The importance of developing atherosclerosis in pseudoexfoliation glaucoma Značaj ateroskleroze u pseudoeksfolijativnom glaukomu

Background/Aim. Pseudoexfoliation syndrome (XPS) is an age-related systemic disorder characterized by increased production and accumulation of elastic microfibrillar material in different tissues of the body: skin, connective tissue portions of visceral organs, periphery blood vessels and the eye, as well. The aim of our study was to determine the significance of atherosclerotic changes in the carotid arteries in the development of XFS and pseudoexfoliation glaucoma (XFG). Methods. The study included 120 patients – 40 patients per each of the three defined groups: XFS group, XFG group and ageand sex-matched control subjects (control group) without XFG. Blood samples were collected from the patients before cataract surgery. Serum levels of total cholesterol, low-density lipoprotein – LDL, high density lipoprotein – HDL and triglycerides were analyzed by standard laboratory techniques. Standard ultrasonography of the carotid blood vessels was performed in all the participants. Results. Lipid’s profile was disturbed in the patients with XFS and XFG with statistical significance p control group (p < 0.01). Systolic and diastolic pressure was elevated in the patients with XFS and XFG (p < 0.01). Resistance index was increased in the patients with XFG (p < 0.01). Intima-media thickness was prolonged in patients with XFG (p < 0.01). Conclusion. A disturbed lipid profile with elevated resistancy index and intima-media thickness and increased systolic and diastolic pressure were compulsory findings in patients with developed XFG. So, these factors could be considered as risk. It seems to be difficult to inhibit the process of pseudoexfolation production in the whole body, but it appears that with proper therapy (antihypertnesive, cardiotoncs, etc.) and adequate nourishing, the process of XFG development could be interrupted.


Introduction
Pseudoexfoliation syndrome (XPS) is an age-related systemic disorder characterized by increased production and accumulation of elastic microfibrillar material in different tissues of the body: skin, connective tissue portions of visceral organs, periphery blood vessels and the eye, as well 1 .
In the eye, pseudoexfoliation (PEX) is associated with high risk for the development of glaucoma, called pseudoexfoliative glaucoma (XFG) 2 .
As PEX can be found in the whole body, especially in the blood vessel wall, it can be associated with different vascular diseases 3 . Exfoliation material was physiologically detected in vessel wall, myocardium, smooth and striated muscle cells, skin and visceral organs 3,4 .
Today, it is not yet clear what is the key factor in the pathogenesis of different vascular diseases. Iris and conjunctival vasculopathy is documented by indocyanin green angiography 5,6 ; exfoliation material is physiologically presented in the vessel's wall and pericytes in the whole body 3, 4, 7 as well as elevated homocystein level in the serum of the patients with PEX 8 . PEX is indicated for high risk for vascular disease: like stroke, myocardial infarction, and venous occlusions. It is also known that PEX can be found in patients with aortic aneurism which can be explained by abnormal fiber accumulation in the vessel wall 9 .
Atherosclerosis is the process closely related with a vascular disease 10 .
Abnormal lipid's profile, deregulated glycemia and high blood pressure can be the potential risk factor for vascular disease in the whole body 11 . The systemic manifestations of XFS and XFG, with emphasis on changes in the blood vessels (carotids) as well as changes in the metabolism of lipid material, can be defined as an atherosclerosis risk factor. The aim of our study was to determine the significance of atherosclerotic changes in carotid arteries in the development of XFS and XFG.

Methods
The study included 120 patients -40 patients per each of the three defined groups: the XFS group, the XFG group and age/sex-matched control subjects without PEX. Complete ophthalmological examination was performed for each participant: measurement of best-corrected visual acuity (Snellen charts), intraocular pressure (IOP) measured by Goldmann applanation tonometry, detailed slit-lamp examination, gonioscopy, perimetry (Octopus 900; Haag Strait, Koeniz, Switzerland), and indirect ophthalmoscopy. Slit lamp examination, as well as gonioscopy, was the basis for the diagnosis of PEX in the eye -exfoliation material on the anterior lens capsule or pupillary margin in at least one eye; and high pigmented iridocorneal angle.
PEX deposition with elevated IOP, optic disc glaucomatous changes [(neuroretinal rim and inferior-superiornasal-temporal (ISNT rule)] and functional failure of the visual field (generalized depression, paracentral scotoma, arcuate or Bjerrum scotoma, nasal step, altitudinal defect tempo-ral wedge, central island) were the entries for XFG group. The patients with the history of inflammatory eye disease, ocular trauma, ocular infection, severe retinal disease, myopia, intraocular surgery within the last 12 months, or laser surgery within the last 3 months were excluded from the study.
Blood samples were collected from the patients before cataract surgery. Biochemical analyses were done for responders fasting for at least 12 hours. Standard laboratory techniques were used for analyzing serum levels of lipid profiles including total cholesterol, low density lipoproteins (LDL), high density lipoproteins (HDL) and triglycerides.
Prior to blood pressure measurement the participants were asked to rest for 5 minutes. Blood pressure was measured, using an Omron M1 plus (OMRON Matsusaka Co. Ltd., Japan) digital blood pressure monitor with an appropriatesized cuff. Arterial hypertension was diagnosed if the systolic blood pressure was 140 and/or diastolic blood pressure 90 mmHg or higher and antihypertensive drugs were used during the past 2 weeks 12 . Three consecutive measurements with a two-minute interval between measurements were performed and the mean value was used for analyses.
Measurements of the resistance index and intimaemedia thickness during the arterial pressure pulse were performed using ultrasonography (conventional ultrasound scanner -Portable Digital Ultrasound machine Scanner system 3.5 Mhz, Convex probe with 3D, Hongkong, China).
The study was conducted in accordance with the Declaration of Helsinki and it was approved by the local ethics committee. All the subjects were informed about the study procedure and they consented to participate. Informed consent was obtained from each participant.
The distribution of the variables was checked with Kolmogorov-Smirnov's test. As all variables were distributed normally, they were expressed as the mean ± SD (Kruskal-Wallis test was used to compare the groups).

