Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes

Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on atrial fibrillation (AF) using a computational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations. HCQ concentrations were positively correlated with the action potential duration (APD), resting membrane potential, refractory period, APD alternans threshold, and calcium transient alternans threshold (P<0.05). In contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (P<0.05). When the therapeutic concentration (Cmax) of HCQ was applied, HCQ increased APD90 by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in PITX2+/- AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at Cmax, rather implying a potential antiarrhythmic role of low-dose HCQ in AF. However, at HCQ of 4-fold Cmax, a rapid pacing rate of 4 Hz could induce prominent APD alternans, particularly in the PITX2+/- AF model. Concomitant PITX2 mutations and HCQ treatments may increase the risk of AF, and this potential arrhythmogenic effect of HCQ should be further investigated.