary Canadian centre. Also, ST–T wave changes, pathological Q waves (pseudo-infarct pattern) and (rarely) epsilon waves can occur. In contrast, the ECG is normal in the majority of patients with clinically silent CS [49]. Figure 7.21 demonstrates that CS can present with features similar to those of ARVC, including an epsilon wave (due to extensive right ventricular involvement), and can fulfil the task force criteria for ARVC.  This was also shown by Vasaiwala et al. [54], who investigated 15 patients who were diagnosed with ARVC

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Fig. 7.19  A 48-year-old patient. Presented with an out-of-hospital cardiac arrest due to ventricular fibrillation. The medical history of the patient involved systemic sarcoidosis. Further examination showed a reduced left ventricular ejection fraction (LVEF) based on the cardiac involvement of sarcoidosis. Patient was treated with prednisolone and sotalol. The LVEF normalized after 1 year. The ECG shows a sinus rhythm with a horizontal QRS axis, a prolonged QRS (115 ms) and characteristic QRS fragmentation. Fragmentation is noted in the precordial leads V1–V3. Ventricular ectopic beats with an LBTB shape and a left superior axis. Exit site appears from the RV free wall

Fig. 7.20  A 31-year-old patient with sarcoidosis, including cardiac involvement. Patient presented with pericardial effusion and sub-epicardial fibrosis with a reduced left ventricular ejection fraction, MRI proven. PET-CT showed high metabolic activity. Patient suffered from arrhythmic events, including non-sustained ventricular tachycardias, and therefore received a TV-ICD. After immunosuppressive therapy, the ejection fraction normalized. The ECG shows atrial fibrillation with a ventricular response rate of 175 bpm with low-voltage QRS complexes in the limb leads (both rhythm and low voltages, likely due to pericardial effusion). The QRS is prolonged due to a (newly diagnosed) RBTB as a result of sarcoid-induced conduction disease

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Fig. 7.21  A 64-year-old patient with PET-CT-proven cardiac sarcoidosis. Extensive fibrosis of the right ventricle. The ECG shows a sinus rhythm with a first-degree AV block, delayed RV conduction (epsilon waves V1–V3) and T-wave inversion in V1–V4, aVF and III

Fig. 7.22  First presentation of a patient with cardiac sarcoidosis. Patient was successfully defibrillated and treated with prednisolone. The ECG shows ventricular tachycardia, with a ventricular rate of 210 beats per minute. The QRS width is almost 200 ms. V1 shows a positive deflection, and the QRS axis is inferior. Exit point of the VT is the base of the left ventricle

on the basis of the task force criteria and found that three of the 15 (18%) patients had sarcoidosis on endomyocardial biopsy (EMB). The rate of malignant ventricular tachycardias in the CS population appears to be more frequent compared to other populations. This is clarified in three large published series; annualized appropriate ICD therapy rates were 8.6%, 13.2% and 14.5%, respectively [55–57]. A lower LVEF was associated with appropriate ICD therapy. However, patients with mildly impaired LV function also had a substantial risk of ventricular arrhythmia. Figure 7.22 demonstrates a patient presented to the emergency room with a hemodynamically

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unstable ventricle tachycardia related to cardiac sarcoidosis with severe systolic impairment. Atrial involvement in CS is common; several observational studies found a substantial prevalence of atrial arrhythmias [48].

Cardiac Amyloidosis The term amyloidosis describes a group of rare diseases characterized by extracellular accumulation of fibrillary proteins (amyloid), leading to loss of tissue architecture. Cardiac amyloidosis is a condition in which the extracellular space of the heart is expanded by the deposition of amyloid [58]. Although there are >30 known amyloidogenic proteins, there are three forms of amyloidosis that commonly affect the heart: first, the acquired monoclonal immunoglobulin light-chain amyloidosis (AL), characterized by clonal plasma cells in the bone marrow, which produce the immunoglobulin lights chains; secondly, the hereditary, transthyretin (TTR)-related form (ATTRm), which can be caused by >100 mutations of TTR, a transport protein synthesized mainly by the liver; lastly, the wild-type (non-mutant) TTR-related amyloidosis (ATTRwt), ‘senile’ amyloidosis, which affects mainly the hearts of elderly men [59, 60]. Amyloid infiltration results in an infiltrative/restrictive cardiomyopathy characterized by poor diastolic relaxation and presents mostly as heart failure with preserved ejection fraction. Findings of right-sided heart failure predominate. In addition to heart failure, patients may present with atrial arrhythmias or conduction system disease [61]. Perivascular amyloid infiltration and impairment of cardiomyocyte function and the subsequent impaired vasoreactivity can result in relative myocardial ischemia and abnormal electrical conduction [1]. The highest frequencies of hemodynamic derangement appear to be the highest in AL cardiomyopathy (mainly because of diastolic dysfunction) and low QRS voltages on ECG [60]. Cardiac amyloidosis can phenotypically also appear as hypertrophic cardiomyopathy [59, 62]. Although the exact prevalence of clinically isolated AL cardiac amyloidosis is unknown, it is likely that it has been underestimated in the past due to the rapid progression to death in undiagnosed patients. The increasingly sophisticated diagnostic tools currently used in heart failure appear to lead to earlier diagnosis, with possibly less missed diagnoses [58].

Electrocardiogram Features and Arrhythmias Infranodal conduction system disease appears to be the primary conduction abnormality [1]. The expansion of the myocardial interstitium secondary to extracellular infiltration typically causes low QRS voltages in cardiac amyloidosis. It is often accompanied with an unusual axis, particularly an extreme right axis [58]. Between the distinctive main types of cardiac amyloidosis, there are marked ECG differences. Two large Italian centres performed a longitudinal study of 233 patients with a clearcut diagnosis by type of cardiac amyloidosis (AL, n = 157; ATTRm, n = 61; ATTRwt, n = 15). Low QRS voltage was observed in 60% of AL amyloidosis, compared to 25% and 40% for ATTRm and ATTRwt, respectively. Any form of conduction delay was seen in all groups, as was the presence of an infarct pattern [60]. In a large survey

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of patients with transthyretin amyloidosis, including 611 symptomatic patients with ATTRm and ATTRwt amyloidosis, the most common ECG findings were conduction abnormalities, being reported in 68.1% of those with hereditary TTR amyloidosis and 72.9% of those with wild-type TTR amyloidosis [63]. A review dedicated to transthyretin cardiomyopathy concluded that conduction system disease is more common in ATTRwt cardiomyopathy (ATTRwt-CM) than in ATTRm cardiomyopathy (ATTRm-CM), with up to one third of patients requiring permanent pacemakers. Atrial arrhythmias are also more common in ATTRwt-CM than in ATTRm-CM, occurring in 40–60% of patients. Atrial fibrillation often occurs with a controlled ventricular response because of underlying conduction disease [59]. Mussinelli et al. [64] studied 337 patients with AL amyloidosis. 52.2% showed an infarct pattern, and nearly 70% of the patients showed low QRS voltages. An Italian cohort of 375 AL cardiac amyloidosis patients focused on fragmented QRS complexes. This was seen in 30% of the patients and was noted as an independent prognostic factor [65]. Lowvoltage ECG often precedes heart failure, and the combination with significant increase in wall thickness on the echocardiogram or CMR (electro-morphological discordance) should raise the possibility of cardiac amyloidosis [58]. Untreated, the median survival from the onset of heart failure is approximately 6 months [63]. Nonsustained ventricular arrhythmias are described in small cohorts [1], although cardiac death in patients with cardiac amyloidosis is likely related to an infranodal conduction disease rather than to a primary malignant tachyarrhythmia, arguing against ICD use [59]. Small studies, however, do show a potential benefit for ICD implantation as 38% of patients with a history of syncope or ventricular extrasystoles received appropriate ICD therapy; unfortunately, it did not show a survival benefit [61]. Due to the progressive amyloid deposition throughout the heart, sinus node dysfunction and conduction disease permanent pacemakers should be considered [1]. Figures 7.23 and 7.24 show characteristic ECG features in cardiac amyloidosis.

