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Background: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed., Objectives: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC., Methods: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias., Results: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia., Conclusions: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events., Competing Interests: Funding Support and Author Disclosures This work was supported by the Paul and Ruby Tsai Family Hypertrophic Cardiomyopathy Career Development Award (Dr Giudicessi); the National Institutes of Health/National Heart, Lung, and Blood Institute R01HL147064 and R01HL164634 (Drs Mestroni and Taylor). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures Dr Martinez has been a consultant for Bristol Myers Squibb and Cytokinetics. Dr Ackerman has been a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Invitae, Medtronic, Tenaya Therapeutics, Thryv Therapeutics, and UpToDate. Dr Ackerman and the Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. Dr Baggish has received funding from the National Institutes of Health/National Heart, Lung, and Blood Institute, the National Football Players Association, the American Heart Association, and the American Medical Society for Sports Medicine to study topics relevant to the content of this paper; and receives compensation for his role as team cardiologist from the U.S. Olympic Committee/U.S. Olympic Training Centers and U.S. Soccer. Dr Day has been a consultant for Lexicon Pharmaceuticals; has received grant funding from Bristol Myers Squibb and Lexicon Pharmaceuticals; and has served on the DMC for Cytokinetics. Dr Putukian has been a General Medical Committee Member, NFL; and has received royalties from UpToDate and Netters Sports Medicine Textbook. Dr Lampert has received honoraria and research support from Medtronic, Abbott-St Jude, and Boston Scientific; and has served on the advisory board of Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: People diagnosed with genetic heart diseases (GHDs) associated with sudden cardiac death (SCD) have historically been restricted from competitive sports. Recent data documenting return-to-play (RTP) experiences following shared decision making (SDM) suggest that cardiac event rates for athletes with a GHD are lower than previously described, thereby suggesting an opportunity to reconsider this paradigm., Objectives: The purpose of this study was to evaluate clinical outcomes among National Collegiate Athletic Association Division I university and professional athletes diagnosed with a GHD., Methods: A multicenter retrospective analysis was performed to examine demographics, clinical characteristics, RTP outcomes, and cardiac events among elite athletes with a GHD., Results: A total of 76 elite (66%, Division I, 34% professional) athletes (age 19.9 ± 5 years, 28% women) diagnosed with a GHD (hypertrophic cardiomyopathy [53%], long QT syndrome, long QT syndrome [26%]) comprise this cohort. Most athletes were asymptomatic (48 of 76, 63%) before diagnosis and had their GHD detected during routine preparticipation cardiovascular screening. Most athletes (55 of 76, 72%) were initially disqualified from their sport but subsequently opted for unrestricted RTP after comprehensive clinical evaluation and SDM. To date, (mean follow-up 7 ± 6 years), only 1 exercise-related (1.3%) and 2 nonexercise-related GHD-associated adverse cardiac events occurred. There have been no fatalities during follow-up., Conclusions: This is the first study describing the experience of athletes with a known SCD-predisposing GHD who are competing at the elite level. After careful evaluation, risk stratification, and tailoring of their GHD therapy, RTP following SDM appears associated with low, nonfatal events rates at elite levels of sport., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (to Dr Ackerman) and Mayo Clinic Center for Clinical and Translational Science through grant number UL1TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Invitae, Medtronic, Tenaya Therapeutics, Thryv Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, and Pfizer; however, none of these entities were involved in this study. Dr Martinez is a consultant for Bristol Myers Squibb and Cytokinetics. Dr Phelan is a consultant for Bristol Myers Squibb, Pfizer, and Caption Health. Dr Baggish has received funding from the National Institute of Health/National Heart, Lung, and Blood Institute, the National Football Players Association, the American Heart Association, and the American Society for Sports Medicine to study cardiovascular outcomes among elite athletes; and receives compensation for his role as team cardiologist from the U.S. Olympic Committee/U.S. Olympic Training Centers, U.S. Soccer, and U.S. Rowing. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Recently, electronic gaming has been reported as a precipitant of life-threatening cardiac arrhythmias in susceptible individuals. However, the prevalence of cardiac events in genetic heart diseases (GHDs) in the setting of electronic gaming has not been established., Objectives: In this study, we sought to define the prevalence of cardiac events occurring in the setting of electronic gaming in GHDs., Methods: Retrospective review of all patients evaluated and treated at Mayo Clinic's genetic heart rhythm clinic from July 2000 to November 2022 was performed to identify patients with a history of playing electronic games at the time of their cardiac event. Cardiac event was used to define events occurring before diagnosis, and breakthrough cardiac event (BCE) was used for events occurring after diagnosis., Results: Of the 3,370 patients with a GHD (mean age at first evaluation 27 ± 19 years, 55% female), 1,079 (32%) had a cardiac event before diagnosis, with 5 patients (0.5%) having an electronic gaming-associated event (3 catecholaminergic polymorphic ventricular tachycardia, 1 long QT syndrome, and 1 premature ventricular contraction-triggered ventricular fibrillation). After diagnosis and treatment, 431 patients (13%) experienced ≥1 BCE during follow-up, of which 1 electronic gaming-associated BCE (0.2%) occurred in a patient with catecholamine-sensitive right outflow tract ventricular tachycardia., Conclusions: Although anecdotal cases of electronic gaming-associated life-threatening arrhythmias have been reported, in this largest single-center study to date, we show that these are extremely rare occurrences. While electronic gaming can have adverse health consequences, the threat of electronic gaming-triggered sudden death should not be used to try to curb time spent gaming., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (Dr Ackerman) and the Mayo Clinic Center for Translational Science Activities through grant no. UL1TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daichii-Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate; and Dr Ackerman and Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics (none of these entities were involved in this study). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Long QT syndrome (LQTS) predisposes individuals to arrhythmic syncope or seizure, sudden cardiac arrest, or sudden cardiac death (SCD). Increased physician and public awareness of LQTS-associated warning signs and an increase in electrocardiographic screening programs may contribute to overdiagnosis of LQTS., Objectives: This study sought to identify the diagnostic miscues underlying the continued overdiagnosis of LQTS., Methods: Electronic medical records were reviewed for patients who arrived with an outside diagnosis of LQTS but were dismissed as having normal findings subsequently. Data were abstracted for details on referral, clinical history, and both cardiologic and genetic test results., Results: Overall, 290 of 1,841 (16%) patients with original diagnosis of LQTS (174 [60%] female; mean age at first Mayo Clinic evaluation, 22 ± 14 years; mean QTc interval, 427 ± 25 milliseconds) were dismissed as having normal findings. The main cause of LQTS misdiagnosis or overdiagnosis was a prolonged QTc interval secondary to vasovagal syncope (n = 87; 30%), followed by a seemingly positive genetic test result for a variant in 1 of the main LQTS genes (n = 68; 23%) that was ultimately deemed not to be of clinical significance. Furthermore, patients received misdiagnoses because of a positive family history of SCD that was deemed unrelated to LQTS (n = 46; 16%), isolated/transient QT prolongation (n = 44; 15%), or misinterpretation of the QTc interval as a result of inclusion of the U-wave (n = 40, 14%)., Conclusions: Knowing the 5 main determinants of discordance between a previously rendered diagnosis of LQTS and full diagnostic reversal or removal (vasovagal syncope, "pseudo"-positive genetic test result in LQTS-causative genes, family history of SCD, transient QT prolongation, and misinterpretation of the QTc interval) increases awareness and provides critical guidance to reduce this burden of overdiagnosed LQTS., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program and the Mayo Clinic Center for Translational Science Activities through grant number UL1TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr Ackerman has received support for this work from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program; has served as a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Invitae, Medtronic, Tenaya Therapeutics, Thryv Therapeutics, and UpToDate, outside this study; and, with Mayo Clinic, has license agreements with AliveCor, Anumana, ARMGO Pharma, and Pfizer, outside this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Within the last 5 years, cardiac society guidelines have begun to acknowledge shared decision making (SDM) for the athlete with sudden cardiac death-predisposing genetic heart diseases (GHDs), such as long QT syndrome (LQTS), and the possibility for that athlete's return to play. Previously, international guidelines embraced a de facto disqualification for all such athletes including athletes with solely a positive genetic test in