Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.

BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics.

BACKGROUND: Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood. METHODS: Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort (Catheterization Genetics). Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review. RESULTS: Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, LMNA-related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in FLNC, MYBPC3, and MYH7 also developed relevant arrhythmogenic cardiomyopathy phenotypes. CONCLUSIONS: In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in LMNA. While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.

Differentiation of Human Induced Pluripotent Stem Cells into Epicardial-Like Cells.

The epicardium is a multipotent cell layer that is vital to myocardial development and regeneration. Epicardial cells contribute to cardiac fibroblast and smooth muscle populations of the heart and secrete paracrine factors that promote cardiomyocyte proliferation and angiogenesis. Despite a central role in cardiac biology, the mechanisms by which epicardial cells influence cardiac growth are largely unknown, and robust models of the epicardium are needed. Here, we review our protocol for differentiating induced pluripotent stem cells (iPSCs) into epicardial-like cells through temporal modulation of canonical Wnt signaling. iPSC-derived epicardial cells (iECs) resemble in vivo epicardial cells morphologically and display markers characteristic of the developing epicardium. We also review our protocol for differentiating iECs into fibroblasts and smooth muscle cells through treatment with bFGF and TGF-ß1, respectively. iECs provide a platform for studying fundamental epicardial biology and can inform strategies for therapeutic heart regeneration.

A Case of Rare Inherited Restrictive Cardiomyopathy With Severe Biatrial Enlargement.

We describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and management of restrictive cardiomyopathy with a focus on genetic etiologies. (Level of Difficulty: Intermediate.).

The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting.

The role of trabeculae carneae in modulating left ventricular (LV) diastolic compliance remains unclear. The objective of this study was to determine the contribution of trabeculae carneae to the LV diastolic compliance. LV pressure-volume compliance curves were measured in six human heart explants from patients with LV hypertrophy at baseline and following trabecular cutting. The effect of trabecular cutting was also analyzed with finite-element model (FEM) simulations. Our results demonstrated that LV compliance improved after trabecular cutting (p < 0.001). Finite-element simulations further demonstrated that stiffer trabeculae reduce LV compliance further, and that the presence of trabeculae reduced the wall stress in the apex. In conclusion, we demonstrate that integrity of the LV and trabeculae is important to maintain LV stiffness and loss in trabeculae leads to more LV compliance.