Objective To elucidate the inter-relationship between ocular perfusion pressure (OPP), blood pressure (BP), intraocular pressure (IOP) profiles and primary open-angle glaucoma (POAG) in a multiethnic Asian population.
Methods Participants were recruited from the Singapore Epidemiology of Eye Diseases Study and underwent standardised ocular and systemic examinations. POAG was defined according to the International Society for Geographical and Epidemiological Ophthalmology criteria. Logistic regression analyses with generalised estimating equation models were performed and used to account for correlation between eyes.
Results A total of 9877 participants (19 587 eyes), including 213 POAG cases (293 eyes) were included. Eyes with lowest quartile levels of systolic OPP (SOPP <110 mm Hg) were 1.85 times (95% CI 1.16 to 2.95) likely to have POAG, compared with eyes with mid-range SOPP levels (123–137 mm Hg; third quartile), after adjusting for relevant covariates and IOP. Consistently, we found that lowest quartile of systolic BP (SBP <124 mm Hg) was 1.69 times (95% CI 1.08 to 2.66) likely to have POAG, compared with mid-range SBP levels (138–153 mm Hg; third quartile). Furthermore, the effect of lower SBP on POAG was more pronounced in eyes with IOP ≥21 mm Hg (OR 3.90; 95% CI 1.24 to 12.30). Both the mean and diastolic profiles of OPP and BP were not significantly associated with POAG, after adjusting for relevant covariates and IOP.
Conclusions In this population-based sample of nearly 10 000 Asian individuals, we showed that low SOPP was associated with POAG. This association was potentially in part secondary to low SBP and high IOP. Our findings provide further clarity on the roles of OPP surrogates and BP profiles in POAG.
- intraocular pressure
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Glaucoma is a leading cause of global irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form of glaucoma and affects 44.1 million individuals worldwide.1 There is good evidence that vascular factors play important roles in the development of glaucoma.2 3 Hypertension, nocturnal hypotension and reduced ocular perfusion have been reported as potential risk factors for glaucoma.4–6 Reduced blood supply or hypoperfusion to the optic nerve head (ONH) may cause ischaemic damage to the retinal ganglion cells, thus leading to glaucomatous damage.2 7
Ocular perfusion pressure (OPP) refers to the pressure available to deliver blood supply through the intraocular vasculature,8 and it is regarded as an important determinant of ocular blood flow to the ONH.9 Nevertheless, the actual perfusion of the ONH cannot be readily measured in a direct manner and is often empirically calculated in clinical studies as the difference between blood pressure (BP) and intraocular pressure (IOP). This simplistic surrogate measurement of OPP has been widely used in epidemiological studies.8 Nevertheless, previous studies have shown inconsistent findings regarding the association between this OPP surrogate and POAG. Population-based studies in African descents, European descents and Hispanic populations indicated that lower OPP was associated with increased risk of POAG.10–13 Conversely, the Blue Mountains Eye Study and the Los Angeles Latino Eye Study reported that higher OPP was associated with higher risk of POAG.13 14 On the other hand, Asian population-based studies in China, Japan and India did not observe significant associations between OPP and POAG.15–17
Despite these reported findings, several knowledge gaps and limitations still remain. First, the clinical usefulness of OPP surrogate as an independent risk factor remains debatable. It was particularly argued that its effect on POAG might be in part secondary to the effects of BP or IOP which are the main components for the calculation of OPP surrogate.8 12 Second, this ambiguity was further deepened by the inconsistent analysis method adopted by previous studies where some adjusted for important factors such as IOP, IOP-lowering, antihypertensive treatments and some did not, when evaluating the association between OPP surrogate and POAG.8 In view of these ambiguities, further comprehensive analysis is required to better clarify the intertwined relationship between OPP surrogate, BP, IOP and POAG.
The aim of this study was to elucidate the inter-relationship between OPP, BP, IOP profiles and POAG in a multiethnic Asian population. Findings in this study will help to better clarify the actual role of OPP surrogate measure and BP in POAG, and provide better understanding on the vascular pathogenesis in POAG.
The Singapore Epidemiology of Eye Diseases (SEED) Study is a population-based cross-sectional study, comprising three major ethnic groups in Singapore: Malays, Indians and Chinese. Details of the study design and methodology of the SEED study have been reported elsewhere.18 19 In brief, a total of 10 333 subjects participated and underwent the study examinations, including 3280 Malays (78.7% response rate), 3400 Indians (75.6%) and 3353 Chinese (72.8%). All participants gave a written informed consent and the conduct of the study adhered to the Declaration of Helsinki.
