Abstract
Purpose:
The study aimed to assess the effect of hypertension, and use of systemic beta blockers (BB) and other antihypertensives on ocular perfusion by optical coherence tomography angiography (OCTA) in normal, suspect, and glaucomatous eyes.
Methods:
Cross-sectional study in tertiary eye care center. Prospectively recruited consenting subjects between 18 and 90 years with or without glaucoma. Measured the optic nerve peripapillary perfusion and flux and macular vessel density (MVD: 6 × 6 and 3 × 3 mm) in the superficial retinal layer using OCTA.
Results:
Included 200 eyes (112 patients). Compared to nonhypertensives or those on non-BB antihypertensives (NBB), hypertensives on BB had lower peripapillary perfusion (43.45,43.40, 42.05%, P = 0.003), and MVD (6 × 6 mm: 16.65, 16.70,15.75 mm/mm2, P = 0.002; 3 × 3 mm: 18.70, 18.50, 18.00 mm/mm2, P = 0.025). Those on systemic BB with vasodilatory properties had similar perfusion parameters as nonhypertensives and NBB. Those on systemic BB without vasodilating properties had significantly lower peripapillary perfusion (42.05 vs 43.30%, P = 0.011) and MVD (6 × 6 mm: 15.15 vs 16.60 mm/mm2, P < 0.001; 3 × 3 mm: 17.40 vs 18.70 mm/mm2, P = 0.005) compared to nonhypertensives. On multivariate analysis, peripapillary perfusion increased with increase in diastolic blood pressure (β:0.051, p: 0.04) and increasing age was the only factor found to be significantly associated with decreased peripapillary and macular perfusion parameters.
Conclusion:
Systemic BB users have worse ocular perfusion parameters compared to those on other medications or nonhypertensives on univariate analysis but similar perfusion on multivariate analysis. Those on BB with vasodilation have better ocular perfusion parameters. All BB cannot be considered equally detrimental to ocular perfusion. Further well-controlled prospective studies are needed to reassess the effects of BB with or without vasodilation on ocular perfusion.
Keywords: Beta-blockers, glaucoma, hypertension, optical coherence tomography angiography, perfusion
Compensatory mechanisms in essential hypertension can affect the caliber as well as the density of small vessels and arterioles. An initial vasoconstriction of the vessels can occur as a response to hypertension in order to maintain uniform blood flow. Later, structural changes like the eutrophic remodeling of vessels can occur where there is reorganization of the existing smooth muscles in the media of the artery resulting in increased thickness of the media and at the same time a reduced lumen diameter as well as the external diameter of the artery.[1,2] Reduction in the number of perfused capillaries (functional rarefaction) can also occur followed by a reduction in the total number of interconnected arteries and capillaries further reducing perfusion.
The retinal arteries close to the disc belong to the category of small arteries (<350 µ) with a mean diameter of 136 µ, at 480 µ from the disc and 123 µ, at 1440 µ from the disc in healthy eyes.[3] Thus, hypertensive changes in retinal vessels are those seen in small arteries arterioles and capillaries. Medication can affect the caliber as well as affect the remodeling of the vessels in hypertensives. Antihypertensives like angiotensin receptor blockers (ARB) are known to reduce the remodeling of vessels beyond that expected by blood pressure (BP) control compared to systemic beta blockers (BB).[2] Additionally, systemic BB is known to reduce ocular perfusion.[4,5] However, not all systemic BB affect vessel caliber equally. Some cause vasodilation by partial alpha 1 receptor blockade (Carvedilol) or by other mechanisms like the release of nitric oxide (Nebivolol).[6]
As decreased ocular perfusion has been proposed as a mechanism for glaucoma, the effect of hypertension and medication in hypertensives becomes more important in patients with or predisposed to glaucoma.[7] Our study aimed to address these gray areas by exploring the macular and peripapillary retinal perfusion in hypertensives on BB versus those on other medications and nonhypertensives. Additionally, we looked at the effect of the use of systemic BB with vasodilatory properties in comparison to other antihypertensives. We also looked at the effect of medication on perfusion in normal and suspect and glaucomatous eyes.
