Abstract 2867: Inhibition of Mitochondrial Na+/Ca2+Exchange Suppresses Arrhythmias and Heart Failure-associated Sudden Cardiac Death
Recent studies indicate that mitochondria Ca2+([Ca2+]m) dynamics plays a key role in energy supply and demand balance in isolated cardiac myocytes. We previously demonstrated that increased cytoplasmic Na+(e.g., in failing heart cells or ouabain-treated cells) or inhibition of [Ca2+]m uptake oxidizes mitochondrial NADH/NAD+, increases oxidative stress, and alters cytoplasmic Ca2+handling when workload increases, with profound effects on myocyte function including increases in spontaneous Ca2+release and delayed afterdepolarizations. Partial inhibition of [Ca2+]m efflux with CGP-37157 (CGP) enhanced [Ca2+]m retention, prevented the detrimental redox changes, and abrogated the abnormal Ca2+responses. Here, we determined if in vivo CGP treatment similarly prevents catecholamine-induced arrhythmias and sudden cardiac death in a guinea-pig model of heart failure (HF; ascending aortic banding). Cardiac arrhythmias were induced by i.p. injection of 1mg/kg isoproterenol (ISO) and surface ECGs were recorded either with or without CGP pretreatment (0.02 or 0.1mg/kg injected 10 min prior to ISO). The incidence of premature ventricular beats (PVB) and ventricular tachycardia (VT) was determined for the 60-min period following ISO administration. CGP had no effect on heart rate (Baseline HR [bpm]: Control=270±14; CGP[0.02]=295±23; CGP[0.1]=277±20; ISO HR: Control=386±7; CGP[0.02]=398±8; CGP[0.1]=372±9). In the absence of CGP, ISO dramatically increased PVB and VT (PVB: 550±5/hr; VT episodes: 35±0.3/hr), whereas CGP significantly reduced the incidence of PVB and VT in a concentration-dependent way (CGP [0.02]: PVB: 282±80/hr, VT episodes: 16±4.3/hr, p<0.001, n=4; CGP [0.1]: PVB: 95±37/hr; VT episode: 4±1.8/hr, p<0.001, n=5). Arrhythmia susceptibility was also examined in HF animals with chronic CGP treatment (via i.p. implanted osmotic pump; delivery rate: 0.03mg/kg/hr). 3 days after surgery, animals were challenged with 5 mg/kg ISO (i.p. injection). In the absence of CGP, 78% of HF animals died due to sudden cardiac death, whereas only 25% of animals died in the CGP treated group (p<0.05). Our results indicate that CGP can attenuate ISO-induced arrhythmias and decrease the incidence of sudden cardiac death.