REVIEW

CURRENT
OPINION Hypertension and the eye
Lazaros Konstantinidis and Yan Guex-Crosier

Purpose of review
Hypertension is the primary risk factor for cardiovascular disease and mortality that consists a major public
health issue worldwide. Hypertension triggers a series of pathophysiological ocular modifications affecting
significantly the retinal, choroidal, and optic nerve circulations that result in a range of ocular effects.
The retina is the only place in the body where microvasculature can be directly inspected, providing
valuable information on hypertension related systemic risks.
The aim of this review is to provide an update on latest advances regarding the detection and significance
of hypertension related eye signs.
Recent findings
It’s been shown that measurable retinal microvascular changes may precede progression of systemic
microvascular disease.
Last years, there are emerging advances in the field retinal imaging and computer software analysis that
have enabled the objective and accurate assessment of retinal vascular caliber, while in association with
latest epidemiological studies several other retinal vascular features have been recognized, such as
vascular length-to-diameter ratio, and wall-to-lumen ratio that may also be associated to hypertension.
Additionally, recent genetic studies have provided some insight to vascular pathophysiological processes
having correlated new chromosome’s loci to hypertensive retinopathy signs.
Summary
Assessment of hypertensive retinopathy signs may convey additional prognostic information on the risk of
end-organ damage and may alert for urgent systemic management or even preventive systemic therapies.
Further development of retinal vascular imaging and computerized system may provide a significant tool to
improve the diagnosis, prognosis, and management of hypertension in clinical practice.
Keywords
hypertensive retinopathy, retina, systemic hypertension

INTRODUCTION that may elucidate pathophysiological processes

Hypertension consists a major public health issue
accounting for 9.4 million deaths worldwide every
year [1].
Hypertension that is defined as a systolic blood
pressure (BP) equal to or above 140 mmHg and/or
diastolic BP equal to or above 90 mmHg [2].
In young adults or adolescents, the definition of
hypertension varies according to percentiles for
age and height [3].
Hypertension triggers a series of pathophysiolog-
ical modifications affecting significantly the retinal,
choroidal, and optic nerve circulations. Hypertensive
retinopathy is the most common manifestation, and
its presence is predictive of stroke [4], congestive
heart failure, and cardiovascular mortality [5].
Last years, there are emerging advances in the
field of hypertensive-related ocular manifestations
retinopathy that include advances in retinal imag-
ing, computer software analysis, and genetic studies
of hypertensive retinopathy. Conversely, retinal
vasculature assessment may allow the study of
new therapies for hypertension [6].
CLINICAL OCULAR MANIFESTATIONS OF
HYPERTENSION
Hypertensive retinopathy
Retinopathy is the most common manifestation of
hypertension, which develops because of acute and/
Jules-Gonin Eye Hospital, FAA, University of Lausanne, Switzerland
Correspondence to Dr Yan Guex-Crosier, MD, Head of Immuno-infecti-
ology Unit, Jules-Gonin Eye Hospital, 15 av. De France, CH-1004
Lausanne, Switzerland. Tel: +41 21 626 8595; fax: +41 21 626
6122; e-mail: yan.guex@fa2.ch
Curr Opin Ophthalmol 2016, 27:514–521
DOI:10.1097/ICU.0000000000000307

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KEY POINTS
! Presence of hypertensive retinopathy may convey
prognostic information on the risk of
cardiovascular disease.
! Retinal arteriolar narrowing is associated with an
increased risk of hypertension and may precede the
development of hypertension.
! Wall-to-lumen ratio of retinal arterioles may be
predictive of end-organ damage. Adaptive optics is a
promising tool allowing precise wall-to-lumen sizing
of arterioles.
! Optical coherence tomography (OCT) may be a useful
tool to assess retinal and choroidal changes in
malignant hypertension.
