Burnham, H. V.; Pena, A.; Gandhi, S. H.; Fritzmann, G.; Barefield, D. Y.

Mutations in the myosin-binding protein H-like (MyBP-HL) gene, MYBPHL, are linked to hereditary dilated cardiomyopathy (DCM), atrial fibrillation, and atrioventricular arrhythmias. MyBP-HL is a sarcomeric protein that is highly expressed in the atria with only scarce, distinct clusters of MyBP-HL positive cells within and surrounding the ventricular conduction system. Constitutive knock-out of MyBP-HL in mice causes atrial dilation, arrhythmia, and DCM. Whether MyBP-HL plays a developmental role, or if knock-down in adulthood will recapitulate a similar phenotype has yet to be examined. Moreover, the significance of the MyBP-HL expressing ventricular cells, or the functional need for differential thick filament regulation is currently unknown. We used a conditional floxed Mybphl mouse to further elucidate the role of MyBP-HL. We crossed this mouse with a ROSA26-Cre(ERT2) LoxP mouse to conditionally knock-down Mybphl after tamoxifen treatment. We also crossed the Mybphl flox mouse with a Contactin-2-Cre mouse that deletes Mybphl solely in the cardiac conduction system from birth. Echocardiography was used to measure contractile function, and conscious telemetry allowed for monitoring of heart rhythm and electrical signal conduction changes. We demonstrate that mice with conditional decrease of MyBP-HL in adulthood develop a hypertrophic phenotype with atrial contractile changes, increased total heart weight to body weight, and increased heart rate variability. Deletion of Mybphl solely within the cardiac conduction system trends toward mild hypercontractility, lower heart rates, and interventricular septal thickening. These data show that MyBP-HL is essential for proper cardiac function, and even minor alteration in protein levels cause a diseased cardiac phenotype.