CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte.

Yasmin L. Hashambhoy, Raimond L. Winslow, Joseph L. Greenstein

Research output: Contribution to journalArticle

Abstract

Cardiac voltage-gated Na(+) channels underlie membrane depolarization during the upstroke of the action potential (AP). These channels also exhibit a late, slowly-inactivating component of current (late I(Na)) that may be enhanced under pathological conditions such as heart failure, and may therefore promote AP prolongation and increase the likelihood of arrhythmia. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functionally modifies Na(+) channels, however it remains unclear if the CaMKII-dependent changes in late I(Na) are a major contributor to cellular arrhythmias such as early after depolarizations (EADs). In this study we develop a model of I(Na), including CaMKII-dependent effects, based on experimental measurements. The Na(+) channel model is incorporated into a computational model of the whole myocyte which describes excitation-contraction coupling via stochastic simulation of individual Ca(2+) release sites. Simulations suggest that relatively small augmentation of late I(Na) is sufficient to significantly prolong APs and lead to the appearance of EADs.

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ASJC Scopus subject areas

  • Signal Processing
  • Biomedical Engineering
  • Computer Vision and Pattern Recognition
  • Health Informatics

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