Enhanced Calcium Uptake into Mitochondria Mitigates Ventricular Arrhythmia in Heart Failure

Abstract

An aberrant increase in diastolic calcium（Ca2+）level is a hallmark of heart failure（HF）and the cause of delayed afterdepolarization and ventricular arrhythmia（VA）. Although mitochondria play a crucial role in Ca2+ regulation, their ability to counteract or compensate for aberrant increases in cytosolic Ca2+ levels, which frequently occur in HF, remains unclear. Therefore, we investigated whether enhanced Ca2+ uptake of mitochondria may compensate for abnormal increases in the Ca2+ of ventricular myocytes in HF to effectively mitigate VA. We used a HF mouse model in which myocardial infarction was induced by permanent left anterior descending coronary artery ligation. The mitochondrial Ca2+ uniporter（MCU）was stimulated by kaempferol. Ca2+ dynamics and membrane potential were measured using an epifluorescence microscope, a confocal microscope, and the perforated patch-clamp technique. We analyzed the inducibility of VA in Langendorff-perfused hearts and in mice administered kaempferol using an implantable osmotic minipump. Hemodynamic parameters were measured using a microtip transducer catheter. Protein expression of MCU did not change between HF and sham mice. Treatment of cardiomyocytes with kaempferol, isolated from HF mice at 28 days after coronary ligation, reduced the appearance of aberrant diastolic Ca2+ waves and sparks and spontaneous action potentials. Kaempferol effectively reduced the inducibility of VA. Intravenous administration of kaempferol did not markedly affect left ventricular hemodynamic parameters. The effects of kaempferol in HF of mice implied that mitochondria may have the potential to compensate for abnormal Ca2+. Mechanisms involved in mitochondrial Ca2+ uptake may provide novel targets to treat HF-associated VA.