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.