Risk factors for recurrent ischemic events in symptomatic carotid artery stenosis on CT angiography

Carotid artery stenosis is a leading cause of recurrent stroke. ¹ However, the efficacy of revascularization for symptomatic carotid stenosis with mild to moderate stenosis has not been established. ² The recurrent ischemia in symptomatic carotid stenosis is associated with vulnerable plaque. ³ With the advancement of medical treatment, new risk stratification including vulnerable plaque is necessary for surgical indication. Recent reports showed that rim sign (plaque adventitial calcification) or ulceration on computed tomography angiography (CTA) is correlated with intraplaque hemorrhage (IPH) or symptomatic carotid artery stenosis.^1,4–6 We aim to investigate the association of recurrent ischemic events in symptomatic mild to moderate carotid stenosis with specific plaque findings on CTA.

This retrospective case–control study included patients with symptomatic carotid artery stenosis who were admitted to our hospital from January 2014 to March 2022 and discussed treatment options (281 patients and 282 carotid arteries). The study protocol was approved by the institutional review board (IRB approval no. M30-013) and the requirement for informed consent was waived due to its retrospective nature.

Patients with stroke due to etiologies other than carotid artery stenosis were excluded from this population. The observation period was 3 months. Patients without available carotid CTA data, those with severe carotid artery stenosis (70–99% by North American Symptomatic Carotid End-arterectomy Trial (NASCET criteria), those who underwent surgical revascularization before a recurrent ischemic event, and those who did not receive the appropriate medical treatment were excluded. An ischemic event was defined as a clinical ipsilateral cerebral infarction or transient ischemic attack attributable to carotid artery stenosis. Recurrent isc-hemic events were defined as the combination of clinical ipsilateral recurrent ischemia and neuroradiographic evaluation despite the appropriate medical treatment. The appropriate medical treatment included maintaining blood pressure under control, treatment of diabetes mellitus by specialists, and aggressive lipid-lowering. The clinical characteristics are listed in the online Supplementary Table.

CTA images were obtained from the aortic arch through the skull vertex. The interactive window/level setting was usually set at W850.L300. ⁶ The images were evaluated by two blinded neurosurgeons (TT and KY). CTA markers included the degree of stenosis (NASCET criteria) and presence of rim sign, ulceration, and intraluminal thrombus. A positive rim sign was defined as adventitial calcification (< 2 mm thickness) with internal soft plaque (> 2 mm thickness) (Figure 1).^1,4–6 Ulceration was determined as a depression of 1 mm or more. ⁷

Figure 1.

Kaplan-Meier curves of the event-free rate in cases with and without the Rim sign in mild to moderate carotid artery stenosis.

Variables were expressed as means ± SD or the number of patients (%), as appropriate. Nominal variables were compared using Fisher’s exact test. Differences were considered statistically significant at p < 0.05.

A total of 81 carotid arteries (81 patients; 76 ± 7 years) with mild to moderate stenosis were included in the analysis. Recurrent ischemic events were observed in 25 (31%) patients. There was no difference in clinical characteristics between the groups in the analysis of the patients. Carotid plaques showed rim sign or ulceration more frequently in the recurrence group than in the nonrecurrence group (rim sign: 72% vs 45%, p = 0.030, odds ratio = 3.1; ulceration: 64% vs 34%, p = 0.016, odds ratio = 3.4).

In Kaplan–Meier curves comparing cases with and without rim sign, the difference in the event-free rates widened as time from the primary ischemic event increased in patients with mild to moderate carotid artery stenosis (p = 0.021) (Figure 1).

This result represents a novel revelation, suggesting that the presence of rim sign could increase the risk of recurrent ischemia in mild to moderate carotid stenosis. Patients with rim sign were found to be more susceptible to recurrent ischemic events early after onset.

Regarding the mechanism of adventitial calcification in rim sign, bone morphogenic protein stimulates pathways leading to vascular adventitial calcification. ⁸ Further, the numbers of CD68-positive cells and CD31-positive microvessels at the edge of carotid plaque were higher in those with thin calcification. ⁹ Adventitial calcification may be a marker of adventitial neo-vessel and inflammatory cells.

Pathological IPH can be identified as high signal intensity on T1-weighted images in magnetic resonance imaging (MRI). ¹ However, CTA has advantages over MRI in visualizing calcifications. ¹⁰ Furthermore, this study suggested that it is possible to detect plaques with a high risk of recurrence in situations where MRI is not available or feasible. ¹⁰

The limitations of this study include its single-center, retrospective design, and the small sample size. Furthermore, the follow-up period is short. Ideally, the follow-up period for clinical outcomes is preferred to be 1–2 years. Patients with severe renal dysfunction were not included as they did not undergo CTA. To further strengthen the conclusions of this study, a large-scale, prospective examination is required.

Rim sign and ulceration are potential indicators for recurrent ischemic events in mild to moderate carotid artery stenosis. These findings may contribute to the treatment approach for symptomatic carotid stenosis.

Supplemental Material

sj-pdf-1-vmj-10.1177_1358863X231225463 – Supplemental material for Risk factors for recurrent ischemic events in symptomatic carotid artery stenosis on CT angiography

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X231225463 for Risk factors for recurrent ischemic events in symptomatic carotid artery stenosis on CT angiography by Takeyoshi Tsutsui, Kiyofumi Yamada, Taichi Ikedo, Yoshiaki Morita, Eika Hamano, Hirotoshi Imamura, Hisae Mori, Koji Iihara and Hiroharu Kataoka in Vascular Medicine