Relationship between Blood Pressure and Retrobulbar Blood Flow in Dipper and Nondipper Primary Open-Angle Glaucoma Patients

Abstract

Purpose

To evaluate the relationship between retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery, and short posterior ciliary artery and 24-hour blood pressure (BP) measurements in dipper and nondipper patients with primary open-angle glaucoma (POAG).

Methods

A prospective, cross-sectional, and observational study was conducted on consecutive patients, referred or recruited, attending the outpatient service of our ophthalmology department. Ambulatory BP monitoring, Doppler imaging, and ocular pulse amplitude measurements were performed on the same day. Patients with nocturnal BP decrease up to 10% of the diurnal BP were defined as dippers and those with BP decrease less than 10% were defined as nondippers.

Results

A total of 114 patients (36 nondippers and 78 dippers) were included in the study. The end-diastolic velocity was significantly lower and the resistivity index (RI) was significantly higher in the dippers than in the nondippers (p<0.0001 and p<0.0001, respectively). The RI in the OA was significantly correlated with daytime and nighttime systolic BP and with the daytime mean arterial pressure in the dippers.

Conclusions

The RI in the OA significantly correlates with BP in patients with POAG with nocturnal BP dips. Additionally, retrobulbar blood flow parameters are reduced in dippers as compared with nondippers with POAG.

Keywords

Blood pressure Blood pressure dips Color Doppler imaging Open-angle glaucoma

Introduction

Although the relationship between blood pressure (BP) and glaucoma remains unclear (1 -7), there is increasing evidence suggesting that nocturnal hypotension may play a role in the pathogenesis of glaucomatous optic neuropathy and anterior ischemic optic neuropathy (5 -8). It was suggested that the decrease in nocturnal BP is higher in patients with glaucoma than in healthy subjects (9, 10).

Additionally, a prospective study published by Costa et al (11) suggested that the behavior of diastolic BP (DBP) in patients with primary open-angle glaucoma (POAG) is distinct from that in healthy subjects.

Moreover, Pillunat et al (12) evaluated the nocturnal BP dipping pattern and its relationship with visual field damage in patients with POAG. The results of this study suggested that it is important to assess not only the nocturnal BP level, but also its relationship with the daytime BP level.

However, the relationship between BP and glaucoma progression seems to be a U-shaped relationship (13). Both low and high BP might be involved in glaucomatous progressive patients.

Ambulatory BP monitoring (ABPM) allows the assessment of BP across a 24-hour period. Additionally, ABPM facilitates the identification of BP decreases, or dips, which typically happens during the night. The information provided for the ABPM may be relevant for patients with POAG, because nocturnal BP dips may be a risk factor for glaucoma progression (12).

However, not all patients with low BP develop glaucoma, suggesting an underlying vascular dysregulation, and not merely low nocturnal BP, as a contributory factor for glaucomatous damage.

Color Doppler imaging (CDI) is a noninvasive method with a high reproducibility, which can be used in any eye disease in which vascular etiology is suspected as a factitive factor (14). It allows the measurement of blood flow velocities including peak systolic velocity (PSV) and end diastolic velocity (EDV) in the retrobulbar vessels. Retrobulbar blood flow velocity reduction and resistivity index elevation in glaucoma patients has already been reported (15, 16). Additionally, retrobulbar blood flow impairment has been suggested as a risk factor for glaucoma progression (17 -20).

The purpose of this study was to evaluate the relationship between the retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary artery (SPCA) and the BP in dipper and nondipper patients with POAG.

Methods

This study was designed as a prospective, cross-sectional, and observational study.

The study was conducted on consecutive patients, referred or recruited, attending the outpatient service of our Ophthalmology Department.

The study protocol was approved by the local ethics committee. All patients were fully informed about the details of the study protocol and patients provided written informed consent.

All participants were required to meet the following inclusion criteria: age equal to or higher than 40 years, clinical diagnosis of POAG, early to moderate visual field defect (21), and willingness to comply with the investigator's and protocol indications. Patients were excluded by any form of glaucoma other than POAG, previous treatment with argon laser trabeculoplasty and/or ocular filtering surgery, diabetes, history of progressive retinal or optic nerve disease of any cause, and pregnancy or lactation.