! Intraocular injections of antivascular endothelial growth
factors (anti-VEGF) may be a useful adjunctive therapy
in the management of some selected cases of severe
hypertensive retinopathy.
or chronic elevations in BP. It is characterized by a
wide spectrum of retinal vessels changes reflecting
the severity and duration of BP elevation [7 ,8–10].
&
Clinical manifestations of retinal damage are
classified in different grades.
The classical classification of hypertensive
retinopathy was provided by the Keith–Wagener–
Barker classification (KWB) [11], and is defined by
four grades of retinal damage: grade 1 (narrowing),
grade 2 (arteriovenous crossings), grade 3 (hemor-
rhages and exudates), and grade 4 (papilloedema).
KWB scale remains the most widely cited grad-
ing system, however, it has been in debate for years
since this classification is not adequately sensitive to
differentiate grade 1 from grade 2 in clinical prac-
tice. More importantly, these lower grades of retin-
opathy have not been shown to be closely correlated
to BP levels as well as validated markers of target
organ damage [7 ].
&
For these reasons a simplified grading system has
been proposed in 2004 by Mitchell–Wong combin-
ing grades 1 and 2 of KWB in one stage [12].
The Mitchell–Wong grading system is defined
by three grades as follows:
Mild: Generalized arteriolar narrowing, focal
arteriolar narrowing, arteriovenous nicking, arterio-
lar wall opacification (silver or copper wiring), or a
combination of these signs.
Moderate: Hemorrhages (blot, dot, or flame-
shaped), microaneurysms, cotton-wool spots, hard
exudates, or a combination of these signs.
Malignant: Signs of moderate retinopathy in
combination with optic disc swelling, in the
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Hypertension and the eye Konstantinidis and Guex-Crosier
presence of severely elevated BP that is defined as
a systolic BP equal to or above 180 mmHg and/or
diastolic BP equal to or above 120 mmHg.
Additionally, in case of malignant hypertensive
retinopathy macular edema may occur, which can
cause an abrupt decline in vision [13].
Recently, another classification proposed based
on fundoscopic and optical coherence tomography
(OCT) features classifying eyes as showing mild to
moderate retinopathy, malignant retinopathy
without subretinal fluid (SRF), and malignant retin-
opathy with SRF. Authors suggested that the
OCT-based retinopathy grades were significantly
correlated to final best-corrected visual acuity
(BCVA) unlike KWB grades [10].
One less recognized sign of severe hypertension
is retinal neovascularization. There are sporadic case
reports [9,14] of hypertension led to a proliferative
retinopathy due to retinal ischemic changes indi-
cating that proliferative ocular disease can be an
advanced stage seen in the natural history of severe,
untreated systemic hypertension.
Another rare reported manifestation of malig-
nant hypertension is the appearance of spontaneous
suprachoroidal hemorrhages [15].
Treatment
The treatment of hypertensive retinopathy
includes introduction of systemic antihyperten-
sive drugs; however, no randomized controlled
studies have evaluated whether treating the
hypertension will reverse established hypertensive
retinopathy changes [16]. Nevertheless, several
reports showed improvement of hypertensive
retinopathy after treatment of malignant
hypertension [17].
It has been suggested that intravitreal anti-VEGF
injections might be a useful adjunctive treatment of
malignant hypertensive retinopathy in some
selected cases [16].
In case of proliferative retinopathy treatment
with panretinal photocoagulation could be under-
taken, while the use of an intravitreal anti-VEGF
agent has been reported to halt its progression [14].
Hypertensive choroidopathy
Highly elevated BP can lead to choroidal fibrinoid
necrosis, choriocapillaris nonperfusion, RPE
ischemic necrosis, outer blood–retinal barrier, and
subretinal fluid accumulation. Hypertensive cho-
roidopathy signs include Elschnig spots (round,
deep, and gray-yellow patches at the level of the
retinal pigment epithelium) and Siegrist streaks
(linear hyperpigmented streaks along choroidal
arteries) [18].
