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Introduction: Long QT syndrome (LQTS) is a cardiac channelopathy characterized by QT prolongation and a potential for arrhythmic syncope, sudden cardiac arrest or deaths (SCA/SCD). It has been speculated that patients with LQTS might have a primary sinoatrial node (SAN) phenotype of chronotropic insufficiency (CI). This has not been demonstrated convincingly before because of the potentially confounding effects of beta blocker (BB) therapy. Herein, we set out to determine whether untreated patients with LQTS demonstrate intrinsic CI., Methods and Results: A retrospective review of all treadmill exercise stress tests (TEST) was performed on patients with one of the three most common LQTS genotypes: LQT1, LQT2, and LQT3. For each patient, the first TEST completed while off BB was analyzed. Patients with prior left cardiac sympathetic denervation (LCSD) therapy were excluded. CI was defined as having an age- and gender-predicted peak heart rate (HR) < 85% and/or a predicted HR reserve (HRR) < 80%. Overall, 463 LQTS patients (245 LQT1, 125 LQT2, and 93 LQT3) were included (267 female [58%]; mean age at time of TEST [29 ± 17 years]). Mean % predicted peak HR for all LQTS patients was 87.6% (range 42.9% - 119.1%) and mean % predicted HRR was 80% (range 19.1% - 153%). Overall, half of all LQTS patients (n = 234; 51%) displayed CI; 64% of patients with LQT1 (n = 157), 37% with LQT2 (n = 46), and 33% with LQT3 (n = 31). Patients with LQT1 were most likely to exhibit CI compared to patients with LQT2 (p < .0001) and LQT3 (p < .0001). CI was significantly more common in LQT1 compared to controls (p < .0001), while there was no difference between LQT2 (p = .5) or LQT3 and controls (p > .9). Presence of CI was not a predictor of LQTS-associated symptoms, BB side effects or likelihood of future breakthrough cardiac events (BCE)., Conclusions: Patients with LQTS, particularly LQT1, demonstrate a SAN phenotype of CI. If assessing BB therapy effect by impact on peak HR, the patient's pretreatment peak HR, rather than an age- and gender-predicted maximum HR, should be used., (© 2024 Wiley Periodicals LLC.)

Objective: To determine the prevalence, penetrance, and disease expression of cardiomyopathy-related genetic variants in an unselected, richly phenotyped Mayo Clinic population in the setting of preemptive sequencing, with return of incidental findings following the American College of Medical Genetics and Genomics recommendations., Patients and Methods: We analyzed a quaternary medical center-based biobank cohort (n=983) for reportable variants in 15 cardiomyopathy genes. Prioritization of genetic variants was performed using an internally developed pipeline to identify potentially reportable variants. Prioritized variants were then manually curated. The correlation of likely pathogenic/pathogenic (LP/P) variants with clinical phenotypes and outcomes was established. Artificial intelligence-enabled electrocardiographic predictions of reduced left ventricular ejection fraction and hypertrophic cardiomyopathy were applied to genotype-positive (G+) participants., Results: Of the 983 patients, 11 (1%) were G+, with 11 LP/P variants found in the MYBPC3, DSG2, MYH7, DSP, and PKP2 genes. All G+ participants underwent electrocardiography, and 10 (90%) underwent echocardiography. Most patients (10 [90%]) did not have a prior diagnosis of cardiomyopathy. Definitive disease penetrance (heart failure or cardiomyopathy) was present in 4 (36%), while 3 (27%) had possible penetrance (structural heart disease identified by echocardiography). Arrhythmias and/or cardiac conduction disease was present in 4 of 11 G+ individuals (36%). Artificial intelligence-electrocardiography was positive for hypertrophic cardiomyopathy or reduced left ventricular ejection fraction in 5 of the G+ participants (45%), of whom 4 (80%) had definitive or possible disease penetrance., Conclusion: Cardiomyopathy-associated LP/P variants are present in a small subset of a quaternary medical center population, and disease penetrance in G+ individuals is high in the form of cardiac structural abnormalities and heart failure., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown., Methods: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples., Results: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1983 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males., Conclusion: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: We have previously reported that genetically positive patients have a more profound early decrease in provocable left ventricular outflow tract gradient compared to genetically negative patients utilizing mavacamten in the first 12 weeks of therapy., Methods and Results: In this current analysis, we found that genetically positive patients have less favorable remodeling as measured by left ventricular wall thickness regression when evaluated long-term as compared