Changes in Retinal Vascular Bifurcation in Eyes with Myopia

doi:10.21203/rs.3.rs-1867328/v1

Objective: To evaluate the effect of myopia on retinal vascular bifurcation.

Methods: A cross-sectional study that retrospectively analyzed the fundus photographs and clinical data of 493 people who participated in routine physical examinations in Huadong Sanatorium. One eye of each subject was included in the analysis. Retinal vascular bifurcation measurements were extracted by using a validated computer program. One-way ANOVA and analysis of covariance were performed to compare the measurements across high myopia, low to moderate myopia, and non-myopia groups.

Results: The mean age was 41.83 ± 10.43 years and 63.49% were women. The mean spherical equivalent refraction (SER) was -4.59 ± 3.07 D. Ninety-nine (20.08%) eyes met the definition of high myopia (SER ≤ -6.0 D), along with 234 (47.46%) low to moderate myopia (-6.0 D< SER <-0.5 D), and 160 (32.45%) non-myopia (SER ≥ -0.5 D). The differences in the arteriolar branching angle, venular branching coefficient, venular asymmetry ratio, venular angular asymmetry, and venular junctional exponent among the three groups remained significant (p<0.05) after multivariate adjustment. Pairwise comparisons showed arteriolar branching angle and venular angular asymmetry in high myopia were significantly lower than low to moderate myopia (p<0.001, p=0.014 respectively) and non-myopia (p=0.007, p=0.048 respectively). Venular asymmetry ratio and venular branching coefficient in high myopia were significantly higher than low to moderate myopia (p=0.029, p=0.001 respectively) and non-myopia (p=0.041, p=0.043 respectively). There was a significant difference in venular junctional exponent between high myopia and low to moderate myopia (p=0.031).

Conclusion: The vascular bifurcation differs in dependence of the myopic refractive error and a significant increase in the difference can be observed in high myopic eyes.

A healthy vascular network is essential for efficient blood transport to various parts of the body, and damage to the network may cause ischemia, leakage, and other pathologic conditions which then lead to many diseases. The retinal vascular network can be directly observed in vivo and has therefore been studied widely in expectation of finding predictors of various diseases. Studies have shown that the retinal vascular network geometry changes are an important sign of vascular damage, which are associated with a variety of systemic and ocular diseases, such as hypertension[1], diabetes[2], cerebral small vessel disease[3], dementia[4], diabetic retinopathy[5], and glaucoma[6].

In myopic eyes, the expansion of sclera stretches and thins the underlying choroid and retina[7], which is responsible for the myopia-related retinal vascular alterations, for instance, narrower arterioles and venules [8–10], higher length to diameter ratios of retinal arterioles[11], straighter arterioles [9], and decreased vascular fractal dimension[12]. However, the relationship between myopia and vascular bifurcation remains controversial. Patton et al. [8] found no association of axial length (AL) with the angles at vessel bifurcations and junctional exponents in a small pseudophakic population. However, Lim et al.[9] demonstrated in a middle-aged and older Malay population that increased myopic refractive errors and longer AL were associated with more acute branching angles in arterioles, and increased branching coefficients in both arterioles and venules. The discrepancy in the results may be due in part to potential or residual confounding. Aging, cardiovascular disease, cardio-active medications, smoking, etc. are known to be associated with the retinal vascular geometry, and are not possibly fully adjusted in a relatively older and heterogeneous study population, which in turn hinders our understanding of the relationship between myopia and retinal vascular geometry. In addition, if the bifurcation parameters change with the myopic elongation of the globe, a dose-response effect should be observed, which however has not been carefully studied yet.

Therefore, we conducted a study investigating the differences in retinal vascular bifurcation parameters among high myopia, low to moderate myopia, and non-myopia in an otherwise healthy and relatively young population.

