ATHEROSCLEROSIS SEVERITY AFFECTS ARTERIAL REMODELING AFTER THE CAROTID ANGIOPLASTY

Highlights

• In the examined human stented internal carotid artery sample, we identified significant differences in remodeling patterns between the initially intact intima and atherosclerotic plaque area.
• Severe restenosis in the initially intact intima was characterized by intensive neutrophilic infiltration, proliferation of vascular smooth muscle cells and fibroblasts, active extracellular matrix remodeling, and immature microvessels.
• Moderate restenosis in the atherosclerotic plaque area was characterized by the absence of neutrophils, notable macrophage infiltration, and mature microvessels.

Abstract

Aim. To perform a histological analysis of arterial remodeling after the carotid angioplasty depending on the extent of atherosclerosis before the surgery.

Methods. Here we examined human internal carotid artery excised during carotid endarterectomy which has been performed because of severe in-stent restenosis. The artery was sectioned into segments with initially intact intima (n = 3) and segments with atherosclerotic plaque (n = 3). Visualization was performed using backscattered scanning electron microscopy (EM-BSEM) after staining the segments with heavy metals, embedding them into epoxy resin, grinding and polishing of embedded specimens, and sputter coating the samples with carbon. We further assessed neointimal thickness, extracellular matrix state, microvessel parameters (total and mean lumen area, vessel density by area and quantity, presence of blood cells within and surrounding vessels), cellular composition, and immune cell infiltration patterns.

Results. Significant differences in patterns of arterial remodeling were observed between the initially intact intima and atherosclerotic plaque area. Restenotic neointima in initially intact regions was thick, loose and disorganized and was notable for high cellular density, severe neutrophilic infiltration, and immature microvessels (i.e., signs of acute inflammation). In contrast, atherosclerotic plaque areas had moderate degree of restenosis, dense neointima, mature microvessels, and macrophage infiltration, altogether suggestive of chronic inflammation. Morphometric analysis revealed a trend toward increased neointimal thickness in the initially intact intima; however, microvascular parameters did not differ significantly between the intact and atherosclerotic areas.

Conclusion. The initial state of the carotid artery wall affects the neointimal composition, extracellular matrix remodeling, angiogenesis and inflammation patterns. Initially intact intima exhibited high reactivity associated with a severe restenosis, loose neointima formation, and acute inflammation. In contrast, plaque areas demonstrate more stable neointimal structure and features of chronic inflammation.

1. Bracale UM, Peluso A, Di Mauro E, Del Guercio L, Di Taranto MD, Giannotta N, Ielapi N, Provenzano M, Andreucci M, Serra R. Carotid Endarterectomy versus Carotid Artery Stenting With Double-Layer Micromesh Carotid Stent: Contemporary Results of a Single-Center Retrospective Study. Ann Vasc Surg. 2022;82:41-46. doi: 10.1016/j.avsg.2021.10.073..

2. Oushy SH, Essibayi MA, Savastano LE, Lanzino G. Carotid artery revascularization: endarterectomy versus endovascular therapy. J Neurosurg Sci. 2021;65(3):322-326. doi: 10.23736/S0390-5616.20.05207-8.

3. Saw J. Carotid artery stenting for stroke prevention. Can J Cardiol. 2014;30(1):22-34. doi: 10.1016/j.cjca.2013.09.030.

4. Thomas MA, Pearce WH, Rodriguez HE, Helenowski IB, Eskandari MK. Durability of Stroke Prevention with Carotid Endarterectomy and Carotid Stenting. Surgery. 2018; 164(6):1271-1278. doi: 10.1016/j.surg.2018.06.041.

5. Gabrielli R, Siani A, Smedile G, Rizzo AR, Accrocca F, Bartoli S. Carotid Artery Stenting versus Carotid Endarterectomy in Terms of Neuroprotection DW-MRI Detected and Neuropsychological Assessment Impairment. Ann Vasc Surg. 2024;98:68-74. doi: 10.1016/j.avsg.2023.05.046.

6. Jácome F, Oliveira-Pinto J, Dionísio A, Coelho A, Ramos JF, Mansilha A. Mini-skin longitudinal incision versus traditional longitudinal incision for carotid endarterectomy in patients with carotid artery stenosis: a systematic review and meta-analysis. Int Angiol. 2024;43(5):533-540. doi: 10.23736/S0392-9590.24.05300-8.

7. Park S, Kim BJ, Choi HY, Chang DI, Woo HG, Heo SH. Risk factors of in-stent restenosis after carotid angioplasty and stenting: long-term follow-up study. Front Neurol. 2024;15:1411045. doi: 10.3389/fneur.2024.1411045.