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Ocular manifestations of systemic disease
Hypertensive optic neuropathy
Papilloedema is generally caused by accelerated or
malignant hypertension and is associated with
increased risk of CVD and mortality; its presence
dictates urgent antihypertensive management.
Possible mechanisms may involve ischemia, raised
intracranial pressure, and hypertensive encephalop-
athy [6].
Vascular complications
Retinal vascular complications of hypertension
include vein occlusions, artery occlusions and
retinal artery macroaneurysms.
THE CURRENT VALUE OF CLINICAL
ASSESSMENT OF HYPERTENSIVE
RETINOPATHY
The value of clinical assessment of hypertensive
retinopathy signs in the management of patients
with hypertension has been questioned [19].
On the basis of several cross-sectional studies
[20], the last European Society of Hypertension and
the European Society of Cardiology guidelines on
2013 has cast some doubt on the predictive ability of
mild retinopathy as a specific sign of target organ
damage and excluded fundoscopy from the list of
routine workup examinations recommended for the
majority of hypertensive patients (grade 1 and 2
hypertensive patients).
Conversely, the last (2011) guidelines of British
Society of Hypertension still suggest a fundus exam-
ination in order to assist the assessment of cardio-
vascular risk and target organ damage.
It has been demonstrated that mild hyperten-
sive retinopathy is an independent risk factor for
cardiovascular death [21,22].
A recent study though, demonstrated lack of
additional predictive value of mild hypertensive
retinopathy when left ventricular (LV) hypertrophy
and renal damage are concomitantly considered.
Therefore, they underline the prognostic value of
fundus signs of severe hypertensive retinopathy
only in patients with LV hypertrophy and renal
damage [23].
In another recent study, grades 3 and 4 retino-
pathy demonstrated a significant association with
LV strain pattern and left atrial enlargement, LV
hypertrophy and reduced LV ejection fraction [24].
Interestingly, on another note a recent study
demonstrated that particularly in individuals of less
than 55 years there was a significant association
between early hypertensive retinopathy and target
organ damage (TOD) [25 ].
&
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ADVANCES IN RETINAL IMAGING
Digital imaging and retinal image analysis
techniques
Recent advances in fundus photography and retinal
image analysis techniques have enabled the objec-
tive and accurate assessment of quantitative retinal
vascular caliber measurement [26–31].
Furthermore, in addition to the measurement of
retinal vascular caliber, several other retinal vascular
features have been recognized, such as branching
angles, bifurcation, fractal dimension, tortuosity,
vascular length-to-diameter ratio, and wall-to-
lumen ratio that may also be associated to hyper-
tension [6,32–35].
It has been demonstrated that retinal arteriolar
narrowing is strongly related to BP [36], while larger
retinal venular caliber has been associated with risk
of cardiovascular disease [37].
In 2015, Triantafyllou et al. [38] in one of the
latest studies on that field, used an innovative
software that was developed to estimate retinal vas-
cular geometry, using novel advances in retinal
digital image analysis which allow precise measure-
ments of features of the whole vascular network
spread across the retina. They demonstrated that
even in ‘naive’ hypertensive patients, all tortuosity
indices measured were increased compared with
normotensive controls.
Retinal vasculature evaluation may also assist
assessment of systemic treatment response.
In 2008, a study demonstrated that BP reduction
was associated with a reduction in arteriolar narrow-
ing, a widening of arteriolar branch angle and an
increase in arteriolar density [39].
In 2009, another study demonstrated differ-
ences in the retinal arteriolar microvasculature
changes in response to different antihypertensive
regimens [40].
Optical coherence tomography
Intensity graph-assisted measurements using spec-
tral-domain optical coherence tomography may
provide objective measurements of retinal vessel
lumen diameters and wall thicknesses [41].
Schuster et al. [42] proposed optical coherence
tomography-based retinal vessel analysis for the
evaluation of hypertensive vasculopathy. They
demonstrated a relationship between mean arterial
BP and OCT-based arterial-venous ratio.
The recent progress of OCT, allows the
additional exploration of the choroid that was until
recently limited.
