Myofilament calcium regulation in human myocardium

Roger J. Hajjar, Robert H.G. Schwinger, Ulrich Schmidt, Catherine S. Kim, Djamel Lebeche, Angelia A. Doye, Judith K. Gwathmey

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Background - We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure. Methods and 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 μmol/L, respectively (P<0.05). Addition of cAMP resulted in a 0.56 μmol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 μmol/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.

Original languageEnglish
Pages (from-to)1679-1685
Number of pages7
JournalCirculation
Volume101
Issue number14
DOIs
StatePublished - 11 Apr 2000
Externally publishedYes

Keywords

  • Calcium
  • Heart failure
  • Myocardium
  • Myocytes
  • cGMP

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