to genetically negative patients, despite an overall better early response to mavacamten. The majority of genetically positive patients were maintained on only 2.5 mg of mavacamten due to early robust response., Conclusion: We hypothesize that this lower dosing attenuated the long-term benefit of mavacamten in genetically positive patients. We believe that the long-term benefit of mavacamten on positive cardiac remodeling is dose-dependent and not solely related to the magnitude of left ventricular outflow gradient decrease., Competing Interests: Conflict of Interest Nothing to report in relation to this specific project., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Guideline-directed device therapy for long QT syndrome (LQTS) has evolved during the years, and indications for an implantable cardioverter-defibrillator (ICD) vary between professional cardiac societies., Objective: We aimed to identify the subset of patients with LQTS who satisfied a class I or class II 2022 European Society of Cardiology guideline-based recommendation for an ICD and to determine the outcomes of those patients who received an ICD compared with those treated without an ICD., Methods: Retrospective analysis was conducted of 2861 patients with LQT1, LQT2, or LQT3 to identify patients meeting contemporary recommendations for guideline-directed device therapy. Basic demographics, clinical characteristics, and frequency/type of breakthrough cardiac events (BCEs) were extracted, and outcomes/complications were compared between patients treated with an ICD and those treated without one., Results: Of the 290 patients (approximately 10%) who met a guideline-based recommendation, 53 (18%) satisfied a class I/level B indication for an ICD; 56 (19%), a class I/level C indication; 19 (7%), a class IIa/level C indication; and 162 (56%), a class IIb/level B indication. However, most patients (156/290 [54%]) did not receive an ICD. Of those who received an ICD, 55 of 134 (41%) experienced ≥1 appropriate ventricular fibrillation-terminating ICD therapy, whereas ICD-related complications occurred in 13 patients (10%). Of those who were treated without an ICD, only 6 of 156 patients (4%) had nonlethal BCEs, which was significantly lower compared with the ICD group (P < .001)., Conclusion: With >1200 years of combined follow-up, the experience and evidence from our 2 LQTS specialty centers suggest that many patients who satisfy a recommendation for an ICD based on the latest 2022 European Society of Cardiology guidelines may not need one. This is particularly true when the indication stemmed from a BCE while receiving beta blocker therapy or in asymptomatic patients with an increased 1-2-3-LQTS-Risk score., Competing Interests: Disclosures Dr Ackerman is a consultant for Abbott, BioMarin Pharmaceutical, Boston Scientific, Bristol Myers Squibb, Illumina, Invitae, Medtronic, Solid Biosciences, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are/were involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, Prolaio, and Thryv Therapeutics., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp., Methods: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2 , and 50 SCN5A ) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, evolutionary scale modeling, version 1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp., Results: Considering variants in all 3 genes, the evolutionary scale modeling, version 1b model had a receiver operating characteristic curve-area under the curve of 0.75 ( P =0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operating characteristic curve-area under the curve of 0.85 ( P <0.0001), sensitivity of 80%, and specificity of 76%., Conclusions: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis., Competing Interests: Dr Ackerman is a consultant for Abbott, BioMarin Pharmaceutical, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Illumina, Invitae, Medtronic, Solid Biosciences, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. However, none of these entities have contributed to this study in any manner. The other authors report no conflicts.

Competing Interests: Disclosures Dr Ackerman is a consultant for Abbott, BioMarin Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Illumina, Invitae, Medtronic, Solid Biosciences, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. Dr Siontis is a consultant for AskBio and Bristol Myers Squibb (fees paid to institution). Dr Geske is a consultant for Cytokinetics and is the principal investigator for clinical trials funded by Bristol Myers Squibb and Cytokinetics. Dr Giudicessi is a consultant for Avidity Therapeutics and serves as a principal investigator for clinical trials sponsored by Tenaya Therapeutics. Drs Ackerman, Siontis, Geske, and Giudicessi and Mayo Clinic have an equity sharing agreement with Prolaio. However, none of these entities participated in this work. Other authors have no relevant conflicts of interest to declare.

