Circulation: Arrhythmia and Electrophysiology Editors' Picks

Sudden Deaths in Young Competitive Athletes: Analysis of 1866 Deaths in the United States, 1980 to 2006

Barry J. Maron, MD; Joseph J. Doerer, BS; Tammy S. Haas, RN; David M. Tierney, MD; Frederick O. Mueller, PhD

Summary

We have estimated the absolute number of sudden deaths in US competitive athletes from a large registry assembled over a 27-year period, using systematic identification and tracking strategies. A total of 1866 athletes who died suddenly (or survived cardiac arrest), 19±6 years of age, were identified throughout the United States from 1980 to 2006 in 38 diverse sports. Sudden deaths were predominantly due to cardiovascular disease (1049 [56%]) but also included deaths due to blunt trauma that caused structural damage (416 [22%]), commotio cordis (65 [4%]), and heat stroke (46 [2%]). Among the 1049 cardiovascular deaths, the highest number of events in a single year was 76 (2005 and 2006), with an average of 66 per year (range, 50–76) over the last 6 years, many of which could not have been identified reliably by preparticipation screening (even with an ECG); 29% of deaths were among blacks, 54% of victims were in high school, 82% of the deaths occurred with physical exertion during competition/training, and only 11% were female. The most common cardiovascular causes were hypertrophic cardiomyopathy (36%) and congenital coronary artery anomalies (17%). In this national registry, the absolute number of cardiovascular sudden deaths in young US athletes was relatively low, with a rate of <100 per year. These data are relevant to the current debate surrounding preparticipation screening programs with ECGs and suggest the need for systematic and mandatory reporting of sudden deaths in athletes to a national registry.

Conclusions

In this national registry, the absolute number of cardiovascular sudden deaths in young US athletes was somewhat higher than previous estimates but relatively low nevertheless, with a rate of <100 per year. These data are relevant to the current debate surrounding preparticipation screening programs with ECGs and also suggest the need for systematic and mandatory reporting of athlete sudden deaths to a national registry.¹

Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy

Paolo Spirito, MD; Camillo Autore, MD; Claudio Rapezzi, MD; Paola Bernabò, MD; Roberto Badagliacca, MD; Martin S. Maron, MD; Sergio Bongioanni, MD; Fabio Coccolo, MD; N.A. Mark Estes, MD; Caterina S. Barillà, MD; Elena Biagini, MD; Giovanni Quarta, MD; Maria Rosa Conte, MD; Paolo Bruzzi, MD, PhD; Barry J. Maron, MD

Summary

In patients with hypertrophic cardiomyopathy, syncope can be neurally mediated or a warning of dangerous arrhythmias or hemodynamic impairment, but its prognostic significance is not clearly established. We assessed the relationship between syncope and sudden death in 1511 consecutive hypertrophic cardiomyopathy patients; 205 (14%) had a history of unexplained or neurally mediated syncope. Over a 5.6-year mean follow-up, 74 patients died suddenly. Unexplained syncope but not neurally mediated syncope was associated with an increased risk of sudden death (hazard ratio, 1.78, P=0.08 compared with patients without syncope). Temporal proximity of unexplained syncope to initial patient evaluation was important. Patients with recent unexplained syncope (≤6 months before initial evaluation) showed a 5-fold increase in risk compared with patients without syncope, a relationship that was maintained throughout all age groups. In adolescents, unexplained syncope was associated with a 60% cumulative risk at 5 years. Older patients (≥40 years) with remote syncope (>5 years before initial evaluation) showed no increased sudden death risk. Thus, unexplained syncope is a marker for increased risk in hypertrophic cardiomyopathy, particularly when it occurs in close temporal proximity to patient evaluation. Remote syncopal events are not a marker of increased risk in older patients.

Conclusions

In the present large cohort of patients with hypertrophic cardiomyopathy, unexplained syncope was a risk factor for sudden death. Patients with syncopal events that occurred in close temporal proximity to the initial evaluation showed a substantially higher risk of sudden death than patients without syncope. Older patients with remote syncopal events did not show an increased risk.²

Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More

Satish R. Raj, MD, MSCI; Bonnie K. Black, RN, CNP; Italo Biaggioni, MD; Sachin Y. Paranjape, BS; Maricelle Ramirez; William D. Dupont, PhD; David Robertson, MD

Summary

Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance that disproportionately affects women of childbearing age. It is characterized by a constellation of symptoms that occur during standing but resolve with sitting or lying down. A most striking feature of this disorder is the excessive increase in heart rate that occurs on standing in the absence of hypotension. Given the striking tachycardia, β-adrenergic blockers would seem like ideal treatments, but prior anecdotal and experimental experience has been disappointing. We report the first placebo-controlled trial of propranolol in POTS. A low dose of propranolol (20 mg) immediately decreased heart rate and orthostatic tachycardia and improved the orthostatic symptoms in patients with POTS. A higher dose of propranolol (80 mg) elicited more complete β-blockade with a further lowering of heart rate but did not further improve symptoms and may have made some symptoms worse. These data suggest that although low doses of propranolol are of benefit in POTS, higher doses might be counterproductive. These data also offer a potential explanation for the conflicting prior results of β-blockers in POTS.

