Relationship between carotid plaque characteristics and new ischemic lesions after stenting detected by computed tomography angiography

Abstract

Background

Although carotid artery stenting achieves definite benefits, it carries a higher rate of embolization compared with carotid endarterectomy. The incidence of embolization may be related to plaque stability.

Purpose

To assess for any relationship between plaque characteristics and cerebral emboli following carotid artery stenting.

Material and Methods

Sixty-three patients with severe carotid stenosis underwent carotid artery stenting. They were divided into two groups according to whether new ischemic lesions were detected on diffusion-weighted imaging after carotid artery stenting. We evaluated the types and locations of calcification in plaques and extent of calcification. We then assessed for a correlation between each of these factors and occurrence of new lesions on diffusion-weighted imaging after carotid artery stenting.

Results

The locations of calcification, percentage of plaque enhancement, and the number of plaques with irregular surface or ulceration were significantly different between the two groups. A peripheral position of calcification (close to the adventitia), enhancing plaques, and plaques with irregular surfaces or ulceration were statistically significant predictors of intracerebral embolization after carotid artery stenting. No significant differences in type of plaque or degree of calcification were found between two groups.

Conclusion

Peripheral calcification, enhancing plaques, and plaques with irregular surfaces were risk factors for intracerebral embolization after carotid artery stenting. These plaque characteristics should be considered when choosing the optimal treatment for patients.

Keywords

Carotid plaque carotid artery stenting computed tomography angiography calcification enhanced plaques ulceration

Introduction

In China, as more patients undergo carotid artery stenting (CAS) to relieve stenosis, the shortcomings of stenting, as well as the benefits, are becoming apparent. Periprocedural embolization occurs more frequently with CAS than with carotid endarterectomy (1). Infarction of a functional region inevitably affects the patient’s quality of life. Therefore, evaluation of plaque characteristics is important to choose the optimal interventional therapy.

Plaque stability is related to many factors, such as the composition of the plaque, the thickness of the fibrous cap, and the severity of the inflammatory reaction. Some studies have revealed that a lipid core is an important marker of carotid plaque vulnerability (2).

Findings regarding the role of calcification in plaque stability have been inconsistent. Some researchers found that calcification is independently associated with unstable plaques and increased cerebrovascular morbidity and mortality (3). Other reports have found that calcified plaques are less likely to be symptomatic and might be more stable than non-calcified plaques (4). This discrepancy may be related to many factors such as differences in inclusion criteria, patient population diversity, and procedural differences. Plaque surface morphology and plaque enhancement are also significant factors associated with plaque stability (5,6).

Compared with catheter-based angiography, some modalities seem less invasive and more prevalent in clinical practice, such as ultrasound (US), computer tomography (CT), and magnetic resonance imaging (MRI). Two-dimensional (2D) US has the advantage of no radiation and low expense. However, this examination is operator-dependent. Intravascular US can evaluate the characteristics of plaque but is invasive. High-resolution MRI is a non-invasive examination. It has the advantage of multiple sequence imaging and high tissue resolution. However, it has some disadvantages that limit its clinical application, such as the long scanning time, which makes it difficult to perform on an emergency basis and in unstable patients, its vulnerability to motion artifact, and its contraindication in patients with artificial pacemakers or other metal implants. Compared with vascular US and MRI, CT angiography (CTA) has the advantages of short scanning time, high spatial resolution, and fewer contraindications. CT is also very sensitive to calcification, making CTA a better methodology for evaluating calcification than MRI. Recently, CTA has been widely used for the detection of carotid plaques and vascular stenoses. Therefore, we also intend to use CTA to investigate the relationship between plaque characteristics and the development of new ischemic lesions after CAS.

Material and Methods

Patient population

A single-center, retrospective trial was conducted from January 2014 to August 2017. We collected data from patients in the Department of Neurosurgery who had undergone CAS. The medical history of all patients was assessed (including the presence of heart diseases or diabetes, history of hypertension, serum lipid concentration, and history of drug use, smoking, and aspirin use). Physical examinations, laboratory testing, and imaging examinations were also conducted including blood biochemistry tests, chest radiography, echocardiography, transcranial Doppler sonography, EKG, CTA, and MRI of the brain.

The inclusion criteria were: an interval of < 3 weeks between preoperative CTA and CAS; performance of preoperative MRI within two weeks before CAS; and performance of postoperative MRI 1–2 days after CAS.

