MODELING THE DILATED CARDIOMYOPATHY WITH ATAXIA SYNDROME (DCMA), A PEDIATRIC MITOCHONDRIAL CARDIOMYOPATHY, USING CARDIOMYOCYTES DERIVED FROM INDUCED PLURIPOTENT STEM CELLS

摘要

BACKGROUND: Cardiomyopathy is a predominant and lethal feature of many inborn metabolic disorders but results from derangements in cellular energetics rather than ischemic myocardial injury. This fundamental difference is likely why standard heart failure medications appear to be ineffective. This problem is exemplified by the dilated cardiomyopathy with ataxia syndrome (DCMA). DCMA is related to Barth syndrome with abnormal cardiolipin and mitochondria causing heart failure, conduction defects and other systemic features. Isolated cases of DCMA have been identified worldwide but the largest known group of patients is found in the Hutterites of southern Alberta. No effective therapy exists and in our cohort there is 39% mortality in early childhood related to cardiac dysfunction despite recommended optimal medical therapy. The lack of useful drugs for mitochondrial cardiomyopathies means that there are few therapies available outside of mechanical circulatory support or heart transplantation. Since the rarity and heterogeneity of the pediatric cardiomyopathies preclude randomized drug trials, the use of patient cells and in vitro drug modeling represents the best possible option to identify effective therapeutics. Here, we describe the creation and characterization of cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) (as an in vitro model of DCMA) from 4 children with DCMA and varying severity of cardiac dysfunction.