Transmural IK(ATP) heterogeneity as a determinant of activation rate gradient during early ventricular fibrillation: Mechanistic insights from rabbit ventricular models

Abstract

Activation rate (AR) gradients develop during ventricular fibrillation (VF), with the highest AR on the surface near Purkinje system (PS) terminals (endocardium in humans and rabbits and epicardium in pigs). The application of glibenclamide to block adenosine triphosphate (ATP)-sensitive potassium current (IK(ATP)) before VF induction eliminates transmural AR gradients and prevents the induction of sustained arrhythmia. It remains unclear whether the PS, which is resistant to ischemia, is also a factor in AR heterogeneity. To dissect IK(ATP) and PS contributions to AR gradients during VF by using detailed computer simulations. We constructed rabbit ventricular models with either subendocardial or subepicardial PS terminals. Physiologically relevant IK(ATP) gradients were implemented, and early VF was induced and observed. Prominent AR gradients were observed only in models with large IK(ATP) gradients. The critical underlying factor of AR gradient maintenance was refractoriness in low-IK(ATP) regions, which blocked the propagation of action potentials from high-IK(ATP) regions. The PS played no role in transmural AR gradient maintenance, but did cause local spatial heterogeneity of AR on the surface adjacent to terminals. Simulated glibenclamide application during VF led to spontaneous arrhythmia termination within a few seconds in most cases, which builds on previous experimental findings of anti-VF properties of glibenclamide pretreatment. Differential IK(ATP) across the ventricular wall is an important factor underlying AR gradients during VF; thus, higher epicardial AR in pigs is most likely due to an abundance of epicardial IK(ATP). For terminating early VF, our results suggest that IK(ATP) modulation is a stronger target than Purkinje ablation.