Heterogeneity and Remodeling of Ion Currents in Cultured Right Atrial Fibroblasts From Patients With Sinus Rhythm or Atrial Fibrillation.

Dorothee Jakob,Alexander Klesen,Rémi Peyronnet,Ursula Ravens,Friedhelm Beyersdorf,Fabian A Kari,Elisa Darkow,Peter Kohl

doi:10.3389/fphys.2021.673891

Abstract

Cardiac fibroblasts express multiple voltage-dependent ion channels. Even though fibroblasts do not generate action potentials, they may influence cardiac electrophysiology by electrical coupling via gap junctions with cardiomyocytes, and through fibrosis. Here, we investigate the electrophysiological phenotype of cultured fibroblasts from right atrial appendage tissue of patients with sinus rhythm (SR) or atrial fibrillation (AF). Using the patch-clamp technique in whole-cell mode, we observed steady-state outward currents exhibiting either no rectification or inward and/or outward rectification. The distributions of current patterns between fibroblasts from SR and AF patients were not significantly different. In response to depolarizing voltage pulses, we measured transient outward currents with fast and slow activation kinetics, an outward background current, and an inward current with a potential-dependence resembling that of L-type Ca2+ channels. In cell-attached patch-clamp mode, large amplitude, paxilline-sensitive single channel openings were found in ≈65% of SR and ∼38% of AF fibroblasts, suggesting the presence of “big conductance Ca2+-activated K+ (BKCa)” channels. The open probability of BKCa was significantly lower in AF than in SR fibroblasts. When cultured in the presence of paxilline, the shape of fibroblasts became wider and less spindle-like. Our data confirm previous findings on cardiac fibroblast electrophysiology and extend them by illustrating differential channel expression in human atrial fibroblasts from SR and AF tissue.

Highlights

Atrial fibrillation (AF) is a common arrhythmia of increasing prevalence due to an aging population (Chugh et al, 2014)
Since conflicting reports exist about the presence of BKCa currents in human atrial fibroblasts [compare Sheng et al (2013) with Poulet et al (2016)], we investigated whether currents with properties of BKCa were present in our cells
Cultured human atrial fibroblasts, obtained by the outgrowth technique and used at passage 0 or 1, exhibit diverse patterns of voltage- and time-dependent currents, independent of whether they are derived from patients with sinus rhythm (SR) or atrial fibrillation (AF)

Summary

Introduction

Atrial fibrillation (AF) is a common arrhythmia of increasing prevalence due to an aging population (Chugh et al, 2014). Fibroblasts are essential for cardiac tissue repair and maintenance of mechanical stability of the heart (Souders et al, 2009). They are able to sense and adapt to a variety of mechanical and chemical signals involved in stress and injury responses. Excessive collagen accumulation may lead to fibrosis in non-lesioned tissue, a process which contributes to AF by increasing mechanical and electrical heterogeneity (Krul et al, 2015). Cardiac fibroblasts (Quinn et al, 2016; Rubart et al, 2018), as well as other non-myocytes such as immune cells (Hulsmans et al, 2017), may modify the electrophysiology of cardiomyocytes through direct electrically conductive contacts. Electrotonic interactions of the two cell types will depolarize cardiomyocytes (due to the less negative resting membrane potential of non-myocytes), and potentially slow conduction [due to the addition of a passive electrical load (Kohl et al, 2005)], which could promote re-entry

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