PMC:6019327 / 42375-43738 JSONTXT

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fibrosis is part of the maladaptive cardiac remodeling in response to cardiac injury164,165 and has been implicated in initiation and maintenance of AF.166 The mechanisms that are responsible for fibrosis and its consequences comprise many phenomena occurring at various scales, including molecular, organelle, cellular, and tissue scales.167 At the molecular scale are dynamics changes in the genome, the transcriptome, and the signaling pathways underlying the generation of profibrotic molecules168; cellular changes involve interactions among the various cardiac cells, including myocytes, fibroblasts or myofibroblasts, and inflammatory cells such as macrophages and neutrophils169; and tissue changes relate to the dynamics of scar, angiogenesis, electrical conduction, and contractility.153 Fibrosis can certainly act as an electrically insulating obstacle. Profibrotic stimuli promote differentiation of fibroblasts into activated myofibroblasts, which electronically couple to myocytes in vitro20,150,151,152; whether this occurs to a significant extent in AF atria in vivo remains uncertain. Fibrosis affects electrical propagation through slow, discontinuous conduction with “zigzag” propagation,170,171 reduced regional coupling,172 abrupt changes in fibrotic bundle size,173 interruption of bundle continuity, and micro-anatomical reentry.174"}