Abstract 14137: Impaired Sodium-Dependent Regulation of Acetylcholine-Activated IK,ACh Modulates Action Potential Rate Dependence in Patients with Chronic Atrial Fibrillation
Introduction- Impaired regulation of intracellular sodium ([Na+]i) has been implicated in the blunted action-potential duration (APD) rate dependence in chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K+-currents (IK1 and IK,ACh) contribute to the regulation of APD and are subject to cAF-dependent remodeling. The effects of [Na+]i on IK1 and IK,ACh in human atrial myocytes and their role in APD rate dependence in sinus rhythm (SR) and cAF are unknown.
Methods- IK1 and IK,ACh were recorded (patch-clamp) in right atrial myocytes from SR and cAF patients with and without the M-receptor agonist carbachol (Fig A) using intracellular solutions with 0, 8 or 60 mmol/L Na+. Proteins were measured by immunoblotting. Computational modeling was used to study the effects on APD.
Results- At physiological [Na+]i, inward (-100 mV) and outward (-10 mV) component of basal current was larger in cAF than in SR. Changing [Na+]i revealed an inhibitory effect of [Na+]i on outward component (but not inward component) of basal current in both SR and cAF (Fig B). Kir3.1 and Kir3.4 were reduced by 46% and 64% in cAF suggesting that stronger reduction of the Na+-sensitive Kir3.4 may impair Na+-dependece of IK,ACh. Indeed, IK,ACh was smaller in cAF and elevation of [Na+]i increased IK,ACh in SR but not in cAF (Fig C). Modeling studies based on a recent human atrial model (Grandi et al. Circ Res 2011) reproduced shorter APD and impaired APD rate dependence in cAF. Including [Na+]i dependence of IK1 and IK,ACh in this model revealed that accumulation of [Na+]i at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. In contrast, [Na+]i-dependent IK,ACh augmentation increased APD rate dependence in SR, but not in cAF (Fig D).
Conclusions- These results identify impaired Na+-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in atrial myocytes from cAF patients.
- © 2012 by American Heart Association, Inc.