Fig. 7.23  A 70-year-old patient with end-stage cardiac AL amyloidosis. The ECG shows atrial fibrillation (amyloid deposition in atria), undefined QRS axis, characteristic low QRS voltages and pseudo-infarct pattern in leads V1 through V3, with normal QRS duration. Downsloping ST depression is seen in the infero-lateral leads

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Fig. 7.24  A 71-year-old African patient with a hereditary transthyretin amyloid cardiomyopathy (genopositive for TTR p.Val142Ile). End-stage heart failure with severely impaired left and right ventricle function. An ICD was implanted as secondary prevention due to episodes of sustained ventricular tachycardia. ECG: atrial fibrillation with a ventricular response rate of 94 bpm, low-­ voltage QRS complexes in the limb leads. Notice the fragmented QRS complexes, best seen in aVF, III and aVL. Frequent premature ventricular complexes are seen with an RBBB shape and superior axis. The last QRs complex is a paced QRS complex (by a biventricular ICD). Het RR interval van die eerdere ‘VESSEN’ is wel erg hetzelfde … laatste complex lijkt inderdaad gepaced echter vind ik het raar dat V1 RBBB shaped is … met een 2kamer ICD

SCN5A The SCN5A gene encodes the alpha subunit of the major voltage-gated sodium channel (Nav1.5), which conducts the inward Na + current. Mutations in SCN5A are known to cause a variety of inheritable arrhythmia syndromes, including long QT syndrome type 3, Brugada syndrome, cardiac conduction disease and atrial fibrillation. Moreover, SCN5A mutations may lead to overlapping phenotypes of more than one syndrome. These arrhythmia syndromes, including the ECG findings, will be discussed further in a different chapter [66, 67]. In this chapter, we will focus on possibly the most surprising cardiac phenotype, namely the association of SCN5A mutations and dilated cardiomyopathy. Historically, DCM-related genes encode for proteins involved in the cytoskeleton and the contractile apparatus. Mutations disrupt the interactions between different cell compartments, thereby leading to ventricular dilatation, impaired contractility and arrhythmogenesis. However, an association of DCM with mutations in SCN5A pleads for an alternative pathological mechanism that may be primarily driven by electrical abnormalities rather than structural defects. So far, >20 different SCN5A mutations have been linked to DCM. DCM shows an age-dependent penetrance with a phenotype at increasing age [67].

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Fig. 7.25  A 23-year-old patient. MRI showed dilatation of the left ventricle with a mildly impaired function due to an SCN5A mutation. ECG: sinus rhythm with a broad, fragmented P wave. Incomplete right bundle branch block, early repolarization

ECG Features Most of the cases exhibit severe conduction defects, including first-/second-degree atrioventricular block and left or right bundle branch block. Moreover, arrhythmias are described in >90% of SCN5A-linked DCM cases, mainly involving atrial fibrillation, sick sinus syndrome, premature ventricular complexes and sometimes ventricular tachycardias [68, 69]. Groenewegen et al. [70] described in a large family for the first time atrial standstill, characterized as the absence of electrical and mechanical activity in the atria. In this study, the pathogenic SCN5a variant was combined with a Cx-40 variant, probably explaining the predominant atrial phenotype. Olson et al. [71] studied SCN5A mutation in 37 individuals in five families. Sixty-five per cent of the carriers had a cardiomyopathy phenotype. Dilated cardiomyopathy was typically preceded by atrial fibrillation (in nearly 50% of the individuals), sinus node dysfunction and conduction block. Figure 7.25 shows a young male with an SCN5A mutation and a discrete DCM phenotype.

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20. Hasselberg NE, Haland TF, Saberniak J, Brekke PH, Berge KE, Leren TP, et al. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation. Eur Heart J. 2018;39(10):853–60. 21. Nishiuchi S, Makiyama T, Aiba T, Nakajima K, Hirose S, Kohjitani H, et  al. Gene-based risk stratification for cardiac disorders in LMNA mutation carriers. Circ Cardiovasc Genet. 2017;10(6):e001603. 22. van den Hoogenhof MMG, Beqqali A, Amin AS, van der Made I, Aufiero S, Khan MAF, et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling. Circulation. 2018;138(13):1330–42. 23. Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. 2015;36(18):1123–35a. 24. Kayvanpour E, Sedaghat-Hamedani F, Amr A, Lai A, Haas J, Holzer DB, et  al. Genotype-­ phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals. Clin Res Cardiol. 2017;106(2):127–39. 25. Parikh VN, Caleshu C, Reuter C, Lazzeroni LC, Ingles J, Garcia J, et  al. Regional variation in RBM20 causes a highly penetrant arrhythmogenic cardiomyopathy. Circ Heart Fail. 2019;12(3):e005371. 26. Sedaghat-Hamedani F, Haas J, Zhu F, Geier C, Kayvanpour E, Liss M, et  al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J. 2017;38(46):3449–60. 27. Kayvanpour E, Sedaghat-Hamedani F, Gi WT, Tugrul OF, Amr A, Haas J, et al. Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals. Clin Res Cardiol. 2019;108(11):1297–308. 28. Li D, Morales A, Gonzalez-Quintana J, Norton N, Siegfried JD, Hofmeyer M, et  al. Identification of novel mutations in RBM20  in patients with dilated cardiomyopathy. Clin Transl Sci. 2010;3(3):90–7. 29. Hey TM, Rasmussen TB, Madsen T, Aagaard MM, Harbo M, Molgaard H, et al. Pathogenic RBM20-variants are associated with a severe disease expression in male patients with dilated cardiomyopathy. Circ Heart Fail. 2019;12(3):e005700. 30. Bermudez-Jimenez FJ, Carriel V, Brodehl A, Alaminos M, Campos A, Schirmer I, et al. Novel desmin mutation p.Glu401Asp impairs filament formation, disrupts cell membrane integrity, and causes severe arrhythmogenic left ventricular cardiomyopathy/dysplasia. Circulation. 2018;137(15):1595–610. 31. Capetanaki Y, Papathanasiou S, Diokmetzidou A, Vatsellas G, Tsikitis M. Desmin related disease: a matter of cell survival failure. Curr Opin Cell Biol. 2015;32:113–20. 32. Taylor MR, Slavov D, Ku L, Di Lenarda A, Sinagra G, Carniel E, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation. 2007;115(10):1244–51. 33. McNally EM, Mestroni L.  Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res. 2017;121(7):731–48. 34. van Tintelen JP, Van Gelder IC, Asimaki A, Suurmeijer AJ, Wiesfeld AC, Jongbloed JD, et al. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm. 2009;6(11):1574–83. 35. Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, et  al. De novo desmin-­ mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet. 2010;19(23):4595–607. 36. Lorenzon A, Beffagna G, Bauce B, De Bortoli M, Li Mura IE, Calore M, et al. Desmin mutations and arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol. 2013;111(3):400–5. 37. Marakhonov AV, Brodehl A, Myasnikov RP, Sparber PA, Kiseleva AV, Kulikova OV, et  al. Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect. Hum Mutat. 2019;40(6):734–41. 38. van Spaendonck-Zwarts KY, van der Kooi AJ, van den Berg MP, Ippel EF, Boven LG, Yee WC, et al. Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D. Neth Heart J. 2012;20(5):219–28.

