Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

AbstractBackground/objectivesCardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.MethodsExperiments were conducted in isolated New Zealand white rabbit hearts (2.0–2.5kg, n=25). The effects of CCM (±20mA, 10ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30×30ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.ResultsCCM significantly shortened MAPD close to the stimulation site (Basal: 102±5 [CCM] vs. 131±6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6±0.6 [CCM] vs. 6.1±0.8 [Control] mA, P<0.01) and was correlated (r2=0.40, P<0.01) with increased MAPD dispersion (26±4 [CCM] vs. 5±1 [Control] ms, P