Experimental models of inherited cardiomyopathy and its therapeutics

Abstract

Cardiomyopathy is a disease of myocardium categorized into three major forms, hypertrophic (HCM), dilated (DCM) and restrictive cardiomyopathy (RCM), which has recently been demonstrated to be a monogenic disease due to mutations in various proteins expressed in cardiomyocytes. Mutations in HCM and RCM typically increase the myofilament sensitivity to cytoplasmic Ca²⁺, leading to systolic hyperfunction and diastolic dysfunction. In contrast, mutations in DCM typically decrease the myofilament sensitivity to cytoplasmic Ca²⁺ and/or force generation/transmission, leading to systolic dysfunction. Creation of genetically-manipulated transgenic and knock-in animals expressing mutant proteins exogenously and endogenously, respectively, in their hearts provides valuable animal models to discover the molecular and cellular mechanisms for pathogenesis and promising therapeutic strategy in vivo. Recently, cardiomyocytes have been differentiated from patient’s induced pluripotent stem cells as a model of inherited cardiomyopathies in vitro. In this review, we provide overview of experimental models of cardiomyopathies with a focus on revealed molecular and cellular pathogenic mechanisms and potential therapeutics.

Keywords: Cardiomyopathy, Gene, Mutation, Animal model, Induced pluripotent stem cell, Therapeutics

Core tip: Current experimental models of inherited cardiomyopathies (hypertrophic cardiomyopathy, dilated cardiomyopathy and restricted cardiomyopathy), including genetically-manipulated mouse models (transgenic and knock-in mice) and patient’s induced pluripotent stem cell-derived cardiomyocyte models, are summarized and discussed with a focus on revealed molecular pathogenic mechanisms and potential drug therapeutics.