Mitochondrial Ca2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Background-Heart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ 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. lsoproterenol-induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ 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 Ca2+ currents, increased Na+-Ca2+ 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 mu mol/L Ru360, a mitochondrial Ca2+ uniporter-specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+-Ca2+ 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 Ca2+ uniporter or the L-type Ca2+ current, consistent with the experimental observations. Conclusions-Mitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.