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Glaucoma and Blood Pressure

Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.118.11507Hypertension. 2019;73:944–950

Arterial hypertension and glaucoma are age-related conditions, and their prevalence is expected to rise in the coming years. Because these conditions are common and age-related, with race playing a major risk factor, they can often coexist.1 There are complex interactions between blood pressure (BP), intraocular pressure (IOP), and ocular perfusion pressure (OPP), which is the difference between mean BP and IOP. This brief review focuses on the role of BP, whether high or low, in the prevalence and in the progression of glaucoma.

We searched the databases of MEDLINE and EMBASE, as well as the reference lists of the retrieved articles, up to 2018. Key words were “glaucoma,” blood pressure,” “nocturnal pressure,” “ocular perfusion pressure,” “antihypertensive.” We privileged systematic reviews, meta-analysis, and the most recent articles.

Glaucoma: Pathophysiology and Treatment

Glaucoma is a leading cause of blindness, and visual impairment and the leading cause of irreversible blindness worldwide, with >60 million people affected.2 The common denominator of glaucomatous optic neuropathy is the loss of axonal nerve fibers and the death of retinal ganglion cells in the inner nuclear layer. Primary open-angle glaucoma (POAG), the most common type of glaucoma, is a chronic, progressive optic neuropathy with characteristic morphological changes at the optic nerve head and retinal nerve fiber layer in the absence of other ocular disease or congenital anomalies. Progressive retinal ganglion cell death and visual field (VF) loss are associated with these changes.3 The axons of the retinal ganglion cells form the nerve fiber layer and leave the eye through the cribriform plate in the sclera forming the optic disc. The central portion of the disc contains no axonal nerve fibers and is called the cup or the excavation. The rim of neuroretinal tissue around the cup contains the axons. Comparing the size of the cup to the overall diameter of the disc (cup-to-disc ratio) allows the observer to quantify the amount of excavation (Figure 1). Deepening and widening of the cup (pathological excavation) is the characteristic morphological change in POAG. It is the result of the loss of retinal ganglion cell axons and of deformation and remodeling of connective tissue. Because loss of the retinal ganglion cell is associated with thinning of the retinal nerve fiber layer, measurement of the thickness of this layer by means of optical coherence tomography is one of the most common methods to diagnose structural glaucomatous damage (Figure 2). The characteristic functional defects in glaucoma are detected by measuring light sensitivity in the central 24° to 30° of the VF by means of standard automated perimetry: static computerized threshold perimetry of the central VF performed with white stimuli on a dimmer white background (Figure 3). The diagnosis of POAG is based on the presence of characteristic structural or functional defects. The definition of POAG does not include IOP because the disease occurs as well in patients with elevated IOP, the so-called high-pressure glaucoma, as in patients with IOP within the normal range, the so-called normal-tension glaucoma (NTG). Nowadays, elevated IOP is defined as a major risk factor for the development and the progression of glaucomatous optic neuropathy and not as a diagnostic biomarker as was done several decades ago.

Figure 1.

Figure 1. Normal and glaucomatous optic discs. Left, A normal disc with a physiological excavation surrounded by a healthy neuroretinal rim. Right, A completely excavated disc with no neuroretinal rim left as seen in end-stage glaucoma.

Figure 2.

Figure 2. Optical coherence tomography (OCT) scans in a healthy subject and in a subject with glaucoma. Left, A circular OCT of the retina surrounding the optic nerves of right and left eye in a healthy person. The green circle in the upper part of the outprint indicates the anatomic site of the measurement. Below is a linear projection of the actual retinal scan. The retinal nerve fiber layer is the area between the green and the red lines. Below the scan is a linear presentation from the temporal to the nasal side of the thickness of the retinal nerve fiber layer (represented by a bold black line) compared with a normal database: the green area includes normal values, the yellow area is borderline and the red is outside normal limits. A more familiar circular presentation is provided in the lower part of the outprint. Right, The thinning of the nerve fiber layer illustrates the structural damage observed in advanced glaucoma. Note the advanced cupping in the more affected left eye. OCT indicates optical coherence tomography; OD, oculus dexter (right eye); and OS, oculus sinister (left eye).

Figure 3.

Figure 3. Functional damage is demonstrated by the automated visual fields. Left, Normal visual fields in a healthy person. Right, Visual fields in a patient with advanced glaucoma showing deep scotomata in the superior hemifields and typical glaucomatous field defects in the lower hemifields in both eyes. CO indicates corrected; MD, mean defect; MS, mean sensitivity; OD, oculus dexter (right eye); OS, oculus sinister (left eye); and sLV, square root of loss variance.

