Abstract
Background and Objectives: Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. The appearance of LF oscillations in ventricular repolarization is, however, not immediate, but it may take up to some minutes. This study seeks to characterize the time course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions.Materials and Methods: A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, β-adrenergic signaling, and mechanics was built. Sympathetic provocation was modeled via phasic changes in β-adrenergic stimulation (β-AS) and mechanical stretch at Mayer wave frequencies within the 0.03–0.15 Hz band.Results: Our results show that there are large inter-individual differences in the time lapse for the development of LF oscillations in APD following sympathetic provocation, with some cells requiring just a few seconds and other cells needing more than 3 min. Whereas, the oscillatory response to phasic mechanical stretch is almost immediate, the response to β-AS is much more prolonged, in line with experimentally reported evidences, thus being this component the one driving the slow development of APD oscillations following enhanced sympathetic activity. If β-adrenoceptors are priorly stimulated, the time for APD oscillations to become apparent is remarkably reduced, with the oscillation time lapse being an exponential function of the pre-stimulation level. The major mechanism underlying the delay in APD oscillations appearance is related to the slow IKs phosphorylation kinetics, with its relevance being modulated by the IKs conductance of each individual cell. Cells presenting short oscillation time lapses are commonly associated with large APD oscillation magnitudes, which facilitate the occurrence of pro-arrhythmic events under disease conditions involving calcium overload and reduced repolarization reserve.Conclusions: The time course of LF oscillatory behavior of APD in response to increased sympathetic activity presents high inter-individual variability, which is associated with different expression and PKA phosphorylation kinetics of the IKs current. Short time lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions.
Highlights
Ventricular repolarization has been shown to exhibit a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity
It is clear that the magnitude of the oscillations is different for the two cells and the time lapse required for LF oscillations of AP duration (APD) to become evident is remarkably distinct
Inter-individual differences in the ionic characteristics of the virtual cells had an impact on τAPD, which ranged from just a few seconds for some virtual cells to more than 3 min for other cells
Summary
Ventricular repolarization has been shown to exhibit a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity. Subsequent studies have investigated inter-individual differences in LF oscillations of ventricular APD, concluding that calcium and potassium currents, ICa and IK (the rapid delayed rectifier IKr and inward rectifier IK1), are major ionic modulators of such inter-individudal differences (Sampedro-Puente et al, 2019). These identified ionic factors are key for the development of arrhythmic events following enhancement of APD oscillations’ magnitude. Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. This study seeks to characterize the time course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions
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