In this cross-sectional study, we retrospectively reviewed the fundus photographs and clinical data of 1100 people who participated in routine physical examinations in Huadong Sanatorium from June 2018 to December 2018. The present study was conducted in accordance with the ethical principles of the Declaration of Helsinki on medical research. The retrospective review of participants’ records and the waiver of consent was approved by the Medical Ethics Committee of Huadong Sanatorium. Subjects with the following conditions were excluded from this study: (1) History of cataract surgery, aphakic or pseudophakic, and self-reported refractive surgery in the selected eye (n = 0); (2) Diabetic retinopathy and other retinal vascular diseases in the selected eye (n = 2); (3) History of smoking, hypertension (medical history or meet the diagnostic criteria of hypertension[systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg][13]), diabetes(medical history or glycosylated hemoglobin ≥ 6.5 mmol/l[14]) (n = 531); (4) Fundus images of poor quality, including those due to media opacities, small size of pupil or images out of focus (n = 74). Of the 1100 available people, 493 people were included in this study.

Each subject underwent a comprehensive ocular examination at the previous physical examination, including pupillary examination, anterior segment examination, and complete retinal evaluation. Noncycloplegic autorefraction was performed using an auto-refractometer (Topcon KR-8900, Japan). Intraocular pressure was measured in mm Hg with a non-contact tonometer (Topcon CT-80A, Japan). Digital fundus photography was taken by using a 45° digital retinal camera (Topcon-NW300; Japan) without mydriasis. Two retinal images of each eye were obtained, one centered at the optic disc and another centered at the fovea.

For each subject, we selected one optic disc-centered photograph from the eye with better photographic quality to perform measurement (when the photographic quality of both eyes is similar, the right eye is selected for analysis). The refractive state of this eye determined the refractive group that the subject was assigned to. Spherical equivalent refraction (SER) was calculated as the sum of the sphere power and half of the cylinder power, and the unit is diopter (D). Refractive errors were defined as high myopia (SER ≤-6.0 D)[15], low to moderate myopia ( -6.0 D < SER <-0.5 D)[15], and non-myopia (SER ≥ -0.5 D).

Measurements Of Retinal Vascular Bifurcation Parameters

For each retinal photograph, a trained grader (SCX), masked to participants’ identities, used a semi-automated computer-assisted program (Singapore I Vessel Assessment [SIVA], version 4.0; National University of Singapore, Singapore) to quantitatively measure a series of retinal vascular bifurcation parameters. During image grading, SIVA divides the retina into three zones with reference to the optic disc location and size. Zone A, B, C are standardized and defined as the region from the disc margin to 1/2-disc diameter from the disc margin, 1/2-disc diameter to 1 disc diameter from the disc margin, and 1 disc diameter to 2-disc diameter from the disc margin, respectively (Fig. 1A). A description of retinal bifurcation parameters is listed in Table 1 and depicted in Fig. 1B. A lowercase “a” or “v” at the end of the parameter name indicates arteriolar or venular measurements. Previous studies reported that SIVA produces repeatable measures of the retinal vasculature in former preterm and term children and in adults; intra-observer and interobserver reproducibility were higher than 66% for vascular geometry[16].

Table 1

Description of the retinal vascular bifurcation parameters measured for each retinal photograph
Parameter	Description
BA	Branching angle	Defined as the first angle subtended between two daughter vessels at each vascular bifurcation.
BC	Branching coefficient	Branching coefficient reflects the ratio between the diameters of the parent vessel and the diameters of its branches. Defined as the summed square of the mean vessel widths of each branch or daughter vessel divided by the square of the mean width of the parent vessel.
AF	Asymmetry ratio	Defined as the ratio of the square of the width of two branching vessel.
AA	Angular asymmetry	Defined as the difference between two daughter angles.
JE	Junctional exponent	Junctional exponent provides an index of caliber sizes of two daughter vessels relative to the parent vessel and is considered to represent an optimality state of microvascular networks[17]. It has been proposed that in an optimal state, the value of junctional exponent is three[17].

Statistical analysis

Statistical analysis was performed using SPSS V.23.0 (SPSS Inc., Chicago, IL). The branching coefficient, branching angle, asymmetry ratio, and angular asymmetry were normally distributed among patients, as well as the logarithmically transformed junctional exponent. Descriptive statistics were presented as mean and standard deviation (SD) for normally distributed data.