Background: The 2014 Heart Rhythm Society consensus statement defines histological (definite) and clinical (probable) diagnostic categories of cardiac sarcoidosis (CS), but few studies have compared their arrhythmic phenotypes and outcomes., Objective: The purpose of this study was to evaluate the electrophysiological/arrhythmic phenotype and outcomes of patients with definite and probable CS., Methods: We analyzed the arrhythmic/electrophysiological phenotype in a single-center North American cohort of 388 patients (median age 56 years; 39% female, n = 151) diagnosed with definite (n = 58) or probable (n = 330) CS (2000-2022). The primary composite outcome was survival to first ventricular tachycardia/fibrillation (VT/VF) event or sudden cardiac death. Key secondary outcomes were also assessed., Results: At index evaluation, in situ cardiac implantable electronic devices and antiarrhythmic drug use were more common in definite CS. At a median follow-up of 3.1 years, the primary outcome occurred in 22 patients with definite CS (38%) and 127 patients with probable CS (38%) (log-rank, P = .55). In multivariable analysis, only a higher ratio of the 18 F-fluorodeoxyglucose maximum standardized uptake value of the myocardium to the maximum standardized uptake value of the blood pool (hazard ratio 1.09; 95% confidence interval 1.03-1.15; P = .003, per 1 unit increase) was associated with the primary outcome. During follow-up, patients with definite CS had a higher burden of device-treated VT/VF events (mean 2.86 events per patient-year vs 1.56 events per patient-year) and a higher rate of progression to heart transplant/left ventricular assist device implantation but no difference in all-cause mortality compared with patients with probable CS., Conclusion: Patients with definite and probable CS had similarly high risks of first sustained VT/VF/sudden cardiac death and all-cause mortality, though patients with definite CS had a higher overall arrhythmia burden. Both CS diagnostic groups as defined by the 2014 Heart Rhythm Society criteria require an aggressive approach to prevent arrhythmic complications., Competing Interests: Disclosures No relevant disclosures by any of the authors., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes., Methods: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events., Results: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88])., Conclusions: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

Cardiac sarcoidosis (CS), an increasingly recognized disease of unknown etiology, is associated with significant morbidity and mortality. Given the limited diagnostic yield of traditional endomyocardial biopsy (EMB), there is increasing reliance on multimodality cardiovascular imaging in the diagnosis and management of CS, with EMB being largely supplanted by the use of 18 F-fluorodeoxyglucose (FDG-PET) and cardiac magnetic resonance imaging (CMR). This article aims to provide a comprehensive review of imaging modalities currently utilized in the screening, diagnosis, and monitoring of CS, while highlighting the latest developments in each area., Competing Interests: Declaration of competing interest Dr. Giudicessi reports a relationship with Avidity Biosciences that includes: consulting or advisory. Dr. Giudicessi reports a relationship with Tenaya Therapeutics that includes: funding grants. Dr. Giudicessi reports a relationship with Prolaio that includes: equity or stocks. Dr. Chareonthaitawee reports a relationship with Clario that includes: consulting or advisory. Dr. Chareonthaitawee reports a relationship with GE Healthcare that includes: consulting or advisory. Dr. Chareonthaitawee reports a relationship with Ionetix that includes: speaking and lecture fees. Dr. Chareonthaitawee has received royalties from UpToDate. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Current guidelines present varying classes of recommendations for implantable cardioverter-defibrillator (ICD) utilization in patients with cardiac sarcoidosis (CS) and left ventricular ejection fraction (LVEF) <50%., Objective: The purpose of this study was to investigate the ventricular arrhythmia risk in CS patients with ICDs and varying degrees of left ventricular systolic dysfunction., Methods: The study included CS patients with an ICD and LVEF <50% at index evaluation. The primary outcome was survival free of sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) after ICD implantation and was assessed comparatively for LVEF ≤35% vs 36%-49% and for primary vs secondary prevention ICD indication., Results: The study included 61 patients (median age 57 years; 61% male) with LVEF 36%-49% (n = 23) or LVEF ≤35% (n = 38). An ICD was implanted for secondary prevention in 24% and 44% of the LVEF ≤35% and 36%-49% groups, respectively (P = .11). The primary outcome did not differ between the 2 groups in univariable analysis (LVEF ≤35% vs 36%-49%: hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.39-1.82; P = .67). In multivariable analysis, secondary prevention ICD indication was the only significant predictor of incident sustained VT/VF (HR 2.86; 95% CI 1.23-6.67; P = .015). Mean sustained VT/VF event burden was higher in the secondary compared with the primary prevention ICD patients (0.47 vs 0.11 events per patient-year; P = .005) but did not differ significantly between LVEF ≤35% and 36%-49% patients., Conclusion: CS patients with ICD indications and LVEF 36%-49% carry similarly high arrhythmic risk as those with LVEF ≤35%. Patients with secondary prevention ICDs have the highest overall risk., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest., Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS., Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023., Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing)., Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia)., Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum., Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Competing Interests: Disclosures M.J.A. is a consultant for Abbott, BioMarin Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Illumina, Invitae, Medtronic, Solid Biosciences, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, Prolaio, and Thryv Therapeutics. However, none of these entities have contributed to this study in any manner.

Background: Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner., Objective: The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases., Methods: The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained., Results: Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since., Conclusion: Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk., (Copyright © 2024. Published by Elsevier Inc.)

