Abstract
Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. The mechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potential measurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, Ito1, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, IKs. In contrast, IKs and the L-type calcium current, ICaL, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassium current, IKr. This highlights both IKs and Ito1 as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of Ito1 channel numbers as an important independent determinant of the magnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of IKs and ICaL channels only become independent determinants of the magnitude of BVR upon complete inhibition of IKr. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition.
Highlights
As with many biological systems, variability in cardiac activity has been experimentally reported at a wide range of temporal and spatial scales from the molecular to the whole organ level [1], [2], [3], [4], [5], [6]
It is important to highlight that for the 17 models, the action potentials (APs) duration (APD) was in range (Fig 2) and the change in APD produced by each of the four pharmacological interventions was in range with experimental data
We develop a methodology to construct experimentally-calibrated sets of stochastic canine AP models and we investigate the contribution of four main ionic currents (IKr, IKs, Ito1, inward calcium current (ICaL)) to several measures of beat variability in repolarization duration (BVR) in control and following pharmacological ionic channel inhibition
Summary
As with many biological systems, variability in cardiac activity has been experimentally reported at a wide range of temporal and spatial scales from the molecular to the whole organ level [1], [2], [3], [4], [5], [6]. Even the same cell exhibits beat-to-beat temporal electrophysiological variability, possibly caused by small random ionic current fluctuations arising from transitions between their channels’ states. BVR in isolated cells may represent a pro-arrhythmia indicator in conditions of reduced repolarization reserve caused by drugs, mutations or disease, and impaired intercellular coupling, both known to enhance variability and pro-arrhythmic abnormalities in the heart [2], [13]. Understanding the ionic mechanisms underlying BVR in isolated cells may help to inform its use as an arrhythmic risk biomarker (for example for drug testing), and to better understand its causal relationship with arrhythmia in conjunction with other mechanisms [14], [15]
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