The role of lipid dysregulation and vascular risk factors in glaucomatous retrobulbar circulation

Monika Modrzejewska1, Wilhelm Grzesiak2, Daniel Zaborski2*, Anna Modrzejewska3

1Department of Ophthalmology, Pomeranian Medical University, Szczecin, Poland, 2Laboratory of Biostatistics, West Pomeranian University of Technology, Szczecin, Poland, 3Department of Ophthalmology, Pomeranian Medical University Hospital, Szczecin, Poland

Corresponding author: Daniel Zaborski, PhD Laboratory of Biostatistics, West Pomeranian University of Technology, Doktora Judyma 10, 71-460 Szczecin, Poland, Phone: +48914496813, Fax: +48914496800, E-mail:

Submitted: 10 January 2015 / Accepted: 9 February 2015


The aim of this study was to evaluate selected lipid-related and vascular factors and their effect on retrobulbar hemodynamics in glaucoma. Fifty-six patients with primary open-angle glaucoma (POAG) [POAG group; mean age 68.32 years (SD±0.21)] and 54 patients in control group [CG, mean age 68.1 years (SD±5.34)] were examined. Peak systolic velocity, end-diastolic velocity, mean velocity, pulsatility index, and resistive index of the ophthalmic artery, the central retinal artery, and the posterior ciliary arteries were measured by Color Doppler Imaging. Selected lipid-related, systemic and local vascular parameters were evaluated. Statistical methods included Shapiro-Wilk, Student-t and Mann-Whitney U tests, and Spearman rank correlations. In POAG group systolic arterial blood pressure, diastolic arterial blood pressure, total cholesterol, low-density lipoprotein cholesterol (LDL-ch), and intraocular pressure were significantly higher; while ocular perfusion pressure, high-density lipoprotein cholesterol (HDL-ch) and diastolic ocular perfusion pressure were significantly lower (p≤0.05). Color Doppler Imaging confirmed blood flow abnormalities in all investigated arteries. In addition, significant correlations of HDL-ch, LDL-ch and triglycerides (TG) with peak systolic velocity, end-diastolic velocity and mean velocity were found in individual arteries (p≤0.05). Also, significant associations of systolic arterial blood pressure, ocular perfusion pressure, systolic ocular perfusion pressure and diastolic ocular perfusion pressure with peak systolic velocity, end-diastolic velocity, mean velocity and resistive index were revealed in the posterior ciliary arteries (p≤0.05). Dysregulation of lipid-related and vascular factors, as well as statistical correlation between the above and retrobulbar blood flow indices, might imply their role in vasoconstrictive processes during glaucomatous endotheliopathy.

KEY WORDS: Primary open angle glaucoma; retrobulbar circulation; color Doppler imaging; vascular and lipid-related risk factors; ocular hemodynamics


Bosn J Basic Med Sci. 2015;15(2):50-56. © 2015 ABMSFBIH


Alterations of both retrobulbar hemodynamics and autoregulatory mechanisms are well-documented risk factors for primary open-angle glaucoma (POAG) as early as at the initial onset of the disease [14]. Many researchers are involved to identify the causes of glaucoma, other than intraocular pressure. Fluctuations in retrobulbar blood flow, intraocular pressure and ocular perfusion pressure accompanied by the changes in blood composition and viscosity. In addition, variations in diastolic arterial blood pressure, may play a crucial role in POAG pathogenesis [13,5]. Glaucoma may be associated with lipid dysregulation expressed not only as peripheral arterial disease, but also as ocular vascular pathology [68].

Prolonged disturbances to plasma lipids may lead to degenerative changes in the retinal and choroidal arterioles, venules, and capillaries, which may result in early ischemic retino-neural angiopathy [9,10]. A consequence of this process is hypoperfusion, causing microcirculation disorders related to ganglion cells, which may provoke permanent visual disturbances [4]. Changes in the inner diameter of the retinal arteries and veins result in altered blood flow velocity and vascular resistance indices in the retrobulbar arteries. So far, only a few studies emphasized the fact that lipid-related risk factors, apart from vascular ones, may affect the alteration of retrobulbar circulation in glaucoma. The above factors, together with the blood flow velocities and vascular resistance parameters measured by Color Doppler Imaging (CDI) might be considered as prognostic indicators of the disease development [4,1113].

