Cardiac and extra-cardiac side effects of common antiarrhythmic agents might be related to drug-induced mitochondrial dysfunction. Supratherapeutic doses of amiodarone have been shown to impair mitochondria in animal studies, whilst influence of propafenone on cellular bioenergetics is unknown. We aimed to assess effects of protracted exposure to pharmacologically relevant doses of amiodarone and propafenone on cellular bioenergetics and mitochondrial biology of human and mouse cardiomyocytes. In this study, HL-1 mouse atrial cardiomyocytes and primary human cardiomyocytes derived from the ventricles of the adult heart were exposed to 2 and 7 μg/mL of either amiodarone or propafenone. After 24 h, extracellular flux analysis and confocal laser scanning microscopy were used to measure mitochondrial functions. Autophagy was assessed by western blots and live-cell imaging of lysosomes. In human cardiomyocytes, amiodarone significantly reduced mitochondrial membrane potential and ATP production, in association with an inhibition of fatty acid oxidation and impaired complex I- and II-linked respiration in the electron transport chain. Expectedly, this led to increased anaerobic glycolysis. Amiodarone increased the production of reactive oxygen species and autophagy was also markedly affected. In contrast, propafenone-exposed cardiomyocytes did not exert any impairment of cellular bioenergetics. Similar changes after amiodarone treatment were observed during identical experiments performed on HL-1 mouse cardiomyocytes, suggesting a comparable pharmacodynamics of amiodarone among mammalian species. In conclusion, amiodarone but not propafenone in near-therapeutic concentrations causes a pattern of mitochondrial dysfunction with affected autophagy and metabolic switch from oxidative metabolism to anaerobic glycolysis in human cardiomyocytes.

Department of Anaesthesia and Intensive Care of The 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

Department of Anaesthesia and Intensive Care of The 3rd Faculty of Medicine and Královské Vinohrady University Hospital OXYLAB Laboratory for Mitochondrial Physiology Charles University Prague Czech Republic

Department of Anaesthesia and Intensive Care of The 3rd Faculty of Medicine and Královské Vinohrady University Hospital OXYLAB Laboratory for Mitochondrial Physiology Charles University Prague Czech Republic; Department of Pharmacology of The 2nd Medical Faculty Charles University Prague Czech Republic

Department of Biochemistry Cell and Molecular Biology and Centre for Research on Nutrition Metabolism and Diabetes 3rd Faculty of Medicine Charles University Prague Czech Republic

References provided by Crossref.org

Personalizing beta-blockade in septic shock: finding the right rhythm and rate for the right patient