International Multicenter Cohort Study on Beta-Blocker-Free Treatment Strategies for Catecholaminergic Polymorphic Ventricular Tachycardia Patients.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, potentially life-threatening genetic heart disease. Nonselective beta-blockers (BBs) are highly effective in reducing CPVT-triggered arrhythmic events. However, some patients suffer from unacceptable BB side effects and might require strategies without a BB.

Novel risk predictor of arrhythmias for patients with potassium channel related congenital Long-QT Syndrome.

Background: Congenital long-QT syndrome (LQTS) is characterized by delayed ventricular repolarization, predisposing to potentially lethal ventricular arrhythmias. The variability in disease severity among patients remains largely unexplored, underscoring the limitations of current risk stratification methods.

Objective: We aimed to evaluate the potential utility of exercise stress test (EST) electrocardiographic markers in identifying high-risk LQTS patients.

Unexplained sudden cardiac arrest and sudden cardiac death in the young: What is killing these young people when nothing is found?

Unexplained sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in the young remains a critical issue for clinicians, researchers, patients and their family members. In this review, we explore the current status of SCA and SCD evaluation in the young, including recent monogenic and polygenic disease discoveries, advancements in cardiac imaging and our growing understanding of the role of the Purkinje system in triggering life threatening and even fatal ventricular arrhythmias. Yet, despite these advancements, over a third of SCA and SCD among individuals with seemingly structurally normal hearts remain unexplained.

Prevalence, Penetrance, and Phenotypic Manifestation of Cardiomyopathy-Associated Genetic Variants in the General Population: Insights from a Mayo Clinic Biobank Study.

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.

Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . 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.

The impact of mavacamten dosing on wall thickness regression: an insight from longer term follow-up based on genetic profile.

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.

Clinical Utility of Protein Language Models in Resolution of Variants of Uncertain Significance in , and Compared With Patch-Clamp Functional Characterization.

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.

KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.

Background And Aims: Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy.

Hypertrophic cardiomyopathy detection with artificial intelligence electrocardiography in international cohorts: an external validation study.

Aims: Recently, deep learning artificial intelligence (AI) models have been trained to detect cardiovascular conditions, including hypertrophic cardiomyopathy (HCM), from the 12-lead electrocardiogram (ECG). In this external validation study, we sought to assess the performance of an AI-ECG algorithm for detecting HCM in diverse international cohorts.

Methods And Results: A convolutional neural network-based AI-ECG algorithm was developed previously in a single-centre North American HCM cohort (Mayo Clinic).

Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, Transgenic Rabbits, and Patients.

Background: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.

Sudden cardiac arrest occurring in temporal proximity to consumption of energy drinks.

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.