Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (HCM), frequently caused by sarcomeric gene mutations, is characterized by cellular dysfunction and asymmetric left-ventricular (LV) hypertrophy. We studied whether cellular dysfunction is due to an intrinsic sarcomere defect or cardiomyocyte remodelling. Cardiac samples from 43 sarcomere mutation-positive patients (HCMmut: mutations in thick (MYBPC3, MYH7) and thin (TPM1, TNNI3, TNNT2) myofilament genes) were compared with 14 sarcomere mutation-negative patients (HCMsmn), eight patients with secondary LV hypertrophy due to aortic stenosis (LVHao) and 13 donors. Force measurements in single membrane-permeabilized cardiomyocytes revealed significantly lower maximal force generating capacity (F-max) in HCMmut (21 1 kN/m(2)) and HCMsmn (26 3 kN/m(2)) compared with donor (36 2 kN/m(2)). Cardiomyocyte remodelling was more severe in HCMmut compared with HCMsmn based on significantly lower myofibril density (49 2 vs. 63 5) and significantly higher cardiomyocyte area (915 15 vs. 612 11 m(2)). Low F-max in MYBPC3(mut), TNNI3(mut), HCMsmn, and LVHao was normalized to donor values after correction for myofibril density. However, F-max was significantly lower in MYH7(mut), TPM1(mut), and TNNT2(mut) even after correction for myofibril density. In accordance, measurements in single myofibrils showed very low F-max in MYH7(mut), TPM1(mut), and TNNT2(mut) compared with donor (respectively, 73 3, 70 7, 83 6, and 113 5 kN/m(2)). In addition, force was lower in MYH7(mut) cardiomyocytes compared with MYBPC3(mut), HCMsmn, and donor at submaximal [Ca-2]. Low cardiomyocyte F-max in HCM patients is largely explained by hypertrophy and reduced myofibril density. MYH7 mutations reduce force generating capacity of sarcomeres at maximal and submaximal [Ca-2]. These hypocontractile sarcomeres may represent the primary abnormality in patients with MYH7 mutations