Anti-malarial drugs: Mechanisms underlying their proarrhythmic effects

Malaria remains the leading cause of parasitic death in the world. Artemisinin resistance is an emerging threat indicating an imminent need for novel combination therapy. Given the key role of mass drug administration, it is pivotal that the safety of anti-malarial drugs is investigated thoroughly prior to widespread use. Cardiotoxicity, most prominently arrhythmic risk, has been a concern for anti-malarial drugs. We clarify the likely underlying mechanisms by which anti-malarial drugs predispose to arrhythmias. These relate to disruption of (1) action potential upstroke due to effects on the sodium currents, (2) action potential repolarisation due to effects on the potassium currents, (3) cellular calcium homeostasis, (4) mitochondrial function and reactive oxygen species production and (5) cardiac fibrosis. Together, these alterations promote arrhythmic triggers and substrates. Understanding these mechanisms is essential to assess the safety of these drugs, stratify patients based on arrhythmic risk and guide future anti-malarial drug development.

Automated summary

Malaria remains the leading cause of parasitic death worldwide, and artemisinin resistance poses a significant threat, necessitating the development of new combination therapies. Prior to widespread use, it is crucial to thoroughly investigate the safety of anti-malarial drugs, with a focus on cardiotoxicity. This research aims to clarify the potential mechanisms by which these drugs contribute to arrhythmias, providing important insights for assessing drug safety, stratifying patients based on arrhythmic risk, and guiding future anti-malarial drug development.