Metabolic changes associated with COVID-19 alter proarrhythmic risk associated with hERG block
The potency of compounds that block the hERG potassium channel and hence infer proarrhythmic risk is known to be sensitive to a variety of pathophysiological states including temperature, electrolyte concentrations and pH (12-15). This is an important consideration in COVID-19 patients. For example, febrile temperature is reported in >90 % of hospitalised COVID-19 cases (8, 34), hypokalaemia in up to 41 % of patients (10) and acidosis in 9 % of cases and 30 % of non-survivors (8). Furthermore, acute kidney injury has been reported in 15 % of in-patient cases and 50 % of non-survivors (8) with potential for further electrolyte imbalances including hyperkalaemia and hypermagnesemia. There is evidence that COVID-19 patients treated with hydroxychloroquine/chloroquine show more severe QTc prolongation than healthy individuals (5), and those patients with acute renal failure exhibited the most extreme effects (35). It is therefore critical that we understand how these altered physiological states in patients affect hERG potency and hence potential proarrhythmic propensity of these drugs.
While it is accepted that each of these factors can affect potency of hERG block, reports of how they do so are conflicting (e.g. acidic pH has been reported to both increase and decrease potency of hERG block (15, 36)) and can differ between drugs (e.g. the effect of temperature on block of hERG is drug-specific (12)). It was therefore important to examine how environmental factors in COVID-19 specifically modify the proarrhythmic risk profile of hydroxychloroquine and chloroquine. Our results show that the effects of temperature were drug specific, decreasing potency for hydroxychloroquine and chloroquine but increasing potency for azithromycin. However, even with elevated temperature, the IC50 for azithromycin (~70 µM) was an order of magnitude higher than the likely plasma Cmax(37). These results suggest that febrile temperatures should not raise additional concern specific to drug-induced arrhythmia. Similarly, lowering pH to pH 7, consistent with severe systemic acidosis that might be observed with respiratory or multi-organ failure, significantly reduced the potency of all drugs between 3 and 5-fold, again suggesting that additional concern relating to drug-induced arrhythmias may be mitigated by profound acidosis. An exception to this might be if local acidosis in the myocardium, in the context of coronary occlusion for example (38), led to spatial differences in the degree of hERG block and hence regional gradients of repolarisation that could act as an electrical substrate for reentry and arrhythmogenesis (39).
Conversely, our data show that some electrolyte imbalances, specifically hypermagnesemia and hypokalemia could increase proarrhythmic risk. Hypermagnesemia significantly increased potency of hERG block (3-fold and 1.4-fold for chloroquine and hydroxychloroquine respectively). Likewise, hypokalaemia increased potency of both drugs (1.4-fold and 2-fold for chloroquine and hydroxychloroquine respectively), and this increase in hERG potency translated to more pronounced prolongation of repolarisation of iPSC cardiomyocytes in the context of reduced extracellular K+ (Figure 3D). These data suggest that particular attention should be given to monitoring drug-induced QT changes COVID-19 patients with these electrolyte abnormalities. Also of potential clinical relevance, our finding that hypermagnesemia increases potency of hERG block suggests that if intravenous magnesium is given as a therapy to avoid or to treat torsade de pointes in COVID-19 patients, then great care should be taken not to overshoot the normal physiologic range.