Once the diagnosis is established, comparison of repeat examinations of retinal nerve fiber layer thickness and VFs with the baseline values will indicate whether the disease is stable or progressive. If progressive, plotting nerve fiber thinning and loss of visual sensitivity against time will give an idea of the speed at which the glaucomatous process advances, the so-called rate of progression. Rate of progression has important implications: patients who are rapid progressors especially those with a long life expectancy need more aggressive therapy as they are more likely to become functionally impaired within their lifetime than slow progressors.

The cause of POAG is unknown, but genetic factors play a role because first degree relatives of a patient with confirmed POAG are at a higher risk of having the disease.4 The disease is unusual under the age of 50 years but has a prevalence of 1.4% in white people at age 60 years and 5.3% at age 80 years. Ethnicity plays a role as the prevalence is several times higher in Americans of African ancestry and Afro-Caribbeans than in whites. The prevalence in Latinos at age 60 years is 2.7%, intermediate between whites and Afro-Caribbeans, but rises to 12.7% at age 80 years.5

In parallel, black populations exhibit a greater prevalence of systemic hypertension, develop symptoms of hypertension at a younger age, and experience more severe organ damage compared to other races and ethnicities. Systemic hypertension is higher among non-Hispanic black (40.3 %) than non-Hispanic white (27.8 %), non-Hispanic Asian (25.0 %), or Hispanic (27.8 %) adults.6 Overall, the percentage of cardiovascular events attributable to hypertension is 36 % in black and 21 % in white populations.7 Hence, projects are developed to improve BP control, for example in the high-risk Caribbean region.8

The pathogenesis of glaucoma is incompletely understood, but the death of axons grouped together at the optic disc implies that this anatomic area is primarily involved. The typical excavation is the result of deformation and remodeling of the connective tissue of the optic nerve head. Axonal injury at this site results in interruption of axonal transport and subsequent death of the ganglion cells in the inner nuclear layer of the retina. Initial ganglion cell death promotes a toxic environment leading to secondary retinal ganglion cell ganglion loss.9,10 The mechanical theory focuses on the role of elevated IOP as the direct or indirect cause of nerve fiber damage at the level of the optic nerve head. The vascular theory emphasizes the importance of vascular perfusion of the optic nerve head and considers glaucomatous optic neuropathy to be the result of unstable blood supply of the optic nerve head due either to vascular dysregulation or to increased IOP, as will be discussed later.11 Both pathogenic pathways probably contribute to cause glaucomatous damage in the same patient, but it seems plausible that mechanical damage is preponderant in patients with high pressure, whereas vascular dysregulation may be the key culprit in normal pressure glaucoma.

The diagnosis of POAG is based on the detection of characteristic structural (excavation of the optic disc and thinning of the retinal never fiber layer) and functional defects (glaucomatous VF defects). Once the diagnosis is established, the only therapeutic option is IOP reduction both in patients with elevated IOP and in patients with IOP within the normal range. A target pressure is calculated taking into account IOP and severity of glaucoma at presentation, life expectancy, and if available, rate of progression of the glaucomatous process. Target IOP is the upper limit of the IOP estimated to be compatible with a rate of progression sufficiently slow to maintain vision-related quality of life in the expected lifetime of the patient.12 Therapeutic modalities include IOP-lowering eye drops (commonly used topical medications include β-blockers, prostaglandin analogs, α-2 agonists, carbonic anhydrase inhibitors, and cholinergic agonists), laser treatment of the trabecular meshwork to increase the outflow (laser-trabeculoplasty), and surgical procedures (filtering procedures). As a last resort, reduction of aqueous humor production can be obtained by destruction of the ciliary processes either by external laser or by endo-photocoagulation.

Several randomized clinical trials have clearly demonstrated the efficacy of IOP reduction in POAG.

  • Lowering IOP reduces the rate of progression both in patients with early13 and advanced glaucoma.14

  • Lowering IOP reduces the rate of progression also in patients with NTG.15

  • Lowering IOP also reduces the incidence of POAG in patients who do not yet have structural or functional defects but who are particularly at risk for POAG because of high IOP values, so-called ocular hypertensives.16

These trials have provided an evidence-based foundation for the treatment of POAG by means of IOP reduction. However, it is a common clinical experience that in many patients, the glaucomatous damage progresses despite good IOP control, and this clinical wisdom was also confirmed by the randomized trials. For instance, in the Collaborative NTG Study,15 progression of glaucomatous damage occurred in 12% of the treated eyes. Glaucomatous optic neuropathy probably has a multifactorial cause, and factors other than IOP should be considered. If we look into the risk factors for POAG, the only one we can readily modify is IOP. Most others are beyond our control: age, family history of glaucoma, race/ethnicity, pseudo-exfoliation, central corneal thickness, and myopia.10

