Gene expression profiles of carotid plaques differ between patients with amaurosis fugax and those with cerebral transient ischemic attack or stroke
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ID: 315827
2026
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Abstract
AIMS: In patients with atherosclerotic internal carotid artery stenosis, the risk of subsequent ischemic stroke is higher in those presenting with a cerebral transient ischemic attack (TIA) than in those with amaurosis fugax (AFX; transient monocular blindness). While AFX is associated with more stable histological characteristics, the underlying molecular mechanisms remain unclear. We hypothesized that biological processes and gene expression profiles in carotid plaques of patients with AFX differ from those with cerebral TIA and stroke. METHODS AND RESULTS: We analyzed carotid plaques from 2,508 patients undergoing endarterectomy between 2002 and 2022. Bulk RNA sequencing (RNA-seq) was performed on 1,088 plaques (136 asymptomatic, 179 AFX, 481 TIA, 292 stroke). Single-cell RNA-seq from 46 previously profiled plaques was used to identify cell-specific transcriptomic signatures. Mass spectrometry-based proteomics (n=189) and targeted plasma proteomics (n=1291) were used to validate the molecular differences.AFX plaques showed fewer lipid-rich cores than those from cerebral TIA (odds ratio [95% CI]: 1.41 [1.03-1.94]) or stroke (1.42 [1.01-1.99]). RNA-seq identified 408 differentially expressed genes (DEGs) between AFX and TIA and 463 between AFX and stroke (FDR < 0.1), while AFX and asymptomatic plaques showed only 10 DEGs. AFX plaques were enriched for vascular smooth muscle cell (VSMC) signatures and extracellular matrix remodelling, while cerebral TIA and stroke plaques exhibited macrophage driven inflammatory molecular signatures. These transcriptomic differences were confirmed by plaque proteomic analyses. In parallel, circulating proteomic profiling revealed higher levels of inflammatory and thrombo-inflammatory markers in cerebral TIA and stroke compared with AFX. CONCLUSIONS: AFX plaques exhibit stable, SMC dominant molecular signatures that differ markedly from the macrophage driven inflammatory profiles of cerebral TIA and stroke plaques. These findings support AFX as a biologically distinct entity with potential implications for risk stratification and personalized treatment.
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| Authors | Tian Lan, Floor B H van der Zalm, Kaylin C A Palm, Yayuan Zhu, Ernest Diez Benavente, Sander W van der Laan, Dominique P V de Kleijn, Ynte M. Ruigrok, Joost A van Herwaarden, Gert J de Borst, H Bart van der Worp, Martin Dichgans, H M Den Ruijter, Gerard Pasterkamp, M Mokry |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag116
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| URL | |
| Keywords | Keywords not found |
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