Relationship between optical perfusion pressure and systemic blood pressure on glaucoma: Case-control study.

AIM: To investigate the relationship between blood pressure (BP), ocular perfusion pressure (OPP), intraocular pressure (IOP) and open angle glaucoma (OAG) in Primary Open Angle Glaucoma (POAG) patients and normal population.
DESIGN: Cross-sectional observation study.
MATERIALS AND METHODS: Hospital-based, case control cross-sectional study conducted on 150 patients, of which 75 people were included in the control group and 75 people in the glaucoma group. The diagnosis of cases was based on disc evaluation, gonioscopy, perimetry and applanation tonometry. Systolic and diastolic blood pressure (SBP and DBP) was measured with a Mercury Sphygmomanometer. Mean ocular perfusion pressure (MOPP) = ⅔ (mean arterial pressure - IOP), where mean arterial pressure (MAP) = DBP + ⅓ (SBP - DBP), systolic perfusion pressure (SPP) = SBP - IOP and diastolic perfusion pressure (DPP) = DBP - IOP was calculated.
RESULTS: DBP, OPP, SPP and DPP showed positive association with POAG. There is positive correlation between IOP and SBP, DBP and there is a negative correlation between IOP, OPP, SPP and DPP. Lower OPP was strongly associated with an increased risk for POAG, with a relative risk of 6.27 and the odds ratio of 0.075 for those with OPP less than 50 mmHg. Similarly, a low DPP less than 55 mmHg were also associated with increased risk for POAG with relative risk of 5.3 and the odds ratio of 0.020.
CONCLUSION: Low MOPP and low DPP show strong association with increased prevalence of POAG and are independent risk factors for OAG. Copyright:

Introduction

Glaucoma is a chronic progressive optic neuropathy characterized by retinal ganglion cell death and associated visual field loss.[1] It is a disease which is classified as an optic neuropathy because it causes damage to the optic nerve leading to visual field loss and blindness in the long term. Worldwide, glaucoma is the second-leading cause of blindness after cataracts.[2] Globally, 60.5 million people had glaucoma in 2010.[3] Despite extensive clinical and experimental studies, the mechanism underlying the development and progression of primary open-angle glaucoma (POAG) remains unclear.[4] The pathophysiology of open-angle glaucoma (OAG) is still not known. There are many risk factors associated with OAG, out of which raised intraocular pressure (IOP) is a well-known risk factor for glaucoma and the only parameter that we can measure to know the progression of the disease.[5] However, studies have shown that not all patients with abnormal IOP have glaucoma and not all patients with glaucoma have abnormal IOP. Although IOP reduction continues to be the only successful treatment to reduce the progression of glaucoma,[67] many patients with apparently “adequate” IOP reduction still show ongoing vision loss.[8] Hence, there is a need to identify risk factors other than IOP, which can be used for identifying and treating patients with glaucoma.

One factor is inadequate blood flow to the optic nerve head (ONH). Several studies have implicated various vascular risk factors in the pathogenesis of glaucoma, of which blood pressure (BP) and ocular perfusion pressure (OPP) were the most studied.[910] This vascular hypothesis is based on the theory that abnormal perfusion and the subsequent ischemia of the ONH play a major role in the glaucomatous damage.[11]

OPP is the difference between BP and IOP (OPP = BP-IOP). On the one hand, some studies indicate that systemic hypertension is a risk factor for glaucoma,[1213] and on the other hand, some studies indicate that low systemic BP is a risk factor for the development and progression of glaucoma.[1415] However, a clear relationship between BP levels and OAG has not been established. However, a clear relationship has been established between ocular perfusion pressure and glaucoma. There exist paucity in Indian literature, and hence, the present study was conducted in individuals with and without OAG to determine the relationship between OPP, BP, and IOP.

