Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Keith F. Decker, Jordi Heijman, Jonathan R. Silva, Thomas J. Hund, Yoram Rudy*

*Corresponding author for this work

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88 Citations (Web of Science)

Abstract

Decker KF, Heijman J, Silva JR, Hund TJ, Rudy Y. Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. Am J Physiol Heart Circ Physiol 296: H1017-H1026, 2009. First published January 23, 2009; doi:10.1152/ajpheart.01216.2008.-Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (I(to1)), the slow component of the delayed rectifier K(+) current (I(Ks)), the L-type Ca(2+) channel current (I(Ca,L)), and the Na(+)-K(+) pump current (I(NaK)) fit to data from canine ventricular myocytes. We found that I(to1) plays a limited role in potentiating peak I(Ca,L) and sarcoplasmic reticulum Ca(2+) release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that I(Ca,L) plays a critical role in APD accommodation and rate dependence of APD restitution. Ca(2+) entry via I(Ca,L) at fast rate drives increased Na(+)-Ca(2+) exchanger Ca(2+) extrusion and Na(+) entry, which in turn increases Na(+) extrusion via outward I(NaK). APD accommodation results from this increased outward I(NaK). Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.

Original languageEnglish
Pages (from-to)H1017-H1026
Number of pages10
JournalAmerican Journal of Physiology-heart and Circulatory Physiology
Volume296
Issue number4
DOIs
Publication statusPublished - Apr 2009

Keywords

  • arrhythmia
  • cardiac electrophysiology
  • mathematical modeling
  • ion channels
  • TRANSIENT OUTWARD CURRENT
  • MAMMALIAN VENTRICULAR MYOCYTES
  • INDUCED HEART-FAILURE
  • LONG-QT SYNDROME
  • I-KS
  • CARDIAC MYOCYTES
  • CYCLE LENGTH
  • ELECTRICAL HETEROGENEITY
  • ENDOCARDIAL MYOCYTES
  • POTASSIUM CURRENT

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