Circulation

BackgroundGenetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating RBM20 variants (RBM20tvs) is unclear. ObjectiveAssess the contribution of RBM20tvs to DCM. MethodsWe assembled an international cohort of DCM patients with RBM20 variants and used data from the geno...

BackgroundPeripartum cardiomyopathy (PPCM) is a life-threatening condition. Despite rising incidence, outcomes have not improved. This study evaluated national inpatient trends, disparities, and independent risk factors for PPCM. MethodsUsing the National Inpatient Sample (2016-2020), we analyzed adults ([≥]18 years) hospitalized between 10 and 42 weeks of gestation. Among 18,844,715 patients, 4,475 had PPCM. We performed uni- and multivariate logistic regression analysis of risk factors for...

BackgroundKCNQ1 loss of function variants are thought to cause type 1 long QT syndrome by reducing IKs. However, we have recently reported that pharmacologic block of IKs in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) produced minimal increases in action potential duration at 90% repolarization (APD90), while genetic loss of KCNQ1 markedly prolonged APD90. We sought here to define mechanisms underlying APD prolongation by genetic loss of KCNQ1. MethodsWe studied iPSC-C...

Background/ObjectivesJervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive disease caused by mutations in KCNQ1 or KCNE1. It is characterized by prolonged QT interval on electrocardiogram, deafness and an increased risk of sudden cardiac death (SCD) (25%). Given the high consanguinity rate (35%) in the Middle East and North Africa region (MENA), an enrichment of JLNS is expected, providing a powerful opportunity to identify ancestry-specific genetic determinants. We report genetic ...

To broaden our understanding of bradyarrhythmias and diseases of the cardiac conduction system, we performed cross-sectional multi-ancestry genome-wide association study meta-analyses in up to 1.3 million individuals for sinus node dysfunction (SND), distal conduction disease (DCD), and pacemaker implantation (PM). We evaluated the biological relevance of bradyarrhythmia loci by analyses of transcriptomes, pleiotropy, and partitioned heritability based on cardiac single cell RNA sequencing data....

IntroductionPeripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy characterized by left ventricular systolic dysfunction. Due to its relative rarity, risk factors are not well established, and a validated risk score is lacking. MethodsWe conducted a retrospective cohort study, analyzing 317,892 deliveries between January 2014-December 2024. PPCM cases were identified by individual clinical chart review and echocardiographic validation. Multivariate logistic ...

BackgroundPathogenic SCN5A variants are associated with inherited arrhythmias such as long QT syndrome, Brugada syndrome, and sick sinus syndrome (SSS). While Nav1.5, an -subunit of the cardiac sodium channel encoded by SCN5A, has been considered to function as a monomer, recent studies reveal that a reduction of sodium current in wild-type (WT) Nav1.5 can be caused by dimerization with loss-of-function (LOF) mutated Nav1.5 through dominant-negative (DN) effects. However, the clinical significan...

BackgroundNaV1.5 channels, encoded by SCN5A, are essential for the genesis and shaping of the cardiac action potential (AP). Gain-of-function (GoF) variants in SCN5A are associated with long QT syndrome (LQTS), whereas loss-of-function (LoF) mutations are linked with Brugada syndrome. MOG1 is an integral part of the NaV1.5 channelosome, increasing both current and membrane expression of NaV1.5. Two LoF variants in MOG1 (E61X and E83D) cause Brugada Syndrome in patients, but no association with L...

BackgroundLong QT syndrome (LQTS) is a life-threatening genetic disorder characterized by prolonged QT intervals on electrocardiograms. Congenital forms are mostly associated with variants in the KCNQ1 and KCNH2 genes. Among pathogenic or likely pathogenic (P/LP) variants, some are associated with a significantly higher incidence of cardiac events compared to others. While therapies have significantly reduced mortality, some patients are unresponsive or intolerant to therapy, perpetuating their ...

