American Journal of Hypertension, 2024, 37, 179–198

https://doi.org/10.1093/ajh/hpad111
Advance access publication 23 November 2023
Original Article

Original Article
The Relevance of Arterial Blood Pressure in the
Management of Glaucoma Progression: A Systematic
Review

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Jan Van Eijgen,1,2,†, Jesus D. Melgarejo,3,4,† Jana Van Laeken,1 Claire Van der Pluijm,2 Hanne Matheussen,2 Micheline Verhaegen,1,2
Karel Van Keer,2 Gladys E. Maestre,3,4,5 Lama A. Al-Aswad,6 Thomas Vanassche,7 Zhen-Yu Zhang,8, and Ingeborg Stalmans1,2,*
1
Department of Ophthalmology, University Hospitals UZ Leuven, Leuven, Belgium;
2
Research Group Ophthalmology, Department of Neurosciences, KU Leuven, Leuven, Belgium;
3
Institute of Neurosciences, School of Medicine, University of Texas Rio Grande Valley, Harlingen, Texas, USA;
4
Rio Grande Valley Alzheimer’s Disease Resource Center for Minority Aging Research (RGV AD-RCMAR), University of Texas Rio Grande Valley, Brownsville, Texas,
USA;
5
Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, USA;
6
Department of Ophthalmology, New York University (NYU) School of Medicine, NYU Langone Health, New York, USA;
7
Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium;
8
Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
*
Corresponding author: Ingeborg Stalmans ([email protected]).
E-mail: [email protected] (J.E.); [email protected] (J.D.M.); [email protected] (J.L.); [email protected] (C.P.); hanne.
[email protected] (H.M.); [email protected] (M.V.); [email protected] (K.K.); [email protected] (G.E.M.); doctoralaswad@
gmail.com (L.A.A.); [email protected] (T.V.); [email protected] (Z.-Y.Z.)
†
Shared first authorship.

BACKGROUND: Glaucoma is one of the leading causes of global blindness and is expected to co-occur more frequently with vascular
morbidities in the upcoming years, as both are aging-related diseases. Yet, the pathogenesis of glaucoma is not entirely elucidated
and the interplay between intraocular pressure, arterial blood pressure (BP) and ocular perfusion pressure is poorly understood.
OBJECTIVES: This systematic review aims to provide clinicians with the latest literature regarding the management of arterial BP in
glaucoma patients.
METHODS: A systematic search was performed in Medline, Embase, Web of Science and Cochrane Library. Articles written in English
assessing the influence of arterial BP and systemic antihypertensive treatment of glaucoma and its management were eligible for
inclusion. Additional studies were identified by revising references included in selected articles.
RESULTS: 80 Articles were included in this systemic review. A bimodal relation between BP and glaucoma progression was found.
Both high and low BP increase the risk of glaucoma. Glaucoma progression was, possibly via ocular perfusion pressure variation,
strongly associated with nocturnal dipping and high variability in the BP over 24 h.
CONCLUSIONS: We concluded that systemic BP level associates with glaucomatous damage and provided recommenda-
tions for the management and study of arterial BP in glaucoma. Prospective clinical trials are needed to further support these
recommendations.

Keywords: 24-h ABPM; blood pressure; blood pressure variability; glaucoma; hypertension; nocturnal dipping.

Glaucoma is one of the leading causes of visual impairment rates of both glaucoma and high IOP are expected to co-­occur
and blindness worldwide.1–3 The disease is characterized by more ­ frequently as their rates keep rising parallel to the
structural and functional damage of the optic nerve head due increasing life expectancy.1,11 To date, IOP is the only modifiable
to progressive loss of retinal ganglion cells and their axons.4,5 risk factor and therapeutic option in glaucoma. Nevertheless,
High intraocular pressure (IOP) is a major risk factor for dis- some patients with normal or ­well-controlled IOP are still at
ease development and progression. Other risk factors include risk for glaucomatous damage. The vascular paradigm sug-
age, family history, ethnicity, diabetes, and myopia.1,6–10 The gests impaired systemic vascular function, thus compromising

Received 28 July 2023; revised 16 November 2023; accepted 17 November 2023.

© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
180 | Van Eijgen et al.

blood supply to the optic nerve head, as a risk factor for disease intraarterial pressure, blood pressure*, hypertensi*, hypotensi*, Disease
progression. Management, Management*, Monitoring, therap*, treatment, adapt*,
The interplay between IOP, blood pressure (BP), and ocular per- change*, approach*, disease control*, risk*, progression*, visual field*.
fusion pressure (OPP) is poorly understood which limits the devel- Filters “English,” “2015–2022,” and “full article” were applied.
opment of a universal consensus around these parameters in the Animal studies were exclude using search blocks. The full search
management of glaucoma.1,9 The exact interaction between the strategy, as well those for the other databases, can be found
course of glaucoma and arterial BP is complex with studies sup- under Supplementary Data.
porting both arterial hypotension and hypertension as protective
and risk factors.1,4–6,8,11–14 The role of BP in relation to glaucoma
risk has been clarified by the use of 24-h ambulatory BP moni- RESULTS
toring. Nocturnal hypotension is considered a potential systemic Study selection
vascular risk factor for glaucoma. Moreover, abnormal circadian
The search of five electronic databases provided a total of 8,681
rhythms—such as an increased nighttime BP, an absence of noc-
citations. After deduplication, 6,581 references remained. Of these,
turnal BP dipping, or an excessive nocturnal BP dip—have been
6,276 were excluded based on title and 181 studies were excluded
associated with target-organ damage and increased cardiovas-

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

based on abstract, since these papers did not meet the inclusion
cular risk.1,2,13,15 However, even with the cumulative evidence on
criteria. Full texts of the remaining 124 papers were thoroughly
dysregulations in BP, evidence-based clinical d ­ecision-making
examined. It appeared that 28 studies did not meet the previously
remains challenging due to conflicting evidence and the poor
described inclusion criteria. Seven additional citations were iden-
understanding of the complex interplay between glaucoma
tified by searching reference lists of relevant papers.
and BP. To address these challenges, we performed a systematic
review of studies evaluating the role of BP and antihypertensive Synthesis of results
medication in glaucoma.
Arterial hypertension
First, the relationship between hypertension and IOP is straight-
METHODS forward. It is hypothesized that high BP increases IOP by a dual
mechanism. First high BP increases the blood flow and capillary
The Preferred Reporting Items for Systematic Reviews and Meta-
perfusion pressure in the ciliary body leading to an increased pro-
Analyses (PRISMA) statement was used as a guidance for this
duction of aqueous humor. Second, high BP, decreases the aque-
review.16
ous outflow through an elevated episcleral venous pressure.1,17
Generally, for every 10 mm Hg increase in BP there is a ca. 0.28
Eligibility criteria
(0.08–0.48) mm Hg increase in IOP.1,9,17–19
Articles that assessed the association between arterial BP and
Large-scale epidemiologic studies in the past aimed to explain
glaucoma were included. Other inclusion criteria were: (i) articles
the relationship between hypertension and glaucoma, with lim-
evaluating arterial BP in glaucoma patients, (ii) articles assess-
ited clinical implications. On the one hand, hypertension and
ing the impact of BP on IOP and parameters of progression such
increased blood flow leading to an increased OPP could com-
as retinal nerve fiber layer changes, ganglion cell layer changes,
pensate elevated IOP. On the other hand, among chronic hyper-
visual field defects, and optic disc hemorrhages, and (iii) articles
tensive patients, progressive endothelial dysfunction through
evaluating the impact of antihypertensive medication in glau-
hypertensive microvascular damage compromises this positive
coma patients/on glaucoma progression.
effect on OPP resulting in suppressed endothelial vasoreactivity,
We excluded articles that (i) already feature in meta-analyses
hypoperfusion of the optic nerve head and progressive glaucoma-
in this review, (ii) articles that only reported on glaucoma prev-
tous neurodegeneration. Of note, measurement of the absolute
alence in hypertensive cohorts. Other exclusion criteria were:
OPP does not exist, therefore arterial BP is used as a proxy meas-
(iii) a non-glaucoma population or animal studies, (iv) meeting
ure.4,6,10,20–26 Several studies evaluating multiple systemic risk
abstracts and conference proceeding, and (v) articles written in
factors including hypertension, as well as a genome-wide asso-
other languages than English.
ciation mendelian meta-analysis, could not find a statistically
significant effect of hypertension on glaucoma progression.27–30
Search strategy However, most studies, including a recent meta-analyses of 16
Articles were identified by searching Medline (via PubMed), studies, showed that hypertension is a risk factor for the devel-
Embase, Web of Science and Cochrane Library. The three concepts opment and progression of glaucoma (cfr. Table 1).31–42 A 2020
“glaucoma,” “arterial blood pressure,” and “management” and meta-analysis concluded that (mostly office) hypertension, next
their synonyms were combined to search several electronic data- to non-physiological BP dipping, was the most significant risk fac-
bases. The “carrot²” search results clustering engine’ was used tor for primary open-angle glaucoma (POAG) among the evalu-
to broaden the concept “management.” After reference import ated systemic vascular factors.7
and deduplication selection based on title, abstract, and full text In accordance, a Nepalese study with 221 hypertensive POAG
was executed respectively. The search was last performed on patients confirmed this finding. Patients with office hypertension,
­28-07-2022 by researchers JVL and JVE and inconsistencies were diabetes mellitus or the combination of both had a higher severity
solved by consensus. Replies on included articles were included of POAG, with an odds ratio for severe visual field defects of 2.75,
to allow critical appreciation by the scientific community but are 4.72, and 19.9 (P = 0.001, P = 0.0031, and P = 0.0046); respectively.
listed separately. Relevant articles found by scanning reference In this study, IOP did not differ between those with or without
lists of included articles but published before 2015 were included arterial hypertension.43 In 2015 a cross-sectional study found that
only when they were cited in multiple included articles. higher systolic BP, diastolic BP and mean arterial pressure (MAP)
The following search terms were used in Medline (Pubmed): were associated with thinner retinal nerve fiber layer thickness.
glaucoma*, arterial pressure*, arterial tension, artery pressure, They also observed a positive correlation between MAP and IOP.44
Table 1: Arterial hypertension

Type of study Study population Patients Eyes Men/women Country/ Age Hypertension Antihypertensives Conclusion Significance
Ethnicity level

Dielemans 1995 Single-center POAG and NTG 4,187 8,374 1,662/2,525 The 55–95 years n.s. 1,747 POAG was significantly P < 0.05
et al.33 prospective Netherlands associated with
cohort study SBP and arterial
hypertension, NTG
was not
Mitchell 2004 Population- Residents in an area 3,654 7,308 n.s. Australia 49–97 years 1,669 Included Systemic hypertensive P < 0.05
et al.39 based cohort West of Sydney subjects, especially
study those with
poorly controlled
hypertension, had
a higher risk of
glaucoma, independent
of other risk factors
Gangwani 2015 Prospective Patients treated 110 n.s. 64/46 China 65.1 ± 9.5 years All patients All patients NTG was the most P < 0.05
et al44. population- with systemic prevalent glaucoma
based study antihypertensives subtype. Higher SBP,
DBP and MAP were
associated with thinner
RNFL thickness.
MAP was positively
correlated with IOP
Actis 2016 Retrospective, POAG 190 377 76/114 Caucasian 61.49 ± 9.58 years n.s. n.s. Among other things n.s.
et al.31 observational systemic hypertension
study was statistically
significant associated
with worsening of
the MD variable
(P < 0.0001)
Feraru 2016 Retrospective POAG 69 69 16/53 Romania Mean 62.3 years 39 n.s. Arterial hypertension P < 0.05
et al.28 study was not significantly
associated with
glaucoma progression.
Progression rate was
only correlated with
the initial and final
MD level
Rim et al.41 2017 Retrospective Systemic 200,124 n.s. 129,577/ 70,547 Korean >40 years 100,062 100,062 Systemic hypertension P < 0.05
propensity- hypertensive (100,062 + was associated with an
score- patients on anti- 100,062) 1.16-fold increased risk
matched hypertensive for POAG development.
cohort study medication and Hypertensive patients
normotensive <65 years were more
controls susceptible to POAG
(HR = 1.17)
Kosior- 2017 Retrosprective NTG 215 280 64/151 Caucasian 70.5 ± 10 years 104 n.s. Systemic hypertension P < 0.05
Jarecka study was 2 times more
et al.45 frequently observed
in NTG patients with
arcuate scotoma
(P < 0.001)
The Relevance of Arterial Blood Pressure | 181

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Table 1. Continued
Type of study Study population Patients Eyes Men/women Country/ Age Hypertension Antihypertensives Conclusion Significance
Ethnicity level

Chan 2017 Retrospective Rapidly and 534 (48 + 486) 540 227/313 Australia Rapid progressors: 339 n.s. Systemic hypertension P < 0.05
et al.27 case-control non-rapidly (54 + 486) 83 ± 9.83 years was not a statistically
study progressing Non-rapid significant risk factor
glaucoma progressors: for rapid progression
79 ± 10.63 years (P = 0.22)
182 | Van Eijgen et al.