The exclusion criteria were cardiogenic embolism, intracranial vascular disease, posterior circulation disease, restenosis after vascular intervention, new ischemic lesions outside the territory of the treated vasculature, and incomplete clinical data.

A total of 63 participants were enrolled in this study. The degree of carotid stenosis of all patients was moderate-to-severe according to NASCET criteria. Each patient signed a written consent. This research conformed to principles outlined in the Declaration of Helsinki.

CTA scanning and postprocessing

Scan parameters

CTA data were acquired with a 128-row multidetector CT scanner (Somatom Force®, Siemens, Munich, Germany). All patients were scanned from the aortic arch to the supraventricular white matter. The scan parameters were: tube voltage = 80 kV; automatic adjustment of the tube current according to the patients’ size; pitch = 1; slice thickness = 0.75 mm; layer spacing = 0.4 mm; rotation time = 0.5 s; field of view = 19–22 cm; matrix size = 512 × 512.

Contrast agent

After the non-contrast scan, the angiographic phase was acquired with 65 mL contrast (Ultravist 370®, BayerSchering Pharma, Berlin, Germany) at a flow rate of 5 mL/s. The precise timing of the injection was obtained with a test-bolus technique.

Postprocessing of the CTA images

Postprocessing of the CTA data was performed on a workstation (syngofastView®, Siemens Healthineers, Erlangen, Germany). We used iterative reconstruction methods and generated volume rendering (VR), maximum intensity projection (MIP), multiplanar reconstruction (MPR), and curved-planar reconstruction (CPR) angiographic images.

Evaluation of plaque type

The window level was set at 100–150 HU and the width at 250–350HU. Two reviewers, who are experienced neuroradiologists, evaluated the CTA images. Eight randomly selected points were chosen in at least three different axial slices to measure the density of each analyzed plaque. A plaque was considered fibrocalcific if the mean attenuation was ≥130 HU and occupied ≥50% of the plaque volume. Otherwise, the plaque was considered fibrofatty (7,8).

Fraction of calcification in the carotid plaque

The volume of plaque was calculated by the following formula: A × B × C/2 (9). Calcification was considered separate if no continuity was observed on the same and adjacent sections. The total percentage volume of calcification was calculated by summing the volume of the non-contiguous calcification in the carotid plaque. The percentage of each plaque calcification (R) was then calculated by the following formula: R = total volume of calcification/volume of carotid plaque.

Location of carotid plaque calcification

The location of the calcification in carotid plaque was scored on enhanced CT as follows: 1 = inner side (adjacent to intima) of the carotid wall only; 2 = inner side more than outer side; 3 = inner side = outer side (mainly located in media); 4 = inner side less than outer side; and 5 = outer side of the carotid wall only (adjacent to adventitia) (Fig. 1) (10).

Assessment of carotid plaque enhancement

The threshold for plaque enhancement was ≥10 HU (11).

Evaluation of plaque surface morphology

Ulceration of plaque was defined as contrast material extending beyond the vascular lumen into the plaque. Plaques were defined as “irregular” if the plaque surface appeared rough without any sign of ulceration. If the plaque was not ulcerated or irregular, it was deemed smooth (Fig. 2).

MRI

MRI scans were conducted using a 3.0-T scanner (MAGNETOM Verio®, Siemens). Two other experienced neuroradiologists who were blinded to CTA results evaluated the MRI.

The imaging protocol and parameters were as follows: transverse T1-weighted imaging (TE = 3.05 ms, TR = 160 ms, section thickness = 5.0 mm); T2-weighted spin-echo (TE = 93 ms, TR = 4700 ms, section thickness = 5.0 mm); fluid-attenuated inversion recovery (TE = 94 ms, TR = 8000 ms, inversion time = 2371.5 ms, section thickness = 5.0 mm), and diffusion-weighted imaging (DWI) (TE = 90 ms, TR = 5500 ms, b = 1000 s/mm², section thickness = 5.0 mm). Apparent diffusion coefficient (ADC) maps were generated in all cases.

Interventional protocol

Patients were asked to take a combination of aspirin (100 mg/day) and clopidogrel (75 mg/day) for 3–5 days before the procedure. If patients had not taken clopidogrel before, they were asked to take a 300 mg loading dose. During CAS, heparin was used before catheterization to maintain an Activated Clotting Time of Whole Blood of 250–300 s.

