What is the clinical evidence from this study?

Study design: Other. Population: Acute regional ischemia. Intervention: IKr reduction (reduced repolarization reserve) vs. 0% IKr reduction (control). Primary outcome: Vulnerable window (VW) for reentry (reduced by 23.5%).

January 1, 2016Open Access

Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

Key Result

In a simulated human ventricular model of acute regional ischemia, a 30% reduction in IKr reduced the vulnerable window for reentry by 23.5% (from 85 ms to 65 ms), whereas a 50% reduction facilitated transmural reentry via electrotonically-triggered early afterdepolarizations.

Structured PICO

Does reduced repolarization reserve (IKr block) increase the vulnerable window for reentry in a human ventricular model of acute regional ischemia?

Population

Computer-based biophysically-detailed model of human ventricles with acute regional ischemia.

Intervention

Reduced repolarization reserve via 30% and 50% reduction of rapidly activating delayed rectifying potassium current (IKr)

Comparator

Normal repolarization reserve (0% IKr reduction)

Outcome

Vulnerable window (VW) for reentry following ectopy at the ischemic border zonesurrogate

Severe reduction in repolarization reserve in a computational model of acute ischemia promotes transmural reentry driven by electrotonically-triggered early afterdepolarizations.

Main Result

Effect estimate: reduced by 23.5%

Absolute Event Rate: 65% vs 85%

Limitations

Investigated primarily mechanistic aspects using a single human ventricles model given computational demands.
Considered only one size, location and severity of the ischemic region.
The Purkinje system was not included in the model.
Did not analyze biophysical mechanisms leading to ectopic excitation.
Did not investigate the potentially important implications of beta-adrenergic stimulation.

Abstract

AIMS: Acute 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 RESULTS: A 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. CONCLUSIONS: Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.

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