Conclusions

Low-dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS. Higher-dose propranolol did not further improve, and may worsen, symptoms.³

Syncope While Driving Clinical Characteristics, Causes, and Prognosis

Dan Sorajja, MD; Gillian C. Nesbitt, MD; David O. Hodge, MS; Phillip A. Low, MD; Stephen C. Hammill, MD; Bernard J. Gersh, MBChB, DPhil; Win-Kuang Shen, MD

Summary

In a large case-control study of 3877 patients with syncope, 381 patients (9.8%) reported an episode of syncope while driving. A peak of syncope while driving was observed among elderly patients. This has potential public health implications because this peak corresponds to an age group with a higher frequency of accidents per driver-year in the general public. The most common cause of syncope while driving was neurally mediated syncope (37.3%). The next most common identifiable causes were cardiac arrhythmias, including bradyarrhythmias, ventricular tachyarrhythmias, and supraventricular tachyarrhythmias (11.8%). Long-term survival among patients who had syncope while driving (driving group) was comparable to that of an age- and sex-matched cohort from the Minnesota population (P=0.15). Among the driving group, syncope recurred in 72 patients, 35 of whom (48.6%) had recurrence >6 months after the initial evaluation. Syncope while driving recurred in 10 patients in the driving group, 7 episodes of which (70%) occurred >12 months after the initial evaluation. The actuarial recurrence of syncope while driving was 0.7% at 6 months and 1.1% at 12 months during follow-up. The causes of syncope, the late recurrences of syncope (during >6 months of follow-up), and the overall low incidence of recurrent syncope while driving provide useful information to supplement current recommendations on driving for these patients.

Conclusions

In our study, neurally mediated syncope was the most common type of syncope while driving. The causes of syncope, the late recurrences of syncope (during >6 months of follow-up), and the overall low incidence of recurrent syncope while driving provide useful information to supplement current recommendations on driving for these patients.⁴

Long-Term Prognosis of Patients Diagnosed With Brugada Syndrome: Results From the FINGER Brugada Syndrome Registry

V. Probst, MD, PhD; C. Veltmann, MD; L. Eckardt, MD; P.G. Meregalli, MD; F. Gaita, MD; H.L. Tan, MD, PhD; D. Babuty, MD, PhD; F. Sacher, MD; C. Giustetto, MD; E. Schulze-Bahr, MD, PhD; M. Borggrefe, MD, PhD; M. Haissaguerre, MD; P. Mabo, MD, PhD; H. Le Marec, MD, PhD; C. Wolpert, MD, PhD; A.A.M. Wilde, MD, PhD

Summary

Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death. Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of sudden cardiac death in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. The registry included 1029 consecutive individuals (72% men). In the registry, 36% of the patients were symptomatic and 64% were asymptomatic. The cardiac event rate per year was 7.7% in patients with aborted sudden cardiac death, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas sex, familial history of sudden cardiac death, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. In the FINGER registry, the rate of cardiac events in the asymptomatic Brugada syndrome patients was low, and the inducibility of ventricular tachyarrhythmias during electrophysiological study did not properly stratify the arrhythmic risk.

Conclusions

In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.⁵

ECG Criteria to Identify Epicardial Ventricular Tachycardia in Nonischemic Cardiomyopathy

Ermengol Vallès, MD; Victor Bazan, MD; Francis E. Marchlinski, MD

Summary

ECG criteria for identifying an epicardial origin of ventricular tachycardia appear to be region and substrate specific. This is an important consideration because many ventricular tachycardias associated with nonischemic cardiomyopathy are epicardial in origin, and most of them originate from substrate-based abnormalities near the superior and lateral mitral valve region. It is imperative to identify which patients are likely to benefit from an epicardial approach. Simple morphological criteria, including the presence of a q wave in lead I, create a high degree of suspicion for a probable epicardial location in the setting of nonischemic cardiomyopathy. A suggested 4-step algorithm that incorporates modified interval criteria and well-defined morphological criteria enhances the diagnostic sensitivity and specificity of ECG assessment for ventricular tachycardia localization and should facilitate the planning and success of catheter ablation of ventricular tachycardia in this setting.

Conclusions

Morphological ECG features that describe the initial QRS vector can help identify basal-superior/lateral epicardial ventricular tachycardias in nonischemic cardiomyopathy.⁶

Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure: Analysis From the Sudden Cardiac Death in Heart Failure Trial

Douglas L. Packer, MD; Jordan M. Prutkin, MD, MHS; Anne S. Hellkamp, MS; L. Brent Mitchell, MD; Robert C. Bernstein, MD; Freda Wood, RN, MSN; John P. Boehmer, MD; Mark D. Carlson, MD; Robert P. Frantz, MD; Steve E. McNulty, MS; Joseph G. Rogers, MD; Jill Anderson, RN; George W. Johnson, BSEE; Mary Norine Walsh, MD; Jeanne E. Poole, MD; Daniel B. Mark, MD, MPH; Kerry L. Lee, PhD; Gust H. Bardy, MD

Summary

The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. This report examined the mode of death in SCD-HeFT. A total of 2521 subjects were randomly assigned to placebo, amiodarone, or shock-only, single-lead implantable cardioverter-defibrillator therapy. Over a median follow-up of 45.5 months, 666 deaths were reviewed by an events committee and categorized as sudden death presumed to be ventricular tachyarrhythmic, heart failure–related, bradyarrhythmic, nonarrhythmic non–heart failure–related, or noncardiac. Implantable cardioverter-defibrillator therapy reduced cardiac and ventricular tachyarrhythmic mortality and had no impact on mortality resulting from heart failure or noncardiac causes compared with placebo. The cardiac and ventricular tachyarrhythmic mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in ventricular tachyarrhythmic mortality with implantable cardioverter-defibrillator therapy was similar in subjects with ischemic and nonischemic disease. Amiodarone compared with placebo had no significant effect on any mode of death, although there was an increase in noncardiac mortality in those with New York Heart Association class III heart failure who were receiving amiodarone. Implantable cardioverter-defibrillator therapy has a beneficial effect on reducing sudden death presumed to be due to ventricular tachyarrhythmias without an effect on heart failure mortality.