All stenting procedures were performed by the same neurosurgeon. Embolic protection devices were used (AngioGuard®, Cordis, Milpitas, CA, USA orSpiderFX®, ev3 Inc., Plymouth, MN, USA). Predilation of the lesion was performed in 49 patients with a single inflation (30 patients in group 1 and 19 patients in group 2). The size of the balloons varied according to the vessel caliber. Stent (Wallstent®, Boston Scientific, Marlborough, MA, USA; Protégé®, ev3 Inc. or Precise®, Cordis) size was determined according to the degree of stenosis. Dilation after stent placement was conducted in 13 patients (eight patients in group 1 and five patients in group 2).

Finally, low-molecular-weight heparin was used for 72 h after CAS; the patients were instructed to take clopidogrel (75 mg/day) and aspirin (100 mg/day) for three months, followed by lifelong clopidogrel (75 mg/day) or aspirin (100 mg/day).

Statistical analysis

Continuous data are presented as mean ± standard deviation. Continuous variables were compared by an independent samples t-test and categorical variables were compared by a Chi-squared test. Logistic regression analysis was performed to assess the association between the occurrence of new lesions on DWI and the carotid plaque characteristics. A P value < 0.05 was considered significant. Inter-rater agreement regarding the degree of stenosis was determined by Cohen’s κ statistic. Commercial software (SPSS v.18®, SPSS Inc., Chicago, IL, USA) was used to analyze the data.

Results

The demographic and clinical characteristics of the population are summarized in Table 1. The participants were divided into a new infarction group (group 1 = 38 cases) and a non-infarction group (group 2 = 25 cases), according to whether a new-onset infarction in the territory of the stented artery was observed on postoperative DWI.

Table 1.

Baseline patient demographics.

	Total (n = 63)	Group 1 (n = 38)	Group 2 (n = 25)	P
Age (years) (mean ± SD)	64.78 ± 8.13	64.47 ± 8.29	65.30 ± 8.05	0.724
Male:female ratio	55:8	33:5	22:3	0.606
Vascular risk factors (n (%))
Hypertension	44 (69.84)	27 (71.05)	17 (68.00)	0.506
Diabetes	22 (34.92)	13 (34.21)	9 (36.00)	0.547
Hyperlipidemia	11 (17.46)	8 (21.02)	3 (12.00)	0.503
Congenital heart diseases	3 (4.76)	1 (2.63)	2 (8.00)	0.557
Atrial fibrillation	1 (1.59)	1 (2.63)	0	0.603
Smoking	36 (57.14)	20 (52.63)	16 (64.00)	0.265
Drinking	25 (39.68)	15 (39.48)	10 (40.00)	0.586
Degree of cartiod stenosis (moderate/severe)	19/44	10/28	9/16	0.581

SD: standard deviation.

No significant differences in age, clinical characteristics, vascular risk factors, or history of smoking or drinking were found between the two groups. No significant differences in CAS-related factors were found between the two groups (Table 2).

Table 2.

CAS-related element.

	Total (n = 63)	Group 1 (n = 38)	Group 2 (n = 25)	P
Balloon size (mm)	4.86 ± 0.74	4.95 ± 0.49	4.57 ± 1.24	0.248
Balloon length (mm)	26.75 ± 5.60	27.14 ± 4.63	25.57 ± 8.20	0.644
Stent diameter (mm)	8.21 ± 1.26	8.24 ± 0.83	8.13 ± 2.10	0.886
Stent length (mm)	37.10 ± 1.50	37.62 ± 6.24	35.63 ± 10.5	0.532
Type of protection devices
AngioGuard	42 (67.67)	25 (65.79)	17 (68.00)	0.600
Spider RX	21 (32.34)	13 (34.21)	8 (32.00)
Type of stent
Wallstent	25 (40.82)	15 (40.63)	10 (40.00)	0.692
Protégé	14 (22.45)	8 (21.88)	6 (24.00)
Precise	24 (36.73)	15 (37.50)	9 (36.00)
Patients for predilation	49 (77.78)	30 (79.04)	19 (76.00)	0.778
Patients for prodilation	13 (20.63)	8 (21.05)	5 (20.00)	0.665
Aortic arch
Type 1	37 (58.73)	23 (60.53)	14 (56.00)	0.932
Type 2	21 (33.33)	12 (31.58)	9 (36.00)
Type 3	5 (7.93)	3 (7.89)	2 (8.00)
Carotid artery for CAS (left/right)	26/37	15/23	11/14	0.461

Values are presented as mean ± SD or n (%).

SD: standard deviation; CAD: carotid artery stenting.