Those patients with systemic hypertension or cardiovascular disease, such as first-degree atrioventricular block or stable coronary artery disease, were not excluded, but their medication dosages must have remained stable for at least 6 months before the visit.

Each subject underwent a standard ophthalmic examination, including a review of medical history, best-corrected visual acuity, slit-lamp examination of the anterior segment with dilated pupils, intraocular pressure (IOP) with dynamic contour tonometer (DCT) and Goldmann applanation tonometry (GAT), automated perimetry with the 24-2 Swedish Interactive Thresholding Algorithm Standard strategy (SITA standard) on the Humphrey visual field analyzer (Carl Zeiss Meditec, Dublin, CA), and dilated funduscopic examination using a 78-D lens. Ocular pulse amplitude (OPA) appeared during the DCT measurement.

Ambulatory BP monitoring (ABPM), IOP, Doppler imaging, and OPA measurements were performed in the same day.

The Tracker NIBP2 (Reynolds Medical Ltd., Hertford, UK) oscillometric monitor was used for ABPM. Each patient used an arm cuff of a similar size to the one used for routine office BP measurement in the nondominant arm. The BP was measured for every 15 minutes between 06:00 and 23:00 hours, and every 30 minutes between 23:00 and 06:00 hours. Patients with nocturnal BP decrease up to 10% of the diurnal BP were defined as dippers, and those with BP decrease less than 10% were defined as nondippers (22).

Daytime systolic BP (DSBP) and DBP (DDBP), night-time systolic BP (NSBP) and DBP (NDBP), and day and nighttime mean arterial pressure (MAP) were measured.

The CDI examinations were performed between 12:00 and 15:00 hours with an imaging system (Sonoline Antares, Siemens, Erlangen, Germany) with a VF13-5 MHz, VX9-4 MHz multifrequency transducer by the same experienced observer (M.M.) (blinded to the study group). The measurements were obtained according to the technique we have used in previous studies (19, 20, 23).

Peak systolic velocity and EDV were determined in the OA, SPCA, and CRA. Although medial and lateral posterior ciliary artery were individually assessed, the mean value of both was used for the statistical analysis. The Pourcelot resistivity index (RI) was calculated according to the formula RI = PSV – EDV/PSV (24). For each vessel, 2 consecutive measurements were obtained and the average value was taken.

The measurements of IOP and OPA were taken on the same day between 08:00 and 11:00 hours by the same ophthalmologist (I.M.). Mean IOP and OPA values were calculated after 3 consecutive measurements with a DCT (Swiss Microtechnology AG, Port, Switzerland). Additionally, GAT measurements were done 3 times with the same Goldmann tonometer (Haag Streit, Switzerland). The OPA values were displayed in mm Hg and measurements with quality 1 and 2 were taken into account.

Statistical analysis

Before the study, it was determined that a sample of at least 36 patients per group was required to detect as statistically significant a Pearson correlation coefficient of 0.45, at a significance level of 0.05, with a power of 0.80.

Only one eye that fulfilled all the inclusion criteria and none of the exclusion criteria was designated as the study eye in each patient; in patients in whom both eyes fulfilled all inclusion criteria and none of the exclusion criteria measurements were met, the right eye was used for statistical analysis.

Descriptive statistics (mean [SD]) and 95% confidence intervals (95% CIs) were used to report demographic and clinical characteristics. Data were tested for normal distribution using a D'Agostino-Pearson test.

As data were normally distributed, a 2-tailed independent sample Student t test was used to compare means between study groups for quantitative variables. Categorical variables were compared using a chi-square test and a Fisher exact test, as needed.

Correlation between BP and retrobulbar hemodynamic parameters such as RI in OA, SPCA, and CRA was assessed for DSBP, DDBP, NSBP, NDBP, daytime MAP (DMAP), and nighttime MAP (NMAP) in dipper and nondipper POAG subjects independently, calculating Pearson correlation coefficients.

Because of the large number of tests, simultaneous inference using the Bonferroni correction was used to correct the p value (α/9). Statistical significance was accepted for p<0.0055.