Conclusions

Implantable cardioverter-defibrillator therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except for an increase in noncardiac mortality in class III patients.⁷

Systematic Assessment of Patients With Unexplained Cardiac Arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)

Andrew D. Krahn, MD; Jeffrey S. Healey, MD; Vijay Chauhan, MD; David H. Birnie, MD; Christopher S. Simpson, MD; Jean Champagne, MD; Martin Gardner, MD; Shubhayan Sanatani, MD; Derek V. Exner, MD; George J. Klein, MD; Raymond Yee, MD; Allan C. Skanes, MD; Lorne J. Gula, MD; Michael H. Gollob, MD

Summary

Cardiac arrest without evident cardiac disease may be caused by genetic conditions that are difficult to diagnose. Provocative testing to unmask a phenotype is often necessary to detect primary electric disease, direct genetic testing, and perform family screening. Patients resuscitated from cardiac arrest that was unexplained after an initial evaluation showed normal left ventricular function and an absence of coronary artery disease underwent systematic testing that included advanced imaging and drug challenge. A diagnosis was obtained in 56% of patients. Key testing included MRI to detect arrhythmogenic right ventricular cardiomyopathy and myocarditis, telemetry and ergonovine challenge to diagnose coronary spasm, and adrenaline/procainamide infusion to diagnose long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. Targeted genetic testing demonstrated evidence of causative mutations in 47% of patients tested, which resulted in detection of disease in 24% of 64 family members screened. This systematic approach to clinical testing unmasked the cause of apparently unexplained cardiac arrest in the majority of patients. This clinical approach assists in directing genetic testing to confirm genetically mediated arrhythmia syndromes and facilitates directed family screening to identify at-risk family members.

Conclusions

Systematic clinical testing, including drug provocation and advanced imaging, results in unmasking of the cause of apparently unexplained cardiac arrest in >50% of patients. This approach assists in directing genetic testing to diagnose genetically mediated arrhythmia syndromes, which results in successful family screening.⁸

Electrocardiographic Features of Arrhythmogenic Right Ventricular Dysplasia

Rahul Jain, MD; Darshan Dalal, MD; Amy Daly, MS; Crystal Tichnell, MGC; Cynthia James, PhD; Ariana Evenson, MHSA; Rohit Jain, MD; Theodore Abraham, MD; Boon Yew Tan, MBChB; Hari Tandri, MD; Stuart D. Russell, MD; Daniel Judge, MD; Hugh Calkins, MD

Summary

Diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) relies on results of diagnostic tests that screen for structural abnormalities of the right ventricle, ventricular arrhythmias, a family history of sudden death or ARVD, and ECG abnormalities that have been linked to ARVD. Among the many diagnostic tests that are used to screen patients for ARVD, the ECG is of particular importance because of its widespread availability and low cost. In this study, we performed a systematic analysis of the 12-lead ECG in ARVD patients compared with controls. To our knowledge, this is the first study to evaluate the ECG features of ARVD patients on the basis of the presence or absence of a complete or incomplete right bundle-branch block (RBBB). This is of particular importance because incomplete RBBB or complete RBBB patterns are commonly observed in patients with ARVD. The results of this study reveal that in the absence of a complete RBBB or incomplete RBBB, T-wave inversion through V₃ is the single ECG parameter that demonstrates optimal sensitivity and specificity. Second, for patients with an incomplete RBBB pattern, T-wave inversion through V₃ is also the single ECG parameter that demonstrates optimal sensitivity and specificity. Third, for patients with a complete RBBB pattern, an r‘/s ratio of <1 in V₁ was the single ECG parameter that demonstrated optimal sensitivity and specificity. It is our hope that the findings of our study will be confirmed in other populations of ARVD patients and that in the future, the ECG can be relied on with greater confidence as a screening tool for ARVD.

Conclusions

We comprehensively evaluated the diagnostic value of ECG markers for ARVD. On the basis of the findings, we propose an algorithm, with examination of QRS morphology being the first step, for ECG evaluation of ARVD patients. Definite criteria are then applied on the basis of the presence of no RBBB, incomplete RBBB, and complete RBBB to obtain the best diagnostic utility of the ECG.⁹

Yield of Genetic Screening in Inherited Cardiac Channelopathies: How to Prioritize Access to Genetic Testing

Rong Bai, MD; Carlo Napolitano, MD, PhD; Raffaella Bloise, MD; Nicola Monteforte, MD; Silvia G. Priori, MD, PhD

Summary

There is a rapid growth in the request of genetic screening for long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Genetic testing is often offered to all patients irrespective of whether they are “clearly” affected or “possibly” affected by one of such diseases, and even family members of unexplained sudden death victims and idiopathic ventricular fibrillation survivors are directed to genotyping in an attempt to clarify the substrate of the arrhythmic event. To help clinicians and third-party payers prioritize access to genotyping when resources are limited, it becomes critical to draw some cost/benefit considerations. We retrospectively analyzed data of 1394 consecutive probands to determine the yield of genetic screening and cost per positive genotyping in patients with either a conclusive or a possible diagnosis of long-QT syndrome, Brugada syndrome, or catecholaminergic polymorphic ventricular tachycardia and in family members of unexplained sudden death victims and idiopathic ventricular fibrillation survivors. We demonstrated that genotyping has the highest cost efficacy in individuals with a clinical conclusive diagnosis of long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. The yield and cost of genotyping is also reasonable in patients with type I Brugada syndrome ECG and atrioventricular block. However, genotyping family members of unexplained sudden death victims and idiopathic ventricular fibrillation survivors had low yield. Family history evaluation might be useful to better target genetic screening.

