Abstract
AimsAcute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia. Methods and resultsA human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase. ConclusionsElectrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.
Highlights
Acute ischemia associated with coronary heart disease is a leading cause of sudden arrhythmic death
Simulations show the establishment of macro-reentry around the ischemic region in the human ventricles following premature excitation during the vulnerable window (VW) for all levels of repolarization reserve
High-resolution simulation data obtained with an anatomicallybased model of the regionally-ischemic human ventricles reveal, for the first time, the electrotonic trigger of early afterdepolarizations (EADs) and their contribution to transmural reentry and increased arrhythmic risk under conditions of reduced repolarization reserve
Summary
Acute ischemia associated with coronary heart disease is a leading cause of sudden arrhythmic death. Electrotonic interactions in well coupled tissue (as is still the case in the early phase of acute ischemia) are known to decrease the propensity of EAD formation in tissue (Weiss et al, 2010; Xie et al, 2010), even if they can be triggered in single cells as in Verkerk et al (2000). It remains unclear what conditions are needed for EADs to be triggered by electrotonic current, as well as the role of EAD formation in the regionally ischemic human heart
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