Role of KATP Channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts
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 KATP channels in human cardiomyopathic hearts and that KATP channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness.
Method 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. KATP subunit expression was compared between cardiomyopathic versus normal hearts and LV endocardium versus epicardium. 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 KATP subunit on the endocardium compared with the epicardium (P<0.02). In an ischemic rat heart model, transmural dispersion of refractoriness (ΔERPTransmural=ERPEpicardium−ERPEndocardium) was verified with pacing protocols. ΔERPTransmural in control was 5±2 ms and increased to 36±5 ms with ischemia. This effect was greatly attenuated by glibenclamide (ΔERPTransmural for glibenclamide+ischemia=4.9±4 ms, P=0.019 versus control ischemia).
Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation in cardiomyopathic human hearts by attenuating the ischemia-dependent spatiotemporal heterogeneity of refractoriness during early VF.
- Received September 20, 2010.
- Revision received September 25, 2011.
- Accepted September 27, 2011.
- © 2011 American Heart Association, Inc.