Intracranial Artery Stenosis is Associated with Retinal Arteriolar Deficit
Retinal imaging has emerged as a non-invasive tool for evaluating subtle abnormalities in the microvasculature of cerebral atherosclerosis. Optical coherence tomography angiography (OCTA) is a novel ophthalmic imaging technique that provides depth-resolved visualization of retinal microvasculature with near histology-level resolution. The retinal microvasculature shares anatomic, embryologic, and physiological characteristics with the cerebral microcirculation and is an extension of the internal carotid artery (ICA). Therefore, changes in the retinal microvasculature may reflect changes in the cerebral microcirculation and ICA. Studying retinal microvascular changes may provide insights into the pathophysiology of atherosclerosis. Using the ophthalmic artery (OA) as a pivotal point, this study investigated retinal microvascular differences using OCTA in individuals with extracranial artery stenosis (ECAS) and intracranial artery stenosis (ICAS).
This study was part of a single-center, cross-sectional study conducted in the Department of Neurology, West China Hospital, Sichuan University. Patients with unilateral severe cerebral large artery stenosis (LAS) in the anterior circulation region, whether with ischemic stroke or transient ischemic attack (TIA), were consecutively recruited from April 2021 to February 2023. The study was approved by the Ethics Committee of West China Hospital of Sichuan University, and written informed consent was obtained from all participants. All procedures adhered to the Declaration of Helsinki. LAS patients were screened using magnetic resonance angiography, computed tomography angiography, or ultrasonography. Those who planned for digital subtraction angiography (DSA) and could cooperate with OCTA examination were included. The severity of stenosis was diagnosed using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria or the Warfarin-Aspirin Symptomatic Intracranial Disease Study (WASID) criteria on DSA. Severe stenosis or occlusion was defined as 70–100% stenosis. Patients with non-atherosclerotic stenosis, non-stenotic cerebral vascular diseases, cardiac disease leading to cerebral embolisms, visual cortex infarction with visual field defects, other neurological diseases, cerebral hemorrhage, multiple severe stenoses in the anterior circulation, or stenosis plaque located at the ophthalmic segment of the internal carotid artery were excluded.
A total of 394 participants (138 ICAS patients and 256 ECAS patients) with 729 eyes were included in the analysis. ECAS patients were older, male-dominant, and had a higher burden of smoking. In contrast, ICAS patients had a higher burden of ischemic symptoms. ICAS patients exhibited reduced arteriolar density but higher superficial vascular plexus (SVC) density compared to ECAS patients. No significant difference was observed in venular density between the two groups.
In subgroup analysis, ipsilateral eyes in ECAS patients showed significantly higher arteriolar density than contralateral eyes. No significant differences were observed between ipsilateral and contralateral eyes in OCTA parameters in ICAS participants. When comparing ipsilateral eyes, ICAS eyes showed lower arteriolar density but higher SVC density compared to ECAS eyes. In the contralateral eyes subgroup, ICAS eyes showed reduced arteriolar density compared to ECAS eyes, with no significant differences in SVC and venular density.
A significant inverse correlation was found between arteriolar density and SVC density. This inverse correlation was also observed in ECAS patients. However, no significant correlation between arteriolar density and SVC density was found in the ICAS group. Hypertension was significantly linked to reduced arteriolar density in all eyes and in ICAS eyes, but this link was not significant in ECAS eyes.
Sensitivity analysis of OCTA parameters between ICAS and ECAS patients showed that ECAS patients had reduced SVC density compared to ICAS patients, while ICAS patients had reduced arteriolar density compared to ECAS patients. No significant differences were observed in venular density between the two groups.
Atherosclerosis in cerebral arteries can cause reduced ophthalmic blood flow, leading to ocular complications. ECAS patients exhibited reduced SVC density compared to ICAS patients, particularly in the ipsilateral eye subgroup. The SVC in the retina, composed of large vessels and capillaries, is the main entry of blood flow into the retina. Atherosclerosis in ECAS patients causes a significant pressure drop in blood flow, leading to reduced blood flow in the SVC and ultimately reduced retinal vascular density. A marginally significant decrease in SVC density was observed in the ipsilateral eyes of ECAS patients compared to contralateral eyes, supporting the hypothesis that stenosis before the OA affects blood flow. This suggests that atherosclerotic stenosis before the OA (ECAS) may directly affect retinal microvasculature.
ICAS patients had lower arteriolar density than ECAS patients. Similarly, in the ipsilateral eyes subgroup, ICAS patients had reduced arteriolar density compared to ECAS patients. The OA is the first intracranial major branch of the internal carotid artery, and segments after the OA are considered part of the intracranial branch, classified as ICAS in this study. ICAS, which affects intracranial (cerebral) circulation, is suggested to be more tightly linked with retinal microcirculation. This suggests that retinal arteriolar changes in ICAS may mirror cerebral arteriolar changes. Conversely, ECAS patients had higher arteriolar density compared to ICAS patients, and ipsilateral eyes in ECAS patients showed higher arteriolar density compared to contralateral eyes. This suggests that stenosis before the OA may act as a protective factor against retinal arteriolar damage by reducing tensile stress on the wall of intracranial arteries, such as the OA.
The study found an inverse correlation between arteriolar density and SVC density, which was also observed in ECAS patients. The SVC consists of arterioles, venules, and capillaries. Since hypertension reduces microvascular density, particularly in arterioles, this inverse correlation may represent a compensatory mechanism. Higher SVC density may balance reduced arteriolar density, compensating the retinal microvascular system from severe damage or impairment.
Previous studies have shown that ICAS has a higher rate of stroke incidence compared to ECAS. A higher incidence of cerebral microvascular damage and neurodegeneration, evident in increased white matter hyperintensity burden and lacunes, has also been found in ICAS. This study found that ICAS patients had lower retinal arteriolar density compared to ECAS patients. Given that retinal arterioles reflect intracranial arteries, this data supports the concept that intracranial atherosclerosis is associated with more severe microvascular dysfunction and clinical microvascular diseases in the brain. Retinal imaging may be a valuable approach to assess small vessel impairment in cerebral atherosclerosis and may help elucidate underlying microvascular pathologies in patients with different plaque locations.
This study has some limitations. The cross-sectional design limits the interpretation of the relationship between retinal microvascular changes and atherosclerosis in different locations. The effects of interventions for atherosclerotic stenosis, such as stenting and endarterectomy, and therapy for vascular risk factors on retinal microvasculature should be investigated to validate the relationship between retinal microvasculature and cerebral artery stenosis. Additionally, this is a single-center study with participants only from China, which limits the generalizability of the findings.
In summary, retinal arteriolar changes differ between ICAS and ECAS, with ICAS associated with lower arteriolar density than ECAS. This study suggests that retinal imaging via OCTA has the potential to detect microvascular changes in atherosclerosis with different plaque locations.
doi.org/10.1097/CM9.0000000000003453
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