Conclusions

Genotyping can be performed at reasonable cost in individuals with conclusive diagnosis of long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia and in patients with type I Brugada syndrome ECG with atrioventricular block. These patients should be given priority to access genetic testing.¹⁰

Atrial Fibrillation Ablation Strategies for Paroxysmal Patients: Randomized Comparison Between Different Techniques

Luigi Di Biase, MD; Claude S. Elayi, MD; Tamer S. Fahmy, MD; David O. Martin, MD; Chi Keong Ching, MD; Conor Barrett, MD; Rong Bai, MD; Dimpi Patel, DO; Yaariv Khaykin, MD; Richard Hongo, MD; Steven Hao, MD; Salwa Beheiry, RN; Gemma Pelargonio, MD; Antonio Dello Russo, MD; Michela Casella, MD; Pietro Santarelli, MD; Domenico Potenza, MD; Raffaele Fanelli, MD; Raimondo Massaro, MD; Paul Wang, MD; Amin Al-Ahmad, MD; Mauricio Arruda, MD; Sakis Themistoclakis, MD; Aldo Bonso, MD; Antonio Rossillo, MD; Antonio Raviele, MD; Robert A. Schweikert, MD; David J. Burkhardt, MD; Andrea Natale, MD

Summary

Whether different ablation strategies affect paroxysmal atrial fibrillation (AF) long-term freedom from AF/atrial tachyarrhythmia (AT) is unclear. This study compared 3 different ablation approaches on the long-term success rate in patients with paroxysmal AF. This is the first prospective study comparing 3 ablation techniques in patients with paroxysmal AF. Complex fractionated atrial electrogram (CFAE) ablation alone had the smallest impact on the freedom from AF/AT at 1-year follow-up. The hybrid strategy, which combines isolation of the pulmonary vein antrum and ablation of CFAEs, was not associated with a better success rate, defined as event freedom from AF or AT at 6-month and 1-year follow-up when compared with pulmonary vein antrum isolation alone. This study reinforces the concept that electric isolation of all the pulmonary veins remains a cornerstone for catheter ablation of paroxysmal AF. The results of this study also indicate that CFAE ablation alone should not be considered as an alternative strategy for paroxysmal patients but should be reserved only for selected patients, unless a better identification of critical CFAE zones becomes widely available and is proven effective.

Conclusions

No difference in terms of success rate was seen between pulmonary vein antrum isolation alone and pulmonary vein antrum isolation associated with defragmentation. CFAE ablation alone had the smallest impact on AF recurrences at 1-year follow-up. These results suggest that antral isolation is sufficient to treat most patients with paroxysmal AF.¹¹

Mechanisms Underlying the Lack of Effect of Implantable Cardioverter-Defibrillator Therapy on Mortality in High-Risk Patients With Recent Myocardial Infarction: Insights From the Defibrillation in Acute Myocardial Infarction Trial (DINAMIT)

Paul Dorian, MD, MSc; Stefan H. Hohnloser, MD; Kevin E. Thorpe, MMath; Robin S. Roberts, MTech; Karl-Heinz Kuck, MD; Michael Gent, DSc; Stuart J. Connolly, MD

Summary

In the Defibrillation in Acute Myocardial Infarction Trial (DINAMIT) study, implanted defibrillators did not reduce mortality in high-risk patients if implanted early after myocardial infarction. In patients randomly assigned to an implantable cardioverter-defibrillator (ICD), sudden deaths were reduced but nonarrhythmic mortality was increased. In an analysis of the potential causes of this finding, patients who are destined to receive therapy from their ICD (compared with those destined not to receive therapy) have clinical features that also increase their risk of nonsudden death, including risks related to heart failure and recurrent ischemic events. During follow-up, patients who receive therapy from their ICD are more likely to have intercurrent cardiac clinical adverse events both before and after ICD therapy compared with patients who receive no therapy or do not have an ICD. In an early post–myocardial infarction setting, the same clinical circumstances that increase the risk of ventricular arrhythmias also increase the risk of nonsudden death; in addition, ICD therapies themselves may increase the risk of subsequent death. These findings underscore the limitations of a strategy of ICD implantation in certain high-risk groups, especially early after acute myocardial infarction.

Conclusions

In patients receiving ICDs early after myocardial infarction, those factors that are associated with arrhythmia requiring ICD therapy are also associated with a high risk of nonsudden death, negating the benefit of ICDs in this setting.¹²

Long-Term Recording of Cardiac Arrhythmias With an Implantable Cardiac Monitor in Patients With Reduced Ejection Fraction After Acute Myocardial Infarction: The Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) Study

Poul Erik Bloch Thomsen, MD; Christian Jons, MD; M.J. Pekka Raatikainen, MD; Rikke Moerch Joergensen, MD; Juha Hartikainen, MD; Vesa Virtanen, MD; J. Boland, MD; Olli Anttonen, MD; Uffe Jakob Gang, MD; Nis Hoest, MD; Lucas V.A. Boersma, MD; Eivin S. Platou, MD; Daniel Becker, MSc; Marc D. Messier, PhD; Heikki V. Huikuri, MD; for the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) Study Group

Summary

Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) reports on long-term cardiac arrhythmias recorded by an implantable cardiac monitor in patients with left ventricular ejection fraction ≤40% after myocardial infarction. Clinically significant bradyarrhythmias and tachyarrhythmias were documented in a substantial proportion of patients, most of them asymptomatic. A large number of the documented arrhythmias would result in device therapy according to the current guidelines. The most significant arrhythmia was intermittent high-degree atrioventricular block, which was associated with a very high risk of cardiac death. However, the study was observational, and whether the use of implantable cardiac monitors in this population could improve clinical outcome should be tested in larger randomized trials.

