Figure 1. Mechanisms contributing to age-related atrial remodeling. Several mechanisms contribute to age-related pathological atrial remodeling: (1) a chronic inflammatory state marked by elevated circulating pro-inflammatory cytokines, including interleukin (IL)-6, -15, and -18; (2) an increase in circulating pro-fibrotic factors, such as transforming growth factor (TGF)-beta, along with dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs); (3) electrophysiological changes, including altered expression and activity of NaV1.5, decreased L-type calcium current (ICaL), increased transient outward (Ito) and sustained (Isus) potassium currents, and downregulation of connexin-43; (4) accumulation of senescent fibroblasts and endothelial cells with a senescence-associated secretory phenotype (SASP), and altered cardiomyocytes that exhibit contractile dysfunction, hypertrophic growth, increased pacing frequency, and secretion of endothelin-3 (EDN3), TGF-beta 2, and growth differentiation factor 15 (GDF15); (5) epigenetic modifications, such as CpG site methylation changes, hypermethylation of paired-like homeodomain 2 (PITX2), and altered expression of histone-modifying enzymes histone deacetylase 2 (HDAC2) and enhancer of zeste homolog 2 (EZH2); and (6) dysregulation of non-coding RNAs, including upregulation of microRNA-21 and microRNA-328, and downregulation of microRNA-26. Collectively, these mechanisms lead to the replacement of healthy myocardium with fibrotic tissue, the development of inflammatory infiltrates, the formation of arrhythmogenic foci, and a prothrombotic state. *These modifications are more specific to atrial fibrillation than aging. Further investigation is needed in this area. Created in BioRender. Gyberg, D. (2005) https://BioRender.com/y38x200.