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here, we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes., Methods: We quantified cell-surface trafficking of 18,796 variants in KCNH2 using a Multiplexed Assay of Variant Effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping (APC). We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1,458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian LQTS penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events., Results: Variant MAVE trafficking scores and APC peak tail currents were highly correlated (Spearman Rank-order ρ = 0.69). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian LQTS penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became non-significant when peak-tail current and penetrance estimates were also available. The area under the ROC for 20-year event outcomes based on patient-specific sex and QTc (AUC 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (AUC 0.86 [0.83-0.89]) or attainable APC peak tail current data (AUC 0.84 [0.81-0.88])., Conclusion: High throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale while LQTS penetrance estimates and APC peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

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.)

Over the past 2 decades, significant efforts have been made to advance gene therapy into clinical practice. Although successful examples exist in other fields, gene therapy for the treatment of monogenic cardiovascular diseases lags behind. In this review, we (1) highlight a brief history of gene therapy, (2) distinguish between gene silencing, gene replacement, and gene editing technologies, (3) discuss vector modalities used in the field with a special focus on adeno-associated viruses, (4) provide examples of gene therapy approaches in cardiomyopathies, channelopathies, and familial hypercholesterolemia, and (5) present current challenges and limitations in the gene therapy field., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To describe our early observations with sudden cardiac arrest (SCA) and sudden death (SD) in patients using vape products., Patients and Methods: A retrospective analysis of Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic and Sudden Death Genomics Laboratory was performed on all SCA survivors and decedents who presented between January 1, 2007, and December 31, 2021, to identify patients/decedents with a history of vaping. Data abstraction included patient demographics, clinical characteristics, and documented use of vape products., Results: Among 144 SCA survivors and 360 SD victims, there were six individuals (1%; 3 females) with unexplained SCA (n=4) or SD (n=2) that was temporally associated with vaping use with a mean age at sentinel event of 23±5 years. The SCA survivors include a 19-year-old male who was resuscitated from documented ventricular fibrillation 40 minutes after vaping and a 19-year-old male who was resuscitated from ventricular fibrillation a few hours post vaping. The first SD victim was a 19-year-old female with exercise-induced asthma who died in her sleep after vaping that evening. Autopsy results showed eosinophilic infiltrates in the lung tissue and death was attributed to bronchial asthma. The second vaping-associated death involved a 26-year-old male whose autopsy attributed the death to acute respiratory distress syndrome., Conclusion: We have identified six young individuals with a history of vaping who experienced a near fatal episode or a tragic SD. Although larger cohort studies are needed to quantify the actual risk of SD, it seems prudent to sound an early warning about vaping's potential lethality., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Long QT syndrome (LQTS) is a potentially life-threatening, but highly treatable genetic heart disease. LQTS-directed therapies often consist of beta-blockers (BBs), left cardiac sympathetic denervation (LCSD), and/or an implantable cardioverter defibrillator (ICD). However, in clinical practice, many patient-specific and genotype-directed permutations exist. Herein, we aim to review the spectrum of treatment configurations utilized at a single, tertiary center specializing in the care of patients with LQTS to demonstrate optimal LQTS-directed management is not amenable to a "one-size-fits-all" approach but instead benefits from patient- and genotype-tailored strategies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: ECG abnormalities are often the first signs of arrhythmogenic right ventricular cardiomyopathy (ARVC) and we hypothesized that an artificial intelligence (AI)-enhanced ECG could help identify patients with ARVC and serve as a valuable disease-detection tool., Methods and Results: We created a convolutional neural network to detect ARVC using a 12-lead ECG. All patients with ARVC who met the 2010 task force criteria and had disease-causative genetic variants were included. All case ECGs were randomly assigned in an 8:1:1 ratio into training, validation, and testing groups. The case ECGs were age- and sex-matched with control ECGs at our institution in a 1:100 ratio. Seventy-seven patients (51% male; mean age 47.2 ± 