Myeloid–fibroblast–cardiomyocyte crosstalk in atrial fibrillation: hypertension and evidence across disease models

Hypertension is a major antecedent of atrial fibrillation, but pressure load alone does not explain the development of an arrhythmogenic atrial substrate. Wall stress and neurohumoral activation can recruit circulating myeloid cells, alter macrophage states, activate fibroblasts, and disrupt cardiomyocyte inflammatory signaling and calcium handling. This review examines evidence from hypertensive animals, mixed-risk-factor models, human atrial tissue, and non-hypertensive models, separating findings demonstrated in each setting from their proposed relevance to hypertension. Macrophage osteopontin promotes fibroblast matrix programs in mixed-risk-factor models. Fibroblast-restricted NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation promotes fibrosis and conduction abnormalities in a non-hypertensive model. Separate experiments link cardiomyocyte NLRP3 or N-terminal gasdermin D signaling to inflammatory output and arrhythmogenic remodeling. These mechanisms may converge, but neither a serial osteopontin–fibroblast NLRP3 pathway nor a complete three-cell causal circuit has been established in hypertension. Blood-pressure-matched experiments, spatially resolved human atrial studies, and interventions that distinguish recruited pathological states from resident reparative macrophages are needed to test these links. Such studies may identify the disease stages and cell states in which immune modulation can complement control of hemodynamic stress.