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39. Begay RL, Tharp CA, Martin A, Graw SL, Sinagra G, Miani D, et al. FLNC gene splice mutations cause dilated cardiomyopathy. JACC Basic Transl Sci. 2016;1(5):344–59. 40. Ortiz-Genga MF, Cuenca S, Dal Ferro M, Zorio E, Salgado-Aranda R, Climent V, et  al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol. 2016;68(22):2440–51. 41. Furst DO, Goldfarb LG, Kley RA, Vorgerd M, Olive M, van der Ven PF. Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol. 2013;125(1):33–46. 42. Hoorntje ET, Te Rijdt WP, James CA, Pilichou K, Basso C, Judge DP, et al. Arrhythmogenic cardiomyopathy: pathology, genetics, and concepts in pathogenesis. Cardiovasc Res. 2017;113(12):1521–31. 43. Valdes-Mas R, Gutierrez-Fernandez A, Gomez J, Coto E, Astudillo A, Puente DA, et  al. Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun. 2014;5:5326. 44. Ader F, De Groote P, Reant P, Rooryck-Thambo C, Dupin-Deguine D, Rambaud C, et  al. FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-­ phenotype correlations. Clin Genet. 2019;96(4):317–29. 45. Brodehl A, Ferrier RA, Hamilton SJ, Greenway SC, Brundler MA, Yu W, et al. Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum Mutat. 2016;37(3):269–79. 46. Augusto JB, Eiros R, Nakou E, Moura-Ferreira S, Treibel TA, Captur G, et al. Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: a comprehensive genotype-­ imaging phenotype study. Eur Heart J Cardiovasc Imaging. 2020;21(3):326–36. 47. Begay RL, Graw SL, Sinagra G, Asimaki A, Rowland TJ, Slavov DB, et al. Filamin C truncation mutations are associated with arrhythmogenic dilated cardiomyopathy and changes in the cell-cell adhesion structures. JACC Clin Electrophysiol. 2018;4(4):504–14. 48. Birnie DH, Sauer WH, Bogun F, Cooper JM, Culver DA, Duvernoy CS, et  al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11(7):1305–23. 49. Birnie DH, Nery PB, Ha AC, Beanlands RS.  Cardiac sarcoidosis. J Am Coll Cardiol. 2016;68(4):411–21. 50. Schuller JL, Olson MD, Zipse MM, Schneider PM, Aleong RG, Wienberger HD, et  al. Electrocardiographic characteristics in patients with pulmonary sarcoidosis indicating cardiac involvement. J Cardiovasc Electrophysiol. 2011;22(11):1243–8. 51. Kusumoto FM, Schoenfeld MH, Barrett C, Edgerton JR, Ellenbogen KA, Gold MR, et  al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;140(8):e382–482. 52. Kandolin R, Lehtonen J, Kupari M. Cardiac sarcoidosis and giant cell myocarditis as causes of atrioventricular block in young and middle-aged adults. Circ Arrhythm Electrophysiol. 2011;4(3):303–9. 53. Nery PB, Beanlands RS, Nair GM, Green M, Yang J, McArdle BA, et  al. Atrioventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged adults. J Cardiovasc Electrophysiol. 2014;25(8):875–81. 54. Vasaiwala SC, Finn C, Delpriore J, Leya F, Gagermeier J, Akar JG, et al. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol. 2009;20(5):473–6. 55. Schuller JL, Zipse M, Crawford T, Bogun F, Beshai J, Patel AR, et  al. Implantable cardioverter defibrillator therapy in patients with cardiac sarcoidosis. J Cardiovasc Electrophysiol. 2012;23(9):925–9. 56. Betensky BP, Tschabrunn CM, Zado ES, Goldberg LR, Marchlinski FE, Garcia FC, et  al. Long-term follow-up of patients with cardiac sarcoidosis and implantable cardioverter-­ defibrillators. Heart Rhythm. 2012;9(6):884–91.

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57. Kron J, Sauer W, Schuller J, Bogun F, Crawford T, Sarsam S, et  al. Efficacy and safety of implantable cardiac defibrillators for treatment of ventricular arrhythmias in patients with cardiac sarcoidosis. Europace. 2013;15(3):347–54. 58. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol. 2016;68(12):1323–41. 59. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872–91. 60. Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, et  al. Systemic car diac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203–12. 61. Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T, Cruz M, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol. 2015;66(21):2451–66. 62. Finocchiaro G, Sheikh N, Biagini E, Papadakis M, Maurizi N, Sinagra G, et al. The electrocardiogram in the diagnosis and management of patients with hypertrophic cardiomyopathy. Heart Rhythm. 2020;17(1):142–51. 63. Coelho T, Maurer MS, Suhr OB. THAOS – the transthyretin amyloidosis outcomes survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63–76. 64. Mussinelli R, Salinaro F, Alogna A, Boldrini M, Raimondi A, Musca F, et  al. Diagnostic and prognostic value of low QRS voltages in cardiac AL amyloidosis. Ann Noninvasive Electrocardiol. 2013;18(3):271–80. 65. Perlini S, Salinaro F, Cappelli F, Perfetto F, Bergesio F, Alogna A, et al. Prognostic value of fragmented QRS in cardiac AL amyloidosis. Int J Cardiol. 2013;167(5):2156–61. 66. Amin AS.  SCN5A-related dilated cardiomyopathy: what do we know? Heart Rhythm. 2014;11(8):1454–5. 67. Wilde AAM, Amin AS. Clinical spectrum of SCN5A mutations: long QT syndrome, Brugada syndrome, and cardiomyopathy. JACC Clin Electrophysiol. 2018;4(5):569–79. 68. Remme CA. Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. J Physiol. 2013;591(17):4099–116. 69. McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, et  al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004;110(15):2163–7. 70. Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuijl L, et al. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003;92(1):14–22. 71. Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005;293(4):447–54.

8

Hypertrophic Cardiomyopathy Charles A. S. Miller, Ethan J. Rowin, and Martin J. Maron

Introduction Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy and is caused by mutations in genes responsible for encoding proteins of the cardiac sarcomere. A clinical diagnosis of HCM is confirmed when unexplained increased left ventricular (LV) wall thickness (range 13–60 mm with average 22 mm) and a non-dilated LV chamber is demonstrated on imaging in the absence of another cardiac, systemic, metabolic or syndromic disease process [1]. Although typically asymmetric in distribution any pattern of LV wall thickening can be seen in HCM, including apical and concentric LV hypertrophy (LVH) in a small minority. Disease heterogeneity also extends to the electrocardiographic (ECG) manifestations, with an enormous diversity in the pattern of ECG findings in HCM. The ECG is abnormal in 90% of HCM patients [1], however no specific ECG pattern can reliably predict phenotype or clinical course [2]. Abnormal ECG findings have also been noted to precede the development of LVH in family members know to have a disease causing sarcomere mutation [3]. The twelve-lead ECG has long been a component of a comprehensive assessment of patients with HCM, thus knowledge of associated findings is important for the practicing clinician. In this chapter we review a variety of characteristic ECG findings associated with this genetic heart disease.

ECG Findings 1. Left Ventricular Hypertrophy 2. Pseudo Q Waves

C. A. S. Miller · E. J. Rowin · M. J. Maron (*) Tufts Medical Center, Boston, MA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. Green et al. (eds.), Electrocardiography of Inherited Arrhythmias and Cardiomyopathies, https://doi.org/10.1007/978-3-030-52173-8_8

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3 . Apical Variants in Hypertrophic Cardiomyopathy 4. Repolarization Abnormalities 5. ECG Manifestations in Genotype Positive, Phenotype Negative Patients

Left Ventricular Hypertrophy An assessment of the left ventricular (LV) wall thickness is important in patients with HCM as their risk of sudden cardiac death is directly related to the magnitude of LVH [4, 5]. Massive hypertrophy anywhere in the LV wall (assessed by echocardiography or cardiovascular magnetic resonance imaging [CMR] of ≥30 mm) has been identified as an important threshold for increased sudden death risk and potentially a recommendation for primary prevention implantable cardioverter defibrillator (ICD) [5]. The amplitude of the electrical signals in the QRS complex are frequently used to make inferences about the degree of LVH, however only a very weak correlation has been observed between QRS voltages and in vivo measurements of maximal LV wall thickness in HCM. Correspondingly, ECG criteria that are commonly applied for the assessment of LVH have poor correlation with the presence or extent of LVH in HCM. In addition, twelve-lead ECG voltages have low sensitivity (20–58% [2, 6]) for the HCM diagnosis and do not reliably identify which HCM patients are at risk for sudden death [2]. Despite this, findings consistent with LVH are still important for clinicians to note as they can raise clinical suspicion and prompt further imaging workup for HCM (Fig. 8.1).

