Macular Choroidal Thickness and Choriocapillaris Vessel Density Alterations in Type 2 Diabetics with High Myopia

According to recent numbers issued by the International Diabetes Federation (IDF), 693 million people worldwide will have diabetes by 2045 [1]. Diabetic retinopathy (DR) is one of the most common and serious complications of diabetes and a common cause of blindness in the middle age and elderly population [2]. The occurrence of DR is due to microvascular injury leading to poor capillary perfusion, which leads to retinal ischemia and hypoxia. Studies have shown that the decrease of choroidal blood flow and perfusion may play an important role in the occurrence and progression of DR [3, 4]. Furthermore, choroidal thickness is an important parameter to research choroid etiology and can be used as an important biological marker of DR progression and treatment response [5]. In previous clinical studies, we found that diabetic patients with high myopia had a lower incidence of DR than those without myopia [6‒8]. In patients with high myopia, choriocapillaris circulation and choroidal thickness are affected in different degrees due to the lengthening of axial length.

The choroid is the vascular layer located under the retina. It has the highest perfusion rate of all blood vessels in the human body. 70% of the blood in the eye is concentrated in choroidal capillaries [9]. Because of their important role in ocular bloodstream, choroidal capillaries play an important role in the development and progression of DR. However, the pathogenesis of a protective role for high myopia against DR remains unclear.

In this study, we used optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) to measure choroidal thickness and choriocapillaris vessel density in the macular area of type 2 diabetics (T2D) with high myopia in the Chinese population, aiming to determine the pattern of changes in the choroidal thickness and choriocapillaris vessel density of T2D with high myopia and seek to examine an association between high myopia and DR in T2D patients with high myopic.

A total of 182 patients were recruited at the Ophthalmology Department of the Affiliated Hospital of Chengde Medical University between January 2018 and December 2021 for this study. 40 T2D patients with high myopia (40 eyes) were included in myopia + diabetes group, 47 T2D patients (47 eyes) without myopia were included in diabetes group, and 45 high myopia patients (45 eyes) were included in myopia group. Another 50 sex-, age-matched healthy volunteers (50 eyes) were included in control group. All the diabetics had no microaneurysm, exudation, and other DR-related fundus lesions by examination and fundus photography.

T2D patients: type 2 diabetes detected at least 1 year before enrollment; controlled serum glucose well (hemoglobin A1C <5.7%), and absence of DR. No diabetes: without diabetes history. High myopia: spherical equivalent (SE) refractive error = -6.0 diopters (D) and axial length =26.5 mm [10]. No high myopia: SE <-1.0 D or emmetropia (no hyperopia was allowed).

Inclusion criteria were as follows: age 30–60 years; intraocular pressure 10–21 mm Hg; all patients exhibited a best corrected visual acuity of 20/40 or better. Exclusion criteria included poor central fixation; patients with glaucoma, macular diseases, fundus retinopathy, or history of ophthalmic surgery; media opacity in the study eye; patients with systemic diseases that may be related to ocular blood vessels and choroidal thickness (such as hypertension, cardiovascular and cerebrovascular diseases, nephropathy, etc.). This study followed the Helsinki Declaration and was approved by the Ethics Committee of the Affiliated Hospital of Chengde Medical University. All subjects and their guardians signed informed consent forms.

All subjects underwent comprehensive eye examinations, including axial length measurement, refractive error, IOP measurement, slit-lamp microscopy, fundus examination, color fundus photographs.

OCT and OCTA images were acquired using DRI Triton OCT (Version 10.18.003.01; Topcon, Tokyo, Japan). All measurements were performed by one operator. The choroidal layer was recognized by OCT. The choroidal thickness was formed automatically and was separately calculated in nine regions (central subfield; temporal, nasal, superior, inferior inner macula; temporal, nasal, superior, inferior outer macula). OCTA images of the choriocapillaris vessel density were generated using the automated software algorithm (IMAGEnet 6, Version 1.28.17642). Based on these default settings, the boundaries of choriocapillaris vessel density extended from the Bruch membrane to 10.4 µm below the Bruch membrane (Fig. 1a–b and Fig. 2a–b). Flow density was separately calculated in five regions (fovea, temporal, superior, nasal, and inferior) based on the ETDRS (Early Treatment Diabetic Retinopathy Study) by the built-in software automatically (IMAGEnet 6 Version 1.28.17642) (Fig.1c, 2c). Figures 1 and 2 are two examples of OCTA images of 2 patients. We used proprietary software to obtain automated perifoveal VD (%). A good set of scans, with a quality index >60 (range 0–100) and no motion artifact for each eye [11], was selected for further analysis.