Conclusions

This is the first study to report on long-term cardiac arrhythmias recorded by an implantable loop recorder in patients with left ventricular ejection fraction ≤40% after myocardial infarction. Clinically significant bradyarrhythmias and tachyarrhythmias were documented in a substantial proportion of patients with depressed left ventricular ejection fraction after acute myocardial infarction. Intermittent high-degree atrioventricular block was associated with a very high risk of cardiac death.¹³

High Efficacy of β-Blockers in Long-QT Syndrome Type 1: Contribution of Noncompliance and QT-Prolonging Drugs to the Occurrence of β-Blocker Treatment “Failures”

G. Michael Vincent, MD; Peter J. Schwartz, MD; Isabelle Denjoy, MD; Heikki Swan, MD; Candice Bithell, BA; Carla Spazzolini, DVM, MS; Lia Crotti, MD, PhD; Kirsi Piippo, MD; Jean-Marc Lupoglazoff, MD, PhD; Elizabeth Villain, MD; Silvia G. Priori, MD, PhD; Carlo Napolitano, MD, PhD; Li Zhang, MD

Summary

β-Blocker noncompliance, the use of QT-prolonging drugs, or both in combination are responsible for almost all cardiac events while patients are “on” β-blockers, rather than “β-blocker failures.” Being β-blocker compliant and receiving no QT-prolonging drugs dramatically reduce cardiac events to a mean yearly rate of 0.06 (range, 0.05–0.07) for cardiac arrest or sudden death. This has equally important ramifications for the selection of therapy for long-QT syndrome type 1 patients. Being so efficacious, β-blockers should be the initial treatment for all asymptomatic patients at diagnosis, those with remote symptoms, and those with syncope (and possible even a cardiac arrest) who were not on a β-blocker at the time of the event. Furthermore, early diagnosis and treatment, before the high-risk time of preteens through the 20s, is very important for preventing cardiac events, particularly cardiac arrest and sudden death. Physicians should carefully discuss the importance of full compliance with β-blockers and the avoidance of any QT-prolonging drugs at the time of first contact and indicate the danger of not adhering to these recommendations. This discussion should be repeated regularly during follow-up. Patients who will not or cannot take β-blockers may be candidates for implantable converter-defibrillators or left stellectomy therapy.

Conclusions

β-Blockers are extremely effective in long-QT syndrome type 1 and should be administered at diagnosis and ideally before the preteen years. β-Blocker noncompliance and use of QT-prolonging drug are responsible for almost all life-threatening “β-blocker failures.” β-Blockers are appropriate therapy for asymptomatic patients and those who have never had a cardiac arrest or β-blocker therapy. Routine implantation of cardiac defibrillators in such patients does not appear justified.¹⁴

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Diagnostic Task Force Criteria: Impact of New Task Force Criteria

Moniek G.P.J. Cox, MD; Jasper J. van der Smagt, MD; Maartje Noorman, MSc; Ans C. Wiesfeld, MD, PhD; Paul G.A. Volders, MD, PhD; Irene M. van Langen, MD, PhD; Douwe E. Atsma, MD, PhD; Dennis Dooijes, PhD; Arjan C. Houweling, MD, PhD; Peter Loh, MD, PhD; Luc Jordaens, MD, PhD; Yvonne Arens, MD, PhD; Maarten J. Cramer, MD, PhD; Pieter A. Doevendans, MD, PhD; J. Peter van Tintelen, MD, PhD; Arthur A.M. Wilde, MD, PhD; Richard N.W. Hauer, MD, PhD

Summary

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive loss of predominantly RV myocardium, which is replaced by fibrofatty tissue. Typically, affected individuals present with ventricular tachycardia between the 2nd and 4th decades of life, but ARVD/C can also cause sudden death in adolescence. Clinical diagnosis is made according to generally accepted task force criteria (TFC). This initial set of criteria, dating from 1994, was highly specific but lacked sensitivity. Therefore, a modified set of TFC was recently proposed. In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C are upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS ≥55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. In the present study, we applied new TFC to 3 groups: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). In total, 35 individuals were newly diagnosed with ARVD/C: 10 of 89 (11%) relatives and 25 of 39 (64%) previously classified as probable index patients. On the contrary, 3 of 105 ARVD/C patients previously classified as “proven” did not fulfill new TFC. ECG criteria and pathogenic mutations especially contributed to new diagnosis. Therefore, newly proposed TFC have a major impact in increasing diagnostic yield of ARVD/C.

Conclusions

In this first study applying new TFC to patients suspected of ARVD/C, 64% of probable ARVD/C patients and 11% of family members were additionally diagnosed. ECG criteria and pathogenic mutations especially contributed to new diagnosis. Newly proposed TFC have a major impact in increasing diagnostic yield of ARVD/C.¹⁵

Left Atrial Appendage: An Underrecognized Trigger Site of Atrial Fibrillation

Luigi Di Biase, MD; J. David Burkhardt, MD; Prasant Mohanty, MBBS, MPH; Javier Sanchez, MD; Sanghamitra Mohanty, MD; Rodney Horton, MD; G. Joseph Gallinghouse, MD; Shane M. Bailey, MD; Jason D. Zagrodzky, MD; Pasquale Santangeli, MD; Steven Hao, MD; Richard Hongo, MD; Salwa Beheiry, MD; Sakis Themistoclakis, MD; Aldo Bonso, MD; Antonio Rossillo, MD; Andrea Corrado, MD; Antonio Raviele, MD; Amin Al-Ahmad, MD; Paul Wang, MD; Jennifer E. Cummings, MD; Robert A. Schweikert, MD; Gemma Pelargonio, MD; Antonio Dello Russo, MD; Michela Casella, MD; Pietro Santarelli, MD; William R. Lewis, MD; Andrea Natale, MD, FHRS