Fig. 8.1  This 49  year old woman presented with exertional shortness of breath and ECG suggested LVH by voltage criteria with associated repolarization abnormalities (ST segment depressions and T wave inversions) across the precordial leads and lateral limb leads. The presence of voltage criteria for LVH prompted further evaluation with echocardiography which demonstrated asymmetric left ventricular hypertrophy with a maximal LV wall thickness of 20 mm confined to the basal ventricular septum

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Pseudo Q Waves Criteria for pathologic Q-waves are present in approximately 25% of patients with HCM and occur in the absence of coronary artery disease, leading to their designation as “pseudo-Q waves” [6]. A variety of patterns for pseudo Q-waves can be seen in HCM, including most commonly in the inferior leads and lateral leads and less frequently in the anterior leads. Pseudo Q waves are more commonly observed in younger HCM patients [7] while appearing to resolve with advancing age [8]. The etiology of pseudo Q-waves in patients with HCM remains unclear, although abnormal conduction through myopathic myocardium in the septum, as well as the loss of electrical forces due to abnormal myocardial substrate, have been proposed as possible mechanisms [8, 9]. No relationship has been noted between presence of pseudo Q waves and myocardial fibrosis as assessed by late gadolinium enhancement with CMR. Pseudo Q waves have also been noted as part of the ECG patterns seen in HCM family members who carry a pathogenic sarcomere gene mutation but do not have LVH [9] (Fig. 8.2).

Apical Variants in Hypertrophic Cardiomyopathy Within the vast heterogeneous phenotypic spectrum of HCM, two apical variant subgroups have emerged with distinct natural histories and management considerations. Apical HCM  HCM with hypertrophy confined to the distal portion of LV chamber creating a “spade” shape at end-systole with normal or hyperdynamic function of all LV segments (i.e. apical HCM). Symmetric T wave inversions deeper than 10 mm

Fig. 8.2  25-year-old asymptomatic man with HCM and pseudo Q pattern seen in the inferior (II, III, aVF) and lateral precordial leads (V4, V5, V6). On CMR evaluation, there was no late gadolinium enhancement (i.e., myocardial fibrosis), underscoring the principle that in HCM Q waves are not due to prior myocardial infarction

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Fig. 8.3  This 12-lead ECG in a young patient presenting to the emergency room with atypical chest pain demonstrates giant symmetric T wave inversions in the inferior leads and precordial leads with associated findings suggestive of LVH by voltage criteria also present. Together these findings suggest hypertrophy localized to the distal portion of the left ventricular chamber (i.e., apical HCM). Cardiovascular imaging confirmed increased wall thickness of 22 mm at the apex with normal wall motion of all LV segments

(i.e., “giant”) distributed across the precordial leads is characteristic of apical HCM and is the only ECG pattern which reliably predicts a specific HCM phenotype [10]. The magnitudes of the negative T waves do not correlate with the degree of LVH at the apex. This T wave inversion pattern is often associated with voltage criteria for LVH in the precordial QRS complexes. The pathophysiologic mechanism responsible for T wave inversions in apical HCM is not well defined (Fig. 8.3). HCM with apical aneurysm  More recently, a novel HCM phenotype has been recognized largely by CMR in which LV apical aneurysms, with thin-walled, scarred and dyskinetic rim, are associated with either apical hypertrophy or more diffuse thickening involving the mid-septum and free wall resulting in an “hourglass” configuration with mid-cavity muscular narrowing and discrete proximal and distal chambers. Transmural scarring of the aneurysmal rim is a morphologic abnormality which is responsible for an increased risk for potentially life threatening ventricular tachyarrythmias as well as thrombus formation resulting in stroke. The increased adverse event rate noted in HCM patients with LV apical aneurysm raises management considerations including primary prevention ICD and anticoagulation therapy [11]. Two common ECG patterns have been noted in these patients. Firstly convex ST-segment elevation (1 mm in 2 contiguous leads), usually in V1 through V4 and associated with T-wave inversion. The other is T-wave inversion without ST-segment

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Fig. 8.4  A 12 lead ECG of a 76 year old woman with history of atrial fibrillation and stroke who presented with recurrent syncope and was found to have HCM with a large apical aneurysm on echocardiogram and frequent non-sustained ventricular tachycardia on telemetry. Note the characteristic convex ST-segment elevation in V3 through V6 with associated T-wave inversion

elevation, usually in V1 through V4. Q or QS waves may also be present in leads V1 through V4 or II, III, and AVL [12]. Clinical correlation is important in these patients as these findings, including ST segment elevation and T wave inversions are not due to an ischemic process (Fig. 8.4).

Repolarization Abnormalities Various abnormal ventricular repolarization patterns are common in HCM due to abnormalities of the myocardial substrate including fibrosis and myocyte disarray. These include J-point elevation [13], as well as changes that can also mimic ischemic ECG patterns such as ST segment depression and T wave inversions. For this reason, HCM patients with repolarization changes that overlap with typical ischemic patterns should be considered for additional evaluation if the clinical profile of the individual patient otherwise supports the possibility of co-existent coronary artery disease (Figs. 8.5 and 8.6).

 CG Manifestations in Genotype Positive, Phenotype E Negative Patients Current guidelines recommend screening echocardiography and ECG in family members of HCM patients starting at puberty and extending every 1–2 years through adolescents and beyond in some patients [14]. The ECG can also be abnormal in up

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Fig. 8.5  This patient with HCM has diffuse repolarization abnormalities that overlap with a pattern also consistent with myocardial ischemia, including diffuse ST segment depressions and ST elevation in lead AVR. Clinical context is important when interpreting HCM ECGs with repolarization patterns that could raise concern for coronary artery disease. In this patient an echocardiogram and cardiac MRI were performed to determine that the changes reflected abnormal conduction related to myocardial disarray/fibrosis from HCM and not an acute coronary syndrome

Fig. 8.6  This ECG demonstrates T wave inversions in leads I and aVL as well as lead T wave flattening in lead V1 and inversion in lead V2. This patient with HCM had asymmetric septal hypertrophy found on imaging workup completed after this ECG. As above, this ECG could suggest ischemia and highlights the importance of clinical context when interpreting ECGs in patients with HCM

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Fig. 8.7  This ECG was obtained on a young patient with a familial history of HCM during routine screening for HCM. LVH is suggested by the R-wave amplitude in the inferior and lateral precordial leads, and T wave inversions are present in the inferior and antero-lateral leads. Echocardiogram was obtained given the concern raised for HCM, but this study demonstrated normal LV wall thickness and function. Genetic testing was performed demonstrating the same HCM disease-causing sarcomere mutation as in the patient’s father

to 50% of genotype positive patients without phenotypically expressed HCM by echocardiography [3]. In this situation, further imaging with CMR would be reasonable to identify if hypertrophy may not have been detected with echocardiography. In addition, abnormal ECG findings can precede the development of LVH.  ECG findings do not follow a predictable pattern in these patients [3] (Fig. 8.7).

