期刊
FRONTIERS IN PHARMACOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2019.01392
关键词
chloroquine; persistent atrial fibrillation; potassium inward rectifiers; I-KACh; I-K1
资金
- National Institutes of Health [R21HL138064, R01HL129136]
- Direccion General de Politica Cientifica de la Generalitat Valenciana [PROMETEO 2016/088]
- ACM SIGHPC/Intel Computational & Data Science fellowship
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.
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