BackgroundRare variant genetics have been associated with peripartum cardiomyopathy (PPCM) but the role of genetics remains unsettled. ObjectiveThe study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients with DCM or PPCM (probands), and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls. MethodsClinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or parti...

BackgroundAnnually 300,000 Americans experience sudden cardiac arrest (SCA). Studies in referral SCA cohorts have observed rare variants in genes associated with arrhythmia and cardiomyopathy. We sought to: (1) establish the population prevalence of rare disease-causing variants in a set of candidate genes and (2) confirm the association of disease-causing variants in these genes with SCA in two prospective population-based studies. MethodsSCA patients (n=3264) were accrued from the Oregon Sudd...

BackgroundCross-sectional studies of various forms of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin ( TTNtv) in 7-30% of patients, but the clinical importance of identifying a TTNtv in an asymptomatic adult is largely unknown. In contrast to cross-sectional studies, prospective cohort studies allow for unbiased estimates of the disease risks associated with a genotype exposure. ObjectivesTo determine the prevalence of cardiac imaging abnormalities and risk o...

BackgroundADRB1 and ADRB2, encoding cardiac myocyte {beta}1- and {beta}2-adrenergic receptors (ARs) that mediate pathologic myocardial remodeling in response to chronically increased signaling, contain N-terminus haplotype variants capable of influencing agonist- or biased ligand-induced receptor internalization that uncouples canonical signaling and initiates EGFR/ERK1/2 cardioprotection. MethodsIn two heart failure (HF) clinical trial genetic substudies we investigated effects of internalizin...

BackgroundBrugada Syndrome (BrS) is an inherited arrhythmia syndrome in which mutations in SCN5A account for 20% of cases. Mutations in other ion channels or channel-modifying genes may account for an additional 10% of cases, though recent analysis has suggested that SCN5A should be regarded as the sole monogenic cause of BrS. ObjectiveWe sought to re-assess the genetic underpinnings of BrS in a large mutligenerational family with a putative GPD1L-A280V mutation. MethodsFine linkage mapping wa...

ImportanceAortic stenosis (AS) is a major public health challenge with a growing therapeutic landscape, but current biomarkers do not inform personalized screening and follow-up. ObjectiveA video-based artificial intelligence (AI) biomarker (Digital AS Severity index [DASSi]) can detect severe AS using single-view long-axis echocardiography without Doppler. Here, we deploy DASSi to patients with no or mild/moderate AS at baseline to identify AS development and progression. Design, Setting, and...

BackgroundThe comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. ObjectivesTo evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. MethodsWe performed summary-level and individual-level Mendelian randomization (MR) analyses. Geneti...

BackgroundSubtle prognostically-important ECG features may not be apparent to physicians. In the course of supervised machine learning (ML), many thousands of ECG features are identified. These are not limited to conventional ECG parameters and morphology. HypothesisNovel neural network (NN)-derived ECG features can predict future cardiovascular disease and mortality Methods and ResultsWe extracted 5120 NN-derived ECG features from an AI-ECG model trained for six simple diagnoses and applied u...

BackgroundDrug-induced QT prolongation (diLQT) is a feared side-effect as exposing susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG channels that generate the repolarizing current (IKr) and thereby regulate the late repolarization phase. There is an important inter-individual susceptibility to develop diLQT which is of unknown origin but can be reproduced in patient-specific i...

BackgroundEpidemiological studies have consistently associated cytomegalovirus (CMV) seropositivity with adverse cardiovascular outcomes. However, the mechanisms by which CMV infection impacts pathophysiological mechanisms in the heart remain poorly understood. In this study, we sought to dissect how latent murine CMV infection impacts cardiac immune cell dynamics at steady-state and during post-myocardial infarction (MI) repair. MethodsExperimental MI studies were conducted in C57BL/6J mice pr...

ImportanceThe effect of high percentage spliced in (hiPSI) TTN truncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations. ObjectiveTo determine the effect of TTNtvs on risk of DCM in diverse population as me...