Materials and Methods

This study was a hospital-based, case–control study conducted on 150 patients attending ophthalmology outpatient department at a tertiary care hospital in Navi Mumbai. The study was conducted over a period of 2 months (July and August 2015), during which 150 patients (75 cases and 75 matched controls) who fulfilled the study criteria and who gave consent for participation in the study were included in the study. Ethical clearance was obtained from the Institutional Ethical Committee prior to the conduct of this study.

150 patients were enrolled in this case-control study of which 75 patients were in the control group and 75 patients were glaucoma cases. The study was carried out over a duration of 2 months from July-August 2015.

Inclusion criteria for cases

Patients with OAG (known cases or recently diagnosed) in the age group of 30–80 years of both sexes, taking no treatment for glaucoma, and with or without family history of glaucoma were included in the study.

Inclusion criteria for controls

All nonglaucoma patients aged 30–80 years of both sexes.

Exclusion criteria for cases and controls

Taking anti-hypertensive medicine

On active glaucoma treatment

Grade 4 hypertensive retinopathy

Diabetic retinopathy

High myopia

Ocular injury

Patients in which IOP cannot be performed like corneal defects

Patients who cannot maintain a relaxed, immobile position

Angle-closure glaucoma and other secondary glaucoma.

Methods

The study was conducted after a voluntary written informed consent of the patients was obtained. In addition, an interviewer-administered questionnaire was used to obtain demographic, ocular, and medical histories. Information pertinent to these studies such as history of any disease in the past such as angina, myocardial infarction, heart failure, diabetes, hypertension, and any surgeries were included in the questionnaire. Participants were asked whether they had a history of glaucoma or any other ocular disease and whether they had been (or were currently being) treated with medications or laser or incisional surgery. Participants were also asked whether they are suffering from hypertension and are on anti-hypertensive medication. After informed consent was obtained, the participants underwent a complete ophthalmic examination, including visual acuity measurement, refraction, and slit-lamp examination. The diagnosis of cases was based on disc evaluation, gonioscopy, perimetry, and applanation tonometry. POAG was diagnosed by the presence of glaucomatous cupping, visual field defects, optic disc damage, and open angles on gonioscopy, with or without raised IOP, after the exclusion of other possible causes. The demographic data, history, examination findings, and IOP readings were recorded in the case record form. IOP of both the eyes was measured by applanation tonometer attached to a slit lamp under local anesthesia. Three readings of IOP were obtained from every patient for each eye, and average of each eye was taken. In this study, IOP of the right eye was used for statistics in the control group for uniformity; and in the cases group, the IOP of the eye with glaucoma was used or if both eyes were affected with glaucoma, the eye with higher pressure was used. The BP of the brachial artery was measured by a single observer. The BP reading of the right brachial artery of the arm with the mercury column approximately in level with the heart was taken with the mercury sphygmomanometer in sitting position (auscultatory technique was used, using the different phases of the Korotkoff sounds as per the American Heart Association BP measurement recommendations). Two readings of the BP were noted down, and the average was taken for analysis.

Using the formula, OPP = 2/3 (MAP-IOP) where OPP is optical perfusion pressure, MAP, and IOP; OPP was calculated. The MAP formula is MAP = DBP + (1/3× [SBP-DBP]); where DBP is diastolic BP, and SBP is systolic BP. OPP obtained was used for analysis. Furthermore, the systolic and diastolic perfusion pressures (DPPs) were calculated using the formulae:

Systolic perfusion pressure (SPP) = SBP-IOP

DPP = DBP-IOP

Results

In this study, a total of 150 participants were included. Seventy-five normal individuals were included in the control group, while 75 glaucoma patients were included in the case group. Detailed demographic data and clinical characteristics of the study population are shown in Table 1. The mean age of control group is 57.33 ± 11.4, and the mean age of cases group is 58.23 ± 11.8. Table 2 shows that DBP, IOP, OPP, SPP, and DPP were statistically significant with P value calculated by Mann–Whitney test to be 0.000. SBP was not found to be statistically significant with P = 0.023.

