Length of Carotid Plaque Impacts Retinal Microvascular Densities of Carotid Artery Stenosis Patients

Abstract

Purpose: We explored the retinal microvascular changes in carotid artery stenosis (CAS) and their relationship with carotid plaque morphology.

Methods: All participants were diagnosed with carotid artery stenosis by a neurologist. Participants underwent digital subtraction angiography (DSA) and optical coherence tomography angiography (OCTA) imaging. The degree and length of carotid plaque were obtained from the DSA tool. OCTA tool measured the densities in the superficial vascular complex (SVC) and deep vascular complex (DVC).

Results: One hundred seventeen patients with CAS patients were included in our data analysis. Eyes with ipsilateral stenosis had reduced retinal microvascular densities when compared to contralateral eyes in patients with CAS (P = 0.016 for SVC, and P = 0.004 for DVC). Microvascular densities correlated with the length of carotid plaque (P = 0.015 for SVC, and P = 0.022 for DVC) in our CAS cohort, although they did not correlate with the degree of carotid plaque (P = 0.264 for SVC, and P = 0.298 for DVC). However, when stratified into moderate and severe subgroups, the degree of carotid plaque correlated with microvascular densities in patients with severe stenosis (P = 0.045 for SVC, and P = 0.038 for DVC).

Conclusions: Our study suggests that OCTA can noninvasively detect retinal microvascular changes in patients with CAS and that these changes correlated with the length of the stenosis, but future studies are required to confirm these findings.

Translational Relevance: Noninvasive and rapid acquisition of the OCTA image might have the potential to be used as a screening tool to detect microvascular changes in carotid artery stenosis.

Introduction

Carotid artery stenosis (CAS) is a complex disease that can result in a broad spectrum of neurological disorders, such as ischemic stroke¹ and dementia.² As the ophthalmic artery directly arises from the internal carotid artery (ICA), ophthalmic manifestations, such as visual impairment³ and amaurosis fugax,⁴ are commonly reported in patients with CAS. 

Previous reports utilized different ophthalmic imaging tools to assess the ocular changes in patients with CAS.⁵ Color Doppler imaging studies showed patients with CAS had reduced ophthalmic blood flow when compared to controls and improved significantly after surgical treatment.⁵ Fluorescein angiography (FA) was previously suggested as a tool for detecting vascular changes associated with CAS; however, this retinal imaging tool does not quantify capillary changes and does not typically show visible changes unless the CAS is very severe.^3,5 

Optical coherence tomography angiography (OCTA) is an ocular imaging modality that can noninvasively provide angiograms of the retinal microvasculature.⁶ OCTA imaging provides in-depth information, allowing the visualization of the retinal microvasculature in different retinal layers.^5,6 Accumulating reports using different OCTA tools showed ipsilateral eyes of patients with CAS have reduced microvascular densities when compared to the contralateral eyes of patients with CAS and controls,^7–10 whereas some studies did not find those differences.^10–12 Recent studies suggested that the degree and length of stenosis influence the blood flow in patients with CAS,^13,14 and are risk factors for ischemic stroke and death; the authors suggested that a higher degree and longer length of stenosis resulted in a significant decrease in ICA flow. However, the impact of the degree and length of stenosis on the retina in CAS is less explored. 

Therefore, our current study aimed to explore retinal microvasculature changes in patients with CAS and investigate the association among stenotic degree, length, and retinal microvasculature. We hypothesize that the retinal microvasculature of eyes with ipsilateral stenosis is reduced when compared with contralateral eyes and retinal microvasculature densities may correlate with the length and degree of stenosis in patients with CAS. 

Methods

This observational study was performed as part of an ongoing prospective study that consecutively recruits patients with CAS. The Ethics Committee of West China Hospital of Sichuan University approved this observational study. Written informed consent was obtained from all participants following the Declaration of Helsinki. 

Inclusion and Exclusion Criteria

Patients with CAS were included from April 2021 to June 2022 in the Neurology Department of West China Hospital. The inclusion criteria of our study were as follows: (1) age ≥ 18 years old, (2) degree of carotid stenosis ≥ 50% and ≤ 99% as confirmed by digital subtraction angiography (DSA), (3) patients who could cooperate with an OCTA examination. Patients with the following were excluded: (1) non-atherosclerotic CAS (e.g. vasculitis and dissection), (2) with arteriovenous malformation or aneurysm affirmed by DSA or with other neurological diseases, like multiple sclerosis, neuromyelitis optica, and Alzheimer's diseases, (3) OCTA image with signal quality less than 8, (4) relevant ophthalmic disorders that could affect the retinal structure (e.g. age-related macular degeneration [AMD], diabetic retinopathy, and glaucoma) or signal quality (e.g. severe cataract), and (5) branch or central retinal artery occlusion. Moderate stenosis was defined as a degree of stenosis ≥ 50% and < 70% while severe was defined as ≥ 70% and ≤ 99 %. Figure 1A shows the recruitment, inclusion, and exclusion flow chart. 

