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

ER Witjas-Paalberends, N Piroddi, Kelly Stam, SJ van Dijk, VS Oliviera, C Ferrara, B Scellini, M Hazebroek, Folkert ten Cate, M van Slegtenhorst, C dos Remedios, HWM Niessen, C Tesi, GJM Stienen, S Heymans, Michelle Michels, C Poggesi, J Velden

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Abstract

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) 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.
Original languageUndefined/Unknown
Pages (from-to)432-441
Number of pages10
JournalCardiovascular Research
Volume99
Issue number3
DOIs
Publication statusPublished - 2013

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