Table 1

Characteristics of patients in glaucoma group and control group

Parameters	Glaucoma group value (n=75)	Control group value (n=75)
Age (years)	58.23±11.8	57.33±11.4
Sex
Male	49	35
Female	26	40
Pulse rate	83.27±5	82.00±4.9
SBP (mmHg)	123.39±11.8	126.47±10.1
DBP (mmHg)	74.73±8.2	81.05±8.3
IOP	26.83±9.6	17.00±2.4
Optical perfusion pressure	33.80±9.8	47.13±5.5
SPP	96.56±13	109.47±10.3
DPP	47.90±11.3	64.05±8

SBP: Systolic blood pressure, DBP: Diastolic blood pressure, IOP: Intraocular pressure, SPP: Systolic perfusion pressure, DPP: Diastolic perfusion pressure

Table 2

Comparison between normal (control) and glaucoma (cases) group

Parameter	Normal (n=75)	Glaucoma (n=75)	Z	P*
SBP
Mean	126.46	123.38	−2.276	0.023
Median	124.00	120.00
DBP
Mean	81.05	74.73	−4.549	0.000
Median	80.00	74.00
IOP
Mean	16.99	26.83	−9.213	0.000
Median	17.30	24.00
OPP
Mean	47.12	33.80	−8.741	0.000
Median	46.26	35.07
SPP
Mean	109.46	96.55	−6.483	0.000
Median	106.40	97.10
DPP
Mean	64.05	47.90	−8.544	0.000
Median	63.40	48.40

*P value obtained by Mann ween normal, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, IOP: Intraocular pressure, SPP: Systolic perfusion pressure, DPP: Diastolic perfusion pressure, OPP: Ocular perfusion pressure

The correlation of Table 3 shows that there is a positive correlation between IOP and SBP, DBP indicating that as IOP increases the SBP and DBP. There is a negative correlation between IOP, OPP, SPP, and DPP showing that as IOP increases OPP and SPP and DPP will decrease.

Table 3

Correlation of intraocular pressure, blood pressure, and ocular perfusion pressure in glaucoma

Correlation	n	IOP Spearman’s rho value (r)	P
SBP	75	0.296	0.010
DBP	75	0.271	0.019
Optical perfusion pressure	75	−0.579	<0.001
SPP	75	−0.340	0.003
DPP	75	−0.391	0.001

SBP: Systolic blood pressure, DBP: Diastolic blood pressure, IOP: Intraocular pressure, SPP: Systolic perfusion pressure, DPP: Diastolic perfusion pressure

A strong association was found between low ocular perfusion pressure (<50) and glaucoma. The association was found to be statistically significant with P value found to be <0.001 [Table 4]. The odds ratio for the same was 0.075, and the relative risk was found out to be 6.27. A similar association was found between low DPP (<55) and glaucoma, with P < 0.001, odds ratio of 0.020, and relative risk of 5.3 [Table 5], but such an association was not found between low SPP and glaucoma with P value found out to be 0.276 [Table 6].

Table 4

Association between low ocular perfusion pressure and glaucoma risk

Group	OPP		Total	χ2	P
	Low OPP <50	High OPP ≥50
Normal	55	20	75	17.259	<0.001
Glaucoma	73	2	75
Total	128	22	150

OR for low OPP (<50)=0.075. Relative risk for low OPP (<50) for glaucoma=6.27. OR: Odds ratio, OPP: Ocular perfusion pressure

Table 5

Association between low diastolic perfusion pressure and glaucoma risk

Group	DPP		Total	χ2	P
	Low DPP <55	High DPP ≥55
Normal	6	69	75	81.595	<0.001
Glaucoma	61	14	75
Total	67	83	150

OR for low DPP (<55)=0.020, Relative risk for low DPP (<55) for glaucoma=5.3. DPP: Diastolic perfusion pressure, OR: Odds ratio

Table 6

Association between low DPP and Glaucoma risk

Group	DPP		Total	Chi square value	P
	Low DPP <55	High DPP ≥55
Normal	6	69	75	81.595	<0.001
Glaucoma	61	14	75
Total	67	83	150

OR for low DPP (<55)=0.020, Relative risk for low DPP (<55) for glaucoma=5.3. DPP: Diastolic perfusion pressure, OR: Odds ratio

Discussion

In our study, an attempt was made to compare and find out the relationship between IOP with ocular perfusion pressure. The key findings of the study suggest that ocular perfusion pressures such as OPP, DPP, and SPP are lower in patients of glaucoma in comparison with normal and have higher relative risk for glaucoma [Graph 1].

