TY - JOUR
T1 - Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy
AU - Witjas-Paalberends, E. Rosalie
AU - Piroddi, Nicoletta
AU - Stam, Kelly
AU - van Dijk, Sabine J.
AU - Oliviera, Vasco Sequeira
AU - Ferrara, Claudia
AU - Scellini, Beatrice
AU - Hazebroek, Mark
AU - ten Cate, Folkert J.
AU - van Slegtenhorst, Marjon
AU - dos Remedios, Cris
AU - Niessen, Hans W. M.
AU - Tesi, Chiara
AU - Stienen, Ger J. M.
AU - Heymans, Stephane
AU - Michels, Michelle
AU - Poggesi, Corrado
AU - van der Velden, Jolanda
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
KW - Cardiomyopathy
KW - Hypertrophy
KW - Sarcomere proteins
KW - Mutation
KW - Contractility
U2 - 10.1093/cvr/cvt119
DO - 10.1093/cvr/cvt119
M3 - Article
C2 - 23674513
SN - 0008-6363
VL - 99
SP - 432
EP - 441
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 3
ER -