This was a retrospective case-control study, and all included cases met the inclusion criteria. SPSS 21.0 statistical software (IBM Corporation, Armonk, NY, USA) was used for statistical analysis. Normally distributed quantitative data are expressed as the mean (standard deviation). The sex composition ratio in the four groups of subjects was compared using a ?² test. One-way ANOVA was performed for comparisons of age, intraocular pressure, SE, axial length, choroidal thickness, choriocapillaris vessel density between the four groups. The Scheffe’s test was used for multiple comparisons. A value of p < 0.05 was considered statistically significant.

This study recruited 182 participants, including 50 subjects in the control group, 47 patients in the diabetes group, 45 patients in the myopia group, and 40 patients in the diabetes + myopia group. There were no significant differences in age, sex, intraocular pressure between the four groups. SE and axial length showed no significant difference between the myopia and the diabetes + myopia groups (p = 0.426, 0.940). Duration of diabetes also showed no significant difference between the diabetes and the diabetes + myopia groups (p = 0.109) (Table 1).

The choroidal thicknesses in four groups were shown in Table 2. There were significant differences in choroidal thicknesses between the four groups in all regions (p < 0.001). The choroidal thicknesses in myopic, diabetes, myopia + diabetes groups were statistically significantly lower than those in control group (p < 0.001). Further pairwise comparisons showed that the choroidal thicknesses in myopia + diabetes group were statistically significantly lower than those in diabetes group (p < 0.001), while no statistically significant differences were found between myopic group and myopia + diabetes group (p > 0.05).

The choriocapillaris vessel densities in four groups were shown in Table 3. There were significant differences in choriocapillaris vessel density between the four groups in all regions (p < 0.001). The choriocapillaris vessel densities in diabetes, myopia + diabetes groups were statistically significantly lower than those in control group (p < 0.001). Interestingly, there was no significant difference in choriocapillaris vessel density between myopia group and control group (p > 0.05). Further pairwise comparisons showed that the choriocapillaris thicknesses in myopia + diabetes group were statistically significantly lower than those in myopia group (p < 0.001), while no statistically significant differences were found between diabetes group and myopia + diabetes group (p > 0.05).

Diabetes mellitus is a chronic metabolic disease affecting the whole body, which can cause systemic multisystem disease. DR is one of the common complications of diabetes, which affects the blood vessels and blood perfusion of the retina and choroid. Choroid is a highly vascularized tissue, which is related to the pathophysiological changes of a series of retinal diseases, and is also the target of a variety of fundus diseases. Choroidal injury will lead to ischemia and hypoxia of the outer retina and greatly damage the structure and function of the macula. The changes of structure and function of choroid may be one of the pathological mechanisms of the occurrence and progression of DR. A meta-analysis of 22,896 diabetic patients from 35 studies worldwide showed that the prevalence of DR was 34.6% [12]. Previous studies show that diabetic patients with high myopia had a lower incidence of DR than those without myopia [6‒8]. Bazzazi et al. [6] found in a study of 116 diabetic patients with high myopia anisometropia that only 27.6% of high myopic eyes had DR and none of them had PDR, but 100% of contralateral eyes had DR and 31% of them had PDR. Wang et al. [13] found that longer axial length might be a protective factor of DR. Man et al. [8] also confirmed this view. However, the pathogenesis of a protective role for high myopia against DR still remains unclear.

We designed this cross-sectional study to determine choroidal thickness and vessel density in myopic and/or diabetic patients without DR to identify the effects of myopia and diabetes on choroidal thickness and vessel density. The choroidal thicknesses in the macular region of the other three groups were lower than those of control group. Abadia et al. [7] found that choroidal thickness also decreases in diabetes patients without DR, which was consistent with the results of our study. However, the results of the studies by Regatieri et al. [14] and Adhi et al. [15] showed that there was no significant difference in choroidal thickness between normal and nonproliferative DR patients. Another study found that choroidal thickness decreased in the early stage of DR and gradually increased with the progress of the disease [4]. There are differences in the above research conclusions. Previous studies have already described that choroidal thickness is related to several factors, such as age, hypertension, duration of diabetes, hemoglobin A1C level, gender, circadian rhythm, smoking, the patients have been treated or not [4, 7, 16‒20]. The influencing factors of choroidal thickness in diabetics are more than those in normal controls. Various confounders, sample selection, and size may lead to the difference of choroidal thickness measurement in diabetics. Myopia is also an important factor affecting choroidal thickness. Ophthalmologists agree that myopia can lead to choroidal thinning, and with the increase of myopic refraction and axial length, the choroidal thickness decreases, especially in patients with high myopia [21, 22]. In this study, we found that both high myopia and diabetes can lead to thinning of choroidal thickness, but the choroidal thickness of diabetic patients with high myopia was not lower than that of high myopia patients, and there was no statistical difference between the two groups.