BP, IOP, OPP, and Glaucoma

There are complex interactions between BP, IOP, and OPP, which can influence glaucoma development and evolution. High BP could increase IOP by increased production of aqueous humor by means of elevated ciliary blood flow and capillary pressure and decrease of aqueous outflow as a result of increased episcleral venous pressure.17,18 However, low BP, whether spontaneous or secondary to antihypertensive therapy, can reduce OPP, leading to ischemic damage of the optic nerve.1,18–21 This may explain why patients can develop NTG, that is, glaucoma despite IOP within the normal range, and why glaucomatous patients can deteriorate their VF despite well-controlled IOP.

Ambulatory BP monitoring provides the average of BP readings over a defined period, usually 24 hours. Compared with office BP, it is a better predictor of hypertension-mediated organ damage and of cardiovascular events, such as stroke or coronary artery disease.22 Normally, BP decreases during the night. Both nondippers (usually defined as a <10 % decrease in nighttime BP compared to daytime BP) and extreme dippers (usually defined as a ≥20 % nocturnal dip) have an increased cardiovascular risk, although data are less convincing for extreme dippers.22,23 There are also variations in the IOP, mainly driven by body position. An increase in IOP is observed in the supine position, which is the sleeping position during the night.19 Consequently, OPP decreases during sleep. In addition to the effect of the normal circadian variation for BP and of the body position for IOP, antihypertensive medications and antiglaucoma medications also can influence OPP.19

Functional vascular dysregulation could play a role in the pathogenesis of glaucomatous optic neuropathy. Fluctuations in OPP from high or low BP can lead to unstable ocular blood flow and oxygen supply and to oxidative stress which may be relevant in the pathogenesis of glaucoma.11 Some glaucoma patients have altered autoregulation of their ocular blood flow, but also present with features of a more generalized vascular dysfunction, such as cold extremities, a syndrome known as primary vascular dysregulation. The Flammer syndrome, which is associated with an increased prevalence of NTG, describes a phenotype of subjects with a variety of symptoms and signs and altered vascular response to stimuli such as cold, physical, chemical, or emotional stress.24

BP and Glaucoma Prevalence

Zhao et al17 performed a systematic review and meta-analysis of the association between BP levels and arterial hypertension with POAG and IOP as endpoints. They identified 60 studies, including 7 longitudinal cohort studies from different parts of the world. The number of studies incorporated in the meta-analysis was 29 for POAG and 18 for IOP. Virtually all studies showed a positive association between systolic BP, diastolic BP, and IOP. The pooled average increase in IOP associated with a 10 mm Hg increase in systolic BP was 0.26 mm Hg, the average increase associated with a 5 mm Hg increase in diastolic BP was 0.17 mm Hg. The association between BP and IOP was considered robust and consistent despite heterogeneity across studies. The association between arterial hypertension and POAG was only significant for cross-sectional studies with a pooled relative risk of 1.24 (95% CI, 1.06–1.44).17

A recent retrospective study with a prolonged survey period (11 years) performed in Korea included hypertensive patients and a matched normotensive comparison cohort.25 Occurrence of POAG was 2 % (n=1961) in hypertensive patients, and 1.7 % (n=1692) in control subjects (P<0.001). Hypertension was associated with an increased incidence of POAG with an adjusted hazard ratio of 1.16 (95 % CI, 1.09–1.24). Patients with higher systolic BP (≥140 mm Hg) were more likely to have POAG compared with subjects with a systolic BP <120 mm Hg.25

An important recent study suggests that antihypertensive treatment may have a preventive effect on the development of glaucoma. Using the National Danish Registry, 41 235 patients with arterial hypertension and glaucoma were identified between 1996 and 2012.26 Definition of both diseases was based on redeemed prescriptions. Although the number of redeemed prescription for glaucoma therapy increased with time, initiation of antihypertensive treatment reduced the rate of prescriptions for glaucoma, suggesting that starting antihypertensive therapy could postpone the onset of glaucoma. Of note, after 2 years, the rate of onset of glaucoma therapy returned to the initial tendency.26

These studies suggest that arterial hypertension slightly but significantly increases the risk of POAG. However, other studies show that low BP could be associated with an increased prevalence of POAG.

In their meta-analysis, Zhao et al17 examined the dose-response relationship from 10 studies that used ≥3 categories of BP or that reported BP as a continuous variable. A J-shaped curve was obtained, implying that both low BP and high BP are associated with increased risk of POAG.