Clinical ocular examinations
All subjects underwent a standardised ocular examinations, as described previously.18 19 In brief, IOP was measured using the Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland) before pupil dilation. One reading was taken from each eye. If the IOP reading was greater than 21 mm Hg, a repeated reading was taken, and the second reading was used for analysis. Gonioscopy was performed with a Goldmann two-mirror lens (Ocular Instruments, Bellevue, Washington, USA) under standard dark illumination in glaucoma suspects, subjects with temporal peripheral Van Herick grade 2 or less. Visual field examinations were performed on all glaucoma suspects using Humphrey Field Analyser II (Carl Zeiss Meditec, Dublin, California, USA) and the Swedish Interactive Threshold Algorithm Fast, 24–2 strategy. A glaucomatous visual field defect was defined as the presence of three or more significant (P<0.05) non-edge contiguous points with at least one at the P<0.01 level on the same side of the horizontal meridian in the pattern deviation plot, and classified as ‘outside normal limits’ on the Glaucoma Hemifield Test, confirmed on two consecutive reliable visual field examinations.
After pupil dilation, the optic disc was evaluated using a +78D lens at 10 times magnification with a measuring graticule (Haag-Streit) during slit lamp funduscopy (Haag-Streit model BQ-900; Haag-Streit, Koeniz, Switzerland). The clinical vertical cup to disc ratio (VCDR) was calculated accordingly, and morphological features such as disc haemorrhage, notching and defects of the RNFL were documented. Optic disc-centred fundus photographs were taken using a 45° digital retinal camera (Canon CR-DGi; Canon, Tokyo, Japan).
A detailed interviewer-administered questionnaire was used to collect demographic data, medical history, ocular history and lifestyle data. Brachial systolic BP and diastolic BPs (SBP, DBP) were measured using a digital automatic BP monitor (Dinamap model Pro Series DP110X-RW, 100V2; GE Medical Systems Information Technologies, Milwaukee, Wisconsin, USA). BP was measured two times, with 5 min apart. A third measurement was taken if previous two SBP readings differed by more than 10 mm Hg or the DBP by more than 5 mm Hg. The mean between the two closest BP readings was then calculated and taken as the BP for each individual. Mean arterial pressure (MAP) was calculated as DBP +1/3 (SBP, DBP). Hypertension was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg, or self-reported history of physician-diagnosed hypertension or use of antihypertensive medications. Diabetes was defined as a non-fasting glucose level ≥11.1 mmol/L or use of diabetic medications, or self-reported history of diabetes. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in metres (kg/m2). Self-reported smoking status was categorised as never, past and current.
Calculation and categorisation of OPP profiles
Mean OPP (MOPP) was defined as 2/3 (MAP) minus IOP level. Systolic OPP (SOPP) was defined as SBP minus IOP level, whereas diastolic OPP (DOPP) was defined as DBP minus IOP level.
Glaucoma diagnostic definitions
Glaucoma was defined according to the International Society of Geographical and Epidemiological Ophthalmology criteria based on three categories.20 Category 1 cases were defined as optic disc abnormality (VCDR/VCDR asymmetry ≥97.5th percentile), with a corresponding glaucomatous visual field defect. Category 2 cases were defined as having a severely damaged optic disc (VCDR or VCDR asymmetry ≥99.5th percentile) in the absence of adequate performance in a visual field test. Category 3 cases were defined as subjects without visual field or optic disc data who were blind (corrected visual acuity, <3/60) and who had previous glaucoma surgery or had IOP >99.5th percentile. Subjects with glaucoma and an open, normal drainage angle with no identifiable secondary pathological processes were defined as having POAG. Primary angle closure glaucoma and secondary glaucoma cases (ie, pseudoexfoliative glaucoma, neovascular glaucoma, traumatic glaucoma) were excluded from the analysis.
We used eye-specific data and generalised estimating equation (GEE) models with exchangeable correlation structures were applied to account for the correlation between pairs of eyes for each individual. Multiple logistic regression with GEE were used to assess the independent effects of OPP, BP status on POAG, while adjusting for potential confounders such as age, gender, ethnicity, diabetes, BMI, antihypertensive medication, IOP-lowering treatment (ie, medication or surgery) and IOP. Presence of multicollinearity was assessed by quantifying variance inflation factor (VIF). Severe collinearity was defined as VIF >10. LOWESS (locally weighted scatterplot smoothing) plots were used to assess the patterns of relationships between OPP and BP profiles with POAG. All statistical analyses were performed using Stata V.12.1.
