Abstract Body (Do not enter title and authors here): Peripheral artery disease, increasingly prevalent in aging populations, is linked to cardiovascular events and limb ischemia. Elevated high-sensitivity C-reactive protein (hs-CRP)reflects residual inflammatory risk, while the RNA-editing enzyme ADARB1 may reprogram immune and vascular signaling, presenting a potential therapeutic target in polyvascular atherosclerosis.

ADARB1 expression was measured in peripheral blood mononuclear cells (PBMCs) from 606 individuals at risk for atherosclerotic vascular disease. Subclinical arterial disease was evaluated by vascular ultrasound, assessing intima-media thickness, maximum carotid wall thickness, and the number of atheromatous plaques in carotid and femoral arteries. Participants were prospectively followed for major adverse cardiovascular events (MACE). Experimental atherosclerosis was investigated in ApoE^−/−ADARB1^−/− double knockout mice fed a Western diet for 20 weeks. Plasma lipids and cytokines were quantified via Luminex assays, and immune cell populations within aortic plaques were profiled using mass cytometry imaging.

After adjustment for traditional risk factors including age, sex, smoking, hypertension, hyperlipidemia, and diabetes mellitus, elevated ADARB1 mRNA expression was independently associated with hs-CRP levels >2 mg/dL, reflecting increased metabolic inflammation likely driven by IL-6. ADARB1 expression also correlated with the presence of coronary artery disease and polyvascular involvement, defined by a) carotid plaque, b) >50% coronary artery stenosis, c) aortic pulse wave velocity >10 m/sec, and d) femoral artery plaque at baseline. Higher ADARB1 levels predicted progression of atheromatosis, with individuals developing ≥2 new arterial plaques in carotid/femoral territories over a median follow-up of 33 months (OR = 3.74, P < 0.05). Moreover, patients in the top ADARB1 tertile had increased risk for MACE after multivariable adjustment.
Mechanistically, ADARB1 knockout mice displayed significantly reduced atherosclerotic lesion formation in both the aorta and brachiocephalic artery, accompanied by features indicative of plaque stabilization, such as reduced necrotic core size. Loss of ADARB1 dampened systemic inflammation, particularly lowering IL-6 levels, and mitigated the western diet-induced elevation in circulating monocyte and neutrophil counts.

Modulating ADARB1 activity could reduce IL6-driven inflammation and address residual cardiovascular risk.