Cardiac electrophysiological mechanisms associated with anti-malarial therapy and its implications for arrhythmogenesis and drug repurposing (COMPARE)

Malaria is a global health problem of high importance. Anti-malarials have significant pro-arrhythmic cardiac effects. Screening for such effects is currently limited to electrophysiological parameters such as QT interval (a repolarisation marker) which does not assess all aspects of arrhythmic risk. Cardiac safety testing concentrates on single therapy rather than combined therapy and ignores potential cardiac effects when used in this way. The hypothesis is that anti-malarial induced prolongation of repolarisation alone does not necessarily lead to increased arrhythmic inducibility and that anti-malarials may alter other cardiac parameters which could be pro or anti-arrhythmic. Preliminary work by measured Ca2+ flux at the cellular level and patch clamp measures of ion channel conductivity demonstrates disturbed calcium homeostasis and sodium channel conductivity induced by anti-malarial drugs. Gene expression alterations in calcium homeostatic genes with anti-malarial exposure were also confirmed. The outcomes defined above will be reassessed with the addition of ion channel blocking drugs to confirm mechanistic pathways and identify potentially new targets.

Project details

Basic Science
Drug-based Strategies

Oct 2022 — Oct 2025

$310,668

United Kingdom