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

ABSTRACT: 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. I(Ks) 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.

SUBMITTER: Decker KF

PROVIDER: S-EPMC2670702 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Decker Keith F KF Heijman Jordi J Silva Jonathan R JR Hund Thomas J TJ Rudy Yoram Y

American journal of physiology. Heart and circulatory physiology 20090123 4

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 ...[more]

PMID: 19168720

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Project description:AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and resultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.

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

Publications

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

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