Cellular and molecular cross-talk in atrial fibrillation: The role of non-cardiomyocytes in creating an arrhythmogenic substrate.

Abstract

Atrial fibrillation (AF) is a complex arrhythmia. Various modulating factors influence its triggers and substrate. Fibroblasts, adipocytes, inflammatory cells and the coagulation system can disrupt cardiomyocyte function. Cardiomyocytes and fibroblasts release inflammatory cytokines that promote local and systemic inflammation, enhancing fibroblast activation and extracellular matrix deposition, leading to myocardial fibrosis. Fibrosis is essential for the induction of reentrant arrhythmias, including AF. Adipocytes contribute to arrhythmogenesis by secreting pro-inflammatory and pro-fibrotic factors, exacerbating inflammation and metabolic dysregulation. Inflammatory mediators activate the coagulation system, which augments this vicious cycle by producing factors promoting inflammation, fibrosis and arrhythmias at the same time as increasing the risk of thrombosis. Understanding these interconnected roles in the development and progress of the atrial arrhythmogenic substrate may point to potential novel therapeutic targets to stabilise or antagonise the atrial substrate and eventually prevent AF. This review examines the role of the interplay between cardiomyocytes, fibroblasts, adipocytes, inflammation and the coagulation system in contributing to the arrhythmogenic substrate for AF initiation and perpetuation.