Key Results:
HCQ blocked IKr and IK1 with
IC50s (10±0.6 and 34±5.0 µM) within clinical therapeutic
ranges, INa and ICaL at higher
IC50s, leaving Ito and
IKs unaffected. AZM produced minor inhibition of
INa, ICaL, IKs, and
IKr,, sparing IK1 and
Ito. HCQ+AZM combined inhibited IKr and
IK1 with IC50s of 7.7±0.8 µM and
30.4±3.0 µM, sparing INa, ICaL and
Ito. Molecular modelling confirmed potential HCQ binding
to hERG. HCQ slowed heart rate and ventricular conduction. It prolonged
PR, QRS and QT intervals, and caused prolonged, more heterogeneous,
action potential durations and intracellular Ca2+transients. These effects were accentuated with combined HCQ+AZM
treatment, which then elicited electrical alternans, re-entrant circuits
and wavebreak. Modelling studies attributed these to integrated HCQ and
AZM actions reducing IKr and IK1, thence
altering cell Ca2+ homeostasis.