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.
Remodeling in atrial fibrillation (AF) underlines the electrical and structural changes in the atria, where fibrosis is a hallmark of arrhythmogenic structural alterations. Fibrosis is an important feature of the AF substrate and can lead to abnormal conduction and, consequently, mechanical dysfunction. The fibrotic process comprises the presence of fibrotic cells, including fibroblasts, myofibroblasts and fibrocytes, which play an important role during fibrillatory dynamics. This work assesses the effect of the diffuse fibrosis density and the intermingled presence of the three types of fibrotic cells on the dynamics of persistent AF. For this purpose, the three fibrotic cells were electrically coupled to cardiomyocytes in a 3D realistic model of human atria. Low (6.25%) and high (25%) fibrosis densities were implemented in the left atrium according to a diffuse fibrosis representation. We analyze the action potential duration, conduction velocity and fibrillatory conduction patterns. Additionally, frequency analysis was performed in 50 virtual electrograms. The tested fibrosis configurations generated a significant conduction velocity reduction, where the larger effect was observed at high fibrosis density (up to 82% reduction in the fibrocytes configuration). Increasing the fibrosis density intensifies the vulnerability to multiple re-entries, zigzag propagation, and chaotic activity in the fibrillatory conduction. The most complex propagation patterns were observed at high fibrosis densities and the fibrocytes are the cells with the largest proarrhythmic effect. Left-to-right dominant frequency gradients can be observed for all fibrosis configurations, where the fibrocytes configuration at high density generates the most significant gradients (up to 4.5 Hz). These results suggest the important role of different fibrotic cell types and their density in diffuse fibrosis on the chaotic propagation patterns during persistent AF.
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