Reduced mitochondrial respiration caused by antimalarial treatments in human ventricular cardiomyocytes

Background

Malaria is still a global public health risk, with the leading cause of parasitic death. For the prevention of malaria, antimalarial agents with diverse mechanisms of action are used, and to avoid the development of drug resistance, combination therapy involving multiple agents is often utilized. Many antimalarial drugs have known cardiac electrophysiological effects, which include various mild heart rate changes to excessive prolongation of the QT interval which may lead to fetal ventricular arrhythmic outcomes such as Torsades de Pointes (TdP) or sudden cardiac death. However, there are major deficiencies in available data bearing on their possible pro-arrhythmic effects; while several cardiac toxicities have been identified using single anti-malarial therapies, the effect of combination therapy remains insufficiently characterized.

Purpose

In this study, we aim to determine whether single antimalarial drug and combination therapies induce pro-arrhythmic alterations through impaired mitochondrial respiratory function in ventricular cardiomyocytes.

Methods

We investigated acute and prolonged effects of single antimalarial drugs and piperaquine-based combination therapy at plasma-level concentrations on mitochondrial respiration in human induced pluripotent stem cell (iPSC)-derived ventricular cardiomyocytes using a Seahorse extracellular flux analyzer and assessed reactive oxygen species (ROS) production by performing MitoSox staining.

Results

The results show that halofantrine reduces basal mitochondrial respiration and ATP-production coupled respiration under both acute and prolonged exposure (p = 0.018 and p = 0.031 vs. vehicle, respectively). Single drugs did not produce notable alterations. However, when mefloquine or dihydroartemisinin are combined with piperaquine, the combination therapy resulted in reduced mitochondrial respiratory function in both acute and prolonged exposure (p = 0.0019 vs. vehicle). Ivermectin reduced ATP-production coupled respiration during acute exposure (p = 0.018 and p = 0.001vs. vehicle); this effect was not observed under prolonged treatment. Additionally, ROS production remained below a statistically significant level across all treatment conditions.

Conclusion

Our findings indicate that antimalarial drug impairs mitochondrial respiratory function, and that piperaquine-based combination therapy further exacerbates this impairment. However, the observed respiratory stress does not appear to be mediated by mitochondrial ROS production. These results underscore antimalarial drug-induced mitochondrial dysfunction in human ventricular cardiomyocytes, implying a potential contribution to pro-arrhythmic risk.

Figure 1. Acute and prolonged exposure of antimalarial drugs resulted in impairment of mitochondrial respiratory function. A, single drug treatment. B, combination therapy, the concentrations of the drugs used are the same as those used in panel A.Figure 1