Abstract 15510: Mitochondrial Ca2+ Flux Contributes to Arrhythmias in Nonischemic Cardiomyopathy Mice
Mitochondria participate in Ca2+ homeostasis and Ca2+ oscillations are thought to be involved in arrhythmogenesis. Nevertheless, the role of mitochondria in arrhythmogenesis is unclear. We investigated the role of mitochondrial Ca2+ handling in arrhythmias in a model of nonischemic cardiomyopathy.
Methods: Nonischemic cardiomyopathy was induced in C57BL6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Cardiomyopathy was evaluted by echocardiography. ECG telemetry recorded arrhythmias from 7 DOCA mice and 7 sham mice at 6 weeks after DOCA treatment. Action potentials (APs) were recorded by perforated current-clamp in isolated mouse ventricular cells. K+ and L-type Ca2+ currents were measured by voltage-clamp. Changes in cytoplasmic and mitochondrial Ca2+ were determined by fluorescent imaging using Fluo-4 and Rhod-2 respectively.
Results: The left ventricular volume was significantly enlarged (105±4 vs. 88±6μL), and the ejection fraction was prominently reduced (37±2% vs.49±4%) in DOCA mice. Isoproteranol-induced premature ventricular contractions (PVCs) were more prevalent in DOCA mice than sham controls (7 vs. 2 with i.p. 0.2mg/kg, p<0.05). At 2.5mg/kg, only DOCA mice showed induced ventricular fibrillation. QTc significantly elongated from 42±1 in sham mice to 52±2 ms in DOCA mice. Myocytes showed decreased Ca2+ transients, a significant increase in the APD90 from 67±21 to 242±45ms, explained by augmented L-type Ca2+ current, increased NCX current, and decreased total K+ current. DOCA ventricular myocytes, 66%, showed EADs compared with 17% of sham myocytes (p<0.05). EADs could be abolished by 10 μM Ru360, a mitochondrial calcium uniporter specific antagonist. Ru360 had no effect on L-type Ca2+ current and total K+ currents. Ru360 inhibited mitochondrial Ca2+ uptake and reduced NCX currents in DOCA mice vetricular cells, implicating mitochondrial Ca2+ handling in modulating the arrhythmic risk by inhibting NCX.
Conclusions: Mitochondrial Ca2+ handling plays an important role in triggered activity seen with nonischemic cardiomyopathy and may represent a novel therapeutic target to reduce arrhythmic risk in this condition.
- © 2013 by American Heart Association, Inc.