Methods
The study adhered to the principles of the Declaration of Helsinki and the ethical committee clearance was obtained. Ours was a cross-sectional study with prospective recruitment of patients reporting to the glaucoma department of a tertiary eye care center from September 2019 to March 2020 after obtaining informed consent. Patients aged between 18 and 90 years with a best-corrected Snellen visual acuity (BCVA) of 6/18 or better were included. Glaucomatous and nonglaucomatous patients and glaucoma suspects were included in the study. Patients were excluded if there was the presence of other ocular comorbidities involving the optic nerve, macula, or retina that could potentially interfere with the acquisition or results of optical coherence tomography angiography (OCTA) or visual fields. Patients with surgeries other than glaucoma surgeries or uncomplicated cataract surgeries were excluded. Patients with multifocal intraocular lenses, those unable to do visual fields, or those with a history of stroke that could interfere with visual field results were also excluded. Unreliable fields (having >20% fixation loss or false negatives or >15% false positives) and OCTA showing a signal strength <6/10 or poor image quality from motion artifacts, media opacities, vitreous floaters, and decentration were also criteria for exclusion.
Willing patients fulfilling the inclusion and exclusion criteria were taken for the study after obtaining a signed informed consent. History of systemic and ocular illness and medication use was obtained from the patients and documented. The BCVA, intraocular pressure (IOP, Goldmann applanation tonometry), indentation gonioscopy, slit lamp anterior segment evaluation, and examination of the posterior segment with indirect ophthalmoscopy and 90 Diopter lenses were done. The BP was recorded (OMRON HBP-1300) prior to dilation with 1% tropicamide eye drop. Following dilation, optical coherence tomography (OCT) and OCTA disc and macula were acquired (CIRRUS HD-OCT 5000 with AngioPlex OCT Angiography; Zeiss, Dublin, California, USA). The average as well as sector-wise retinal nerve fiber layer (RNFL) thickness and macular ganglion cell+ inner plexiform layer thickness was assessed on OCT. Four parameters were assessed on OCTA. Optic nerve head (ONH) radial peripapillary capillary perfusion (density of vessels) and flux index (total area of perfused vasculature per unit area in a region of interest) and the macular vessel density in the superficial retinal layer measured with the 6 × 6 and 3 × 3 OCTA scans were the ocular perfusion parameters measured and used for analysis. Visual fields were assessed with Humphrey visual fields (HVF) 24-2 (HFA3 850, Carl Zeiss Meditec, Dublin, CA) Swedish Interactive Threshold Algorithm (SITA) standard in all glaucoma patients and 24-2 SITA Faster or SITA standard in normal patients and glaucoma suspects and the mean deviation (MD) noted. Glaucomatous eyes were defined as those with optic nerve head and RNFL findings clinically suggestive of glaucoma with corresponding glaucomatous changes on HVF 24-2 SITA standard. For the purpose of analysis, the normal eyes, i.e., eyes without any ocular disease other than cataract and primary angle closure suspect (PACS) eyes were categorized as “normal”. The “diseased” group included the suspect and glaucoma eyes. The suspect category included the primary angle closure (PAC), ocular hypertension, and disc suspect eyes. The impact of antihypertensive medication on OCTA parameters was assessed overall and within each glaucoma disease category.
Statistical analysis
Descriptive statistics were obtained for continuous variables and frequency distribution was calculated for qualitative variables. Histogram and Kolmogorov–Smirnov test were used to determine the normality of data. Chi-square test was used to determine the difference in distribution of categorical variables. Kruskal–Wallis and Mann–Whitney tests were used to find the difference in median ranks between groups with nonparametric data. Multivariate analysis was done using linear mixed model analysis. Any statistical test with a P value less than 0.05 was considered as significant. All statistical tests were performed using SPSS V 20.0.
We did a post-hoc analysis using G*power (version 3.1.9.6; Heinrich–Heine–Universität Düsseldorf, Düsseldorf, Germany) for power calculation and effect size using data from peripapillary OCTA keeping alpha error of 0.05 and total sample size 195 and 3 groups. The effect size calculated was 0.24 and the power of the test was 85.2%.
Results
Two hundred eyes of 112 patients were included. Five patients were hypertensives with missing antihypertensive medication data and were excluded from analysis. Table 1 shows the demographic and ocular characteristics of the study population. Nonhypertensives were significantly younger than hypertensives on BB or other medications (median age 54 versus 65 and 63 years, <0.001). The median HVF MD was similar (P = 0.136) among the nonhypertensives (−3.06 dB, interquartile range (IQR): −5.76 to −1.85 db), hypertensives on BB (−4.22 db, IQR: −7.21 to − 1.99 dB) and hypertensives on other medication (−4.22, IQR: −5.56 to −1.41 dB) groups [Table 1].
Table 1.