Results

Of the 191 screened patients, 114 fulfilled the respective demands of the inclusion and exclusion criteria, 36 patients in the nondipper group and 78 in the dipper group. Patient demographic and clinical characteristics are summarized in Table I.

Table I

Demographic and clinical characteristics of the study population

	Study groups
	Nondippers (n = 36)	Dippers (n = 78)	p
Age, y
Mean (SD)	63.6 (15.2)	64.1 (11.7)	0.8262
95% CI	58.4 to 68.7	61.5 to 66.8
Sex, n (%)
Male	26 (72.2)	52 (66.7)	0.6661^a
Female	10 (27.8)	26 (33.3)
DCT IOP, mm Hg
Mean (SD)	16.1 (2.3)	16.2 (3.1)	0.9019
95% CI	15.3 to 16.9	15.5 to 16.9
GAT IOP, mm Hg
Mean (SD)	12.9 (1.9)	13.0 (2.5)	0.8915
95% CI	12.3 to 13.5	12.5 to 13.6
MD, dB
Mean (SD)	-3.97 (3.86)	-2.89 (3.96)	0.1735
95% CI	-5.27 to −1.99	-3.78 to −1.99
PSD, dB
Mean (SD)	3.31 (1.93)	2.56 (2.08)	0.0703
95% CI	2.66 to 3.96	2.09 to 3.03
CD ratio
Mean (SD)	0.54 (0.17)	0.41 (0.15)	<0.0001
95% CI	0.48 to 0.60	0.37 to 0.48
Glaucoma medication, n (%)^b
PA	28 (77.8)	56 (71.8)	0.4516^c
BB	8 (22.2)	8 (10.3)
DTFC	4 (11.1)	10 (12.8)
AA	4 (11.1)	4 (5.1)
HBP medications, n (%)^b
BB	4 (25.0)	10 (13.3)	0.9672^c
CCB	7 (43.8)	15 (50.0)
Diuretics	3 (18.8)	8 (26.7)
Other	5 (31.3)	9 (30.0)

AA = alpha agonist; BB = beta-blocker; CCB = calcium channel blockers; CD = cup to disc; CI = confidence interval; DCT = dynamic contour tonometry; DTFC = dorzolamide/timolol fixed combination; GAT = Goldmann applanation tonometry; HBP = high blood pressure; IOP = intraocular pressure; MD = mean defect; PA = prostaglandin analogue; PSD = pattern standard deviation.

Fisher exact test.

The total amount can be higher than 100% because patients can take more than one drug.

Chi-square test.

Mean (SD) age was 63.6 (15.2) years in the nondipper group and 64.1 (11.7) years in the dipper group (p = 0.8262). There was no statistically significant difference between the 2 groups in most of the demographic and clinical data shown in Table I, except in cup to disc ratio, which was significantly higher in the nondipper group (p<0.0001).

As regards systemic hypertension or antiglaucoma medication, there were no statistically significant differences in number of treatments or type of medications (Tab. I).

While there were no significant differences between dippers and nondippers in daytime measurements, the nighttime measurements were significantly lower in the dippers group. Regarding the OPA, there was no difference between study groups (Tab. II).

Table II

Overview of the blood pressure and ocular pulse amplitude parameters of the study population

	Study groups
	Nondippers (n = 36)	Dippers (n = 78)	p
DSBP, mm Hg
Mean (SD)	138.4 (10.1)	135.5 (15.6)	0.2362
95% CI	135.0 to 141.9	132.0 to 139.1
DDBP, mm Hg
Mean (SD)	77.3 (7.9)	78.2 (8.5)	0.5992
95% CI	74.7 to 80.0	76.3 to 80.1
DMAP, mm Hg
Mean (SD)	97.7 (6.6)	97.3 (10.0)	0.8113
95% CI	95.5 to 99.9	95.1 to 99.6
NSBP, mm Hg
Mean (SD)	129.2 (19.7)	118.8 (15.8)	0.0032
95% CI	122.5 to 135.8	115.2 to 122.3
NDBP, mm Hg
Mean (SD)	70.9 (7.8)	67.7 (7.8)	0.0444
95% CI	68.3 to 73.6	66.0 to 69.5
NMAP, mm Hg
Mean (SD)	90.4 (10.4)	84.3 (8.7)	0.0016
95% CI	86.8 to 93.9	82.4 to 86.3
OPA, mm Hg
Mean (SD)	2.53 (1.07)	2.94 (1.20)	0.078
95% CI	2.16 to 2.89	2.67 to 3.21

