title: Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  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.
  
  
  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). Low Fmax in MYBPC3mut, TNNI3mut, HCMsmn, and LVHao was normalized to donor values after correction for myofibril 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⁺].
  
  
  CONCLUSIONS
  Low cardiomyocyte Fmax in HCM patients is largely explained by hypertrophy and reduced myofibril density. MYH7 mutations reduce force generating capacity of sarcomeres at maximal and submaximal [Ca²⁺]. These hypocontractile sarcomeres may represent the primary abnormality in patients with MYH7 mutations.
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Institute for Cardiovascular Research, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. e.paalberends@vumc.nl
authors.forename: E Rosalie
authors.initials: ER
authors.lastname: Witjas-Paalberends
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Piroddi
authors.forename: Kelly
authors.initials: K
authors.lastname: Stam
authors.forename: Sabine J
authors.initials: SJ
authors.lastname: van Dijk
authors.forename: Vasco Sequeira
authors.initials: VS
authors.lastname: Oliviera
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferrara
authors.forename: Beatrice
authors.initials: B
authors.lastname: Scellini
authors.forename: Mark
authors.initials: M
authors.lastname: Hazebroek
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: ten Cate
authors.forename: Marjon
authors.initials: M
authors.lastname: van Slegtenhorst
authors.forename: Cris
authors.initials: C
authors.lastname: dos Remedios
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesi
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Michelle
authors.initials: M
authors.lastname: Michels
authors.forename: Corrado
authors.initials: C
authors.lastname: Poggesi
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D024722:Cardiac Myosins / Q000235:genetics* / Q000502:physiology*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D049108:Cell Enlargement; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D009210:Myofibrils / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000502:physiology*; D012518:Sarcomeres / Q000473:pathology / Q000502:physiology; D055815:Young Adult
chemical_list: C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains; D002118:Calcium
keywords: Cardiomyopathy; Contractility; Hypertrophy; Mutation; Sarcomere proteins