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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. [ABSTRACT FROM AUTHOR]

Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Practically, this finding suggests that SCAD, particularly when shorter or more distal arterial segments are involved, has the potential to go unrecognized if the post-mortem examination is limited to a standard death scene investigation and conventional autopsy ( I Figure 1 i ). Additionally, the SCAD autopsy cases have several notable differences that contrast with prospective and retrospective registry reports.[1] The proportion of men in the SCAD autopsy series is higher than contemporary registries, including the UK Spontaneous Coronary Artery Dissection Study comparator.[4] Whether this observation reflects that sentinel SCD is more common in male SCAD patients, or if other factors, such as sex differences in diagnostic testing, accuracy, or autopsy rates influenced this finding, is of interest. [Extracted from the article]

Background: Heart rate-corrected QT interval (QTc) prolongation, whether secondary to drugs, genetics including congenital long QT syndrome, and/or systemic diseases including SARS-CoV-2-mediated coronavirus disease 2019 (COVID-19), can predispose to ventricular arrhythmias and sudden cardiac death. Currently, QTc assessment and monitoring relies largely on 12-lead electrocardiography. As such, we sought to train and validate an artificial intelligence (AI)-enabled 12-lead ECG algorithm to determine the QTc, and then prospectively test this algorithm on tracings acquired from a mobile ECG (mECG) device in a population enriched for repolarization abnormalities.Methods: Using >1.6 million 12-lead ECGs from 538 200 patients, a deep neural network (DNN) was derived (patients for training, n = 250 767; patients for testing, n = 107 920) and validated (n = 179 513 patients) to predict the QTc using cardiologist-overread QTc values as the "gold standard". The ability of this DNN to detect clinically-relevant QTc prolongation (eg, QTc ≥500 ms) was then tested prospectively on 686 patients with genetic heart disease (50% with long QT syndrome) with QTc values obtained from both a 12-lead ECG and a prototype mECG device equivalent to the commercially-available AliveCor KardiaMobile 6L.Results: In the validation sample, strong agreement was observed between human over-read and DNN-predicted QTc values (-1.76±23.14 ms). Similarly, within the prospective, genetic heart disease-enriched dataset, the difference between DNN-predicted QTc values derived from mECG tracings and those annotated from 12-lead ECGs by a QT expert (-0.45±24.73 ms) and a commercial core ECG laboratory [10.52±25.64 ms] was nominal. When applied to mECG tracings, the DNN's ability to detect a QTc value ≥500 ms yielded an area under the curve, sensitivity, and specificity of 0.97, 80.0%, and 94.4%, respectively.Conclusions: Using smartphone-enabled electrodes, an AI DNN can predict accurately the QTc of a standard 12-lead ECG. QTc estimation from an AI-enabled mECG device may provide a cost-effective means of screening for both acquired and congenital long QT syndrome in a variety of clinical settings where standard 12-lead electrocardiography is not accessible or cost-effective. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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Keywords: genetics; genotype; long QT syndrome; penetrance; phenotype EN genetics genotype long QT syndrome penetrance phenotype 495 497 3 04/20/20 20200211 NES 200211 Long-QT syndrome (LQTS) is a 1:2500 genetic disorder characterized clinically by heart rate-corrected QT interval (QTc) prolongation and risk of torsadogenic syncope/seizures and sudden death.[1] Although 75% of LQTS cases stem from disease-causative variants in the 3 canonical LQTS-susceptibility genes ( I KCNQ1 i , I KCNH2 i , and I SCN5A i ), 5% to 10% of cases are attributed to 14 minor LQTS-susceptibility genes.[1] However, many of these minor LQTS-susceptibility genes were discovered before the burden of rare, and presumably innocuous, amino acid-altering genetic variation was illuminated by large-scale sequencing studies.[2] Therefore, we sought to couple the Genome Aggregation Database (gnomAD),[3] a harmonized database of >140 000 exomes/genomes derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large LQTS registry to reassess the strength of minor LQTS gene-disease associations (GDAs). Two functional KCNE2 variants (p.Thr10Met-KCNE2 and p.Met54Thr-KCNE2) deemed previously to cause KCNE2-LQTS were observed in LQTS patients, but only in those who also possessed a disease-causative variant in a canonical LQTS-susceptibility gene. [Extracted from the article]