A recent study aimed to determine which BP parameters are associated with an increased risk of glaucoma. Of 185 eyes evaluated (93 subjects), 19 had signs of glaucomatous optic neuropathy. Multivariate analysis showed that extreme dipping, but not 24-hour, daytime, or nighttime BP, was associated with an increased risk of glaucomatous damage.27 The nighttime period is particularly critical for OPP because IOP increases in the supine position and BP most often decreases during the night.19

BP and Glaucoma and IOP Progression

As stated above, OPP decreases during sleep. Studies relating BP and glaucoma progression mainly focused on the 24-hour variations in BP and, especially, on nocturnal BP.

A meta-analysis included 5 studies (286 patients) with well-described 24-hour ambulatory BP monitoring method, clear report of daytime BP, nighttime BP and nocturnal dipping, and assessment of VF over an observation period of at least 2 years. Patients with POAG and NTG, and with or without arterial hypertension, were included. Although systolic and diastolic diurnal and nocturnal BP between patients with or without progressive VF loss were not different, nocturnal dips over 10 % in systolic or diastolic BP were significantly associated with deterioration of the VF.28

In a cross-sectional study including 314 consecutive patients with POAG or NTG (202 hypertensive and 112 normotensive), extreme dippers with daytime systemic normotension had more VF loss than extreme dippers with daytime systemic hypertension.29 Based on these results, a Dresden safety range was defined as a mean nocturnal BP between 65 and 90 mm Hg, provided IOP is well controlled (12 mm Hg in this study). The authors suggest that patients within this range are expected not to progress or to have a slower glaucoma progression compared to patients outside this range. However, given the cross-sectional design of the study, no follow-up data are provided.29

In a multivariable analysis in 65 patients with NTG, who had baseline 24-h IOP and BP monitoring, low nocturnal diastolic OPP at baseline was a significant predictive risk factor for VF progression at 5 years.30

A retrospective study performed in Korea included 72 NTG patients who had regular VF examinations and 24-hour ambulatory BP monitoring and who had a follow-up period of at least 20 years.31 Hypertensive patients were excluded. In the multivariate model, low OPP was associated with glaucomatous VF progression. The dipping pattern was also associated with VF deterioration, a more pronounced dipping being associated with a more VF worsening.31

Comparable results were obtained in another Korean prospective case-control study. In 349 consecutive patients with NTG with a minimal follow-up of 3 years (25 % hypertensive, all treated), extreme dipping was a significant risk factor for optic disk hemorrhage, and VF deterioration compared with nondipping and physiological dipping.32

In a prospective longitudinal study, 85 consecutive patients with NTG (32 % hypertensive, most treated) underwent regular VF examination and had 48-hour BP monitoring at baseline and during follow-up. After 1 year, the magnitude and duration of nighttime BP below 10 % of daytime BP identified patients with VF deterioration.33

A study examined the timing of antihypertensive drugs administration (in the morning or in the morning and the evening) on several visual characteristics and ambulatory BP.34 After a first evaluation, patients with POAG and controlled arterial hypertension were randomized into 2 groups, one taking antihypertensive treatment only in the morning (n=43) and the other taking antihypertensive treatment in the morning and in the evening (n=45). A second evaluation was performed 6 months later. Although 24-hour systolic BP and diastolic BP were similar in the 2 groups, patients taking antihypertensive drugs in the evening had lower nocturnal BP and more pronounced dipping, lower nocturnal OPP, greater VF loss, and more pronounced alteration in visual evoked potentials and in the flow in ocular and orbital vessels examined by Doppler ultrasound.34

However, studies suggest that high BP could adversely affect the natural tendency of IOP to decrease with age in certain ethnic groups. In 3188 Malay and Indian adults without glaucoma living in Singapore, with IOP and BP measurements at baseline and during 6-year follow-up examination, the age-related decrease in IOP was blunted in individuals who had an increase in BP, that is, the higher the BP increase, the lower the IOP decrease over the 6-year observation period. Data on VF or glaucomatous optic neuropathy are unfortunately not provided.35

Effect of Antihypertensive Drugs on IOP and Glaucoma

Some large-scale population-based studies have examined the relation between antihypertensive drugs and IOP. The EPIC (European Prospective Investigation into Cancer)-Norfolk Eye Study included 7093 participants who had their IOP measured and medications recorded by a research nurse during a health examination.36 Patients treated for glaucoma were excluded. Mean IOP ranged from 14.87 to 16.57 mm Hg. Analysis using a multivariable linear regression model showed that the use of β-blockers and nitrates was associated with a lower IOP (respectively by 0.92 and 0.63 mm Hg). There was no significant association between other antihypertensive drugs and IOP.36