CI = confidence interval; DDBP = daytime diastolic blood pressure; DMAP = daytime mean arterial pressure; DSBP = daytime systolic blood pressure; NDBP = nighttime diastolic blood pressure; NMAP = nighttime mean arterial pressure; NSBP = nighttime systolic blood pressure; OPA = ocular pulse amplitude.

As regards the retrobulbar hemodynamic parameters, the EDV in the SPCA and in the CRA were significantly lower in the dippers group as compared with the nondippers group, p = 0.0469 and p<0.0001, respectively. On the other hand, the RI in the SPCA and in the CRA were significantly higher in the dippers group than in the nondippers group, p = 0.0361 and p<0.0001, respectively (Tab. III).

Table III

Retrobulbar hemodynamic parameters of the study population

	Study groups
	Nondippers (36)	Dippers (78)	p
PSV OA, cm/s
Mean (SD)	37.1 (12.4)	37.9 (8.9)	0.7438
95% CI	32.9 to 41.3	35.9 to 39.9
EDV OA, cm/s
Mean (SD)	11.6 (5.7)	11.4 (4.6)	0.8051
95% CI	9.7 to 13.6	10.3 to 12.4
RI OA
Mean (SD)	0.69 (0.09)	0.70 (0.08)	0.5256
95% CI	0.66 to 0.72	0.66 to 0.72
PSV SPCA, cm/s
Mean (SD)	23.3 (3.2)	22.6 (5.4)	0.4639
95% CI	22.6 to 24.0	20.1 to 24.4
EDV SPCA, cm/s
Mean (SD)	8.2 (1.7)	7.4 (2.2)	0.0469
95% CI	7.9 to 8.6	6.6 to 8.1
RI SPCA
Mean (SD)	0.64 (0.07)	0.67 (0.06)	0.0361
95% CI	0.63 to 0.66	0.65 to 0.66
PSV CRA, cm/s
Mean (SD)	16.1 (2.8)	14.8 (3.3)	0.0611
95% CI	15.1 to 17.0	14.1 to 15.6
EDV CRA, cm/s
Mean (SD)	6.0 (1.8)	4.0 (1.4)	<0.0001
95% CI	5.4 to 6.6	3.7 to 4.4
RI CRA
Mean (SD)	0.63 (0.08)	0.72 (0.07)	<0.0001
95% CI	0.60 to 0.66	0.71 to 0.74

CI = confidence interval; CRA = central retinal artery; EDV = end-diastolic velocity; OA = ophthalmic artery; PSV = peak systolic velocity; RI = resistivity index; SPCA = short posterior ciliary arteries.

Our study found a significant correlation between the RI in the OA and some of the BP parameters in the dippers group, namely DSBP, DDBP, DMAP, NSBP, and NMAP. However, when a Bonferroni correction is applied, only the DSBP, DMAP, and NSBP remained significant. Interestingly, we did not find any significant correlation between the retrobulbar hemodynamic parameters and the blood flow parameters in the nondippers group (Tab. IV).

Table IV

Correlation between resistivity indices in the retrobulbar vessels and vascular parameters in the different study groups

