Regulator Of G-Protein Signalling 4 (Rgs4) Ko Mice Show Increased Susceptibility To Atrial Fibrillation

Susceptibility to atrial fibrillation (AF) depends strongly on parasympathetic activity. Since RGS4 inhibits parasympathetic signaling in the sinoatrial node, we explore whether changes in RGS4 levels altered the susceptibility of atrial fibrillation. Consistent with this possibility, RGS4 levels were decreased in atria of tachypaced dogs prior to their development of chronic AF. Moreover, in vivo ECG recordings of anaesthetized mice showed greater susceptibility to AF while optical mapping of isolated atrial preparations using a voltage‐sensitive dye revealed greatly increased susceptibility to rotor formation when rgs4 was ablated. Consistent with altered parasympathetic signaling in the myocardium of rgs4 −/− mice, acetylcholine‐sensitive potassium currents (I KACh ) evoked by carbachol application were greater in isolated atrial myocytes from rgs4 −/− mice. These I KACh changes were, as expected, associated with marked enhancements of action potential duration shortening in response to parasympathetic activation, but not to slower conduction velocities. Together, our findings establish that RGS4 protects atrial tissues from excess parasympathetic signaling that predispose to atrial fibrillation. Technical and financial assistance for this work was provided by the Heart and Stroke Foundation of Ontario Grant‐in‐Aid Program grants T6799, and Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship Program.