Abstract Background Mitral valve prolapse (MVP), including the recently described arrhythmogenic bileaflet MVP syndrome (ABiMVPS), is associated with repolarization abnormalities and may represent an underestimated cause of sudden cardiac death. The impact of concomitant MVP or ABiMVPS on long QT syndrome (LQTS) clinical severity is unknown. Methods and results Retrospective review of 754 LQTS patients [445 females (58%) and mean QTc 471 ± 41 ms] with available echocardiographic data was performed to identify LQTS patients with not only MVP, but also a pro-arrhythmic ABiMVPS phenotype defined as bileaflet MVP, inferolateral T-wave inversions, and frequent complex ventricular ectopy/arrhythmia. As expected, 18/754 (2%) LQTS patients had concomitant MVP. Of these, 5/18 (28%) LQTS patients with MVP satisfied ABiMVPS diagnostic criteria. No difference in symptomatology, degree of QT prolongation, or clinical management was observed between LQTS patients with and without MVP. In contrast, LQTS plus ABiMVPS resulted in a severe cardiac phenotype as illustrated by symptomatic status (LQTS-ABiMVPS; 5/5; 100%; vs LQTS: 279/736; 39%; p =.008), degree of baseline QTc prolongation (LQTS-ABiMVPS: 536 ± 58 ms; vs LQTS: 470 ± 40 ms; p =.009), and number of patients experiencing ≥1 on-therapy break-through cardiac event (LQTS-ABiMVPS: 4/5; 80%; vs LQTS: 48/736; 7%; p <.001]. Lastly, individuals with LQTS plus ABiMVPS were more likely to experience appropriate ICD therapies post-cardiac denervation (LQTS-ABiMVPS: 2/3; 67% vs LQTS: 4/49; 8%; p =.03]. Conclusions and relevance The co-existence of LQTS and ABiMVPS may lead to a rare, but malignant, clinical entity characterized by potentially life-threatening arrhythmias despite maximal LQTS therapy. Highlights • Typical MVP has no impact on LQTS clinical severity. • The co-existence of LQTS and ABiMVP results in a malignant clinical entity. • The efficacy of conventional LQTS therapies is limited in LQTS plus ABiMVP. [ABSTRACT FROM AUTHOR]

Abstract Background Sudden cardiac arrest (SCA) may be the sentinel expression of a sudden cardiac death-predisposing genetic heart disease (GHD). Although shown to underlie many unexplained SCAs in the young, the contribution of GHDs to sentinel SCA has never been quantified across the age spectrum. Thus, we sought to determine the contribution of GHDs in single-center referral cohort of non-ischemic SCA survivors. Methods and results Retrospective analysis of 3037 patients was used to identify all individuals who experienced a sentinel event of SCA. Following exclusion of patients with ischemic or complex congenital heart disease, cases were classified by clinical diagnoses. Overall, 180 (5.9%) referral patients experienced a sentinel SCA (average age at SCA 28 ± 15 years, 99 females). An etiology was identified in 113/180 patients (62.8%) including channelopathies in 26.7%, arrhythmogenic bileaflet mitral valve prolapse in 10.6%, cardiomyopathies in 9.4%, other etiologies in 6.7%, acquired long QT syndrome in 6.7%, and multiple disorders in 2.8%. The remaining 67/180 (37.2%) cases were classified as idiopathic ventricular fibrillation (IVF). Interestingly, the contribution of GHDs declined precipitously after the first decade of life [90.0% (age 0–9; n = 20), 58.7% (age 10–19; n = 46), 28.1% (age 20–29; n = 32), 23.8% (age 30–39; n = 42), 16.7% (age 40–49; n = 24), and 12.5% (age 50+; n = 16)]. Conclusions Within a referral population enriched for GHDs, the ability of a comprehensive cardiac evaluation, including genetic testing, to elucidate a root cause in non-ischemic SCA survivors declined with age. Although rare, GHDs can underlie SCA into adulthood and merit consideration across the age spectrum. Highlights • The diagnostic yield in non-ischemic cardiac arrest survivors is age-dependent. • The yield of genetic testing in unexplained sudden cardiac arrest is low. • Arrhythmic mitral valve prolapse is a frequent cause of non-ischemic SCA in adults. [ABSTRACT FROM AUTHOR]

