Computational models of the failing myocyte: Relating altered gene expression to cellular function

R. L. Winslow, J. L. Greenstein, G. F. Tomaselli, B. O'Rourke

Research output: Contribution to journalReview article

25 Scopus citations

Abstract

Studies of both message and expressed protein levels in patients and animal models of heart failure (HF) have demonstrated reduced message levels of genes encoding outward potassium (K+) currents in end-stage HF. These same studies have also shown altered expression of calcium-handling proteins, specifically down regulation of the sarcoplasmic reticulum (SR) Ca2+-ATPase, and up regulation of the Na+-Ca2+ exchanger. We have tested the hypothesis that this minimal model of end-stage HF can account for action potential (AP) prolongation, and reduced Ca2+ transient amplitude and decay rate observed in failing myocytes. To do this, we have developed a computer model of the normal and failing canine myocyte that describes properties of both membrane currents as well as intracellular calcium cycling. Model simulations closely reproduce AP and Ca2+ transient properties measured experimentally in failing myocytes. Simulations also indicate that the predominant mechanism of AP prolongation in canine HF is reduction of Ca2+-dependent inactivation of L-type Ca2+ current in response to reduced SR Ca2+ levels. These reduced SR Ca2+ levels are, in turn, a consequence of HF-induced down regulation of the SR Ca2+-ATPase, and up regulation of the Na+-Ca2+ exchanger. The hypothesis that intracellular Ca2+ cycling has important influences on AP duration changes in HF is supported by a measured close correlation between AP duration and Ca2+ transient amplitude when myocytes are stimulated from rest.

Original languageEnglish (US)
Pages (from-to)1187-1200
Number of pages14
JournalPhilosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
Volume359
Issue number1783
DOIs
StatePublished - Jun 15 2001

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Keywords

  • Calcium
  • Computer model
  • Excitation-contraction coupling
  • Heart failure
  • Ventricular myocyte

ASJC Scopus subject areas

  • Mathematics(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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