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.
- Sarcomere proteins