The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation

Abstract

[EN] In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (I-K1 and I-KACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking I-K1 and I-KACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of I-K1 and I-KACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of I-K1 and I-KACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of I-K1 block by chloroquine was similar to that of I-KACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of I-K1 and I-KACh can be a targeted therapeutic strategy for persistent atrial fibrillation. ; This work was supported in part by National Institutes of Health grants R21HL138064, R01HL129136, by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEO 2016/088), and by the ACM SIGHPC/Intel Computational & Data Science fellowship. ; Tobón, C.; Palacio, LC.; Chidipi, B.; Slough, DP.; Tran, T.; Tran, N.; Reiser, M. (2019). The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation. Frontiers in Pharmacology. 10:1-12. https://doi.org/10.3389/fphar.2019.01392 ; S ; 1 ; 12 ; 10 ...