Chi-square test (categorical variables) and one-way ANOVA (normally distributed continuous variables) were used to perform comparisons among different refractive error statuses. The multivariable-adjusted model was tested for each dependent variable with correction for confounding variables in analysis of covariance (ANCOVA). Age[18], glycosylated hemoglobin[19] (HbA1c), mean arterial pressure[1] (MAP, calculated as 1/3SBP + 2/3DBP[20]), body mass index[21] (BMI, calculated as weight in kilograms divided by the square of height in meters) and intraocular pressure[6] (IOP) were known to influence retinal vascular bifurcation parameters and included as covariates. In order to further identify which particular differences between pairs are significant, we use pairwise comparison to explore differences among three groups. Moreover, we use complete case analysis to deal with a small number of missing data on HbA1c (n = 19), BMI(n = 23), IOP(n = 7) and MAP (n = 4).

Retinal photographs of unilateral eyes from 493 people were included in this study. The mean age was 41.83 ± 10.43 year-old (ranged from 17 to 75 year-old ), with 180 men (36.51%) and 313 women (63.49%). The mean SER was -4.59±3.07 D. Ninety-nine (20.08%) eyes met the definition of high myopia (ranged from -16.13 D to -6.00 D), along with 234 (47.46%) low to moderate myopia (ranged from -5.88 D to -0.63 D), and 160 (32.45%) non-myopia (ranged from -0.50 D to +6.13 D). Systemic demographics and retinal vascular bifurcation parameters of the participants grouping by the refractive error status are summarized in Table 2. In general, myopic subjects were younger, and with lower HbA1c. Mean BAa, BCa, BCv, AFv, AAv, and JEa were significantly different among the three different refractive error status groups.

Table 2. Clinical characteristics and retinal vascular bifurcation measurements, by refractive error status

Parameter	High myopia	Low to moderate myopia	Non-myopia	p value
Number	99	234	160
Age (years)	38.67 (10.56)	39.35 (8.95)	45.48 (10.70)	<0.001*
Female, n (%)	62 (62.62%)	142 (60.68%)	109 (68.13%)	0.486
Spherical equivalent (D)	-8.62 (2.23)	-2.99 (1.44)	0.26 (0.92)	<0.001*
IOP (mmHg)	15.37 (2.76)	15.40 (2.58)	15.14 (2.46)	0.750
BMI (kg/m²)	23.33 (3.78)	22.48 (2.64)	23.11 (2.84)	0.208
HbA1c (%)	5.30 (0.35)	5.24 (0.28)	5.41 (0.31)	<0.001*
Total cholesterol (mmol/L)	4.96 (0.68)	4.95 (0.83)	5.05 (0.81)	0.299
SBP (mmHg)	115.01 (13.89)	113.19 (12.35)	115.19 (11.16)	0.481
DBP (mmHg)	71.04 (9.86)	69.38 (8.36)	69.67 (8.68)	0.398
BAa (°)	70.11 (11.73)	76.59 (11.41)	75.30 (10.66)	<0.001*
BAv (°)	74.51 (12.69)	76.61 (9.94)	75.97 (10.70)	0.277
BCa	1.48 (0.21)	1.41 (0.18)	1.47 (0.19)	0.001*
BCv	1.31 (0.18)	1.26 (0.14)	1.27 (0.15)	0.014*
AFa	0.82 (0.07)	0.82 (0.06)	0.81 (0.07)	0.112
AFv	0.74 (0.10)	0.71 (0.10)	0.72 (0.10)	0.041*
AAa (°)	30.28 (13.52)	33.76 (11.44)	32.56 (11.25)	0.051
AAv (°)	37.21 (13.55)	41.39 (13.41)	41.02 (12.46)	0.026*
Log JEa	0.41 (0.06)	0.43 (0.05)	0.41 (0.05)	0.002*
Log JEv	0.45 (0.06)	0.46 (0.05)	0.46 (0.05)	0.224

All data were expressed as mean (SD) or number (percentages), as appropriate.

