Abstract 13355: Remodeling of Fibroblast K+ Channels in Atrial Profibrillatory Pathologies
Background: Cardiac fibroblasts (FBs) are important in arrhythmogenesis by virtue of their role in fibrosis and possibly via electrical interactions with cardiomyocytes. K+ channels are expressed in FBs but their role is unknown. Atrial tachycardia remodeling (ATR), as seen in AF, and congestive heart failure (CHF) have AF-promoting effects mediated at least in part by activating FBs; fibrosis plays a particularly important role in CHF. This study characterized atrial FB K+ currents in control, ATR, and CHF dogs, and assessed their role in FB proliferation.
Methods: K+ currents were recorded with whole-cell patch clamp. Proliferation was examined by [3H]-thymidine incorporation; cell cycle was studied with flow cytometry. Atrial FBs were studied freshly-isolated (F-I), the day of isolation (enzymatic dispersion/ differential centrifugation), or in short-term culture.
Results: F-I FBs displayed outward time/voltage dependent K+ currents, which were downregulated by 52% in ATR and 84% in CHF (Fig. A). TEA (30 mM) reversibly suppressed K+ currents by 52-69% in all groups: TEA-sensitive currents were downregulated over a wide voltage range (Fig. B). Membrane capacitance increased in ATR and CHF FBs (Fig C), suggesting myofibroblast differentiation. TEA treatment of control FBs to mimic K+ current reductions in ATR/CHF increased cultured-FB DNA synthesis (Fig. D) by 32% (0.1 mM) and 77% (1 mM). Cell-culture alters FB phenotype, so flow cytometry was used as an index of cell-division in F-I control, ATR and CHF FBs. Percentage of G2/M cells (index of active division) was increased by 60% in ATR and 96% in CHF (Fig. E). TEA treatment (1 mM) for 48 hrs significantly increased G2/M cell percentage (Fig. F).
Conclusions: Atrial FBs show robust K+ currents that are TEA sensitive. ATR and CHF downregulate FB K+-currents. K+-current inhibition increases FB proliferation, suggesting that K+-current downregulation may contribute to arrhythmogenic FB activation in AF substrates.
- © 2012 by American Heart Association, Inc.