Cardiac contractility modulation (CCM) is an electrical therapy under investigation for heart failure (HF) where electrical signals are applied during ventricular refractoriness[1]. We have previously shown the acute effects of CCM via stimulated noradrenaline (NA) release, β1-adrenoceptor activation causing shortening of monophasic action potential duration (MAPD) [2]. Adrenergic activation is known to increase arrhythmia vulnerability hence it is important to determine the effects of CCM on ventricular arrhythmia susceptibility. The aims of this study were to determine the effects of CCM on ventricular fibrillation threshold (VFT). Experiments were conducted on New Zealand white rabbit hearts (2.5-3Kg,n=10). Animals were pre-medicated with ketamine (10mg/kg), medetomidine hydrochloride (0.2mg/kg) and butorphanol (0.05mg/kg) (i.m.) and killed by sodium pentobarbitone overdose (111mg/kg, i.v.) with heparin (1000IU). Hearts were excised and perfused under constant flow (40ml/min). CCM signals were applied to the left ventricle (LV) (amplitude=20mA, duration=20ms), timed to coincide with the plateau of a local MAP. The effects of CCM on LV basal (CCMB) and apical (CCMA) MAPD were assessed during pacing (200bpm). Susceptibility to ventricular fibrillation (VF) was assessed using VFT, defined as the minimum current required to induce sustained VF with rapid pacing (30x30ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (MET,1.8μM). Spatial effects of CCM on LV APD were assessed using optical mapping with di-4-ANNEPS. Data represent mean±SEM. CCM caused a shortening of MAPD (n=6) from baseline [BL] close to the site of delivery during both CCMB (105±5[CCMB] vs. 127±5[BL] ms, P<0.001) and CCMA (109±4[CCMA] vs. 131±5[BL] ms, P<0.05). In both cases this resulted in an increase in MAPD apico-basal (max-min) dispersion. VFT was reduced from 5.6±0.4 mA to 4.3±0.6 mA (P<0.01) and 4.6±0.2mA (P<0.05) during CCMB and CCMA respectively. Decreased VFT was correlated with increased MAPD dispersion (r2=0.29, P<0.05,n=6). The effects of CCM on MAPD (131±4[MET+CCMB] vs. 128±2[MET] ms, P>0.05) and VFT (5.4±0.8[MET+CCM(B)] vs. 5.4±0.7MET] ms, P>0.05) were abolished during MET perfusion (n=6). Optical mapping studies revealed a greater range of CCM induced shortening with basal stimulation than with apical stimulation (Fig. 1,n=4). We show that CCM increases susceptibility to ventricular fibrillation via a β1-adrenoceptor mechanism that is related to an increase in MAPD dispersion. These data are in keeping with the known pro-arrhythmic consequences of adrenergic activation. Differential responses to CCM may reflect regional distribution of sympathetic nerves, ion channels and/or coronary flow. The localised effects of CCM, promoting heterogeneities of repolarisation, raises concern over its clinical use.