Khatri 2018 Hospital-based, POAG 221 442 107/114 Nepal 54.4 ± 15.9 years 81 All patients with Patients with arterial P < 0.05
et al.43 cross- hypertension hypertension, diabetes
sectional mellitus or both have
descriptive significantly more
study severe POAG (based
on anatomical and
functional loss) and
could represent
“high-risk patients”
with POAG (OR 2,75,
P = 0.001)
Cantor 2018 Cross-sectional POAG and controls 1,272 (196 + 1,076) n.s. 443/829 Colombia ≥50 years All patients All patients High values of diastolic P < 0.05
et al.20 study (non-glaucoma) BP (>90 mm Hg) and
with treated low values of OPP
systemic (<40 mm Hg) and DPP
hypertension (≤50 mm Hg) were
associated with a ± two
times higher risk of
confirmed POAG. These
relationships were not
modified by the type
of AHT
Krishnan 2018 Descriptive NTG 41 81 15/26 India 51.75 ± 10.91 years 13 n.s. Arterial hypertension P < 0.05
et al.56 study is an important risk
factor for NTG. A
DPP <50 mm Hg was
statistically significant
inverse correlated with
the VFD
Hussain 2019 Hospital-based POAG cases and 100 n.s. n.s. Pakistan ≥50 years All patients All patients were DBP >90 mm Hg was P < 0.05
et al.8 cohort study suspects treated with associated with
AHT for at increased IOP and a
least 1 year 2.2 times higher risk to
before the have confirmed POAG
inclusion (P = 0.08). The type of
AHT did not modify
this relationship

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Table 1. Continued

Type of study Study population Patients Eyes Men/women Country/ Age Hypertension Antihypertensives Conclusion Significance
Ethnicity level

55
Gore et al. 2019 Hospital-based, OAG and controls 150 (75 + 75) 150 84/66 India 30–80 years n.s. Excluded Conventional defined P < 0.001
case control systemic hypertension
cross- and OAG were not
sectional associated. DPP <55
observation mm Hg and OPP
study <50 mm Hg are
significantly associated
with a 5–6 times
(respectively) increased
risk for POAG
Kuang 2020 Case-control POAG and controls 562,300 n.s. 296,145/ 266,155 Han-Chinese Average 59 years 296,975 296,975 POAG was, among other P ≤ 0.05
et al.36 study (112,929 + things, significantly
449,840) associated with prior
systemic hypertension
(P < 0.001)
Park et al.25 2020 Cross-sectional POAG and controls 103 and 58 179 and 92 41.8% and 40.2% South Corea 58.5 and 52.6 31.8% and n.s. In POAG participants with P = 0.003
retrospective 18.6% disc hemorrhage, high
study BP was associated with
reduction in macular
vessel density
Dascalu 2020 Prospective OAG 102 139 Romania 51 35 n.s. Glaucoma progression
et al.32 cohort study was associated with
systemic vascular
risk factors including
diastolic low BP,
ischemic cardiac
disease, peripheral
vasospasm, and
hypertension
Marshall 2021 Prospective, Early manifest 1,222 2,444 601/621 Australia 63.9 ± 11.1 years 467 Included Systemic hypertension P < 0.05
et al.38 longitudinal POAG and AHT were
study significantly associated
with both structural
(P = 0.006 and P = 0.010,
respectively) and
functional (P = 0.013
and P = 0.010)
progression
Ch’ng et 2021 Prospective POAG, NTG, and 164 164 43/17, 30/22, 63.0 ± 9.4, 44, 38, and 29 Included Moderate to severe P < 0.05
al.21 cohort study PCAG and 19/33 59.6 ± 10.3, and glaucomatous optic
62.3 ± 8.5 damage was associated
with lower systolic and
diastolic BP
Gillespie 2021 Clinical trail POAG 1,118 1,118 330/269 and 57.9 ± 0.9 and 37 486 Office hypertension P < 0.05
et al.35 registry 240/279 65.3 ± 9.3 significantly associates
with slope changes
in visual field defects,
with estimates ranging
from −0.33 dB/year to
−0.18 dB/year
The Relevance of Arterial Blood Pressure | 183

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

 184 | Van Eijgen et al.

A study regarding normal-tension glaucoma (NTG) patients

Significance
found that systemic hypertension was two times more frequently

Abbreviations: OAG: open-angle glaucoma; POAG: primary open-angle glaucoma; NTG: normal-tension glaucoma; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; RNFL: retinal
P < 0.05

P < 0.05

nerve fiber layer; IOP: intraocular pressure; MD: mean deviation; HR: hazard ratio; OPP: ocular perfusion pressure; DPP: diastolic perfusion pressure; AHT: antihypertensive treatment; VFD: visual field defect; n.s.: not
observed in NTG patients with arcuate scotomas. They hypothe-
level

n.s.
sized that the systemic vascular profile of the patient could pre-
dict the morphology of early scotoma in NTG.45

Mendelian randomization
hypertension (OR, 1.64;

hypertensive and non-

hypertensive patients

relationship of BP on
IOP change or POAG
Patients with NTG had

VF progression rate
significantly higher

difference between
No significant OCT or
Circadian BP dysregulations
rates of systemic

support a causal
analysis did not
Nocturnal hypotension

prevalence
P = 0.004)
Conclusion

Systemic BP is a dynamic parameter that follows a normal circadian

rhythm. During the night, BP physiologically decreases between
10% and 20% compared to the daytime BP level, this is categorized
as normal dipping.46 However, in certain conditions, the nighttime
Antihypertensives

BP either decreases too much (extreme dipping), does not suffi-

315 and 266

ciently decrease (non-dipping), or even increases instead (reverse

dipping). Studies indicated that people with an abnormal noctur-

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

nal dipping are at a higher risk of developing target-organ damage,
n.s.

n.s.

including damage in the optic nerve head.1,8 The introduction of

Hypertension

ambulatory BP monitoring enabled the continuous assessment of

181 and 148

BP over a 24-h period, providing detailed insights into the relation-

ship between glaucoma and low BP.47,48 Despite some discordance
n.s.
44

in literature, most studies concluded that nocturnal hypotension

and extreme nocturnal BP dipping are risk factors for the devel-
66.3 ± 10.3 years
69.5 ± 10.5 and

opment and progression of open-angle glaucoma (cfr. Table 2).

68.9 ± 10.0

Patients with a nocturnal MAP drop greater than 10 mm Hg or

10% are at a higher risk for visual field progression.6,12,15,37,47,49–53 In
Age

n.s.

addition, nocturnal BP decrease seems to be accompanied by IOP

increase (due to the supine resting position) resulting in reduced
USA (European
asian, black,
United States

american)

or African

OPP at night. When extremes of both phenomena occur simulta-

ancestry)
hispanic,

ancestry
European
(white,

neously, OPP drops substantially resulting in short-term ischemia

native
Ethnicity
Country/

of the optic nerve head and significant risk for glaucoma progres-
sion.54 Therefore, nighttime could be considered as a critical period
for glaucoma patients.8,14,19
159/118 in both

Given that the abovementioned cut-off values for nocturnal

Men/women

BP dipping, fall partly within the physiological range,17 a deficient

57/62

autoregulation mechanism is very likely. A study by Melgarejo et

n.s.

al.50 suggested that an increase in glaucoma risk is more likely to

be due to the extreme dipping (dips > 20%) of nocturnal BP inde-
pendently of the overall nocturnal BP level. Low diastolic OPP
would particularly influence OPP as it determines the perfusion
Eyes

277

191

n.s.

pressure to organs, explaining why is considered an independent

risk factor for open-angle glaucoma.5,8,19,20,26,55–57 One study reported
that a diastolic OPP <35 mm Hg result in progression of glaucoma
2.3 times more likely.5 In a cross-sectional study including POAG
and NTG patients, patients with nocturnal over dipping and diur-
Patients

70,832

nal systemic normotension (both treated and untreated) had more

277

119

visual field loss (mean deviation = −16.6 dB, IQR: −18.9 to −2.7 dB)
than patients with nocturnal over dipping and diurnal systemic
POAG and controls
NTG and healthy

hypertension (mean deviation = −3.9 dB, IQR: −6.2 to −1.9 dB).

Study population

They concluded that at the time of a 24-h ambulatory BP moni-

controls

toring, nocturnal dipping patterns, and diurnal BP means should

be analyzed in function of each other.47 Two other studies stated
POAG

the importance of taking the cumulative nocturnal hypotension,

meta-analysis

the duration and magnitude of the nocturnal dip into account.12,53

case-control

longitudinal

Genome-wide
association
Retrospective
Type of study

Two study groups defined a comparable safety range for the

Prospective,

nocturnal BP. Pillunat et al.47 proposed the Dresden safety range

study

study

study

for nocturnal MAP in POAG ranging between 65 and 90 mm Hg.

Table 1. Continued

Kwon et al.12 defined optimal values of trough diastolic BP at night

between 60 and 70 mm Hg. Patients with controlled IOP and a
2022

2022

2022

nocturnal BP within these safety ranges have slower progression

rates than patients below this optimal value or might not be
et al. 29

Plotnikov
et al.34

et al.30

specified
Changet

expected to progress at all.