Summary

Several studies have shown that together with the pulmonary veins, many extrapulmonary vein areas may be the source of initiation and maintenance of atrial fibrillation. The most common sites are the superior vena cava, ligament of Marshall, coronary sinus, crista terminalis, and left atrial posterior wall. This study is the first to report firing from the left atrial appendage as a possible site of origin of atrial fibrillation in a consecutive series of patients. The prevalence of this finding in our population was 27%, and in 8.7% of patients, the left atrial appendage was the only target of ablation during redo procedures. We performed electric isolation of the left atrial appendage. Similar to what was observed for the isolation of the pulmonary veins, isolation of the left atrial appendage with segmental or circumferential lesions led to a higher probability of achieving long-term freedom from atrial fibrillation/atrial tachyarrhythmia than focal ablation. The clinical relevance of left atrial appendage isolation and its consequences with respect to potential complications require further investigation.

Conclusions

The left atrial appendage appears to be responsible for arrhythmias in 27% of patients presenting for repeat procedures. Isolation of the left atrial appendage could achieve freedom from atrial fibrillation in patients presenting for a repeat procedure when arrhythmias initiating from this structure are demonstrated.¹⁶

Incidence and Risk Factors of Arrhythmic Events in Catecholaminergic Polymorphic Ventricular Tachycardia

Meiso Hayashi, MD; Isabelle Denjoy, MD; Fabrice Extramiana, MD, PhD; Alice Maltret, MD; Nathalie Roux Buisson, MD; Jean-Marc Lupoglazoff, MD, PhD; Didier Klug, MD; Miyuki Hayashi, MD; Seiji Takatsuki, MD; Elisabeth Villain, MD; Joël Kamblock, MD; Anne Messali, MD; Pascale Guicheney, PhD; Joël Lunardi, MD, PhD; Antoine Leenhardt, MD

Summary

Catecholaminergic polymorphic ventricular tachycardia is a rarely recognized but important cause of sudden cardiac death in the young. This multicenter observational study of 101 subjects (50 probands, 51 family members) was conducted to characterize the clinical course of the disease. Catecholaminergic polymorphic ventricular tachycardia was diagnosed from clinical features in 84 subjects and from genotyping in 17 subjects. During the follow-up of 7.9±4.9 years, 27 patients (27%), including 2 silent gene mutation carriers, had syncope, aborted cardiac arrest, or sudden cardiac death events that were fatal or near-fatal in 13 subjects. The estimated 8-year event rate was 32%, with a 13% rate of fatal or near-fatal events. The event rates between the probands and family members were comparable. A younger age at diagnosis, a history of aborted cardiac arrest, and the absence of β-blockers were predictors of events, but β-blocker therapy was not completely protective. These results suggest that β-blockers should be prescribed even if the diagnosis is made from genotyping when there is not a history of symptomatic arrhythmias. Additional therapies, including implantable defibrillators, verapamil, or left cardiac sympathetic denervation, should be considered in patients with markers of increased risk.

Conclusions

Cardiac and fatal or near-fatal events were not rare in both catecholaminergic polymorphic ventricular tachycardia probands and affected family members during the long-term follow-up, even while taking β-blockers, which was associated with a lower event rate. Further studies evaluating concomitant therapies are necessary to improve outcome in these patients.¹⁷

Genetic Testing for Long-QT Syndrome: Distinguishing Pathogenic Mutations From Benign Variants

Suraj Kapa, MD; David J. Tester, BS; Benjamin A. Salisbury, PhD; Carole Harris-Kerr, PhD; Manish S. Pungliya, MS; Marielle Alders, PhD; Arthur A.M. Wilde, MD, PhD; Michael J. Ackerman, MD, PhD

Summary

Genetic testing for congenital long-QT syndrome (LQTS) has become an established part of the clinical armamentarium for physicians encountering patients with a personal or family history of ventricular tachyarrhythmias and sudden cardiac death. However, the presence of a positive genetic test result must be reviewed carefully. Most mutations identified in cases of LQTS are novel missense mutations and thus must be distinguished as either background noise or function-altering/disease-causing mutations. Specifically, even in the general healthy population, genetic variation, including known polymorphisms and novel, rare variants, may be demonstrated. Thus, the presence of a genetic mutation should be interpreted as a probabilistic measure of likelihood of disease rather than as a binary indicator of its presence or absence. This work indicates that mutation type, mutation location, and ethnic-specific background rates are critical factors in predicting the pathogenicity of novel mutations. However, in certain cases, distinguishing pathogenic mutations from rare variants may not be possible without additional functional characterization or linkage analyses. Although mutations localizing to certain specialized regions may be expected with high probability to be disease causing, mutations in other regions should be seen as variants of uncertain significance and should be interpreted in the clinical context and lead to further investigation rather than prompting assumption of disease presence and resulting therapeutic interventions. This classification of genetic test results as a probabilistic rather than absolute measure of disease causation has potential implications when counseling patients, especially as genetic testing becomes less expensive, more easily available, and more commonly used. These findings may also have implications for other genetic disorders involving mutational analysis in which benign genetic variation is sure to exist and must be distinguished from disease-causing mutations.