Patient characteristics
| Non hypertensives (104) | Hypertensives on BB (44) | Hypertensives on other medication (47) | P | |
|---|---|---|---|---|
| Distribution: Percentage (n) | ||||
| Gender | 0.455 | |||
| Females | 40% (42) | 30% (13) | 36% (17) | |
| Males | 60% (62) | 71% (31) | 64% (30) | |
| Category: | 0.002 | |||
| Normal | 38% (39) | 11% (5) | 43% (20) | |
| Suspect and glaucoma | 63% (65) | 89% (39) | 57% (27) | |
| Characteristics: Median (IQR) | ||||
| Age (Years) | 54 (45–60) | 65 (55–71) | 63 (56–68) | <0.001 |
| Systolic BP (mmHg) | 130 (121–140) | 134 (128–148) | 134 (123–148) | 0.164 |
| Diastolic BP (mmHg) | 80 (70–82) | 73 (70–80) | 78 (72–84) | 0.034 |
| IOP (mmHg) | 16 (14–18) | 15 (13–17) | 16 (13–18) | 0.273 |
| Ocular perfusion pressure (mmHg) | 48 (43–52) | 50 (46–53) | 49 (43–55) | 0.408 |
| HVF MD (dB) | −3.06 (−5.76– −1.85) | −4.22 (−7.21– −1.99) | −3.08 (−5.56– −1.41) | 0.136 |
| Average RNFL thickness (µ) | 82 (68–93) | 77 (63–85) | 86 (74–93) | 0.024 |
BB: Beta blockers, BP: blood pressure, IQR: Interquartile range, IOP: Intraocular pressure, HVF MD: Humphrey visual field mean deviation, dB: Decibels, RNFL: Retinal nerve fiber layer, ONH: optic nerve head
For the purpose of analysis, we also included PACS eyes in the normal group. We expected them to have similar vascular parameters on OCTA, which was found to be true on analysis (normal vs PACS median values: ONH perfusion − 44.25 vs 44.60%, P = 0.984; ONH flux – 0.42 vs 0.41, P = 0.501; 6 × 6 m macular vessel density – 16.75 vs 16.75 mm/mm2, P = 0.488; 3 × 3 mm macular vessel density P 18.95 vs 18.70 mm/mm2, P = 0.676).
The median perfusion parameters and univariate analysis in all eyes and subdivided according to glaucoma disease category (normal vs suspect and glaucoma) are shown in Table 2. Factors studied include hypertensive status, antihypertensive use, use of calcium channel blockers (CCB) or angiotensin-converting enzyme (ACE) inhibitors and ARB.
Table 2.
Univariate analysis - Hypertensive status and antihypertensive use with median and interquartile range
| Factor (eyes) | ONH perfusion (%) | ONH flux | 6 × 6 mm macula (mm/mm2) | 3 × 3 mm macula (mm/mm2) | ||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|||||
| Median (IQR) | P | Median (IQR) | P | Median (IQR) | P | Median (IQR) | P | |
| ALL EYES | ||||||||
| Hypertension | 0.059 | 0.038 | 0.005 | 0.013 | ||||
| Yes (104) | 42.90 | 0.39 | 16.30 | 18.20 | ||||
| (40.60–44.20) | (0.35–0.42) | (14.25–17.00) | (16.90–19.10) | |||||
| No (95) | 43.45 | 0.40 | 16.65 | 18.70 | ||||
| (41.23–45.08) | (0.37–0.43) | (15.50–17.60) | (17.33–19.70) | |||||
| Hypertension and medication used | 0.003 | 0.055 | 0.002 | 0.025 | ||||
| Hypertensives not on systemic BB (47) | 43.40 | 0.41 | 16.70 | 18.50 | ||||
| (41.80–44.60) | (0.36–0.42) | (15.85–17.20) | (17.20–19.20) | |||||
| Hypertensives on systemic BB (44) | 42.05 | 0.39 | 15.75 | 18.00 | ||||
| (38.25–43.80) | (0.35–0.40) | (13.73–16.78) | (16.23–19.00) | |||||
| Non hypertensives (104) | 43.45 | 0.40 | 16.65 | 18.70 | ||||
| (41.23–45.08) | (0.37–0.43) | (15.50–17.60) | (17.33–19.70) | |||||
| CCB use in hypertensives | 0.628 | 0.543 | 0.307 | 0.685 | ||||
| Yes (41) | 42.50 | 0.40 | 16.10 | 17.60 | ||||
| (40.95–44.15) | (0.36–0.41) | (14.00–16.80) | (16.80–19.10) | |||||
| No (54) | 43.15 | 0.39 | 16.40 | 18.45 | ||||
| (40.50–44.33) | (0.34–0.42) | (14.95–17.08) | (16.90–19.03) | |||||
| ACE inhibitor use in hypertensives | 0.149 | 0.709 | 0.015 | 0.429 | ||||
| Yes (51) | 43.40 | 0.39 | 16.70 | 18.50 | ||||
| (40.80–44.40) | (0.36–0.42) | (15.35–17.15) | (16.90–19.10) | |||||