References 1. Maron BJ. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med. 2018;379(7):655–68. 2. Montgomery JV, Harris KM, Casey SA, Zenovich AG, Maron BJ. Relation of electrocardiographic patterns to phenotypic expression and clinical outcome in hypertrophic cardiomyopathy. Am J Cardiol. 2005;96(2):270–5. 3. Maron BJ, Yeates L, Semsarian C. Clinical challenges of genotype positive (+) - phenotype negative (-) family members in hypertrophic cardiomyopathy. Am J Cardiol. 2011;107(4):604–8. 4. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ.  Magnitude of left ventricular m and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342(24):1778–85. PubMed PMID: 10853000. 5. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions; Society of Thoracic

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Surgeons. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):2761–96. 6. Reichek N, Devereux RB. Left ventricular hypertrophy: relationship of anatomic, echocardiographic and electrocardiographic findings. Circulation. 1981;63(6):1391–8. PubMed PMID: 6452972. 7. Maron BJ.  Q waves in hypertrophic cardiomyopathy: a reassessment. J Am Coll Cardiol. 1990;16(2):375–6. PubMed PMID: 2373814. 8. Dumont CA, Monserrat L, Soler R, Rodríguez E, Fernandez X, Peteiro J, Bouzas A, Bouzas B, Castro-Beiras A. Interpretation of electrocardiographic abnormalities in hypertrophic cardiomyopathy with cardiac magnetic resonance. Eur Heart J. 2006;27(14):1725–31. PubMed PMID: 16774982. 9. Lakdawala NK, Thune JJ, Maron BJ, Cirino AL, Havndrup O, Bundgaard H, Christiansen M, Carlsen CM, Dorval JF, Kwong RY, Colan SD, Køber LV, Ho CY. Electrocardiographic features of sarcomere mutation carriers with and without clinically overt hypertrophic cardiomyopathy. Am J Cardiol. 2011;108(11):1606–13. 10. Maron BJ, Wolfson JK, Ciró E, Spirito P.  Relation of electrocardiographic abnormalities and patterns of left ventricular hypertrophy identified by 2-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Am J Cardiol. 1983;51(1):189–94. 11. Rowin EJ, Maron BJ, Haas TS, Garberich RF, Wang W, Link MS, Maron MS. Hypertrophic cardiomyopathy with left ventricular apical aneurysm: implications for risk stratification and management. J Am Coll Cardiol. 2017;69(7):761–73. 12. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, Lesser JR, Udelson JE, Ackerman MJ, Maron BJ.  Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation. 2008;118(15):1541–9. PubMed PMID: 18809796. 13. Maron MS. J point elevation in hypertrophic cardiomyopathy: riding a new wave in risk stratification? JACC Clin Electrophysiol. 2017;3(10):1143–5. PubMed PMID: 29759497. 14. American College of Cardiology Foundation/American Heart Association Task. Force on Practice; American Association for Thoracic Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons, Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. 2011;142(6):e153–203. https://doi.org/10.1016/j.jtcvs.2011.10.020. PubMed PMID: 22093723.

9

The PRKAG2 Cardiac Syndrome Wael Alqarawi, Michael H. Gollob, and Martin Green

Introduction PRKAG2 syndrome is a rare autosomal-dominant condition. Clinical features include left ventricular hypertrophy (LVH), ventricular pre-excitation, atrial arrhythmias, as well as sinus node disease (SND) and/or atrioventricular blocks (AVBs) [1, 2]. In 1986, Green and Cherry [1] described the clinical phenotype of this syndrome in a five-generation French-Canadian family, with autosomal-dominant inheritance and different combinations of ventricular hypertrophy, pre-excitation, atrial arrhythmias, sinus node dysfunction, and atrioventricular conduction disease. The syndrome may present at any time in life. Childhood onset has been observed [3]. Sudden cardiac death may occur and appears to be secondary to abrupt heart block or ventricular fibrillation, mainly due to ventricular fibrillation deteriorating from pre-excited atrial fibrillation [4]. Many patients require pacemaker implantation by the fourth decade of life. The role of prophylactic ICD has not been established [5]. Catheter ablation of accessory pathways may be indicated in some patients with atrioventricular reciprocating tachycardia (AVRT) or pre-excited atrial arrhythmias. However, many patients have atypical complex pre-excitation due to multiple accessory pathways, as well as fasciculoventricular accessory pathways

W. Alqarawi Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada M. H. Gollob Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada M. Green (*) Department of Medicine, University of Ottawa, Ottawa, ON, Canada e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. Green et al. (eds.), Electrocardiography of Inherited Arrhythmias and Cardiomyopathies, https://doi.org/10.1007/978-3-030-52173-8_9

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that do not participate in reentrant tachycardia. The PR interval may be short even in the absence of a delta wave. In 2001, Gollob et al. identified a mutation in the PRKAG2 gene as responsible for the syndrome [2]. Although slightly variable phenotypic expressions were noticed depending on the underlying culprit variant, all mutations reported have some similar clinical and electrocardiographic features [4, 6]. The PRKAG2 gene encodes for the γ2 regulatory subunit of the 5′ adenosine-­ monophosphate-­activated protein kinase (AMPK). AMPK serves a critical role in regulating cellular glucose and fatty acid metabolic pathways. The protein kinase AMPK may be activated by high levels of adenosine monophosphate (AMP). Activation of this enzyme affects both lipid and glucose metabolism. Attenuation of the enzyme function may cause alterations in secondary pathways, leading to dysfunctional ion channels, glycogen accumulation, and abnormal atrioventricular septation. These derangements in cardiac metabolism give rise to the phenotypes described [4]. The PRKAG2 cardiac syndrome should be suspected in patients with both ventricular hypertrophy and pre-excitation. The exact prevalence of this condition is not known; however, it is estimated that 1% of patients with both ventricular hypertrophy and conduction disturbances may have PRKAG2 syndrome [5]. The remainder of this chapter will focus upon the key electrocardiographic findings in the PRKAG2 cardiac syndrome under the following descriptive headings.

ECG Findings 1. LVH 2. Atrial myopathy 3. Accelerated A-V nodal conduction 4. Complex pre-excitation 5. Complex atrioventricular block

LVH (Fig. 9.1) ECG Description High voltages. Pathophysiologic Explanation In the PRKAG2 syndrome, LVH is dependent on the extent of myocyte enlargement secondary to glycogen accumulation, which is associated with minimal fibrosis. As such, unlike other conditions with LVH such as amyloidosis, LVH may be associated with extremely high voltages.

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Fig. 9.1  Ventricular hypertrophy. Legend: This ECG was recorded from a 22 year old man with the PRKAG2 cardiac syndrome. The voltage is standard 10mm/1mV. Please note the markedly increased voltages in leads I, II, and midprecordial leads V3 and V4. His echocardiogram demonstrated severe asymmetric nonobstructive LVH with hypertrophy of all walls. The interventricular septum was most severely involved with septal thickness of 4.0 cm

Abnormal P Wave Morphology (Fig. 9.2) ECG Description Abnormal axis and morphology with progressive atrial conduction abnormality. Pathophysiologic Explanation AMPK dysfunction may lead to cellular apoptosis, which can lead to atrial myopathy and atrial conduction abnormality.

 hort PR Interval and Failure of AV Nodal S Decremental Conduction Sinus Node Dysfunction (Fig. 9.3a, b) ECG Description • Short PR interval with no delta wave and short PR segment. • Sinus node dysfunction: sinus bradycardia, PACs, and pauses.