19.9), including 56 patients with PKP2, 7 with DSG2, 6 with DSC2, 6 with DSP, and 2 with JUP were included. The model was trained using 61 case ECGs and 5009 control ECGs; validated with 7 case ECGs and 678 control ECGs and tested in 22 case ECGs and 1256 control ECGs. The sensitivity, specificity, positive and negative predictive values of the model were 77.3, 62.9, 3.32, and 99.4%, respectively. The area under the curve for rhythm ECG and median beat ECG was 0.75 and 0.76, respectively., Conclusion: Our study found that the model performed well in excluding ARVC and supports the concept that the AI ECG can serve as a biomarker for ARVC if a larger cohort were available for network training. A multicentre study including patients with ARVC from other centres would be the next step in refining, testing, and validating this algorithm., Competing Interests: Conflict of interest: No conflicts of interests related to this algotihm. However, KCS, SJA, ZIA and PAF are co-inventors on AI-ECG algorithms via Mayo Clinic and could benefit from their commercialization., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Myocardial inflammation contributes to the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a clinically and genetically heterogenous disorder. Due to phenotypic overlap, some patients with genetic ACM may be evaluated for an underlying inflammatory cardiomyopathy. However, the cardiac fludeoxyglucose (FDG) positron emission tomography (PET) findings in ACM patients have not been elucidated., Methods: All genotype-positive patients in the Mayo Clinic ACM registry (n = 323) who received a cardiac FDG PET were included in this study. Pertinent data were extracted from the medical record., Results: Collectively, 12/323 (4%; 67% female) genotype-positive ACM patients received a cardiac PET FDG scan as part of their clinical evaluation (median age at scan 49 ± 13 years). Amongst these patients, pathogenic/likely pathogenic variants were detected in LMNA (n = 7), DSP (n = 3), FLNC (n = 1) and PLN (n = 1). Of note, 6/12 (50%) had abnormal myocardial FDG uptake, including diffuse (entire myocardium) uptake in 2/6 (33%), focal (1-2 segments) uptake in 2/6 (33%) and patchy (3+ segments) in 2/6 (33%). Median myocardial standardized uptake value ratio was 2.1. Interestingly, LMNA-positive patients accounted for 3 out of 6 (50%) positive studies (diffuse uptake in 2 and focal uptake in 1)., Conclusion: Abnormal myocardial FDG uptake is common in genetic ACM patients undergoing cardiac FDG PET. This study further supports the role of myocardial inflammation in ACM. Further investigation is needed to determine role of FDG PET in diagnosis and management of ACM and investigate the role of inflammation in ACM., Competing Interests: Conflict of interest Dr. Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daichii Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. MJA and Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. However, none of these entities were involved in this study. Other authors declare no conflicts., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures None.

Hypertrophic cardiomyopathy (HCM) is a genetically heterogenous condition with about half of cases remaining genetically elusive or non-genetic in origin. HCM patients with a positive genetic test (HCM Sarc ) present earlier and with more severe disease than those with a negative genetic test (HCM Neg ). We hypothesized these differences may be due to and/or reflect proteomic and phosphoproteomic differences between the two groups. TMT-labeled mass spectrometry was performed on 15 HCM Sarc , 8 HCM Neg , and 7 control samples. There were 243 proteins differentially expressed and 257 proteins differentially phosphorylated between HCM Sarc and HCM Neg . About 90% of pathways altered between genotypes were in disease-related pathways and HCM Sarc showed enhanced proteomic and phosphoproteomic alterations in these pathways. Thus, we show HCM Sarc has enhanced proteomic and phosphoproteomic dysregulation observed which may contribute to the more severe disease phenotype., (© 2023. Springer Nature Limited.)

Mitral valve prolapse (MVP) is a heart valve disease that is often familial, affecting 2%-3% of the general population. MVP with or without mitral regurgitation can be associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Research on familial MVP has specifically focused on genetic factors, which may explain the heritable component of the disease estimated to be present in 20%-35%. Furthermore, the structural and electrophysiological substrates underlying SCD/ventricular arrhythmia risk in MVP have been studied postmortem and in the electrophysiology laboratory, respectively. Understanding how familial MVP and rhythm disorders are related may help patients with MVP by individualizing risk and working to develop effective management strategies. This contemporary, state-of-the-art, expert review focuses on genetic factors and familial components that underlie MVP and arrhythmia and encapsulates clinical, genetic, and electrophysiological issues that should be the objectives of future research., (© 2023 Heart Rhythm Society. Published by Elsevier Inc.)

