Glaucoma, one of the major causes of blindness worldwide, is a chronic optic neuropathy, characterized by progressive loss of retinal ganglion cells and specific perimetric defects (1,2). The main risk factor for the onset and progression of glaucomatous damage is considered high intraocular pressure (IOP), which is also the main target of the therapeutic arsenal of glaucoma (2,3). In clinical practice, a significant proportion of cases experience progression, even when IOP is under control and, in normal-tension glaucoma, optic disc changes and visual field defects appear while IOP is considered normal.

Clinical studies have aimed to identify correlations with other risk factors, such as myopia, age, race, family history, central corneal thickness, and diabetes (4,5). There is strong evidence that systemic vascular abnormalities play an important role in the pathophysiology of glaucoma (6-9). Ocular blood flow (OBF) is a key factor for the health of retinal ganglion cells. According to Ohm's law, it depends on ocular perfusion pressure (OPP) and the vascular resistance ratio; the mechanisms of retinal autoregulation can modify the latter (9,10). Clinical data show that OPP correlates better with the occurrence and progression of glaucomatous lesions compared to blood pressure (BP) or IOP alone (9,11,12).

Retinal autoregulation is the complex physiological process by which constant blood flow is ensured despite significant variations in the OPP. The blood flow of the retina is controlled by complex mechanisms that include myogenic, metabolic and hormonal factors (6,13-15). The high consumption of oxygen in the human retina is crucial for normal functioning of the organ. Vascular dysregulation is a primary step initiating glaucomatous damage via OBF instability, affecting the optic nerve and retina by the enhancement of ischemic injury and promoting the apoptosis of retinal ganglion cells. Primary vascular dysregulation, endothelial dysfunction, astrocyte activation and neuronal dysfunction induce compromised neurovascular coupling (6). This leads to periods of reduced nutrient supply (including oxygen and glucose) during neuronal stimulation. Such periods are more likely to occur when OPP is reduced or fluctuates. Changes in arteriolosclerosis additionally bring a vulnerability factor of the optic nerve to small variations in perfusion eye pressure by compromising auto-regulation (15). On the other hand, vascular dysregulation may increase the vulnerability of the optic nerve to slight variations of IOP, BP or metabolic needs of retinal ganglion cells, because in this case, small variations of OPP may cause a significant decrease in OBF, beyond normal limits, resulting in retinal ganglion cell ischemia (6,7,15).

The objective of this study was to estimate the association of the risk of progression in glaucomatous patients with vascular dysregulation-related comorbidities as an independent factor despite maintaining normal IOP under antiglaucomatous topical therapy.

A 4-year-prospective study was carried out in 204 patients diagnosed with open-angle glaucoma and compensated values of intraocular pressure (IOP) under medical treatment, admitted to the Department of Ophthalmology, Emergency University Hospital Bucharest, Romania, during 2015-2019. The Ethics Committee of The Emergency University Hospital Bucharest approved the study, and signed informed consent of all patients enrolled was obtain, according to the Declaration of Helsinki. Two comparative study groups were designed: Group A (no associated vascular comorbidities) (n=102 patients) and group B (with associated vascular pathology) (n=102 patients). The groups were matched in regards to glaucoma stage and sex ratio. The two groups were not age-matched, due to the increased incidence of vascular comorbidities, especially arterial hypertension and ischemic coronary disease with age.

All of the patients underwent complex ophthalmological examination, automated perimetry (Optopol PTS-910), fundus photography and optical coherence tomography (OCT) analysis of the optic nerve and peri-papillary retina (SD-OCT, Zeiss). An extensive anamnesis was carried out at admission to document all cardiovascular comorbidities and other possible risk factors for progression. The two groups were comparatively studied for glaucoma progression. Only one eye, the eye with the most advanced glaucomatous lesions, was included in the study. Based on severity of glaucomatous optic nerve damage and visual field (VF) loss the patients were arranged in 4 groups: Preperimetric, early, moderate and advanced glaucoma (Table I).

Exclusion criteria included: Visual acuity <0.3, other retinal or neurologic pathology which could be a possible cause of decreased vision and VF abnormalities, and secondary glaucoma. After the initial enrollment, the patients were evaluated every six months by applanation tonometry, VF, OCT and fundus examination, for 48 months.

Out of the total of 204 patients, at the time of enrollment in the study, 57 (27.9%) patients represented newly diagnosed cases, and 147 (72.1%) were patients previously diagnosed with primitive open-angle glaucoma. Most were female (139 cases), with a sex ratio F:M of 2.13:1. The distribution by age groups showed a peak around 50-55 years, with a mean age 51±2.1 years. In group ʻAʼ, with no vascular comorbidities, the mean age was 48±2.3 years. In group ʻBʼ, with associated vascular pathology, the mean age was 62±1.8 years. Age and glaucoma stage distribution of the patients in the study groups are presented in Table II.

