Atrial fibrillation begets atrial fibrillation - serum-driven amplification of atrial electrical instability

Rationale: Atrial fibrillation (AF) is sustained by electrical triggers and atrial substrate, but whether AF itself generates circulating factors that acutely reinforce arrhythmogenesis is unknown. Objective: To determine whether rhythm-dependent serum bioactivity directly destabilizes atrial electrophysiology and to identify associated cellular mechanisms and circulating mediators. Methods and Results: Cardiac samples were obtained from patients with persistent atrial fibrillation (AF) during AF and after restoration of sinus rhythm (SR) using electrical cardioversion. In isolated Langendorff-perfused mouse hearts, AF serum increased the duration, frequency, and cumulative burden of spontaneous atrial depolarizations compared with paired control perfusate. In human induced pluripotent stem cell derived atrial cardiomyocytes, AF patient serum decreased Ca2-transient amplitudes without significant effect on kinetics or Ca2 spark activity. Moreover, AF serum reduced peak sodium current without materially altering voltage-dependent gating or paced action-potential properties. Data-independent acquisition proteomics identified rhythm-associated changes in extracellular-matrix, proteolytic, inflammatory, and signaling proteins, including MMP9, Ccathepsin G, and 14-3-3 family members. Targeted pathway perturbation differentially modified serum-induced Ca2 phenotypes, indicating context-dependent, multifactorial bioactivity. Serum-induced Ca2 responses were not associated with indices of atrial disease severity, including low-voltage substrate burden and left atrial pressure. Conclusions: Persistent AF is accompanied by rhythm-dependent circulating bioactivity that acutely promotes atrial electrical instability and Ca2-dependent trigger formation. These findings extend the concept that AF begets AF beyond tissue-intrinsic remodeling and identify a potentially reversible serum-mediated feed-forward mechanism linking rhythm status and circulating proteomic signals in an atrial substrate severity independent fashion. Keywords: atrial fibrillation; serum; atrial cardiomyopathy; calcium signaling; circulating factors; proteomics