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

BACKGROUND: Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. However, it is unclear how HCQ affects atrial electrophysiology and the risk of atrial fibrillation (AF). METHODS: We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on AF using a computational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations. RESULTS: The 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). By contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (p < 0.05). When the therapeutic concentration (C(max)) of HCQ was applied, HCQ increased APD(90) by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in paired-like homeodomain transcription factor 2 (PITX2)(+/-) AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at C(max), instead implying a potential antiarrhythmic role of low-dose HCQ in AF. However, at an HCQ concentration of fourfold C(max), a rapid pacing rate of 4 Hz induced prominent APD alternans, particularly in the PITX2(+/-) AF model. CONCLUSION: Our in silico analysis suggests a potential antiarrhythmic role of low-dose HCQ in AF. Concomitant PITX2 mutations and high-dose HCQ treatments may increase the risk of AF, and this potential genotype/dose-dependent arrhythmogenic effect of HCQ should be investigated further. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00059-023-05162-w) contains supplementary material, which is available to authorized users.