Does the influence of hydroxychloroquine in a hypoxic ventricle differ from that of a non-hypoxic ventricle under congenital LQTS1 ?

Abstract

Factors inducing Hydroxychloroquine (HCQ) car-diotoxicity are still unclear, and this paper attempts to understand whether the presence of hypoxia in a congenital long QT syndrome1 (LQTS1) ventricular tissue can affect the outcome of HCQ interaction. This is facilitated by analysing the combination of LQTS1, HCQ and, mild and severe hypoxic conditions in a) the three types of cardiomyocytes: endocardial, midmyocardial and epicardial, as well as b) by generating pseudo ECGs from a 2D transmural anisotropic ventricular tissue model that has been excited with premature beats (PBs) to understand the possibility of arrhythmic occurrence. Results show that inclusion of HCQ in LQTS1 conditions prolongs the action potential duration(APD) in all cell types, leading to early after depolarisations (EADs) in M-cells alone. In contrast, on including hypoxia, the APDs are shortened in all cell types. Pseudo ECGs show a QT interval prolongation on adding HCQ with LQTS1 condition. In addition to LQTS1, mild and severe hypoxia, induces QT interval reduction, with low amplitude notched or inverted T-wave respectively. In presence of PBs, premature ventricular complexes (PVCs) are generated only in presence of HCQ with LQTS1. However, no significant effect of HCQ is observed in both hypoxia severities. Clinical relevance-This in-silico ventricular model indicates that although LQTS1 patients might be contraindicated for HCQ treatment, the combination of mild hypoxia and LQTS1 doesn't pose a risk factor and could help guide HCQ therapy