In this prospective study in community-dwelling elderly people, our main finding was that both retinal arteriolar and venular diameters at baseline were not related to an increased risk of OAG. In line with these observations, the retinal vessel diameters did not predict incident optic disc changes.
A potential limitation of our study is the reduced number of participants at follow-up, owing to the large number of deaths that occurred during follow-up in this elderly cohort. If persons who died before the follow-up examination had OAG before death more often than those who survived, this would have biased the results toward the null value. However, we have previously shown that people who have OAG are not at an increased risk of death, excluding the possibility that survival bias explains our negative findings.
32 Furthermore, persons who died before the follow-up examination and those who refused to participate showed statistically significant differences from the participants in cardiovascular profile, but the retinal vessel diameters were not different, suggesting a limited role for selective nonresponse. This loss to follow-up probably resulted in the imprecision of an underlying association, leading to larger confidence intervals. Hence, we cannot rule out the possibility that we were unable to detect small effects due to the small number of incident cases. Another limitation was that photographs were not taken synchronized on the cardiac cycle, leading to variation in vessel diameter due to pulsatility.
33 However, because photography was independent of any characteristics of the participants, this would have caused random misclassification.
Strengths of the present study are its prospective population-based design, a large number of community-dwelling elderly persons, accurate and objective quantification of retinal vessel diameters, and standardized definitions for iOAG.
In systemic hypertension, the increased peripheral vascular resistance may impair ocular perfusion.
34 In the Rotterdam Study, blood pressure was associated with prevalent high-tension OAG (OR per standard deviation increase in pulse pressure: 1.32; 95% CI: 1.03–1.69), but not with prevalent normal-tension OAG (OR: 0.97; 95% CI: 0.82–1.15) (Hulsman et al., personal communication, November 2004). The increased risk of high-tension OAG was partly due to the positive correlation between blood pressure and IOP.
7 11 However, it remains unclear whether high blood pressure, independent of its effect on IOP, is related to OAG.
34 No such relationship was established in either the Barbados Eye Study (OR: 1.29; 95% CI: 0.65–2.59),
11 or the Baltimore Eye Survey (OR: 1.32; 95% CI: 0.60–2.92).
7 Alternatively, hypotension rather than hypertension has been proposed to be deleterious to the optic nerve function.
9 34 A decreased diastolic perfusion pressure was related to prevalent OAG (OR: 3.29; 95% CI: 2.06–5.28).
11 It remains to be determined, however, to what extent systemic blood pressure is representative of the local perfusion of the optic nerve head and the retinal ganglion cell layer.
11
Few studies thus far have examined the relationship between retinal vessel abnormalities and OAG. One study showed that patients with OAG had significantly smaller arteriolar diameters (
n = 281; mean: 91 ± 20 μm), measured on optic disc photographs, than age-matched control subjects (
n = 173; mean: 104 ± 18 μm).
12 In a population-based cross-sectional study, prevalent OAG cases (
n = 59; mean: 183 μm) also had smaller arteriolar diameters compared with control cases (
n = 3065; mean: 194 μm).
35 Conversely, in another study involving digital scanning laser fluorescein angiography, no differences in either arteriolar or venular diameters were observed in patients with OAG compared with control subjects, although retinal arteriovenous circulation time was substantially prolonged.
36 Clinically, it is also known that reduced retinal blood perfusion, such as in central retinal artery occlusion or nonarteritic anterior ischemic optic neuropathy, often does not lead to glaucomatous cupping.
14 37 Our prospective data provide evidence against a retinal vascular cause in the pathogenesis of retinal ganglion cell loss and the subsequent development of GVFL. Only in the categorized analysis did it seem that larger venular diameters were related to iOAG. However, there was no clear trend, and this association disappeared after additional adjustments. The results of the linear models for iOAG
(Table 2)and the models for optic disc changes
(Table 4)also support the view that this association is a spurious finding.
For proper interpretation of these results, local differences in ocular circulation should be discussed.
9 38 The inner part of the retina (including the retinal ganglion cell layer) and the surface layer of the optic nerve head are vascularized by the retinal arterioles, whereas the main sources of blood supply to the optic nerve head are the short posterior ciliary arteries, either directly or from the circle of Haller and Zinn.
38 It has been reported that the autoregulation in the short posterior ciliary arteries seems to be less efficient than in the retinal circulation.
9 Also, in contrast to the retinal vessels, the optic nerve head vasculature has no proper blood–tissue barrier, making it more sensitive to fluctuating levels of vasoactive molecules (such as angiotensin-II).
9 Because of these differences, the short posterior ciliary arteries may be more vulnerable to vascular damage than the retinal vessels. This notion is supported by several studies suggesting that, in OAG, impairment in blood flow is more prominent in the short posterior ciliary arteries than in the retinal arteries.
13 15 39
Animal models have also suggested that the retinal circulation may not be causally related to OAG.
40 Administration of endothelin-1, a vasoconstrictive agent that reduces, among others, the retinal blood flow, resulted in loss of retinal ganglion cells and their axons in rats,
40 probably mediated by apoptosis.
41 However, this type of vascular injury did not lead to optic disc cupping.
40 It has been suggested that remodeling of the extracellular matrix, irrespective of the origin of retinal ganglion cell loss, is the hallmark of optic disc cupping.
40 Activation of quiescent astrocytes (for example by an increase in IOP) could lead to an increased expression of metalloproteinases, enzymes that play an important role in remodeling the optic disc and eventually leading to cupping.
42
In conclusion, we have shown that baseline retinal vessel diameters did not increase the risk of iOAG or incident glaucomatous optic disc changes. The results reported herein provide no evidence for a retinal vascular role in the pathogenesis of OAG. Further prospective studies should be conducted to confirm these findings and to elucidate the possible role of vascular factors in the pathophysiology of OAG.