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Fig. 9.2  Atrial myopathy. Legend: This figure illustrates progression of atrial conduction disturbance over 13 years from a woman with PRKAG2 cardiac syndrome. All strips show leads I, II and III during atrial pacing from a permanent pacemaker implanted in the right atrial appendage. Note that in 2006, at age 29, the p wave duration was very short and the PR interval approximately 110 ms. Over time the p wave morphology and duration change but there is no significant isoelectric PR segment. By 2019 the p wave duration has increased to 200 ms with terminal negativity in leads II and III suggesting interatrial conduction block. The patient had already experienced an episode of atrial fibrillation in 2013

Pathophysiologic Explanation This is thought to be due to enhanced conduction through the atrioventricular (AV) node likely due to accumulation of glycogen.

Complex Pre-excitation (Fig. 9.4) ECG Description Patients with the PRKAG2 cardiac syndrome often have complex pre-excitation. There may be multiple accessory pathways present including both typical atrioventricular accessory pathways as well as atypical pathways, especially fasciculoventricular pathways with atypical pre-excitation. Pathophysiologic Explanation During cardiogenesis, the disruption of the annulus fibrosus by glycogen-filled myocytes interferes with the normal atrioventricular separation and can lead to ventricular pre-excitation.

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a

b

Fig. 9.3 (a) Legend: This ECG was recorded from a 27 -year-old woman with the PRKAG2 cardiac syndrome. Note the relatively narrow P wave and the short PR interval. The short PR interval is largely due to the absence of a PR segment, indicating failure of the AV node to delay atrial impulses before conduction to the ventricles. There is no delta wave. (b) Atrial myopathy and failure of AV nodal decremental conduction Legend: ECG monitor strips recorded from the same woman as in Figure 9.3a with symptomatic sinus node dysfunction. The narrow P wave, short PR interval and sinus node dysfunction are characteristic of the atrial abnormality in PRKAG2 cardiac syndrome. Note that even with shortening of the P-P input interval during runs of atrial tachycardia there is little or no change in the PR interval. This indicates failure of normal decremental conduction within the AV node

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a

Fig. 9.4  Panel (a): Complex pre-excitation. Legend: ECG from a 24 year old man with PRKAG2 cardiac syndrome. The ECG shows typical features including narrow P wave, short PR interval and subtle ventricular pre-excitation best seen in leads V2 and V3. He had multiple accessory pathways at EP study (b): Legend: Same patient as in Panel a. This ECG demonstrates pre-excited tachycardia with anterograde conduction via the right-sided accessory pathway demonstrated at EP study. (c): Legend: ECG leads I, II, III, V1, and V6 as well as intracardiac leads from the right atrium (HRA), His bundle region (HIS), and the RV apex (RVa), as well as intracardiac electrograms recorded from an ablation catheter on the anterolateral tricuspid annulus (ABL1,2). Note that the ventricular electrogram (arrow) seen in the ablation catheter precedes the delta wave by about 30 ms, indicating the ventricular insertion point of the accessory pathway. Panel (d): Legend: ECG leads I, II, III, V1, and V6 as well as intracardiac electrograms from the high right atrium (HRA), His bundle(His), coronary sinus from proximal (CS9,10) to distal (CS 1,2) as well as the RV apex (RVa) following radiofrequency ablation of the right-sided accessory pathway. Demonstrated is right atrial pacing with a premature atrial beat. The first paced beat conducts with a wide QRS, a positive slurred upstroke in V1, and early local ventricular activation in the distal coronary sinus (CS 1,2)(*), indicating left-sided pre-excitation. The atrial premature beat conducts with a different QRS morphology, the slurred upstroke in V1 is absent, and with late activation of the left ventricle in the distal coronary sinus lead (**), indicating block in the left-sided accessory pathway. During conduction of that beat, the H-V interval remains short (local H-V = 20 ms), indicating continued pre-excitation over a third accessory pathway, in this case, a septal fasciculoventricular accessory pathway

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b

c

d

Fig. 9.4 (continued)

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Complex Atrioventricular Block ECG Description AV block that may occur below the AV node and may still be associated with preexcitation (Fig. 9.5). Pathophysiologic Explanation Inappropriate embryonic atrioventricular septation as well as excessive AV junctional glycogen accumulation may contribute to AV conduction block (Fig. 9.5). a

Fig. 9.5  Atrioventricular block. Panel (a): Legend: This ECG recorded in 2014 is from a 34-year-­ old man with the PRKAG2 cardiac syndrome. The ECG shows evidence of pre-excitation and 1:1 A-V conduction during sinus rhythm. The delta wave is positive in leads V1 and V2, indicating pre-excitation over a left-sided accessory pathway. Panel (b): Legend: This ECG recorded in 2018 from the same patient as Panel a demonstrates 2:1 A-V block during sinus rhythm. The conducted beats show a delta wave (best seen in leads II, V5, and V6), but there is no longer evidence of left-­ sided pre-excitation, as was seen in Panel a. It is likely that the left-sided accessory pathway is no longer able to conduct. The pre-excitation is dependent on AV nodal conduction, indicating a proximal insertion below the AV node (nodoventricular) or below the proximal His bundle (fasciculoventricular). The conducting accessory pathway is likely fasciculoventricular, as is commonly seen in the PRKAG2 syndrome

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b

Fig. 9.5 (continued)

References 1. Cherry JM, Green MS. Familial cardiomyopathy: a new autosomal dominant form [abstract]. Clin Invest Med 1986;9:B131. 2. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, Ahmad F, Lozado R, Shah G, Fananapazir L, Bachinski LL, Roberts R.  Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001;344:1823–31. 3. Gollob MH, Seger JJ, Gollob TN, Tapscott T, Gonzales O, Bachinski L, Roberts R.  Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Circulation. 2001;104:3030–3. 4. Porto AG, Brun F, Severini GM, Losurdo P, Fabris E, Taylor MRG, Mestroni L, Sinagra G. Clinical Spectrum of PRKAG2 syndrome. Circ Arrhythm Electrophysiol. 2016;9:e003121. 5. Murphy RT, Mogensen J, McGarry K, Bahl A, Evans A, Osman E, Syrris P, Gorman G, Farrell M, Holton JL, Hanna MG, Hughes S, Elliott PM, Macrae CA, McKenna WJ. Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and WolffParkinson-White syndrome: natural history. J Am Coll Cardiol. 2005;45:922–30. 6. Zhang BL, Xu RL, Zhang J, Zhao XX, Wu H, Ma LP, Hu JQ, Zhang JL, Ye Z, Zheng X, Qin YW. Identification and functional analysis of a novel PRKAG2 mutation responsible for Chinese PRKAG2 cardiac syndrome reveal an important role of non-CBS domains in regulating the AMPK pathway. J Cardiol. 2013;62:241–8.

Part III ECG in Athletes

ECG in Athletes

10

Mark Abela and Sanjay Sharma

Introduction Sudden cardiac death (SCD) is the leading cause of mortality during intense physical activity [1]. Such deaths are relatively rare events; however, they have a huge impact on the community who perceive these individuals as being the healthiest segment of the population and consider some as role models. Most deaths are due to structural or electrical disorders that are detectable during life for which several therapeutic modalities exist to minimise the risk of SCD.  Over 80% of affected athletes are asymptomatic and SCD is the first presentation; therefore, a cost-­ effective screening strategy is required to identify vulnerable athletes. The 12-lead electrocardiogram (ECG) is effective for detecting athletes with electrical diseases but is also helpful in identifying those with cardiomyopathy. ECG-based screening is now mandated by several sporting bodies. Regular intense physical training is also associated with structural and functional changes that have an impact on the ECG. The type and magnitude of these changes is governed by a number of demographic variables including age, gender, ethnicity, together with sporting discipline and intensity of exercise [2]. Some athletes reveal electrical remodelling that may overlap with cardiac pathology. Distinguishing between the two entities is of paramount importance, since an erroneous diagnosis

M. Abela Cardiology Clinical Academic Group, St. George’s, University of London, St. George’s University Hospitals NHS Foundation Trust, London, UK Faculty of Medicine & Surgery, University of Malta, Mater Dei Hospital, Msida, Malta S. Sharma (*) Cardiology Clinical Academic Group, St. George’s, University of London, St. George’s University Hospitals NHS Foundation Trust, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. Green et al. (eds.), Electrocardiography of Inherited Arrhythmias and Cardiomyopathies, https://doi.org/10.1007/978-3-030-52173-8_10

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has potentially serious implications. The aim of this chapter is to provide an account of the normal spectrum of ECG patterns in the athlete and highlighting ECG patterns that are highly suggestive of cardiac pathology.