| No (44) | 42.45 | 0.39 | 15.95 | 17.60 | ||||
| (39.53–44.08) | (0.34–0.41) | (13.50–16.70) | (16.83–19.08) | |||||
| NORMAL EYES | ||||||||
| Hypertension | 0.056 | 0.356 | 0.280 | 0.393 | ||||
| No (39) | 44.70 | 0.42 | 16.70 | 19.00 | ||||
| (43.70–45.80) | (0.39–0.45) | (15.50–18.00) | (17.30–20.00) | |||||
| Yes (25) | 44.00 | 0.42 | 16.80 | 18.60 | ||||
| (42.95–45.15) | (0.39–0.43) | (15.85–17.00) | (17.45–19.40) | |||||
| Hypertension and medication used | 0.034 | 0.617 | 0.481 | 0.223 | ||||
| Hypertensives not on systemic BB (20) | 44.30 | 0.42 | 16.80 | 18.70 | ||||
| (43.33–45.73) | (0.40–0.43) | (16.40–17.00) | (17.80–19.63) | |||||
| Hypertensives on systemic BB (5) | 43.00 | 0.40 | 16.10 | 17.30 | ||||
| (40.75–44.15) | (0.36–0.44) | (13.80–17.20) | (15.95–18.80) | |||||
| Non hypertensives (39) | 44.70 | 0.42 | 16.70 | 19.00 | ||||
| (43.70–45.80) | (0.39–0.45) | (15.50–18.00) | (17.30–20.00) | |||||
| CCB use in hypertensives | 0.832 | 0.090 | 0.466 | 0.154 | ||||
| Yes (7) | 44.00 | 0.43 | 16.80 | 18.40 | ||||
| (43.30–45.10) | (0.41–0.44) | (12.70–16.90) | (16.70–19.10) | |||||
| No (18) | 43.85 | 0.41 | 16.80 | 18.70 | ||||
| (42.85–45.40) | (0.38–0.42) | (16.20–17.08) | (17.60–19.70) | |||||
| ACE inhibitor use in hypertensives | 0.739 | 0.292 | 0.042 | 0.005 | ||||
| Yes (15) | 44.10 | 0.41 | 17.00 | 19.00 | ||||
| (43.00–45.20) | (0.39–0.42) | (16.50–17.30) | (18.50–19.70) | |||||
| No (10) | 43.90 | 0.43 | 16.25 | 17.45 | ||||
| (42.43–45.30) | (0.39–0.44) | (12.60–16.83) | (16.58–18.65) | |||||
| SUSPECT AND GLAUCOMA EYES | ||||||||
| Hypertension | 0.858 | 0.218 | 0.011 | 0.021 | ||||
| No (65) | 42.20 | 0.38 | 16.60 | 18.40 | ||||
| (39.70–44.50) | (0.35–0.42) | (15.50–17.50) | (17.25–19.55) | |||||
| Yes (70) | 42.30 | 0.38 | 16.05 | 18.05 | ||||
| (39.38–43.95) | (0.34–0.40) | (14.03–-17.00) | (16.38–19.00) | |||||
| Hypertension and medication used | 0.289 | 0.433 | 0.007 | 0.096 | ||||
| Hypertensives not on systemic BB (27) | 42.90 | 0.36 | 16.30 | 18.20 | ||||
| (41.30–43.80) | (0.33–0.42) | (15.30–17.30) | (16.90–18.80) | |||||
| Hypertensives on systemic BB (39) | 42.00 | 0.39 | 15.70 | 18.00 | ||||
| (38.10–-43.90) | (0.35–0.40) | (13.70–16.70) | (16.30–19.00) | |||||
| Non hypertensives (65) | 42.20 | 0.38 | 16.60 | 18.40 | ||||
| (39.70–44.50) | (0.35–0.42) | (15.50–17.50) | (17.25–19.55) | |||||
| CCB use in hypertensives | 0.897 | 0.356 | 0.745 | 0.617 | ||||
| Yes (34) | 42.30 | 0.39 | 15.95 | 17.60 | ||||
| (39.38–44.10) | (0.35–0.41) | (14.10–16.73) | (16.80–19.20) | |||||
| No (36) | 42.50 | 0.38 | 16.05 | 18.20 | ||||
| (39.13–43.88) | (0.32–0.40) | (13.93–17.10) | (15.73–18.88) | |||||
| ACE inhibitor use in hypertensives | 0.267 | 0.685 | 0.167 | 0.553 | ||||
| Yes (36) | 43.10 | 0.39 | 16.10 | 18.20 | ||||
| (40.50–44.10) | (0.34–0.41) | (14.08–17.13) | (16.13–18.88) | |||||
| No (34) | 41.95 | 0.38 | 15.70 | 17.80 | ||||
| (39.08–43.28) | (0.33–0.40) | (13.70–16.63) | (16.88–19.20) | |||||
IQR: Interquartile range, BB: beta blocker, CCB: Calcium channel blocker, ACE: Angiotensin converting enzyme
Hypertensive status: Hypertensives had lower ONH flux (0.39 vs 0.40, P = 0.038), 6 × 6 mm (16.30 vs 16.65 mm/mm2, P = 0.005), and 3 × 3 mm (18.20 vs 18.70 mm/mm2, P = 0.013) macular vessel density compared to nonhypertensives when assessing all eyes [Table 2]. Suspect and glaucomatous eyes of hypertensives had a significantly lower 6 × 6 mm (16.05 vs 16.60 mm/mm2, P = 0.011) and 3 × 3 mm (18.05 vs 18.40 mm/mm2, P = 0.021) macular vessel density compared to nonhypertensives.
