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Blood Pressure and Glaucoma Vital P. Costa, MD1,2; Enyr S. Arcieri, MD1,3; Alon Harris, PhD, MS4. 1. Department of Ophthalmology, University of Campinas, Brazil. 2. Department of Ophthalmology, University of São Paulo, Brazil. 3. Department of Ophthalmology, Federal University of Uberlândia, Brazil. 4. Department of Ophthalmology, Indiana University, Indianapolis, USA. Address for correspondence: Vital P. Costa, MD Director, Glaucoma Service, University of Campinas, Brazil Rua Pará 269 apto 142. São Paulo SP 01243-020 Brazil Email: [email protected] Abstract Although intraocular pressure (IOP) is considered the main risk factor for the development of glaucoma and the only parameter subject to treatment, there is sufficient evidence to suggest that glaucoma may continue to progress despite lowering patients' IOP to targeted levels. Several studies have implicated vascular risk factors in the pathogenesis of glaucoma. Among them, blood pressure (BP) and ocular perfusion pressure have become increasingly important. Although clinicians cannot currently visualize ocular blood flow directly, they can easily measure glaucoma patients' BP and IOP to calculate their ocular perfusion pressure and quantify the vascular changes. The purpose of this review article is to discuss the relationship between BP and IOP, BP and glaucoma, and perfusion pressure and glaucoma. We discuss the importance of autoregulation to maintain the adequate perfusion of the optic nerve head, and suggest that ocular perfusion pressure and its fluctuation may be parameters that need to be measured in glaucoma patients. Glaucoma is a multifactorial disease characterized by loss of retinal ganglion cells that leads to typical damage of the optic nerve and visual field. Glaucoma is the second leading cause of blindness worldwide, and affects more than 50 million people1. Although intraocular pressure (IOP) is considered the main risk factor for the development of glaucoma and the only parameter subject to treatment, there is sufficient evidence to suggest that glaucoma may continue to progress despite lowering patients' IOP to targeted levels2-4. Several studies have implicated vascular risk factors in the pathogenesis of primary open-angle glaucoma (POAG)5-29. Among them, blood pressure (BP) and ocular perfusion pressure (OPP) have become increasingly important. Perfusion pressure is defined as the difference between arterial and venous pressure. In the eye, venous pressure is equal to or slightly higher than IOP. OPP can therefore be defined as the difference between arterial BP and IOP. OPP can be further broken down into diastolic perfusion pressure (diastolic BP minus IOP) and systolic perfusion pressure (systolic BP minus IOP)30. The purpose of this review article is to discuss the relationship between BP, perfusion pressure and glaucoma. 1. BLOOD PRESSURE AND INTRAOCULAR PRESSURE Several epidemiological studies have shown that elevated systemic BP is associated with a slight increase in IOP11-13,16. In the Blue Mountains Eye Study14,21, mean IOPs of the two eyes increased from 14.3 mmHg for systolic BP levels < 110 mmHg to 17.7 mmHg for systolic BP levels ≥ 200 mmHg. Mean IOPs of the two eyes increased from 15.2 mmHg for diastolic BP levels < 70 mmHg to 18.6 mmHg for diastolic BP levels of ≥120 mmHg. Mean IOP in right eyes increased by 0.28 mmHg for each 10-mm Hg increase in systolic BP, or by 0.52 mmHg for each 10-mmHg increase in diastolic BP. In the Beijing Eye Study28,31,32, multivariate regression analysis revealed significant associations between IOP and both systolic (P<0.001) and diastolic BP (P<0.001). Hennis et al19 examined the longitudinal relationship between systemic hypertension and a 4-year IOP change in residents of Barbados aged ≥ 40 years. Overall, mean IOP increased by 2.5 ± 3.9 mmHg in black participants during the 4-year period of follow-up. Participants with elevated systolic and diastolic BP at baseline, or those receiving antihypertensive therapy had greater increases in IOP than did others. Klein et al23 investigated the association between change in systemic BP and change in IOP in Beaver Dam. Five years after baseline, the authors performed a follow-up examination of 3684 participants. In cross sectional analyses at baseline and follow up, it was found that a 10 mmHg increase in systolic BP was associated with a 0.3 mmHg increase in IOP, whereas a 10 mmHg increase in diastolic BP was associated with a 0.6 mmHg increase in IOP. Over the 5 year interval, an increase of 10 mmHg in systolic BP was associated with an increase of about 0.2 mmHg in IOP, and an increase of 10 mmHg in diastolic BP was associated with a 0.4 mmHg increase in IOP. The Egna-Neumarkt Glaucoma Study16 evaluated the association between systemic BP and age-adjusted IOP. The correlation between BP and IOP was statistically significant (r>0.94; P<0.001) for both systolic and diastolic BP. A 10-mmHg increase in systolic BP was associated with a 0.24 mmHg increase in IOP, whereas the same 10-mmHg increase in diastolic BP was associated with a 0.4 mmHg increase in IOP. In summary, increases in IOP in response to a 10-mmHg increase in systolic and diastolic BP vary from 0.20 to 0.44 mmHg and 0.40 to 0.85 mmHg, respectively. Therefore, although real, the IOP increase in association with systemic hypertension is of modest proportion, which indicates that the clinical importance of BP increase in the pathogenesis of glaucoma may be limited. 