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Abstract
A premature truncation (R255X) in MYBPHL associates with human dilated cardiomyopathy (DCM) and arrhythmias. Loss of Mybphl in mice causes DCM and arrhythmia. MYBPHL encodes myosin binding protein H-like (MyBP-HL) and is expressed highly in the atria. We hypothesize that MyBP-HL is required for proper conduction system function. Immunofluorescence microscopy on normal human atria showed MyBP-HL staining in all atrial cardiomyocytes with a sarcomere A-band pattern. Atria from the heterozygous (het) MYBPHL R255X mutant carrier lacked MyBP-HL staining. Human induced pluripotent stem cell-derived cardiomyocytes from the het MYBPHL R255X carrier and control cell lines were also examined. MyBP-HL was found in a subset of control cardiomyocytes, whereas R255X cells showed no MyBP-HL, suggesting that the R255X allele exerts a dominant-negative effect on the normal MYBPHL allele. Immunofluorescence microscopy in wild-type (WT) 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 het ventricles have 10% as many MyBP-HL-positive cells compared to WT. Surface telemetry revealed atrioventricular block and atrial bigeminy and intracardiac pacing revealed a shorter atrial relative refractory period and inducible atrial tachycardia in Mybphl -null mice. Ca 2+ transients measured with confocal microscopy revealed that isolated Mybphl -null atrial cardiomyocytes had an increased occurrence of triggered Ca 2+ waves and more heterogenous Ca 2+ release than WT controls. Super-resolution microscopy revealed ryanodine receptor disorganization in Mybphl het and null atrial cardiomyocytes compared to WT controls. Abnormal Ca 2+ release, shorter atrial refractory period, and dilated atria could account for the observed atrial arrhythmias, bigeminy, and atrial tachycardia.
Published Version
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