Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.

Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors con...

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Autores principales:	Jordi Heijman, Antonio Zaza, Daniel M Johnson, Yoram Rudy, Ralf L M Peeters, Paul G A Volders, Ronald L Westra
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5b17bf03146049a39498d6762beb9c64
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spelling	oai:doaj.org-article:5b17bf03146049a39498d6762beb9c642021-11-18T05:53:38ZDeterminants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.1553-734X1553-735810.1371/journal.pcbi.1003202https://doaj.org/article/5b17bf03146049a39498d6762beb9c642013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23990775/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3. We developed stochastic implementations of 13 major ionic currents and fluxes in a model of canine ventricular-myocyte electrophysiology. Combined stochastic gating of these components resulted in short- and long-term variability, consistent with experimental data from isolated canine ventricular myocytes. The model indicated that the magnitude of stochastic fluctuations is rate dependent due to the rate dependence of action-potential (AP) duration (APD). This process (the "active" component) and the intrinsic nonlinear relationship between membrane current and APD ("intrinsic component") contribute to the rate dependence of BVR. We identified a major role in physiological BVR for stochastic gating of the persistent Na(+) current (INa) and rapidly activating delayed-rectifier K(+) current (IKr). Inhibition of IKr or augmentation of INa significantly increased BVR, whereas subsequent β-adrenergic receptor stimulation reduced it, similar to experimental findings in isolated myocytes. In contrast, β-adrenergic stimulation increased BVR in simulated long-QT syndrome type 1. In addition to stochastic channel gating, AP morphology, APD, and beat-to-beat variations in Ca(2+) were found to modulate single-cell BVR. Cell-to-cell coupling decreased BVR and this was more pronounced when a model cell with increased BVR was coupled to a model cell with normal BVR. In conclusion, our results provide new insights into the ionic mechanisms underlying BVR and suggest that BVR reflects multiple potentially proarrhythmic parameters, including increased ion-channel stochasticity, prolonged APD, and abnormal Ca(2+) handling.Jordi HeijmanAntonio ZazaDaniel M JohnsonYoram RudyRalf L M PeetersPaul G A VoldersRonald L WestraPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 8, p e1003202 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jordi Heijman Antonio Zaza Daniel M Johnson Yoram Rudy Ralf L M Peeters Paul G A Volders Ronald L Westra Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
description	Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3. We developed stochastic implementations of 13 major ionic currents and fluxes in a model of canine ventricular-myocyte electrophysiology. Combined stochastic gating of these components resulted in short- and long-term variability, consistent with experimental data from isolated canine ventricular myocytes. The model indicated that the magnitude of stochastic fluctuations is rate dependent due to the rate dependence of action-potential (AP) duration (APD). This process (the "active" component) and the intrinsic nonlinear relationship between membrane current and APD ("intrinsic component") contribute to the rate dependence of BVR. We identified a major role in physiological BVR for stochastic gating of the persistent Na(+) current (INa) and rapidly activating delayed-rectifier K(+) current (IKr). Inhibition of IKr or augmentation of INa significantly increased BVR, whereas subsequent β-adrenergic receptor stimulation reduced it, similar to experimental findings in isolated myocytes. In contrast, β-adrenergic stimulation increased BVR in simulated long-QT syndrome type 1. In addition to stochastic channel gating, AP morphology, APD, and beat-to-beat variations in Ca(2+) were found to modulate single-cell BVR. Cell-to-cell coupling decreased BVR and this was more pronounced when a model cell with increased BVR was coupled to a model cell with normal BVR. In conclusion, our results provide new insights into the ionic mechanisms underlying BVR and suggest that BVR reflects multiple potentially proarrhythmic parameters, including increased ion-channel stochasticity, prolonged APD, and abnormal Ca(2+) handling.
format	article
author	Jordi Heijman Antonio Zaza Daniel M Johnson Yoram Rudy Ralf L M Peeters Paul G A Volders Ronald L Westra
author_facet	Jordi Heijman Antonio Zaza Daniel M Johnson Yoram Rudy Ralf L M Peeters Paul G A Volders Ronald L Westra
author_sort	Jordi Heijman
title	Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
title_short	Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
title_full	Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
title_fullStr	Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
title_full_unstemmed	Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
title_sort	determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/5b17bf03146049a39498d6762beb9c64
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Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.

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