Atrial fibrillation (AF), the most common sustained arrhythmia in humans, is a major cause of stroke and heart failure. AF promotes atrial ionic and structural remodeling, with fibrosis being a key structural change that is both a cause and a consequence of disease progression. In fibroblasts—the primary drivers of fibrosis—disrupted Ca 2+ signaling is increasingly implicated in profibrotic remodeling; however, the molecular mechanisms underlying Ca 2+ (mis)handling are not well understood. Importantly, no fibrosis-targeted therapies currently exist for AF. To address this, we combined experimental measurements with computational modeling to quantitatively identify and investigate Ca 2+ -handling mechanisms in human atrial fibroblasts (haFbs) from patients in normal sinus rhythm (nSR) and those in chronic atrial fibrillation (cAF). We used whole-cell patch-clamp recordings of Ca 2+ -influx pathways and K + currents in haFbs to construct biophysically detailed ion-channel models. These data were then integrated into a comprehensive haFb model, parameterized for both nSR and cAF, built upon established cardiomyocyte and vascular smooth muscle cell modeling frameworks. Our findings showed significant upregulation of Ca 2+ influx through TRPC3 channels in cAF haFbs compared to nSR. Additionally, K + efflux is upregulated in cAF compared to nSR via SK1-3 channels, promoting membrane potential hyperpolarization and enhancing the driving force for Ca 2+ entry. Together, these changes amplify Ca 2+ loading in cAF haFbs relative to nSR. This study establishes the first mechanistic model of Ca 2+ handling and electrophysiology in haFbs under nSR and cAF conditions, providing a framework to investigate Ca 2+ -driven fibroblast remodeling and ultimately to identify potential targets for fibrosis-specific therapy in AF.
Wu et al. (Sun,) studied this question.