Training-Related ECG Changes The electrical manifestations of regular intense exercise are due to increased vagal tone and increased cardiac mass. More than 70% of health athletes demonstrate these training-related ECG changes, which do not warrant further investigation in asymptomatic athletes [3, 4]. Recognised training-related ECG changes include sinus bradycardia, first-degree atrioventricular (AV) block, voltage criteria for left and right ventricular hypertrophy, incomplete right bundle branch block (RBBB) and early repolarisation (ER).

Bradyarrhythmias Sinus bradycardia is present in up to 80% of highly trained athletes [5] and is most prevalent in endurance athletes [6]. Sinus bradycardia is generally attributed to increased vagal tone; however, intrinsic sinus node remodelling and downregulation of HCN4 pacemaker channels in the sinus node also seems to play a role [7, 8]. A junctional (nodal) rhythm (Fig. 10.1) is noted when the ventricular response is faster than the sinus rate and is present in 8% of all healthy athletes at rest [9]. The QRS is narrow in a high nodal rhythm, and sinus rhythm is restored by increasing heart rate through gentle exercise. The QRS may however be wide if conduction

Fig. 10.1  Long-distance male runner showing predominant junctional rhythm

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disease is present below the AV node, or in athletes with pre-existing bundle branch block. A junctional rhythm with a wide QRS should be evaluated as it may represent conduction disease. An ectopic atrial rhythm is also common in athletes. Ectopic p waves often have a negative polarity in the inferior leads (Fig. 10.2). As with junctional rhythm, sinus rhythm is restored at the onset of mild physical activity. First-degree AV block (200–399 ms) and Mobitz Type 1 second-degree AV block (Fig. 10.3) are common and present in up to 7% [10] and 10% [11–14] athletes, respectively. Both anomalies are due to suppression of AV nodal conduction from increased vagal tone [15, 16].

Fig. 10.2  Young academy football player showing a low atrial rhythm with widespread negative p waves

Fig. 10.3  Asymptomatic cyclist showing sinus bradycardia with Mobitz Type 1

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Fig. 10.4  Asymptomatic female recreational athlete with an isolated short PR interval (110 ms) on a routine ECG

Short PR Interval A short PR in isolation (38 °C could promote fatal arrhythmias; therefore, long endurance sports such as marathon running, triathlon and cycling sportifs are not recommended. ST-segment elevation in the anterior leads is a common manifestation in athletes and is present in 90% black athletes and 45% white athletes [9, 38]. J point elevation often coexists with a high ST segment which can occasionally overlap with the Brugada ECG pattern particularly in black athletes with an elevated ST segment (section “Black Athletes”) [71]. The convex nature of the ST segment in black athletes means that it is elevated 80 ms after the J point, whereas the steep downslope

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of the ST segment in BrS means that the ST segment is depressed 80 ms after the J-point. Therefore, the STJ/STJ + 80 ms ratio is 1 in BrS and offers a 99% diagnostic accuracy for differentiating anterior repolarisation in athletes from the Brugada ECG pattern (Fig. 10.13) [72]. Some athletes may reveal a Type 2 Brugada ECG patterns which is characterised by an rSr’ and concave ST-segment elevation in V1 and V2. In the absence of symptoms or family history, the latest Shanghai criteria do not recommend further evaluation in the Type 2 pattern [30]. Our practice is to perform a high lead ECG with leads V1 and V2 in the second intercostal. Conversion to the Type 1 pattern with this manoeuvre is highly suggestive of BrS and should be confirmed with drug provocation test using a sodium channel blocker (Ajmaline or Fleicanide) [30, 73–75]. V1

V2

V3

STJ

STJ80

STJ

a

STJ80

b

Fig. 10.13  Differentiating ST elevation in athlete’s Heart (a) from the Type 1 Brugada pattern (b) with an upsloping ST-segment elevation (STJ/STJ + 80 ms 90 °) have been shown to be more common in patients with arrhythmogenic cardiomyopathy compared to patients with idiopathic outflow tract ectopy [82]. Ectopics with a broad RBBB morphology and a superior axis originating from the MV annulus or LV free wall are more likely to be present in the context of LV scar [82, 83]. Complex ventricular arrhythmias are uncommon in athletes and increase the likelihood of structural heart disease up to 15-fold [79, 83].

ECG Interpretation Criteria in Athletes The overlap between training related ECG changes and pathological ECG patterns has historically been the reason for a significantly high false-positive rate in the athlete’s ECG [84]. Over the past decade, there have been several refinements of ECG interpretation in athletes. According to the latest international recommendations (Fig. 10.16), only 3% of white athletes have a positive test, with a specificity of more than 97% and a sensitivity of 92% [85, 86].

Normal ECG Findings

Abnormal ECG Findings

• Increased QRS voltage for LVH or RVH • Incomplete RBBB • Early repolarization/ST segment elevation • ST elevation followed by T wave inversion V1-V4 in black athletes • T wave inversion V1-V3 age 140 ms duration Epsilon wave Ventricular pre-excitation Prolonged QT interval Brugada Type 1 pattern Profound sinus bradycardia < 30 bpm PR interval > 400 ms Mobitz Type II 2° AV block 3° AV block > 2 PVCs Atrial tachyarrhythmias Ventricular arrhythmias

2 or more Further evaluation required to investigate for pathologic cardiovascular disorders associated with SCD in athletes

Fig. 10.16  ECG abnormalities in athletes (AV atrioventricular block, LBBB left bundle branch block, LVH left ventricular hypertrophy’, RBBB right bundle branch block, RVH right ventricular hypertrophy, PVC premature ventricular contraction, SCD sudden cardiac death) [1]

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Conclusion The 12-lead ECG is commonly used to identify young athletes with potentially serious electrical or structural cardiac abnormalities. Athletic training itself is associated with electrical alterations that may resemble serious disease, particularly among black athletes. Over the past decade, there have been several refinements in ECG interpretation in athletes that have reduced false-positive results without compromising specificity.

