Acute and prolonged effects of anti-malarial drugs on mitochondrial respiration in atrial cardiomyocytes for cardiac safety evaluation

Abstract

Malaria is a global public health problem, causing significant morbidity and mortality, particularly in low and middle-income countries (LMICs). While mass drug administration (MDA) programs are central to elimination efforts, their effectiveness is limited by concerns over cardiotoxicity, resistance, and impacts on mitochondrial function. This study investigates the acute and prolonged effects of single and combination anti-malarial drugs on mitochondrial respiration in atrial cardiomyocytes. Treatment with mefloquine (MFQ) and its combinations reduced mitochondrial respiration, suggesting impaired energy generation in cardiomyocytes. Moreover, prolonged exposure to halofantrine (HFN) resulted in significantly lower maximal respiration and spare respiratory capacity, indicating compromised mitochondrial respiration in cardiomyocytes. In contrast, acute and prolonged exposure to amodiaquine (AMD), artemether (ART), chloroquine (CQ), and piperaquine (PPQ) did not lead to significant changes in mitochondrial respiration in atrial cardiomyocytes. Similarly, ivermectin (IVM), an anti-parasitic drug used within malaria treatment programmes, did not cause acute alterations in mitochondrial respiration. However, its prolonged exposure resulted in reduced coupling efficiency while preserving other mitochondrial parameters. These findings provide valuable insights into the effects of anti-malarial drugs on mitochondrial function in cardiomyocytes. Further studies should aim to elucidate the mechanisms by which these drugs and their combinations affect mitochondrial and cellular functions.