Of the 10 033 subjects, 156 subjects had incomplete or missing measurements of IOP or BP, leaving a total of 9877 subjects (19 587 eyes) for this analysis. Among the included participants, POAG was present in 213 participants (293 eyes). Overall, participants who had POAG were older, more likely to be male, Malays and hypertensive (all P≤0.017) (table 1). In addition, POAG eyes had significantly higher IOP, higher SOPP, lower DOPP and larger clinical VCDR (all P≤0.010) (table 1).
Table 2 shows the associations between respective OPP profiles and POAG. While adjusting for age, gender, ethnicity, diabetes, BMI, smoking status and antihypertensive medication, we observed that lower MOPP and DOPP were associated with higher odds of POAG (per SD decrease, all P≤0.015). Furthermore, eyes in the lowest quartile of MOPP were 1.96 times (95% CI 1.30 to 2.98; P=0.002) likely to have POAG, compared with eyes in the highest quartile of MOPP. Similarly, eyes in the lowest quartile of DOPP were 1.78 times (95% CI 1.17 to 2.71; P=0.007) likely to have POAG, compared with eyes in the highest quartile of DOPP. Nevertheless, these MOPP-related and DOPP-related associations with POAG became non-significant when further adjusting for IOP-lowering treatment and IOP. Consistently, table 3 shows that MAP and DBP profiles were also not significantly associated with POAG after adjusting for relevant covariates, IOP-lowering treatment and IOP (all P≥0.089).
On the other hand, as shown in table 2, compared with eyes with mid-range SOPP levels (123–137 mm Hg; third quartile), both low SOPP (first quartile, OR 1.85; 95% CI 1.16 to 2.95; P=0.009) and high SOPP (fourth quartile, OR 1.72; 95% CI 1.13 to 2.61; P=0.011) levels were significantly associated with higher odds of POAG, while adjusting for age, gender, ethnicity, diabetes, BMI, smoking status, antihypertensive medication, IOP-lowering treatment and IOP. In addition, we also found that low levels of SBP (<124 mm Hg; first quartile) was 1.69 times (95% CI 1.08 to 2.66; P=0.022) likely to have POAG, compared with mid-range SBP levels (138–153 mm Hg; third quartile) (table 3, model 2). This association between low SBP and POAG was especially more pronounced in eyes with IOP ≥21 mm Hg (OR 3.90; 95% CI 1.24 to 12.30; P=0.020) (table 4), but not significant in eyes with IOP <21 mm Hg (P=0.077).
We evaluated the inter-relationships between OPP surrogate, BP, IOP and POAG in this study of nearly 10 000 multiethnic Asian individuals. We observed intriguing and potentially insightful findings. First, in contrast with previous studies, MOPP, DOPP, were not associated with POAG, after adjusting for relevant confounders and IOP. Second, we observed that both low and high levels of SOPP were associated with POAG, compared with mid-range SOPP level, suggesting a ‘Ú-shaped’ association between SOPP and POAG. Third, low SBP was also associated with POAG and this effect was especially more pronounced among eyes with ocular hypertension, further indicating that identification of concurrent low SBP and ocular hypertension may also be a useful approach in stratifying POAG risk group. To date, this is the first population-based study which comprehensively demonstrated that the effect of OPP surrogates on POAG was in part secondary to either high IOP or low SBP. Our findings collectively provided additional clarity on the roles of OPP surrogates and BP profiles in POAG.