Funk

In NTG patients, the association between nocturnal BP

and glaucoma damage seems to offer particular insights. A
Table 2: Nocturnal dipping and hypotension

Type of study Study Patients Eyes Men/ Country/ Age Systemic Conclusion Significance
population women Ethnicity AHT level

Topouzis 2013 Cross-sectional, POAG, PXG and 2,261 2261 1240/1021 Greece 70.8 ± 5.8 years Included Borderline significant association P < 0.05
et al.26 population- controls (94 + 41 + 2,126) between low DOPP and POAG
based study (P = 0.059)
Charlson 2014 Prospective, NTG 85 166 28/57 United Average 65 Included Cumulative nocturnal hypotension P ≤ 0.05
et al.53 longitudinal States years (>10 mm Hg under DMAP)
study predicts visual field loss (P < 0.02)
Pillunat 2015 Cross-sectional POAG and NTG 314 (147 + 167) 314 113/201 Caucasian >40 years Included Over-dippers with systemic P < 0.05
et al.47 study normotension (with or without
AHT) had more visual field loss
than over-dippers with systemic
hypertension (MD = −16.6 dB
vs. MD = −3.9 dB, respectively;
P < 0.004)
Bowe et al.6 2015 Systematic POAG and NTG n.a. n.a. n.a. n.a. 28–85 years n.s. Nocturnal systolic or diastolic BP P < 0.05
review and dips > 10% (no differentiation
meta-analysis between physiological- or
over-dipping) is a risk factor
for progressive visual field loss
in glaucoma (P < 0.001 and
P = 0.009, respectively; OR 3.32
and 2.09, respectively)
Lee et al.52 2015 Longitudinal, Untreated NTG 237 237 116/121 Korean 55.83 ± 9.33 Included Significantly higher daytime P < 0.05
retrospective, years or nighttime MAP and OPP
observational variabilities were found in over-
study dipper NTG patients compared
to non-dipper and dipper NTG
patients. Baseline increased
daytime MAP and OPP standard
deviation significantly predicted
future VFP in NTG
Chiotoroiu 2015 Prospective OAG 45 90 n.s. Romania n.s. n.s. The dipper group (dips >10%) n.s.
et al.51 observational presented the most important
and progression of glaucoma
interventional (objectified by visual field and
study OCT) compared to the non-
dipper (dips <10%) and arterial
hypertension group
Marjanovic 2015 Prospective, NTG and NTG 57 (37 + 20) 57 18/39 Serbia ≥50 years Included No statistically significant P < 0.05
et al.13 cross- suspects difference was found between
sectional and (all arterial NTG and NTG suspects in either
observational hypertension) DSBP or NSBP, nor in DDBP or
study NDBP. NTG patients had a lower
nocturnal systolic and diastolic
BP fall than NTG suspects
Marjanovic 2016 Prospective, POAG 114 114 78/36 Serbia ≥40 years Included There is a significant relationship P < 0.0055
et al.48 cross- between BP measurements
sectional and (DSBP, DMAP and NSBP) and
observational the RI in the OA in the dipper
study group. Retrobulbar blood flow
parameters (EDV) are reduced in
dippers (P < 0.001)
The Relevance of Arterial Blood Pressure | 185

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Table 2. Continued
Type of study Study Patients Eyes Men/ Country/ Age Systemic Conclusion Significance
population women Ethnicity AHT level

Jin et al.49 2017 Retrospective POAG and NTG 106 (34 + 72) 106 56/50 Korean POAG: Excluded Nocturnal BP dip (systolic and/ P < 0.05
cohort study 59.14 ± 10.18 or diastolic) and paracentral
years NTG: scotoma are significantly
55.88 ± 11.23 correlated (occurrence/
years progression) in early NTG but
not significantly in early POAG.
186 | Van Eijgen et al.

Large variations in BP affect the

occurrence and progression of
paracentral scotoma
Kwon et al.86 2017 Prospective NTG 349 698 168/181 Korean 55.9 ± 9.5 years Included Nocturnal over-dipping is a risk P < 0.05
case-control factor for the occurrence of
study ODH in NTG (P < 0.001), which
is a significant prognostic factor
for glaucomatous VFP in this
study (P < 0.001). Increased
variabilities of BP and OPP over
24 h are associated with a greater
likelihood of glaucomatous
VFP (P = 0.017 and P = 0.01,
respectively)
Kocatürk 2017 Prospective, POAG, NTG and 129 (44 + 43 + 42) n.s. 75/54 Turkey 63–72 years Excluded Systolic BP levels (24 h and P < 0.05
et al.83 randomized, controls nocturnal) and mPP values
case-control (24-h, day- and night-time)
study were significantly lower in NTG
patients compared to POAG
and controls. The number
of extreme dippers was not
significantly higher in the NTG
compared to the POAG group.
The physiopathology’s of NTG
and POAG may vary
Raman 2018 Prospective, NTG 65 65 32/33 Malaysia 68.2 ± 9.8 years Included Baseline DBP and diastolic pressure P < 0.05
et al.5 longitudinal parameters were significantly
study lower in patients who progressed
(P < 0.05) and were significant
factors in 5-year VFP among NTG
patients. Low nocturnal DOPP
is an independent predictor of
glaucomatous VFP
Melgarejo 2018 Observational, NTG, NTG 93 185 12/81 Hispanic Mean 61.9 Included Extreme dipping (dips >20%) of P < 0.05
et al.50 cross- suspects and years nocturnal BP levels, rather than
sectional healthy eyes nocturnal hypotension per se,
study increases glaucoma risk
Kwon et al.12 2019 Prospective NTG 119 119 51/68 Korean 54.15 ± 12 Included Low nocturnal trough DBP (−10 P < 0.05
cohort study years mm Hg increased risk of VFP
by 63.5%) and the duration and
magnitude of the nocturnal dip
(DBP dip area: 10 mm Hg × h
increase of risk of VFP by 19.5%)
at baseline are significant
predictors of subsequent VFP

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Table 2. Continued
Type of study Study Patients Eyes Men/ Country/ Age Systemic Conclusion Significance
population women Ethnicity AHT level

Yoshikawa 2019 Observational, Glaucoma 817 (109 + 708) 817 391/426 Japan Glaucoma: Included
Significant association between P < 0.05
et al.2 cross- (POAG, PACG, 71 ± 11.2 glaucoma and increased NSBP
sectional SG and EG) Controls: (P = 0.001)and the non-dipper
study and healthy 70.8 ± 6.8 pattern of BP (P < 0.001),
controls years independent of known risk
factors
Karadag 2019 Observational POAG and PXG 18 (10 + 8) n.s. 10/8 Turkey POAG: Excluded In both groups, nighttime IOP was P < 0.05
et al.9 study 57.5 ± 8.5 significantly higher than the
years PXG: daytime values. Nighttime SBP
67.3 ± 6.2 and DBP were significantly lower
years than the daytime values
Baek et al.58 2020 Retrospective NTG 102 102 37/65 South 62.3 ± 14.1 n.s. Fluctuations of DBP in 24-h P < 0.05
cohort study Korea BP, diurnal IOP fluctuations
and ODH were significantly
associated with NTG progression
Yilmaz 2020 Retrospective POAG and 75 (35 + 40) n.s. 30/45 Turkey POAG: Included The NSBP, whole day SBP and P < 0.05
et al.4 case-control controls 65.03 ± 14.56 mean DBP were significantly
study years lower in patients with POAG.
Controls: Daytime, nighttime and whole
59.98 ± 14.40 day SBP were identified as
years independent risk factors for
developing POAG in the multiple
regression analysis. Hypotension
is more significant in the
etiopathogenesis of POAG
Lee et al.37 2020 Retrospective NTG 166 166 n.s. South 56.3 ± 15.3 Included Patients with a minimum SBP P < 0.05
cohort study Korea years ≤107 mm Hg showed more
peripapillary RNFL thinning
(P < 0.001) and patients with a
minimum DBP ≤63 mm Hg had
more progression of macular
GCIPL thinning (P < 0.001)
Leet et al. 60 2020 Retrospective NTG 110 220 48/62 South Average 56.75 Included Extreme dipping (dips >20%) and P < 0.05
study Korea years arterial hypertension were
independent predictors of
VFD (P = 0.048 and P = 0.045
respectively)
Shin et al.59 2021 Observational, NTG 88 88 35/53 South 56.0 ± 12.4 Included If choroidal microvascular drop-out P < 0.034
cross- Korea was present on angiography-
sectional OCT, the worse the glaucoma
study severity (OR 0.786) and the more
nighttime dips (OR 1.951)
Melgarejo 2021 Observational, NTG 93 93 12/81 South 61.9 ± 12.9 Included 24-h reading-to-reading mean P < 0.05
et al.64 cross- America arterial pressure (MAP) variability
sectional relates to glaucomatous optic
study neuropathy (OR, 1.93; 95% CI,
1.10-3.41) regardless the absolute
MAP level
The Relevance of Arterial Blood Pressure | 187

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

 188 | Van Eijgen et al.

Significance
retrospective study from 2017 found that nocturnal dipping (aver-
age amount of nocturnal decrease of BP) and large variations in
systolic BP accorded to higher incidence of paracentral scotoma
P < 0.05

Abbreviations: OAG: open-angle glaucoma; POAG: primary open-angle glaucoma; NTG: normal-tension glaucoma; PACG: primary angle-closure glaucoma; SG: secondary glaucoma; EG: exfoliation glaucoma; PXG:

pressure; NSBP: nighttime systolic blood pressure; MD: mean deviation; RI: resistivity index; OA: ophthalmic artery; EDV: end diastolic velocity; ODH: optic disc haemorrhage; RNFL: retinal nerve fiber layer; GCIPL:
pseudoexfoliation glaucoma; AHT: antihypertensive treatment; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; DSBP: daytime systolic blood pressure; DMAP: daytime mean arterial

ganglion cell-inner plexiform layer; OCT: optical coherence tomography; MAP: mean arterial pressure; VFP: visual field progression; VFD: visual field defects; OPP: ocular perfusion pressure; DOPP: diastolic ocular
in early NTG patients.49 In their prospective case–control study,
level

Kwon et al. surmised an IOP-unrelated mechanism of progression.

They concluded that nocturnal dipping exerts its effect on glau-
ranged from 2.25 to 3.39; 95% CI

and extreme dips in the diurnal

comatous visual field progression through the occurrence of optic

associated with high variability

pressure associates with faster
24-h MAP level associates with
Dips rather than increases in the

glaucomatous optic damage is

Lower MAP and diastolic arterial

MAP while structural damage

disc hemorrhages.15 This was supported by a retrospective study
increased risk of POAG (OR

seems more vulnerable to

from 2020, that found a significant association between optic disc
ranged from 1.31 to 8.46)

Progression of functional

nocturnal hypotension
hemorrhages and fluctuations of diastolic BP and diurnal IOP on
one side, and a greater probability of NTG disease progression on
rates of RNFL loss

the other side.58 Miscellaneously, higher percentages nighttime

diastolic BP dips and more severe glaucoma were reported in NTG
patients with choroidal capillary drop-out on angiography-OCT.59
Conclusion

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Daytime hypotension
A 2020 retrospective cohort study found that minimum daytime
systolic BP and diastolic BP could be, similar to nocturnal dipping
61.9 ± 13.3 and Included

Included

Included
Systemic

or nocturnal hypotension, a potential risk factor for structural

AHT

glaucomatous progression. Patients with a minimum systolic BP

≤107 mm Hg showed more peripapillary retinal nerve fiber layer
thinning (P < 0.001) and patients with a minimum diastolic BP
63.2 ± 11.9

≤63 mm Hg had more progression of macular ganglion cell-inner

64.5 ± 12.5

68.5 ± 10.8

plexiform layer thinning (P < 0.001).60 These findings reinforce the

importance of maintaining a minimal daytime BP level instead of
Age

an overall mean threshold level.