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues. [ABSTRACT FROM AUTHOR]

The article discusses that the core vital signs including heart rate, respiratory rate, body temperature, and blood pressure can be assessed rapidly and provide critical, objective, and quantitative insights into the state of the body's essential functions; and mentions the heart rate–corrected QT interval (QTc), which represents a dynamic measurement of the time required to reset the heart's electric system, fell squarely into this latter category.

The coordinated generation and propagation of action potentials within cardiomyocytes creates the intrinsic electrical stimuli that are responsible for maintaining the electromechanical pump function of the human heart. The synchronous opening and closing of cardiac Na+, Ca2+, and K+ channels corresponds with the activation and inactivation of inward depolarizing (Na+ and Ca2+) and outward repolarizing (K+) currents that underlie the various phases of the cardiac action potential (resting, depolarization, plateau, and repolarization). Inherited mutations in pore-forming α subunits and accessory β subunits of cardiac K+ channels can perturb the atrial and ventricular action potential and cause various cardiac arrhythmia syndromes, including long QT syndrome, short QT syndrome, Brugada syndrome, and familial atrial fibrillation. In this Review, we summarize the current understanding of the molecular and cellular mechanisms that underlie K+-channel-mediated arrhythmia syndromes. We also describe translational advances that have led to the emerging role of genetic testing and genotype-specific therapy in the diagnosis and clinical management of individuals who harbor pathogenic mutations in genes that encode α or β subunits of cardiac K+ channels. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. At baseline females have transcriptional upregulation of hypertrophy pathways. HCM abolishes sex specific differences. Females with HCM have increased dysregulation. Made with Biorender.com. [Display omitted] • At baseline females have transcriptional activation of hypertrophy pathways. • HCM abolishes normal sex-specific differences in cardiac tissue. • Females with HCM have increased dysregulation as compared to males with HCM. [ABSTRACT FROM AUTHOR]

Introduction Methods and Results Conclusions 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.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).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. [ABSTRACT FROM AUTHOR]

Key Points: Question: Cardiac arrest frequently occurs without explanation, even after a thorough clinical evaluation. Can a simple maneuver clinically diagnose calcium release deficiency syndrome (CRDS), a newly described cause of sudden death? Findings: In this international, multicenter, case-control study, a provoked measure of T-wave amplitude on an electrocardiogram ascertained cases of CRDS with high accuracy. The genetic mouse models recapitulated the human findings and suggested a pathologically large systolic calcium release from the sarcoplasmic reticulum was responsible. Meaning: These preliminary results suggest that the repolarization response on an electrocardiogram to brief tachycardia followed by a pause may effectively diagnose CRDS. Given the frequency of unexplained cardiac arrest, should these findings be confirmed in larger studies, this readily available maneuver may provide clinically actionable information. 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. Case-control study including individual cases of calcium release deficiency syndrome (CRDS), 3 patient control groups, and genetic mouse models assesses the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. [ABSTRACT FROM AUTHOR]

