Colchicine attenuates the electrical remodeling of post-operative atrial fibrillation through inhibited expression of immune-related hub genes and stabilization of microtubules

Rationale: Acute inflammation is a major risk factor for post-operative atrial fibrillation (POAF), and epicardial adipose tissue (EAT) is considered as a source of inflammatory mediators.However, underlying mechanisms and pharmacological targets of POAF are poorly understood.Methods: Integrative analysis of array data from EAT and right atrial appendage (RAA) samples was conducted to identify potential hub genes.Lipopolysaccharide (LPS)-stimulated inflammatory models in mice and in induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) were used to examine the exact mechanism underlying POAF.Electrophysiological analysis, multi-electrode array, and Ca 2+ imaging was employed to explore the alterations of electrophysiology and Ca 2+ homeostasis under inflammation.Flow cytometry analysis, histology and immunochemistry were performed to investigate immunological alterations.Results: We observed electrical remodeling, enhanced atrial fibrillation (AF) susceptibility, immune cell activation, inflammatory infiltration, and fibrosis in LPS-stimulated mice.LPS-stimulated iPSC-aCMs showed arrhythmias, abnormal Ca 2+ signaling, reduced cell viability, disrupted microtubule network and increased α-tubulin degradation.VEGFA, EGFR, MMP9 and CCL2 were identified as hub genes simultaneously targeted in the EAT and RAA of POAF patients.Notably, treatment of colchicine in LPS-stimulated mice resulted in a U-shape dose-response curve, where greatly improved survival rates were observed only at doses between 0.10-0.40mg/kg.At this therapeutic dose level, colchicine inhibited the expression of all the identified hub genes and effectively rescued the pathogenic phenotypes observed in LPS-stimulated mice and iPSC-aCM models.Conclusions: Acute inflammation promotes α-tubulin degradation, induces electrical remodeling, and both recruits and facilitates the infiltration of circulating myeloid cells.A certain dose of colchicine attenuates electrical remodeling and decreases the recurrence of AF.