Abstract 13077: Effect of Fibroblast Electrical Remodeling on Atrial Arrhythmogenesis in Atrial Fibrillation
Background: Atrial fibrosis promotes AF. Fibroblasts (FBs) proliferate with fibrosis and may influence cardiomyocyte bioelectricity to promote arrhythmogenesis. Here, we assessed the potential role of FB ion current remodeling in the fibrotic AF substrates caused by heart failure (HF).
Methods: FB ion currents were recorded by patch clamp from control (CTL) dogs and dogs with tachypacing induced HF (240 bpm x 2 wks). Mathematical models of atrial cardiomyocytes (CMs; RNC) and FBs (MacCannell) were used to assess the impact of HF-induced FB remodeling on cellular activity and reentrant dynamics in a 2D sheet of atrial tissue with realistic FB-CM distribution.
Results: HF increased FB inward rectifier current (IK1) by 44% and decreased voltage gated K current (IKv) by 79% (Panel A, B). IKv downregulation reduced FB outward current, making FBs act as a current source during the CM action potential (AP); IK1 upregulation had opposite effects. Thus, FB IK1 upregulation hyperpolarized CMs, shortened AP duration (APD), enhanced conduction velocity (CV) and reduced wavelength (WL; Panel C, green). FB IKv downregulation depolarized cardiomyocytes, prolonged APD, slowed CV and increased WL (Panel C, red). In simulated AF, FB IKv downregulation was antiarrhythmic by increasing WL and rotor meandering, leading to reentry termination (Panel D, second column). FB IK1 upregulation was profibrillatory by decreasing WL and stabilizing rotors, leading to sustained reentry (Panel D, third column). Applying a FB IKv blocker in IK1-upregulated conditions terminated reentry (Panel D, fourth column).
Conclusion: 1) FB ion-current remodeling occurs in the HF-induced AF promoting fibrotic substrate. 2) Altered FB K-currents can significantly affect atrial reentrant dynamics and AF sustainability, with upregulation of FB IK1 favoring AF maintenance and IKv downregulation having the opposite effect. 3) FB IKv blockade may be a novel AF-selective target for antiarrhythmic drug action.
- © 2013 by American Heart Association, Inc.