Jammal et al.54 report a significant faster rate of RNFL loss in
America

Europe
Ethnicity
Country/

glaucoma patients with lower mean BP, systolic BP or diastolic BP

States

Europe
United
and
South

with and without antihypertensive treatment after correction for

age, gender, race, glaucoma diagnosis, CCT, follow-up time, and
baseline RNFL thickness in the Duke Glaucoma Registry.
1577/2399
93 and 12/81 and
40/56
women

Abnormal BP variability over 24-h

65/45
Men/

Ambulatory BP monitoring permits the quantification of

­reading-to-reading BP variability over 24-h. In the hypertension
7,501
96
Eyes

and cardiovascular fields, high variability in the 24-h BP increases

110

the risk of cardiovascular diseases independently of the aver-

with 48 healthy

age 24-h BP level.61 High variability in the BP suggests impaired

cases matched
93 and 48 OAG

perfusion pressure; IOP: intraocular pressure; n.s.: not specified; n.a.: not applicable

autonomous central nervous system mechanisms to maintain

a constant BP level, which is the case in patients with diabetes,
contros

obesity, or previous cardiovascular diseases. Increased BP varia-

Patients

3,976

bility would not be regulated in eyes with glaucomatous damage

110

as their autoregulatory mechanisms to maintain the ocular blood

flow and supply would be impaired. Therefore, beyond the abso-
NTG and POAG

POAG, other

lute level and nocturnal hypotension, it is hypothesized that high

variability in the BP over 24-h could increase the risk of glaucoma
population

suspect,
Glaucoma

damage by impaired OPP related to abnormal changes in the sys-

POAG
Study

temic BP.
Compared to the cumulative evidence on nocturnal hypo-
tension, few studies have addressed the potential role of 24-h
retrospective

retrospective
2022 Observational,

2022 Observational,

2022 Observational,
longitudinal

longitudinal

BP variability and glaucoma risk. In 237 patients with NTG, Lee

Type of study

sectional

et al.52 documented that patients with nocturnal BP dipping greater

cross-

study

study

study

than 20% had significantly increased reading-to-reading daytime

BP variability and OPP (defined as by Bill et al.62) compared to nor-
mal dippers or non-dippers. Moreover, an increased daytime MAP
or OPP variability predicted the progression of visual field defects.
Table 2. Continued

Similar findings have been replicated in case–control studies of

patients with NTG,58,63 with additional documentation of fluctua-
tions in the diastolic OPP related to the progression of glaucoma
Melgarejo

Melgarejo
et al.66

et al.54

et al.65

damage.58 In a study including 93 participants and 23 cases of

Jammal

open-angle glaucomatous damage, researchers reported that the

association between high 24-h MAP variability and glaucoma risk
 The Relevance of Arterial Blood Pressure | 189

is independent of the 24-h MAP average level.64 Even more, high established that systemic β-blockers, especially non-selective
24-h MAP variability related to higher glaucoma progression.65 types, have a lowering effect on IOP. However, in the Gütenberg
From a pathophysiological perspective, it is hypothesized that Health Study, Höhn et al. could not detect a significant trend of
drops in the BP due to high variability is what leads to impaired lower IOP (selective BB: −0.12 mm Hg; non-selective BB: −0.7 mm
OPP. Apart from nocturnal hypotension, the quantification of 24-h Hg) in non-glaucoma subjects. This finding was attributed to a
BP variability relies on indexes such as standard deviation, coef- long-term “drift” effect.74
ficient of variation, or variability independent of the mean. Each Regarding calcium channel blockers (CCB), mixed findings have
of these indexes gives an absolute number usually reported in also been reported. On one hand, it has been suggested that CCB
publications with the symbol “±.” This refers to how far apart data delay visual field deterioration (possibly due to a neuroprotective
points (e.g., BP recordings) are from the center of the distribu- effect).3,14,75 Hu et al.76 documented that nimodipine benefits patients
tion (e.g., 24-h BP average). The extrapolation of this definition to with NTG by increasing the macular capillary vessel density eval-
the pathophysiology of glaucoma suggests that the association uated on OCT-angiography. On the other hand, studies have found
between variability and glaucoma needs to be addressed. In this that CCB increase the risk of POAG after controlling for systemic
regard, the Leuven research group conducted a study to test the hypertension (OR 1.70 P = 0.03).34 Zheng et al. found that CCB, espe-
hypothesis that the association between high 24-h MAP variabil- cially amlodipine, were the most significant drug class to be asso-

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

ity and glaucoma risk was driven by sporadic drops in the MAP ciated with a 26% risk increase of POAG (having had at least one
rather than peaks.66 To test this hypothesis, they equitably quan- glaucoma procedure) (OR 1.26, 95% CI: 1.18–1.35). No dose-response
tified the five largest drops and peaks in the MAP over 24 h (n = 94 relationship was identified. β-blocker use was associated with a 23%
and n = 96). Dips rather than peaks in the 24-h MAP related to lesser incidence of POAG (OR 0.77; 95% CI: 0.72–0.83). No associa-
open-angle glaucoma damage. This could be explained by the fact tion between POAG and the use of loop diuretics or angiotensin-­
that patients with normal but highly variable BP are more likely converting enzyme (ACE) inhibitors could be established.42 A more
to reach lower OPP repeatedly, and secondly, because patients recent study underlines the relative higher accordance between CCB
with high BP exhibit higher BP variability, being more likely to and filtration surgery in POAG compared to thiazides. Other drugs
excessively drop in BP, reducing OPP. With this in mind, physicians investigated in this study, such as angiotensin-II receptor block-
should consider that the majority of glaucoma patients have nor- ers (ARB), had no significant association with POAG progression.77
mal or high BP—the last might explain why arterial hypertension Caution must be made since these findings often do not correct for
relates to glaucoma risk as depicted in the first paragraph.7,31–43 the existence of concomitant hypertension.
Antihypertensive medication should therefore aim to stabilize BP A retrospective study investigating a cohort from the Groningen
variability, avoiding extreme dips in the BP, while ensuring noc- Longitudinal Glaucoma study observed a good and highly signifi-
turnal BP is normal. This in turn should decrease the risk of glau- cant interaction between age and angiotensin-II receptor blockers
coma associated with sporadic or constant low BP. in relation to glaucoma progression. This suggests a higher benefit
of ARB on glaucoma progression in elderly individuals. A significant
association between ACE inhibitors, ARB and lower suspect POAG
Systemic antihypertensive medication was also reported.70 On the other hand, a large ­ cross-sectional
Studies investigating the role of antihypertensive medication in population-based study in a multi-ethnic Asian population found
glaucoma are often not corrected for the presence or severity of that patients using antihypertensive medication, particularly ACE
existing hypertension and yield contradictory conclusions (cfr. inhibitors and diuretics, had significantly thinner retinal nerve
Table 3).17,67 fiber layers and ganglion cell-inner plexiform layers.67
The Thessaloniki Eye Study reported that iatrogenic DBP <90 Synergistic or antagonistic effects of certain antihypertensive
mm Hg leads to increased cupping and decreased rim area com- agents with certain topical glaucoma therapies have been consid-
pared to spontaneous DBP <90 mm Hg.68 Hence, some postulate ered. The addition of a topical β-blocker may not induce a signif-
that the (over)treatment of hypertension, rather than the disease icant reduction in IOP if the patient has already been prescribed
itself, is a significant modifier of glaucoma.11,56 Aggressive decrease an oral β-blocker. Moreover, all drug combinations could increase
in the BP due to antihypertensive treatment could potentially lead the risk for adverse effects.3 A long-term case–control study
to low DBP and consequently low OPP.56,57,69,70 Thus, when treating investigating how systemic antihypertensive medications influ-
systemic hypertension, an increase in glaucoma risk could exist ence the change in IOP after initiating prostaglandin drop therapy
if OPP decreases.11 Some studies found a correlation between pro- did not find a significant impact of antihypertensive medication
gression and the number of antihypertensive agents54,67 whereas on the IOP-reduction after topical prostaglandin initiation.73
another did not.71 Ocular blood flow could potentially be improved
in hypertensive patients with drug-induced low nocturnal BP by
adapting their medical regime.57,72 For instance, changing the time Autoregulation
of medication intake from the evening to morning.4,73 In healthy eyes, retinal blood flow is autoregulated and a rela-
On the other hand it is also believed that undertreatment of tively constant blood flow is maintained despite changes in the
hypertension may influence the disease progression of hyperten- local metabolic environment and changes in OPP.19,22,44 Constant
sive glaucoma patients and that some antihypertensive drugs perfusion can be assured within the range of approximately 20
may have protective effects on glaucoma development.1,14 A mm Hg around the patients usual MAP.53 When OPP falls out of
Danish registry database study reported that antihypertensive this range, autoregulation fails.
medication seems to delay glaucoma onset but not necessarily Some glaucoma patients have impaired autoregulation of
reduce the immediate risk thereof. They also found a greater pro- ocular blood flow (cfr. Table 4). In these patients, ocular blood
tective effect proportional to the cumulative number of different flow instability may predispose the optic disc structures to
antihypertensive drugs.69 ischemia-reperfusion damage. It has been documented that both
The effect of systemic antihypertensive medication on glau- tails of the arterial BP distribution relates with impaired autoreg-
coma risk can be either IOP- or non-IOP related.3,74 It has been ulatory mechanism in the eyes to maintain an adequate blood
Table 3: Antihypertensive medication

Type of study Study population Patients Eyes Men/ women Country/ Age Antihypertensives Conclusion Significance
Ethnicity level

Topouzis 2006 Cross-sectional Non-glaucoma 232 232 138/94 Greece Mean 71 years Included but n.s. A DBP<90 mmHg resulting from AHT is P < 0.05
et al.68 population- population associated with increased optic disc
based cupping and decreased rim area.
epidemiologic
study
190 | Van Eijgen et al.

Suïc et al.57 2015 Prospective Glaucoma 64 n.s. 36/28 Croatia ♂: 65,32 years ♀: Included Statistically significant lower DBP in the P < 0.05
cohort study patients 62,45 years progressive group.
with treated
systemic
hypertension
Horwitz 2017 Registry Danish 41,235 n.a. n.s. Denmark 40-95 years Antiadrenergics Antihypertensive medication seems P < 0.05
et al.69 database glaucoma Diuretics to delay the onset of developing
study patients with Vasodilators glaucoma but does not necessarily
hypertension Beta blockers reduces the immediate risk. A greater
CCB A2RBs ACE protective effect was found depending
inhibitors on the cumulative number of different
antihypertensive drugs.
Höhn 2017 Population- Non-glaucoma 13,527 n.s. 6,849/ 6,678 Germany Mean 54,3 years Peripheral vasodilators Non-selective beta blockers showed a P < 0.0038
et al.74 based, population Diuretics Beta statistically non-significant trend
prospective, blockers CCB RAB of slightly lower IOP. All the other
observational ACE inhibitors ARB cardiovascular medication did not
cohort study Nitrates Other AHT show an association.
medication
Zheng 2018 Database study POAG and 36780 n.a. 17,847/ 3,166 United States Mean 72 years Beta blockers CCB (mainly Amlodipine) were associated P < 2.3 × 10−5
et al.42 controls (6,130 + CCB A2RB ACE with POAG requiring filtration surgery.
30,650) inhibitors Loop Beta blockers had a protective
diuretics association with POAG.
Siddiqui 2019 Retrospective, POAG 111 n.a. 48/63 Caucasian + Mean 70 years ACE inhibitors ARB There was no significant impact n.s.
et al.73 long-term, Hispanic + Beta blockers from systemic antihypertensive
case-control others Thiazides Loop medication on IOP reduction after
analysis diuretics CCB topical prostaglandin initiation.
Systemic antihypertensives use was
not correlated with nonresponse to
prostaglandin therapy.
Wang et al.77 2019 Cohort study OAG n.s. n.a. n.s. United States n.s. A2RB Thiazide There is more rapid progression to P < 0.05
diuretics CCB glaucoma filtration surgery in patients
taking CCB as compared with thiazides.
This relationship was not found for the
other drugs investigated.
Pappelis 2019 Retrospective POAG cases and 362 (250 + 112) 362 185/177 Caucasian Mean between Diuretics ARB ACE None of the systemic medications were P < 0.05
et al.70 cohort study suspects 55-62 years inhibitors CCB Beta associated with POAG VFP. A2RBs
blockers significantly delayed progression in
older patients. ACE inhibitors and A2RBs
were significantly associated with a
lower risk of POAG suspect conversion.
Chong 2020 Population- Data form the 4,699 n.s. 2292/2407 Multi-ethnic 58.8 ± 8.5 years ACE inhibitors A2RB The use of antihypertensive medication, P < 0.05
et al.67 based, cross- Singapore Asian CCB Diuretics Beta especially ACE inhibitors and
sectional Epidemiology blockers diuretics, were significantly associated
study Eye Diseases with thinner RNFL and GCIPL. A
Study greater number of antihypertensive
medications was also associated with
thinner RNFL and GCIPL.

