Abstract MP111: Loss of Myosin Binding Protein H-like Causes Cardiacconduction Abnormalities

Abstract

A premature truncation variant in MYBPHL in humans and a loss of Mybphl in mice associates with dilated cardiomyopathy (DCM), atrial and ventricular arrhythmias, and atrial enlargement. MYBPHL encodes myosin binding protein H-like (MyBP-HL) and is expressed highly in the atria and in foci throughout the ventricle. We hypothesize that MyBP-HL is required for proper formation and function of the conduction system. Surface telemetry found atrioventricular block and atrial bigeminy, while intracardiac pacing revealed a faster atrial relative refractory period and atrial tachycardia in Mybphl -null mice. Ca 2+ transient analysis revealed that isolated Mybphl -null atrial cardiomyocytes had an increased occurrence of triggered Ca 2+ waves and more heterogenous Ca 2+ release than wild-type (WT) controls. Super-resolution microscopy revealed ryanodine receptor disorganization in Mybphl het and null atrial cardiomyocytes compared to WT controls. Immunofluorescence microscopy in WT adult mouse ventricles identified MyBP-HL-positive ventricular cardiomyocytes that co-localized with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers. Mybphl heterozygous ventricles showed 10% as many MyBP-HL-positive cells compared to WT. Lightsheet microscopy of perinatal day 5 hearts showed enrichment of MyBP-HL-positive cells within and immediately adjacent to the Cntn2-positive ventricular conduction system in WT hearts, but this association was not apparent in Mybphl heterozygous null hearts. These data, abnormal Ca 2+ release, shorter atrial refractory period, and atrial dilation could account for the observed atrial arrhythmias, bigeminy, and atrial tachycardia, whereas the proximity of MyBP-HL-positive cells with the ventricular conduction system provides insight into how a predominantly atrial expressed gene could cause ventricular arrhythmias.