Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation

Authors: TeBay C, McArthur JR, Mangala M, Kerr N, Heitmann S, Perry MD, Windley MJ, Vandenberg JI, and Hill AP.

British Journal of Pharmacology, 2021.

Scientists combine in vitro testing and in silico simulations to examine the potential impact of patient-specific factors on the development of drug-induced cardiac arrhythmias

Although subsequent research has not demonstrated the efficacy of hydroxychloroquine (HCQ), chloroquine (CQ), and azithromycin (AZM) for the treatment of COVID-19, the medications have been administered as single or combination agents to people infected with the virus and research into the underlying mechanisms of the drugs’ cardiac side effects is ongoing. All three medications are known to block hERG potassium channels in the heart, which can lead to life-threatening arrhythmias. In this study, scientists used high-throughput hERG potency screening, computer simulations, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to examine how patient-specific factors including altered physiological states, pre-existing diseases, and genetic backgrounds affect the proarrhythmic risk of HCQ, CQ, and AZM.

To examine the impact of HCQ and AZ on cardiac repolarization in hiPSC-CMs under different physiological conditions and to assess how long-term exposure may contribute to proarrhythmic effects, researchers used Axion’s Maestro multielectrode array (MEA) platform. The overall findings from MEA and other methods revealed that low exposure to HCQ and AZ caused additional prolongation of repolarization and demonstrated that metabolic changes including fever, acidosis, and electrolyte imbalance—all common occurrences in patients with COVID-19 infection—can modify hERG potency and thus increase proarrhythmic risk. Additionally, in silico prediction of population risk showed that specific genetic backgrounds and disease factors are linked to the emergence of arrhythmia in response to hydroxychloroquine. Taken together, these findings demonstrate that metabolic changes and pre-existing disease can worsen the proarrhythmic risk of certain medications and suggest that the use of high-throughput in vitro screening combined with computer simulation provides a suitable platform for assessing therapeutics both in preclinical screening and in the clinical management of patients.