The Dilated Cardiomyopathy-Associated MYH7 Mutation R369Q Displays Different Phenotypes Across a Multiscale Study of Contraction

Abstract

Heart failure is a debilitating condition whose mortality rate is currently increasing. Dilated cardiomyopathy (DCM) is one major contributor to heart failure cases, yet little is known about the pathogenesis of the disease and medications only serve to manage symptoms. Many cases of DCM are genetically associated with pathogenic variants of the sarcomeric proteins which make up the contractile machinery of cardiomyocytes, the contractile cells of the heart. Here, we present a multiscale study of the DCM-associated likely pathogenic β-myosin heavy chain variant R369Q, which is thought to impede contractility through alteration of thin filament interactions. Beginning from the tissue level, we demonstrate that engineered heart tissues recapitulate the DCM phenotype but that suggested results are not necessarily consistent on smaller levels such as the cell. Only by probing several scales of contraction from the tissue down to the molecule were we able to propose a nuanced mechanism of disease pathogenesis that aligned with our various experimental models. Thus, we suggest that a multiscale approach is powerful and necessary to understand the mechanisms of disease progression and must serve as the foundation for development of novel therapeutics for heart failure and DCM.