Stem Cell Models Reveal Sarcomere Inhibition As A Potential Treatment For Pediatric Restrictive Cardiomyopathy

Introduction: Pediatric Restrictive Cardiomyopathy (RCM) is a genetic cardiomyopathy resulting from profoundly increased stiffness of the wall of the cardiac ventricle with normal or low normal contractility. Treatment options are limited, with most patients necessitating heart transplant. Therapies that can improve diastolic function are needed for this severe disease. Recently, direct inhibition of the sarcomere with mavacamten, a cardiac myosin antagonist, has been shown to be effective in treating a related disease, Hypertrophic Cardiomyopathy (HCM), in adults. However, whether it would be useful for the diastolic dysfunction seen in RCM is unknown. Hypothesis: Treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients with mavacamten will rescue diastolic deficits. Methods: Cardiomyocytes were differentiated from induced pluripotent stem cells (iPSCs) originally derived from a pediatric patient with RCM, as well as a paired isogenic CRISPR-corrected line. Cells were treated with increasing doses of mavacamten and contractility and resting tension were measured using a novel traction force microscopy platform. Results: At baseline, RCM cells showed elevated contractility, resting tension, and calcium sensitivity compared to their isogenic control. Mavacamten treatment decreased both contractility and resting tension of RCM cardiomyocytes. Conclusions: Mavacamten improves both systolic and diastolic derangements in an hiPSC model of RCM.