Type of antihypertensive: When assessing the effect of the type of antihypertensive used on perfusion parameters in all eyes, a significant difference was noted in ONH perfusion (P = 0.003) and macular vessel density parameters (6 × 6 mm P = 0.002, 3 × 3 mm P = 0.025, Table 2).
There was a significant difference in the age of the participants (P < 0.001, Table 1) when comparing nonhypertensive, hypertensives on BB, and hypertensives on other medications. However, there was no significant difference in age of the hypertensive group on systemic BB versus those on other medications (median age 65 vs 63 years, P = 0.375).
On doing a paired subanalysis according to the category of antihypertensives used, the eyes of patients on antihypertensives other than systemic BB had similar perfusion values as the nonhypertensives when assessing all eyes as well as the normal and the suspect and glaucoma categories. On comparing the eyes of those in systemic bb versus nonhypertensive groups, in the normal as well as suspect and glaucoma categories, significant differences were seen. In the normal category, compared to nonhypertensives, those on systemic BB had reduced ONH perfusion (43.00 vs 44.70%, P = 0.013). In the suspect and glaucoma category, compared to nonhypertensives, those on systemic BB reduced macular vessel density parameters in (6 × 6 mm − 15.70 vs 16.60 mm/mm2, P = 0.003, 3 × 3 mm − 18.00 vs 18.40 mm/mm2, P = 0.046).
When comparing those hypertensives on BB versus those on other medication, the median HVF MD (−4.22 vs −3.08 dB, P = 0.115) and age (65 vs 63 yrs, P = 0.375) were similar on assessing all eyes. The median HVF MD was also similar among the two groups in the normal (−1.66 vs −1.82 dB, P = 0.541) and the suspect and glaucoma categories (−5.15 vs −4.27 dB, P = 0.804) also. The median age was significantly different with overlap in IQR. Hypertensives on BB were significantly younger than those on other medication in the normal category (51 vs 64.5 yrs, IQR: 45–61 vs 61.5–69 yrs, P = 0.008) and significantly older in the suspect and glaucoma categories (65 vs 60 yrs, IQR: 57–72 vs 55-67 yrs, P = 0.042). On assessing perfusion, in the suspect and glaucoma categories, reduced 6 × 6 mm macular vessel density was seen in the eyes of those on systemic BB compared to those on other antihypertensives (15.70 vs 16.30 mm/mm2, P = 0.026).
Use of systemic betablocker with versus without vasodilation: The perfusion parameters of the eyes of patients on BB with vasodilation versus those on BB without vasodilation or those on other antihypertensives are shown in Tables 3 and 4. The eyes of patients on BB with vasodilatory properties had similar perfusion parameters as those of nonhypertensives [Tables 3 and 4].
Table 3.