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 type 2 (LQT2) is caused by pathogenic variants in KCNH2. LQT2 may manifest as QT prolongation on an electrocardiogram and present with arrhythmic syncope/seizures and sudden cardiac arrest/death. Progestin-based oral contraceptives may increase the risk of LQT2-triggered cardiac events in women. We previously reported on a woman with LQT2 and recurrent cardiac events temporally related and attributed to the progestin-based contraceptive medroxyprogesterone acetate ("Depo-Provera" [Depo] MilliporeSigma, Catalog# 1378001, St. Louis, MO)., Objective: The purpose of this study was to evaluate the arrhythmic risk of Depo in a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of LQT2., Methods: An iPSC-CM line was generated from a 40-year-old woman with p.G1006Afs∗49-KCNH2. A CRISPR/Cas9 gene-edited/variant-corrected isogenic control iPSC-CM line was generated. FluoVolt (Invitrogen, F10488, Waltham, MA) was used to measure the action potential duration after treatment with 10 μM Depo. Erratic beating patterns characterized as alternating spike amplitudes, alternans, or early afterdepolarization-like phenomena were assessed using multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment., Results: Depo treatment shortened the action potential duration at 90% repolarization of G1006Afs∗49 iPSC-CMs from 394 ± 10 to 303 ± 10 ms (P < .0001). Combined Depo + ISO treatment increased the percentage of electrodes displaying erratic beating in G1006Afs∗49 iPSC-CMs (baseline: 18% ± 5% vs Depo + ISO: 54% ± 5%; P < .0001) but not in isogenic control iPSC-CMs (baseline: 0% ± 0% vs Depo + ISO: 10% ± 3%; P = .9659)., Conclusion: This cell study provides a potential mechanism for the patient's clinically documented Depo-associated episodes of recurrent ventricular fibrillation. This in vitro data should prompt a large-scale clinical assessment of Depo's potential proarrhythmic effect in women with LQT2., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Unfortunately, some patients with long QT syndrome (LQTS) experience breakthrough cardiac events (BCEs) despite maximal therapy. Small studies have shown that refractory LQTS cases may benefit from intentional permanent atrial pacing (IPAP). As such, we sought to determine the genotype-specific utilization and efficacy of IPAP in a single-center LQTS registry., Methods and Results: In this retrospective study, electronic medical records from 1065 patients diagnosed with LQTS were used to identify individuals that received IPAP. Pre- and post-IPAP heart rate, heart rate-corrected QT (QTc) values, annual BCE rate, and IPAP-related complications were compared between genotypes. BCEs were defined as LQTS-associated syncope/seizures, sustained ventricular arrhythmia (VA)-terminating ICD therapies, and sudden cardiac arrest/death. Overall, 52 out of 1065 LQTS patients received adjunctive IPAP therapy (77% female; median age 18.5 [interquartile range, 1-35.5] years; 73% with prior VA). Over an average IPAP follow-up of 121 ± 82 months, the average heart rate increased from 65.8 ± 20.4 bpm to 78.9 ± 17.1 bpm; (p < .01) and the average QTc decreased from 533.4 ± 66.6 to 488.3 ± 52.4 ms; (p < .01). The mean BCE rate dropped from 0.88 to 0.19 per patient-year (p = .01), driven by a marked decrease in the LQT2 cohort (1.01 BCE/year to 0.02 BCE/year; p = .003). No serious IPAP-related complications were observed., Conclusion: In high-risk LQTS patients, namely those with recalcitrant LQT2, IPAP appears to be a safe and efficacious adjunct therapy. The beneficial effects of IPAP may stem from attenuating the QTc and circumventing a pause-dependent trigger. Whether IPAP might obviate the need for an ICD in some instances warrants further study., (© 2021 Wiley Periodicals LLC.)

Background: Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient's novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5's local anesthetic binding domain., Objective: The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)., Methods: Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT., Results: V 1/2 of inactivation was right-shifted significantly in F1760C cells (-72.2 ± 0.7 mV) compared to wild-type (WT) cells (-86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P = .0005). Baseline APD to 90% repolarization (APD 90 ) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD 90 , and treatment with 5μM PHT significantly decreased APD 90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001)., Conclusion: PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Long-QT syndrome (LQTS) is characterized by QT prolongation and increased risk for syncope, seizures, and sudden cardiac death. The majority of LQTS stems from pathogenic mutations in KCNQ1 , KCNH2 , or SCN5A . However, ≈10% of patients with LQTS remain genetically elusive. We utilized genome sequencing to identify a novel LQTS genetic substrate in a multigenerational genotype-negative LQTS pedigree., Methods: Genome sequencing was performed on 5 affected family members. Only rare nonsynonymous variants present in all affected family members were considered. The candidate variant was characterized functionally in patient-derived induced pluripotent stem cell and gene-edited, variant corrected, isogenic control induced pluripotent stem cell-derived cardiomyocytes., Results: A missense variant (p.G6S) was identified in ALG10B -encoded