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

 The Relevance of Arterial Blood Pressure | 191

flow and supply.78 As previously mentioned, hypertensive glau-

Significance coma patients also have, microvascular damage which further

angiotensin receptor blockers; A2RBs: angiotension II receptor blockers; ACE inhibitors: angiotensin-converting enzyme inhibitor; RAB: Renin-angiotensin blockers; VFP: visual field progression; n.a.: not applicable; n.s.:
P = 0.022
P ≤ 0.007
disrupts autoregulation mechanisms and increases susceptibility

P < 0.05
P ≤ 0.04 to glaucoma progression. Studies reporting nocturnal hypoten-
level

Abbreviations: OAG: open-angle glaucoma: POAG: primary open-angle glaucoma; AHT: antihypertensive treatment; DBP: diastolic blood pressure; IOP: intraocular pressure; CCB: calcium channel blockers; ARB:
sion and increased variability of BP and OPP as risk factors for
Nimodipine increased superficial macular

associated with NTG, including systemic

glaucoma also supported that functional vascular dysregulation

use of angiotensin-converting enzyme

could be involved in the pathogenesis of glaucoma.13,22,24,49,79,80 This

inhibitor or calcium channel blocker

treatment for lowering BP was not.

hypotension and hypertension. The

progression of glaucoma damage.

pressure with low diastolic blood
Numerous vascular risk factors were

hypothesis may also explain why lowering IOP beyond a critical

Combination of low mean arterial

pressure with high intraocular

development of OAG whereas

pressure increases the risk of

Low BP was associated with the

value is sufficient to restore OBF in certain patients, but may be
were associated with NTG. inadequate as a treatment in patients with significant autoregu-
capillary vessel density

latory dysfunction.14
Some glaucoma patients also present with features of a more
generalized vascular dysfunction. Lindemann et al.79 found a
higher occurrence of impaired autonomic cardiovascular dysreg-
Conclusion

ulation in NTG. The Lifelines Cohort Study found that low heart

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

rate variability, a measurement for autonomic modulation of the
heart, was associated with glaucoma.81 Binggeli et al. used nail-
fold capillaroscopy with cold provocation to examine the relation
CCB Diuretics Beta

CCB Diuretics Beta

CCB Diuretics Beta

ACE inhibitors A2RB

ACE inhibitors A2RB

ACE inhibitors A2RB

between BP and vascular dysregulation in glaucoma patients.

Antihypertensives

Their study revealed that patients with vascular dysregulation

have on average lower systolic and diastolic BP. Both vascular dys-
Nimodipine

blockers

blockers

blockers

regulation and low BP are core elements of Flammer syndrome, of

which the prevalence is higher in NTG.82
Kocatürk et al. assessed the BP charts of healthy patients and
glaucoma patients. They noted that the systolic and diastolic BP
between 32–68

graphs of glaucoma patients seemed blunted compared to those

86 between 40
69.5 and 68.9

of healthy patients, especially in the early morning. This suggests

57.3–72.9)

and 80+
53.7 years

64.5 (IQR,

that early morning blunted sympathetic activity may play a role

in the pathophysiology of glaucoma.83
Age

Another study investigated the autonomic regulation to carbo-

hydrate ingestion and postural change in 19 NTG, 18 POAG and 36
United States

United States

7,336/13,479 United States

control patients, age and gender matched. They concluded that

Ethnicity
Men/ women Country/

both NTG and POAG manifest some systemic autonomic dysregu-

China

lation, but that the characteristics of the dysregulation may differ

between the two subtypes.84
1,580/2,399
236 /318

DISCUSSION
17:3

This systematic review provides an up-to-date evaluation of

7501
Eyes

the interplay between systemic BP and glaucoma progression.

n.s.

n.s.
20

Although there is some discordance, there appears to exist a

bimodal, U-shaped relation between BP and glaucoma progres-
sion.20,57 Both low and high BP relate to lower RNFL and ganglion
277/ 277
Patients

cell thickness, especially in the absence of adequate autoregula-

20,815
3,976

tion on both sides.78 Low BP, whether intrinsic or drug-induced,

20

leads to low OPP and, in the absence of sufficient autoregulation,

Study population

Duke Glaucoma

possibly to ischemia of the optic nerve head. High BP is associ-

glaucoma or
registry of

suspected
glaucoma

ated with higher IOP, higher BP variability and microvascular dis-

controls
NTG and

ease which in turn leads to lower perfusion. Next to nocturnal

NTG

OAG

over-dipping, this review highlights high BP variability as an addi-

tional glaucoma progression risk factor.50,64–66,85 Recent evidence
indicated that an increased reading-to-reading variability and
cohort study

cohort study
case-control

longitudinal

longitudinal
Retrospective,

Retrospective,
Retrospective
Type of study

drops in MAP over 24-h related to progression visual field defects

Prospective

cohort

in patients with POAG,85 especially during the daytime.65 The

study

relation between antihypertensive treatment and glaucoma—in

studies often uncorrected for the presence or severity of hyper-
tension—is insufficiently understood, mostly given the bias of
Table 3. Continued

existing refractory hypertension. Lastly, the correlation of glau-

2021

2022

2022

2022

coma with nocturnal BP dipping has been established and sys-

temic hypotension should be ruled out in case of glaucomatous
not specified
Funk et al.34

Lee et al.71
Hu et al.76

progression, especially in patients with normal or well-controlled

et al.54
Jammal

IOP.4 A simple, non-invasive method such as 24-h ABPM proves to

be a valuable tool in BP assessment.14,37,83 Intensive BP treatment
Table 4: Autoregulation

Type of study Type of Patients Eyes Men/ Country/ Age Systemic Conclusion Significance
glaucoma/ women Ethnicity AHT level
population

Modrzejewska 2015 Case-control POAG and 110 (56 + 54) 110 n.s. Poland Mean 68 years Excluded POAG was associated with P ≤ 0.05
et al.80 study controls significantly higher arterial BP,
increased resistance indices
and significantly lower OPP,
192 | Van Eijgen et al.

DOPP and blood flow velocities.

Vascular factors could have
a vasoconstrictive role in the
glaucomatous endotheliopathy.
Binggeli et al.82 2018 Retrospective Glaucoma 57 n.a. 22/35 Switzerland 17–92 years n.s. Patients with vascular P < 0.05
study patients dysregulation had on average
lower systolic and diastolic BP.
Lindemann 2018 Prospective POAG, 146 (37 + 27 + 82) n.a. 74/72 Germany POAG: 69.9 ± 9.9 Included There is a higher occurrence P < 0.01
et al.79 clinical NTG and years of BP and HRV in NTG which
validation controls NTG: 69.8 ± 8.5 indicates impaired autonomic
study years cardiovascular dysregulation.
Controls:
60.7 ± 15.9 years
Cao et al.84 2018 Case-control POAG, 73 (18 + 19 + 36) n.a. 60/13 Australia 50–80 years Excluded Both NTG and POAG manifest P < 0.05
study NTG and some systemic autonomic
controls dysregulation to carbohydrate
ingestion and postural change,
but the characteristics of
the dysregulation may differ
between the two subtypes.
Kiyota et al.24 2020 Prospective- OAG 16 28 7/9 Japan 55.7 ± 13.4 years Included Weaker ONH tissue vasoreactivity P < 0.05
longitudinal to systemic hyperoxia was,
study among other things, associated
with rapid VFP.
Asefa et al.81 2020 Prospective Primary 86,841 n.s. 35,459/ The Glaucoma: Included Low HRV (a measurement for P ≤ 0.05
population- glaucoma 51,382 Netherlands 53.4 ± 12.7 autonomic modulation of the
based and years Controls: heart), high BP, hypertension and
cohort controls 46.1 ± 12.6 years antihypertensive medication
study were associated with glaucoma.
Papellis et al.78 2021 Prospective Healthy 96 96 58/38 The Average ranged Included Inner retinal thinning was P ≤ 0.045
cohort subjects Netherlands from 55.9 to 57.2 associated with low but
study years old also high BP levels, and with
ineffective autoregulation.

Abbreviations: NTG: normal-tension glaucoma; POAG: primary open-angle glaucoma; BP: blood pressure; OPP: ocular perfusion pressure; DOPP: diastolic ocular perfusion pressure; ONH: optic nerve head; VFP: visual
field progression; HRV: heart rate variability; n.a.: not applicable; n.s.: not specified

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

 The Relevance of Arterial Blood Pressure | 193

and the time of antihypertensive drug intake could increase the Regarding ACE inhibitors, only two studies provided evidence
effect of nocturnal dipping depending on the patients susceptibil- against its use. Chong et al.67 found that ACE inhibitors (and diu-
ity.86 If nocturnal hypotension is detected, change in pharmaco- retics) were associated with more RNFL and GCL thinning after
logical treatment might be considered. Although morning intake adjustment of covariates. Langman et al.100 report higher inci-
would theoretically reduce the risk of nocturnal dipping, the dence of POAG in this group both in current as past intake, which
Hygia and MAPEC trials point to a more pronounced reduction brings the authors to point towards uncontrolled hypertension
of cardiovascular mortality associated with nighttime dosing.4,73,87 rather than the class of medication as culprit.
The clinical implementation of the findings of the SPRINT Taken together the authors speculate that as first line treat-
trial, STEP trial and the most recent guidelines concerning the ment for hypertension in glaucoma patients thiazides and/or to a
treatment of systemic hypertension may have a key role in lesser extent ACE inhibitors or β-blockers, depending on concom-
the management of glaucoma the coming years.11,88,89 The trial itant comorbidities as heart failure, lung or kidney disease, could
demonstrated that treating arterial hypertension to a target of be considered (rather than CCBs). However, validation studies are
less than 120 mm Hg reduced cardiovascular events and the needed to support such clinical recommendations.
overall risk of death in all hypertensive patients.88 Following Ophthalmologists do not commonly treat hypertension and pro-
those findings, the 2017 ACA/AHA hypertension guidelines fessionals who do, haven’t established preferred practice patterns