The aim of this study was to investigate the association of selected lipid and vascular parameters with retrobulbar blood flow velocities and resistance indices in the ophthalmic artery (OA), the central retinal artery (CRA) and the posterior ciliary arteries (PCA): nasal (NPCA) and temporal (TPCA), in the POAG patients.


Study population

CDI of the retrobulbar arteries was performed in glaucoma patients and healthy volunteers, who agreed to participate in the study. The study was in accordance with the Declaration of Helsinki for research involving human subjects. An informed consent was received from all the patients and healthy subjects, and the study was approved by the University Ethics Committee (approval no. F147/08). Two study groups were identified for comparison: a group of 56 patients with POAG [POAG group; 56 examined eyeballs; age range 60-72 years; mean age 68.32 years (SD±0.21)] and a control group comprising healthy individuals [CG; 54 subjects, 54 examined eyeballs, age range 59-74 years; mean age 68.1 years (SD±5.34)]. All the participants were age and gender matched.

Exclusion criteria for controls included: cardiovascular and carotid or vertebral artery diseases, hypertension, diabetes, proliferative diabetic retinopathy, smoking, alcohol consumption, ophthalmic disease with high refractive myopia, optical disorders, ocular trauma or use of any general medications as well as estrogen replacement therapy in women [14]. Moreover, prior to CDI, each subject was requested to abstain from caffeine, intense exercise and consumption of large meals.

The POAG group, treated with anti-glaucomatous beta-blocker topical drops, consisted of patients in whom chronic POAG [mean duration of the disease 8.34 years (SD±2.31)] was confirmed by the results of a detailed ophthalmologic examination involving: typical glaucomatous optic neuropathy changes in indirect ophthalmoscopy and GDX (scanning laser polarimeter, Carl Zeiss AG, Germany), visual field lesions in threshold static automated perimetry and intraocular pressure elevation in applanation tonometry. Moreover, atheromatic plaques in the internal carotid arteries in CDI were seen in all the studied patients, but they did not affect hemodynamic blood flow.

Ophthalmic and physical examinations

The ophthalmic examination included the best-corrected visual acuity (Snellen Letter Chart), anterior segment slit lamp and indirect ophthalmoscopic fundus examinations (Volk glass 90D and XL, USA), gonioscopy and Goldmann applanation for intraocular pressure.

Data on mean arterial blood pressure, measured in a supine position before CDI examination, were collected directly from the subjects. The ranges between ≤ 120 mmHg and ≤ 80 mmHg (for systolic and diastolic arterial blood pressure, respectively) were considered normal. Vascular markers, such as systolic and diastolic systemic arterial blood pressure, ocular perfusion pressures, systolic and diastolic ocular perfusion pressure, were estimated according to the formulae [15]:

OPP = 2/3 [ABPd + (ABPs -ABPd)/3] - IOP (1)

OPPs = ABPs – IOP (2)

OPPd = ABPd – IOP (3)

where: OPP – ocular perfusion pressure; OPPs – systolic ocular perfusion pressure; OPPd – diastolic ocular perfusion pressure; ABPs – systolic arterial blood pressure; ABPd – diastolic arterial blood pressure; IOP – intraocular pressure.

Biochemical analyses

Selected plasma lipids levels: total cholesterol, HDL-ch, LDL-ch, and triglycerides were established using Roche kits and Clinilab automatic analyzer (bioMerieux, Craponne, France). The following reference values were used: total cholesterol ≤180 mg/dl, HDL-ch≥45–75 mg/dl, LDL-ch ≤65–100 mg/dl, triglycerides ≤150 mg/dl.

Imaging analyses

CDI of the OA, CRA, NPCA and TPCA was performed using Voluson 730 PRO, GE Medical Systems device (Milwaukee, WI, USA), with a multi-frequency 7.5-MHz linear probe. Each measurement was calculated three times for each vessel and averaged, maintaining a constant Doppler angle of about 30º in the CRA and both NPCA and TPCA, and 60º in the OA. The examinations were performed by the same experienced investigator, who automatically and, later on, manually, identified the peak, trough and velocity waveform according to the technique proposed by Harris et al. [16], in accordance with the guidelines recommended in the literature [16,17].