Europe., Objectives: This study sought to examine the prevalence and outcomes of athletes with sudden cardiac death-predisposing GHDs, particularly LQTS, after their return to play., Methods: A retrospective review of the electronic medical record was performed on all athletes with GHD, with a primary analysis for those with LQTS, who were evaluated, risk stratified, and treated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic by a single genetic cardiologist between July 1, 2000, and July 31, 2020., Results: There were 672 athletes with GHD overall including 494 athletes with LQTS (231 female athletes [46.8%]; mean age at diagnosis 14.8 ± 10.5 years; mean follow-up 4.2 ± 4.8 years) who were given return-to-play approval. Overall, 79 of 494 athletes with LQTS (16.0%) were symptomatic before diagnosis, and 58 (11.7%) had an implantable cardioverter-defibrillator. In 2,056 combined years of follow-up, there was no GHD-sports associated mortality. Instead, 29 patients (5.9%) had ≥1 nonlethal, LQTS-associated breakthrough cardiac event. Of those, 15 (3.0%) were athletes at the time of the breakthrough cardiac event, with 3 (0.6%) experiencing a sports-related breakthrough cardiac event, and 12 (2.4%) a non-sports-related event. Overall, the event rate was 1.16 nonlethal events per 100 athlete-years of follow-up., Conclusions: This 20-year single center experience challenges the status quo of disqualification for all athletes with LQTS and provides additional observational evidence, albeit from a single center, in support of the more contemporary SDM approaches to this complex issue., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program and Mayo Clinic Center for Clinical and Translational Science through grant UL1TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr. Ackerman has served as a consultant for Abbott, ARMGO Pharma Inc., Audentes Therapeutics, Biotronik, Boston Scientific, Daiichi-Sankyo, Invitae, LQT Therapeutics, Medtronic, MyoKardia, and UpToDate. Dr. Ackerman and Mayo Clinic have a potential equity and/or royalty relationship with AliveCor Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Fatkin has received support from the Victor Chang Cardiac Research Institute, Estate of the Late R.T. Hall, New South Wales Health, Australian Genomics, National Health and Medical Research Council of Australia. Dr. Kovacic has received research support from the National Institutes of Health (R01HL130423, R01HL135093, R01HL148167–01A1) and New South Wales Health (RG194194). Dr. Giudicessi has modest equity interest in 3M, GlaxoSmithKline, Medtronic, MyoKardia, and Pfizer. Dr. Ackerman is a consultant for Abbott, ARMGO Pharma, Audentes Therapeutics, Boston Scientific, Daiichi-Sankyo, Invitae, LQT Therapeutics, Medtronic, MyoKardia, and UpToDate; and he and the Mayo Clinic are involved in an equity/royalty relationship with AliveCor (AliveCor was not involved in this study)., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological features including myocyte hypertrophy, myocyte disarray, and interstitial fibrosis., Objectives: This study sought to correlate myocardial histopathology with clinical characteristics of patients with obstructive HCM and post-operative outcomes following septal myectomy., Methods: The authors reviewed the pathological findings of the myocardial specimens from 1,836 patients with obstructive HCM who underwent septal myectomy from 2000 to 2016. Myocyte hypertrophy, myocyte disarray, interstitial fibrosis, and endocardial thickening were graded and analyzed., Results: The median age at operation was 54.2 years (43.5 to 64.3 years), and 1,067 (58.1%) were men. A weak negative correlation between myocyte disarray and age at surgery was identified (ρ = -0.22; p < 0.001). Myocyte hypertrophy (p < 0.001), myocyte disarray (p < 0.001), and interstitial fibrosis (p < 0.001) were positively associated with implantable cardioverter-defibrillator implantation. Interstitial fibrosis (p < 0.001) and endocardial thickening (p < 0.001) were associated with atrial fibrillation pre-operatively. In the Cox survival model, older age (p < 0.001), lower degree of myocyte hypertrophy (severe vs. mild hazard ratio: 0.41; 95% confidence interval: 0.19 to 0.86; p = 0.040), and lower degree of endocardial thickening (moderate vs. mild hazard ratio: 0.75; 95% confidence interval: 0.58 to 0.97; p = 0.019) were independently associated with worse post-myectomy survival. Among 256 patients who had genotype analysis, patients with pathogenic or likely pathogenic variants (n = 62) had a greater degree of myocyte disarray (42% vs. 15% vs. 20%; p = 0.022). Notably, 13 patients with pathogenic or likely pathogenic genetic variants of HCM had no myocyte disarray., Conclusions: Histopathology was associated with clinical manifestations including the age of disease onset and arrhythmias. Myocyte hypertrophy and endocardial thickening were negatively associated with post-myectomy mortality., Competing Interests: Funding Support and Author Disclosures This study was supported by the Paul and Ruby Tsai and Family to Dr. Schaff. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The ability to identify those patients at the highest phenotypic risk for long QT syndrome (LQTS)-associated life-threatening cardiac events remains suboptimal., Objectives: This study sought to validate the association between electromechanical window (EMW) negativity, as derived from echocardiography, and symptomatic versus asymptomatic status in patients with LQTS., Methods: We analyzed a cohort of 651 patients with LQTS (age 26 ± 17 years; 60% females; 158 symptomatic; 51% LQTS type 1; 33% LQTS type 2; 11% LQTS type 3; 5% multiple mutations) and 50 healthy controls. EMW was calculated as the difference between the interval from QRS onset to aortic valve closure midline, as derived for continuous-wave Doppler, and the electrocardiogram-derived QT interval for the same beat., Results: A negative EMW was found among nearly all patients with LQTS compared to controls, with more profound EMW negativity in patients with symptomatic LQTS compared to those with asymptomatic LQTS (-52 ± 38 ms vs. -18 ± 29 ms; p < 0.0001). Logistic regression identified EMW, heart rate-corrected QT interval (QTc), female sex, and LQTS genotype as univariate predictors of symptomatic status. After multivariate analysis, EMW remained an independent predictor of symptomatic status (odds ratio for each 10-ms decrease in EMW: 1.37; 95% confidence interval: 1.27 to 1.48; p < 0.0001). EMW outperformed QTc in predicting symptomatic patients (area under the curve: 0.78 vs. 0.70; p = 0.01). After training and implementation, EMW correlation from echocardiographic sonographers showed excellent reliability (intraclass correlation coefficient: 0.93; 95% confidence interval: 0.89 to 0.96)., Conclusions: In this validation study, patients with a history of LQTS-associated life-threatening cardiac events had a more profoundly negative EMW. EMW outperformed heart rate-corrected QT interval as a predictor of symptomatic status. EMW is now a clinically validated risk factor. In December 2019, our institution's echocardiography clinical practice committee approved use of EMW for patients with LQTS, making it a routinely reported echocardiographic finding., Competing Interests: Author Disclosures Dr. Ackerman is a consultant for Abbott, Audentes Therapeutics, Boston Scientific, Daiichi-Sankyo, Invitae, LQT Therapeutics, Medtronic, MyoKardia Inc., and UpToDate. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is an uncommon but important cause of sudden cardiac death., Objectives: This study sought to develop an artificial intelligence approach for the detection of HCM based on 12-lead electrocardiography (ECG)., Methods: A convolutional neural network (CNN) was trained and validated using digital 12-lead ECG from 2,448 patients with a verified HCM diagnosis and 51,153 non-HCM age- and sex-matched control subjects. The ability of the CNN to detect HCM was then tested on a different dataset of 612 HCM and 12,788 control subjects., Results: In the combined datasets, mean age was 54.8 ± 15.9 years for the HCM group and 57.5 ± 15.5 years for the control group. After training and validation, the area under the curve (AUC) of the CNN in the validation dataset was 0.95 (95% confidence interval [CI]: 0.94 to 0.97) at the optimal probability threshold of 11% for having HCM. When applying this probability threshold to the testing dataset, the CNN's AUC was 0.96 (95% CI: 0.95 to 0.96) with sensitivity 87% and specificity 90%. In subgroup analyses, the AUC was 0.95 (95% CI: 0.94 to 0.97) among patients with left ventricular hypertrophy by ECG criteria and 0.95 (95% CI: 0.90 to 1.00) among patients with a normal ECG. The model performed particularly well in younger patients (sensitivity 95%, specificity 92%). In patients with HCM with and without sarcomeric mutations, the model-derived median probabilities for having HCM were 97% and 96%, respectively., Conclusions: ECG-based detection of HCM by an artificial intelligence algorithm can be achieved with high diagnostic performance, particularly in younger patients. This model requires further refinement and external validation, but it may hold promise for HCM screening., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS., Objectives: This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS., Methods: A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of "potentially informative," ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed., Results: Overall, 53 of 419 (12.6%) SIDS cases had ≥1 "potentially informative," GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a "potentially informative" GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5%]) versus European control subjects (30 of 973 [3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a "pathogenic" or "likely pathogenic" variant., Conclusions: Less than 15% of more than 400 SIDS cases had a "potentially informative" variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families., (Copyright © 2018 American College of Cardiology Foundation. All rights reserved.)

Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy with a 1% to 5% annual risk of LQTS-triggered syncope, aborted cardiac arrest, or sudden cardiac death., Objectives: This study sought to evaluate LQTS outcomes from a single center in the contemporary era., Methods: The authors conducted a retrospective study comprising the 606 patients with LQTS (LQT1 in 47%, LQT2 in 34%, and LQT3 in 9%) who were evaluated in Mayo Clinic's Genetic Heart Rhythm Clinic from January 1999 to December 2015. Breakthrough cardiac events (BCEs) were defined as LQTS-attributable syncope or seizures, aborted cardiac arrest, appropriate ventricular fibrillation-terminating implantable cardioverter-defibrillator shocks, and sudden cardiac death., Results: There were 166 (27%) patients who were symptomatic prior to their first Mayo Clinic evaluation. Median age at first symptom was 12 years. Treatment strategies included no active therapy in 47 (8%) patients, beta-blockers alone in 350 (58%) patients, implantable cardioverter-defibrillators alone in 25 (4%) patients, left cardiac sympathetic denervation alone in 18 (3%) patients, and combination therapy in 166 (27%) patients. Over a median follow-up of 6.7 (IQR: 3.9 to 9.8) years, 556 (92%) patients have not experienced an LQTS-triggered BCE. Only 8 of 440 (2%) previously asymptomatic patients have experienced a single BCE. In contrast, 42 of 166 (25%) previously symptomatic patients have experienced ≥1 BCE. Among the 30 patients with ≥2 BCEs, 2 patients have died and 3 LQT3 patients underwent cardiac transplantation., Conclusions: Although outcomes have improved markedly, further optimization of treatment strategies is still needed given that 1 in 4 previously symptomatic patients experienced at least 1 subsequent, albeit nonlethal, LQTS-triggered cardiac event., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On February 26-27, 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF)., Background: JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca(2+) handling and modulation of ryanodine receptor Ca(2+) channels (RyR2). Whereas defective RyR2-mediated Ca(2+) release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias., Methods: Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudoknock-in (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation., Results: PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF than wild type (WT)-PKI mice, whereas A399S-PKI mice expressing a hypertrophic cardiomyopathy-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca(2+) release events. These changes were attributed to reduced binding of E169K-JPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca(2+) spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients and an increased frequency of spontaneous Ca(2+) release events., Conclusions: Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2/RyR2 ratios can promote SR Ca(2+) leak and atrial arrhythmias, representing a potential novel therapeutic target for AF., (Copyright © 2013. Published by Elsevier Inc.)

