In this cross-sectional study of 481 young people with T1D, VDD was associated with a twofold increased risk of DR. However, VDD was not associated with changes in retinal vascular caliber or with differences in branching angle, length-diameter ratio, or tortuosity. In fact, normal 25OHD levels were associated with marginally greater fractal dimension. These results suggest that VDD may exert its effect at a later stage in the pathogenesis of DR or different factors may influence changes in retinal geometric parameters.
Assessment of retinal geometry has emerged as a useful biomarker of DR as well as other microvascular complications, stroke, and coronary vascular disease. Changes in retinal vascular caliber may underlie some of the pathophysiological changes associated with vascular complications [5
]. We have demonstrated that mean CRVE was greater in those with DR compared with those without. In the WESDR, larger caliber venules were associated with increased 6-year incidence of DR, risk of DR progression, and incidence of proliferative DR [6
]. It would appear that early increases in venular caliber persist throughout the development and progression of DR.
These findings are in contrast to earlier longitudinal studies from our group and others demonstrating that widening of retinal arterioles is associated with an increased incidence of DR [7
]. Our group with DR had higher CRAE (168.4 versus 165.9μ
m) but this was not statistically significant. The current group was older (mean age 14.9 years versus 13.5 years) and had longer diabetes duration (6.7 years versus 6.3 years) than the previous studies. It is possible that these early arteriolar changes, which may reflect early endothelial dysfunction, resolve prior to the development of features of DR.
VDD has been implicated in the development of microvascular and macrovascular diseases [20
]. In animal models of retinopathy, calcitriol inhibits angiogenesis and reduces retinal endothelial cell viability, processes which are thought to be involved in the pathogenesis of DR [12
]. We found that fractal dimension was marginally decreased in VDD patients, suggesting reduced angiogenesis. We did not measure parathyroid hormone (PTH) levels nor 1,25-hydroxyvitamin D levels in this cohort. It is possible that normal or elevated 1,25-hydroxyvitamin D levels, associated with elevated PTH in the VDD group, resulted in inhibition of angiogenesis. An alternative explanation is that 25OHD acts as a cofactor or promoter at an earlier time point in the development of DR, possibly via increased inflammation.
Although we did not demonstrate an association between VDD (using a level of 50
nmol/L to define deficiency) and retinal vascular caliber changes, we speculated whether there might be a level at which changes in vascular caliber would be seen. This might help to establish the level of 25OHD required to prevent the development of DR. Earlier studies have used varying levels of 25OHD to define deficiency [22
]. However, we did not find evidence of differences in retinal geometry measures in patients grouped according to 25OHD quartiles.
Changes in other measures of retinal vascular geometry, such as length-diameter ratio, tortuosity, and fractal dimension, are useful in the prediction of incident DR [9
] and are also associated with the presence of DR [11
]. Identification of reversible factors associated with these early changes could be used for prevention of this significant microvascular complication. However, we did not demonstrate any association between VDD and length-diameter ratio, curvature tortuosity and branching angles.
A possible explanation for these findings may be the decreasing incidence of DR in our clinic [25
], reducing the power of the study to detect between group differences. Therefore, although the study population was relatively large, it may not have been adequate to detect a difference in retinal vascular geometric measures between those with and without VDD. Also, duration of diabetes was relatively short compared with earlier adult studies. In addition, retinal vascular caliber measurements were performed on central arterioles and venules. It is possible that vitamin D may cause changes in peripheral retinal vasculature which would not have been detected in this study.
The strength of this study is the use of established methods in a well-characterised cohort.
One limitation is the cross-sectional nature of this study. Further studies could examine longitudinal changes in vascular geometric parameters with presence of VDD at baseline.