Role of K ATP Channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts

Abstract

Rationale: Ventricular fibrillation (VF) leads to global ischemia. The modulation of ischemia-dependent pathways may alter the electrophysiological evolution of VF. Objective: We addressed the hypotheses that there is regional disease-related expression of K ATP channels in human cardiomyopathic hearts and that K ATP channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness. Methods and Results: In a human Langendorff model, electric mapping of 6 control and 9 treatment (10 μmol/L glibenclamide) isolated cardiomyopathic hearts was performed. Spontaneous defibrillation was studied and mean VF cycle length was compared regionally at VF onset and after 180 seconds between control and treatment groups. K ATP subunit gene expression was compared between LV endocardium versus epicardium in myopathic hearts. Spontaneous VF termination occurred in 1 of 6 control hearts and 7 of 8 glibenclamide-treated hearts ( P =0.026). After 180 seconds of ischemia, a transmural dispersion in VF cycle length was observed between epicardium and endocardium ( P =0.001), which was attenuated by glibenclamide. There was greater gene expression of all K ATP subunit on the endocardium compared with the epicardium ( P <0.02). In an ischemic rat heart model, transmural dispersion of refractoriness (ΔERP Transmural =ERP Epicardium −ERP Endocardium ) was verified with pacing protocols. ΔERP Transmural in control was 5±2 ms and increased to 36±5 ms with ischemia. This effect was greatly attenuated by glibenclamide (ΔERP Transmural for glibenclamide+ischemia=4.9±4 ms, P =0.019 versus control ischemia). Conclusions: K ATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of K ATP channels promotes spontaneous defibrillation in cardiomyopathic human hearts by attenuating the ischemia-dependent spatiotemporal heterogeneity of refractoriness during early VF.