	Nondippers			Dippers
	RI OA	RI SPCA	RI CRA	RI OA	RI SPCA	RI CRA
DSBP
R	0.24	-0.13	-0.02	0.37	0.13	-0.04
95% CI	-0.09 to 0.53	-0.44 to 0.21	-0.35 to 0.31	0.17 to 0.55	-0.09 to 0.34	-0.26 to 0.18
p Value	0.1469	0.4418	0.8794	0.0007	0.253	0.7026
DDBP
R	0.24	-0.22	-0.24	0.22	0.05	0.01
95% CI	-0.29 to 0.37	-0.46 to 0.11	-0.53 to 0.09	0.00 to 0.43	-0.17 to 0.27	-0.21 to 0.23
p Value	0.8018	0.2312	0.1544	0.0481	0.6633	0.9294
DMAP
R	0.16	-0.23	-0.21	0.32	0.1	-0.02
95% CI	-0.18 to 0.46	-0.46 to 0.17	-0.50 to 0.13	0.11 to 0.51	-0.13 to 0.31	-0.24 to 0.21
p Value	0.3511	0.2716	0.2269	0.0042	0.4021	0.8837
NSBP
R	0.14	-0.03	0.03	0.38	0.17	-0.06
95% CI	-0.20 to 0.45	-0.35 to 0.30	-0.30 to 0.35	0.17 to 0.55	-0.05 to 0.38	-0.28 to 0.17
p Value	0.4212	0.8701	0.8734	0.0007	0.1351	0.6296
NDBP
R	0.06	-0.28	-0.00	0.20	0.03	0.03
95% CI	-0.28 to 0.38	-0.56 to 0.05	-0.33 to 0.33	-0.02 to 0.41	-0.20 to 0.23	-0.20 to 0.25
p Value	0.7391	0.0952	0.9841	0.0716	0.8168	0.8115
NMAP
R	0.12	-0.15	0.02	0.28	0.08	-0.02
95% CI	-0.22 to 0.43	-0.46 to 0.18	-0.31 to 0.34	0.06 to 0.48	-0.15 to 0.29	-0.24 to 0.25
p Value	0.5002	0.3558	0.9277	0.012	0.5138	0.8736
OPA
R	0.26	-0.04	-0.08	0.15	0.10	-0.16
95% CI	-0.08 to 0.54	-0.37 to 0.29	-0.40 to 0.25	-0.08 to 0.36	-0.13 to 0.31	-0.37 to 0.06
p Value	0.1265	0.7977	0.6288	0.146	0.3843	0.1501

CI = confidence interval; CRA = central retinal artery; DDBP = daytime diastolic blood pressure; DMAP = daytime mean arterial pressure; DSBP = daytime systolic blood pressure; NDBP = nighttime diastolic blood pressure; NMAP = nighttime mean arterial pressure; NSBP = nighttime systolic blood pressure; OA = ophthalmic artery; OPA = ocular pulse amplitude; R = Pearson correlation coefficient; RI = resistivity index; SPCA = short posterior ciliary artery.

As regards the OPA, we did not find any significant correlation between OPA and the retrobulbar hemodynamic parameters in either nondippers or dippers (Tab. IV).

Discussion

The results of our study found a significant correlation between BP measurements (DSBP, DMAP, and NSBP) and RI in the OA in the dipper patients group. Our study also found that the EDV was significantly lower and the RI significantly higher in the SPCA and CRA in the dippers group. However, our study failed to find any significant correlation between BP and retrobulbar parameters in SPCA and CRA in either nondippers or dippers.

There are few studies evaluating the relationship between the ABPM and the retrobulbar hemodynamic parameters in patients with POAG with or without nocturnal BP dips.

Gherghel et al (10) reported, in open-angle glaucoma patients, that the EDV was significantly lower and the RI significantly higher in overdipping glaucoma patients compared with nondippers or dippers. We did not differentiate between dippers and overdippers, but our results are in line with theirs.

Our study may be compared with that of Karadag et al (8). They evaluated the OPA, IOP, and retrobulbar hemodynamic parameters in dipper and nondipper healthy (no glaucoma) subjects. The results of this study suggested that the OPA is significantly lower in the dippers group as compared with that in the nondippers group. Additionally, the authors did not find any significant difference between dippers and nondippers regarding their retrobulbar hemodynamic parameters. The results of our study found no differences in the OPA between dippers and nondippers with glaucoma, but found significant differences regarding the retrobulbar hemodynamic parameters. However, Karadag et al (8) evaluated healthy subjects, while our study studied patients with POAG. The lack of differences in the OPA between dippers and nondippers with glaucoma found in our study might be related to the fact that BP components including systolic and diastolic BP and ocular perfusion pressure (OPP) may be not the primary determinants of OPA or have any signiﬁcant effect on OPA. Furthermore, while Karadag et al (8) did not report differences regarding BP measurements between dippers and nondippers, our study found that the BP at night was significantly lower in the dippers group.