α-1,2-glucosyltransferase B protein. ALG10B (alpha-1,2-glucosyltransferase B protein) is a known interacting protein of KCNH2 -encoded K v 11.1 (HERG [human Ether-à-go-go-related gene]). Compared with isogenic control, ALG10B-p.G6S induced pluripotent stem cell-derived cardiomyocytes showed (1) decreased protein expression of ALG10B (p.G6S, 0.7±0.18, n=8 versus control, 1.25±0.16, n=9; P <0.05), (2) significant retention of HERG in the endoplasmic reticulum ( P <0.0005), and (3) a significantly prolonged action potential duration confirmed by both patch clamp (p.G6S, 531.1±38.3 ms, n=15 versus control, 324.1±21.8 ms, n=13; P <0.001) and multielectrode assay ( P <0.0001). Lumacaftor-a compound known to rescue HERG trafficking-shortened the pathologically prolonged action potential duration of ALG10B-p.G6S induced pluripotent stem cell-derived cardiomyocytes by 10.6% (n=31 electrodes; P <0.001)., Conclusions: Here, we demonstrate that ALG10B-p.G6S downregulates ALG10B, resulting in defective HERG trafficking and action potential duration prolongation. Therefore, ALG10B is a novel LQTS-susceptibility gene underlying the LQTS phenotype observed in a multigenerational pedigree. ALG10B mutation analysis may be warranted, especially in genotype-negative patients with an LQT2-like phenotype.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy. Currently, hypertrophy pathways responsible for HCM have not been fully elucidated. Their identification could serve as a nidus for the generation of novel therapeutics aimed at halting disease development or progression. Herein, we performed a comprehensive multi-omic characterization of hypertrophy pathways in HCM., Methods: Flash-frozen cardiac tissues were collected from genotyped HCM patients (n=97) undergoing surgical myectomy and tissue from 23 controls. RNA sequencing and mass spectrometry-enabled deep proteome and phosphoproteomic assessment were performed. Rigorous differential expression, gene set enrichment, and pathway analyses were performed to characterize HCM-mediated alterations with emphasis on hypertrophy pathways., Results: We identified transcriptional dysregulation with 1246 (8%) differentially expressed genes and elucidated downregulation of 10 hypertrophy pathways. Deep proteomic analysis identified 411 proteins (9%) that differed between HCM and controls with strong dysregulation of metabolic pathways. Seven hypertrophy pathways were upregulated with antagonistic upregulation of 5 of 10 hypertrophy pathways shown to be downregulated in the transcriptome. Most upregulated hypertrophy pathways encompassed the rat sarcoma-mitogen-activated protein kinase signaling cascade. Phosphoproteomic analysis demonstrated hyperphosphorylation of the rat sarcoma-mitogen-activated protein kinase system suggesting activation of this signaling cascade. There was a common transcriptomic and proteomic profile regardless of genotype., Conclusions: At time of surgical myectomy, the ventricular proteome, independent of genotype, reveals widespread upregulation and activation of hypertrophy pathways, mainly involving the rat sarcoma-mitogen-activated protein kinase signaling cascade. In addition, there is a counterregulatory transcriptional downregulation of the same pathways. Rat sarcoma-mitogen-activated protein kinase activation may serve a crucial role in hypertrophy observed in HCM.

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: The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the KCND3 -encoded Kv4.3 pore-forming α-subunit. KCND3 gain-of-function mutations have been reported previously as a pathogenic substrate for J wave syndromes (JWS), including the Brugada syndrome and early repolarization syndrome, as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. Acacetin may be a novel therapeutic for KCND3 -mediated J wave syndrome., Methods: KCND3-V392I was identified in an 18-year-old male with J wave syndrome/early repolarization syndrome, and a history of cardiac arrest including ventricular tachycardia/ventricular fibrillation and atrial fibrillation/atrial flutter. Pathogenic KCND3 mutation was engineered by site-directed mutagenesis and co-expressed with wild-type KChIP2 in TSA201 cells. Gene-edited/variant-corrected isogenic control and patient-specific pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from the p. Val392Ile-KCND3-positive patient were generated. I to currents and action potentials were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression., Results: KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak I to current density by 92.2% ( P <0.05 versus KCND3-WT). KCND3 expression was significantly increased in KCND3-V392I-derived iPSC-CMs ( P <0.05 versus isogenic control). While KCND3-WT revealed an IC50 of 7.2±1.0 µmol/L for acacetin effect, 30 µmol/L acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96.2% ( P <0.05 versus before Acacetin). Ito was also increased by 60.9% in Kv4.3-V392I iPSC-CM ( P <0.05 versus isogenic control iPSC-CM). Ten micromoles per liter acacetin, a concentration approaching its IC50 value, inhibited Ito by ≈50% in patient-derived iPSC-CMs and reduced the accentuated action potential notch displayed in KCND3-V392I-derived iPSC-CMs., Conclusions: This preclinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated J wave syndrome by inhibiting I to and abolishing the accentuated action potential notch in patient-derived iPSC-CMs.