The following parameters were evaluated: peak systolic velocity (cm/s), end-diastolic velocity (cm/s), mean velocity (cm/s), pulsatility index, and vascular resistance index. The highest velocity value achieved during the cardiac systole was defined as peak systolic velocity and was calculated from the frequency of the peak in the Doppler-shifted waveform. End-diastolic velocity was described as the minimum velocity occurring during the diastole and was recorded as the frequency of the trough in the Doppler-shifted waveform. The pulsatility index, also referred to as the Gosling index, was defined as the ratio of the difference between the systolic and diastolic velocity to the mean blood flow velocity. Pourcelot’s vascular resistance index was defined as the ratio of the difference between the systolic and diastolic velocity to the systolic blood flow velocity.

Statistical analysis

Calculations were performed on the logarithmically transformed data, except for the mean and standard deviation of the original data, which are presented in the descriptive analysis. The Shapiro-Wilk, Student-t and Mann-Whitney U tests were applied using Statistica 10 software (StatSoft, Inc., Tulsa, OK, USA). Statistical significance of the differences between the mean values of the analyzed blood flow velocity parameters was determined. In addition, statistical correlations of the vascular and lipid-related risk factors with blood flow velocity parameters were calculated. Due to the variability of the measurements and, consequently, a significant departure from the normal distribution, the Spearman rank correlation test was employed to estimate the relationships between the parameters. Statistical significance was considered at p≤0.05.


In glaucoma patients, the best-corrected visual acuity with full optical correction (Snellen Letter Chart) was 0.65 (SD±0.28), whereas it was 0.98 (SD±0.12) in healthy individuals. Intraocular pressure was elevated and differed markedly from that in the controls. Arterial blood pressure (systolic and diastolic) was significantly higher in the POAG group (Table 1), whereas ocular perfusion pressure and diastolic ocular perfusion pressure were significantly lower. Total cholesterol and LDL-ch were markedly elevated in the POAG group, while HDL-ch was significantly lower in comparison with CG group. Triglycerides concentration remained within the normal ranges.

Table 1. Comparisons of values of arterial blood pressure, ocular perfusion pressure, intraocular pressure and plasma lipid profile in glaucoma patients (POAG, n=56) and controls (CG, n=54)


In POAG group, CDI confirmed blood flow abnormalities in all the investigated arteries (OA, CRA and PCAs), with significantly lower blood flow velocities (except for peak systolic velocity in the OA) and increased resistance indices (except for resistance index in the OA), as compared with CG (Table 2).

Table 2. Comparisons of values of systolic velocity, end-diastolic velocity, mean velocity, pulsatility and resistance indices in the retrobulbar arteries in glaucoma patients (POAG, n=56) and controls (CG, n=54)


Statistically significant and negative moderate correlations between vascular factors and ocular blood flow velocity parameters were found only in the TPCA and NPCA. These included the correlations of peak systolic velocity, end-diastolic velocity, mean velocity and resistance index with arterial blood pressures (correlation coefficients ranging from r=-0.58 to r=-0.47 for the TPCA and from r =-0.46 to r=-0.27 for the NPCA) and those of peak systolic velocity and mean velocity with ocular perfusion pressure (r=-0.31 and r=-0.35, respectively, for the TPCA and r=-0.29 and r=-0.33, respectively, for the NPCA). Moreover, peak systolic velocity, end-diastolic velocity, mean velocity and resistance index were correlated with systolic ocular perfusion pressure (correlation coefficients ranging between r=-0.58 and r=-0.41 for the TPCA and between r=-0.41 and r=-0.28 for the NPCA) and diastolic ocular perfusion pressure (except for resistance index in the NPCA, correlation coefficients ranging from r=-0.58 to r=-0.47 for the TPCA and from r=-0.48 to r=-0.26 for the NPCA).

