A Multiscale Investigation of Repolarization Variability and Its Role in Cardiac Arrhythmogenesis

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,...

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Bibliographic Details
Published in:Biophysical journal 2011-12, Vol.101 (12), p.2892-2902
Main Authors: Pueyo, Esther, Corrias, Alberto, Virág, László, Jost, Norbert, Szél, Tamás, Varró, András, Szentandrássy, Norbert, Nánási, Péter P., Burrage, Kevin, Rodríguez, Blanca
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Arrhythmias, Cardiac - physiopathology
Cardiac arrhythmia
Cells
Cellular Biophysics and Electrophysiology
Computer Simulation
Dogs
Guinea Pigs
Heart Conduction System - physiopathology
Heart Rate
Humans
Ions
Models, Cardiovascular
Myocytes, Cardiac
Pathology
Physiology
potassium
risk
Species Specificity
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Summary: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 (IKs) 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 IKs in modulating temporal and spatial variability in ventricular repolarization in human and guinea pig. Results show that under physiological conditions: i), stochastic fluctuations in IKs 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 IKs 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 IKs noise at cellular and tissue level, resulting in enhanced ventricular variability and abnormalities in repolarization such as afterdepolarizations and alternans.
ISSN:0006-3495
1542-0086
DOI:10.1016/j.bpj.2011.09.060