8. Kumar R, Batchelder A, Saratzis A, AbuRahma AF, Ringleb P, Lal BK, Mas JL, Steinbauer M, Naylor AR. Restenosis after Carotid Interventions and Its Relationship with Recurrent Ipsilateral Stroke: A Systematic Review and Meta-analysis. Eur J Vasc Endovasc Surg. 2017;53(6):766-775. doi: 10.1016/j.ejvs.2017.02.016.

9. Texakalidis P, Tzoumas A, Giannopoulos S, Jonnalagadda AK, Jabbour P, Rangel-Castilla L, Machinis T, Rivet DJ, Reavey-Cantwell J. Risk Factors for Restenosis After Carotid Revascularization: A Meta-Analysis of Hazard Ratios. World Neurosurg. 2019;125:414-424. doi: 10.1016/j.wneu.2019.02.065.

10. Achim A, Lackó D, Hüttl A, Csobay-Novák C, Csavajda Á, Sótonyi P, Merkely B, Nemes B, Ruzsa Z. Impact of Diabetes Mellitus on Early Clinical Outcome and Stent Restenosis after Carotid Artery Stenting. J Diabetes Res. 2022;2022:4196195. doi: 10.1155/2022/4196195.

11. Déglise S, Bechelli C, Allagnat F. Vascular smooth muscle cells in intimal hyperplasia, an update. Front Physiol. 2023;13:1081881. doi: 10.3389/fphys.2022.1081881.

12. Haybar H, Pezeshki SMS, Saki N. Platelets in In-stent Restenosis: From Fundamental Role to Possible Prognostic Application. Curr Cardiol Rev. 2020;16(4):285-291. doi: 10.2174/1573403X15666190620141129.

13. Datz JC, Steinbrecher I, Meier C, Hagmeyer N, Engel LC, Popp A, Pfaller MR, Schunkert H, Wall WA. Patient-specific coronary angioplasty simulations - A mixed-dimensional finite element modeling approach. Comput Biol Med. 2025;189:109914. doi: 10.1016/j.compbiomed.2025.109914.

14. Gharaibeh Y, Lee J, Zimin VN, Kolluru C, Dallan LAP, Pereira GTR, Vergara-Martel A, Kim JN, Hoori A, Dong P, Gamage PT, Gu L, Bezerra HG, Al-Kindi S, Wilson DL. Prediction of stent under-expansion in calcified coronary arteries using machine learning on intravascular optical coherence tomography images. Sci Rep. 2023;13(1):18110. doi: 10.1038/s41598-023-44610-9.

15. Tan RP, Hung JC, Chan AHP, Grant AJ, Moore MJ, Lam YT, Michael P, Wise SG. Highly reproducible rat arterial injury model of neointimal hyperplasia. PLoS One. 2023; 18(8): e0290342. doi: 10.1371/journal.pone.0290342.

16. Inoue T, Uchida T, Yaguchi I, Sakai Y, Takayanagi K, Morooka S. Stent-induced expression and activation of the leukocyte integrin Mac-1 is associated with neointimal thickening and restenosis. Circulation. 2003;107(13):1757-63. doi: 10.1161.

17. Chakraborty R, Chatterjee P, Dave JM, Ostriker AC, Greif DM, Rzucidlo EM, Martin KA. Targeting smooth muscle cell phenotypic switching in vascular disease. JVS Vasc Sci. 2021;2:79-94. doi: 10.1016/j.jvssci.2021.04.001.

18. Libby P. Inflammation during the life cycle of the atherosclerotic plaque. Cardiovasc Res. 2021;117(13):2525-2536. doi: 10.1093/cvr/cvab303.

19. Kapnisis K, Stylianou A, Kokkinidou D, Martin A, Wang D, Anderson PG, Prokopi M, Papastefanou C, Brott BC, Lemons JE, Anayiotos A. Multilevel Assessment of Stent-Induced Inflammation in the Adjacent Vascular Tissue. ACS Biomater Sci Eng. 2023;9(8):4747-4760. doi: 10.1021/acsbiomaterials.3c00540.

20. Danilovich A.I., Tarasov R.S. Long-term outcomes of myocardial and cerebral revascularization with combined or staged percutaneous interventions and carotid endarterectomy. Complex Issues of Cardiovascular Diseases. 2020;9(1):42-51. (In Russ.) doi: 10.17802/2306-1278-2020-9-1-42-51.

21.