Objectives: The aim of this study was to investigate the prevalence of mitral valve prolapse (MVP) and its association with ventricular arrhythmias in a cohort with "unexplained" out-of-hospital cardiac arrest., Background: Ventricular arrhythmias are an important cause of sudden unexpected death in the young. The role of MVP in sudden unexpected death remains controversial., Methods: Of 1,200 patients evaluated between July 2000 and December 2009 in the Mayo Clinic's Long QT Syndrome/Genetic Heart Rhythm Clinic, all 24 (16 women, median age 33.5 years) with idiopathic out-of-hospital cardiac arrest (i.e., negative for ischemia, cardiomyopathy, and channelopathy) were reviewed., Results: All 24 patients had implantable cardioverter-defibrillators (ICDs). Out-of-hospital cardiac arrest was the sentinel event in 22 (92%). Bileaflet MVP was found in 10 (42%). Compared with patients with normal mitral valves, patients with bileaflet MVP: 1) were over-represented by women (9 of 10 [90%] vs. 7 of 14 [50%], p = 0.04); 2) had a higher prevalence of biphasic or inverted T waves (7 of 9 [77.8%] vs. 4 of 14 [29%], p = 0.04); and 3) on Holter interrogation had higher prevalence of ventricular bigeminy (9 of 9 [100%] vs. 1 of 10 [10%], p < 0.0001), ventricular tachycardia (7 of 9 [78%] vs. 1 of 10 [10%], p = 0.006), and premature ventricular contractions originating from the outflow tract alternating with the papillary muscle or fascicular region (7 of 9 [78%] vs. 2 of 10 [20%], p = 0.02). Over a median 1.8 years (range: 0.1 to 11.9 years) from ICD placement, 13 of 24 patients (54%) received appropriate ventricular fibrillation-terminating ICD shocks. Only bileaflet MVP was associated with ventricular fibrillation recurrences requiring ICD therapy on follow-up (logistic regression odds ratio: 7.2; 95% confidence interval: 1.1 to 48; p = 0.028)., Conclusions: The authors describe a "malignant" subset of patients with MVP who experienced life-threatening ventricular arrhythmias. This phenotype is characterized by bileaflet MVP, female sex, and frequent complex ventricular ectopic activity, including premature ventricular contractions of the outflow tract alternating with papillary muscle or fascicular origin., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

There are few areas in cardiology in which the impact of genetics and genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, 3 are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these 3 diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing, including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important it is to understand the ways that genotype can affect clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these heritable arrhythmia syndromes and the proper use and interpretation of clinical genetic testing should remain the standard of care., (Copyright © 2013. Published by Elsevier Inc.)

Objectives: The aim of this study was to determine the efficacy of implantable cardioverter-defibrillators (ICDs) in children and adolescents with hypertrophic cardiomyopathy (HCM)., Background: HCM is the most common cause of sudden death in the young. The availability of ICDs over the past decade for HCM has demonstrated the potential for sudden death prevention, predominantly in adult patients., Methods: A multicenter international registry of ICDs implanted (1987 to 2011) in 224 unrelated children and adolescents with HCM judged at high risk for sudden death was assembled. Patients received ICDs for primary (n = 188) or secondary (n = 36) prevention after undergoing evaluation at 22 referral and nonreferral institutions in the United States, Canada, Europe, and Australia., Results: Defibrillators were activated appropriately to terminate ventricular tachycardia or ventricular fibrillation in 43 of 224 patients (19%) over a mean of 4.3 ± 3.3 years. ICD intervention rates were 4.5% per year overall, 14.0% per year for secondary prevention after cardiac arrest, and 3.1% per year for primary prevention on the basis of risk factors (5-year cumulative probability 17%). The mean time from implantation to first appropriate discharge was 2.9 ± 2.7 years (range to 8.6 years). The primary prevention discharge rate terminating ventricular tachycardia or ventricular fibrillation was the same in patients who underwent implantation for 1, 2, or ≥3 risk factors (12 of 88 [14%], 10 of 71 [14%], and 4 of 29 [14%], respectively, p = 1.00). Extreme left ventricular hypertrophy was the most common risk factor present (alone or in combination with other markers) in patients experiencing primary prevention interventions (17 of 26 [65%]). ICD-related complications, particularly inappropriate shocks and lead malfunction, occurred in 91 patients (41%) at 17 ± 5 years of age., Conclusions: In a high-risk pediatric HCM cohort, ICD interventions terminating life-threatening ventricular tachyarrhythmias were frequent. Extreme left ventricular hypertrophy was most frequently associated with appropriate interventions. The rate of device complications adds a measure of complexity to ICD decisions in this age group., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS)., Background: Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective., Methods: Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented., Results: Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol., Conclusions: Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)-susceptibility genes discovered to date in a single large cohort of unrelated BrS patients., Background: BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V1 to V3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events., Methods: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only)., Results: Overall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients and was significantly greater among young men<20 years of age with clinically diagnosed BrS and among patients who had a prolonged PQ interval., Conclusions: We identified putative pathogenic mutations in ∼20% of our BrS cohort, with BrS genes 2 through 12 accounting for <5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to assess myocardial blood flow (MBF) using positron emission tomography in patients with hypertrophic cardiomyopathy (HCM) according to genetic status., Background: Coronary microvascular dysfunction is an important feature