Agonistic autoantibodies targeting AT1R and ETAR: Mechanistic insights and emerging implications in cardiovascular disease

Autoimmune mechanisms are increasingly recognized as contributors to cardiovascular disease, extending beyond the traditional view of autoantibodies as passive markers of tissue injury. Among functional autoantibodies, those targeting the angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR) represent a distinctive class capable of inducing sustained, ligand-independent activation of vasoactive G protein-coupled receptors. Emerging experimental and translational evidence suggests that these agonistic autoantibodies may contribute to endothelial dysfunction, microvascular injury, and adverse cardiac remodelling through persistent receptor stimulation and downstream pro-inflammatory and pro-fibrotic signalling. Clinical observations, particularly in reperfused ST-elevation myocardial infarction, support an association with impaired myocardial reperfusion and unfavourable outcomes, although causality remains unproven. In this perspective, we aim to delineate the mechanistic framework of AT1R- and ETAR-targeting agonistic autoantibodies, critically appraise the available clinical evidence, and outline key priorities for their translational validation in cardiovascular disease. Further investigation is required to determine their potential role in risk stratification and as therapeutic targets. Integrating immunological markers into cardiovascular research may provide new avenues for translational advancement, while necessitating rigorous validation in well-designed clinical studies.