title: Contractile dysfunction irrespective of the mutant protein in human hypertrophic cardiomyopathy with normal systolic function.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation.
  
  
  RESULTS
  Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n=17), mutation negative HCM patients without an identified sarcomere mutation (HCM(mn); n=11), and nonfailing donors (n=12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33±5%, and similar in HCM(mn) compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCM(mn). Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCM(mn,) compared with donor (26.4±2.9, 28.0±3.7, and 37.2±2.3 kN/m(2), respectively), and higher myofilament Ca(2+)-sensitivity (EC(50)=2.5±0.2, 2.4±0.2, and 3.0±0.2 μmol/L, respectively). The sarcomere length-dependent increase in Ca(2+)-sensitivity was significantly smaller in both patient groups compared with donor (ΔEC(50): 0.46±0.04, 0.37±0.05, and 0.75±0.07 μmol/L, respectively). Protein kinase A treatment restored myofilament Ca(2+)-sensitivity and length-dependent activation in both patient groups to donor values.
  
  
  CONCLUSIONS
  Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression.
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sabine J
authors.initials: SJ
authors.lastname: van Dijk
authors.forename: E Rosalie
authors.initials: ER
authors.lastname: Paalberends
authors.forename: Aref
authors.initials: A
authors.lastname: Najafi
authors.forename: Michelle
authors.initials: M
authors.lastname: Michels
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Diederik W D
authors.initials: DW
authors.lastname: Kuster
authors.forename: Marjon
authors.initials: M
authors.lastname: van Slegtenhorst
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.forename: Cris
authors.initials: C
authors.lastname: dos Remedios
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: ten Cate
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D003971:Diastole / Q000502:physiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009200:Myocardial Contraction / Q000502:physiology*; D010766:Phosphorylation; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology; D013599:Systole / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology*; D000099163:Myosin Binding Protein C
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D000099163:Myosin Binding Protein C