Comparison of ocular perfusion parameters in hypertensives on beta blockers with or without vasodilating properties
| Factor (eyes) | ONH perfusion (%) | ONH flux | 6×6 mm macula (mm/mm2) | 3×3 mm macula (mm/mm2) | ||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|||||
| Median (IQR) | P | Median (IQR) | P | Median (IQR) | P | Median (IQR) | P | |
| ALL EYES | ||||||||
| Medication use - antihypertensive | 0.028 | 0.265 | 0.006 | 0.022 | ||||
| Systemic BB no vasodilation (34) | 42.05 | 0.40 | 15.15 | 17.40 | ||||
| (39.08–43.68) | (0.35–0.41) | (13.65–16.70) | (15.85–19.03) | |||||
| Systemic BB with vasodilation (10) | 43.65 | 0.39 | 16.60 | 18.70 | ||||
| (37.70–44.30) | (0.34–0.41) | (15.68–17.15) | (18.08–19.73) | |||||
| On other antihypertensives (57) | 43.40 | 0.40 | 16.50 | 18.50 | ||||
| (41.85–44.85) | (0.36–0.42) | (14.80–17.20) | (17.05–19.15) | |||||
| Not hypertensive (99) | 43.30 | 0.39 | 16.60 | 18.70 | ||||
| (40.90–45.00) | (0.37–0.43) | (15.55–17.55) | (17.30–19.70) | |||||
ONH: Optic nerve head, IQR: Interquartile range, BB: Beta blocker
Table 4.
Comparison of ocular perfusion parameters in all eyes according to systemic antihypertensive use
| Factor |
P
|
|||
|---|---|---|---|---|
| ONH perfusion | ONH flux | 6×6 mm | 3×3 mm | |
| ALL EYES | ||||
| BB with vasodilating properties vs non hypertensives | 0.395 | 0.219 | 0.596 | 0.596 |
| BB without vasodilation vs non hypertensives | 0.011 | 0.129 | <0.001 | 0.005 |
| BB with vs without vasodilation | 0.747 | 0.547 | 0.075 | 0.036 |
| BB with vasodilation vs antihypertensives other than BB | 0.423 | 0.338 | 1.000 | 0.205 |
| BB without vasodilation vs antihypertensives other than BB | 0.003 | 0.178 | 0.026 | 0.167 |
| Non BB antihypertensive vs non hypertensive | 0.582 | 0.431 | 0.241 | 0.128 |
ONH: Optic nerve head, BB: Beta blockers, vs: Versus
Though not always statistically significant, the eyes of patients on BB without vasodilating properties mostly showed lower ocular perfusion parameters compared to those on BB with vasodilation across all groups. When assessing all eyes, those on BB without vasodilation had significantly lower macular 3 × 3 mm vessel density compared to those on BB with vasodilation (P = 0.036).
In the suspect and glaucoma group, the eyes of those on systemic BB with vasodilation had similar parameters to those on systemic BB without vasodilation. However, in comparison to the eyes of patients on systemic BB without vasodilation, those on BB with vasodilation had significantly worse visual fields (median HVF MD −4.12 vs −8.99 dB, P = 0.042). Compared to nonhypertensives, the eyes of patients on BB without vasodilating properties had significantly lower ONH perfusion (43.30 vs 42.05%, p=0.011), 3 × 3 mm (18.70 vs 17.40 mm/mm2, p=0.005), and 6 × 6 mm (16.60 vs 15.15 mm/mm2, p<0.001) macular vessel density when assessing all eyes [Table 4].
Multivariate analysis: In multivariate analysis of factors found significant in univariate analysis, increasing age was the only factor found to be significantly associated with decreased peripapillary and macular perfusion parameters [Table 5]. Significantly better peripapillary perfusion and flux were also seen in the normal group compared to the suspect and glaucoma group. Additionally, increased diastolic BP was associated with better peripapillary perfusion.
Table 5.
Significant factors affecting peripapillary and macular perfusion on multivariate analysis
| Independent parameter | ẞ | 95% CI | P |
|---|---|---|---|
| ONH perfusion | |||
| Normal and PACS eyes | 2.234 | 1.352 to 3.116 | <0.001 |
| Age | −0.040 | −0.072 to−0.007 | 0.016 |
| Diastolic BP | 0.051 | 0.002 to 0.100 | 0.040 |
| ONH flux | |||
| Normal and PACS eyes | 0.028 | 0.014 to 0.041 | <0.001 |
| Age | −0.001 | −0.002 to-0.001 | <0.001 |
| 6×6 mm macula | |||
| Age | −0.036 | −0.065 to−0.008 | 0.013 |
| 3×3 mm macula | |||
| Age | −0.038 | −0.061 to−0.016 | 0.001 |
CI: Confidence interval, ONH: Optic nerve head peripapillary, PACS: primary angle closure suspect, BP: Blood pressure; *Factors found significant on univariate analysis – type of antihypertensive use, disease category (normal and PACS vs suspect and glaucoma), age, diastolic BP were included in the model during multivariate analysis
Discussion
Since the development of the vascular theory for glaucoma, several systemic and ocular factors affecting the ocular blood flow have been studied for their association with glaucoma and its progression. Systemic factors like stroke, aging, systemic hypertension, and migraine have been found to be associated with the progression of normal tension glaucoma.[8]
Our study focused on the superficial retinal layer in the macula and the superficial retinal peripapillary vessels around the optic nerve head as these are more prominently affected in glaucoma.[9]
PACS patients by definition do not have structural or functional disc damage or elevated IOP. We, thus, expected them to have similar vascular parameters on OCTA, which was found to be true on analysis. Hence, they were combined together in the normal group to compare with perfusion parameters of eyes in the suspect and glaucoma categories. Though we have analyzed suspect and glaucoma eyes together, as the suspect group is a heterogenous group consisting of PAC, ocular hypertensives, and disc suspect eyes, it is, therefore, possible that we may also have a few normal eyes and eyes with preperimetric glaucoma in this category.
