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

Abstract

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.

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology

“…6 shows example APs simulated for control (blue traces) and following block of I Kr caused by application of a 0.01 μM concentration of dofetilide (red traces). I Kr block caused by dofetilide induces both APD prolongation and increased APD variability, in agreement with previous studies (11). Fig.…”

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…By this approach, we have documented that, together with depressed diastolic performance, reduction in Kv K + and L‐type Ca 2+ current densities, protracted electrical recovery, and enhanced temporal dispersion of repolarization are initial functional defects of the myocardium dictated by diabetes. The process linking reduced ionic currents with the enhanced beat‐to‐beat variability of electrical recovery of the diabetic heart may involve complex multiscale mechanisms, from ion channels to the whole organ 22, 23, 54, 55. The reduced repolarizing effect of Kv currents has attenuated the repolarization reserve of diabetic myocytes, potentially unmasking fluctuations of ionic currents caused by stochastic behavior of ion channel gating, normally concealed by K + efflux.…”

Techniques for Ventricular Repolarization Instability Assessment From the ECG

“…The use of combined experimental and computational approaches can be a useful tool for such investigations [82]. In [83], [84] and [85] it was hypothesized that fluctuations in ionic currents caused by stochasticity in ion channel behavior contribute to variability in cardiac repolarization, particularly under pathological conditions. Also it was postulated that electrotonic interactions through intercellular coupling act to mitigate spatiotemporal variability in repolarization dynamics in tissue, as compared to isolated cells.…”

“…Also it was postulated that electrotonic interactions through intercellular coupling act to mitigate spatiotemporal variability in repolarization dynamics in tissue, as compared to isolated cells. The approaches taken in [83], [84] and [85] combine experimental and computational investigations in human, guinea pig and dog. Multiscale stochastic models of ventricular electrophysiology are used, bridging ion channel numbers to whole organ behavior.…”