Inhibiting Mitochondrial Na+/Ca2+ Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure

Rationale:In cardiomyocytes from failing hearts, insufficient mitochondrial Ca2+ accumulation secondary to cytoplasmic Na+ overload decreases NAD(P)H/NAD(P)+ redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca2+ with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na+/Ca2+ exchanger. Objective:Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). Methods and Results:Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily β-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pres...