Chi-square test (categorical variables) and one-way ANOVA (normally distributed continuous variables) were used to perform comparisons. P-values were corrected for multiple comparisons using the Bonferroni method.

*Statistical difference (p < 0.05) among participants with different refractive error status.

The differences in the BAa, BCv, AFv, AAv and JEv among three groups remained significant after adjusting for age, HbA1c, MAP, BMI and IOP (Table 3). Figure 2 showed BAa and AAv in high myopia were significantly lower than low to moderate myopia (p<0.001, p=0.014 respectively) and non-myopia (p=0.007, p=0.048 respectively). AFv and BCv in high myopia were significantly higher than moderate myopia (p=0.029, p=0.001 respectively) and non-myopia (p=0.041, p=0.043 respectively). There was a significant difference in JEv between the high myopia group and the low to moderate myopia group (p=0.031). However, the difference of JEv in non-myopia and high myopia were not statistically significant (p=0.504).

Table 3 The comparison of the retinal vascular bifurcation measurements among participants with different refractive error statuses.

Parameter	High myopia Adjusted mean (95% CI)	Low to moderate myopia Adjusted mean (95% CI)	Non-myopia Adjusted mean (95% CI)	P
BAa (°)	70.21 (67.64, 72.78)	76.30 (74.60, 78.00)	75.75 (73.49, 78.02)	<0.001*
BAv (°)	74.47 (72.03, 76.92)	76.80 (75.17, 78.42)	76.13 (73.98, 78.28)	0.299
BCa	1.46 (1.42, 1.51)	1.41 (1.39, 1.44)	1.46 (1.42, 1.50)	0.071
BCv	1.33 (1.30, 1.37)	1.25 (1.23, 1.28)	1.27 (1.24,1.30)	0.001*
AFa	0.82 (0.81, 0.84)	0.82 (0.81, 0.83)	0.81 (0.80, 0.82)	0.321
AFv	0.74 (0.72, 0.77)	0.71 (0.69, 0.72)	0.71 (0.69, 0.73)	0.021*
AAa (°)	30.60 (27.89, 33.31)	33.79 (31.99, 35.58)	33.14 (30.75, 35.53)	0.151
AAv (°)	36.10 (33.07, 39.13)	41.35 (39.34, 43.37)	41.19 (38.52, 43.85)	0.014*
Log JEa	0.41 (0.40, 0.43)	0.42 (0.42, 0.43)	0.42 (0.40, 0.43)	0.251
Log JEv	0.44 (0.43, 0.46)	0.46 (0.45, 0.47)	0.46 (0.44, 0.47)	0.036*

CI, confidence interval; Model adjusted for age, HbA1c, MAP, BMI, and IOP. P-values were corrected for multiple comparisons using the Bonferroni method.

*Statistical difference (p < 0.05) among participants with different refractive error statuses.

Figure 3 depicts the changes of BAa, AFv, BCv, JEv, and AAv with SER. It is observed that a sharp change of the slope occurred during the transition to higher myopia (roughly -6D~-10D) in figure 3 (A~D) diagram. The slope for BAa by SER went steeper when SE ≤ -6D. For AFv, BCv, and JEv, the cutoffs were -10D, -8D, and -8D, respectively. No clear cut-off point was observed for the chart of AAv (Fig 3E).

Retinal vascular bifurcation parameters are potential markers of the changes in microvascular structure and could be early indicators of ocular and systemic disease[1, 22]. In the present study on an otherwise healthy and relatively young population, we first validated the association between retinal vascular bifurcation parameters and myopia; then we demonstrated for the first time a threshold effect of high myopia on the association, which implies that excessive globe elongation can trigger an abrupt deterioration in blood supply to the inner retina.

We observed that arteriolar BA was significantly smaller in the high myopia group than in low to moderate myopia group and non-myopia group. Murray proposed in 1926 that the optimal arteriolar BA to be 75 degrees[23], and any deviation from this was seen as less optimal for the retinal circulatory system. Patients with high myopia deviated more from the theoretical optimal BA than patients with low to moderate myopia and non-myopia (70.11°±11.73° versus 76.59°±11.41° versus 75.30°±10.66°, p < 0.001). Deviations from an optimal retinal branching network are considered to result in impaired microcirculatory transport, increased shear stress, reduced efficiency, and hence greater risk of vascular damage[2].

