Abstract 14553: Mitochondrial Calcium Uptake via Mitochondrial Calcium Uniporter Suppress Ventricular Arrhythmia in the Ischemic Heart Failure Mice

Background: Delayed after depolarization by calcium (Ca 2+ ) leak from sarcoplasmic reticulum (SR) via Ryanodine receptor is one of the causes of ventricular arrhythmias (VAs) in heart failure (HF). Ca 2+ uptake into mitochondria via mitochondrial calcium uniporter (MCU) is participated in Ca 2+ handling, but the relationship between VAs in HF and Ca 2+ uptake into mitochondria is unclear. Purpose: We sought to investigate whether increased Ca 2+ uptake into mitochondria via MCU reduces diastolic Ca 2+ leak and suppresses VAs in ischemic HF mice. Methods: Ten-week-old male C57BL/6J mice were divided into 2 groups; sham operation mice (Sham) or HF mice (HF) in which myocardial infarction was induced by left coronary artery ligation. After 4-6 weeks, cardiomyocyte or mitochondria were isolated respectively from the myocardium of Sham and the non-infarct myocardium of HF. Ca 2+ waves (CaWs) were measured on an epifluorescence microscopy. Calcium transients and calcium sparks were measured on a confocal microscope in linescan mode. Mitochondrial Ca 2+ uptake were measured by estimating the extra-mitochondrial Ca 2+ reduction with Fluo-5N on a spectrofluoro-photometer. VAs was induced in the Langendorff perfused hearts. Left ventricular (LV) pressure was measured using a microtip transducer catheter . Results: HF mice showed left ventricular dysfunction and increased heart and lung weights compared to Sham. Kaempferol, a MCU activator, increased mitochondrial Ca 2+ uptake in the isolated mitochondria both in Sham and HF. CaWs and Ca spark frequency in the presence of isoproterenol was attenuated by 10 μM Kaempferol. Kaempferol did not show significant changes in Ca 2+ transient amplitude, however increased the time to 50% decay significantly. The incidence of induced VAs was suppressed by Kaempferol. In vivo measurements, intravenous administration of Kaempferol (5mg/kg) did not show significant changes in hemodynamic parameters in HF mice. Conclusions: Ca 2+ uptake into mitochondria via MCU suppresses VAs in HF. Despite the adverse influence of the traditional antiarrhythmic drugs for HF condition, a novel strategy that promotes Ca 2+ uptake into mitochondria might be a potential therapeutic approach for VA treatment in HF patients.