Conclusions

Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic-specific background rates are critical factors in predicting the pathogenicity of novel mutations. Novel mutations in low-estimated predictive value regions such as the interdomain linker of SCN5A should be viewed as variants of uncertain significance and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the transmembrane, linker, and pore of KCNQ1 and KCNH2 may be defined confidently as high-probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.¹⁸

Predicting Ventricular Arrhythmias in Patients With Ischemic Heart Disease: Clinical Application of the ECG-Derived QRS-T Angle

C. Jan Willem Borleffs, MD; Roderick W.C. Scherptong, MD; Sum-Che Man, MD; Guido H. van Welsenes, MS; Jeroen J. Bax, MD, PhD; Lieselot van Erven, MD, PhD; Cees A. Swenne, PhD; Martin J. Schalij, MD, PhD

Summary

A depressed left ventricular ejection fraction identifies a large number of high-risk patients who receive implantable cardioverter-defibrillators (ICDs) for primary sudden death prevention. The minority, however, will have an appropriate therapy for ventricular tachycardia/fibrillation, and a similar number may have complications or unnecessary therapy (often shocks). Thus, there remains a need for better risk stratification to identify patients likely to benefit. This investigation evaluated the ECG-derived QRS-T angle for predicting spontaneous arrhythmias and mortality in an observational study of 412 primary prevention defibrillator recipients with ischemic heart disease and a left ventricular ejection fraction ≤40%. A widened spatial QRS-T angle predicted spontaneous ventricular tachycardia/fibrillation, with an adjusted hazard ratio of 7.3. Interestingly, in patients with a spatial QRS-T angle ≤100°, the incidence of life-threatening arrhythmias was as low as 2% during study follow-up. Similar characteristics were observed for the planar QRS-T angle, which is the frontal projection of the QRS-T angle but with lower discriminative power (adjusted hazard ratio, 2.9). Further study of the spatial QRS-T angle for risk stratification is warranted.

Conclusions

A wide QRS-T angle is a strong predictor of appropriate device therapy in primary prevention ICD recipients with ischemic heart disease. Furthermore, a spatial QRS-T angle ≤100° might be of value in the identification of patients in whom, although currently indicated, ICD treatment should be reconsidered.¹⁹

J Wave, QRS Slurring, and ST Elevation in Athletes With Cardiac Arrest in the Absence of Heart Disease: Marker of Risk or Innocent Bystander?

Riccardo Cappato, MD; Francesco Furlanello, MD; Valerio Giovinazzo, MD; Tommaso Infusino, MD; Pierpaolo Lupo, MD; Mario Pittalis, MD; Sara Foresti, MD; Guido De Ambroggi, MD; Hussam Ali, MD; Elisabetta Bianco, MD; Roberto Riccamboni, MD; Gianfranco Butera, MD; Cristian Ricci, PhD; Marco Ranucci, MD, Antonio Pelliccia, MD; Luigi De Ambroggi, MD

Summary

The ECG pattern of early repolarization (ie, J wave, QRS slurring, and/or ST-segment elevation) in the inferior and lateral ECG leads is a common finding in the general population and is even more frequently observed in athletes. Recent studies have suggested a potential proarrhythmic significance of these findings in the general population, but data are lacking in athletes. We investigated whether QRS-ST changes are markers of risk for cardiac arrest or sudden death in athletes without underlying heart disease. In a selected group of 21 young competitive athletes who had cardiac arrest in the absence of heart disease, the prevalence of J wave and/or QRS slurring in the inferior (II, III, and aVF) and lateral leads (V₄ to V₆) was significantly higher in cases than in control athletes. After sport discontinuation during 36-month follow-up, arrhythmia recurrences did not differ between subgroups with and without J wave or QRS slurring. Because of discrepancy between the frequency of early repolarization pattern on 12-lead ECG and the rarity of cardiac arrest/sudden death, the incidental finding of a J wave/QRS slurring in a healthy athlete should be considered as a marker that minimally increases the arrhythmic risk. The present findings provide novel insights on clinical profiles of athletes at possible risk of cardiac arrest.

Conclusions

J wave and/or QRS slurring was found more frequently among athletes with cardiac arrest/sudden death than in control athletes. Nevertheless, the presence of this ECG pattern appears not to confer a higher risk for recurrent malignant ventricular arrhythmias.²⁰

New ECG Criteria in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Moniek G.P.J. Cox, MD; Jasper J. van der Smagt, MD; Arthur A.M. Wilde, MD, PhD; Ans C.P. Wiesfeld, MD, PhD; Douwe E. Atsma, MD, PhD; Marcel R. Nelen, PhD; Luz-Maria Rodriguez, MD, PhD; Peter Loh, MD, PhD; Maarten J. Cramer, MD, PhD; Pieter A. Doevendans, MD, PhD; J. Peter van Tintelen, MD, PhD; Jacques M.T. de Bakker, PhD; Richard N.W. Hauer, MD, PhD

