Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation

Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (I-Kv,I-fb) was significantly downregulated (by similar to 44%), whereas the Ba2+-sensitive inward rectifier current (I-Kir,I-fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (-53 +/- 2 mV vs. -42 +/- 2 mV in controls) and the capacitance was increased (29.7 +/- 2.2 pF vs. 17.8 +/- 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. I-Kir,I-fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. I-Kv,I-fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of I-Kv,I-fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with I-Kv,I-fb downregulation and I-Kir,I-fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K+-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.