Introduction: Catecholamingergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by adrenergically-induced VT, syncope, and sudden cardiac arrest (SCA). In the absence of structural disease, exercise-provoked premature ventricular contractions in bigeminy/couplets and non-sustained VT are highly predictive of CPVT. As such, we sought to determine the proportion of missed or delayed CPVT diagnoses attributable to exercise testing miscues in a cohort of young SCA survivors. Methods: Retrospective analysis of 3,194 patients was used to identify all patients < 35 years of age referred to our Genetic Heart Rhythm Clinic for evaluation following a sentinel SCA. Patients with structural heart disease were excluded. Prior investigations were reviewed for evidence of CPVT. The proportion of SCA survivors with a missed CPVT diagnosis due to overlooked evidence or a delayed CPVT diagnosis due to lack of either an exercise stress test (EST) or catecholamine provocation test (CPT) post-SCA was then assessed. Results: Among the 109 patients who experienced a sentinel SCA, 42 (39%) were exertion/emotion-associated (EEA-SCA). An EST/CPT was included in the local post-SCA investigations in 22/42 (52%) EEA-SCA cases and 28/67 (42%) non-EEA-SCA cases (p=NS). Following their primary post-SCA investigations, a probable root cause was established in 20/42 EEA-SCA cases (48%, CPVT in 8) and 40/67 Non-EEA-SCA cases (60%, CPVT in 2, p=NS). Of the remaining 22 unexplained EEA-SCA survivors, 14 (64%) had their first EST/CPT prior to evaluation at our institution. Secondary review of these prior EST/CPTs revealed clear evidence of CPVT in 2/14 (14%) cases that was missed. Lastly, among the 8 remaining unexplained cases of EAA-SCA who never had an EST/CPT, their first EST at our institution led to a CPVT diagnosis in 3 patients (38%; average time elapsed since SCA 14 ± 7 months). Conclusions: Among the 15 SCA survivors ultimately established to have genetically confirmed CPVT as their root cause, one-third had a significant delay in diagnosis because EST was either never performed or performed but misdiagnosed. EST/CPT must become the standard of care following SCA in the young, especially if the SCA occurred during exertion/emotion. [ABSTRACT FROM AUTHOR]

Introduction: Long QT syndrome (LQTS) affects ~1 in 2,500 individuals and is characterized clinically by QT prolongation, syncope/seizures, and sudden death. Currently, 17 LQTS-susceptibility genes have been published. However, many minor LQTS-susceptibility genes were discovered before the true burden of rare, and presumably innocuous, background genetic variation was known. As such, we sought to re-assess the nature of minor LQTS gene-disease associations using a single center LQTS registry and public exome databases. Methods: Analysis of 1,063 patients clinically diagnosed with LQTS was used to identify patients with potential disease-causative variants in ANK2 , CACNA1C , CALM1-3 , CAV3 , KCNE1 , KCNE2 , KCNJ5 , SCN4B , and SNTA1. The Genome Aggregation Database (gnomAD) was used to determine allele frequencies for putative disease-causative rare variants identified in LQTS cases as well as functionally disruptive rare variants in the literature. An excess of rare variants previously deemed to be LQTS-causative in gnomAD was used to identify those genes unlikely to cause penetrant, monogenic forms of LQTS. Results: Overall, 42/1,063 (4.0%) LQTS patients hosted one of 18 distinct rare variants in a non-syndromic, minor LQTS-susceptibility gene. Surprisingly, 14/18 (78%) of these putative LQTS-causative variants were present in gnomAD at a frequency that exceeded the anticipated prevalence for a ≤ 1% contributor to LQTS (1:250,000). Whereas the majority of CACNA1C (8/10), CALM1-3 (10/10), CAV 3 (2/3), KCNE1 (4/8), and SCN4B (1/1) rare variants observed in our LQTS cases and/or the literature were absent from gnomAD, nearly every alleged LQTS-causative rare variant in AKAP9 (1/1), ANK2 (5/6), KCNE2 (3/3), KCNJ5 (1/1), and SNTA1 (2/2), including those variants used to establish the original gene-disease associations, was observed at an unacceptably high frequency in gnomAD. Conclusions: The excess presence of rare variants used to establish the primary AKAP9 , ANK2 , KCNE2 , KCNJ5 , and SNTA1 gene-disease associations in gnomAD suggests that these minor LQTS-susceptibility genes are unlikely to result in penetrant, monogenic forms of LQTS. Consensus, regarding if and how such genes should be included on genetic testing panels, is needed urgently. [ABSTRACT FROM AUTHOR]

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 (HCMSarc) present earlier and with more severe disease than those with a negative genetic test (HCMNeg). 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 HCMSarc, 8 HCMNeg, and 7 control samples. There were 243 proteins differentially expressed and 257 proteins differentially phosphorylated between HCMSarc and HCMNeg. About 90% of pathways altered between genotypes were in disease-related pathways and HCMSarc showed enhanced proteomic and phosphoproteomic alterations in these pathways. Thus, we show HCMSarc has enhanced proteomic and phosphoproteomic dysregulation observed which may contribute to the more severe disease phenotype. [ABSTRACT FROM AUTHOR]