Graph 1

Comparison between normal (control) and glaucoma (cases) group

Glaucoma is a multifactorial disease process. The exact pathophysiology of POAG remains unknown. Our study adds further support to the hypothesized vascular mechanism in the development of glaucoma. The vascular hypothesis for the development of glaucomatous optic nerve damage suggests that ischemia as a result of inadequate perfusion of the ONH, and the retinal ganglion cell layer is at least partly responsible. The maintenance of ocular perfusion pressure depends on a complex regulation process that balances BP and IOP to ensure adequate irrigation of ocular tissues. The underlying cause of abnormal perfusion in glaucoma, therefore, is likely to be a disruption of the normal mechanisms that regulate perfusion pressure.

Abnormal perfusion occurs when this process is altered due to vascular dysregulation, which has been proposed as an underlying cause for glaucoma damage. Alterations of ocular perfusion could cause ischemia and poor irrigation of tissues in the optic nerve, thus having deleterious effects. These effects could be especially relevant for the causation of OAG, an optic neuropathy of unknown origin, which presents with a distinctive pattern of nerve changes and visual field loss. This reduction, however, is not linear, because of the autoregulatory mechanisms that are normally in effect,[16] at extremely low levels, however, Ocular perfusion pressure (OPP) can fall below the critical autoregulatory range and indeed cause a significant reduction in blood flow.[17] Furthermore, glaucoma patients are believed to have abnormalities in their autoregulatory mechanisms that control blood flow to the ONH.[1819]

In our study, the mean ocular perfusion pressure (MOPP), SPP, and DPP were found to be lower in patients of POAG as compared to the control group and were statistically significant. Individuals with glaucoma had lower perfusion pressure in our study. These findings are similar to studies conducted by the Singapore Malay Eye Study (Rosman et al.), Los Angeles Latino Eye Study (LALES) (Memarzadeh et al.), and the Barbados Eye Study (Leske et al.).

In the LALES, it was found that low MOPP, DPP, and systolic OPP were associated with increased prevalence of OAG in Latinos.[20] Similarly, in the Singapore Malay Eye Study, it was found that low DBP and low MOPP are independent risk factors for OAG in ethnic Malays.[21] Our findings were in contrast to those reported by the Beijing Eye Study in the Chinese, in which no significant association was found between perfusion pressure and OAG.[22] The discrepancy between our findings and those from the Beijing Eye Study may be attributed to differences in the definition of glaucoma between our study and theirs. The Beijing Eye Study relied only on ONH appearance for diagnosing glaucoma cases, or it may be due to different genetic background and/or unmeasured lifestyle factors.

We also documented in our study that there was a positive correlation seen in SBP, DPP, and glaucoma, and a negative correlation between optical perfusion pressure, SPP, DPP, and glaucoma. This indicates that as IOP increases the SBP and DBP will also increase and vice versa.

Many population-based studies have also reported a positive association or correlation between SBP, DBP, and IOP.[2324] In study conducted by Deb et al., systemic hypertension, perfusion pressure, and glaucoma IOP were seen to have a moderately positive correlation with MAP (r = 0.29) that was not statistically significant (P = 0.12), this may be as their study used hypertensive patients.[25] A negative correlation was found between OPP, SPP, DPP, and IOP, which was found to be statistically significant (P < 0.001, 0.003, and 0.001, respectively), thus indicating that as OPP, SPP, and DPP decreases, IOP will increase and vice versa.

