Atrial Fibroblasts-Derived Extracellular Vesicles Exacerbate Atrial Arrhythmogenesis.

Cardiac fibroblasts (CFs) secrete exosomes, and their cargo represents a new means of cellular communication in cardiovascular diseases, including atrial fibrillation (AF). We aimed to explore the contribution of atial CFs (ACFs)-derived exosomes to AF development. Cultured primary human ACFs (hACFs) and rat ACFs are treated with angiotensin II, and the secreted exosomes are transferred to rats. Action potential duration and L-type calcium current (I_Ca) are tested. Global microRNA-224-5p knock-in and fibroblast-specific microRNA-224-5p knock-in (FMKI) mice underwent an inducible AF test. Transferred exosomes of Ang II-induced hACFs and primary adult rat ACFs increased AF incidence and prolonged AF duration. The inhibitor of exosomes and knockdown of Dicer rescued the AF phenotype. MicroRNA array suggested upregulated microRNA-224-5p level in both primary adult rat ACFs and ACFs-secreted exosomes. microRNA-224-5p agonist shortened atrial effective refractory period (AERP) and promoted AF. Mechanistically, microRNA-224-5p bound to CACNA1C and inhibited its transcription. Moreover, global microRNA-224-5p knock-in and FMKI mice exhibited increased inducible AF incidence, accompanied by diminished I_Ca current in ACMs. Exosome microRNA-224-5p is enhanced in ACFs isolated from atria and plasma of AF patients, and positively correlated with recurrence after radiofrequency ablation. In summary, ACFs-derived exosome microRNA-224-5p contributes to AF by inhibiting CACNA1C to drive atrial electrical remodeling.