Chua et al.[5] studied eyes of hypertensives without other ocular disease and found there was a significant reduction in capillary density in macular deep vascular plexus in patients with poorly controlled BP (>140/90) and higher ambulatory BP. However, there was no effect of these factors on the superficial vascular plexus. This is unlike our univariate analysis results where we had reduced ocular perfusion parameters in hypertensives compared to nonhypertensives similar to the results by Hua et al.[10] and in a metanalysis by Tan et al.[11] Our study included glaucoma patients and suspects which may partly explain this difference.
Thom et al.[12] studied fundus photographs of hypertensives and noted that those on amlodipine had a smaller arteriolar length: diameter ratio compared to those on atenolol, which was attributed to the vasodilatory effect of amlodipine causing visible emergence of branching side vessels. Our results did not show any difference in ocular perfusion between CCB users versus nonusers. Peng et al.[13] noted better superficial vascular plexus perfusion in those hypertensives on a combination of CCB and ACE inhibitors/ARB versus those on monotherapy. We noted better macular perfusion in the superficial plexus in those on ACE inhibitors/ARB blockers compared to those on other antihypertensives.
Our study showed hypertensives and hypertensives on systemic BB had reduced median ocular perfusion parameters compared to nonhypertensives and those on other medication when assessing all eyes. This effect of systemic BB on ocular perfusion is similar to the results of Madej et al.[14] where they found a significantly lower peak systolic and diastolic velocity as well as increased resistance index in patients after intake of oral bisoprolol but no significant difference was found after intake of cilazapril on Doppler ultrasonography of the central retinal artery. An interesting finding in our study was that the eyes of hypertensives on BB with vasodilatory properties like nebivolol and carvedilol did not have a statistically significant difference in ocular perfusion parameters compared to those of nonhypertensives when assessing all eyes as well as in the subgroup (normal and diseased, i.e., suspect and glaucoma) analysis. This must be kept in mind when taking medication history in patients and all BB cannot be considered equally detrimental to ocular perfusion. When assessing the BB without versus with vasodilation, better ocular perfusion parameters were seen across all groups in those on BB with vasodilation except in the suspect and glaucomatous eyes category where reduced ONH perfusion parameters were seen. Part of the reason could be the worse HVF MD (and, therefore, more advanced disease) in patients on systemic BB with vasodilation compared to those on other BB in the suspect and glaucoma group. Though nonvasodilatory BB generally had lower values, a significantly reduced perfusion was seen only in the 3 × 3 mm macular vessel density of all eyes. These results cannot be directly extrapolated as this study is not sufficiently powered to assess this outcome due to the small sample size of those on vasodilatory BB. However, the relatively better perfusion parameters despite worse MD seems promising.
Multivariate analysis showed similar ocular perfusion parameters irrespective of antihypertensive use. Increasing age was also found to cause a decrease in all ocular perfusion parameters. The slightly higher age in hypertensives on systemic BB compared to those on other antihypertensives in the suspect and glaucoma group may have partly been responsible for decreased perfusion values on univariate analysis. Future studies with a larger sample size in the subgroups can give a clearer picture regarding this.
A strength of this study is that we assessed the effect of different categories of systemic antihypertensives on ocular perfusion. However, the presence of systemic disease and medication use was either self-reported by the patients or obtained from any medical records they may have had. A section of undiagnosed patients may have been missed by this method. This being a cross-sectional study we were also unable to assess the effect on causation and progression of glaucoma by the factors studied.