Figure 1.

 

Flow chart of patient inclusion and exclusion, OCTA imaging, and DSA assessment.

DSA and Measurement of Length and Degree of Stenosis

A neuro-interventional neurologist performed the inter-arterial DSA imaging using a transfemoral artery approach. Imaging of each carotid bifurcation was obtained in both lateral and anterior-posterior projections. The degree of carotid plaque was measured as the NASCET method.¹⁵ Length of carotid plaque was defined as the distance between the proximal and distal endings where the degree of stenosis inclined to 80% of its maximum,¹⁶ in projection which best elongated the stenosis. Figure 1B shows the measurement details. Carotid plaque surface morphology was classified as ulcerated or smooth,¹⁷ and eccentric or non-eccentric¹⁸ by an expert (author Dr. Bo Wu). Plaques were classified as ulcerated if there was evidence of irregularity, on at least one angiographic view, which was considered likely to be an ulcer. 

Enrolled patients with CAS underwent the following examinations: optic nerve head (ONH) and fundus imaging using fundus photography. Photographs of the ONH were evaluated by an ophthalmologist (author Dr. Ruilin Wang) and patients with ophthalmic disorders, such as exudates, retinal hemorrhages, microaneurysms, cotton wool spots, and blurred optic discs, were excluded. 

OCT/OCTA Imaging

With a central wavelength of 1050 nm and a scan rate of 200,000 A-scan per second, the OCT/OCTA tool (VG200S; version 2.1.016; SVision Imaging, Henan, China) which contained a swept-source laser was used to image the retinal microvasculature in all participants. The tool was set with an eye-tracking function based on an integrated confocal scanning laser ophthalmoscope to remove eye-motion artifacts. The axial resolution, lateral resolution, and scan depth were 5 µm, 13 µm, and 3 mm, respectively. 

Structural OCT imaging of the macula was done with 18 radial B-scans positioned on the fovea. Each B-scan line was generated by 2048 A-scans, was 12 mm long, and separated from adjacent lines by 10 degrees. ONH imaging was also performed using 6 × 6 mm² scans. OCT imaging was done to evaluate the ONH and retinal structure, which is sensitive to ocular pathologies, and excluded patients with disorders that could affect our data. 

OCTA fundus images were obtained with a raster scan protocol of 384 horizontal B-scans that covered an area of 3 × 3 mm² centered on the fovea. The B-scans, which contained 384 A-scans each, were repeated 8 times and averaged. En face angiograms of the superficial vascular complex (SVC) and deep vascular complex (DVC) were obtained by the OCTA tool. Microvascular densities of each plexus were measured by the OCTA tool. Segmentation of the SVC and DVC was set in the inner two-thirds and outer one-third of the ganglion cell-inner plexiform layer, as shown in Figure 1. OCTA data displayed in our study followed the OSCAR-IB quality criteria¹⁹ and APOSTEL recommendation.²⁰ Figure 1C shows the OCTA imaging. OCTA images with ophthalmic disorders, such as AMD, severe cataract, optic neuritis, diabetic retinopathy, glaucoma, and optic neuritis. If a participant presented with any of these disorders in one eye, the other eye was used; if both eyes had the disorders aforementioned, the participant was excluded from the study. An ophthalmologist (author Dr. Ruilin Wang) assessed OCT and OCTA images to exclude patients with ocular pathologies. 

Statistics Analysis

Continuous variables were described by mean ± standard deviation (SD) because of normal distribution, and categorical variables were presented as frequency and percentages. The t-test was used for continuous variables and the Fisher exact test was used for categorical variables when comparing the characteristic difference between final patients with CAS and excluded patients. A linear model was conducted to compare the OCTA parameters between ipsilateral eyes and contralateral eyes. Covariates of the linear model were age, gender, and vascular risk factor (smoking, drinking, hypertension, diabetes, and dyslipidemia), considering those factors could affect the retinal microvasculature. A multivariate linear regression was performed to explore the relationship among OCTA parameters, degree, and length of the stenosed segment in eyes with ipsilateral stenosis while adjusting for risk factors. Subgroup analysis was conducted in the moderate stenosis and severe stenosis group. Sensitivity analysis was performed in eyes with ipsilateral stenosis but without transient mono-blindness (TMB). Any P values less than 0.05 were considered statistically significant. Data analysis and plotting were performed in R version 4.0.3. 

