Abstract
Background/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<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation. ConclusionsCCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.
Highlights
We have previously demonstrated that the acute effects of contractility modulation (CCM) are mediated via stimulated norepinephrine (NE) release resulting in cardiac β1-adrenoceptor activation and shortening of locally recorded monophasic action potential duration (MAPD); in the crystalloid perfused normal rabbit heart [4]
Contact MAPD was measured at 90% repolarisation (MAPD90) averaged over 20-cardiac cycles recorded during steady state before and immediately on cessation of CCM stimulation due to signal interference from the current used during CCM
Analysis of left ventricular (LV) epicardial pacing, when basal CCM data are removed from the dataset, reveals a trend of correlation between Ventricular fibrillation threshold (VFT) and max-min monophasic action potential duration at 90% repolarization (MAPD90) dispersion (Fig. 5Eiii), similar to that seen with LV and RV endocardial pacing
Summary
We have previously demonstrated that the acute effects of CCM are mediated via stimulated norepinephrine (NE) release resulting in cardiac β1-adrenoceptor activation and shortening of locally recorded monophasic action potential duration (MAPD); in the crystalloid perfused normal rabbit heart [4]. Efferent and afferent sympathetic and parasympathetic nerves richly innervate the cardiac ventricle and it has long been known that afferent nerves relay sensory information from the myocardium to the intracardiac and intra-thoracic ganglia, spinal cord and the brain for integration to regulate cardiac function [5]. The aims of this study were to investigate: 1) the role of pre and post-ganglionic signalling in CCM, 2) any role for ACh in modulating the acute ventricular response to CCM and 3) the effects of CCM on ventricular electrophysiology and arrhythmia susceptibility
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