The plaques were all located near the carotid bifurcation. In group 1,17 patients had fibrocalcified plaque and 21 patients had fibrofatty plaque. In group 2, 11 patients had fibrocalcified plaque and 14 patients had fibrofatty plaque. No significant differences in plaque types were found between the two groups (Table 3).

Table 3.

The characteristics of plaque.

	Total (n = 63)	Group 1 (n = 38)	Group 2 (n = 25)	P
Plaque length (cm)	1.71 ± 0.66	1.74 ± 0.71	1.61 ± 0.53	0.600
Fibrocalcified plaque	28 (44.45)	17 (44.70)	11 (44.00)	0.580
Fibrofatty plaques	35 (55.55)	21 (55.30)	14 (56.00)
Fraction of calcification (%)	43.21 ± 25.1	37.84 ± 21.2	51.38 ± 28.8	0.073
Ca location score	3.04 ± 1.33	3.53 ± 1.24	2.29 ± 1.10	0.001
Enhanced plaque	15 (23.81)	14 (36.84)	1 (4.0)	0.002
Volume of plaque (cm³)	2.03 ± 1.75	1.87 ± 1.47	2.59 ± 2.53	0.384
Plaques with irregular surface or ulceration	34 (53.97)	26 (68.42)	8 (32.00)	0.048

Values are presented as mean ± SD or n (%).

SD: standard deviation; CAS: carotid artery stenting.

The mean scores for the location of calcification in groups 1 and 2 were 3.53 ± 1.24 and 2.29 ± 1.10, respectively, with a significant difference (P = 0.001) (Table 3, Fig. 3).

The volume of plaque in groups 1 and 2 were 1.87 ± 1.47 cm³ and 2.59 ± 2.53 cm³, respectively. The fraction of calcification in groups 1 and 2 were 37.84 ± 21.2% and 51.38 ± 28.8%. There was no significant difference for the two factors between the two groups (Table 3).

In groups 1 and 2, 14 (36.84%) cases and 1 (4.00%) case, respectively, had enhancing plaques (P = 0.002) (Table 3, Fig. 4).

In groups 1 and 2, 26 (68.42%) cases and 8 (32.00%) cases, respectively, had plaques with irregular surface or ulceration (P = 0.048) (Table 3, Fig. 5).

The logistic regression test was used to detect the correlation between the occurrence of new lesions on DWI and the carotid plaque characteristics. We found that a peripheral position of the calcification, plaque enhancement, and plaques with irregular surfaces or ulceration were risk factors for embolization after CAS (P = 0.034, 0.022, 0.049; odds ratios = 13.89, 21.84, 1.92) (Table 4).

Table 4.

Logistic regression analysis of assessment of plaque characteristics of carotid bifurcation as risk factors.

Plaque	Group 1	Group 2	P	OR	95% CI
Ca location score	3.53 ± 1.24	2.29 ± 1.10	0.034	13.89	1.22–157.7
Enhanced plaque	14 (36.84)	1 (4.00)	0.022	21.84	1.57–304.1
Ca fraction (%)	37.84 ± 21.2	51.38 ± 21.8	0.146	0.31	0.06–1.50
Type of plaque	21 (55.30)	14 (56.00)	0.068	8.14	0.80–80.59
Volume of plaque (cm³)	1.87 ± 1.47	2.59 ± 2.53	0.200	0.35	0.07–1.73
Plaques with irregular surface or ulceration	26 (68.42)	8 (32.00)	0.049	1.92	1.00–3.67

Values are presented as mean ± SD or n (%).

OR: odds ratio; CI: confidence interval; SD: standard deviation.

Five cases, all in group 1, had new symptoms after CAS. Two cases developed dyskinesia: one case made a full recovery after two days, the other could not return to preoperative level before leaving hospital. One case had somatosensory impairment but made a full recovery after one day; one case had dizziness and one case had transient memory loss. These above symptoms disappeared over 1–3 days.

Some patients followed up in local hospitals instead of returning to our hospital. Fifty-one cases followed up in our hospital after one month. During the follow-up, four had new DWI lesions inside the treated vascular territory. One patient had a Transient Ischemic Attack on the side of the stent without new DWI lesions.

Discussion

Periprocedural embolization is a major disadvantage of CAS. The incidence of new infarctions is absolutely higher after CAS than after carotid endarterectomy (12). We found that the plaque characteristics contribute to this condition. These factors must be evaluated when clinicians choose the most suitable therapeutic methods for patients.

