title: Myofilament calcium regulation in human myocardium.
abstract: BACKGROUND
  We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure.
  
  
  RESULTS
  Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F(max)) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01+/-0.22 versus 0.86+/-0.13 micromol/L, respectively (P<0.05). Addition of cAMP resulted in a 0. 56 micromol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 micromol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts.
  
  
  CONCLUSIONS
  We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium.
authors.affiliation: Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: R H
authors.initials: RH
authors.lastname: Schwinger
authors.forename: U
authors.initials: U
authors.lastname: Schmidt
authors.forename: C S
authors.initials: CS
authors.lastname: Kim
authors.forename: D
authors.initials: D
authors.lastname: Lebeche
authors.forename: A A
authors.initials: AA
authors.lastname: Doye
authors.forename: J K
authors.initials: JK
authors.lastname: Gwathmey
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D002102:Cadaver; D002118:Calcium / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000378:metabolism / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006352:Heart Ventricles; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D010710:Phosphates / Q000378:metabolism
chemical_list: D010710:Phosphates; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D002118:Calcium