Circulation: Genomic and Precision Medicine

BackgroundMitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease (HTAD) gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium (MAC) registry. MethodsMAD was determined by direct measurement of echocardiographic images. MR and MVP were define...

BackgroundTruncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy (ACM), however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. MethodsIndividuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family...

BackgroundHypertrophic cardiomyopathy (HCM) is a complex disease with variable clinical presentation and familial impact. Age at diagnosis may influence phenotypic expression, but it is unclear if age also affects clinical outcomes, genetic findings, and yield of family screening. MethodsRetrospective cohort study of families screened for HCM in Eastern Denmark (2006-2023). Probands were analyzed by age at diagnosis both continuously and in quartiles: 18-45, 46-56, 57-65, and >65 years. Result...

BackgroundPathogenic variants in the desmin gene (DES) are implicated in diverse cardiomyopathy and skeletal myopathy phentoypes with high rates of major adverse cardiac events (MACE). Although pediatric cases have been reported, the genetic profile, clinical features and outcomes in affected children remain poorly defined. This study aimed to comprehensively characterize these aspects in the pediatric population. MethodsWe conducted a systematic review and individual patient data meta-analysis...

BackgroundThere is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general, adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional and arrhythmic disease features. MethodsUK Biobank participants who had undergone whole exome sequencing (WES), ECG and cardiov...

ImportancePolygenic background modifies variant penetrance in hypertrophic (HCM) and dilated (DCM) cardiomyopathy, diseases with opposing morphologic characteristics and inversely related genetic pathways. Whether polygenic susceptibility for one disease protects against monogenic risk for the other remains unexplored. ObjectiveTo characterize if polygenic background bidirectionally modifies pathogenicity of established rare variants associated with HCM and DCM. DesignCross-sectional study. S...

BackgroundCardiovascular health (CVH) and genetic susceptibility to adverse left ventricular (LV) remodeling are each linked to cardiovascular diseases (CVD); however, their combined role remains unclear. MethodsFramingham Heart Study participants [n=1,255 Offspring-Exam 8 (2005-2008), n=2,835 Generation 3-Exam 1 (2002-2005)] had assessment of modifiable risk factors comprising the American Heart Associations Lifes Essential 8 (LE8) score with higher scores indicating better CVH health. A Polyg...

BackgroundPrimary hypertrophic cardiomyopathy (HCM) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exists on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indians (SAI), that is necessary for minimizing disparities in interpreting ancestry-specific variants. ObjectivesThe ClinGen Hereditary Cardiovascular Disorders (HCVD) Gene Curation Expert P...

BackgroundIndividuals with familial hypercholesterolemia (FH) require intensive lipid-lowering therapy, starting with high-intensity statins and adding ezetimibe and PCSK9 inhibitors (PCSK9i) as needed to reach target LDL-C levels. There are limited data on disparities in the use of these therapies among individuals with FH in the US. MethodsWe queried a large US healthcare claims repository consisting of 324 million individuals, focusing on prescriptions for high-intensity statins, ezetimibe, ...

BackgroundAlternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arr...

BackgroundPatients with stable coronary artery disease (CAD) represent a clinically heterogeneous group, with varying psychosocial, metabolic, and cardiovascular profiles that may differentially influence prognosis. We sought to identify distinct clinical phenogroups among patients with stable CAD and to evaluate their associations with cardiovascular disease (CVD)-specific and all-cause mortality. MethodsWe pooled data from 949 participants with stable CAD enrolled in two related studies. To i...

BackgroundGenetic testing is now recommended for select patients with early-onset atrial fibrillation (AF). Hemochromatosis is an autosomal recessive syndrome that occurs in patients who carry two pathogenic or likely-pathogenic (P/LP) variants in HFE. HFE is included on some genetic testing panels used for patients with AF. Hemochromatosis causes cardiomyopathy due to iron overload in the ventricle; however, it is unknown whether AF can be an early manifestation that is identified by genetic te...

BackgroundMeasures of genetic predisposition can improve prediction of risk of cardiometabolic diseases but more data is needed in groups under-represented in genomics research. In this study, we investigated the impact of genetic risk factors for coronary heart disease (CHD) - polygenic risk, monogenic risk [in the form of familial hypercholesterolemia (FH)], and family history (FamHx) - on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults - eMERGE IV (eIV) and Al...

BackgroundFlecainide and other class-Ic antiarrhythmic drugs (AADs) are widely used in Andersen-Tawil syndrome type 1 (ATS1) patients. However, class-Ic drugs might be proarrhythmic in some cases. We investigated the molecular mechanisms of class-I AADs proarrhythmia and whether they might increase the risk of death in ATS1 patients with structurally normal hearts. Methods and ResultsOf 53 ATS1 patients reviewed from the literature, 54% responded partially to flecainide, with ventricular arrhyt...

IntroductionRisk stratification of patients with the SCN5A-E1784K mutation is challenging because they can express Brugada syndrome, long QT syndrome (LQTS), or both phenotypes (overlap syndrome). This study compared arrhythmic risk in patients with overlap syndrome versus single phenotype presentations. MethodsWe retrospectively enrolled patients aged 12 and older carrying the SCN5A-E1784K mutation. The primary outcome was major cardiac events (MCEs) defined as sustained ventricular arrhythmia...

BackgroundFamilial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. Related mutations contributing to hypercontractility and poor relaxation in HCM have been incompletely understood. The purpose of this study was to explore and verify a novel variant in cardiac myosin-binding protein C3 (MYBPC3) in a HCM family. MethodsClinical information was collected and cardiac evaluation was performed in the pedigree. Second-generation sequencing technology was used to i...

BackgroundThe real-world prevalence of sudden cardiac death (SCD)-related gene mutations and their relationship with implantable cardioverter-defibrillator (ICD) implantation in dilated cardiomyopathy (DCM) has not been clearly investigated. MethodsThis study included patients with sporadic DCM with persistent left ventricular ejection fraction (LVEF) [&le;] 35% even after 3 months of guideline-directed medical treatment or those with an ICD for secondary prevention and LVEF < 50%. Genetic test...

Currently, coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. We designed a novel and general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. MSGene supports decision making about CAD prevention related to any of these states. We analyzed longitudinal data from 480,638 UK Biobank pa...

AimsEarly prediction of acute coronary syndrome (ACS) is a major goal for prevention of coronary heart disease (CHD). Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individuals genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. Methods a...

IntroductionRelatives of a victim of sudden cardiac death in the young (SCDY) may be at risk for hereditary cardiomyopathies and arrhythmias. Family leaders are often responsible for communicating risk to surviving family at a difficult time. PurposeExplore barriers and facilitators to communication about cascade screening in families who have lost a family member to SCDY MethodsSemi-structured interviews (n = 14) were conducted with family members of a SCDY decedent. Participants were recruit...