Abstract 16567: Mitochondrial Ca2+ Influx Contributes to Early After Depolarizations in Nonischemic Cardiomyopathic Mice
Introduction: Heart failure (HF) is associated with increased arrhythmic risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.
Hypothesis: Therefore, we tested whether mitochondrial Ca2+ flux contributed to early afterdepolarizations (EADs) in HF.
Methods: A model of nonischemic HF (NI-HF) was induced in C57BL/6 mice by hypertension. Tail-cuff plethysmography, echocardiography, ECG telemetry, patch-clamp, cytoplasmic (and mitochondrial) Ca2+ transient measurement, real-time PCR and Western blotting techniques were used.
Results: The left ventricular end-diastolic volume was significantly enlarged and the ejection fraction was substantially reduced in cardiomyopathic mice. Meanwhile, NI-HF mice developed a significant augmentation of both systolic and diastolic blood pressure. Isoproterenol-induced premature ventricular contractions and ventricular fibrillation were more prevalent in NI-HF mice than sham controls. Isolated myopathic myocytes showed a substantial decreased cytoplasmic Ca2+ transients, a prominent increased mitochondrial Ca2+ transients and a significant increase in the action potential duration at 90% repolarization (APD90). The alteration of APD90 was consistent with in vivo QTc elongation and could be explained by augmented L-type Ca2+ currents, increased Na+-Ca2+ exchange currents (NCX) and decreased total K+ currents. Sixty-six percent of myopathic ventricular myocytes showed EADs compared with 17% of sham myocytes (p<0.05). Intracellular application of 1 μM Ru360, a mitochondrial Ca2+ uniporter (MCU) specific antagonist, could reduce mitochondrial Ca2+ transients, decrease APD90 and ameliorate EADs. Furthermore, knock down MCU could inhibit mitochondrial Ca2+ uptake, reduce NCX, decrease APD90 and depress EADs in NI-HF mice ventricular cells which led to less ventricular fibrillation in NI-HF mice, implicating mitochondrial Ca2+ handling in modulating the arrhythmic risk through NCX induced EADs.
Conclusions: Mitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a novel therapeutic target to reduce arrhythmic risk in this condition.
Author Disclosures: A. Xie: None. H. Liu: None. A. Zhou: None. G. Shi: None. M. Liu: None. C. Rutledge: None. E. Jeong: None. S.C. Dudley: None.
- © 2016 by American Heart Association, Inc.