Results

Characteristics of Participants

Our final data analysis included 179 eyes from 117 patients with CAS (104 male patients and 13 female patients); 91 ipsilateral eyes and 88 contralateral eyes in our CAS cohort. Of the 117 CAS cohort, 20 had ulcerated plaque whereas 97 had smooth plaque has measured on DSA; importantly, 65 had eccentric plaque whereas 52 had non-eccentric plaque, as shown in the Table. Out of the 117 patients, 64 patients had severe stenosis whereas 15 had TMB. In patients with TMB, 2 had ulcerated plaque and 13 had smooth plaque; 11 patients had eccentric plaque and 4 had non-eccentric plaque. The mean stenosis length was 25.42 mm (SD = 14.04) and the mean stenotic degree was 74.95% (SD = 11.52). The Table displays the characteristics, carotid vessel information, and OCTA parameters of our included participants. The characteristics between our included patients with CAS and excluded patients are displayed in Supplementary Table S1. 

Table.

 

Characteristics of Study Participants

 

Comparison of OCTA Parameters Between Ipsilateral and Contralateral Eyes

After adjusting for age, gender, and vascular risk factors, ipsilateral eyes showed significantly reduced microvascular densities compared with contralateral eyes (P = 0.016 for SVC, and P = 0.004 for DVC; Fig. 2). After excluding eyes with TMB, the significant difference remained (P = 0.024 for SVC, and P = 0.013 for DVC; see Fig. 2). There were no significant differences in the SVC (P = 0.298) and DVC (P = 0.068) densities when eyes with TMB and eyes without TMB were compared in our study cohort. 

Figure 2.

 

Difference of retinal microvasculature between ipsilateral eyes and contralateral eyes. (A) Represents all patients, whereas (B) is for patients after excluding TMB. Retinal microvasculature had been adjusted for age, gender, and vascular risk factors.

Association Among OCTA Parameters, Length, and Degree of Stenosis

Both SVC and DVC showed a significant correlation with length of stenosis (P = 0.015 for SVC, and P = 0.022 for DVC; Fig. 3), although no significant correlation between retinal microvasculature and stenosis degree was observed (P = 0.264 for SVC, and P = 0.298 for DVC; Fig. 4A). However, when patients were stratified into moderate and severe stenosis groups, a significant correlation was seen between the retinal microvasculature and the degree of stenosis in the severe subgroup (P = 0.045 for SVC, and 0.038 for DVC; Fig. 4B). After further adjusting for carotid plaque morphology (i.e. ulcer or smooth), the correlation between OCTA parameters and DSA parameters of patients with CAS remained as shown in Supplementary Table S2. 

Figure 3.

 

Relationship between retinal microvasculature and length of carotid stenosis in all patients with CAS.

Figure 4.

 

Relationship between retinal microvasculature and degree of carotid stenosis. (A) Represents all patients with CAS, whereas (B) is for the patients with CAS related after stratified as having moderate and severe stenosis.

Discussion

We showed ipsilateral eyes had reduced retinal microvascular densities when compared to contralateral eyes in patients with CAS; after excluding eyes with TMB, significant differences remained. In our CAS cohort, microvascular densities only correlated with the length of stenosis, but not with stenosis degree. In the subgroup analysis, a significant association of stenosis degree with microvascular densities was found in the patients with severe stenosis. We suggest that the length of carotid stenosis in CAS may be linked with retinal microvascular changes. 

CAS has been suggested to result in substantial decreases in ocular blood flow. Previous reports using different ophthalmic imaging tools have shown that patients with CAS have reduced retinal blood flow compared to controls.^21,22 Similarly, reports using OCTA have shown that ipsilateral eyes have reduced retinal microvasculature when compared to contralateral eyes,^7,8,10,23,24 which is consistent with our findings. Moreover, in our study, after excluding eyes with TMB, significant differences remained. TMB or amaurosis fugax, an important clinical symptomatic manifestation of CAS,^4,25 is linked with low retinal perfusion. Identifying these retinal microvascular changes during the asymptomatic phase of CAS may help clinicians to apply earlier implementations of treatment which may help slow down the progression of the disease. 

The length of carotid artery stenosis is suggested as an important predictor of ischemic stroke and relevant death¹⁶ because patients with longer stenosis length are more likely to suffer embolism due to the increased risk of dislodging atherosclerotic fragments or thrombus. Besides, it is suggested that the length of carotid stenosis may have a significant impact on the antegrade blood flow of ICA and cerebral artery blood flow¹⁴ in the setting of CAS. We showed that there was a significant correlation between reduced retinal microvascular densities and the length of carotid stenosis in our CAS cohort, indicating that the longer the carotid plaque length, the lower the retinal microvascular densities and vice versa. 

