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Editor,—I read with interest the article by Iannaccone et al 1 on the connection between venous plasma endothelin-1 (ET-1) level and retinal vein occlusions (RVO). The authors conclude that elevated ET-1 concentration in the peripheral circulation in their patients may be a systemic marker for retinal venous occlusions. Also, they think it possible that the elevated ET-1 level they found in the peripheral blood samples could directly promote the development of retinal vascular occlusions (RVOs).
This latter conclusion seems to be unlikely since local retinal vasoconstriction is supposed to be influenced much more by the local ET-1 concentration than the elevation of the systemic venous ET-1 level. If elevated ET-1 concentrations in the peripheral circulation induce RVO, one would suppose it to be experienced in many RVO cases—for example, in normal pressure glaucoma, which is frequently associated with elevated plasma ET-1 values.2 3 On the contrary it is primary open angle glaucoma with elevated intraocular pressure and mild to moderate systemic hypertension that is frequently associated with RVOs.4 Both of these conditions are characterised by normal venous ET-1 concentrations.1 5These clinical considerations suggest that the direct influence of peripheral ET-1 levels on the retinal microcirculation is very unlikely.
The authors’ main conclusion that RVOs cause a significant elevation in peripheral venous ET-1 concentrations seems to be relevant. However, the authors should have shown some more data to exclude a few factors with a potential influence on their result. Was there any difference in the severity of systemic hypertension between hypertensive RVO patients and the uncomplicated hypertensive control subjects? Severe hypertension does influence the systemic ET-1 level. One supposes that all patients were on medication at the time of the blood sampling for ET-1 measurements. Several medicines including antihypertensive drugs and, possibly, β receptor blocker eye drops have an influence on systemic ET-1 levels. Systemic and topical medications should have been compared between the groups in order to rule out their impact on the ET-1 level. It would have been especially interesting and might have supported the authors’ hypothesis on the marker role of venous ET-1 level, if time dependency of the ET-1 level had been investigated individually, at least in the early cases. One may speculate that, early after the development of RVO, systemic ET-1 level may increase, then decrease later till the onset of retinal neovascularisation, which might induce an increase again possibly via an increased expression of vascular endothelial growth factor (VEGF), since VEGF can cause an increased expression of endothelin converting enzyme.6Interindividual differences might mask the time dependent changes. This may be a reason for the lack of time dependency found by the authors who plotted all individual ET-1 values as a function of time elapsed between the vein occlusion and blood sampling for ET-1 measurement. Finally, I congratulate the authors on their very interesting article.
Editor,—We would like to thank Dr Hólló for his interest in our work. He raises a variety of important issues, which gives us the opportunity to clarify and expand some points that we raised in the discussion of our paper. First and foremost, we very much agree with him on the very low likelihood that the elevated endothelin-1 (ET-1) plasma concentrations we observed in our patient population may have pre-existed, or be the cause of, the retinal vascular occlusion (RVO). Although we cannot provide conclusive evidence to rule out this possibility, which could be addressed only by a large prospective study on ET-1 levels in a population at risk for RVOs, by no means do we support it. In fact, we concluded that the elevated ET-1 levels are likely to be a consequence of the occlusive event.
We also agree that establishing a precise relation between ET-1 concentrations and time elapsed from RVO diagnosis may indeed be crucial in understanding the role that ET-1 plays in RVOs. Similar to what has been observed in patients with myocardial infarction, it is quite possible that, immediately following the occlusion, ET-1 concentrations may have been elevated to a greater extent, and that ischaemic neovascular complications ensued only in those patients in whom ET-1 levels persisted above a certain threshold level. By inducing experimentally ischaemic branch RVOs, Pournaras and colleagues showed that ischaemic retinal areas are always hypoxic, yet progression to neovascularisation occurs in only about 50% of cases. They postulated the need for persistence of critically low Po 2 levels for neovascularisation to develop. We suggest that elevated intraretinal ET-1 levels in the area of the occluded vessel may be at least one of the critical factors in causing the low Po 2retinal levels. A self reinforcing cycle may be taking place locally, in which ET-1 released by endothelial cells following RVO could diffuse in the vicinity of the occluded vessel to the abluminal side of neighbouring pericytes and induce capillary non-perfusion. The ensuing ischaemia could further enhance ET-1 release by retinal endothelial cells, maintaining and extending retinal non-perfusion. Long lasting hypoxia can induce upregulation of vascular endothelial growth factor (VEGF) receptors, VEGF overexpression, and lead to retinal neovascularisation. Recent experimental evidence supports the possibility that elevated ET-1 levels occur in retinal neovascularisation and precede VEGF upregulation. Since ET-1 also exerts a dose dependent mitogenic effect on retinal pericytes, it is tempting to speculate that persistence of ET-1 about a putative threshold level could perpetuate the ischaemic condition and contribute, hand in hand with VEGF, to the complex chain of events that leads to retinal neovascularisation in RVOs. These hypotheses, although intriguing and well substantiated, await further verification.
The potential effect of confounding factors on ET-1 determinations is also very important. Maximal care was placed in selecting the outpatient population. In fact, nearly half of the population we examined clinically was excluded from the study because it did not meet our stringent inclusion criteria. Lerman and colleagueshave shown elegantly that ET-1 elevations are proportional to the severity of the associated vasculopathy. Other than the RVO itself, we have no evidence to suggest that the control group of uncomplicated hypertensive subjects may have had less severe hypertensive vascular damage than the investigated RVO population. In addition, if this were the case, it would contradict the hypothesis that the observed peripheral ET-1 elevations reflected the local retinal event, on which both Dr Hólló and we seem to agree. All but one of our RVO hypertensive patients (No 18 in the study) were on either mono- or multitherapy for hypertension (range 1–3). Pre-RVO medications included angiotensin converting enzyme (ACE) inhibitors (n=6), calcium channel blockers (n=4), nitrates (n=3), diuretics (n=2), and β blockers (n=1). Although not exactly matched, uncomplicated hypertensives had a similar medication pattern. It has been suggested that ACE inhibitors may reduce ET-1 plasma levels in some disease states. Our RVO patients on ACE inhibitors, however, did not have ET-1 concentrations (15.05 (SD 5.2) pg/ml) significantly different from the mean ET-1 levels observed in the study (14.22 (4.6) pg/ml) for all RVO patients, yet significantly greater than both normals and uncomplicated hypertensives (p <0.01). The same applied to the RVO patients on calcium channel blockers (16.82 (4.52) pg/ml). We also plotted ET-1 concentrations as a function of the number of hypertensive medications (data not shown), which failed to reveal significant correlations (R = 0.396; p = 0.26). All seven RVO patients with a history of elevated intraocular pressure were on topical β blockers, but, as addressed in our paper, they had ET-1 plasma levels superimposable to those of RVO patients with normal ocular pressure. Therefore, there is no indication that our measurements may have been influenced by either systemic or topical treatment regimens. These additional considerations, prompted by Dr Hólló’s acute remarks, further confirm our conclusion that the elevated ET-1 levels are most likely accountable for by the retinal occlusive event.