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 (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.