Impact of functional autoantibodies against angiotensin-II receptor type 1 in atherosclerosis

Background The renin-angiotensin-aldosterone system (RAAS) plays a key role in atherosclerosis progression and plaque vulnerability. Angiotensin-II binds to its G protein-coupled receptor (AT1R), regulating vascular inflammation, smooth muscle cell proliferation, extracellular matrix deposition, and vascular remodeling. Direct agonist autoantibodies against AT1R (AT1R-AAs) have been identified in various clinical settings and can activate these receptors. However, their roles in the progression and composition of atherosclerotic plaques remain unclear. Purpose This study aimed to analyze the association between AT1R-AAs and plaque composition and perivascular inflammation in patients with carotid atherosclerotic plaques undergoing carotid thromboendarterectomy. Methods Patients admitted to the Vascular and Endovascular Surgery Clinic with significant carotid stenosis and indications for carotid thromboendarterectomy were enrolled between 11/11/2024 and 28/03/2025. For each patient, data from preoperative CT angiography of the supra-aortic trunks were collected and used to assess the % of stenosis, plaque thickness and volume, plaque composition, and perivascular fat attenuation index (pFAI). Blood collected on the day of surgery was used to isolate serum for subsequent determination of AT1R-AAs using ELISA. Results Thirty patients (median age, 74.8 years; 57% women) were enrolled in the study. A significant correlation between AT1R-AAs levels and pFAI was found (ρ 0.38; p=0.045). Stratification of the population by tertiles of AT1R-AAs showed a progressive increase in median pFAI values from the first to the third tertile, confirming the relationship between antibody titer and pFAI values (Figure 1; p = 0.027). This association remained significant after separate adjustments for age, sex, and chronic therapy with statins, ACE inhibitors, or ARBs. Conversely, no statistically significant correlations were found between anti-AT1R levels and % stenosis (ρ = 0.04; p = 0.83) or maximum plaque thickness (ρ = -0.12; p = 0.54). Patients with higher AT1R-AAs levels showed a tendency to have slightly more calcified plaques than those in the lower tertiles, without reaching statistical significance (p=0.357). No significant differences were observed in plaque composition or in pFAI values, % stenosis, or maximum plaque thickness in relation to chronic use of statins, ARBs, or ACE inhibitors. Conclusions Higher levels of anti-AT1R autoantibodies are associated with increased perivascular inflammation in patients with carotid atherosclerosis. These results suggest that an immune-mediated mechanism may play a role in the progression and stability of atherosclerotic plaques and indicate that such autoantibodies may represent potential biomarkers or therapeutic targets.