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

Abstract

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.