Conclusion
Systemic BB users have worse ocular perfusion parameters compared to those on other medications or nonhypertensives on univariate analysis but similar perfusion on multivariate analysis. Those on BB with vasodilation have better ocular perfusion parameters. All BB cannot be considered equally detrimental to ocular perfusion. Further well-controlled prospective studies are needed to reassess the effects of BB with or without vasodilation on ocular perfusion. Future studies can help assess the risk of the contributory factors for different individuals and, accordingly, the need to modify the systemic and ocular medication.
Financial support and sponsorship:
Nil.
Conflicts of interest:
There are no conflicts of interest.
References
- 1.Heagerty AM, Heerkens EH, Izzard AS. Small artery structure and function in hypertension. J Cell Mol Med. 2010;14:1037–43. doi: 10.1111/j.1582-4934.2010.01080.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Laurent S, Boutouyrie P. The structural factor of hypertension: Large and small artery alterations. Circ Res. 2015;116:1007–21. doi: 10.1161/CIRCRESAHA.116.303596. [DOI] [PubMed] [Google Scholar]
- 3.Goldenberg D, Shahar J, Loewenstein A, Goldstein M. Diameters of retinal blood vessels in a healthy cohort as measured by spectral domain optical coherence tomography. Retina. 2013;33:1888–94. doi: 10.1097/IAE.0b013e31829477f2. [DOI] [PubMed] [Google Scholar]
- 4.Chua J, Chin CWL, Tan B, Wong SH, Devarajan K, Le TT, et al. Impact of systemic vascular risk factors on the choriocapillaris using optical coherence tomography angiography in patients with systemic hypertension. Sci Rep. 2019;9:5819.. doi: 10.1038/s41598-019-41917-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Chua J, Chin C, Hong J, Chee ML, Le TT, Ting DSW, et al. Impact of hypertension on retinal capillary microvasculature using optical coherence tomographic angiography. J Hypertens. 2019;37:572–80. doi: 10.1097/HJH.0000000000001916. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Katzung B, Masters S, Trevor A. New York: McGraw-Hill Medical; 2009. Basic and Clinical Pharmacology. [Google Scholar]
- 7.Flammer J, Orgul S. Optic nerve blood-flow abnormalities in glaucoma. Prog Retin Eye Res. 1998;17:267–89. doi: 10.1016/s1350-9462(97)00006-2. [DOI] [PubMed] [Google Scholar]
- 8.Ernest PJ, Schouten JS, Beckers HJ, Hendrikse F, Prins MH, Webers CA. An evidence-based review of prognostic factors for glaucomatous visual field progression. Ophthalmology. 2013;120:512–9. doi: 10.1016/j.ophtha.2012.09.005. [DOI] [PubMed] [Google Scholar]
- 9.Rao HL, Pradhan ZS, Suh MH, Moghimi S, Mansouri K, Weinreb RN. Optical coherence tomography angiography in glaucoma. J Glaucoma. 2020;29:312–21. doi: 10.1097/IJG.0000000000001463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hua D, Xu Y, Zeng X, Yang N, Jiang M, Zhang X, et al. Use of optical coherence tomography angiography for assessment of microvascular changes in the macula and optic nerve head in hypertensive patients without hypertensive retinopathy. Microvasc Res. 2020;129:103969.. doi: 10.1016/j.mvr.2019.103969. [DOI] [PubMed] [Google Scholar]
- 11.Tan W, Yao X, Le TT, Tan ACS, Cheung CY, Chin CWL, et al. The application of optical coherence tomography angiography in systemic hypertension: A meta-analysis. Front Med (Lausanne) 2021;8:778330.. doi: 10.3389/fmed.2021.778330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Thom S, Stettler C, Stanton A, Witt N, Tapp R, Chaturvedi N, et al. Differential effects of antihypertensive treatment on the retinal microcirculation: An anglo-scandinavian cardiac outcomes trial substudy. Hypertension. 2009;54:405–8. doi: 10.1161/HYPERTENSIONAHA.109.133819. [DOI] [PubMed] [Google Scholar]
- 13.Peng Q, Hu Y, Huang M, Wu Y, Zhong P, Dong X, et al. Retinal neurovascular impairment in patients with essential hypertension: An optical coherence tomography angiography study. Invest Ophthalmol Vis Sci. 2020;61:42.. doi: 10.1167/iovs.61.8.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Madej A, Gierek-Ciaciura S, Haberka M, Madej JL, Basiak M, Domanska O, et al. Effects of bisoprolol and cilazapril on the central retinal artery blood flow in patients with essential hypertension—preliminary results. Ups J Med Sci. 2010;115:249–52. doi: 10.3109/03009734.2010.487951. [DOI] [PMC free article] [PubMed] [Google Scholar]