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 (HCMSarc) present earlier and with more severe disease than those with a negative genetic test (HCMNeg). 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 HCMSarc, 8 HCMNeg, and 7 control samples. There were 243 proteins differentially expressed and 257 proteins differentially phosphorylated between HCMSarc and HCMNeg. About 90% of pathways altered between genotypes were in disease-related pathways and HCMSarc showed enhanced proteomic and phosphoproteomic alterations in these pathways. Thus, we show HCMSarc has enhanced proteomic and phosphoproteomic dysregulation observed which may contribute to the more severe disease phenotype. [ABSTRACT FROM AUTHOR]

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. In this study, we sought to define the prevalence of cardiac events occurring in the setting of electronic gaming in GHDs. 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

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. This study sought to identify the diagnostic miscues underlying the continued overdiagnosis of LQTS. 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. 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%). 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT.Methods: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope.Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]).Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT. [ABSTRACT FROM AUTHOR]

Introduction: The incidence and etiologies underlying sudden cardiac arrest (SCA) in the young are derived from population- and referral-based cohorts of young SCA survivors. The extent to which the use of these cohorts contributes to discrepancies in our understanding of SCA in the young is unknown. As such, we sought to determine and compare the spectrum of SCA etiologies observed in young SCA survivors evaluated at a single tertiary center on both a primary and referral basis. Methods: Retrospective review of 940 young SCA survivors evaluated between 1990 and 2017 was used to identify all individuals ≤ 50 years of age that experienced a SCA. SCA root cause was determined by review of the medical records and diagnoses classified as ischemic, primary electrical, structural, or unexplained. SCA survivors that initially presented to our institution were classified as primary, while those who presented for secondary evaluation received a referral classification. Results: Overall, 566 SCA survivors were identified (age at event 33 ± 14 years; 39% females). In comparison to primary SCA survivors, referral SCA survivors were younger at the time of SCA (39 ± 12 vs. 30 ± 14 years; p<0.0001) and less likely to experience pre-SCA symptoms (45% vs. 27%; p<0.0001). Among all SCA survivors, the most common etiologies were idiopathic ventricular fibrillation (27%), acute coronary syndrome (21%), long QT syndrome (10%), and hypertrophic (7%) and dilated (6%) cardiomyopathies. Ischemic etiologies were less common (45% vs. 25%; p<0.0001) and primary electrical disorders more common (6% vs. 23%; p<0.0001) in referral SCA survivors. Conversely, genetic heart diseases (hypertrophic cardiomyopathy, long QT syndrome, etc.) were over-represented in referral cases (8% vs. 29%; p<0.0001), whereas no difference was observed in the number of primary and referral SCAs that remained unexplained. Conclusion: This study demonstrates, for the first time, that differences in SCA root cause exist between young SCA survivors evaluated at the same tertiary medical center on a primary vs. referral basis. Ongoing comparison of SCA etiologies between primary and referral SCA survivors may help resolve discrepancies regarding the contribution of specific disorders to SCA in the young. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. • In this large arrhythmogenic cardiomyopathy (N = 323) cohort, 12 patients received cardiac PET FDG scan as part of their evaluation. • Notably, 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%). • Further investigation is needed to determine role of FDG PET in diagnosis and management of ACM and investigate the role of inflammation in ACM. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]

