A multiscale investigation of repolarization variability and its role in cardiac arrhythmogenesis

Esther Pueyo, Alberto Corrias, László Virág, Norbert Jost, Tamás Szél, András Varró, Norbert Szentandrássy, Péter P. Nánási, Kevin Burrage, Blanca Rodríguez

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75 Citations (Scopus)


Enhanced temporal and spatial variability in cardiac repolarization has been related to increased arrhythmic risk both clinically and experimentally. Causes and modulators of variability in repolarization and their implications in arrhythmogenesis are however not well understood. At the ionic level, the slow component of the delayed rectifier potassium current (I Ks) is an important determinant of ventricular repolarization. In this study, a combination of experimental and computational multiscale studies is used to investigate the role of intrinsic and extrinsic noise in I Ks in modulating temporal and spatial variability in ventricular repolarization in human and guinea pig. Results show that under physiological conditions: i), stochastic fluctuations in I Ks gating properties (i.e., intrinsic noise) cause significant beat-to-beat variability in action potential duration (APD) in isolated cells, whereas cell-to-cell differences in channel numbers (i.e., extrinsic noise) also contribute to cell-to-cell APD differences; ii), in tissue, electrotonic interactions mask the effect of I Ks noise, resulting in a significant decrease in APD temporal and spatial variability compared to isolated cells. Pathological conditions resulting in gap junctional uncoupling or a decrease in repolarization reserve uncover the manifestation of I Ks noise at cellular and tissue level, resulting in enhanced ventricular variability and abnormalities in repolarization such as afterdepolarizations and alternans.

Original languageEnglish
Pages (from-to)2892-2902
Number of pages11
JournalBiophysical journal
Issue number12
Publication statusPublished - Dec 21 2011

ASJC Scopus subject areas

  • Biophysics

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