The present study with CTA showed that a peripheral position of calcification in plaque was an independent predictor of intraoperative and postoperative embolization. Calcification in the vascular wall can increase the incidence of cardiovascular events and the mortality by 3–4 times (13). More and more studies provide a relationship between calcification and post-procedural complications following CAS. Khan et al. found calcification was associated with a higher stroke rate compared with lesions without calcification after CAS (14). Jang et al. also detected calcification as a risk factor leading to postoperative stroke. Heavy calcification in a lesion may cause difficulties in stent positioning, lesion dilatation, and adequate stent expansion, which might result in a higher rate of embolization (15). A single-center study found concentric calcification of the carotid artery could also increase the risk of myocardial infarction, death, and all complications (16). Our study further found that a peripheral location of calcification was more highly correlated with post-procedural stroke following CAS. Calcification in the adventitia and tunica media is the dominant predictive factor for cardiovascular mortality, more so than in the intima (17). Calcification in the elastic layer or adventitia of the artery can lead to stiffening of the arterial wall and reduced compliance of the plaque (17). However, the luminal gain achieved by stent placement primarily depends on plaque compression and stretching of the vessel wall (18). Compared with microcalcification locating in intima, calcification in the tunica media intend to be sheet-like (19) and diffuse calcification was also prevalent in the collagen-rich tissue (18). Therefore, calcification in the tunica media tend to be larger and could lead to less elastic tissue and less plaque compliance. Thus, calcification in adventitia and the tunica media may lower the success rate of CAS and increase the incidence of distal embolization. It has been suggested that, when expanding the lumen and stretching the calcified plaque and vascular wall, high-pressure balloon inflation should be used to overcome resistance of calcific adventitia or tunica media (20,21). The high stress is likely to increase the unbalanced stress at the interface between the calcification and non-calcified tissue (22). Therefore, the carotid plaque easily ruptures in patients with a more peripheral calcification in the plaque.

The percentage of plaque enhancement was also different between the two groups. The vasa vasorum tend to proliferate and grow into plaque in the course of atherosclerosis. Neovascularization is a sign of plaque inflammation, which is a characteristic of plaque instability (23). This plays an important role in the progression of a plaque and contributes to fibrous cap rupture and intraplaque hemorrhage (24). Some studies have shown that enhancement of carotid plaques on CTA was more frequently observed in symptomatic lesions (25). Hence, enhancement is significantly associated with the vulnerability of the plaque. Detecting plaque enhancement may help neurosurgeons to determine whether patients are suitable for CAS.

The plaque surface morphology was significantly different between the two groups. A fibrous cap can rupture under the stress of blood flow, leading to an irregular surface. Components of plaque enter the vascular lumen through the rupture. The site of ulceration is mostly proximal to the most stenotic site. Because of this, when a guidewire is passed through the most stenotic site during CAS, it comes in contact with the ulcerated surface, which may lead to embolization. Liu et al. reported that ulcerated plaques could increase the incidence of ischemic stroke after CAS (26).

There was no significant difference for fibrocalcific or fibrofatty plaques when evaluating the risk of intracerebral embolization after CAS. This result differs with a study by Stojanov et al., who reported that fibrofatty plaques were associated with a significantly higher number of new cerebral lesions (27). Some factors might contribute to this inconsistency, including the small sample size of patients with new embolism after CAS in Stojanov et al., diverse features of participants. As this was a retrospective study, some patients deemed unsuitable for CAS may have been excluded, which may have introduced selection bias.

There were several limitations in this study. First, the sex ratio of the participants was unbalanced. However, it might indicate the trend of cerebrovascular disease in China, more male patients than female patients. The sex ratio of participants between the two groups had no significant differences; we also found no influence when taking sex ratio as a covariant quantity. Second, when evaluating enhanced plaque in our analysis, breathing and deglutition could alter the position of the carotid artery between the baseline and contrast scans. In order to match the two phase images, we manually matched the two images and drew the region of interest. However, this was operator-dependent. Third, when evaluating plaque enhancement, the CTA scans did not include a delayed phase (28). However, plaque enhancement in the arterial phase was still significantly different between the two groups. Fourth, the sample size was small and we lacked complete follow-up data on the participants.

In conclusion, peripheral position of calcification in plaques, enhancement of carotid plaques, and plaques with irregular surface or ulceration are risk factors for new embolization and infarction after CAS. CTA is an important technique for evaluating vascular stenosis and characteristics of plaque before treatment. To some degree, this research has some practical value.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors received financial support from Beijing Municipal Administration of Hospitals’ Ascent Plan (Code: DFL20180802).

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