Our study found a significant correlation between the RI in the OA and some of the ABPM measurements in the dippers group but not in the nondippers group. This could be explained by the fact that 93% (71/76) and 70% (25/36) had early-stage POAG in the dippers and nondippers group, respectively. This might suggest that there is still some degree of autoregulation in these patients. The autoregulatory capacity may be exceeded in the dippers group but not in the nondippers group; this fact may explain the lack of correlation between the retrobulbar blood flow and the BP in the nondippers group.

Additionally, our study did not find any significant correlation between the OPA and the retrobulbar circulation in either dippers or nondippers.

In agreement with our results, Stalmans et al (25) found a significant relationship between the OPA and the RI in the retrobulbar vessels in healthy subjects, but not in glaucoma patients.

Conversely, Abegão Pinto et al (26), evaluating the correlation between retrobulbar blood flow velocities and OPA in glaucoma patients using CDI, found a significant relationship between OPA and retrobulbar CDI parameters not only in healthy subjects but also in patients with POAG. The differences with our study may be related to differences in methodology and study population.

Nevertheless, the results of our study are is in agreement with previous reports that have failed to prove any correlation between OPA and vascular systemic and ocular parameters in glaucoma patients (27).

Interestingly, our study also found that the EDV was significantly lower and the RI significantly higher in the SPCA and CRA in the dippers group. The superficial retinal nerve fiber layer (RNFL) is principally supplied by recurrent arterioles branching from the CRA, while the temporal RNFL may have an arterial contribution from the cilioretinal artery branch of the SPCA.

Although our previous studies, as well as other authors, did not find any correlation between the blood flow parameters in the CRA and glaucoma progression (17, 19, 20), other authors found that the hemodynamic parameters in the CRA may predict the progression of the glaucomatous damage (18, 28). The different designs and samples of the studies, as well as the different techniques used, make comparison of results difficult.

Our study has some limitations that should be taken into account. The first limitation is the fact that only a single measurement of IOP and CDI was performed. According to the published literature, it seems that 24-hour IOP and OPP fluctuations may have detrimental effects in glaucomatous eyes (29). However, not all centers have the facilities for performing 24-hour studies. That is why it would be important to identify the exact relationship among BP, IOP, OPP, and ocular blood flow, and the clinical relevance of the fluctuations of these parameters in glaucoma patients (29). Nevertheless, the purpose of our study was not to identify the role of the fluctuation of IOP, OPP, BP, or retrobulbar blood flow parameters on glaucoma progression, but rather to study a possible relationship between BP and retrobulbar hemodynamic parameters based on the BP pattern.

The second limitation results from the use of CDI for assessing the ocular hemodynamic parameters. Although this method has been used in many studies for evaluating retrobulbar circulation (8, 10, 17 -20, 23, 25), CDI measurements do not reflect blood volume, and only blood velocity can be estimated. Additionally, the measurement of the SPCA shows greater variability because the technical problems are greater. Nevertheless, all CDI measurements were performed by the same experienced user and it is well-known that the reliability and reproducibility of the CDI depends on the experience of the user (30). Another issue to consider is that the study was conducted in a Caucasian population with POAG. Appropriate caution is therefore recommended when extending the results to other populations.

Despite these limitations, our study suggests that retrobulbar blood flow parameters are impaired in patients with POAG with nocturnal BP dips as compared with those without nocturnal BP dips. On the other hand, the BP parameters were significantly correlated with the OA CDI parameters in the dippers group, suggesting that the autoregulatory capacity is exceeded in this group.

The clinical relevance of these findings depends on whether those patients with BP dips have a greater vulnerability for glaucoma progression.

Further studies are needed to elucidate the role of BP variations and their relationship with retrobulbar circulation in dipper/nondipper subjects, especially in patients with POAG, and the effect of these changes on glaucomatous optic nerve damage.

Footnotes

Financial support: No financial support was received for this submission.

Conflict of interest: None of the authors has conflict of interest with this submission.

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