Is it time to look into the carotid plaque DNA?

Assessing the risk of a carotid plaque has long been a “size-centric” discussion.

Based on pivotal trials(1,2) current 2021 ESO guidelines (3) recommend endarterectomy within two weeks in patients with symptomatic ≥50% carotid stenosis or stenting if patient is <70 years-old. In patients with mild (<50%) symptomatic carotid artery stenosis, a very-low quality evidence recommendation is stated against revascularization. However, is the risk of stroke from a carotid plaque solely determined by the degree of stenosis? What if we move from the concept of a stenotic plaque towards a vulnerable plaque? In the same pivotal trials, control arm data have shown us that 40% of patients with stroke on follow-up had <50% stenosis and long-term risk of ipsilateral stroke in these patients was 18.7% in the NASCET and 8.2% in the ECST trials.(4) In CARE-II study (5), a cross-sectional 1047 patient study, maximum wall thickness was a stronger indicator of high risk plaque than luminal stenosis. On the other hand, stroke risk in stenotic plaques was partly accounted the parallel increase in plaque surface irregularity and thrombus formation.(6) How should we then define a vulnerable plaque? My suggestion is that we look into the Dimension, Nature and Activity of the plaque.  In the Dimension category, we should value the volume and thickness beyond the degree of the stenosis. Volume represents better plaques that grow outward and PARISK study (7) – a 5-year longitudinal study of 244 patients with symptomatic plaques, 96% of which had <50% stenosis - has shown volume to be clearly associated with stroke recurrence. Thickness (a cut-off of 3mm has been proposed(8)), which is more easily measured, has also shown a trend towards recurrent event in the same study. In the Nature section, one should take into several features. First, the morphology of the lumen surface. Irregularity and, particularly, ulceration (>1mm depth defect) are highly thrombogenic.(9) Second, the content of the plaque. Intraplaque hemorrhage (IPH) (assessed by T1-fat sat MRI) has been, in PARISK, the strongest imaging parameter associated with recurrence. A lipid-rich necrotic core (LRNC) associated with a thin fibrous cap has also shown to be associated with plaque vulnerability.(10) In the absence of MRI, ultrasound is a valuable tool, since an echolucent/hipoecogenic (dark) which may correspond to either IPH or LRNC is deemed as a high risk feature.(11–13) Imaging inflammation and neovascularization by PET and contrast-enhanced ultrasound also may guide us in assessing vulnerability(14). As far as Activity is concerned, plaque growth,(15) silent MRI embolic lesions(15,16) and microembolic signals(17) are examples of an active and, therefore, vulnerable plaque. A comprehensive “DNA” approach to a carotid plaque may inform us better on the stroke etiology and appropriate treatment. Therefore, aggressive medical therapy and even revascularization could be considered in symptomatic nonstenotic plaques.(8,18)

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 References:

1. North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics, and progress. Stroke. 1991 Jun;22(6):711–20.
2. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998 May 9;351(9113):1379-87. PMID: 9593407
3. Bonati LH, Kakkos S, Berkefeld J, de Borst GJ, Bulbulia R, Halliday A, et al. European Stroke Organisation guideline on endarterectomy and stenting for carotid artery stenosis. Eur Stroke J. 2021 Jun;6(2):I–XLVII.
4. Singh N, Marko M, Ospel JM, Goyal M, Almekhlafi M. The Risk of Stroke and TIA in Nonstenotic Carotid Plaques: A Systematic Review and Meta-Analysis. AJNR Am J Neuroradiol. 2020 Aug;41(8):1453–9.
5. Zhao X, Hippe DS, Li R, Canton GM, Sui B, Song Y, et al. Prevalence and Characteristics of Carotid Artery High-Risk Atherosclerotic Plaques in Chinese Patients With Cerebrovascular Symptoms: A Chinese Atherosclerosis Risk Evaluation II Study. J Am Heart Assoc. 2017 Aug 14;6(8).
6. Rothwell PM, Gibson R, Warlow CP. Interrelation between plaque surface morphology and degree of stenosis on carotid angiograms and the risk of ischemic stroke in patients with symptomatic carotid stenosis. On behalf of the European Carotid Surgery Trialists’ Collaborative  Group. Stroke. 2000 Mar;31(3):615–21.
7. van der Toorn JE, Bos D, Ikram MK, Verwoert GC, van der Lugt A, Ikram MA, et al. Carotid Plaque Composition and Prediction of Incident Atherosclerotic Cardiovascular Disease. Circ Cardiovasc Imaging. 2022 Mar;15(3):e013602.
8. Ospel JM, Kappelhof M, Ganesh A, Kallmes DF, Brinjikji W, Goyal M. Symptomatic non-stenotic carotid disease: current challenges and opportunities for diagnosis and treatment. J NeuroInterventional Surg. 2023 Apr 17;jnis-2022-020005.
9. Sitzer M, Müller W, Siebler M, Hort W, Kniemeyer HW, Jäncke L, et al. Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. Stroke. 1995 Jul;26(7):1231–3.
10. Saba L, Saam T, Jäger HR, Yuan C, Hatsukami TS, Saloner D, et al. Imaging biomarkers of vulnerable carotid plaques for stroke risk prediction and their potential clinical implications. Lancet Neurol. 2019 Jun;18(6):559–72.
11. Kakkos SK, Griffin MB, Nicolaides AN, Kyriacou E, Sabetai MM, Tegos T, et al. The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke. J Vasc Surg. 2013 Mar 1;57(3):609-618.e1.
12. Brinjikji W, Rabinstein AA, Lanzino G, Murad MH, Williamson EE, DeMarco JK, et al. Ultrasound Characteristics of Symptomatic Carotid Plaques: A Systematic Review and Meta-Analysis. Cerebrovasc Dis. 2015;40(3–4):165–74.
13. Jashari F, Ibrahimi P, Bajraktari G, Grönlund C, Wester P, Henein MY. Carotid plaque echogenicity predicts cerebrovascular symptoms: a systematic review and meta-analysis. Eur J Neurol. 2016;23(7):1241–7.
14. Demeure F, Bouzin C, Roelants V, Bol A, Verhelst R, Astarci P, Gerber BL, Pouleur AC, Pasquet A, de Meester C, Vanoverschelde JJ, Vancraeynest D. Head-to-Head Comparison of Inflammation and Neovascularization in Human Carotid Plaques: Implications for the Imaging of Vulnerable Plaques. Circ Cardiovasc Imaging. 2017 May;10(5):e005846.
15. Mono ML, Karameshev A, Slotboom J, Remonda L, Galimanis A, Jung S, et al. Plaque Characteristics of Asymptomatic Carotid Stenosis and Risk of Stroke. Cerebrovasc Dis. 2012 Nov 14;34(5–6):343–50.
16. Baradaran H, Gialdini G, Mtui E, Askin G, Kamel H, Gupta A. Silent Brain Infarction in Patients With Asymptomatic Carotid Artery Atherosclerotic Disease. Stroke. 2016 May;47(5):1368–70.
17. Altaf N, Kandiyil N, Hosseini A, Mehta R, MacSweeney S, Auer D. Risk Factors Associated With Cerebrovascular Recurrence in Symptomatic Carotid Disease: A Comparative Study of Carotid Plaque Morphology, Microemboli Assessment and the European Carotid Surgery Trial Risk Model. J Am Heart Assoc. 3(3):e000173.
18. Larson A, Nardi V, Brinjikji W, Benson J, Lanzino G, Savastano L. Endarterectomy for symptomatic non-stenotic carotids: a systematic review and descriptive analysis. Stroke Vasc Neurol. 2021 Jul 8;7(1):6–12.