In our study, lower MOPP and DOPP surrogates were associated with POAG without adjustment for IOP. However, these associations became non-significant after further adjusting for IOP-lowering treatment and IOP. This suggests that the apparent associations between MOPP and DOPP surrogates with POAG (shown in table 2, model 1) were mainly attributed to the IOP ‘component’ on the calculation of MOPP and DOPP surrogates. These current findings were consistent with that of Beijing Eye Study which also adjusted for IOP.15 Furthermore, longitudinal evaluation in the Rotterdam Study also showed no significant association between MOPP and incident POAG after adjusted for IOP.12 In contrast, previous findings from the Barbados Eye Study and Los Angeles Latino Eye Study showed that lower MOPP surrogates were associated with POAG even after adjusting for IOP.11 21 Nevertheless, these studies’ analyses did not sufficiently take into account other important confounders which may also affect perfusion, such as antihypertensive treatment, diabetes and BMI. Previous work by Khawaja et al, illustrated that when IOP was adjusted in a regression model for the evaluation between OPP profiles and POAG, it should be interpreted as the OR for POAG per unit change in OPP profile while holding IOP constant.22 If IOP is held ‘constant’ in a regression model, the only way for OPP status to vary is for the BP component of OPP to vary. Hence, such IOP-adjusted regression model may more reflect the association of BP profiles on POAG, and may not entirely represent the effect of OPP profiles on POAG. For this reason, in addition to OPP profiles, we also further evaluated the effect of MAP and DBP profiles on POAG while adjusted for the same covariates, and consistently found that both MAP and DBP were also not associated with POAG (table 3). In addition, we also observed that hypertension was not associated with POAG in our study (P=0.125, data not shown in tables).
On the other hand, we observed that both low and high levels of SOPP were associated with POAG, compared with mid-range SOPP level, even after adjusting for relevant covariates and IOP, suggesting an apparent Ú-shaped’ association between SOPP and POAG. Nevertheless, when further evaluating the SBP profile with POAG, we found that only low levels of SBP were associated with higher odds of POAG. This indicates that association of low SOPP with POAG was in part, attributed to low SBP. Similarly, it was previously reported in Barbados Eye Study that lower SBP was associated with incident POAG.21 A possible reason may be that low SBP indirectly compromises ocular blood supply to the ONH, causing ischaemic damage to retinal ganglion cells and initiating glaucomatous development.2 23 Furthermore, we demonstrated that the effect of low SBP on POAG was even more pronounced among ocular hypertensive eyes (OR=3.90). This indicates that low SBP coupled with high IOP may further result in reduced perfusion to the ONH.2 23 Our finding coincides well with the theoretical model proposed by Guidoboni et al, which predicted that individuals with both low BP and high IOP are even more susceptible to dysfunctional regulation of blood flow.24 This is because individuals with low BP generally have poorer ability to regulate blood flow,25 combining this factor with the presence of high IOP where venous collapse is likely to occur,24 impairment to blood flow would be further exacerbated. Altogether, these findings suggest that identification of concurrent low SBP and ocular hypertension may potentially be a direct and useful approach in further stratifying glaucoma risk group. Future longitudinal evaluation is still required to validate this potential risk stratification approach.
The strengths of our study include large population datasets across the three main ethnicities in Asia with larger number of POAG cases compared with previous population-based studies, and thus greater statistical power. Furthermore, our analysis included a comprehensive list of important confounding factors such as the use of antihypertensive and IOP-lowering treatment which were not sufficiently taken into account in previous studies. These two medication-related factors affect the measurement of BP, IOP, and thus subsequent calculation of OPP surrogate, and should be taken into account in analysis. However, this study also has limitation. BP and IOP measurements were only performed for one time point in the day. The effect of circadian perfusion pressure on glaucoma could not be assessed due to our study design. Second, the observed U-shaped association between SOPP and POAG indicates that conventional regression model may not be fully adequate in evaluating the complex relationship between OPP and POAG. As proposed by Guidoboni et al,24 a novel and more complex analytical method is needed to even more accurately elucidate the role of OPP while accounting for the interplay between OPP, BP and IOP. Third, other important physiological factors such as haemodynamics and autoregulation of blood flow were not taken into account in our study, nevertheless, these factors are intrinsically difficult to be measured and quantified in a population-based study setting like ours. Hence, our current findings on OPP surrogates should be interpreted with these limitations in mind.
In conclusion, in a population-based sample of nearly 10 000 Asian individuals, we showed that low SOPP was associated with POAG, this association was potentially in part secondary to low SBP and high IOP. Our findings provide further clarity on the roles of OPP surrogates and BP profiles in POAG.
Contributors Conception and design: YCT, TYW, C-YC. Data collection: YCT, S-HL, PG, TA, TYW, C-YC. Analysis and interpretation: YCT. Drafting of manuscript: YCT, C-YC. Final revision of manuscript: YCT, S-HL, PG, TA, TYW, C-YC.
Funding CYC is supported by the National Medical Research Council, Singapore (CSA/033/2012).
Competing interests None declared.
Ethics approval The study was approved by the Institutional Review Board of Singapore Eye Research Institute.
Provenance and peer review Not commissioned; externally peer reviewed.