Background: β-Blockers (BBs), sodium channel blockers (SCBs), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs) are used to prevent or counter long QT syndrome (LQTS)-triggered syncope, seizures, and sudden cardiac death. The spectrum and extent of side effects/complications associated with these guideline-directed therapies (GDTs) remain unknown., Objective: The purpose of this study was to identify the types/prevalence of treatment-associated side effects/complications for patients with the most common LQTS subtypes after GDT., Methods: Retrospective analysis was performed on 1310 patients with type 1, 2, or 3 LQTS evaluated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic (average age at the time of diagnosis 22 ± 18 years; average length of follow-up 5 ± 5 years) and treated with ≥1 of the common GDTs for LQTS., Results: BBs were used in 1102 (84%), SCBs in 104 (8%), LCSD in 197 (15%), and an ICD was used in 251 (19%) patients. Overall, 727 (55%) patients reported at least 1 treatment-associated side effect/complication. A total of 490 of 1102 patients treated with BBs (44%) reported side effects, with fatigue (381 [35%]) being the most common; 28 of 104 SCB-treated patients (27%) reported side effects, most common being gastrointestinal distress/vomiting (18 [17%]); 80 of 197 patients (41%) reported side effects after LCSD, most reporting neuropathic pain (57 [29%]); and 129 of 251 patients (51%) experienced ≥1 complication after ICD implantation, including inappropriate shocks (46 [18%])., Conclusion: Although LQTS-triggered sudden cardiac death is uncommon in the properly treated patient, this study demonstrates that contemporary GDTs for LQTS are not innocuous. Their treatment-related side effects are not trivial and should compel an ongoing quest for new LQTS therapies., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy causing ventricular tachycardia following adrenergic stimulation. Pathogenic variants in RYR2-encoded ryanodine receptor 2 (RYR2) cause CPVT1 and cluster into domains I-IV, with the most N-terminal domain involving residues 77-466. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated for RYR2-F13L, -L14P, -R15P, and -R176Q variants. Isogenic control iPSCs were generated using CRISPR-Cas9/PiggyBac. Fluo-4 Ca 2+ imaging assessed Ca 2+ handling with/without isoproterenol (ISO), nadolol (Nad), and flecainide (Flec) treatment. CPVT1 iPSC-CMs displayed increased Ca 2+ sparking and Ca 2+ transient amplitude following ISO compared with control. Combined Nad treatment/ISO stimulation reduced Ca 2+ amplitude and sparking in variant iPSC-CMs. Molecular dynamic simulations visualized the structural role of these variants. We provide the first functional evidence that these most proximal N-terminal localizing variants alter calcium handling similar to CPVT1. These variants are located at the N-terminal domain and the central domain interface and could destabilize the RYR2 channel promoting Ca 2+ leak-triggered arrhythmias., Competing Interests: Conflict of interests M.J.A. is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi Sankyo, Invitae, LQT Therapeutics, and Medtronic. M.J.A. and/or Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, Pfizer, and UpToDate. However, none of these entities were involved in this study in any manner. A.R.M. and Columbia University own shares in ARMGO Pharma, a biotech company developing RyR-targeted therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Most of the long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1, KCNH2, or SCN5A. However, ∼10%-20% of LQTS index cases remain genotype-negative., Objective: The purpose of this study was to identify and characterize functionally a novel LQTS genetic substrate in a multigenerational, "genotype-negative" LQTS pedigree., Methods: The patient was a 40-year-old woman with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 "gene-corrected" isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated., Results: No ultrarare, nonsynonymous heterozygous variants cosegregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316G>T) was present in all affected individuals. Reverse transcription polymerase chain reaction analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316G>T creates a novel 89 base-pair exon that results in a frameshift variant (p.S1112Pfs∗171). Action potential duration (APD 90 ) was significantly longer in p.S1112Pfs∗171-iPSC-CMs (602.4 ± 12.2 ms; n =70) compared to isogenic control iPSC-CMs (425.7 ± 9.3 ms; n = 61; P <.0001). Further, field potential duration was significantly longer in p.S1112Pfs∗171-iPSC-CMs (358.9 ± 7.7 ms; n = 65) compared to isogenic control iPSC-CMs (282.2 ± 10.8 ms; n = 51; P <.0001)., Conclusion: A novel deep intronic KCNH2 variant was identified in a multigenerational, genetically elusive LQTS pedigree. The iPSC-CMs establish that the variant is the monogenetic cause for this family's LQTS. Deep intronic variants within the 2 most common LQTS-susceptibility genes should be considered in patients with seemingly genetically elusive LQTS., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)