All patients in the study group achieved target IOP under medical treatment. In group B, the most frequent associated pathologies were: Arterial hypertension and type 2 diabetes (34.3%), followed by ischemic cardiac disease (22.55%) (Table III).

Of the total 204 patients, monitored over a 48-month period, 67 had perimetrically and/or imagistic documented progression of the glaucomatous disease, despite normal IOP under topical antiglaucomatous therapy. Progression was encountered in 57 (55.9%) patients from group B (with vascular comorbidities) and only in 10 (9.8%) patients from group A (Table IV). The mean age of patients who presented progression was significantly higher than the general average both for group A (52±2.7 vs. 48±2.3 years, P=0.014), and group B (62±1.8 vs. 66±8.3 years, P=0.02), thus age was positively associated with progression.

The percentages in which different systemic vascular conditions were found in the entire study group and in the group of patients who had functional or structural confirmed glaucoma progression were studied comparatively (Table V).

Statistical analysis found that cardio-vascular ischemic diseases, diastolic hypotension, peripheral vasospasm and chronic arterial hypertension were strongly associated with glaucoma progression (OR: 5.826, 5.444, 3.108 and 2.593 respectively) (Table V). In the present study, 7 patients out of a total of 204 (3.43%) presented low diastolic blood pressure (below 65 mmHg), either permanent or with documented nocturnal dips (by 24-h Holter monitoring). Progression was documented in 5 of these cases.

Diabetes was not a significant risk factor for glaucoma progression in the present study. This associated pathology was common both in the population without progression and in the group in which the disease progressed (OR: 0.874 vs. OR: 1.467). One explanation would be that patients with diabetic retinopathy were not included in the study, in order not to influence the assessment of the perimetric progression of glaucomatous disease. Therefore, being present only in patients with diabetes, but without retinopathy, we can consider that the vascular impairment related to diabetes is insignificant for the retinal autoregulation in these cases.

Ocular blood flow (OBF) is a key factor for the health of retinal ganglion cells. According to Ohm's law, it depends on ocular perfusion pressure (OPP) and vascular resistance ratio; the mechanisms of retinal autoregulation can modify the latter (10). OPP represents the arterial-venous pressure driving blood through the retinal vasculature. Although direct measurement of OPP can be performed experimentally, it is a complicated procedure. In practice, it can be approximated that the mean arterial pressure in the ophthalmic artery is equal to 2/3 of the pressure measured at the level of the brachial artery and that retinal venous pressure is similar to IOP. However, venous flow is known to occur in the retinal circulation (16). The venous pressure must slightly exceed IOP (13,14). OPP is the result of the balance that is established between blood pressure (BP) and IOP.

A constant OBF can be maintained in normal subjects up to an increase of IOP at values of 27-30 mmHg, which would mean a decrease in the perfusion eye pressure of 40-50% at the average BP of 100 mmHg; but also, in the case associated with an increase of OPP up to 20-60%, as happens during isometric physical exercise (7,15). In experimental studies, increased IOP induces retinal vasodilation to increase compensatory OBF (7,15,17). This is achieved by modifying the vascular caliber via Ca⁺⁺ blocking channels, which generate vasodilation. The mediators of these mechanisms include oxygen, carbon dioxide, angiotensin-II, adenosine, nitric oxide (NO), and endothelin-1 (14,18). Metabolic factors, such as variations in the partial pressures of O₂ and CO₂, are triggers for endothelin-1-mediated vasoconstriction and respectively vasodilation-mediated by NO (19). Retinal ganglion cells and their axons, endothelium and glial cells, such as astrocytes, form a ʻneurovascular unitʼ, which contributes to the homeostasis of the microenvironment and OBF in optic nerve head (ONH) and retina, via vascular autoregulation, glial support, the balance between ET-1 and NO, trophic supply, proper blood-brain barrier (BBB) and controlled immunity (20). In the central nervous system, astrocytes have a well-known neuroprotective effect, through multiple mechanisms: Angiogenetic, immunomodulatory, neurogenic, antioxidant and modulating synaptic transmission (21). In a normal state, astrocytes support the axons they ensheathe, but in response to injury/disease, they remodel and become reactive, inducing changes in gene expression, morphology and function (22). There is a standing question in glaucoma research, whether reactive astrocytes in the lamina region are harmful or beneficial for visual outcome. As in the brain, blood flow in the retina is also controlled by neurovascular coupling (15,22). This means that the retina increases its blood flow to regions in which neurons are activated, via prostaglandin-mediated vasodilatation. This is carried out to provide more oxygen and glucose to the active neurons. In recent years, evidence suggests that astrocytes play a crucial role in mediating this vasodilator signal (22,23).