Atrial fibroblast metabolic reprogramming in atrial fibrillation: a candidate mechanism within multicellular atrial cardiomyopathy

Atrial fibrillation (AF) commonly coexists with obesity, diabetes, and other cardiometabolic disorders. However, how systemic metabolic stress creates an arrhythmogenic atrial substrate remains unclear. This narrative review evaluates atrial fibroblast metabolic reprogramming as a testable mechanism within multicellular atrial cardiomyopathy, not as an established causal pathway. We organize the evidence by source: human atrial fibroblasts, human atrial tissue, atrial animal models, non-atrial cardiac fibroblasts, extracardiac fibroblasts, and reduced experimental systems. Studies of non-atrial cardiac and extracardiac fibroblasts independently implicate enhanced glycolysis, glutaminolysis, altered fatty acid metabolism, and redox or mechanosensitive signaling in myofibroblast activation. However, these processes were examined across different tissues and models and have not been shown to form a unified program in human atrial fibroblasts. Human atrial tissue and animal studies link metabolic stress, fibroblast activation, fibrosis, and AF but rarely establish fibroblast-specific metabolic causality. No study in the cited evidence set directly measured metabolism in human atrial fibroblasts; direct reports instead assessed activation, contraction, migration, and matrix output. We therefore position fibroblasts within a broader network of cardiomyocytes, endothelial cells, immune cells, adipocytes, smooth muscle cells, autonomic signaling, and thrombotic pathways. Therapeutic studies may support prevention or reverse atrial remodeling, but they do not show correction of human atrial fibroblast metabolism or regression of established atrial fibrosis. Direct cell-resolved profiling and atrium-specific, fibroblast-restricted perturbation are required to determine whether this mechanism is causal, reversible, and therapeutically actionable.