Our results, along with those of numerous other epidemiologic studies, provide evidence that low perfusion pressure is an important vascular factor associated with a higher prevalence of OAG.

Ocular perfusion pressure <50 had a risk factor of 6.27 [Table 5], showing us that in person with OPP <50 had six times more risk of developing OAG than those with OPP ≥50. On statistical analysis, these results are statistically significant (P < 0.001). This is in accordance with the LALES, in which they found that in patient with MOPP ≤50 mmHg, the odds ratio was equal to 3.6.[20] In the Barbados Eye Study, the relative risk for MOPP ≤40 mmHg was found to be 2.6.[14] Low DPP is said to be an independent risk factor for OAG. In our study, DPP <55 had a risk factor of 5.3 [Table 6], showing us that in person with DPP <55 had five times more risk of developing OAG than those with DPP ≥55. This result was found to be statistically significant (P < 0.001). Our result was similar to the one found in the Baltimore Eye Study, in which DOPP <30 mmHg had six times increased risk of developing POAG compared to individuals with DOPP >56 mmHg.[26] Many other epidemiological studies showed the same results. In the Proyecto VER study, DOPP <50 mmHg had a four times increased the risk of developing OAG than DOPP >80 mmHg;[27] in LALES, DOPP ≤40 mmHg had a risk of 1.9,[20] whereas in Barbados Eye Study, DOPP ≤53 mmHg had a relative risk of 2.1.[14] In our study, the odds ratio for DPP <55 is 0.020, whereas in the Rotterdam study, DOPP <50 mmHg had an odds ratio of 0.25 but that was in patients taking BP-lowering treatment,[28] which were not included in our study. SPP ≤125 mmHg had an heart rate = 1.39, P = 0.0328 in the Early Manifest Glaucoma Study[29] which shows that it was statistically significant, but a similar result was not found in our study [Table 7], as we got an P = 0.276 for SPP <125, which shows that it was not statistically significant.

Table 7

Association between low systolic perfusion pressure and glaucoma risk

Group	SPP		Total	χ2	P
	<125	>125
Normal	69	6	75	2.113	0.276
Glaucoma	73	2	75
Total	142	8	150

SPP: Systolic perfusion pressure

Our study found no association between OAG and conventionally defined systemic hypertension. There are pathophysiological mechanisms which show that high BP may be a risk factor for glaucoma. The theory is that those with high BP may develop a decrease in vessel diameter, which over time may cause arteriosclerosis that could compromise vascular autoregulation, as well as impair nutrient exchange in the capillary beds at the ONH. The results found in our study contradicts such as the Blue Mountains Eye Study,[12] Egna–Neumarkt Glaucoma Study,[13] and the Rotterdam Eye Study[23] which found that systemic hypertension increases susceptibility to glaucoma. In our study, we found glaucoma individuals had low DBP in comparison to control, and it was statistically significant [Table 3]. This is in accordance with the LALES, low DBP (DBP ≤60 mmHg) was associated with an increased prevalence of OAG.[20] It may be hypothesized that patients with low DBP suffer from low OPP at the ONH. Using the earlier theory of high BP, it may indicate that low OPP can occur secondary to any of high IOP, low BP, or local atherosclerosis. However, a similar association is not seen with SBP as seen in the LALES study done, which showed that the relationship between glaucoma prevalence and DBP is “U” shaped, indicating that patients at both extremes of the BP spectrum are at greater risk of glaucoma. This difference in study results may be partially explained by the difference in the criteria used to define hypertension, the inclusion or exclusion of IOP in the definition of OAG, the impact of IOP or BP-lowering therapy, or the variable susceptibility of people of different ancestries to OAG.

In our study, we found a significant association between low OPP, DPP, and POAG. Thus, it can be said that lowering the perfusion pressure can improve the condition in glaucoma patients. More research on effects of medication on ocular perfusion pressure in glaucoma is recommended to be done in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.