Regional and Temporal Changes in Atrial Electrophysiology Contribute to Atrial Fibrillation in Angiotensin II Induced Hypertension

Abstract

Atrial fibrillation (AF) is highly prevalent in hypertensive heart disease and is associated with altered angiotensin II (Ang II) signaling. We have recently demonstrated that chronic hypertension (3 weeks of Ang II infusion) in mice increases AF susceptibility in association with distinct patterns of structural and electrical remodelling of the right and left atrium. However, the progressive effects of Ang II infusion on atrial electrophysiology have not been investigated. Accordingly, the goal of this study was to characterize the effects of Ang II infusion on mouse atrial electrophysiology at three different timepoints (3, 10, 21 days). AF susceptibility was increased to 35.7% following 10 days and 53.8% after 21 days of Ang II infusion. This occurred in association with progressive increases in P wave duration and AERP measurements at 3, 10, and 21 days of Ang II infusion. In isolated right atrial myocytes, action potential (AP) morphology and potassium currents (IK) were not altered after 10 days of Ang II infusion whereas AP duration was prolonged and potassium currents (IK) were reduced following 21 days of Ang II infusion. In contrast, AP morphology was differentially altered in the left atrium at all timepoints investigated. Specifically, AP upstroke velocity was reduced after 10 and 21 days of Ang II infusion with a corresponding reduction in sodium current at these timepoints. In addition, AP duration was similarly prolonged following 3, 10, and 21 days of Ang II infusion and IK was reduced to a similar extent at each of these timepoints. Collectively, these data demonstrate that Ang II infusion is associated with distinct regional and temporal alterations in atrial electrophysiology. These alterations provide insight into the changes in atrial electrophysiology that create a substrate for AF.