Mitochondrial Ca(2+) Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

BACKGROUND: Heart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca(2+) handling is thought to underlie triggered activity, and mitochondria participate in Ca(2+) homeostasis. METHODS AND RESULTS: A model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca(2+) transients, increased mitochondrial Ca(2+) transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca(2+) currents, increased Na(+)‐Ca(2+) exchange currents, and decreased total K(+) currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca(2+) uniporter–specific antagonist, could reduce mitochondrial Ca(2+) transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca(2+) uniporters inhibited mitochondrial Ca(2+) uptake, reduced Na(+)‐Ca(2+) exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca(2+) uniporter or the L‐type Ca(2+) current, consistent with the experimental observations. CONCLUSIONS: Mitochondrial Ca(2+) handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.