Atherosclerosis as a Neuroimmune and Neurovascular Disorder: Pharmacological Opportunities Beyond Lipid Lowering.

Abstract

Introduction/objective: Atherosclerosis is traditionally defined as a lipid-driven inflammatory disease of medium and large arteries, but vascular inflammation also interacts with immune, autonomic, metabolic, and brain vascular pathways. This narrative review synthesizes evidence supporting an artery-immune-brain framework and identifies pharmacological opportunities beyond lipid-lowering and antithrombotic therapy.

Methods: A targeted narrative review was performed using PubMed/MEDLINE, Google Scholar, and publisher databases, with priority given to randomized trials, guidelines, meta-analyses, and high-quality translational studies. Evidence was interpreted in accordance with translational maturity, distinguishing established clinical evidence from mechanisms that remain preclinical, indirect, or hypothesis-generating.

Results: Established evidence supports intensive lipid lowering, residual inflammatory-risk assessment, and selected anti-inflammatory and cardiometabolic strategies in atherosclerotic disease. Translational evidence further suggests that adventitial immune-neural niches, autonomic imbalance, trained immunity, gut-derived metabolites, vascular senescence, blood-brain barrier dysfunction, and neurovascular-unit injury may amplify vascular and cognitive risk. These mechanisms differ substantially in clinical readiness.

Discussion: The artery-immune-brain model helps explain residual vascular risk that is not fully captured by LDL-C, luminal stenosis, or recurrent ischemic events alone. It also supports trial designs that combine vascular, inflammatory, neuroimaging, cognitive, safety, and health-economic endpoints.

Conclusion: Atherosclerosis should be viewed as a lipid-inflammatory disease with clinically established vascular consequences, and additional neuroimmune and neurovascular mechanisms that are promising but require phenotype-specific validation before therapeutic translation.