How can the vascular component cause glaucoma?

Luís Abegão Pinto, MD, PhD

Central Lisbon Hospital North. Visual Sciences Study Center, Faculty of Medicine, University of Lisbon, Portugal.

From a pathophysiological point of view, the study of glaucoma may be characterized primarily by two lines of thinking which seek to explain the selective apoptosis of retinal ganglion cells. One of the most popular theories – the mechanical theory – argues that cell damage is induced by compression of neuronal structures associated with the intraocular pressure (IOP). However, the fact that a significant number of patients develop or show disease progression in spite of their low IOP values suggests that other factors may be relevant in this degenerative process. One of the causes most frequently discussed in this non-mechanical component is vascular dysfunction. 

In fact, it has been consistently shown that glaucoma patients – especially those with normal-tension glaucoma – show several local and systemic signs of vascular dysfunction1,2. These patients are know to have reduced flow velocity in retrobulbar arteries and at the optic disc level, peripheral vasospasm and cardiovascular conditions secondary to dysfunctions in the autonomic nervous system 35.

The difficulty however in translating the vascular lesion concept into clinical practice is its complexity. The classic concept of ischemia induced by maintained tissue hypoperfusion does not seem compatible with glaucomatous disease. Diseases where a proven chronic tissue hypoperfusion exists - such as diabetic retinopathy and central retinal vein occlusion - do not show neither the typical disc excavation of glaucomatous disease nor the selective loss of ganglion cells. Furthermore, if there was indeed a connection between glaucoma and chronic and  permanent tissue hypoperfusion, the association of glaucoma with cardiovascular risk factors such as atherosclerosis and dyslipidemia would have a magnitude that has not been observed in epidemiological studies carried out so far6.

It appears, then, that glaucoma patients may have instead an impaired regulation of blood supply to ganglion cells. Glaucoma patients would  have some dysfunction in the mechanisms that help maintain a constant tissue perfusion pressure, in what  would be either caused by autonomic nervous system damage, vascular endothelial dysfunction or by another process that has not been fully clarified7,8. This dysfunction would result in a higher probability of there being vasoconstriction periods (causing ischemia) alternating with normal tissue perfusion periods. This could lead to the well-known ischemia-reperfusion injuries which have been quite well characterized in other body areas such as the myocardium and the brain9,10.

In ischemia-reperfusion injuries, the areas suddenly deprived of oxygen have an energy metabolism that is less efficient because of disruption in oxidative phosphorylation mechanisms. This leads to anaerobic energy production, resulting in mitochondrial dysfunction, lower intracellular pH and the production of free oxygen radicals once the blood supply is finally restored. Depending on the degree and extent of such changes, the injury can result in diminished mitochondrial function or even trigger cellular apoptosis11. The optic nerve head – due to the absence of a myelin sheath - has a high energy need and hence a high mitochondrial concentration. This particular anatomic location is therefore extremely vulnerable to this ischemic-induced oxidative stress. At the same time, endothelin and matrix metalloproteinase-9 production resulting from the ischemia-reperfusion injury may lead to a blood-brain barrier disruption around the optic nerve and to an acceleration of the natural ageing of the optic nerve. This endothelin increase would further cause an additional reduction of ocular blood flow, interfere with axonal transport and induce the activation of the local astrocytes. Astrocyte activation will dramatically change the microenvironment in the optic nerve head, including promoting an upregulation of nitric oxide synthase 2 and therefore increasing the local concentration of nitric oxide. Although this molecule does not damage the cells per se, it does result in the formation of peroxynitrite by diffusing to ganglion cell axons, which are already vulnerable due to the accumulation of superoxide radicals produced during the ischemia-reperfusion injury. Peroxynitrite is a potent oxygen free radical responsible for the disruption of cell membrane integrity and for injuries to the mitochondrial DNA12.

 These processes induced by vascular instability can be synergetic with mechanical compression injuries. This opens the possibility of both theories being partially correct. Support towards integrating both theories begin to accumulate. For instance, there are reports of a reduced disease progression in patients with high-IOP glaucoma by treating them with calcium-channel blockers or statins (vasoregulation modulator drugs)13,14. On the other hand, even in normal-tension glaucoma, there is a beneficial effect in lowering IOP15, thus implying that even in these vascular-prone patients IOP remains an important player in the pathophysiological process. Overall, it could be argued that vascular instability induces a state of cell fragility that makes retinal ganglion cells more prone to IOP values that would otherwise be harmless.

This vascular instability is particularly relevant in the group of patients known as big dippers. In this group - which shows a night-time drop in blood pressure over 20% -, vascular regulation mechanisms may not be able to fully compensate perfusion pressure fluctuations of this magnitude. Several centers have documented that disease progression is faster in such cases and suggest several measures to try to reduce this. One of the approaches focuses on increasing intravascular volume - so to avoid excessive vasoconstriction - by promoting an increase in water intake, night-time fludrocortisone administration or even an increasing in salt intake. Alternatively, other centers suggest oral administration of calcium-channel blockers in sub-therapeutic doses. This is intended to decreased flow instability caused by vasospasm of resistance arterioles, thus avoiding night-time hypotension. Overall, it is suggested that any change in the therapeutic regimen should be coordinated with the physicians prescribing blood-pressure lowering drugs, promoting regimens that favour morning (rather than evening) administrations, while advocating against direct blood-pressure lowering drugs (such as phosphodiesterase inhibitors) before bedtime. The rationale behind these measures is to prevent an iatrogenic aggravation of a night-time arterial hypotension which would significantly decrease ocular perfusion pressure. However, data from epidemiological studies seem to suggest the prevalence of the disease could be effected by the type of anti-hypertensive medication the patient may be on. Indeed, both the Thessaloniki or the EPIC-Norfolk studies have suggested angiotensine-conversor enzyme inhibitor (ACEi) or systemic beta-blockers to be associated with milder forms of the disease or a milder IOP levels16-17. On the other hand, the Rotterdam Eye Study suggesting being on calcium channel blockers to be associated with higher prevalence of the disease18. This data highlights the little we do know about how vascular aspects interfere with disease pathogenesis and how careful must the physician be in his counselling both his patient and talking to the patient’s GP or cardiologist.     

It should be noted however that all these strategies were derived from the work and clinical experience of only a few centers and from a limited group of patients19-22. The complex pathophysiology of glaucoma makes it difficult to design trials to validate strategies that could balance the autonomic dysfunction these patients may have. Nevertheless, as more ground is being covered concerning the nature of this vascular dysfunction, the closer we get to better address this clinical important issue. 


4th Edition – May 2017