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Index

A Adenosine monophosphate activated protein kinase (AMPK), 126 Andersen-Tawil syndrome (ATS) ECG description, 18 pathophysiology, 8, 9, 19 Arrhythmogenic cardiomyopathy (ACM) ARVC (see Arrhythmogenic right ventricular cardiomyopathy) aspects, 85 cardiac amyloidosis, 108–110 clinical evaluation, 85 definition, 85 DES, 99–101 FLNC description, 101 features, 102 SCD, 102–104 ventricular arrhythmias, 102–104 LMNA (see Lamin A and C (LMNA)) phenotypes, 85, 86 PLN (see Phospholamban (PLN)) RBM20 (see RNA binding motif protein 20 (RBM20)) sarcoidosis cardiac involvement, 105, 106 description, 103, 105 extensive fibrosis, 105, 107 fragmentation, 105 patient presentation, 107, 108 screening tool, 105 ventricular fibrillation, 105, 106 SCN5A gene, 110, 111 Arrhythmogenic right ventricular cardiomyopathy (ARVC) compound heterozygosity, 86 depolarization and conduction abnormalities

epsilon wave, 87, 88 TAD, 88, 89 desmosomal genes, 86 diagnostic criteria, 86 electrocardiographic features, 86, 87 management, 86 non-desmosomal genes, 86 non-sustained ventricular tachycardia, 88–90 repolarization abnormalities, 87 sustained VT, 88 Athletes abnormal ECG AV block, 145 BrS, 149, 150 LBBB, 148 LQTS, 151, 152 non-specific IVCD, 147, 148 Q waves, 147 ST segment depression, 148 TWI, 148, 149 ventricular ectopics, 152, 153 ventricular pre-excitation, 145, 146 borderline ECG atrial enlargement, 144 axis deviation, 144 RBBB, 144, 145 international recommendations, 153 training-related ECG, 138 bradyarrhythmia, 138, 139 early repolarization, 141, 142 RBBB, 141 short PR interval, 140 TWI, 142–144 voltage criteria, 140, 141 Atrioventricular (AV) node, 128, 132 abnormal ECG, 145

© Springer Nature Switzerland AG 2020 M. Green et al. (eds.), Electrocardiography of Inherited Arrhythmias and Cardiomyopathies, https://doi.org/10.1007/978-3-030-52173-8

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Index

160 B BDVT, 73–76 Bradyarrhythmia, 138, 139 Brugada syndrome (BrS) abnormal ECG, 149, 150 atrioventricular and intraventricular conduction disturbances, 32, 33 coved type 1 pattern augmentation, 32 definition, 26 drug-induced pattern, 27, 28 drugs, 29 early recovery phase, 32 fever-induced pattern, 29, 31 guidelines, 30 high-lead configuration, 27 intermittent pattern, 27, 29 pharmacokinetic profile, 30 phenocopies, 32 right precordial leads, 27, 29 sodium-channel blocking agents, 30, 31 spontaneous, 26 diagnostic criteria, 35, 36 ERP, 34 fQRS, 32, 33 pathophysiology, 34, 35 peripheral leads, 34 right ventricular delay, 32 Tpeak-Tend dispersion, 34 C Cardiac adaptation, 144 Cardiac amyloidosis, 108–110 Cardiac sarcoidosis (CS) cardiac involvement, 105, 106 description, 103, 105 extensive fibrosis, 105, 107 fragmentation, 105 patient presentation, 107, 108 screening tool, 105 ventricular fibrillation, 105, 106 Cardiovascular magnetic resonance (CMR) technology, 105 Catecholaminergic polymorphic ventricular tachycardia (CPVT), 19 cessation of exercise/catecholamine infusion, 76, 77 exercise-induced PVCs BDVT/PMVT, 73–76 bigeminy and couplets/triplets, 71–73 single PVCs, 69, 70, 72 gain-of-function variants, 68 intracellular calcium handling, 68 normal baseline, 69–71

Chronic anabolic androgen, 45 Complete right bundle branch block (CRBBB), 87 Corrected QT interval (QTc), 5 D Delayed after depolarization (DADs), 19, 68 Depolarization hypothesis, 35 Desmin (DES), 99–101 E Early repolarization pattern (ERP), 34, 141, 142 Early repolarization syndrome (ERS) definition, 52–54 diagnosis, 57, 58, 60 management, 60, 61 patient history, 62, 63 risk markers JPE, 55–57 pre-symptomatic individuals, 53 risk stratification, 53, 54 ST-segment slope, 56, 58 T-wave amplitude, 56, 57, 59 Shanghai Score System, 60 Epsilon wave, 87, 88 F Filamin C (FLNC) description, 101 features, 102 SCD, 102–104 ventricular arrhythmias, 102–104 H Hypertrophic cardiomyopathy (HCM) apical variants, 119–121 genotype positive patients, 121, 123 LVH, 118 phenotype negative patients, 121, 123 pseudo Q-waves, 119 repolarization abnormalities, 121, 122 I Idiopathic ventricular fibrillation (IVF), 55 definition, 79 genetic architecture, 79, 82 short-coupled PVCs, 79 Implantable cardioverter defibrillator (ICD), 118 Intraventricular conduction delay (IVCD), 147, 148

Index J J wave, 53 J-point elevation (JPE) amplitude, 55, 56 definition, 52–54 distribution, 55 dynamicity, 55–57 risk stratification, 53, 54 L Lamin A and C (LMNA) cardiac manifestation, 93 clinical phenotypes, 93 features, 94–96 mutations, 93 MVA, 95, 97 SCD, 95, 96 Late gadolinium enhanced (LGE) technology, 105 Left bundle branch block (LBBB), 148 Left ventricular hypertrophy (LVH), 123, 140, 141, 118120 HCM, 118 PRKAG2 syndrome, 126, 127 Long QT syndrome (LQTS) abnormal ECG, 151, 152 ATS ECG description, 18 pathophysiology, 8, 9, 19 ECG findings, 21 hypertrophic cardiomyopathy, 17 QT interval dynamic changes, 10, 12, 14, 19, 20 prolonged, 4, 5, 10–12 severe hypocalcaemia, 16 SQTS, 44 STEMI, 17 TdP, 18 T wave macrovolt alternans, 15, 16, 21 morphology, 5–7, 13, 18 L-type calcium channel (LTCC), 68 M Malignant ventricular arrhythmias (MVA), 95, 97 P Phospholamban (PLN) cardiomyopathy, 91, 93 definition, 89, 91 electrocardiographic features, 91 disease progression, 92, 94

161 mild LV dysfunction, 91, 92 mutation carrier, 91, 92, 94 Polymorphic ventricular tachycardia (PMVT), 18, 73–76 Premature ventricular contractions (PVCs), 18, 30, 47, 48 PRKAG2 syndrome abnormal P wave morphology, 127, 128 atrioventricular block, 132 complex pre-excitation, 128, 130 LVH, 126, 127 short PR interval, 127, 129 Pseudo Q-waves, 119 Q QRS fragmentation (fQRS), 32, 33 QT interval dynamic changes ECG description, 19, 20 pathophysiology, 10, 12, 14, 19, 20 prolonged ECG description, 10–12 pathophysiology, 4, 5, 12 SQTS, 45–47 R Repolarization theory, 35 Right bundle branch block (RBBB) borderline ECG, 144, 145 training-related ECG, 141 Right ventricular hypertrophy (RVH), 140 RNA binding motif protein 20 (RBM20) diagnosis, 97 features, 97, 98 heart failure and sudden cardiac death, 98, 99 meta-analysis, 97 mutation carriers, 97 S SCN5A gene, 110, 111 Short QT syndrome (SQTS) cardiac arrest, 46 diagnosis, 45, 46 ECG findings, 41–43 genetics, 44, 45 PVC, 47, 48 reversible factors, 45 Sinus bradycardia, 138, 139 Sodium-calcium exchanger (NCX), 68 Sokolow-Lyon voltage criterion, 140, 141 Spontaneous diastolic calcium release (SDCR), 68

Index

162 ST-segment elevation myocardial infarction (STEMI), 17 Sudden cardiac death (SCD), 95, 96, 102–104 athletes (see Athletes) (see Brugada Syndrome (BrS)) HCM, 118 RBM20, 98, 99 T Tangent method, 4, 11 TdP, 18 Terminal activation duration (TAD), 88, 89 T-wave macrovolt alternans ECG description, 21 pathophysiology, 15, 16, 21 morphology

ECG description, 13 pathophysiology, 5–7, 18 T wave inversion (TWI), 87, 142 adolescent athletes, 143, 144 black athletes, 142, 143 clinical relevance, 148 inferior TWI, 148, 149 lateral TWI, 148, 149 V Ventricular arrhythmias (VA), 102–104 Ventricular ectopics (VEs), 152, 153 W Wolff-Parkinson-White syndrome (WPW), 146