of HCM, associated with ventricular remodeling and heart failure. We recently demonstrated the increased prevalence of systolic dysfunction in patients with HCM with sarcomere myofilament gene mutations and postulated an association between genetic status and coronary microvascular dysfunction., Methods: Maximum MBF (intravenous dipyridamole, 0.56 mg/kg; Dip-MBF) was measured using (13)N-labeled ammonia in 61 patients with HCM (age 38 ± 14 years), genotyped by automatic DNA sequencing of 8 myofilament-encoding genes (myosin-binding protein C, beta-myosin heavy chain, regulatory and essential light chains, troponin T, troponin I, troponin C, alpha-tropomyosin, and alpha-actin). In 35 patients, cardiac magnetic resonance imaging was performed., Results: Fifty-three mutations were identified in 42 of the 61 patients (genotype positive; 69%). Despite similar clinical profiles, genotype-positive patients with HCM showed substantially lower Dip-MBF compared with that of genotype-negative patients (1.7 ± 0.6 ml/min/g vs. 2.4 ± 1.2 ml/min/g; p < 0.02). A Dip-MBF <1.5 ml/min/g had 81% positive predictive value for genotype-positive status and implied a 3.5-fold independent increase in likelihood of carrying myofilament gene mutations (hazard ratio: 3.52; 95% confidence interval: 1.05 to 11.7; p = 0.04). At cardiac magnetic resonance imaging, the prevalence of late gadolinium enhancement was greater in genotype-positive patients (22 of 23 [96%] compared with 8 of 12 [67%] genotype-negative patients; p = 0.038)., Conclusions: Patients with HCM with sarcomere myofilament mutations are characterized by more severe impairment of microvascular function and increased prevalence of myocardial fibrosis, compared with genotype-negative individuals. These findings suggest a direct link between sarcomere gene mutations and adverse remodeling of the microcirculation in HCM, accounting for the increased long-term prevalence of ventricular dysfunction and heart failure in genotype-positive patients., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result., Background: ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test., Methods: Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database., Results: The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2., Conclusions: This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS)., Background: Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited., Methods: The Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry., Results: Multivariate analysis demonstrated that corrected QT interval (QTc) duration (≥500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events., Conclusions: Children and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals., Background: Current data regarding the outcome of patients with concealed LQTS are limited., Methods: Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (≤ 440 ms [n = 469]), LQTS with prolonged QTc interval (> 440 ms [n = 1,392]), and unaffected family members (genotyped negative with ≤ 440 ms [n = 1,525])., Results: The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age > 13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002)., Conclusions: Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort., Background: In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported., Methods: A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC)., Results: Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease., Conclusions: Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS)., Background: Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology., Methods: Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events., Results: For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1-S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location-type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in alpha-helical domains than in subjects with mutations in beta-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent beta-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001)., Conclusions: The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.

Objectives: This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc)., Background: Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts., Methods: Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45)., Results: Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons., Conclusions: Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.

Objectives: This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy)., Background: The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously., Methods: The study population of 3,323 patients with QT interval corrected for heart rate (QTc) > or =450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life., Results: The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc > or =500 ms, heart rate < or =100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p < 0.01) for ACA or SCD during ages 1 to 10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD but not for those who survived ACA in infancy., Conclusions: Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset., (2009 by the American College of Cardiology Foundation)

Objectives: The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations., Background: Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin., Methods: We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes., Results: Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes., Conclusions: CARP abnormalities may be involved in the pathogenesis of HCM.

Over the last 2 decades, the pathogenic basis for the most common heritable cardiovascular disease, hypertrophic cardiomyopathy (HCM), has been investigated extensively. Affecting approximately 1 in 500 individuals, HCM is the most common cause of sudden death in young athletes. In recent years, genomic medicine has been moving from the bench to the bedside throughout all medical disciplines including cardiology. Now, genomic medicine has entered clinical practice as it pertains to the evaluation and management of patients with HCM. The continuous research and discoveries of new HCM susceptibility genes, the growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM make it essential that the modern-day cardiologist understand the diagnostic, prognostic, and therapeutic implications of HCM genetic testing.

