Journal
HEART RHYTHM
Volume 19, Issue 10, Pages 1725-1735Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2022.05.034
Keywords
Calcium waves; Delayed afterdepolarization; Heart failure; Mitochondrial calcium uniporter; Mitochondrial calcium uptake; Ventricular arrhythmia
Categories
Funding
- Japan Society for the Promotion of Science KAKENHI [18K08058, 18K15874, 19K17584]
- U.S. National Institutes of Health [R01GM071779]
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The study aimed to investigate whether enhanced Ca2+ uptake of mitochondria could compensate for an abnormal increase in the diastolic calcium concentration ([Ca2+] ;) in ventricular myocytes in heart failure (HF) to effectively mitigate ventricular arrhythmia (VA). The results demonstrated that stimulating the mitochondrial Ca2+ uniporter could reduce the abnormal [Ca2+] ; induced by HF and effectively decrease the occurrence of VA. This finding provides a novel therapeutic target for treating HF-associated VA.
BACKGROUND An aberrant increase in the diastolic calcium concentration ([Ca2+] ; ) level is a hallmark of heart failure (HF) and the cause of delayed afterdepolarization and ventricular arrhythmia (VA). Although mitochondria play a role in regulating [Ca2+] ; , whether they can compensate for the [Ca2+] ; abnormality in ventricular myocytes is unknown. OBJECTIVE The purpose of this study was to investigate whether enhanced Ca2+ uptake of mitochondria may compensate for an abnormal increase in the [Ca2+] ; of ventricular myocytes in HF to effectively mitigate VA. METHODS We used a HF mouse model in which myocardial infarction was induced by permanent left anterior descending coronary artery ligation. The mitochondrial Ca2+ uniporter was stimulated by kaempferol. Ca2+ dynamics and membrane potential were measured using an epifluorescence microscope, a confocal microscope, and the perforated patch-damp technique. VA was induced in Langendorff-perfused hearts, and hemodynamic parameters were measured using a microtip transducer catheter. RESULTS Protein expression of the mitochondrial Ca2+ uniporter, as assessed by its subunit expression, did not change between HF and sham mice. Treatment of cardiomyocytes with kaempferol, isolated from HF mice 28 days after coronary ligation, reduced the appearance of aberrant diastolic [Ca2+] ; waves and sparks and spontaneous action potentials. Kaempferol effectively reduced VA occurring in Langendorff-perfused hearts. Intravenous administration of kaempferol did not markedly affect left ventricular hemodynamic parameters. CONCLUSION 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 for treatment of HF-associated VA. (C) 2022 Heart Rhythm Society. All rights reserved.
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