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

redefined office hypertension as a systolic BP of 130 mm Hg or on the management of arterial BP in their glaucoma patients.17
higher or DBP of 80 mm Hg or higher.90 These stricter targets The importance of arterial BP in glaucoma management has also
broaden the group of patients needing antihypertensive treat- not yet been addressed in recent studies or most guidelines on the
ment and will increase the number of patients with coexisting diagnosis and treatment of arterial hypertension.101 Glaucoma fea-
systemic hypertension and glaucoma. In this group, glauco- tured for the first time in the new hypertension guideline released
matous progression due to medication-induced hypotension is in 2023 by the European Society of Hypertension. Most of our rec-
likely to become more frequent, despite well-controlled IOPs, ommendations below are in line with this guideline.102 Of note, the
causing a clinical dilemma between cardiologists and ophthal- recommendation puts β-blockers forward as mainstay treatment
mologists. Although reducing cardiovascular mortality takes in hypertensive patients with glaucoma, based on one study and
precedence over preserving vision, the impact of visual impair- an possible IOP-lowering effect.42,103,104 Although, β-blockers seem
ment on psychosocial well-being and quality of life should also at least harmless in glaucoma (if not potentially beneficial also
be considered. A balance between quality adjusted life years, due to their IOP-lowering effect), in terms of mortality reduc-
­disability-adjusted life years, and years of life lost must be con- tion, β
­ -blockers seem to be inferior to thiazides or ACE inhibitors
sidered when evaluating patients with glaucoma and concom- and β-blockers lead to greater DBP reduction than thiazides.105–107
itant hypertension. A hypothetical approach could give priority Therefore, this recommendation may be reconsidered in a future
to the independent increase of diastolic BP, given some—older— update of the Hypertension Guidelines.
studies pointing to systolic BP as only modifier of cardiovascular Further studies investigating BP targets and their impact on
risk and the proven importance of diastolic BP in glaucoma.91,92 glaucoma incidence and progression are needed. Additional
Recently some additional evidence regarding the choice of anti- sub-analyses studying the effect of antihypertensive drugs on
hypertensive in association with glaucoma risk has been pub- glaucoma incidence and progression also merit to be investigated
lished. A retrospective study on antihypertensive use in 31,170 more.
glaucoma vs. non-glaucoma participants with arterial hyperten- Limitations of this review are methodological in nature and
sion did not show higher incidence of glaucoma in the groups on inherent to the represented research. Only papers in English were
single diuretics, ACE inhibitors or β-blockers, but did show higher included, OPP and BP parameters are heterogeneously reported,
odds ratios in the groups on ARB monotherapy, CCB monother- and a lot of studies do not adjust for continuous BP levels, or even
apy, and various combination treatments.93 Additionally, a study the mere presence of arterial hypertension, nor other covariates.
on glaucoma entries in the UK biobank (n = 427,480) led to the Based on our systemic literature review, we propose some clinical
conclusion that CCB treatment is associated with a 1.39 odds recommendations for the management of glaucoma patients with
ratio (P = 0.001) on having glaucoma.94 The deleterious effect of concomitant systemic hypertension, summarized in Figure 1, and
CCB on glaucoma incidence was in line with two other recent some research recommendations for future studies on this topic.
meta-analyses.95,96 A possible causal mechanism of this CCB
effect is that impairment of autoregulation might result in no
further pharmaceutical dilation in affected zones and that dila- Clinical recommendations
tion of other—more healthy—capillary beds shunt away blood to - If a patient presents with glaucomatous progression
unaffected areas.96,97 Previously, CCBs (more specifically nifedip- despite normal or well-controlled IOP, 24-h ABPM is use-
ine) and ACE inhibitors have been argued beneficial in the dis- ful to rule out nocturnal systemic hypotension or high BP
cussion around endothelial dysfunction and Flammer syndrome. variability.
This highlights the necessity to adjust for vascular comorbidity - In glaucoma patients with concomitant systemic hyper-
as these drugs might be used in patient groups that are prone to tension a low threshold to perform a 24-h ABPM is justified.
glaucoma due to a vascular cause.98 This also prompts the idea - Antihypertensive adjustment should be based on 24-h
for studies designed to further quantify autoregulation and reti- ABPM. Repeated 24-h ABPM is recommended after medica-
nal vascular response before and after start of antihypertensive tion changes.
medication including the different classes of CCBs. - Diagnosed nocturnal (over-)dipping or high BP variabil-
Regarding β-blockers, one meta-analysis also points to a ity in a glaucoma patient should prompt a collaborative
decreased glaucoma incidence (OR 0.83 [0.75–0.92]). However, treatment strategy between the treating physician and
only in one of the included studies, adjustment for covariates as ophthalmologist.
BMI, smoking status, age, gender, and incident hypertension was - In case of high daytime BP fluctuation, high (to normal) BP
executed. In this study, the lower OR for β-blockers and glaucoma and relatively absent nocturnal dipping, intensification of
incidence was barely significant (0.91 [0.83–0.99]).95,99 the antihypertensive treatment could lower BP variability.
194 | Van Eijgen et al.

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Figure 1. Figure of a simplified, individual example of a 24-h ABPM with overlay of recommended BP levels. The recommendations are based on
the cited references that are also mentioned in the manuscript text, where the daytime upper limits are derived from the ACA/AHA hypertension
guidelines.90 This includes the daytime systolic optimum between 107 and 130 mm Hg,60 the daytime diastolic optimum between 63 and 80 mm Hg,60
the nocturnal MAP Dresden safety range between 65 and 90 mm Hg47 and the nocturnal diastolic optimum between 60 and 70 mm Hg.12 High BP
variability features in this review as glaucoma progression risk factor, however clear cut-off values have not been put forward yet.50,64–66,85 This patient
exhibits all mentioned risk factors for glaucoma progression except overall nocturnal MAP that is still in the Dresden safety range.47 These overlays
could visually aid the clinician in evaluating 24-h ABPMs. ABPM, ambulatory blood pressure measurement; DBP, diastolic blood pressure; MAP, mean
arterial pressure; SBP, systolic blood pressure.

- In case of nocturnal (over-)dippers, morning dosing of anti- reports financial support for clinical trials from Aerie during
hypertensive medication could be considered (taking into the conduct of the study; and grants and personal fees from
account the pros and cons as discussed above). Omikron, Santen and Thea, personal fees from Allergan/AbbVie,
- Up till now there is insufficient evidence to justify decrease Elios Vision, EyeD, Horus, Omikron, Santen, Théa, and personal
of antihypertensive medication in case of merely nocturnal fees and intellectual property from Mona outside the submitted
over-dipping. work.
- Currently available evidence suggests that CCB may not be
recommended as first line treatment in patients with both
glaucoma and arterial hypertension. Instead, thiazides
REFERENCES
and/or to a lesser extent ACE inhibitors might be more
suitable. β-blockers might also be potentially beneficial in 1. Leeman M, Kestelyn P. Glaucoma and blood pressure.
glaucoma. However, additional evidence is needed to sup- Hypertension 2019; 73:944–950.
port such clinical recommendations. 2. Yoshikawa T, Obayashi K, Miyata K, Saeki K, Ogata N.
Increased nighttime blood pressure in patients with glaucoma
­cross-sectional analysis of the LIGHT Study. Ophthalmology 2019;
Research recommendations 126:1366–1371.
- Future research might benefit from BP data being presented 3. Wu AN, Khawaja AP, Pasquale LR, Stein JD. A review of systemic
continuously, and when categorized, being presented by medications that may modulate the risk of glaucoma. Eye 2020;
different cut-off values to enable comparison.108 34:12–28.
- Future research should correct for covariates, including the 4. Yilmaz KC, Gungor SS, Ciftci O, Akman A, Muderrisoglu H.
presence of hypertension, when comparing different types Relationship between primary open angle glaucoma and blood
of antihypertensive medication. pressure. Acta Cardiol 2020; 75:54–58.
5. Raman P, Suliman NB, Zahari M, Kook M, Ramli N. Low noctur-
nal diastolic ocular perfusion pressure as a risk factor for NTG
Supplementary Data progression: a 5-year prospective study. Eye (London, England)
Supplementary materials are available at American Journal of 2018; 32:1183–1189.
Hypertension (http://ajh.oxfordjournals.org). 6. Bowe A, Grünig M, Schubert J, Demir M, Hoffmann V, Kütting F,
Pelc A, Steffen HM. Circadian variation in arterial blood pres-
sure and glaucomatous optic neuropathy—a systematic review
Acknowledgments and meta-analysis. Am J Hypertens 2015; 28:1077–1082.
Jan Van Eijgen received a PhD fellowship fundamental research 7. Grzybowski A, Och M, Kanclerz P, Leffler C, De Moraes CG.
from the Research Fund Flanders (11B1321N). Primary open angle glaucoma and vascular risk factors: a
review of population based studies from 1990 to 2019. J Clin Med
2020; 9:761.
Conflict of Interest 8. Hussain SD, Quratulain, Afzal R. ANALYSIS OF EFFECTS OF
None regarding to this publication. The authors report no con- BLOOD PRESSURE IN IOP IN PRIMARY OPEN ANGLE GLAUCOMA.
flict of interest regarding the submitted work. Ingeborg Stalmans Indo Am J Pharm Sci 2019; 6:4834–4837.
 The Relevance of Arterial Blood Pressure | 195

9. Karadag R, Koyun E, Ozsoy I, Caliskan M. Evaluation of the of open-angle glaucoma with perfusion pressure status in the
24-hour intraocular pressure and systemic blood pressure at Thessaloniki Eye Study. Am J Ophthalmol 2013; 155:843–851.
the same time. J Fr Ophtalmol 2019; 42:739–745. 27. Chan TCW, Bala C, Siu A, Wan F, White A. Risk factors for
10. Holappa M, Vapaatalo H, Vaajanen A. Many faces of rapid glaucoma disease progression. Am J Ophthalmol 2017;
renin-angiotensin system—focus on eye. Open Ophthalmol J
­ 180:151–157.
2017; 11:122–142. 28. Feraru C, Chiselita D, Pantalon A. Long-term progression and
11. De Moraes CG, Cioffi GA, Weinreb RN, Liebmann JM. New rec- risk factors in primary open-angle glaucoma in clinical care.
ommendations for the treatment of systemic hypertension Spektrum Der Augenheilkunde 2016; 30:181–189.
and their potential implications for glaucoma management. J 29. Chang AY, Tsamis E, Blumberg DM, Al-Aswad LA, Cioffi GA,
Glaucoma 2018; 27:567–571. Hood DC, Liebmann JM, De Moraes CG. The role of intraocular
12. Kwon J, Jo YH, Jeong D, Shon K, Kook MS. Baseline systolic ver- pressure and systemic hypertension in the progression of glau-
sus diastolic blood pressure dip and subsequent visual field comatous damage to the macula. J Glaucoma 2022; 31:317–321.
progression in normal-tension glaucoma. Ophthalmology 2019; 30. Plotnikov D, Huang Y, Khawaja AP, Foster PJ, Zhu Z, Guggenheim
126:967–979. JA, He M. High blood pressure and intraocular pressure: a
13. Marjanovic I, Marjanovic M, Stojanov V, Hentova-Sencanic P, Mendelian randomization study. Invest Ophthalmol Vis Sci 2022;