The prospective Gutenberg Health Study enrolled 13 527 subjects taking cardiovascular medications and had IOP measurements. Patients with topical IOP-lowering medications or previous ocular surgery, thus most glaucoma patients, were excluded. Only systemic β-blockers were associated with a negligible reduction in IOP, in these nonglaucoma subjects.37

The Singapore Epidemiology of Eye Diseases Study examined 8063 subjects without glaucoma who had interviewer-administered questionnaire to collect data on medications.38 Mean IOP was 15.1 mm Hg. The use of β-blockers was independently associated with a lower IOP (by 0.45 mm Hg), whereas the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was associated with a higher IOP (respectively, 0.33 and 0.40 mm Hg). Although statistically significant, these associations were considered modest. The use of other antihypertensive drugs was not related to significant differences in IOP.38

Using the National Danish Registry, 41 235 patients treated with glaucoma medications and antihypertensive agents were identified. All antihypertensive drugs, except vasodilators, such as hydralazine, delayed the development of glaucoma.26

A study examined the association between systemic medications, not specifically antihypertensive drugs, and POAG using the United States insurance claims data.39 Prescription drug use was calculated for a 5-year period before a POAG procedure (cases, n=6130) or cataract surgery (controls, n=30 650). Logistic regression showed that the use of calcium channel blockers (odds ratio, 1.26; 95 % CI, 1.18–1.35) and angiotensin II antagonists (odds ratio, 1.19; 95 % CI, 1.10–1.28) was associated with an increased risk of POAG, whereas the use of β-blockers was associated with a reduced risk (odds ratio, 0.77; 95 % CI, 0.72–0.83).39

Concerns From Glaucoma Specialists Regarding the 2017 American College of Cardiology/American Heart Association Guidelines

There is no doubt that treatment of arterial hypertension reduces the incidence of major complications, such as cardiovascular death, myocardial infarction, and stroke. The landmark SPRINT study (Systolic Blood Pressure Intervention Trial) shows that a systolic BP target of <120 mm Hg is more protective than the conservative systolic BP target of <140 mm Hg.40 In 2017, the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines recommended a target BP of <130 mm Hg (systolic) and <80 mm Hg (diastolic) for most hypertensive patients.7 Consequently, the number of over-dippers and of patients with glaucoma progression could potentially increase in the next decades in treated hypertensive patients.1 Unfortunately, to our knowledge, neither the SPRINT trial nor other studies comparing outcomes with different BP targets did include assessment of glaucoma incidence or progression.

In Summary

  • Both high BP and low BP are associated with an increased risk of glaucoma.

  • There is mounting evidence that low nighttime BP or excessive dipping could adversely affect glaucoma progression.

  • If any, systemic antihypertensive drugs have minimal effect on IOP.

What Could Be Recommended

  • Patients with high BP should be screened for glaucoma, and patients with glaucoma should be screened for arterial hypertension.

  • Patients with coexisting glaucoma and high BP should undergo closer ophthalmologic examinations.1

  • Ambulatory BP monitoring should be performed in glaucoma patients with unexplained deterioration of their VF, and perhaps in all patients with coexisting arterial hypertension and glaucoma.1,18

  • Identification of a low nocturnal BP or over-dipping should prompt discussion between glaucoma and hypertension specialists in charge of the patient. However, to date, no specific recommendation can be proposed to limit over-dipping. Importantly, the nocturnal BP fall has prognostic implications, reduced and reverse dipping being associated with a significantly higher rate of cardiovascular events.23

  • In such an uncomfortable situation (glaucoma progression and over-dipping), there may be room for precision medicine and tailored management, always prioritizing BP control for optimal cardiovascular protection, taking into account that one size does not fit all.

Glaucoma and hypertension scientific societies should join their efforts to stimulate and raise funding for research and studies to determine the best treatment strategy for systemic hypertensive patients with concomitant glaucoma. In particular, the role of 24-hour ambulatory BP monitoring should further be studied, as it shows promise as a useful tool for identifying those patients at highest risk for glaucoma progression.18 Although not referred in the most recent American or European hypertension guidelines,7,22 future recommendation should at least raise awareness on the delicate balance between BP and IOP in these patients.

Footnotes

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.118.11507.

Correspondence to Marc Leeman, Hypertension Clinic, Erasme University Hospital, route de Lennik 808, B-1070 Brussels, Belgium. Email

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