The vascular endothelial growth factor is the major cytokine in the pathogenesis of DR showing a strong relationship between the increase in intraocular VEGF levels and the severity of DR17. There are various studies, showing the association between long AL and its protective role against DR5,6,7. Wang et al., in their meta-analysis, suspected that longer eyes might have lower VEGF levels, which may prevent the occurrence of DR. They showed that when each millimeter increase in AL was analyzed as a continuous variable for myopia, it was significantly associated with a decreased risk of DR6. Pierro et al. showed that considering all the confounding factors, the presence of retinopathy was associated with shorter axial length18. Jain et al. in their study observed that myopic refractive error in cases with diabetic retinopathy was always less than 5 diopters, thus concluding that myopia was protective against diabetic retinopathy3. Lim et al. observed that long axial length (AL), and deeper anterior chamber depth (ACD) were associated with less likelihood of developing any DR4. Our study also demonstrated that longer AL was associated with lesser VEGF in the eye.
Several studies have reported a negative correlation between the intraocular concentration of VEGF and AL in subjects without retinal diseases8,9,10,11. In this study, we have demonstrated that the VEGF levels in eyes with DR also show a negative trend with axial elongation which may explain the fact that longer eyes are protected against DR due to relatively lower secretion of the VEGF.
We observed a statistically significant decrease (P< 0.05) in the levels of VEGF concentration in humor of patients with AL ≥ 23.30 mm as compared with AL ≤ 23.30 mm in non-diabetic as well as diabetic patients. On further comparing and analysing VEGF concentrations within each subgroups, we also found a statistically significant trend in the decrement of VEGF concentrations as the eye elongates. In non-diabetic subjects, the mean VEGF was 112.59 pg/ml in shorter eyes and 53.93 pg/ml in longer eyes (P= 0.001). Similarly, in diabetic patients but without presence of DR, the mean VEGF was 89.398 pg/ml in shorter eyes whereas it was 58.503 pg/ml in longer eyes (P= 0.002). In eyes with presence of DR, the mean VEGF levels were 125.256 pg/ml in shorter eyes and 75.959 pg/ml in longer eyes (P= 0.025). Above implies that as the eye elongates, there is less secretion of VEGF in non-diabetics as well in diabetics with or without DR.
We also compared the VEGF levels and the AL among the eyes with different severity level of NPDR. The mean AL in patients with moderate and mild NPDR was higher as compared to those with severe NPDR (moderate > mild > severe). The corresponding VEGF level was maximum in severe NPDR group as expected. However, the VEGF level was lower in the moderate NPDR group than the mild NPDR group which may be associated with longer AL in the moderate NPDR group. The intraocular VEGF level increases with increase in severity of DR . However, in this study, the VEGF level in patients with mild and moderate NPDR corresponded to the AL rather than the severity of DR. This highlights the importance of AL in intraocular VEGF level. However, this difference was not statistically significant. There have been no study yet which reports similar findings. This will need further analysis in a larger cohort to establish if such findings have strong statistical support.
The exact mechanisms underlying the protective effect of myopia on DR are currently unclear. Most have centered around the pathologic changes associated with axial globe elongation19,20,21,22,23,24,25. One possible explanation is that the VEGF in the anterior chamber and the vitreous cavity might be diluted because of longer axial length and therefore, increased intraocular volume11. Complete posterior vitreous detachment (PVD) and vitreous syneresis are also more common in myopes. It has been reported that the clearance of growth and permeability factors from the retina is enhanced following vitrectomy due to decreases viscosity after removal of vitreous gel19. As PVD increases the fluidity and thereby decreases the viscosity of the vitreous, it might be associated with a faster turnover of VEGF out of the eye. Chorioretinal thinning, another frequent finding in myopes, also might have a protective effect by reducing the metabolic demand and facilitating the diffusion of oxygen through the retina19. The thinning might cause relatively increased choroidal perfusion and decreased retinal hypoxia resulting in decreased VEGF production. Studies have also demonstrated the correlation between neurodegeneration and retinal neuron dysfunction with axial elongation22,23. These changes decrease the metabolic demand in the outer retina, which helps to attenuate the effects of hypoxia in diabetics, which might further decrease the VEGF levels in these eyes.
The general limitations of this study include a lower number of participants, which may have led to an increased variance in our results. Also, we assessed the levels of VEGF in aqueous humor and not vitreous humor, which might have affected our cytokine levels although studies have shown that aqueous VEGF levels correlate with the VEGF activity in the retina13,14. We also did not have subjects with high axial length and staphyloma. Further study in a larger cohort will help in gaining more insight.
In conclusion, this study provides evidence to support the well-described clinical impression that myopic eyes are less likely to develop DR, particularly more severe stages of DR. This study showed that as the axial length increases, the VEGF levels decrease in both diabetics and non-diabetics. This study contributes further insights into the pathogenetic pathways for DR and may help clinicians in their assessment of the risk of DR in patients with myopia.