Statistically significant low to moderate correlations were also observed between lipid-related factors and ocular blood flow velocity parameters in the OA, CRA, TPCA, and NPCA. These included the correlations of peak systolic velocity with HDL-ch (r=0.40), as well as peak systolic velocity and end-diastolic velocity with LDL-ch (r=-0.47 and r=-0.42, respectively) in the OA. Moreover, peak systolic velocity was correlated with HDL-ch, LDL-ch and triglycerides (correlation coefficients ranging between r=-0.37 and r=0.30) in the CRA, while peak systolic velocity and mean velocity were associated with HDL-ch (r=0.31 and r=0.31, respectively) and LDL-ch (r=-0.38 and r=-0.25, respectively) in the TPCA. Finally, peak systolic velocity and mean velocity were also correlated with HDL-ch (r=0.29 and r=0.29, respectively) and LDL-ch (r=-0.34 and r=-0.25) in the NPCA.


Atherosclerosis is hardly ever taken into account as a risk factor for glaucoma incidence [1820]. Damage to the vessel wall (hypertension, bacterial toxins, atherogenic lipoproteins aggregation) and uncontrolled smooth muscle cell proliferation facilitate the process of atherosclerotic plaque formation. Reduced level of endothelial substances exhibiting a relaxing activity is also worth mentioning [2123]. The aforementioned risk factors, including also genetic predisposition to low HDL-ch (<35 mg/dl), as well as free radical oxidation of LDL-ch and lipoprotein Lp(a) fractions, hyperbetalipoproteinemia, homocystinuria, oxidative modification of LDL-ch, together with the so-called uninhibited stimulated inflammatory response of leukocytes/endothelial cells, induce the cascade of atherosclerotic processes [2,3,10,2325]. Apart from lipid-related factors, the role of disturbances in the level of vasodilatory nitric oxide (NO) and vasoconstrictive endothelin-1 (ET-1) agents affecting the retino-choroidal microcirculation is emphasized in the literature. The results of decreased NO and increased ET-1 levels in glaucoma patients have been widely described [18,22,2631].

In this study, the importance of vascular factors such as decreasing ocular perfusion pressure, instability of blood pressure and lipid profile alterations were shown in glaucoma. It is known that glaucomatous ischemia and hemodynamic dysregulation might be caused e.g. by the lack of NO/ET-1 balance, being a response to endotheliopathy [32,33]. Moreover, the agents above are also involved in the apoptosis of glaucomatous retinal ganglion cells and dysregulation of aqueous outflow through the trabecular meshwork [28,29,34]. Experimental studies indicated that a local production of ET-1 can be stimulated by oxidized LDL (Ox-LDL), the compound indicative of hypercholesterolemia, which may intensify vasoconstrictive stimulation of ciliary arteries [32,3438].

The outcomes of the present study emphasize the role of lipid dysregulation in the phenomenon mentioned above. It was confirmed by a significant increase in some lipids, especially total cholesterol and LDL-ch, and a decrease in HDL-ch level (with reference to laboratory standards) in contrast to triglycerides, which did not demonstrate any significant alterations (Table 1). Moreover, statistically significant correlations of LDL-ch with peak systolic velocity and end-diastolic velocity in the OA may partially confirm our previously formulated hypothesis. The study has proved that the effect of atherosclerotic factors on the ocular circulation disturbances in glaucoma cannot be excluded.

In the studied glaucoma group, significantly decreased blood flow velocities were also associated with higher blood pressure. This may confirm the hypothesis that the disturbances of retrobulbar circulation may appear as a response to systemic pressure alteration, conceivably occurring as a vascular spasm or vasoconstrictive hypersensitivity [33,39]. Such a relationship was shown by Jonas et al. [40], Rader et al. [41], and Kerr et al. [42] in the region of peripapillary retinal vessels.

It should be mentioned that a statistically significant decrease in blood flow velocities in all the retrobulbar glaucomatous arteries has been confirmed by Doppler measurements in many studies [4,913,43,44].