Summary

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive loss of predominantly right ventricular myocardium, which is replaced by fibrofatty tissue. Typically, affected individuals present with ventricular tachycardia between the 2nd and 4th decade of life, but ARVD/C is also a major cause of sudden death in adolescence. Clinical diagnosis was made according to generally accepted task force criteria (TFC). These criteria are highly specific but lack sensitivity. After demonstration of high sensitivity and specificity in a previous study, we showed that our newly proposed additional ECG criteria improved ARVD/C diagnosis. Patients highly suspected of ARVD/C, that is, with 3 points according to current TFC (TFC3), were studied, being 21 index patients and 12 family members of patients with proven ARVD/C. Prolonged terminal activation duration is a new parameter on right ventricular activation delay. Although only 1 of these patients had an ε wave, 15 (45%) showed right ventricular activation delay by prolonged terminal activation duration, mainly family members. The new parameters on ventricular tachycardia morphology, ventricular tachycardia with left bundle-branch block morphology and superior-axis and multiple ventricular tachycardia morphologies, were recorded in 12 of 21 (57%) TFC3 index patients but not in family members. Altogether, 70% of highly suspicious patients fulfilled ARVD/C diagnosis when newly proposed criteria were applied additionally to current TFC. Thus, adding our newly proposed ECG criteria would improve sensitivity of current TFC and thereby ARVD/C diagnosis. By this means, affected individuals can be recognized in an earlier stage of disease, and appropriate therapeutic measures can be taken to prevent arrhythmias and sudden death.

Conclusions

Adding the newly proposed criteria to current TFC for ARVD/C will improve identification of affected individuals importantly, independent of outcome of DNA analyses.²¹

Clinical Characteristics and Genetic Background of Congenital Long-QT Syndrome Diagnosed in Fetal, Neonatal, and Infantile Life: A Nationwide Questionnaire Survey in Japan

Hitoshi Horigome, MD; Masami Nagashima, MD; Naokata Sumitomo, MD; Masao Yoshinaga, MD; Hiroya Ushinohama, MD; Mari Iwamoto, MD; Junko Shiono, MD; Koh Ichihashi, MD; Satoshi Hasegawa, MD; Tadahiro Yoshikawa, MD; Tamotsu Matsunaga, MD; Hiroko Goto, MD; Kenji Waki, MD; Masaki Arima, MD; Hisashi Takasugi, MD; Yasuhiko Tanaka, MD; Nobuo Tauchi, MD; Masanobu Ikoma, MD; Noboru Inamura, MD; Hideto Takahashi, PhD; Wataru Shimizu, MD; Minoru Horie, MD

Summary

The congenital long-QT syndrome (LQTS) diagnosed at perinatal life and through infancy is associated with high morbidity and mortality rates. However, data on the clinical presentation and genotype-phenotype correlation of this youngest age group of LQTS are limited. A nationwide survey was conducted in Japan, and 58 cases (18 fetuses, 31 neonates, and 9 infants) were registered. Among them, the peak age at diagnosis was 0–2 days, and the 3 most frequent clinical presentations included sinus bradycardia, ventricular tachycardia/torsade des pointes, and atrioventricular block. The genotype was confirmed in 29 (71%) of 41 patients who underwent genotyping; the incidence resembled that of child LQTS. Patients who presented with early-onset ventricular tachycardia/torsade des pointes and atrioventricular block were almost exclusively those with LQT2 and LQT3 among the 3 major genes, but a considerable number of genetically unidentified ones were included. Sudden cardiac death/aborted cardiac arrest were prevalent in the latter. LQT1 patients tended to show only sinus bradycardia or positive family history of LQTS. These results mean that many life-threatening episodes observed in early-onset LQTS should be treated immediately and aggressively even without knowledge of the genotype. On the other hand, the present study was encouraging in that the outcome of patients was favorable with multiple pharmaceutical agents, typically with β-blockers, mexiletine, and magnesium and with pacemaker implantation/implantable cardioverter-defibrillator, independent of the genotype. Further application of gene testing is needed to establish the most appropriate genotype-specific strategy for these patients.

Conclusions

Patients with LQTS who showed life-threatening arrhythmias at perinatal periods were mostly those with LQT2, LQT3, or no known mutations. Independent of the genotype, aggressive intervention resulted in effective suppression of arrhythmias, with only 7 deaths recorded.²²

Outcomes of Early Risk Stratification and Targeted Implantable Cardioverter-Defibrillator Implantation After ST-Elevation–Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention

Sarah Zaman, MBBS; Gopal Sivagangabalan, MBBS, FRACP; Arun Narayan, RN; Aravinda Thiagalingam, MBChB, FRACP, PhD; David L. Ross, MBBS, FRACP; Pramesh Kovoor, MBBS, PhD, FRACP

Summary

Selection of myocardial infarction (MI) survivors to receive prophylactic implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death requires further elucidation. Although there is a mortality benefit for patients with significantly depressed left ventricular function when ICDs are implanted late after MI, a recent study found no benefit for patients implanted early after MI, despite studies demonstrating a higher risk of sudden death during the early months after MI that decreases with time. The optimal clinical approach to protecting these patients is not known, and data in the present era of primary percutaneous coronary intervention are limited. Our study recruited consecutive patients treated with primary percutaneous coronary intervention for acute ST-elevation–myocardial infarction (STEMI). Patients with left ventricular ejection fraction ≤40% underwent electrophysiological study followed by ICD implantation in those with inducible ventricular tachycardia ≥200-ms cycle length. The overall mortality of 3% at 1 year was low compared with previous primary prevention studies, and there was no evidence of excess mortality with ICD implantation early after MI. In addition, patients with inducible ventricular tachycardia selected to receive an ICD had a relatively high rate of spontaneous ICD therapy for ventricular arrhythmias of 22%. Although not randomized, this study suggests favorable outcomes with a uniform, systematic primary prevention protocol integrated within an STEMI primary percutaneous coronary intervention service. This approach appears to be a rational approach to safely allocate ICD implantation early after STEMI.

Conclusions

Early ICD implantation limited to patients with inducible ventricular tachycardia enables a low overall mortality in patients with impaired left ventricular ejection fraction after primary percutaneous coronary intervention for STEMI.²³

Footnotes