Aurora Semerano, MD
@semerano_aurora

Ganji M, Nardi V, Prasad M, Jordan KL, Bois MC, Franchi F, Zhu XY, Tang H, Young MD, Lerman LO, Lerman A. Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression. Stroke. 2021.

Investigating mechanisms of plaque instability is needed to better treat patients with carotid atherosclerosis. In parallel, the search for reliable biomarkers, including blood parameters and imaging features, is required to identify patients with carotid plaques at the highest risk of embolism. Within this effort of providing new knowledge in the field, this study1 recently published in Stroke aimed at investigating the histological characteristics of plaque instability. The authors were specifically interested in exploring the role of xanthine oxidase, the enzyme that catalyzes the synthesis of uric acid, which acts as an indicator of oxidative homeostasis and has been previously associated with atherosclerosis and increased cardiovascular risk.2

The study examined 88 randomly selected carotid artery specimens from symptomatic (within the previous 6 months) and asymptomatic patients. No difference was observed in the relative percentage of traditional histological components of atherosclerosis (such as fibrosis, plaque hemorrhage, calcium, and lipid core). The amount of macrophage infiltration was also comparable between specimens from symptomatic and asymptomatic patients. Interestingly, the authors found significantly higher expression of xanthine oxidase in symptomatic carotid plaques. Further, in a subset of 27 samples, they observed that percentage of macrophages expressing xanthine oxidase was increased in symptomatic plaques. Moreover, xanthine oxidase expression in the plaques positively correlated with uric acid levels in the blood.

This study adds to the growing and conflicting literature about this metabolic pathway in cerebrovascular diseases. The role of xanthine oxidase and uric acid in stroke is indeed under active investigation, with controversial results: Whereas elevated circulating levels of uric acid have been shown to be associated with greater risk of cardiovascular events,2 uric acid has been also evaluated as a neuroprotective agent during the acute phase of ischemic stroke.3 Remarkably, in the paper by Ganji et al., macrophages have been found to differentially express xanthine oxidase in symptomatic and asymptomatic carotid plaques. This observation is in line with the increasing evidence that inflammatory cells are key players in plaque instability: In a milestone paper by Fernandez et al.,4 indeed, single-cell analysis showed that macrophage subsets in symptomatic plaques display unique signatures consistent with distinct pro-inflammatory and reparative functions.

Overall, this study supports the concept that prompt identification of high-risk patients is required to optimize treatment efficacy. Further investigation of the underlying mechanisms is needed to evaluate whether anti-oxidant or immunotherapies may be beneficial in reducing the risk of athero-embolic stroke in these patients.

References:

  1. Ganji M, Nardi V, Prasad M, Jordan KL, Bois MC, Franchi F, et al. Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression. Stroke. 2021 Jun 10:STROKEAHA120032964.
  2. Wang R, Song Y, Yan Y, Ding Z. Elevated serum uric acid and risk of cardiovascular or all-cause mortality in people with suspected or definite coronary artery disease: a meta-analysis. Atherosclerosis 2016;254:193–199.
  3. Chamorro Á, Lo EH, Renú A, van Leyen K, Lyden PD. The future of neuroprotection in stroke. J Neurol Neurosurg Psychiatry. 2021 Feb;92(2):129-135. doi: 10.1136/jnnp-2020-324283.
  4. Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019 Oct;25(10):1576-1588.