In this study, there was a significant difference in choroidal vessel density between control group, myopia group, diabetes group, and myopia + diabetes group. Interestingly, there was no significant difference in choriocapillaris vessel density between control group and myopia group. Meanwhile, there was no significant difference in choroidal vessel density between diabetes group and myopia + diabetes group but lower than that in control group. Al-Sheikh et al. [23] and Paolo et al. [24] found that the choriocapillaris vessel density decreased in patients with high myopia, which was inconsistent with the results of our study. However, Mo J et al. [25] found that there was no significant difference in choriocapillaris vessel density between the emmetropia group and the high myopia group (without pathologic myopia), but the choriocapillaris vessel density of pathologic myopia group was significantly lower than that of emmetropia group and high myopia group. Patients with pathologic myopia were not included in our study. It can be speculated that the retinal microvascular perfusion in the macular region may decrease when high myopia progresses to the pathologic myopia stage. However, there was no choriocapillaris vessel density research on myopia + diabetes patients in the previous studies. Our study found that choriocapillaris vessel density of myopia + diabetes patients was not further decreased due to high myopia. There was no significant difference in choriocapillaris vessel density between myopia + diabetes group and diabetes group.

High myopia leads to the thinning of choroidal thickness in diabetes patients, but the choriocapillaris vessel density does not decrease. Is this one of the reasons for the low incidence of DR in patients with diabetes and high myopia? Fundus changes in high myopia are often accompanied by thinning and atrophy of the choroidal and retinal tissue, mitochondrial atrophy, greatly reducing retinal metabolism. Retinal atrophy and choroid thickness reduction may decrease oxygen requirements. The choroid is the structure with the most abundant blood vessels in the eye, and the choroidal blood flow accounts for more than 70% of the total ocular blood flow [9]. Al-Sheikh et al. [23] found that the thickness of the choroid does not affect the perfusion of choriocapillaris. The decrease of retinal and choroidal oxygen demand but no significant decrease of choriocapillaris perfusion in high myopia + diabetes may be the reason why the incidence of DR in diabetes with high myopia is lower than that in diabetes alone.

This study has some limitations. First limitation was the relatively small number of patients in the study groups. In the future, a multicenter study including a larger sample of subjects may provide more accurate outcome. Second, though the 3 × 3 mm scan pattern has better repeatability and more accuracy than the 6 × 6 mm scan pattern [26], scanning range of the former is more limited. Third, because there are diurnal variations in choroidal thickness [27], the thicknesses measured at different time points may differ. In this study, the participants did not undergo OCT examination at a fixed time.

In conclusion, the choroidal thickness of the patients with high myopia and diabetes (without DR) was significantly lower than that of normal people and diabetic patients, but the choriocapillaris vessel density was not significantly different from that of normal people. High myopia reduces choroidal thickness but not choriocapillaris vessel density in diabetic patients, which may be one of the protective mechanisms of high myopia against DR. Our results increased our understanding of the pathophysiology of choroidal thickness and choriocapillaris vessel density changes in diabetic patients with high myopia.

The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical approval was approved by the Ethics Committee of Chengde Medical University (CYFYLL2020231). The subjects had given written informed consent and all the procedures being performed were part of the routine examinations.

The authors have no conflicts of interest to declare.

This study was supported by the Hebei Provincial Natural Science Foundation of China (H2020406019); Technology Innovation Guidance Project-Science; and Technology Work Conference of Hebei Provincial Department of Science and Technology.

Ruifeng Su and Xiaobo Tan conceived and designed the study. Ruifeng Su contributed to literature search, figures, data analysis, original draft preparation, editing, and revising. Zhiwei Qi contributed to data collection and data analysis. All authors read and approved the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.