2. PHYSIOLOGY BEHIND THE RELATIONSHIP BETWEEN IOP AND BP The physiological meaning of the correlation between BP and IOP remains speculative. Bill33 demonstrated that variations in systolic BP resulted in small changes in aqueous humor formation, possibly related to increased capillary pressure in the ciliary body. In fact, when monkeys are rapidly bled to a femoral arterial BP of about 60mmHg, the rate of aqueous formation is reduced about 20%. Blood pressure may also affect the episcleral venous pressure, modifying aqueous humor outflow28. There are two theories that speculate on the specific mechanism which controls the relationship between BP and IOP. The first suggests the role of the autonomic nervous system, which could control IOP by changing the balance between aqueous humor formation and outflow34. The second proposes that the renin-angiotensin system may regulate both IOP and BP, which is supported by a number of studies where olmesartan and ACE inhibitors have been reported to lower IOP in rabbits, monkeys and humans35-40. Tissue or local renin-angiotensin system has been found in the eye by a number of investigators41-44. This evidence is further supported by a recent finding that intravitreally administered angiotensin (1-7) reduces IOP in normotensive rabbit eyes48. Since both of these systems are involved in the control of BP and there is evidence of these actions in the control of IOP, further investigation is necessary to elucidate if the two systems are connected in some way. While it is not clear by what mechanism IOP might be influenced by systemic BP, it is reasonable to speculate how the effect of elevated BP can raise IOP. Hvidberg et al45 investigated the effect of PCO2 changes and body positions on IOP during general anesthesia. This study found that when CO2 administration was removed, a rapid simultaneous reduction in IOP occurred, which had therefore to be of vascular origin, presumably due to change in choroidal volume. Gupta46 described how coughing raises intracranial pressure, which produces an instantaneous effect on choroidal volume and IOP due to mechanical deformation of ocular structures. These two reports, while not explaining how BP and IOP are directly related, support the hypothesis that elevated systemic BP might produce increased choroidal volume, which in turn increases IOP. 3. BLOOD PRESSURE AND GLAUCOMA The relationship between BP and the prevalence and progression of glaucoma remains controversial. While some studies indicated systemic hypertension as a significant risk factor for glaucoma8,16,47-56, others have identified BP reductions as an important risk factor for the development and progression of glaucoma57-63. 3.1 SYSTEMIC HYPERTENSION AND GLAUCOMA Several studies found correlation between arterial hypertension and glaucoma (Table 1). In the Blue Mountains Eye Study21, systemic hypertension was found to be significantly associated with an increased risk of POAG, independently of the effect of BP on IOP. Interestingly, systemic hypertension accounted for the greatest attributable risk for POAG than any other risk factors found in the study. In the Egna-Neumarkt Study16, when risk factors for POAG were evaluated, the use of antihypertensive medication, and the presence of systemic hypertension led to age- and sex-adjusted odds ratios greater than 1, although the confidence limits were broad. Overall, this may suggest a correlation between POAG and systemic hypertension regardless of age. To assess the importance of vascular risk factors in glaucoma, data from the medical history of 2,879 POAG patients and 973 age-matched controls were collected and analyzed by Orzalesi et al26 in an observational survey. Mean systolic BPs were 139.2 mmHg in POAG patients vs. 137.1 mmHg in controls (P=0.001), while mean diastolic BPs were 82.4 mmHg in POAG patients vs. 81.5 mmHg in controls (P=0.001). The small magnitude of the between-groups difference for systolic and diastolic BP persisted after adjustment for confounding variables such as age, gender, and history of systemic hypertension. 3.2 SYSTEMIC HYPOTENSION AND GLAUCOMA On the other hand, a number of studies have found a higher risk for development and progression of glaucoma in people with low BP, especially in normal tension glaucoma (NTG) (Table 1). In a series of 4 glaucoma patients with rapid glaucoma progression despite normal or well controlled IOP, low systemic BP in tandem with sustained BP drop during sleep was observed64. Kaiser et al65 monitored 24-hour BP in 78 POAG patients, 39 NTG patients, and 32 controls, and found that both POAG patients with progression despite well controlled IOP and patients with NTG had a markedly reduced systolic BP during day and night. Leske et al29 evaluated the risk factors for POAG in 3222 participants of the Barbados Eye Studies over 9 years of follow-up and found a high POAG incidence of 4.4%. Evaluations of systolic BP, diastolic BP, pulse pressure, and arterial pressure consistently indicated a trend toward a negative relationship with POAG risk. The relative risks (RR) per mmHg were decreased for these four variables (0.89–0.92 per 10 mmHg higher). When BP measurements were grouped as high, medium, and low, the lowest categories of systolic BP and diastolic BP had RR > 1, indicating an increased risk for glaucoma. Recently, the Thessaloniki Eye Study25 evaluated the association between BP and optic disk structure as measured with the Heidelberg Retina Tomograph (HRT) in 462 eyes. The authors found that subjects with diastolic BP < 90 mmHg as a result of antihypertensive therapy presented with increased cup area, greater C/D ratio, and decreased rim area compared with subjects with diastolic BP≥ 90 mmHg or with subjects with normal diastolic BP (< 90 mmHg without antihypertensive treatment). Similarly, low perfusion pressure was also associated with decreased rim area, increased cup area, and greater C/D ratio. Additional evidence suggesting the influence of low BP on the pathogenesis of glaucoma comes from reports of glaucomatous-like optic nerve and visual field damage secondary to a spontaneous fall in BP as a result of transient shocklike state6,66-72. In individuals with glaucoma and repeated hemodynamic