Objective

Sarcomeric cardiomyopathies, including hypertrophic cardiomyopathy (HCM), are an important cause of morbidity and mortality. Clinically, HCM is characterized by ventricular wall thickening, preserved ejection fraction concurrent with diastolic dysfunction, and arrhythmias. One of the most common forms of HCM arises from a missense mutation in the gene encoding the beta-myosin heavy chain protein (MYH7), resulting in a change of amino acid 403 from arginine to glutamine (R403Q). A major hindrance to detailed study of sarcomeric cardiomyopathies in humans has been lack of an appropriate cardiac tissue model. Here, we use human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the functional consequence of the HCM MYH7 R403Q mutation. HiPSC-CMs were generated through  reprogramming of somatic cells from a patient carrying the HCM MYH7 R403Q mutation. In addition, we use genome engineering strategies to correct the mutation, creating an isogenic control. Moreover, we developed an induced hypertrophy model by exposing control hiPSC-CMs to endothelin-1 (ET-1). Both inherited and induced models display classic hallmarks of hypertrophy, including up-regulation of fetal genes, cytoskeletal rearrangements, and increased hiPSC-CM size. In addition, the HCM MYH7 R403Q hiPSC-CMs display abnormal electrophysiological properties and calcium handling properties including significantly slower calcium decay rates and prolonged calcium handling kinetics (i.e., time to peak and time to baseline) concurrent with contractile dysfunction. These data illustrate the advantages of disease modeling using hiPSC technology. We conclude that patient-specific hiPSC-CMs exhibit classic clinical phenotypes relative to control. We show that the induced and inherited HCM phenotype hiPSC-CMs have common structural and functional features. In total, hiPSC technology enables a reliable and reproducible disease model not previously attainable for sarcomeric cardiomyopathy mechanistic elucidation and novel therapeutic research.