Martinez and Sanchez [4] and Galassi et al. [45], reported a six-fold higher risk of the progression of glaucomatous visual field deficiency with an end-diastolic velocity decrease and a vascular resistance increase above 0.78, in the OA. It is also known that the rise in the risk of glaucoma development to about 90.5% appears with resistance index higher than 0.72. Taken together, our study results are compliant with the above mentioned ones, indicating a rise in resistance index in the OA, CRA, and PCAs, although in the case of the OA, this increase was not statistically significant.

According to Swietliczko and David [46], similar follow-ups in healthy individuals with an experimentally increased intraocular pressure indicated hemodynamic alterations of the short posterior ciliary arteries. The results of in vitro studies by Spencer et al. [47] showed a linear increase of resistance index, provoked by a spasm involving the vessels of the smallest size, concurrent with an increase in intraocular pressure [22,43]. Similar observations were made in the present study.

The phenomenon worth mentioning and observed in the studied POAG patients was a decrease in blood flow velocity parameters accompanied by increased vascular resistance indices in the retrobulbar arteries, despite applying beta-blocker ophthalmic drops. Considering the effects of beta-blockers on lipid profiles, this suggests their subtle influence on the retrobulbar circulation [8]. Opinions on the mechanisms behind the effects of these drugs on the retino-choroidal microcirculation remain controversial. Steigerwalt et al. [48], and Grunwald et al. [25] did not report any significant differences in the retrobulbar blood flow in eyeballs with either high or normal intraocular pressure. However, Collignon and Collignon-Brach [49] described an extension of retinal vessel diameter after 12-24 months of betaxolol therapy in comparison with placebo.

Among the vascular factors affecting blood flow in the glaucomatous optic nerve, the decreases in ocular perfusion pressure and diastolic ocular perfusion pressure have been the most often emphasized recently, especially their fall below 30 and even 50 mmHg, respectively [50,51]. These data have been confirmed in the Egna-Neumarkt study [1], Baltimore Eye Survey [51], ProYecto VER project [52] and the Barbados Incidence Study of Eye Diseases [53]. Additionally, Tielsch et al. [51] reported a six-fold higher risk of glaucoma occurrence with ocular perfusion pressure <30 mmHg in relation to about 50 mmHg in healthy individuals, taking also into account significant differences in systolic and diastolic ocular perfusion pressure. According to Leske et al. [53,54], diastolic ocular perfusion pressure lower than normal was associated with three times higher risk of POAG prevalence.

Choi et al. [55] proved that the changes in ocular perfusion pressure induced by the circadian fluctuation of blood pressure might account for the progression index in normal tension glaucoma.

It is believed that hypertension may cause an increase in blood flow velocity in the peripapillary vessels. However, it is also acknowledged that, concurrently, a long-lasting process of maintaining excessive hypertension, changes the threshold of autoregulatory mechanisms with a consequence of their dysregulation and decrease in the retrobulbar blood flow [2,26]. An example of the above may be statistically significant correlations between systolic arterial blood pressure, systolic ocular perfusion pressure, diastolic ocular perfusion pressure and blood flow parameters in the PCAs revealed in our study.

Finally, two limitations of our work need to be discussed. Firstly, beta-blockers in our research did not have a significant effect on resistance parameters in retrobulbar vessels. Moreover, a few reports in the literature emphasize the fact that these drugs alter lipid levels in the blood serum, which needs to be confirmed by further research with relation to the ischemic origin of glaucoma. Secondly, the sample size used in our study was relatively small. Therefore, we consider that our observations on lipid dysregulation require confirmation on a larger group of glaucoma patients. With a greater number of subjects, it would also be possible to apply regression analysis, which would allow more meaningful interpretation of the relationships among lipid-related and vascular factors and retrobulbar blood flow parameters in comparison with the correlation coefficients alone. Regression equations can also be used for predictions, provided that the magnitude of the coefficient of determination be sufficiently large. Correlation analysis provides only an overview of the relations between the investigated factors and the values of correlation coefficients only suggest the existence of such associations, which should also be proved by other methods.