crises, it becomes difficult to differentiate between real glaucoma progression and progressive ischemic damage. Patients who experience large fluctuations in BP at night may have a higher risk of glaucomatous progression compared with individuals whose BP fluctuates within normal limits60,63,73-76. Previous reports have indicated that a nocturnal BP reduction (dip) of 10-20% can be considered physiologic77,78. Ambulatory BP monitoring studies in NTG, POAG, and anterior ischemic optic neuropathy (AION) disclosed a significantly (P=0.0028) lower nighttime mean diastolic BP and significantly (P=0.0044) greater mean percentage drop in diastolic BP in NTG than in AION patients. Furthermore, arterial hypertensive patients on oral hypotensive therapy showed a significant association between progressive visual field deterioration and nocturnal hypotension70. Graham et al61 found that, in 37 patients with progressive visual field defects, compared with 15 patients with stable visual fields, there was a significantly greater drop in the systolic (P=0.001), diastolic (P=0.060), and mean (P=0.016) BP during the night in those with visual field deterioration. On the other hand, others have observed that small nocturnal BP dips or lack of dips were associated with glaucoma progression79-81. Tokunaga et al81 assessed prospectively the relationship between nocturnal BP reduction and progression of the visual field in 38 patients with NTG or POAG who had been followed for at least 4 years. Glaucoma patients with a dip of < 10% were assigned to the nondipper group, those with a dip of 10%–20% to the physiologic dipper group, and those with a dip of > 20% to the extreme dipper group. The nondipper and the extreme dipper groups were defined as nonphysiologic dippers. The nonphysiologic dippers had a significantly higher incidence of progression compared with the physiologic dippers (P=0.05). Among the glaucoma patients in the nondipper and dipper categories only, those who progressed had significantly smaller dips (P=0.02). Since there were only four extreme dippers, it was not possible to evaluate this group separately. PHYSIOLOGY BEHIND THE RELATIONSHIP BETWEEN BP AND GLAUCOMA The vascular or ischemic hypothesis postulates that glaucomatous damage may be caused or facilitated by inadequate perfusion of the proximal portion of the optic nerve. In order to elucidate the relationship between BP and glaucoma, it is fundamental to understand the concept of autoregulation. Autoregulation is a term applied to the physiologic phenomenon in which the resistance changes dynamically to keep flow at whatever constant level is required by the local and metabolic activity despite changes in perfusion pressure, e.g., when arterial pressure changes or when venous pressure is affected by IOP82-87. According to Anderson87, when venous pressure at the exit point from the eye is elevated by IOP, the arteriovenous pressure difference is reduced, and nutrition is maintained only because of blood flow autoregulation. IOP–induced ischemia can result if autoregulation is impaired, either because of an innate deficiency, or as a result of vasospastic disease. Autoregulation can also be impaired if another disease has caused much of the autoregulatory capacity to be already utilized, so that little is left to respond to the additional challenge of IOP. In glaucoma, any increase in IOP above orbital venous pressure will reduce perfusion pressure of intraocular beds, which represents a challenge to the circulation. Hence, microcirculatory disturbances in both POAG and NTG is simply a matter of how much the IOP exceeds the orbital venous pressure and whether the autoregulatory mechanisms can compensate for that degree of challenge. When the ability to regulate is adequate, an IOP somewhat above the normal range will not produce inadequate vascular perfusion. However, if the regulatory mechanisms are compromised, blood flow may not be adequate beyond some critical level of IOP, but can be restored by lowering the IOP. Several pathophysiological mechanisms have been proposed to explain the association between hypertension and glaucoma20,60,61,74,88-94. Direct microvascular damage from systemic hypertension could impair blood flow to the optic disk74,90. This notion is supported by studies linking glaucoma to abnormal ocular blood flow20,91 and narrowing of the retinal vasculature89,93. Hayreh et al studied the effects of systemic cardiovascular disease in monkey eyes with chronic, experimentally increased IOP 95,96. The authors induced atherosclerosis97 and chronic arterial hypertension98 in 24 of 38 monkeys for several years before experimentally increasing the IOP. Their morphologic study suggested that vascular disease may influence glaucomatous damage, with damage being greater in those with atherosclerosis-hypertension. Hypertension could also compromise the autoregulation of the posterior ciliary artery circulation, which is already impaired in glaucoma88. On the other hand, systemic hypotension and antihypertensive treatment could induce hypotensive episodes, especially at night60,61, which could reduce blood flow to the optic disk, resulting in glaucomatous damage69. Similarly, this deleterious effect would be enhanced by an impaired autoregulation. As mentioned above, the lack of nocturnal BP dips may also be harmful to glaucoma patients. It has been suggested that an insufficient nocturnal BP decrease may cause impaired microcirculation, possibly due to excessive production of free radicals or other harmful molecules that are toxic to neurons or glial cells81. A similar finding has been reported to cause glomerular damage to the kidney99. In summary, both systemic hypertension and hypotension, as well as the diurnal fluctuation of BP, could, through different mechanisms, be risk factors for glaucoma. In any case, the balance between IOP and BP, and the ability to deal with an eventual unbalance, are determinant to the development of glaucoma. For this reason, the concept of perfusion pressure may be highly important, as discussed below. 4. PERFUSION PRESSURE AND GLAUCOMA Reduced OPP in POAG patients has been reported in a number of studies, including large epidemiologic surveys12,16,17,21,26. Population-based studies have identified low perfusion pressure as a risk factor for the development of glaucoma (Table 2). The Baltimore Eye Survey indicated that individuals with diastolic perfusion pressures lower than 30 mmHg had a six-fold higher risk of developing the disease than individuals with diastolic perfusion pressures greater than 50 mmHg12. In the Barbados Study, subjects with the lowest 20% of diastolic perfusion pressures were 3.3 times more likely to develop glaucoma13. In this study, all lower OPPs were positively related to OAG risk, with RR at least doubling in the lowest perfusion pressure categories. In a subsequent study among participants of the Barbados Eye Study, risk factors for the incidence of glaucoma over 9 years of follow-up were evaluated. Again, lower systolic BP, and lower OPPs were identified as risk factors29. Similarly, the Egna-Neumarkt study reported a 4.5% increase in the prevalence of the disease in patients with diastolic perfusion pressures < 50 mmHg compared with those whose diastolic perfusion pressures were 65 mmHg16. In the Proyecto Ver Study100 patients who presented with a diastolic perfusion pressure of 45 mmHg had a three times greater risk of developing glaucoma than those with measurements of 65 mmHg. Although these population-based studies examined individuals from different geographic locations and various ethnic origins, they all found that low diastolic perfusion pressure is an important risk factor for the prevalence of glaucoma. Furthermore, recently published data from the Early Manifest Glaucoma Trial (EMGT) established lower systolic perfusion pressure as a new predictor for disease progression, suggesting a 50% increase in risk101. According to the EMGT, exfoliation, worse baseline mean defect on perimetry, bilateral disease, disc hemorrhages and lower systolic perfusion pressure (< 125 mmHg) increased the risk of glaucoma progression in all individuals. When assessing the role of systolic blood pressure on progression, the authors found that it was not a risk factor in those with higher baseline IOP (defined as IOP > 21 mmHg), but was a risk factor in those with lower IOP (< 21 mmHg). These findings indicate that vascular factors may be an important determinant of glaucoma progression. Additionally, cardiovascular disease was found to be a risk factor for glaucoma progression in patients with higher baseline IOP. 5. PERSPECTIVES The measurement of ocular blood flow is complicated by the fact that the posterior pole of the eye is nourished by two different vascular beds, the retina and the choroid102. These two vascular systems significantly differ in terms of physiological and pathological properties103. The utility of several instruments developed to measure blood flow in various ocular beds is limited. Each technology only assesses a small portion of the ocular vasculature. Abnormal ocular blood flow in glaucoma has been documented in the optic disk, choroid, retina, and retrobulbar circulation104. At present, because no single blood-flow device can assess all the relevant vascular beds, a comprehensive analysis using several modalities is needed to fully evaluate a patient's ocular blood flow. Moreover, due to the complexity of the various datasets and the analysis necessary to interpret these outcomes, it is essentially only possible for scientists who are highly trained in imaging and who have a background in vascular physiology to complete a comprehensive examination of ocular blood flow. Although clinicians cannot currently visualize ocular blood flow directly, they can easily measure glaucoma patients' BP and IOP to calculate their OPP and quantify the vascular changes. Diurnal fluctuations in IOP have been identified as a possible risk factor for glaucomatous progression105-108. We hypothesize that investigating patients' OPP, and measuring perfusion pressure throughout a 24-hour period may allow physicians to be more comprehensive when determining patients' risk for progression. Recently, Choi et al75 performed a retrospective chart review of 113 eyes with NTG to investigate systemic and ocular hemodynamic risk factors for glaucomatous damage. Systolic BP and diastolic BP fluctuations were defined as the difference between the highest and lowest SBP and DBP recorded during the 24-hour period. Of the functional and anatomic outcome variables, circadian mean OPP fluctuation was the most consistent clinical risk factor for glaucoma severity in eyes with NTG. Some patients may benefit from an assessment of their 24-hour perfusion pressures. Measuring uncontrolled elevations in IOP and undesirable reductions in blood pressure during a 24-hour period may identify a risk for changes in the optic disc. In the first case, patients would require further reduction in IOP. When their BP is low and they are on antihypertensive therapy, as illustrated in Figures 1, 2, and 3, modifications in patients' medical regimens are warranted. CONCLUSION
For years, fierce discussions have occurred between supporters of the
mechanical and vascular theories for the pathogenesis of glaucoma. The concept of OPP and the identification of this as an important risk factor for the development and progression of glaucoma brought together the vascular and mechanical components of glaucoma. We believe that it is the balance between IOP and BP, influenced by the autoregulatory capacity of the eye, that determines whether an individual will develop optic nerve damage. However, further research is required to evaluate the importance of OPP and its fluctuation as parameters to be measured in glaucoma patients. Acknowledgments: The participation of Alon Harris is supported in part by an unrestricted research grant from Research to Prevent Blindness, New York, NY. The authors would also like to thank Lynne McCranor for her assistance in the preparation of this manuscript. Table 1 – Studies showing a relationship between glaucoma and blood pressure. Author(s) Number of patients Study type Correlation with Arterial hypertension Arterial hypertension Arterial hypertension Leighton & Phillips50 Arterial hypertension Arterial hypertension Goldberg et al52 Arterial hypertension Arterial hypertension Arterial hypertension Rouhiainen & Teräsvirta54 Arterial hypertension Arterial hypertension Kashiwagi et al55 Arterial hypertension Arterial hypertension Mitchell et al21 Arterial hypertension Orzalesi et al26 Arterial hypertension Arterial hypotension Demailly et al58 Arterial hypotension Arterial hypotension Arterial hypotension Arterial hypotension Arterial hypotension Collignon et al62 Arterial hypotension Graham & Drance63 Arterial hypotension Topouzis et al25 Arterial hypotension CCS – case control series; CSS – cross-sectional study; CR – case report; ES – epidemiological study; RCA – retrospective chart analysis. Table 2 – Studies investigating the association between perfusion pressure and glaucoma. Number of patients 5308 participants Diastolic PP < 30 mm Hg had a 6-fold higher risk of developing POAG 4087 participants Increased prevalence of 210 POAG patients POAG in patients with diastolic PP < 70 mmHg Quigley et al100 4774 participants Prevalence of POAG 94 POAG patients increased 4-fold at lower diastolic PP (OR = 0.96) 2989 participants at Systolic PP < 101 mmHg – Diastolic PP < 55 mmHg – RR = 3.2 Mean PP < 42 mmHg – RR = 3.1 Mitchell et al21 3654 participants 108 POAG patients increased by 10% for each 10 mmHg increase in systolic PP (OR = 1.09) Systolic PP < 125 mmHg – without treatment Hulsman et al27 5317 participants Low diastolic PP (<50 associations in a mmHg) inversely population- associated with NTG (OR = 0.25) and positively associated with POAG (OR = 4.68) 3222 participants Cohort study – Systolic PP < 101 mmHg – Diastolic PP < 55 mmHg – RR = 2.2 Mean PP < 42 mmHg – RR = 2.2 PP = perfusion pressure; POAG = primary open angle glaucoma; OR = odds ratio; RR = relative risk; OH = ocular hypertension; EMGT = early manifest glaucoma trial; NTG = normal tension glaucoma. 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Figure 1 – 24-hour IOP measurements of a treated patient with progressive glaucoma despite normal IOPs. The IOP fluctuates between 9 and 12 mmHg in both eyes.
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06:00 09:00 12:00 15:00 18:00 21:00 00:00
Figure 2 – The same patient's systolic and diastolic blood pressures showing a drop at 6:00 am (circle). 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Figure 3 – The same patient´s diastolic perfusion pressure throughout the 24 hours. Clinicians can use the cutoff value of 30 mm Hg, as suggested by the Baltimore Eye Survey4, as an indicator of low diastolic perfusion pressure. REFERENCES: 1. Congdon N, Friedman DS, Lietman T. Important causes of visual impairment in the world today. JAMA 2003;290:2057-60.
2. Bengtsson B. The prevalence of glaucoma. Br J Ophthalmol 1981;65:46-9.
3. Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study
monograph. An ophthalmological and epidemiological study of cataract, glaucoma,
diabetic retinopathy, macular degeneration, and visual acuity in a general population
of 2631 adults. 1973-1975. Surv Ophthalmol 1980;24(suppl):335-610.
4. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore
Eye Survey. Arch Ophthalmol 1991;109:1090-5.
5. François J, Neetens A. The deterioration of the visual field in glaucoma and the blood pressure. Doc Ophthalmol 1970;28:70-132.
6. Drance SM. Some factors in the production of low tension glaucoma. Br J Ophthalmol 1972;56:229-42.
7. Leske MC. The epidemiology of open-angle glaucoma: a review. Am J Epidemiol 8. Wilson MR, Hertzmark E, Walker AM, et al. A case-control study of risk factors in open-angle glaucoma. Arch Ophthalmol 1987;105:1066-71.
9. Drance SM, Douglas GR, Wijsman K, et al. Response of blood flow to warm and cold in normal and low-tension glaucoma patients. Am J Ophthalmol 1988;105:35-
9.
10. McLeod SD, West SK, Quigley HA, et al. A longitudinal study of the relationship between intraocular and blood pressures. Invest Ophthalmol Vis Sci 1990;31:2361-6.
11. Dielemans I, Vingerling JR, Algra D, et al. Primary open-angle glaucoma, intraocular pressure, and systemic blood pressure in the general elderly population.
The Rotterdam Study. Ophthalmology 1995;102:54-60.
12. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol
1995;113:216-21.
13. Leske MC, Connell AM, Wu SY, et al. Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol 1995;113:918-24.
14. Mitchell P, Smith W, Attebo K, et al. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103:1661-9.
15. Bonomi L, Marchini G, Marraffa M, et al. Prevalence of glaucoma and intraocular pressure distribution in a defined population. The Egna-Neumarkt Study.
Ophthalmology 1998;105:209-15.
16. Bonomi L, Marchini G, Marraffa M, et al. Vascular risk factors for primary open angle glaucoma: the Egna-Neumarkt Study. Ophthalmology 2000;107:1287-93.
17. Leske MC, Wu SY, Nemesure B, et al. Incident open-angle glaucoma and blood pressure. Arch Ophthalmol 2002;120:954-9.
18. Leske MC, Heijl A, Hussein M, et al; Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the Early Manifest
Glaucoma Trial. Arch Ophthalmol 2003;121:48-56.
19. Hennis A, Wu SY, Nemesure B, et al; Barbados Eye Studies Group. Hypertension, diabetes, and longitudinal changes in intraocular pressure. Ophthalmology
2003;110:908-14.
20. Fuchsjäger-Mayrl G, Wally B, Georgopoulos M, et al. Ocular blood flow and systemic blood pressure in patients with primary open-angle glaucoma and ocular
hypertension. Invest Ophthalmol Vis Sci 2004;45:834-9.
21. Mitchell P, Lee AJ, Rochtchina E, et al. Open-angle glaucoma and systemic hypertension: The Blue Mountains Eye Study. J Glaucoma 2004;13:319-26.
22. Varma R, Ying-Lai M, Francis BA, et al; Los Angeles Latino Eye Study Group. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los
Angeles Latino Eye Study. Ophthalmology 2004;111:1439-48.
23. Klein BE, Klein R, Knudtson MD. Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study. Br J Ophthalmol
2005;89:284-7.
24. Suzuki Y, Iwase A, Araie M, et al; Tajimi Study Group. Risk factors for open-angle glaucoma in a Japanese population: the Tajimi Study. Ophthalmology
2006;113:1613-7.
25. Topouzis F, Coleman AL, Harris A, et al. Association of blood pressure status with the optic disk structure in non-glaucoma subjects: the Thessaloniki Eye Study. Am J
Ophthalmol 2006;142:60-67.
26. Orzalesi N, Rossetti L, Omboni S; OPTIME Study Group (Osservatorio sulla Patologia glaucomatosa, Indagine Medico Epidemiologica); CONPROSO (Collegio
Nazionale dei Professori Ordinari di Scienze Oftalmologiche). Vascular risk factors
in glaucoma: the results of a national survey. Graefes Arch Clin Exp Ophthalmol
2007;245:795-802.
27. Hulsman CA, Vingerling JR, Hofman A, et al. Blood pressure, arterial stiffness, and open-angle glaucoma: the Rotterdam study. Arch Ophthalmol 2007;125:805-12.
28. Xu L, Wang H, Wang Y, et al. Intraocular pressure correlated with arterial blood pressure: the Beijing eye study. Am J Ophthalmol 2007;144:461-2.
29. Leske MC, Wu SY, Hennis A, et al; BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology 2008;115:85-93.
30. Sehi M, Flanagan JG, Zeng L, et al. Relative change in diurnal mean ocular perfusion pressure: a risk factor or the diagnosis of primary open-angle glaucoma.
Invest Ophthalmol Vis Sci 2005;46:561-7.
31. Wang S, Xu L, Jonas JB, et al. Retinal vascular abnormalities in adult Chinese in rural and urban Beijing: the Beijing Eye Study. Ophthalmology 2006;113:1752-7.
32. Xu L, Wang Y, Wang S, et al. High myopia and glaucoma susceptibility: the Beijing Eye Study. Ophthalmology 2007;114:216-20.
33. Bill A. The role of ciliary body blood flow and ultrafiltration in aqueous humor formation. Exp Eye Res 1973;16:287-98.
34. Ghergel D, Hosking SL, Orgul S. Autonomic nervous system, circadian rhythms, and primary open-angle glaucoma. Surv Ophthalmol 2004;49:491-508.
35. Watkins RW, Baum T, Cedeno K et al. Topical ocular hypotensive effects of the novel angiotensin converting enzyme inhibitor SCH 33861 in conscious rabbits. J
Ocul Phamacol 1987;3:295-307.
36. Constad WH, Fiore P, Samson C, et al. Use of an angiotensin converting enzyme inhibitor in ocular hypertension and primary open-angle glaucoma. Am J
Ophthalmol 1988;105:674-7.
37. Vogh BP, Godman DR. Effects of inhibition of angiotensin converting enzyme and carbonic anhydrase on fluid production by ciliary process, choroid plexus, and
pancreas. J Ocul Pharmacol 1989;5:303-11.
38. Shah GB, Sharma S, Mehta AA, et al. Oculohypotensive effect of angiotensin- converting enzyme inhibitors in acute and chronic models of glaucoma. J
Cardiovasc Pharmacol 2000;36:169-75.
39. Wang RF, Podos SM, Mittag TW, Yokoyoma T. Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes. Exp
Eye Res 2005;80:629-32.
40. Inoue T, Yokoyoma T, Mori Y et al. The effect of topical CS-088, an angiotensin AT1 receptor antagonist on intraocular pressure and aqueous humor dynamics in
rabbits. Curr Eye Res 2001;23:133-8.
41. Danser AHJ, Derkx FHM, Admiraal PJJ, et al. Angiontensin levels in the eye. Invest Ophthalmol Vis Sci 1994;35:1008-18.
42. Sramek SJ, Wallow HL, Tewksbury DA, et al. An ocular renin angiotensin system. Immunohistochemistry angiotensinogen. Ophthalmol 43. Wagner J, Jan Danser AH, Derkx FH, et al. Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin-convertings enzyme mRNA expression in
the human eye: Evidence for an intraocular renin-angiotensin system. Br J
Ophthalmol 1996;80:159-63.
44. Savaskan E, Loffler KU, Meier F, et al. Immunohistochemical localization of angiotensin-converting enzyme, angiotensin II, and AT1 receptor in human ocular
tissues. Ophthalmic Res 2004;36:312-20.
45. Hvidberg A, Kessing SV, Fernandes A. Effect of changes in PCO2 and body positions on intraocular pressure during general anaesthesia. Acta Ophthalmol
(Copenh) 1981;59:465-75.
46. Gupta VK. Is benign cough headache caused by intraocular haemodynamic aberration? Med Hypotheses 2004;62:45-8.
47. Kümmell R. Untersuchungen über Glaukom und Blutdruck. Graefes Arch Ophthalmol 1911;79:183-209.
48. Charlin C. Die Aetiologie des Glaukoms eine Folge von Veränderungen des Gefäßsystems bei den Glaukomkranken. Klin Monatsbl Augenheilkd 1923;70:123-
33.
49. Calhoun FP. The vascular state in glaucoma. Am J Ophthalmol 1929;12:265-9.
50. Leighton DA, Phillips CI. Systemic blood pressure in open angle glaucoma, low
tension glaucoma, and the normal eye. Br J Ophthalmol 1972;56:447-53.
51. Levene RZ. Low tension glaucoma: a critical review and new material. Surv Ophthalmol 1980;24:621-64.
52. Goldberg I, Hollows FC, Kass MA, et al. Systemic factors in patients with low- tension glaucoma. Br J Ophthalmol 1981;65:56-62.
53. Klein BE, Klein R, Moss SE. Intraocular pressure in diabetic persons. 54. Rouhiainen HJ, Teräsvirta ME. Hemodynamic variables in progressive and non- progressive low tension glaucoma. Acta Ophthalmol (Copenh) 1990;68:34-6.
55. Kashiwagi K, Hosaka O, Kashiwagi F, et al. Systemic circulatory parameters. Comparison between patients with normal tension glaucoma and normal subjects
using ambulatory monitoring. Jpn J Ophthalmol 2001;45:388-96.
56. Wang N, Peng Z, Fan B, et al. Case control study on the risk factors of primary open angle glaucoma in China. Zhonghua Liu Xing Bing Xue Za Zhi 2002;23:293-6.
57. Sachsenweger R. Der Einfluß des Bluthochdrucks auf die Prognose des Glaukoms. Klin Monatsbl Augenheilkd 1963;142:625-33.
58. Demailly P, Cambien F, Plouin PF, et al. Do patients with low tension glaucoma have particular cardiovascular characteristics? Ophthalmologica 1984;188:65-75.
59. Kaiser HJ, Flammer J, Burckhardt D. Silent myocardial ischemia in glaucoma patients. Ophthalmologica 1993;207:6-7.
60. Hayreh SS, Zimmerman MB, Podhajsky P, et al. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol
1994;117:603-24.
61. Graham SL, Drance SM, Wijsman K, et al. Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip. Ophthalmology 1995;102:61-9.
62. Collignon N, Dewe W, Guillaume S, et al. Ambulatory blood pressure monitoring in glaucoma patients. The nocturnal systolic dip and its relationship with disease
progression. Int Ophthalmol 1998;22:19-25.
63. Graham SL, Drance SM: Nocturnal hypotension: role in glaucoma progression. Surv Ophthalmol 1999;43(Suppl 1):S10-6.
64. Kaiser HJ, Flammer J. Systemic hypotension: a risk factor for glaucomatous damage? Ophthalmologica 1991;203:105-8.
65. Kaiser HJ, Flammer J, Graf T, et al. Systemic blood pressure in glaucoma patients. Graefes Arch Clin Exp Ophthalmol 1993;231:677-80.
66. Drance SM, Morgan RW, Sweeney VP. Shock-induced optic neuropathy: A cause of nonprogressive glaucoma. N Engl J Med 1973;288:392-5.
67. Drance SM, Sweeney VP, Morgan RW, et al. Studies of factors involved in the production of low tension glaucoma. Arch Ophthalmol 1973;89:457-65.
68. Drance SM, Wheeler C, Pattullo M. Uniocular open-angle glaucoma. Am J Ophthalmol 1968;65:891-902.
69. Hayreh SS, Podhajsky P, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica 1999;213:76-96.
70. Hayreh SS. The role of age and cardiovascular disease in glaucomatous optic neuropathy. Surv Ophthalmol 1999;43(Suppl 1):S27-42.
71. Hayreh SS. The blood supply of the optic nerve head and the evaluation of it - myth and reality. Prog Retin Eye Res 2001;20:563-93.
72. Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog Retin Eye Res 2001;20:595-624.
73. Detry M, Boschi A, Ellinghaus G, et al. Simultaneous 24-hour monitoring of intraocular pressure and arterial blood pressure in patients with progressive and non-
progressive primary open-angle glaucoma. Eur J Ophthalmol 1996;6:273-8.
74. Flammer J, Orgül S, Costa VP, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002;21:359-93.
75. Choi J, Kim KH, Jeong J, et al. Circadian fluctuation of mean ocular perfusion pressure is a consistent risk factor for normal-tension glaucoma. Invest Ophthalmol
Vis Sci 2007;48:104-11.
76. Orgül S, Gugleta K, Flammer J. Physiology of perfusion as it relates to the optic nerve head. Surv Ophthalmol 1999;43(Suppl 1):S17-26. 77. Kario K, Matsuo T, Kobayashi H, et al. Nocturnal fall of blood pressure and silent cerbrovascular damage in elderly hypertensive patients. Advanced silent
cerebrovascular damage in extreme dippers. Hypertension 1996;27:130-5.
78. Halberg F, Cornelissen G, Halberg E. Chronobiology of human blood pressure. In: Halberg F, Cornelissen G, Halberg E, editors. Medtronic continuing medical education seminars, 2nd edition. Minneapolis, Medtronic; 1987, p.234. 79. Detry M, Boschi A, Ellinghaus G, et al. Simultaneous 24-hour monitoring of intraocular pressure and arterial blood pressure in patients with progressive and non-
progressive primary open-angle glaucoma. Eur J Ophthalmol 1996;6:273-8.
80. Collignon N, Dewe W, Guillaume S, et al. Ambulatory blood pressure monitoring in glaucoma patients. The nocturnal systolic dip and its relationship with disease
progression. Int Ophthalmol 1998; 22:19-25.
81. Tokunaga T, Kashiwagi K, Tsumura T, et al. Association between nocturnal blood pressure reduction and progression of visual field defect in patients with primary
open-angle glaucoma or normal-tension glaucoma. Jpn J Ophthalmol 2004;48:380-
5.
82. Anderson DR. Glaucoma, capillaries and pericytes: 1. Blood flow regulation. Ophthalmologica 1996;210:257-62. 83. Anderson DR. Optic nerve blood flow, in Drance SM, Anderson DR (eds): Optic Nerve in Glaucoma. New York, Kugler Publications, 1995, pp 311-31. 84. Berne RM, Levy MN. Physiology. St. Louis, Mosby Year Book, 1993, ed 3, pp 472, 85. Guyton AC. Textbook of Medical Physiology. Philadelphia, W. B. Saunders, 1986, 86. Haefliger IO, Anderson DR. Blood flow regulation in the optic nerve head, in Ritch R, Shields MB, Krupin T (eds): The Glaucomas, Vol. 1. St. Louis, Mosby, 1996, pp 189-97. 87. Anderson DR. Introductory comments on blood flow autoregulation in the optic nerve head and vascular risk factors in glaucoma. Surv Ophthalmol 1999;43(Suppl 1):S5-9. 88. Grunwald JE, Riva CE, Stone RA, et al. Retinal autoregulation in open-angle glaucoma. Ophthalmologyl 1984;91:1690-4.
89. Jonas JB, Nguyen XN, Naumann GO. Parapapillary retinal vessel diameter in normal and glaucoma eyes. I. Morphometric data. Invest Ophthalmol Vis Sci
1989;30:1599-603.
90. Piltz-seymour JR, Grunwald JE, Hariprasad SM, et al. Optic nerve blood flow is diminished in eyes of primary open-angle glaucoma suspects. Am J Ophthalmol
2001;132:63-9.
91. Logan JF, Rankin SJ, Jackson AJ. Retinal blood flow measurements and neuroretinal rim damage in glaucoma. Br J Ophthalmol 2004;88:1049-54.
92. Langman M, Lancashire R, Cheng K, et al. Systemic hypertension and glaucoma: mechanisms in common and co-occurrence. Br J Ophthalmol 2005;89:960-3.
93. Mitchell P, Leung H, Wang JJ, et al. Retinal vessel diameter and open-angle glaucoma: the Blue Mountains Eye Study. Ophthalmology 2005;112:245-50.
94. Wong TY, Mitchell P. The eye in hypertension. Lancet 2007;369:425-35.
95. Hayreh SS, Jonas JB, Zimmerman MB. Parapapillary chorioretinal atrophy in
chronic high-pressure experimental glaucoma in rhesus monkeys. Invest Ophthalmol
Vis Sci 1998;39:2296-303.
96. Hayreh SS, Pe'er J, Zimmerman MB. Morphologic changes in chronic high- pressure experimental glaucoma in rhesus monkeys. J Glaucoma 1999;8:56-71.
97. Hayreh SS, Piegors DJ, Heistad DD. Serotonin induced constriction of ocular arteries in atherosclerotic monkeys: Implications for ischemic disorders of retina and
optic nerve head. Arch Ophthalmol 1997;115:220-8.
98. Hayreh SS, Servais GE, Virdi PS, et al. Fundus lesions in malignant hypertension: III. Arterial blood pressure, biochemical, and fundus changes. Ophthalmology
1986;93:45-59.
99. Timio M, Venanzi S, Lolli S, et al. "Non-dipper" hypertensive patients and progressive renal insufficiency: a 3-year longitudinal study. Clin Nephrol 1995;43:382-7. Quigley HA, West SK, Rodriguez J, et al. The prevalence of glaucoma in a population-based study of Hispanic subjects: Proyecto VER. Arch Ophthalmol
2001;119:1819-26.
Leske MC, Heijl A, Hyman L, et al. EMGT Group. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology 2007;114:1965-
72.
Schmetterer L, Garhofer G. How can blood flow be measured? Surv Ophthalmol 2007;52(Suppl 2):S134-8.
Bill A, Sperber GO. Control of retinal and choroidal blood flow. Eye Harris A, Chung HS, Ciulla TA, et al. Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular
degeneration. Prog Retin Eye Res 1999;18:669-87.
Bergea B, Bodin L, Svedbergh B. Impact of intraocular pressure regulation on visual fields in open-angle glaucoma. Ophthalmology 1999;106:997-1004.
Asrani SG, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in IOP are an independent risk factor in glaucoma patients. J Glaucoma 2000;9:134-42.
Oliver JE, Hattenhauer MG, Herman D, et al. Blindness and glaucoma: a comparison of patients progressing to blindness from glaucoma with patients
maintaining vision. Am J Ophthalmol 2002;133:764-72.
Nouri-Mahdavi K, Hoffman D, Coleman AL, et al; Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in
the Advanced Glaucoma Intervention Study. Ophthalmology 2004;111:1627-35.

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