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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.)

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.)

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.)

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.)