Mitochondrial Ca2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy. Issue 8 (11 September 0207)

• Record Type: Journal Article
• Authors: Xie, An; Song, Zhen; Liu, Hong; Zhou, Anyu; Shi, Guangbin; Wang, Qiongying; Gu, Lianzhi; Liu, Man; Xie, Lai‐Hua; Qu, Zhilin; Dudley, Samuel C.
• Is Part Of: Journal of the American Heart Association. Volume 7:Issue 8(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 0207-09-11
• Subjects: mitochondria -- heart failure -- arrhythmia -- calcium; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.117.007805
• Languages: English
• ISSNs: 2047-9980

Abstract

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.