Results
The biochemical parameters of the elected groups are given in Figure 1 .65 mg/mL, HDL: 46.322 ± 6.38 mg/mL (p < 0.01). The mean serum total cholesterol, LDL, and triglycerides levels were significantly higher and the mean serum HDL level was significantly lower in the PEX group (XFG and XFS) than in the control group (p < 0.01).

Disscusion
Pseudoexfoliation syndrome is an age-related disorder in which white flakes accumulate in different tissues in the anterior eye as well as in the whole body, caused by a generalized fibrillopathy 7 . Its pathogenesis is not completely known, but it results in electron-dense microfibrils tissue deposition 13 . The gray-white material can be presented on anterior lens surface and pupillary margin, and can be scraped by papillary movement 14,15 . Concomitant pigment dispersion with its deposition on anterior chamber structures can be obtained by detailed slit-lamp examination and gonioscopy 15 . Exfoliation material can be found in many different organs: skin, heart, liver, brain, kidney, and eye, too 1 . Earlier studies indicated that iris vasculopathy was described in XFS/XFG 5, 6 ; PEX material can be histologically detected in the vessel wall, and pericytes in the whole body 3,4 and homocystein concentration was elevated 1 . All those findings indicate that vascular diseases could be in a tight junction with XFS/XFG including transient ischemic attacks, hypertension, angina, myocardial infarction, cerebrovascular and cardiovascular disease, aortic aneurysm, Alzheimerdisease and hearing loss 8 . Deregulated parasympathetic vascular control and baroreflex sensitivity, increased vascular resistance and decreased blood flow velocity, arterial endothelial dysfunction, high levels of plasma homocystein and arterial hypertension have been described in PEX patients 16 .
The association between different systemic vascular diseases and XFS/XFG remains controversial, despite earlier exposed data 1,3,4 . Thus, studies in this ophthalmological field are inconsistent. Our study indicates an association between elevated serum total cholesterol, LDL and triglycerides levels, and the mean systolic and diastolic blood pressures, which were significantly higher where the mean serum HDL level was significantly lower in PEX patients than in control subjects. We can find earlier data about elevated homocystein concentration 8 , as well as human cartilage glycoprotein-39 (YKL-40) levels, a new biomarker of inflammation and vascular dysfunction 17,18 , so it can be interlocked with a high incidence of vascular disease in XFS/XFG subjects. Some studies indicated disturbed lipid's profile in PEX patients 18,19 , so previously stated facts can be implicated in the pathogenesis of PEX cardiovascular diseases. Our results concurred with some of numerous studies, in which serum total cholesterol, LDL, and triglycerides levels were significantly higher and the serum HDL level was significantly lower in the PEX groups (XFG and XFS) than in the control group (p < 0.01). On the other hand, some data show no significant differences between cholesterol and triglyceride levels in patients with and without PEX 16 . Also, higher arterial pressure, which we observed in our study, represents the risk factor for the development of serious vascular disease 16,18 . Atherosclerosis is a compound process in the vessel wall, and final effect is the increased resistance and decreased blood flow, so tissue nourishment can be unsettled 19,20 . Some atherosclerosis markers are the elements of lipid's profile and are useful to evaluate blood flow in the tissue. Also, ultrasonography research is a very important method for rating blood flow in the blood vessel and in the tissue, too. A high resistance index and elevated intima-media thickness are in tight junction with atherosclerotic process and can signify for decreased blood flow, which corresponds to our results. They are also directly associated with disturbed lipid's status. Glaucoma is an ocular disease characterized by disturbed oxidative/antioxidative status activated by increased intraocular pressure and decreased blood flow in the retinal blood vessel, and with the loss of retinal ganglion cells by the apoptotic process 21,22 . Decreased blood flow of the optic head is the main step of its glaucomatous changes with appropriate functional visual field changes 21,22 . Increased IOP in XFG is due to accumulated PEX material in the outflow of the humor aqueous; and decreased blood flow in the optic head 2 . Decreased blood flow of the head of optical nerve is due to increased vascular resistance in the carotid and other smaller cranial arteries due to disturbed lipid's profile, elevated homocystein and YKL-40 level 8,16,18 .
Systemic and ocular blood flow changes, vascular resistance and arterial endothelial dysfunction, high levels of plasma homocystein and arterial hypertension have all been demonstrated in PEX subjects [23][24][25] .

Conclusion
Based the obtained results, as well as on some earlier results, we can suggest new strategies for restraining of pseudoexfoliation glaucoma development. A disturbed lipid profile with elevated resistancy index and intima-media thickness and increased systolic and diastolic pressure were compulsory findings in patients with developed XFG. So, these factors could be considered as risk.
In this moment, it seems to be difficult to inhibit the process of pseudoexfoliation production in the whole body, but it appears that with proper therapy (antihypertnesive drugs, cardiotonics, etc.) and adequate nourishing, the process of pseudoexfoliation glaucoma development can be arrested.