In summary, our preliminary observations on lipid dysregulation and the coexistence of fluctuations in blood pressure, ocular perfusion pressure, and intraocular pressure might suggest a vasoconstrictive role of the lipid-related and vascular factors in the glaucomatous endotheliopathy. This hypothesis is additionally supported by concomitant correlations between the selected lipid and vascular factors and retrobulbar blood flow velocities found in our study. Decreased blood flow velocities and increased resistance indices observed not only in the CRA (nourishing mainly retinal ganglion cells) but also in both PCAs (supplying the optic nerve axons) might indicate a significance of these parameters in the ischemic origin of glaucoma.


The authors declare no conflict of interest.


1. Bonomi L, Marchini G, Marraffa M, Bernardi P, Morbio R, Varotto A, Vascular risk factors for primary open angle glaucoma: The Egna-Neumarkt StudyOphthalmology 2000; 107: 71287-93.

2. Harris A, Evans D, Martin B, Zalish M, Kagemann L, McCranor L, Nocturnal blood pressure reduction: effect on retrobulbar hemodynamics in glaucomaGraefes Arch Clin Exp Ophthalmol 2002; 240: 5372-8.

3. Flammer J, Haefliger IO, Orgül S, Resink T, Vascular dysregulation: A principal risk factor for glaucomatous damage?J Glaucoma 1999; 8: 3212-9. 9906000-00012.

4. Martinez A, Sanchez M, Predictive value of colour Doppler imaging in a prospective study of visual field progression in primary open-angle glaucomaActa Ophthalmol Scand 2005; 83: 6716-22.

5. Carter CJ, Brooks DE, Doyle DL, Drance SM, Investigations into a vascular etiology for low-tension glaucomaOphthalmology 1990; 97: 149-55.

6. Dewey M, Comprehensive assessment of peripheral artery disease using magnetic resonance imaging, angiography, and spectroscopyJ Am Coll Cardiol 2009; 54: 7636-7.

7. Choi J, Joe SG, Seong M, Choi JY, Sung KR, Kook MS, C-reactive protein and lipid profiles in Korean patients with normal tension glaucomaKorean J Ophthalmol 2009; 23: 3193-7.

8. Stewart WC, Osterman J, Serum lipid physiology and the influence of glaucoma medicationsSurv Ophthalmol 1998; 43: 3233-44.

9. Deokule S, Vizzeri G, Boehm AG, Bowd C, Medeiros FA, Weinreb RN, Correlation among choroidal, parapapillary, and retrobulbar vascular parameters in glaucomaAm J Ophthalmol 2009; 147: 4736-43.e2

10. Wong TY, Klein R, Sharrett AR, Nieto FJ, Boland LL, Couper DJ, Retinal microvascular abnormalities and cognitive impairment in middle-aged persons. The atherosclerosis risk in communities studyStroke 2002; 33: 61487-92.

11. Modrzejewska M, Ostanek L, Bobrowska-Snarska D, Karczewicz D, Wilk G, Brzosko M, Ocular circulation in systemic lupus erythematosusMed Sci Monit 2009; 15: s11CR573-8.

12. Modrzejewska M, Pieńkowska-Machoy E, Grzesiak W, Karczewicz D, Wilk G, Predictive value of color Doppler imaging in an evaluation of retrobulbar blood flow perturbation in young type-1 diabetic patients with regard to dyslipidemiaMed Sci Monit 2008; 14: s10MT47-52.

13. Harris A, Arend O, Kopecky K, Caldemeyer K, Wolf S, Sponsel W, Physiological perturbation of ocular and cerebral blood flow as measured by scanning laser ophthalmoscopy and color Doppler imagingSurv Ophthalmol 1994; 38 Suppl: S81-6.

14. Dimitrova G, Kato S, Color Doppler imaging of retinal diseasesSurv Ophthalmol 2010; 55: 3193-214.

15. Topouzis F, Coleman AL, Harris A, Jonescu-Cuypers C, Yu F, Mavroudis L, Association of blood pressure status with the optic disk structure in non-glaucoma subjects: the Thessaloniki eye studyAm J Ophthalmol 2006; 142: 160-7.

16. Harris A, Januleviciene I, Siesky B, Schmetterer L, Kageman L, Stalmans I, Weinreb RN, Harris A, Clinical measurement of ocular blood flowOcul. Blood Flow Glaucoma 6th Consens. Rep. World Glaucoma Assoc 2009; Amsterdam: Kugler Publications;

17. Stalmans I, Vandewalle E, Anderson DR, Costa VP, Frenkel RE, Garhofer G, Use of colour Doppler imaging in ocular blood flow researchActa Ophthalmol 2011; 89: 8e609-30.

18. Güngör İU, Güngör L, Özarslan Y, Arıtürk N, Beden Ü, Erkan D, Is symptomatic atherosclerotic cerebrovascular disease a risk factor for normal-tension glaucoma?Med Princ Pract 2011; 20: 3220-4.

19. Pavljašević S, Ašćerić M, Primary open-angle glaucoma and serum lipidsBosn J Basic Med Sci 2009; 9: 185-8.

20. Martin M, Hulley SB, Browner WS, Kuller LH, Wentworth D, Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 menLancet 1986; 2: 8513933-6.

21. Gasser P, Flammer J, Blood-cell velocity in the nailfold capillaries of patients with normal-tension or high-tension glaucomaAm J Ophthalmol 1991; 111: 5585-8.

22. Flammer J, The vascular concept of glaucomaSurv Ophthalmol 1994; 38 Suppl: S3-6. 41-8.

23. Klein BE, Klein R, Linton KL, Franke T, Cigarette smoking and lens opacities: the Beaver Dam Eye StudyAm J Prev Med 1993; 9: 127-30.

24. Hayreh SS, Bill A, Sperber GO, Effects of high intraocular pressure on the glucose metabolism in the retina and optic nerve in old atherosclerotic monkeysGraefes Arch Clin Exp Ophthalmol 1994; 232: 12745-52.

25. Grunwald JE, Piltz J, Hariprasad SM, Dupont J, Maguire MG, Optic nerve blood flow in glaucoma: Effect of systemic hypertensionAm J Ophthalmol 1999; 127: 5516-22.

26. Pache M, Dubler B, Flammer J, Peripheral vasospasm and nocturnal blood pressure dipping–two distinct risk factors for glaucomatous damage?Eur J Ophthalmol 2003; 13: 3260-5.

27. Su WW, Cheng ST, Ho WJ, Tsay PK, Wu SC, Chang SH, Glaucoma is associated with peripheral vascular endothelial dysfunctionOphthalmology 2008; 115: 71173-8.e1

28. Haefliger IO, Meyer P, Flammer J, Lüscher TF, The vascular endothelium as a regulator of the ocular circulation: A new concept in ophthalmology?Surv Ophthalmol 1994; 39: 2123-32.

29. Schmetterer L, Polak K, Role of nitric oxide in the control of ocular blood flowProg Retin Eye Res 2001; 20: 6823-47.

30. Cohen R, Padilla J, Light D, Diller R, Carotid artery occlusive disease and ocular manifestations: Importance of identifying patients at riskOptometry 2010; 81: 7359-63.

31. Shoji T, Sakurai Y, Sato H, Chihara E, Ishida M, Omae K, Serum low-density lipoprotein cholesterol level is strong risk factor for acquired color vision impairment in young to middle-aged Japanese men: The Okubo Color Study Report 2Atherosclerosis 2010; 210: 2542-7.

32. Haefliger IO, Dettmann E, Liu R, Meyer P, Prünte C, Messerli J, Potential role of nitric oxide and endothelin in the pathogenesis of glaucomaSurv Ophthalmol 1999; 43: Suppl 1S51-8.

33. Emre M, Orgül S, Gugleta K, Flammer J, Ocular blood flow alteration in glaucoma is related to systemic vascular dysregulationBr J Ophthalmol 2004; 88: 5662-6.

34. Furchgott RF, Zawadzki JV, The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholineNature 1980; 288: 5789373-6.

35. Zhu P, Dettmann ES, Resink TJ, Lüscher TF, Flammer J, Haefliger IO, Effect of Ox-LDL on endothelium-dependent response in pig ciliary artery: Prevention by an ET (A) antagonistInvest Ophthalmol Vis Sci 1999; 40: 51015-20.