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Markovic V, Bozic M, Vukcevic-Milosevic G. The role of 24-hour 63:29.
ambulatory blood pressure monitoring in hypertensive 31. Actis AG, Versino E, Brogliatti B, Rolle T. Risk factors for Primary
patients with normal-tension glaucoma. Srp Arh Celok Lek 2015; Open Angle Glaucoma (POAG) Progression: a study ruled in
143:525–530. Torino. Open Ophthalmol J 2016; 10:129–139.
14. Levine RM, Yang A, Brahma V, Martone JF. Management of blood 32. Dascalu AM, Stana D, Nicolae VA, Cirstoveanu C, Vancea G,
pressure in patients with glaucoma. Curr Cardiol Rep 2017; 19:8. Serban D, Socea B. Association between vascular comorbidity
15. Kwon J, Lee J, Choi J, Jeong D, Kook MS. Association between and glaucoma progression: a four-year observational study. Exp
nocturnal blood pressure dips and optic disc hemorrhage in Ther Med 2021; 21:283.
patients with normal-tension glaucoma. Am J Ophthalmol 2017; 33. Dielemans I, Vingerling JR, Algra D, Hofman A, Grobbee DE, de
176:87–101. Jong PT. Primary open-angle glaucoma, intraocular pressure,
16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP. Preferred and systemic blood pressure in the general elderly population:
reporting items for systematic reviews and meta-analyses: The The Rotterdam Study. Ophthalmology 1995; 102:54–60.
PRISMA statement. PLoS Med 2009; 6:e123–130. 34. Funk RO, Hodge DO, Kohli D, Roddy GW. Multiple systemic vas-
17. Skrzypecki J, Ufnal M, Szaflik JP, Filipiak KJ. Blood pressure and cular risk factors are associated with low-tension glaucoma. J
glaucoma: at the crossroads between cardiology and ophthal- Glaucoma 2022; 31:15–22.
mology. Cardiol J 2019; 26:8–12. 35. Gillespie BW, Niziol LM, Ehrlich JR, Johnson CA, Caprioli J,
18. Tsai ASH, Aung T, Yip WF, Wong TY, Cheung CYL. Relationship of VanVeldhuisen PC, Lichter PR, Musch DC. Demographic, comor-
intraocular pressure with central aortic systolic pressure. Curr bid, and clinical variables associated with pointwise visual field
Eye Res 2016; 41:377–382. damage in glaucoma: data from the AGIS and CIGTS Clinical
19. Chung HJ, Hwang HB, Lee NY. The association between primary Trials. Transl Vis Sci Technol 2021; 10:28.
open-angle glaucoma and blood pressure: two aspects of hyper- 36. Kuang TM, Xirasagar S, Kao YW, Shia BC, Lin HC. Association
tension and hypotension. Biomed Res Int 2015; 2015:827516. of systemic hypertension with primary open-angle glaucoma:
20. Cantor E, Mendez F, Rivera C, Castillo A, Martinez-Blanco A. a population-based case–control study. Am J Ophthalmol 2020;
Blood pressure, ocular perfusion pressure and open-angle glau- 218:99–104.
coma in patients with systemic hypertension. Clin Ophthalmol 37. Lee SU, Park HS, Kim BJ, Kim HS, Heo JH, Im SI. Association of
(Auckland, N.Z.) 2018; 12:1511–1517. dipping status of blood pressure, visual field defects, and retinal
21. Ch’ng TW, Chua CY, Ummi Kalsom MA, Azhany Y, Gong V, nerve fiber layer thickness in patients with normotensive glau-
Rasool A, Liza-Sharmini AT. Ocular perfusion pressure and coma. Medicine (Baltim) 2020; 99:e23565.
severity of glaucoma: is there a link? J Curr Glaucoma Pract 38. Marshall H, Mullany S, Qassim A, Siggs O, Hassall M, Ridge
2021; 15:78–85. B, Nguyen T, Awadalla M, Andrew NH, Healey PR, Agar A,
22. Choi J, Kook MS. Systemic and ocular hemodynamic risk factors Galanopoulos A, Hewitt AW, MacGregor S, Graham SL, Mills R,
in glaucoma. Biomed Res Int 2015; 2015:141905. Shulz A, Landers J, Casson RJ, Craig JE. Cardiovascular disease
23. Chua J, Chin CWL, Hong J, Chee ML, Le TT, Ting DSW, Wong predicts structural and functional progression in early glau-
TY, Schmetterer L. Impact of hypertension on retinal capillary coma. Ophthalmology 2021; 128:58–69.
microvasculature using optical coherence tomographic angiog- 39. Mitchell P, Lee AJ, Rochtchina E, Wang JJ. Open-angle glaucoma
raphy. J Hypertens 2019; 37:572–580. and systemic hypertension: the blue mountains eye study. J
24. Kiyota N, Shiga Y, Yasuda M, Aizawa N, Omodaka K, Tsuda S, Pak Glaucoma 2004; 13:319–326.
K, Kunikata H, Nakazawa T. The optic nerve head vasoreactive 40. Nislawati R, Taufik Fadillah Zainal A, Ismail A, Waspodo N, Kasim
response to systemic hyperoxia and visual field defect progres- F, Gunawan AMAK. Role of hypertension as a risk factor for
sion in open-angle glaucoma, a pilot study. Acta Ophthalmologica open-angle glaucoma: a systematic review and m ­ eta-analysis.
2020; 98:e747–753. BMJ Open Ophthalmol 2021; 6:e000798.
25. Park CK, Lee K, Kim EW, Kim S, Lee SY, Kim CY, Seong GJ, Bae HW. 41. Rim TH, Lee SY, Kim SH, Kim SS, Kim CY. Increased incidence
Effect of systemic blood pressure on optical coherence tomog- of open-angle glaucoma among hypertensive patients: an
raphy angiography in glaucoma patients. Eye (London, England) 11-year nationwide retrospective cohort study. J Hypertens 2017;
2021; 35:1967–1976. 35:729–736.
26. Topouzis F, Wilson MR, Harris A, Founti P, Yu F, Anastasopoulos 42. Zheng W, Dryja TP, Wei ZY, Song DY, Tian HJ, Kahler KH, Khawaja
E, Pappas T, Koskosas A, Salonikiou A, Coleman AL. Association AP. Systemic medication associations with presumed advanced
196 | Van Eijgen et al.

or uncontrolled primary open-angle glaucoma. Ophthalmology 59. Shin JW, Jo YH, Song MK, Won HJ, Kook MS. Nocturnal blood
2018; 125:984–993. pressure dip and parapapillary choroidal microvasculature
43. Khatri A, Shrestha JK, Thapa M, Khatri BK, Kharel M. Severity dropout in normal-tension glaucoma. Sci Rep 2021; 11:206.
of primary open-angle glaucoma in patients with hypertension 60. Lee K, Yang H, Kim JY, Seong GJ, Kim CY, Bae HW. Risk factors
and diabetes. Diabetes Metab Syndr Obes 2018; 11:209–215. associated with structural progression in normal-tension glau-
44. Gangwani RA, Lee JW, Mo HY, Sum R, Kwong AS, Wang JH, coma: intraocular pressure, systemic blood pressure, and myo-
Tsui WW, Chan JC, Lai JS. The correlation of retinal nerve fiber pia. Invest Ophthalmol Vis Sci 2020; 61:35.
layer thickness with blood pressure in a Chinese Hypertensive 61. Mena LJ, Felix VG, Melgarejo JD, Maestre GE. 24-Hour blood pres-
Population. Medicine (Baltim) 2015; 94:e947. sure variability assessed by average real variability: a system-
45. Kosior-Jarecka E, Wrobel-Dudzinska D, Lukasik U, Zarnowski atic review and meta-analysis. J Am Heart Assoc 2017; 6:e006895.
T. Ocular and systemic risk factors of different morpholo- 62. Bill A. Glaucoma: conceptions of a disease: pathogenesis, diag-
gies of scotoma in patients with normal-tension glaucoma. J nosis, therapy. In Heilmann K, Richardson KT (eds), Physiological
Ophthalmol 2017; 2017:1480746. Aspects of the Circulation in the Optic Nerve. Saunders: Philadelphia,
46. O’Brien E, Sheridan J, O’Malley K. Dippers and non-dippers. 1978, pp. 97–103.
Lancet 1988; 2:397. 63. Plange N, Kaup M, Daneljan L, Predel HG, Remky A, Arend O.

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

47. Pillunat KR, Spoerl E, Jasper C, Furashova O, Hermann C, 24-h blood pressure monitoring in normal tension glaucoma:
Borrmann A, Passauer J, Middeke M, Pillunat LE. Nocturnal blood night-time blood pressure variability. J Hum Hypertens 2006;
pressure in primary open-angle glaucoma. Acta Ophthalmologica 20:137–142.
2015; 93:e621–e626. 64. Melgarejo J, Maestre GE, Mena LJ, Lee JH, Petitto M, Chavez CA,
48. Marjanovic I, Marjanovic M, Martinez A, Markovic V, Bozic M, Calmon G, Silva E, Thijs L, Al-Aswad LA, Terwilliger J, De Moraes
Stojanov V. Relationship between blood pressure and retrobul- CG, Wei FF, Vanassche T, Verhamme P, Staessen JA, Zhang ZY.
bar blood flow in dipper and non-dipper primary open-angle Normal-tension glaucomatous optic neuropathy is related
glaucoma patients. Eur J Ophthalmol 2016; 26:588–593. to blood pressure variability in the Maracaibo aging study. J
49. Jin SW, Seo HR, Rho SS, Rho SH. The effects of nocturnal Hypertens 2021; 39:e142.
dip and blood pressure variability on paracentral scotoma 65. Melgarejo JD, Eijgen JV, Wei D, Maestre GE, Al-Aswad LA, Liao
in early open-angle glaucoma. Semin Ophthalmol 2017; 32: CT, Mena LJ, Vanassche T, Janssens S, Verhamme P, Keer KV,
504–510. Stalmans I, Zhang ZY. Progression of functional and structural
50. Melgarejo JD, Lee JH, Petitto M, Yepez JB, Murati FA, Jin Z, Chavez glaucomatous damage in relation to diurnal and nocturnal dips
CA, Pirela RV, Calmon GE, Lee W, Johnson MP, Mena LJ, Al-Aswad in mean arterial pressure. Front Cardiovasc Med 2022; 9:1024044.
LA, Terwilliger JD, Allikmets R, Maestre GE, De Moraes CG. 66. Melgarejo JD, Eijgen JV, Maestre GE, Al-Aswad LA, Thijs L, Mena
Glaucomatous optic neuropathy associated with nocturnal dip LJ, Lee JH, Terwilliger JD, Petitto M, Chavez CA, Brito M, Calmon G,
in blood pressure: findings from the Maracaibo Aging Study. Silva E, Wei DM, Cutsforth E, Keer KV, De Moraes CG, Vanassche
Ophthalmology 2018; 125:807–814. T, Janssens S, Stalmans I, Verhamme P, Staessen JA, Zhang ZY.
51. Chiotoroiu SM, Stefaniu O, Noaghi M, Teodorescu A, Taina L. Open-angle glaucomatous optic neuropathy is related to dips
THE ROLE OF SYSTEMIC BLOOD PRESSURE IN GLAUCOMA rather than increases in the mean arterial pressure over 24-h.
PROGRESSION. Rom J Ophthalmol 2015; 59:141–147. Am J Hypertens 2022; 35:703–714.
52. Lee J, Choi J, Jeong D, Kim S, Kook MS. Relationship between day- 67. Chong RS, Chee ML, Tham YC, Majithia S, Thakur S, Teo ZL, Da
time variability of blood pressure or ocular perfusion pressure Soh Z, Chua J, Tan B, Wong DWK, Schmetterer L, Sabanayagam
and glaucomatous visual field progression. Am J Ophthalmol C, Cheng CY. Association of antihypertensive medication with
2015; 160:522–537.e1. retinal nerve fiber layer and ganglion cell-inner plexiform layer
53. Charlson ME, de Moraes CG, Link A, Wells MT, Harmon G, thickness. Ophthalmology 2020; 128:393–400.
Peterson JC, Ritch R, Liebmann JM. Nocturnal systemic hypoten- 68. Topouzis F, Coleman AL, Harris A, Jonescu-Cuypers C, Yu F,
sion increases the risk of glaucoma progression. Ophthalmology Mavroudis L, Anastasopoulos E, Pappas T, Koskosas A, Wilson
2014; 121:2004–2012. MR. Association of blood pressure status with the optic disk
54. Jammal AA, Berchuck SI, Mariottoni EB, Tanna AP, Costa structure in non-glaucoma subjects: the Thessaloniki eye study.
VP, Medeiros FA. Blood pressure and glaucomatous pro- Am J Ophthalmol 2006; 142:60–67.
gression in a large clinical population. Ophthalmology 2022; 69. Horwitz A, Klemp M, Jeppesen J, Tsai JC, Torp-Pedersen C, Kolko
129:161–170. M. Antihypertensive medication postpones the onset of glau-
55. Gore V, Shah P, Kanhere M, Gore S. Relationship between optical coma: evidence from a nationwide study. Hypertension 2017;
perfusion pressure and systemic blood pressure on glaucoma: 69:202–210.
case–control study. Oman J Ophthalmol 2019; 12:150–155. 70. Pappelis K, Loiselle AR, Visser S, Jansonius NM. Association of
56. Krishnan VM, Gulnar PD, Anand RV, Vijayakumar C, systemic medication exposure with glaucoma progression and
Balasubramaniyan G. Ocular and systemic risk factors and glaucoma suspect conversion in the Groningen Longitudinal
correlation with glaucomatous damage in normal tension glau- Glaucoma Study. Invest Ophthalmol Vis Sci 2019; 60:4548–4555.
coma. Cureus 2018; 10:19. 71. Lee EB, Hu W, Singh K, Wang SY. The association among blood
57. Suić SP, Skegro I, Jandroković S, Kordić R, Kutija MB. Influence pressure, blood pressure medications, and glaucoma in a
of diastolic blood pressure on glaucoma progression in glau- nationwide electronic health records database. Ophthalmology
coma patients with systemic hypertension. Coll Antropol 2015; 2022; 129:276–284.
39:719–722. 72. Gracitelli CPB, De Faria NVL, Almeida I, Dias DT, Vieira JM,
58. Baek SU, Ha A, Kim DW, Jeoung JW, Park KH, Kim YK. Risk factors Dorairaj S, Kanadani FN, Prata TS. Exercise-induced changes in
for disease progression in low-teens normal-tension glaucoma. ocular blood flow parameters in primary open-angle glaucoma
Br J Ophthalmol 2020; 104:81–86. patients. Ophthalmic Res 2019; 63:309–313.
 The Relevance of Arterial Blood Pressure | 197