Objectives: This study sought to clarify the frequency, clinical phenotype, and prognosis of those patients with hypertrophic cardiomyopathy (HCM) who present with a normal electrocardiogram (ECG)., Background: Hypertrophic cardiomyopathy is the most common cause of sudden death in young people. Screening advocates have recommended a 12-lead ECG for the early detection of HCM in athletes, yet the clinical outcomes of those presenting with a normal ECG remains to be fully delineated., Methods: Baseline characteristic and echocardiographic data were collected on all patients with HCM who initially presented to our institution with a diagnostic echocardiogram but a normal ECG. Follow-up was obtained and compared with the prognosis of HCM patients who presented with abnormal ECGs., Results: We compared 135 HCM patients with a normal ECG with 2,350 HCM patients with an abnormal ECG. The latter group was more likely to have worse symptoms, have higher gradients, and a greater degree of septal wall thickness than the patients with a normal ECG. Severe obstructive symptoms requiring surgical myectomy and implantation of an implantable cardioverter-defibrillator were more common in patients with abnormal ECGs. Cardiac survival was significantly better in the group with a normal ECG at presentation-none of these patients had a cardiac death at follow-up., Conclusions: Almost 6% of patients presenting with demonstrable echocardiographic evidence of HCM had a normal ECG at the time of diagnosis. This subset of patients with normal ECG-HCM appears to exhibit a less severe phenotype with better cardiovascular outcomes.

Objectives: This study was designed to investigate the clinical course of women with long QT syndrome (LQTS) throughout their potential childbearing years., Background: Only limited data exist regarding the risks associated with pregnancy in women with LQTS., Methods: The risk of experiencing an adverse cardiac event, including syncope, aborted cardiac arrest, and sudden death, during and after pregnancy was analyzed for women who had their first birth from 1980 to 2003 (n = 391). Time-dependent Kaplan-Meier and Cox proportional hazard methods were used to evaluate the risk of cardiac events during different peripartum periods., Results: Compared with a time period before a woman's first conception, the pregnancy time was associated with a reduced risk of cardiac events (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.10 to 0.76, p = 0.01), whereas the 9-month postpartum time had an increased risk (HR 2.7, 95% CI 1.8 to 4.3, p < 0.001). After the 9-month postpartum period, the risk was similar to the period before the first conception (HR 0.91, 95% CI 0.55 to 1.5, p = 0.70). Genotype analysis (n = 153) showed that women with the LQT2 genotype were more likely to experience a cardiac event than women with the LQT1 or LQT3 genotype. The cardiac event risk during the high-risk postpartum period was reduced among women using beta-blocker therapy (HR 0.34, 95% CI 0.14 to 0.84, p = 0.02)., Conclusions: Women with LQTS have a reduced risk for cardiac events during pregnancy, but an increased risk during the 9-month postpartum period, especially among women with the LQT2 genotype. Beta-blockers were associated with a reduction in cardiac events during the high-risk postpartum time period.

Objectives: The aims of this study were: 1) to evaluate risk factors influencing the clinical course of mutation-confirmed adult patients with long QT syndrome (LQTS), 2) to study life-threatening cardiac events as a specific end point in adults, and 3) to examine the protective effect of beta-blocker therapy on cardiac events in adult LQTS patients with known cardiac channel mutations., Background: The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with LQTS have not been previously investigated., Methods: The clinical characteristics of 812 mutation-confirmed LQTS patients age 18 years or older were studied with both univariate and multivariate analyses to determine the genotype-phenotype factors that influence the clinical course of adult patients with this disorder., Results: Female gender, corrected QT (QTc) interval, LQT2 genotype, and frequency of cardiac events before age 18 years were associated with increased risk of having any cardiac events between the ages of 18 and 40 years. Female gender, QTc interval > or =500 ms, and interim syncopal events during follow-up after age 18 years were associated with significantly increased risk of life-threatening cardiac events in adulthood. Beta-blockers provided a 60% reduction in risk of any cardiac event and life-threatening events, with somewhat greater effect in higher-risk subjects., Conclusions: The severity of LQTS in adulthood can be risk stratified with information regarding genotype, gender, QTc duration, and history of cardiac events. Beta-blockers effectively reduce but do not eliminate the risk of both syncopal and life-threatening cardiac events in adult patients with mutation-confirmed LQTS.

Objectives: This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD)., Background: Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases., Methods: From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 +/- 10.9 years) were referred by medical examiners/coroners to Mayo Clinic's Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation., Results: Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 +/- 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p < 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases., Conclusions: In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD.