Purpose
To investigate the association of open-angle glaucoma (OAG), primary open-angle glaucoma (POAG), and pseudoexfoliative glaucoma (PEXG) with ocular perfusion pressure status (ocular perfusion pressure with or without antihypertensive treatment).
Design
Cross-sectional, population-based study.
Methods
A total of 2554 randomly selected, ≥ 60-year old subjects participated in the Thessaloniki Eye Study. Only clinic-visit participants (n = 2261), who had uniformly collected data, were included in the analyses. A logistic regression model was run for OAG in all clinic-visit participants; covariates included age, sex, diastolic ocular perfusion pressure, antihypertensive treatment, intraocular pressure (IOP), IOP-lowering treatment, pseudoexfoliation, and vascular factors identified as risk factors for glaucoma in a previous analysis. Similar logistic regression models were run separately for POAG and PEXG. In addition, logistic regression models were run for OAG, POAG, and PEXG in subjects with and without antihypertensive treatment. Also, logistic regression models were run to assess the role of systolic ocular perfusion pressure in OAG, POAG, and PEXG.
Results
Among clinic-visits, 1212 subjects (53.7%) were using antihypertensive treatment. An association of borderline significance was found between low diastolic ocular perfusion pressure and POAG (OR = 0.84 per 10 mm Hg, 95% CI = 0.70-1.01, P = .059). The effect of antihypertensive treatment on POAG was not statistically significant (OR = 1.20, 95% CI = 0.75-1.91, P = .45). In subgroup analyses, diastolic ocular perfusion pressure was significantly associated with POAG in subjects using antihypertensive treatment (OR = 0.78 per 10 mm Hg, 95% CI = 0.62-0.97, P = .028). No association was found between diastolic ocular perfusion pressure and PEXG, regardless of the use of antihypertensive treatment. No associations were found between systolic ocular perfusion pressure and OAG, POAG, or PEXG, regardless of the use of antihypertensive treatment.
Conclusions
Low diastolic ocular perfusion pressure may be associated with increased risk for POAG. This association was confirmed in subjects treated for systemic hypertension in subgroup analysis. This may support the hypothesis that the concept of ocular perfusion pressure status may be more relevant to glaucoma pathogenesis than ocular perfusion pressure alone.
Ocular perfusion pressure, calculated as systemic blood pressure (BP) minus intraocular pressure (IOP), describes a physiologic mechanism related to the metabolic needs of ocular tissues. As was recently suggested, the balance between BP and IOP, and the ability of the ocular vasculature to cope with an eventual unbalance, are potential determinants to glaucomatous damage. Therefore, in addition to evaluating BP and IOP independently, investigators have focused on the concept of ocular perfusion pressure and its relationship with open-angle glaucoma (OAG). To date, cross-sectional population-based studies and longitudinal cohort studies have provided important evidence on an association between low ocular perfusion pressure and OAG prevalence, incidence, and progression. Although the reported associations do not refer to the physiologic ocular perfusion pressure but to its measured surrogate, the consistency of published data suggests a vascular component in the multifactorial OAG process.
Although consistent, the observed associations between ocular perfusion pressure and OAG require careful interpretation. As was discussed in a recent review, we have limited understanding of the complexity of ocular perfusion pressure in itself and of potential confounders in the ocular perfusion pressure–glaucoma relationship. The use of antihypertensive treatment is one of the factors that could influence this relationship. Specifically, the role of ocular perfusion pressure on glaucoma susceptibility may depend on whether subjects are treated for hypertension or not. Initial evidence for this hypothesis has been provided by a previous Thessaloniki Eye Study report, involving a subset of 232 consecutive, nonglaucomatous subjects examined with the Heidelberg Retina Tomograph. In this study, diastolic BP <90 mm Hg was associated with the optic disc structure only in subjects treated for systemic hypertension. Accordingly, ocular perfusion pressure status, meaning ocular perfusion pressure with or without antihypertensive treatment, may be more relevant to glaucoma pathogenesis than ocular perfusion pressure alone. In some studies, the association found between low ocular perfusion pressure and increased OAG risk was adjusted for the use of antihypertensive treatment. However, this is not similar to stratifying the analysis by use of antihypertensive treatment. In addition, no data exist on the association of ocular perfusion pressure with glaucomatous damage in primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG) identified in the same population-based setting. Based on our findings from a previous Thessaloniki Eye Study report, vascular risk factors were associated only with POAG but not with PEXG. The purpose of the present study was to investigate the potential association of ocular perfusion pressure status with OAG in the Thessaloniki Eye Study population. In addition, because the role of ocular perfusion pressure may be different in POAG and PEXG, we investigated this association separately in these 2 common types of OAG.
Methods
The Thessaloniki Eye Study is a cross-sectional population-based study of chronic eye diseases in the population of Thessaloniki, which is the major urban center in Northern Greece. Details of the recruitment process and random selection have been previously described. Briefly, the initial recruitment frame of the Thessaloniki Eye Study consisted of 5000 people, 60 years of age or older, who were randomly selected in February 1999 from approximately 321 000 persons registered in the municipality registers of the city of Thessaloniki. Subjects from the Thessaloniki Eye Study recruitment group were contacted by phone or mail to ascertain their willingness to participate in the study. Subjects who agreed to participate were invited to the Thessaloniki Eye Study center at the Aristotle University of Thessaloniki for an extensive ophthalmic screening examination. A home-visit eye examination was arranged for persons unable to visit the study examination center because of illness or major disability. Among the 3617 eligible subjects, 2554 participated in the study (participation rate 71%); of these, 2261 (89%) had the clinic-visit examination and 293 (11%) had the home-visit examination. Only clinic-visit participants, who had uniformly collected data, were included in the present analyses.
Details of observation procedures are described elsewhere. All clinic-visit participants were interviewed for demographic data (age, sex), ophthalmic history, systemic diseases (including hypertension, diabetes, and coronary artery bypass or vascular surgery), and systemic medications (including use of antihypertensive and diabetes treatment). In order to minimize any recall bias related to the use of systemic medications, subjects had been specifically instructed during phone contact to bring all medications that they received to the examination center. All medications were recorded by study personnel. BP was considered as the average of 2 readings taken with an automated sphygmomanometer (model 705CP; OMRON Matsusaka Co Ltd, Matsusaka City, Japan) at least 5 minutes apart in the same arm, with the cuff approximately level with the heart. Readings were obtained after the participant was seated for 10 minutes. The ophthalmic examination involved visual acuity measurement, Humphrey automated perimetry (Carl Zeiss Meditec, Dublin, California, USA), slit-lamp examination, applanation tonometry, gonioscopy, and dilated fundus examination. Specifically, all subjects underwent 76-Suprathreshold visual field testing, followed by 30-2 Full Threshold or Swedish interactive threshold algorithm (SITA)-Standard C-30 visual field testing in case of unreliable or abnormal results. Also, IOP was measured using a calibrated Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland). The mean IOP of 3 readings in each eye was defined as the pressure for that eye. Gonioscopy was performed in all study participants using a 4-mirror Sussmann lens (Ocular instruments Inc, Bellevue, Washington, USA), in dim ambient illumination, with a shortened slit that does not fall on the pupil. The angle was graded according to the Spaeth gonioscopic grading system. An angle was considered occludable if the pigmented trabecular meshwork was not visible in >180 degrees of angle in static gonioscopy. In addition, dilation was conducted in all study participants; those with an occludable angle underwent laser peripheral iridotomy and were subsequently examined under pupil dilation.
The study and data accumulation were carried out with prospective approval from the Aristotle University Medical School Ethics Committee. The Institutional Review Board of the University of California, Los Angeles approved the plans for data analyses. All study procedures adhered to the principles outlined in the Declaration of Helsinki for research involving human subjects and all participants gave written informed consent prior to their participation.
Definitions
Details about glaucoma definition are described elsewhere. In summary, a 2-scale definition of glaucoma was used to avoid omitting subjects with mildly atypical findings or those with some missing data. Definition 1 was based on conservative and strict criteria that required the presence of both structural and functional damage, irrespective of IOP. Specifically, structural damage required the presence of thinning or notching or cup-to-disc (C/D) ratio asymmetry of more than 0.2 and functional damage required a confirmed threshold glaucomatous visual field defect. A glaucomatous visual field defect was considered confirmed when it was repeated in at least 2 of the 3 visual field examinations (1 month and 3 months after the first abnormal visual field test) involving the same index on test and retest and occurring in the same field location. In addition, subjects were classified with glaucoma when the clinical judgment was strongly in favor of the presence of glaucoma even though the strict criteria (requiring both visual field defect and optic disc abnormality) were not fulfilled (Definition 2). This was applied in (1) cases with missing data (unable or unreliable visual field test secondary to low vision), (2) cases with only visual field damage presenting typical characteristics of glaucomatous visual field defect, (3) cases with only optic disc damage (thinning or notching of the optic disc rim combined with matching asymmetry of more than 0.2 C/D ratio), or (4) cases with high IOP or a history of high IOP combined with optic disc findings (thinning or notching of the optic disc rim or asymmetry between the 2 eyes of more than 0.2 C/D ratio). Three independent ophthalmologist graders were responsible for the assessment of the presence of glaucomatous appearance of the optic disc (thinning or notching). A consensus agreement between at least 2 of them was required to assign the diagnosis of glaucoma. When disagreement between the graders existed, an open discussion for final classification and diagnosis was carried out. The principal investigator (F.T.) examined all study participants and was responsible for the final adjudication of diagnosis.
The definition of pseudoexfoliation was described in a previous report. In brief, pseudoexfoliation was defined as the presence of pseudoexfoliative material at the pupil margin or on the lens capsule. Prior to pupil dilation a detailed high-magnification slit-lamp assessment of the pupil margin was performed. After pupil dilation, the anterior lens surface from each eye was scanned from left to right using a narrow slit-lamp beam and then was examined using a vertical broad slit-lamp beam, looking specifically for early signs of pseudoexfoliation, including pregranular radial lines and established granular deposits.
Subjects were classified as having POAG if they had glaucoma and open, normal-appearing anterior chamber angle and absence of other secondary causes of glaucoma in either eye. Subjects were classified as having PEXG if they had glaucoma and pseudoexfoliation in either eye. OAG was considered as the combination of POAG and PEXG.
Statistical Analyses
Systolic ocular perfusion pressure was calculated as systolic BP minus IOP and diastolic ocular perfusion pressure was calculated as diastolic BP minus IOP. Ocular perfusion pressure status was defined as ocular perfusion pressure with or without antihypertensive treatment. In subjects with unilateral glaucomatous damage, IOP in the glaucomatous eye was used in the analysis. In all other subjects, higher IOP between 2 eyes was used in the analysis.
Subjects with OAG were compared with subjects without OAG with regard to the following clinical characteristics: age, sex, IOP, IOP-lowering treatment, pseudoexfoliation, systolic BP, diastolic BP, systolic ocular perfusion pressure, diastolic ocular perfusion pressure, use of antihypertensive treatment, and vascular factors identified as risk factors for glaucoma in a previous analysis (coronary artery bypass or vascular surgery and diabetes treated with insulin). In these comparisons, Kruskal-Wallis test was used for continuous variables and Fisher exact test was used for categorical variables.
A logistic regression model was run for OAG in all clinic-visit participants. The following covariates were included: age, sex, diastolic ocular perfusion pressure, antihypertensive treatment, coronary artery bypass or vascular surgery, diabetes treated with insulin, IOP, IOP-lowering treatment, and pseudoexfoliation. To assess the role of the aforementioned variables specifically in POAG and PEXG, similar logistic regression models were run in those who did not have pseudoexfoliation and in those who had pseudoexfoliation, respectively.
To assess the role of diastolic ocular perfusion pressure status in OAG, meaning the role of diastolic ocular perfusion pressure with or without antihypertensive treatment, logistic regression models were run separately in subjects with and without antihypertensive treatment. To assess the role of diastolic ocular perfusion pressure status specifically in POAG and PEXG, similar logistic regression models were run among those who did not have pseudoexfoliation and among those who had pseudoexfoliation, respectively.
In addition, logistic regression models were run to assess the role of systolic ocular perfusion pressure in OAG, POAG, and PEXG.
Results
Among clinic-visit participants, 135 OAG (94 POAG and 41 PEXG) subjects and 2126 non-OAG subjects were identified and included in the analyses. Characteristics of clinic-visit participants are presented in Table 1 . Subjects with OAG were older (mean ± standard deviation [SD] 73.2 ± 6.0 years vs 70.7 ± 5.7 years, P < .001), had higher IOP (mean ± SD 18.8 ± 5.8 mm Hg vs 15.7 ± 3.7 mm Hg, P < .001), and presented more frequently with pseudoexfoliation (41/135; 30.4% vs 229/2126; 10.8%, P < .001), compared with the non-OAG group. With regard to vascular parameters, subjects with OAG had lower diastolic ocular perfusion pressure (mean ± SD 65.1 ± 13.4 mm Hg vs 69.4 ± 13.0 mm Hg, P < .001) and presented more frequently with coronary artery bypass or vascular surgery (23/135; 17.0% vs 216/2126; 10.2%, P = .020) and diabetes treated with insulin (10/135; 7.4% vs 50/2126; 2.4%, P = .002), compared with the non-OAG group. Sex, systolic BP, diastolic BP, systolic ocular perfusion pressure, and use of antihypertensive treatment were not statistically significantly different between the groups.
| Characteristics | All (N = 2261) | OAG (N = 135) | Non-OAG (N = 2126) | P Value a |
|---|---|---|---|---|
| Age (y), mean ± SD | 70.8 ± 5.8 | 73.2 ± 6.0 | 70.7 ± 5.7 | <.001 b |
| Male sex, n (%) | 1240 (54.8%) | 77 (57.0%) | 1163 (54.7%) | .66 c |
| IOP (mm Hg), mean ± SD | 15.9 ± 3.9 | 18.8 ± 5.8 | 15.7 ± 3.7 | <.001 b |
| IOP-lowering treatment, n (%) | 134 (5.9%) | 56 (41.5%) | 78 (3.7%) | <.001 c |
| Pseudoexfoliation, n (%) | 270 (11.9%) | 41 (30.4%) | 229 (10.8%) | <.001 c |
| Systolic BP (mm Hg), mean ± SD | 145.4 ± 22.8 | 147.1 ± 20.6 | 145.3 ± 22.9 | .18 b |
| Diastolic BP (mm Hg), mean ± SD | 85.0 ± 12.9 | 83.9 ± 13.3 | 85.1 ± 12.8 | .43 b |
| SPP (mm Hg), mean ± SD | 129.5 ± 22.5 | 128.3 ± 20.6 | 129.6 ± 22.6 | .78 b |
| DPP (mm Hg), mean ± SD | 69.2 ± 13.0 | 65.1 ± 13.4 | 69.4 ± 13.0 | <.001 b |
| Use of antihypertensive treatment | 1214 (53.7%) | 81 (60.0%) | 1133 (53.3%) | .13 c |
| Coronary artery bypass or vascular surgery, n (%) | 239 (10.6%) | 23 (17.0%) | 216 (10.2%) | .020 c |
| Diabetes treated with insulin, n (%) | 60 (2.7%) | 10 (7.4%) | 50 (2.4%) | .002 c |
a Bold characters indicate statistical significance.
Unadjusted and adjusted results on potential risk factors for OAG are presented in Table 2 . Based on the logistic regression model, older age (odds ratio [OR] = 1.04 per year, 95% confidence intervals [CI] = 1.01-1.08, P = .021), pseudoexfoliation (OR = 2.39, 95% CI = 1.52-3.76, P < .001), and increased IOP (OR = 1.10 per mm Hg, 95% CI = 1.06-1.14, P < .001) were all statistically significantly associated with increased OAG risk. Diastolic ocular perfusion pressure and antihypertensive treatment were not statistically significantly associated with OAG.
| Variable | Unadjusted Analysis | Adjusted Analysis a | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P Value b | OR | 95% CI | P Value b | |
| Age (per year) | 1.07 | 1.04-1.10 | <.001 | 1.04 | 1.01-1.08 | .021 |
| Sex (female vs male) | 0.91 | 0.64-1.29 | .60 | 0.83 | 0.55-1.23 | .35 |
| DPP (per 10 mm Hg) | 0.76 | 0.66-0.88 | <.001 | 0.89 | 0.76-1.04 | .14 |
| Antihypertensive treatment (yes vs no) | 1.32 | 0.92-1.87 | .13 | 1.11 | 0.74-1.67 | .61 |
| Coronary artery bypass or vascular surgery (yes vs no) | 1.82 | 1.14-2.91 | .013 | 1.71 | 0.99-2.97 | .056 |
| Diabetes treated with insulin (yes vs no) | 3.32 | 1.65-6.71 | <.001 | 2.09 | 0.86-5.07 | .10 |
| Pseudoexfoliation (yes vs no) | 3.61 | 2.44-5.35 | <.001 | 2.39 | 1.52-3.76 | <.001 |
| IOP (per mm Hg) | 1.14 | 1.10-1.18 | <.001 | 1.10 | 1.06-1.14 | <.001 |
| IOP-lowering treatment (yes vs no) | 18.61 | 12.35-28.05 | <.001 | 13.42 | 8.63-20.86 | <.001 |
a The logistic regression model included all variables presented in the table.
When the analysis was run in those who did not have pseudoexfoliation, there was some evidence for an association between low diastolic ocular perfusion pressure and POAG, but this was of borderline statistical significance (OR = 0.84 per 10 mm Hg, 95% CI = 0.70-1.01, P = .059). The effect of antihypertensive treatment on POAG was not statistically significant (OR = 1.20, 95% CI = 0.75-1.91, P = .45). In addition, no association was found between diastolic ocular perfusion pressure or antihypertensive treatment and PEXG (data not shown).
Unadjusted and adjusted results on the association of diastolic ocular perfusion pressure status with OAG, POAG, and PEXG are presented in Table 3 . There was some evidence for an association between diastolic ocular perfusion pressure and OAG in subjects using antihypertensive treatment, although statistical significance was not reached (OR = 0.83 per 10 mm Hg, 95% CI = 0.68-1.01, P = .062). In logistic regression models for POAG, diastolic ocular perfusion pressure was significantly associated with POAG in subjects using antihypertensive treatment (OR = 0.78 per 10 mm Hg, 95% CI = 0.62-0.97, P = .028). In subjects who did not use antihypertensive treatment, no association was found between diastolic ocular perfusion pressure and OAG or POAG. Because of these findings, we investigated the interaction between diastolic ocular perfusion pressure and antihypertensive treatment in the overall model for POAG, but results were not statistically significant (OR = 0.93 per 10 mm Hg, 95% CI = 0.65-1.32, P = .67). No association was found between diastolic ocular perfusion pressure and PEXG, regardless of the use of antihypertensive treatment.
| Effect | In Subjects Without Antihypertensive Treatment | In Subjects With Antihypertensive Treatment | ||||||
|---|---|---|---|---|---|---|---|---|
| N | OR | 95% CI | P Value j | N | OR | 95% CI | P Value j | |
| Association with OAG | ||||||||
| DPP (per 10 mm Hg) (unadjusted) | 1039 a | 0.72 | 0.57-0.92 | .008 | 1212 c | 0.78 | 0.66-0.93 | .006 |
| DPP (per 10 mm Hg) (adjusted) f | 1.05 | 0.81-1.35 | .731 | 0.83 | 0.68-1.01 | .062 | ||
| Association with POAG i | ||||||||
| DPP (per 10 mm Hg) (unadjusted) | 922 b | 0.80 | 0.59-1.07 | .13 | 1060 d | 0.69 | 0.56-0.85 | <.001 |
| DPP (per 10 mm Hg) (adjusted) f | 0.98 | 0.72-1.33 | .891 | 0.78 | 0.62-0.97 | .028 | ||
| Association with PEXG i | ||||||||
| DPP (per 10 mm Hg) (unadjusted) | 117 | 0.76 | 0.51-1.13 | .18 | 152 e | 1.10 | 0.79-1.52 | .58 |
| DPP (per 10 mm Hg) (adjusted) f | 1.39 g | 0.81-2.37 | .235 | 0.90 h | 0.58-1.41 | .653 | ||
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