Previous studies have shown increased retinal vascular oxygen saturation and tortuosity with progression of DR.
11–14 Here, alterations in retinal vascular morphologic and oxygenation metrics at stages of DR were demonstrated and associations between these metrics were reported for the first time. The results confirmed the hypothesis that higher perifoveal vessel tortuosity was correlated with higher retinal venous oxygen saturation and lower fraction of extracted oxygen.
In the current study, an increase in retinal SO
2A was shown in PDR compared to less advanced stages of DR. This finding is in agreement with previous studies that showed elevation of SO
2A with increasing severity of DR.
9,11,13,32–34 Previous studies in DR have reported increased SO
2V14,15,33 and decreased retinal arteriovenous SO
2 difference and OEF.
12,13 In the current study, OEF was not found to be significantly decreased, although a trend in OEF reduction was observed. Maintained OEF suggests the relative rate of oxygen metabolism to delivery was not altered, despite potential changes in either parameter. Previous studies have shown reduced OEF in NPDR.
15,17 Heterogeneity of DR, as well as separate grouping of stages of NPDR and limited sample size in the current study, likely contributed to an undetected statistically significant reduction in OEF. Several factors may account for the observed elevation retinal vascular SO
2 in DR. First, increased glycosylated hemoglobin has been shown to exhibit higher affinity to oxygen.
35–37 Therefore, oxygen may be more tightly bound to hemoglobin and diffuses less readily to the tissue, which can account for higher SO
2 as oxygen remains in the lumen and attached to hemoglobin.
37 Second, endothelial dysfunction and loss of regulatory cells due to DR
19,20,38 may adversely affect the maintenance of homeostasis and the permeability to oxygen. Third, cellular dysfunction or loss due to hyperglycemia or vascular supply may result in a reduction in oxygen demand by the retinal tissue.
VD was reduced in moderate to severe NPDR and PDR, consistent with previous studies.
22,23,39 The reduction in vessel density is due to capillary nonperfusion and the progressive loss of capillary cells.
23 Previous studies have shown increased retinal vessel tortuosity during progression of DR.
23,25,26 An increase in advanced glycation end products causes pericyte loss in DR
18,40 and impairs the ability of cells to respond to certain biochemical signals, such as nitric oxide, which is important in the functioning of smooth muscle cell relaxation during vasodilation.
38 Studies have shown reduced flow-mediated vasodilation in DR, suggesting endothelial dysfunction.
19,21 Overall, increased vessel tortuosity in DR is likely due to impairment of the retinal vessel endothelial support and function,
18 as well as due to tissue hypoxia.
41
The results showed correlations of increased VTI with increased SO
2V and decreased OEF, although a causal relation between these metrics is not indicated, requiring a different study design. Increased vessel tortuosity can occur in DR due to impairment of the retinal vessel endothelial support and function
18,19,33 coupled with increased blood flow.
42,43 Moreover, retinal vessels have been shown to be tortuous and elongated under DR, hypobaric hypoxia, and central retinal vein occlusion.
41,44,45 On the other hand, decreased OEF (ratio of oxygen metabolism to oxygen delivery) is due to a decrease in oxygen metabolism and / or an increase in oxygen delivery. A decrease in OEF in DR can result with increased SO
2V, which is suggestive of reduced oxygen metabolism coupled with increased blood flow, causing an increase in oxygen delivery.
The current study presented certain limitations. The relatively small sample size in some DR groups may have limited the statistical power to detect some differences among groups. Nevertheless, the sample size of all subjects had adequate power to establish correlations that were not influenced by DR stage. Additionally, the findings were based on data obtained in treated and untreated DR, hence heterogeneity of subjects may have had a variable effect on other aspects of retinal pathophysiology. Under normal physiology, the retinal and choroidal circulations predominately supply oxygen to the inner retinal neurons and photoreceptors, respectively. However, oxygen supply by the dual circulations may be altered under pathologic conditions. Using enhanced depth imaging OCT, several studies have investigated changes in the choroid due to DR.
46 Overall, changes in the choroidal thickness were shown to be variable, whereas choroidal vascularity metrics were abnormal and decreased with worsening of DR. One limitation of the current study was that vascular oxygen saturation was only evaluated in the retinal circulation, thus the potential contribution of choroidal circulation to the findings was not considered. The effect of history of uncontrolled hypertension on the results was not considered, although at the time of imaging, subjects had similar BP. Because oxygenation and tortuosity measurements were obtained from different retinal regions, future studies are needed to assess the effect of retinal region and vessel size on these relationships. In addition, VTI measurements consisted of manual selection of vessel segments on a binary image based on an observer's subjective identification of locations of vessel branching. Therefore, in future studies, development of automatic segmentation for VTI measurements will improve the methodology. As technology advances, the current measurement methods may be improved, however, to our knowledge, the methods used in this study are among the best-established techniques in the field today.
In conclusion, the study showed a positive correlation of VTI with SO2V and a negative correlation with OEF, suggesting changes in these parameters develop under similar hyperglycemic situations and the pathological processes common in DR. The findings provide a better understanding of DR and may eventually lead to improved management of people with diabetes.