The degree of carotid stenosis is considered an indicator of increased ischemic stroke risk of patients with CAS in several studies.^26–30 Shakur et al.¹³ used magnetic resonance angiography (MRA) and DSA to show that increasing degree of stenosis resulted in significantly decreased antegrade ICA blood flow in patients with CAS. A previous study³¹ using the retinal camera in patients with CAS demonstrated that as the degree of carotid artery stenosis increased, the diameter of the retinal vessels around the optic nerve head decreased significantly. However, we showed that an increased degree of stenosis plaque only correlated with decreased retinal microvascular densities in our patients with severe CAS. We suggest that retinal microvascular changes are more sensitive to severe stenosis degree, and retinal microvasculature may not be affected by moderate or even mild stenosis. Future studies with larger sample sizes are needed to validate our hypothesis. 

Recent reports^32,33 suggest that carotid plaque length is an important predictor of stroke; similarly, retinal microvascular changes are suggested to be a risk of stroke.^34,35 The significant correlation between retinal microvascular changes and carotid plaque length in our CAS cohort could indicate that quantitative measurement of the retinal microvasculature may help identify CAS individuals with a high risk of stroke. A thorough understanding of the retinal microvasculature can help assess the clinical validity of carotid plaque length in patients with CAS. Such an in vivo quantitative means of assessing disease may allow monitoring of CAS and enable the assessment of purported treatments to prevent the incidence of stroke. The development of a scoring system based on imaging features of plaque vulnerability with retinal imaging may also provide clinicians with better tools for managing the disease. 

Although the carotid duplex ultrasound is suggested as a screening tool for assessing carotid stenosis and measurement of plaque, it has the following limitations: (1) quality of the ultrasound image and judgement regarding the plaque are influence by the clinician's expertise; and (2) position of the carotid ultrasound on the patient during examination may lead to weak blood flow signal which may affect the results. DSA is considered as the “gold standard” for carotid artery stenosis diagnosis and has a high accuracy value in determining the degree and length of carotid plaque.³⁶ Although retinal imaging cannot replace the DSA in assessing the morphology of the carotid plaque, we showed a novel association between the retinal microvascular densities of the retinal plexuses and the length of stenosis in our CAS cohort suggesting that microvascular changes are affected by the length of stenosis. Thus, retinal imaging offers a complementary approach to the DSA tool and has considerable clinical potential. 

We would like to acknowledge some limitations in this study. First, our sample size was relatively small. This was due to our strict sampling criteria and increased incidence of ophthalmic diseases, such as AMD and severe cataracts in patients with CAS. Moreover, our patients did not undergo comprehensive ophthalmological examinations, such as axial length examination and intraocular pressure examination; although our study excluded patients with high myopia, adjusting for axial length may result in precise data. Fundus photographs were reviewed by an ophthalmologist to help exclude confounding ocular disease; however, fundus photographs alone cannot exclude mild ocular pathologies that could have confounded the OCTA results, such as mild glaucoma. Moreover, even though ONH imaging was done in our study participants, we did not analyze their structural and microvascular parameters. Another limitation of our study was that we only analyzed the retinal microvasculature in patients with CAS. Future studies may explore the ONH and retinal structure in patients with CAS. In addition, our study did not include a comparison group, which should be considered in future studies; the effects of interventions like carotid artery stenting or endarterectomy could be investigated in the future. 

Conclusions

In conclusion, we demonstrated reduced microvascular densities of ipsilateral eyes when compared to contralateral eyes in patients with CAS and these changes occur in the asymptomatic phase. We also showed retinal microvascular changes are related to stenosis length in patients with CAS. However, the correlation between the degree of stenosis and retinal microvasculature was only found in patients with severe carotid stenosis but not in all patients with CAS. Taken together, we suggest the OCTA tool can noninvasively detect retinal microvascular changes in patients with CAS; but future studies are required to confirm these findings. 

Acknowledgments

Supported by the National Natural Science Foundation of China (82071320, 8601022), the 1.3.5 project for disciplines of excellence of West China Hospital, Sichuan University (ZYGD18009), Post Doctor Research Project, West China Hospital, Sichuan University (2021HXBH081), Sichuan Science and Technology Program (2023NSFSC1558), Medical-Engineering Integration Interdisciplinary Talent Training Fund Project of West China Hospital, Sichuan University, and University of Electronic Science and Technology of China (HXDZ22011/ZYGX2022YGRH017). 

Data Access Statement: The data that support the findings of this study are available on request from the corresponding author. 

Ethics Statement: The West China Hospital of Sichuan University Ethics Committee approved the study (Ethics number 2020[922]). 

Disclosure: L. Cao, None; H. Wang, None; W.R. Kwapong, None; R. Wang, None; J. Liu, None; B. Wu, None