Aims 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. Methods and results 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 (Fmax) in HCMmut (21±1 kN/m2) and HCMsmn (26±3 kN/m2) compared with donor (36±2 kN/m2). 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 μm2). LowFmax in MYBPC3mut, TNNI3mut, HCMsmn, and LVHao was normalized to donor values after correction formyofibril density.However, Fmax was significantly lower in MYH7mut, TPM1mut, and TNNT2mut even after correction for myofibril density. In accordance, measurements in single myofibrils showed very low Fmax in MYH7mut, TPM1mut, and TNNT2mut compared with donor (respectively, 73±3, 70±7, 83±6, and 113±5 kN/m2). In addition, force was lower in MYH7mut cardiomyocytes compared with MYBPC3mut, HCMsmn, and donor at submaximal [Ca2+]. Conclusion Low cardiomyocyte Fmax inHCM patients is largely explained by hypertrophy and reduced myofibril density.MYH7mutations reduce force generating capacity of sarcomeres at maximal and submaximal [Ca2+]. These hypocontractile sarcomeres may represent the primary abnormality in patients with MYH7 mutations.

Cardiomyopathy, Contractility, Hypertrophy, Mutation, Sarcomere proteins
dx.doi.org/10.1093/cvr/cvt119, hdl.handle.net/1765/85164
Cardiovascular Research
Department of Cardiology

Witjas-Paalberends, E.R, Piroddi, N, Hoogestijn-Stam, K, Van Dijk, S.J, Oliviera, V.S, Ferrara, C, … van der Velden, J. (2013). Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. Cardiovascular Research, 99(3), 432–441. doi:10.1093/cvr/cvt119