73. Siddiqui M, Iltis J, Yanev P, Sladic J, Huynh C, Nolan D, Singer Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman
M. Effect of systemic antihypertensives on change in intraocu- WC, Cheung AK, Ambrosius WT; SPRINT Research Group. A ran-
lar pressure after initiating topical prostaglandins for primary domized trial of intensive versus standard blood-pressure con-
open-angle glaucoma. Clin Ophthalmol (Auckland, N.Z.) 2019; trol. N Engl J Med 2015; 373:2103–2116.
13:207–213. 89. Zhang W, Zhang S, Deng Y, Wu S, Ren J, Sun G, Yang J, Jiang Y, Xu
74. Hohn R, Mirshahi A, Nickels S, Schulz A, Wild PS, Blettner M, X, Wang TD, Chen Y, Li Y, Yao L, Li D, Wang L, Shen X, Yin X, Liu W,
Pfeiffer N. Cardiovascular medication and intraocular pressure: Zhou X, Zhu B, Guo Z, Liu H, Chen X, Feng Y, Tian G, Gao X, Kario
results from the Gutenberg Health Study. Br J Ophthalmol 2017; K, Cai J; STEP Study Group. Trial of intensive blood-­pressure
101:1633–1637. control in older patients with hypertension. N Engl J Med 2021;
75. Anton-Lopez A, Moreno-Montanes J, Duch-Tuesta S, Corsino 385:1268–1279.
Fernandez-Vila P, Garcia-Feijoo J, Milla-Grino E, Munoz-Negrete 90. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ,
FJ, Pablo-Julvez L, Rodriguez-Agirretxe I, Urcelay-Segura JL, Himmelfarb CD, DePalma SM, Gidding S, Jamerson KA, Jones
Ussa-Herrera F, Villegas-Perez MP; y Grupo Español de Estilos de DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer
Vida y Glaucoma. Lifestyles guide and glaucoma (II) diet, sup- CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson
plements, drugs, sleep, pregnancy, and systemic hypertension. JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

Arch Soc Esp Oftalmol 2018; 93:76–86. ASPC/NMA/PCNA Guideline for the prevention, detection, eval-
76. Hu X, Wang X, Dai Y, Qiu C, Shang K, Sun X. Effect of Nimodipine uation, and management of high blood pressure in adults. J Am
on macular and peripapillary capillary vessel density in patients Coll Cardiol 2018; 71:e127–e248.
with normal-tension glaucoma using optical coherence tomog- 91. Benetos A, Thomas F, Bean K, Gautier S, Smulyan H, Guize L.
raphy angiography. Curr Eye Res 2021; 46:1861–1866. Prognostic value of systolic and diastolic blood pressure in
77. Wang SV, Li N, Rice DS, Grosskreutz CL, Dryja TP, Prasanna G, Lii treated hypertensive men. Arch Intern Med 2002; 162:577–581.
J, Gagne JJ. Using healthcare databases to refine understanding 92. Lindenstrøm E, Boysen G, Nyboe J. Influence of systolic and dia-
of exploratory associations between drugs and progression of stolic blood pressure on stroke risk: a prospective observational
open-angle glaucoma. Clin Pharm Ther 2019; 106:874–883. study. Am J Epidemiol 1995; 142:1279–1290.
78. Pappelis K, Jansonius NM. U-shaped effect of blood pressure on 93. Lee JS, Cha HR, Bae HW, Lee SY, Choi W, Lee SW, Kim CY. Effect
structural OCT metrics and retinal perfusion in ophthalmolog- of antihypertensive medications on the risk of open-angle glau-
ically healthy subjects. Invest Ophthalmol Vis Sci 2021; 62:5. coma. Sci Rep 2023; 13:16224.
79. Lindemann F, Kuerten D, Koch E, Fuest M, Fischer C, Voss A, 94. Kastner A, Stuart KV, Montesano G, De Moraes CG, Kang JH,
Plange N. Blood pressure and heart rate variability in primary Wiggs JL, Pasquale LR, Hysi P, Chua SYL, Patel PJ, Foster PJ,
open-angle glaucoma and normal tension glaucoma. Curr Eye Khaw PT, Khawaja AP; UK Biobank Eye and Vision Consortium.
Res 2018; 43:1507–1513. Calcium channel blocker use and associated glaucoma and
80. Modrzejewska M, Grzesiak W, Zaborski D, Modrzejewska A. The related traits among UK biobank participants. JAMA Ophthalmol
role of lipid dysregulation and vascular risk factors in glau- 2023; 141:956–964.
comatous retrobulbar circulation. Bosn J Basic Med Sci 2015; 95. Leung G, Grant A, Garas AN, Li G, Freeman EE. A Systematic
15:50–56. review and meta-analysis of systemic antihypertensive medica-
81. Asefa NG, Neustaeter A, Jansonius NM, Snieder H. Autonomic tions with intraocular pressure and glaucoma. Am J Ophthalmol
dysfunction and blood pressure in glaucoma patients: the 2023; 255:7–17.
Lifelines Cohort Study. Invest Ophthalmol Vis Sci 2020; 61:25. 96. Vergroesen JE, Schuster AK, Stuart KV, Asefa NG, Cougnard-
82. Binggeli T, Schoetzau A, Konieczka K. In glaucoma patients, Grégoire A, Delcourt C, Schweitzer C, Barreto P, Coimbra R,
low blood pressure is accompanied by vascular dysregulation. Foster PJ, Luben RN, Pfeiffer N, Stingl JV, Kirsten T, Rauscher
EPMA J 2018; 9:387–391. FG, Wirkner K, Jansonius NM, Arnould L, Creuzot-Garcher CP,
83. Kocaturk T, Akgullu C, Evlicoglu GE, Omurlu IK, Cakmak H, Stricker BH, Keskini C, Topouzis F, Bertelsen G, Eggen AE, Bikbov
Eryilmaz U, Dayanir V. Diurnal blood pressure parameters in MM, Jonas JB, Klaver CCW, Ramdas WD, Khawaja AP; European
normal tension glaucoma, primary open angle glaucoma, and Eye Epidemiology Consortium. Association of systemic medica-
healthy subjects. Anatol J Cardiol 2017; 18:62–67. tion use with glaucoma and intraocular pressure: The European
84. Cao L, Graham SL, Pilowsky PM. Carbohydrate ingestion induces Eye Epidemiology Consortium. Ophthalmology 2023; 130:893–906.
differential autonomic dysregulation in normal-tension glau- 97. Araie M, Mayama C. Use of calcium channel blockers for glau-
coma and primary open angle glaucoma. PLoS One 2018; 13:21. coma. Prog Retin Eye Res 2011; 30:54–71.
85. Melgarejo JD, Eijgen JV, Wei D, Maestre GE, Al-Aswad LA, Liao CT, 98. Barthelmes J, Nägele MP, Ludovici V, Ruschitzka F, Sudano I,
Mena LJ, Vanassche T, Janssens S, Verhamme P, Zhang ZY, Keer Flammer AJ. Endothelial dysfunction in cardiovascular disease
KV, Stalmans I. Effect of 24-h blood pressure dysregulations and and Flammer syndrome-similarities and differences. Epma J
reduced ocular perfusion pressure in open-angle glaucoma pro- 2017; 8:99–109.
gression. J Hypertens 2023; 41:1785–1792. 99. Yuan Y, Wang W, Shang X, Xiong R, Ha J, Zhang L, Zhu Z, He M.
86. Kwon J, Lee J, Choi J, Jeong D, Kook MS. Association between Use of antihypertensive medications and the risk of glaucoma
nocturnal blood pressure dips and optic disc hemorrhage in onset: findings from the 45 and Up Study. Clin Exp Ophthalmol
patients with normal-tension glaucoma. Am J Ophthalmol 2017; 2022; 50:598–607.
181:177–178. 100. Langman MJ, Lancashire RJ, Cheng KK, Stewart PM. Systemic
87. Ho CLB, Chowdhury EK, Doust J, Nelson MR, Reid CM. The effect hypertension and glaucoma: mechanisms in common and
of taking blood pressure lowering medication at night on car- co-occurrence. Br J Ophthalmol 2005; 89:960–963.
diovascular disease risk: a systematic review. J Hum Hypertens 101. Bowe A, Demir M, Hoffmann V, Kütting F, Steffen HM. Response
2021; 35:308–314. to “Circadian arterial blood pressure variation and glaucoma
88. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, progression: more questions than answers?” Am J Hypertens
Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, 2015; 28:1184–1185.
198 | Van Eijgen et al.

102. Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, medication and intraocular pressure in a British population: the
Januszewicz A, Muiesan ML, Tsioufis K, Agabiti-Rosei E, EPIC-Norfolk Eye Study. Ophthalmology 2014; 121:1501–1507.
Algharably EAE, Azizi M, Benetos A, Borghi C, Hitij JB, 104. Ho H, Shi Y, Chua J, Tham YC, Lim SH, Aung T, Wong TY, Cheng CY.
Cifkova R, Coca A, Cornelissen V, Cruickshank JK, Cunha PG, Association of systemic medication use with intraocular pressure
Danser AHJ, Pinho RM, Delles C, Dominiczak AF, Dorobantu in a multiethnic Asian Population: The Singapore Epidemiology
M, Doumas M, Fernández-Alfonso MS, Halimi JM, Járai Z, of Eye Diseases Study. JAMA Ophthalmol 2017; 135:196–202.
Jelaković B, Jordan J, Kuznetsova T, Laurent S, Lovic D, Lurbe 105. Wright JM, Musini VM, Gill R. First-line drugs for hypertension.
E, Mahfoud F, Manolis A, Miglinas M, Narkiewicz K, Niiranen Cochrane Database Syst Rev 2018; 4:CD001841.
T, Palatini P, Parati G, Pathak A, Persu A, Polonia J, Redon J, 106. Chen YJ, Li LJ, Tang WL, Song JY, Qiu R, Li Q, Xue H, Wright JM.
Sarafidis P, Schmieder R, Spronck B, Stabouli S, Stergiou G, First-line drugs inhibiting the renin angiotensin system versus
Taddei S, Thomopoulos C, Tomaszewski M, Van de Borne P, other first-line antihypertensive drug classes for hypertension.
Wanner C, Weber T, Williams B, Zhang ZY, Kjeldsen SE. 2023 Cochrane Database Syst Rev 2018; 2018:Cd008170.
ESH Guidelines for the management of arterial hyperten- 107. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-
sion The Task Force for the management of arterial hyper- blockers for hypertension. Cochrane Database Syst Rev 2017;
tension of the European Society of Hypertension: endorsed 1:CD002003.

Downloaded from https://academic.oup.com/ajh/article/37/3/179/7444792 by guest on 23 October 2024

by the International Society of Hypertension (ISH) and 108. Barbosa-Breda J, Abegão-Pinto L, Van Keer K, Jesus DA, Lemmens
the European Renal Association (ERA). J Hypertens 2023; S, Vandewalle E, Rocha-Sousa A, Stalmans I. Heterogeneity in
41:1874–2071. arterial hypertension and ocular perfusion pressure definitions:
103. Khawaja AP, Chan MP, Broadway DC, Garway-Heath DF, Luben towards a consensus on blood pressure-related parameters for
R, Yip JL, Hayat S, Wareham NJ, Khaw KT, Foster PJ. Systemic glaucoma studies. Acta Ophthalmol 2019; 97:e487–e492.