Fibroblast p38-MAPK signaling modulates cardiac function and phenotype in mouse models of inherited dilated and hypertrophic cardiomyopathy

Abstract

Inherited cardiomyopathies are common causes of heart failure in the general population that present with two main clinical phenotypes: dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Little is known regarding the pathogenesis and subsequent clinical impact of early extracellular matrix (ECM) remodeling in these diseases. By genetically modulating the ECM via fibroblast p38-MAPK, the mechanical basis of ECM-cardiomyocyte feedback and consequence on whole heart remodeling in DCM and HCM was examined via non- invasive and invasive physiology metrics. Both structural and functional phenotype was demonstrated to be susceptible to matrix modifications at the whole heart and cardiomyocyte level. This study demonstrates that fibroblast state and downstream matrix remodeling play an active role in the pathogenesis of cardiomyopathies and offers insights into early diagnostic tools and targeted therapeutic approaches.