Myosin Heavy Chain 7 Mutation and Hypertrophic Cardiomyopathy

Lay Summary: Genetically based cardiomyopathies are an increasingly recognized cause of heart failure and sudden death. Mutations in myosin heavy chain 7 (MYH7) cause multiple types of cardiomyopathies but are difficult to model in rodents, which express minimal MYH7. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) thus provide a novel platform to model human genetic cardiomyopathies. We identified a cohort with familial cardiomyopathy (FCM) associated with a MYH7 mutation (E848G) and middle-age onset of systolic dysfunction and arrhythmias. Patient-specific iPSC-CMs from affected and wild-type individuals were generated and studied as single cells with aligned myofibrils and as engineered heart tissues. At ~30 days post-differentiation, no difference in contractile function was seen at the single-cell level, but by ~50 days the wild-type cells increased their systolic shortening, whereas FCM-CMs failed to mature. No genotype-dependent differences in Ca2+ transients were noted. In engineered heart tissues there was a ~75% reduction in systolic force generation in FCM samples compared to controls, with minimal difference in relaxation kinetics. Yeast two-hybrid analysis revealed that the E848G mutation disrupts the interaction between the S2 domain of MYH7 and the C1C2 domain of cardiac myosin binding protein C (cMyBP-C), phenocopying mutations in the interaction domain of cMyBP-C. Thus, disruption of the S2:C1C2 interaction in hiPSC-CMs derived from individuals with MYH7 E848G-associated systolic cardiomyopathy recapitulates the contractile dysfunction seen clinically. A relatively subtle defect at the single-cell level was readily detected using tissue engineering. We believe that therapies that restore protein-protein interaction may be beneficial for this type of cardiomyopathy.