The antimalarial chloroquine reduces the burden of persistent atrial fibrillation

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 (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. 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 IK1 block by chloroquine was similar to that of IKACh. 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 IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation. Copyright © 2019 Tobón, Palacio, Chidipi, Slough, Tran, Tran, Reiser, Lin, Herweg, Sayad, Saiz and Noujaim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

• Fecha de publicación: 2019
• Institución: Universidad de Medellín
• Repositorio: Repositorio UDEM
• Idioma: eng
• OAI Identifier: oai:repository.udem.edu.co:11407/5701
• Acceso en línea: http://hdl.handle.net/11407/5701
• Palabra clave: Chloroquine; IK1; IKACh; Persistent atrial fibrillation; Potassium inward rectifiers; antimalarial agent; apixaban; chloroquine; inwardly rectifying potassium channel subunit Kir2.1; inwardly rectifying potassium channel subunit Kir3.1; metoprolol; potassium channel; unclassified drug; action potential duration; aged; amebiasis; Article; clinical article; disease burden; drug effect; drug mechanism; drug protein binding; female; human; IC50; laboratory test; mathematical model; molecular docking; molecular model; patch clamp technique; persistent atrial fibrillation; potassium current
• License: http://purl.org/coar/access_right/c_16ec