Increased venular BC was significantly associated with high myopia. BC increases when the diameter of the branching venules increases disproportionately to that of the parent vessel. The increase in the diameter of branching vessels may be due to vasodilation and result in thinning of the vessel wall. The thinner walls of branching venules may be less resistant to wall shear stress than parent venules, resulting in endothelial inflammation. It also has been suggested that an increased venular BC may reflect inflammation and endothelial dysfunction triggered by hyperglycaemia in diabetes[24].

Our findings indicate a relationship between decreased venular AA and high myopia, and between increased venular AF and high myopia. It is of interest to evaluate the possible pathophysiological basis of these results. Although we are not aware of any studies that have investigated how varying angular asymmetry and asymmetry ratio would affect stress in the vasculature, and what effect these changes will have on the retina of high myopia. Some studies have reported that venular AF changes may precede Alzheimer's disease. Cabrera et al. observed that the venular AF was significantly higher in patients with cognitive impairment than in age-matched controls[25]. Frost et al. observed venular AF was higher in healthy individuals with high plaque burden, that change may be occurring early in Alzheimer's disease pathogenesis [26]. It is possible that increased venular AF was associated with microvascular damage.

A strength of the present study in comparison with previous reports is that we selected a more homogenous otherwise healthy population to minimize potential or residual confounding. Second, by studying the dose-effect of myopia on retinal vascular bifurcation parameters, we demonstrated that compared to the lower myopia, it seems that high myopia compromises the integrity of retinal vasculature at an accelerated rate. The finding of the current study contributes to the body of evidence about the interaction between myopia and retinal vessels – myopia stretches the globe as well as the domestic vascular system, while the latter in turn depletes the blood supply to the eye, which may lead to the anatomic and functional damage of high myopia, and play a role in the pathogenesis of pathologic myopia.

We acknowledge that some limitations affect the present study: first, the cross-sectional design limits the ability to infer causality. Second, the axial length was not measured in the current study. However, in a healthy and relatively young population, SER can be a very good proxy for the axial length[27]. Third, the number of high myopia participants in our study was insufficient for subgroup modeling.

In summary, the vascular bifurcation differs in dependence of the myopic refractive error and a significant increase in the difference can be observed in high myopic eyes. We believe that our study is the first to show the markedly deleterious effect of high myopia on retinal bifurcation. And if the finding is validated in future longitudinal study, it will deepen our understanding of the pathophysiology of the progression of myopia.

Ethic approval and consent to participate: All procedures adhered to the tenets of the Declaration of Helsinki, and local approval was received from the Medical Ethics Committee of Huadong Sanatorium. Medical Ethics Committee of Huadong Sanatorium waive the need for informed consent due to retrospective review of participants’ records.

Consent for publication: Not applicable.

Availability of data and materials: The datasets generated and/or analyzed during the current study are not publicly available due further analysis of data is in progress, but are available from the corresponding author on reasonable request.

Conflict of interest: The authors declare that they have no conflict of interest.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions: Caixia Sun, Yuanzhi Yuan, Jing Cong, and Xinyuan Wu wrote the main manuscript text and prepared figures and tables. Tingli Chen and Jing Wang collected clinical data and fundus photographs of participants. All authors reviewed the manuscript.

Acknowledgements: Not applicable.

Authors’ information:¹Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, China; ²Department of Ophthalmology, Huadong Sanatorium, Wuxi, Jiangsu Province, China; ³Department of Ophthalmology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, Fujian Province, China; ⁴Center for Evidence-based Medicine, Fudan University, Shanghai, China

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Changes in Retinal Vascular Bifurcation in Eyes with Myopia

Status:

Version 1

Abstract

Figures

Introduction

Methods

Measurements Of Retinal Vascular Bifurcation Parameters

Statistical analysis

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1