Introduction: Loss-of-function (LOF) and gain-of-function (GOF) pathogenic variants in the KCNH2 -encoded Kv11.1 potassium channel cause type 2 long QT syndrome(LQT2) and type 1 short QT syndrome (SQT1), respectively. Given the prevalence of KCNH2- mediated heart disease (1 in 8000 for LQT2,1 in 100,000 for SQT1) and the reduced penetrance/variable expressivity seen in LQTS and SQTS, large databases such as the Genome Aggregation Database (gnomAD, n=141,352 individuals) might harbor subjects with unidentified LQT2/SQT1-causative mutations. Objective: To determine which "ultra-rare" KCNH2 missense variants (MVs) in gnomAD are most likely to be LQT2- or SQT1-causative. Methods: A list of gnomAD-derived MVs in KCNH2 was compiled. The frequency of each MV in gnomAD was assessed. Each MV was analyzed by 8 in silico pathogenicity prediction tools. MVs that were seen once in gnomAD and predicted damaging by all 8 tools were considered possible LQT2/SQT1-causative MVs worthy of functional validation via whole-cell patch clamp. Results: Overall, 233/474 (49%) of gnomAD KCNH2 MVs were seen in just 1 of >140,000 subjects. Of these, 2 (0.4%) MVs (S320W, S379Y) were predicted damaging by 8 in silico tools. Both S320W and S379Y localize to the N-terminus of the Kv11.1 potassium channel. There was no significant change in peak or tail current density between heterozygously expressed KCNH2-S320W (n=13, p=NS) and KCNH2-WT (n=13). However, heterozygous KCNH2-S379Y (n=12) produced a marked increase in peak current density across the range -30 mV to +20 mV and shifted the V1/2 of activation by -17 mV (p < 0.001). Also, tail current density of S379Y channels significantly increased across the range -20 mV to +20 mV and the V1/2of deactivation shifted by -26 mV (p < 0.001). Conclusion: With this stringent requirement of ultra-rarity, universal prediction of damaging impact, and functionally abnormal electrophysiological properties, one SQT1-causative pathogenic variant in gnomAD was identified consistent with the predicted frequency of SQTS. The search continues among the remaining 32 ultra-rare MVs in KCNH2 where at least 75% of the in silico tools predicted deleterious impact of the MV to find the 15-20 subjects in gnomAD's population who ought to have an LQT2-causative MV. [ABSTRACT FROM AUTHOR]

Introduction: Loss-of-function (LOF) variants in the KCNH2 -encoded Kv11.1 potassium channel cause type 2 long QT syndrome (LQT2). To date, hundreds of KCNH2 missense variants (MVs) have been published as "disease-causative". However, it has been suggested that 10% of rare LQTS variants in the literature may be "false positives". Objective: To determine previously published KCNH2 variants that are likely false positives and warrant demotion to at least likely benign status. Methods: A list of all case-derived LQT2-associated MVs from six large published compendia was compiled. The frequency of each MV within the Genome Aggregation Database (gnomAD, n = 141,352 individuals) was recorded. Eight in silico variant assessment tools were used to grade each MV. Variants (n=8) absent in gnomAD but predicted "benign" by all 8 tools were considered potential false positives, despite being ultra-rare, and were characterized functionally using whole-cell patch clamp. Results: Overall, 339 KCNH2 MVs were identified among LQTS cases. Of these, 13 (4%) were seen at a minor allele frequency (MAF) > 0.0004 in gnomAD. This MAF cut-off is derived from the frequency of R176W-KCNH2, a well-established albeit weakly penetrant (i.e. < 20%) LQT2-causative MV. Variants seen at MAF > R176W-KCNH2 are unlikely to be LQT2-contributing. However, 253 MVs (75%) were absent in gnomAD. Of these, 8 (4%) MVs (I96V, G187S, A203T, P241L, H254Q, G314S, P935S, and P963T) were predicted by all 8 in silico tools to be benign and had never been characterized functionally. Patch clamp studies did not demonstrate any LOF perturbation for these 8 MVs. Conclusion: This study offers compelling evidence for the demotion from LQT2-causative status to likely benign status for 21 (6%) of the 339 previously published LQT2 MVs based either on i) gnomAD MAF unacceptably high for a 1:8000 disorder (LQT2) for 13 MVs or ii) ultra-rarity (never seen in gnomAD) but in silico variant assessment tools predicting benign impact of the amino acid substitution and in vitro functional validation studies devoid of LOF for 8 additional MVs. This meticulous "pruning" exercise must be conducted for all published variants previously implicated as the monogenic cause for LQTS in particular and all genetic heart diseases in general. [ABSTRACT FROM AUTHOR]