Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). However, targeted drugs like myosin ATPase inhibitors have not been evaluated in children.

Caroline Kinnear from Dr. Seema Mital’s group at the Hospital for Sick Children, Toronto, will describe how the team generated patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C) and MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). Compared with isogenic and healthy controls, variant-positive CMs showed hypertrophy, sarcomere disorganization, higher contractility, calcium transients, and ATPase activity.

Kinnear will also highlight how targeted myosin ATPase inhibitors showed complete rescue of the phenotype in variant-positive CMs and in cardiac biowires to mirror isogenic controls. The response was superior to verapamil or metoprolol. The findings indicate myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.