Conclusions
There have been more than 200 clinical trials registered for hydroxychloroquine and/or chloroquine each considering different dosing regimes and different combinations with drugs including azithromycin (www.clinicaltrials.gov). Although these drugs are generally well tolerated when used for their approved indications, there is ample evidence that both can cause QT prolongation and carry a risk of drug-induced arrhythmia (7). Preliminary data from observational studies points to QT prolonging effects being more pronounced in COVID-19 patients than heathy individuals (5). Furthermore, patient comorbidities such as renal failure may add to the proarrhythmic risk in COVID-19 patients (35) . In the current absence of gold-standard randomized clinical trial data that is sufficiently powered to assess cardiac safety, coupled with the urgent need to identify potential therapies for COVID-19, there is a critical need for a comprehensive preclinical assessment of the cardiac safety profile of these drugs, in relation to COVID-19 patients. Our data indicate a significant proarrhythmic risk for hydroxychloroquine and chloroquine at doses being proposed to treat COVID-19 that can be increased by electrolyte imbalances reported in these patients (Graphical Abstract). Thus, it would be prudent to implement long term QT interval monitoring in these patients, particularly those with electrolyte imbalances. More broadly, our study demonstrates how the proarrhythmic risk associated with drugs that prolong cardiac repolarisation can be modified by disease related metabolic changes that occur in patients and acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations can integrate these effects into preclinical screening for proarrhythmic risk.