Atherosclerotic plaque instability in symptomatic non-significant carotid stenoses

• Published in: JVS-vascular science Vol. 6; p. 100280
• Main Authors: Cyréus, Paul, Wadén, Katarina, Hellberg, Sofie, Bergman, Otto, Lengquist, Mariette, Karlöf, Eva, Buckler, Andrew, Matic, Ljubica, Roy, Joy, Marlevi, David, Chemaly, Melody, Hedin, Ulf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2025; Elsevier
• Subjects: Atherosclerotic plaque instability; Degree of stenosis; Hypoxia; Stroke risk; Symptomatic carotid stenosis; Atherosclerotic plaque instability; Hypoxia; Stroke risk; Degree of stenosis; Symptomatic carotid stenosis
• ISSN: 2666-3503; 2666-3503
• DOI: 10.1016/j.jvssci.2025.100280

Carotid endarterectomy for symptomatic carotid stenosis is recommended for patients with >70% stenosis, but not in those with <50%. Because non-significant, low-degree stenoses may still cause strokes, refined risk stratification is necessary, which could be improved by assessing biological features of plaque instability. To challenge risk-stratification based on luminal narrowing, we compared biological features of carotid plaques from symptomatic patients with low-degree (<50%) vs high-degree (>70%) stenosis and explored potential mechanisms behind plaque instability in low-degree stenoses. Endarterectomy specimens were taken from symptomatic patients with high-degree (n = 204) and low-degree (n = 34) stenosis, all part of the Biobank of Karolinska Endarterectomies. Patient demographics, image-derived plaque morphology, and gene expression analyses of extracted lesions were used for comparisons. Plaque biology was assessed by transcriptomics using dimensionality reduction, differential gene expression, and gene-set enrichment analyses. Immunohistochemistry was used to study proteins corresponding to upregulated genes. The demographics of the two groups were statistically similar. Calcification, lipid-rich necrotic core, intraplaque hemorrhage, plaque burden, and fibrous cap thickness were similar in both groups, whereas the sum of lipid-rich necrotic core and intraplaque hemorrhage was higher (P = .033) in the high-degree stenosis group. Dimensionality reduction analysis indicated poor clustering separation of plaque gene expression in low-compared with high-degree stenosis lesions, whereas differential gene expression showed upregulation of hypoxia-inducible factor 3A (log2 fold change, 0.7212; P = .0003), and gene-set enrichment analyses identified pathways related to tissue hypoxia and angiogenesis in low-degree stenoses. Hypoxia-inducible factor 3-alpha protein was associated with smooth muscle cells in neo-vascularized plaque regions. Plaques from symptomatic patients with non-significant low-degree carotid stenoses showed morphologic and biological features of atherosclerotic plaque instability that were comparable to plaques from patients with high-degree stenoses, emphasizing the need for improved stroke risk stratification for intervention in all patients with symptomatic carotid stenosis irrespective of luminal narrowing. An increased expression of hypoxia-inducible factor 3A in low-degree stenotic lesions suggested mechanisms of plaque instability associated with tissue hypoxia and plaque angiogenesis, but the exact role of hypoxia-inducible factor 3A in this process remains to be determined. Carotid plaques from symptomatic patients with <50% stenosis show morphologic and biological features of plaque instability, comparable to high-degree stenosis, which emphasizes the need for improved stroke risk stratification beyond stenosis severity. [Display omitted]