Mitochondrial Ca Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy.

BACKGROUND

Heart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca handling is thought to underlie triggered activity, and mitochondria participate in Ca 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 transients, increased mitochondrial Ca 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 currents, increased Na-Ca exchange currents, and decreased total K currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca uniporter-specific antagonist, could reduce mitochondrial Ca transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca uniporters inhibited mitochondrial Ca uptake, reduced Na-Ca 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 uniporter or the L-type Ca current, consistent with the experimental observations.

CONCLUSIONS

Mitochondrial Ca handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.