Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations.

Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, is one of the most common heritable cardiovascular diseases. The myosin regulatory light chain (MYL2) mutation R58Q has been associated with severe cardiac hypertrophy and sudden cardiac death (SCD). Herein, we provide the first patient-specific, induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of MYL2-R58Q. The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60. The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells. MYL2-R58Q iPSC-CMs had significantly decreased peak ΔF/F0 of calcium transients and delayed decay time than controls. Additionally, the L-type Ca2+ channel (LTCC) (ICa,L) density at 0 mV was reduced significantly by 45.3%. Overall, the MYL2-R58Q iPSC-CMs recapitulated the HCM phenotype by exhibiting hypertrophy, myofibrillar disarray, increased irregular beating, decreased [Ca2+]i transients, and unexpectedly a nearly 50% reduction in LTCC peak current.