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 articlepeer-review

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

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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