36. Resch H, Garhofer G, Fuchsjäger-Mayrl G, Hommer A, Schmetterer L, Endothelial dysfunction in glaucomaActa Ophthalmol 2009; 87: 14-12.

37. Rosenthal R, Fromm M, Endothelin antagonism as an active principle for glaucoma therapyBr J Pharmacol 2011; 162: 4806-16.

38. Babizhayev MA, Bunin AY, Lipid peroxidation in open-angle glaucomaActa Ophthalmol (Copenh) 1989; 67: 4371-7.

39. Garhöfer G, Fuchsjäger-Mayrl G, Vass C, Pemp B, Hommer A, Schmetterer L, Retrobulbar blood flow velocities in open angle glaucoma and their association with mean arterial blood pressureInvest Ophthalmol Vis Sci 2010; 51: 126652-7.

40. Jonas JB, Fernandez MC, Naumann GO, Parapapillary atrophy and retinal vessel diameter in nonglaucomatous optic nerve damageInvest Ophthalmol Vis Sci 1991; 32: 112942-7.

41. Rader J, Feuer WJ, Anderson DR, Peripapillary vasoconstriction in the glaucomas and the anterior ischemic optic neuropathiesAm J Ophthalmol 1994; 117: 172-80.

42. Kerr J, Nelson P, O'Brien C, A comparison of ocular blood flow in untreated primary open-angle glaucoma and ocular hypertensionAm J Ophthalmol 1998; 126: 142-51.

43. Modrzejewska M, Karczewicz D, Wilk G, Use of color Doppler ultrasonography in primary vasospastic syndrome and assessment of ocular blood flow in patients with transient monocular blindnessPol J Radiol 2007; 72: 29-14.

44. Harris A, Kagemann L, Ehrlich R, Rospigliosi C, Moore D, Siesky B, Measuring and interpreting ocular blood flow and metabolism in glaucomaCan J Ophthalmol 2008; 43: 3328-36.

45. Galassi F, Sodi A, Ucci F, Renieri G, Pieri B, Baccini M, Ocular hemodynamics and glaucoma prognosis: A color Doppler imaging studyArch Ophthalmol 2003; 121: 121711-5.

46. Swietliczko I, David NJ, Fluorescein angiography in experimental ocular hypertensionAm J Ophthalmol 1970; 70: 3351-63.

47. Spencer JA, Giussani DA, Moore PJ, Hanson MA, In vitro validation of Doppler indices using blood and waterJ Ultrasound Med 1991; 10: 6305-8.

48. Steigerwalt RD, JrLaurora G, Belcaro GV, Cesarone MR, De Sanctis MT, Incandela L, Ocular and retrobulbar blood flow in ocular hypertensives treated with topical timolol, betaxolol and carteololJ Ocul Pharmacol Ther 2001; 17: 6537-44.

49. Collignon NJ, Collignon-Brach JD, Effect of topical beta blockers on human retinal vessels diametersInt Ophthalmol 1997-1998; 21: 4199-203. 1005918922700.

50. Gugleta K, [Vascular risk factors in glaucoma-diagnostics]Praxis (Bern 1994) 2009; 98: 4201-7.German

51. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC, Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessmentArch Ophthalmol 1995; 113: 2216-21.

52. Quigley HA, West SK, Rodriguez J, Munoz B, Klein R, Snyder R, The prevalence of glaucoma in a population-based study of Hispanic subjects: Proyecto VERArch Ophthalmol 2001; 119: 121819-26.

53. Leske MC, Connell AM, Wu SY, Nemesure B, Li X, Schachat A, Incidence of open-angle glaucoma: the Barbados Eye Studies. The Barbados Eye Studies GroupArch Ophthalmol 2001; 119: 189-95.

54. Leske MC, Wu SY, Nemesure B, Hennis A, Incident open-angle glaucoma and blood pressureArch Ophthalmol 2002; 120: 7954-9.

55. Choi J, Jeong J, Cho HS, Kook MS, Effect of nocturnal blood pressure reduction on circadian fluctuation of mean ocular perfusion pressure: a risk factor for normal tension glaucomaInvest Ophthalmol Vis Sci 2006; 47: 3831-6.