Fluctuations in the choroidal thickness have
been associated to systolic BP in healthy subjects
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[43]. A recent study demonstrated that choroidal
thickness, measured with spectral-domain optical
coherence tomography, decreases in patients with
systemic arterial hypertension. This was attributed
to arteriolar sclerosis and vascular contraction
caused by high intravascular pressure in the choroid
[44].
In contrast to these findings though, Gök et al.
[45] reported that systemic hypertension did not
influence subfoveal choroidal thickness in compari-
son to healthy controls.
In another study, severe hypertension was
associated to SRF accumulation, and increased cho-
roid thickness. Furthermore, the presence of SRF was
associated with choroidal thickening and with poor
visual outcome in patients with severe hyperten-
sion. Thus, OCT may be useful to document
hypertensive retinopathy and choroidopathy
severity [10].
Adaptive optics
High resolution imaging of retinal vessels by adap-
tive optics allows quantitative microvascular phe-
notyping, which may contribute to a better
understanding of the link between retinal vessels
and hypertension [46–49].
An increase of the wall-to-lumen ratio (WLR) is a
hallmark of hypertensive microangiopathy and is
predictive of end-organ damage [32,50].
The idea of assessing the WLR ratio of retinal
arterioles as an in-vivo parameter of vascular dam-
age goes back to the finding that remodeling of
arterioles and small arteries, indicated by the
increase in the media to lumen ratio of the periph-
eral arterial resistance vessel, represents an early
step, possibly the earliest step, in hypertension-
associated vascular damage and target organ
disease [32].
Adaptive optics imaging of retinal arterioles
offers an opportunity to explore microvascular
changes in vivo at a near-histology level and
could be considered an excellent tool to assess
WLR ratio and other characteristics of retinal
arterioles.
In a recent study [47] using adaptive optics
imaging BP was associated to increased WLR of
retinal arterioles by thickening arterial wall. What’s
more, remodeling reversal observed in treated and
controlled hypertensive patients comprising WLR
normalization associated with combined wall
decrease and lumen dilatation.
Therefore, adaptive optics imaging of retinal
arterioles could provide biomarkers that may
improve stratification of the risk of end-organ
damage [46].
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Hypertension and the eye Konstantinidis and Guex-Crosier
Scanning laser Doppler flowmetry
Scanning laser Doppler flowmetry demonstrated
that BP emerged as an independent determinant
of the wall-to-lumen ratio of retinal arterioles [33].
In conclusion, while retinal image analysis pro-
vided exciting possibilities to study the pathogen-
esis of these diseases, its direct applicability in a
clinical setting as a ‘test’ to predict cardiovascular
diseases is yet to be established, particularly within
the context of being used as a population screening
tool [28].
Nevertheless, further development of retinal
vascular analyses and standardized measurement
protocols, evaluation of the clinical use of retinal
vascular imaging in assessing cardiovascular risk
prediction, and using retinal vascular imaging to
test antihypertensive treatments may allow the
translation of retinal vascular imaging as a tool to
improve the diagnosis, prognosis, and management
of hypertension in clinical practice [51]. Addition-
ally, new preventive therapeutic strategies could be
envisaged in hypertension that are targeted specially
at improving microvascular structure.
GENETIC STUDIES
Genetic studies may provide some insight to vascu-
lar pathophysiological processes linked to hyper-
tensive retinopathy signs.
New data from various studies indicate a signifi-
cant genetic contribution to retinal vascular caliber,
an area that is under investigation [52–54].
In 2010, a population-based genome-wide
association study demonstrated four novel loci
(19q13, 6q24, 12q24, and 5q14) associated with
retinal venular caliber, an endophenotype of the
microcirculation associated with clinical cardiovas-
cular disease. Of these four loci, the locus on locus
12q24 was also associated with coronary heart dis-
ease and hypertension [55].
Narrow arterioles in the retina have been shown
to predict hypertension as well as other vascular
diseases, likely through an increase in the peripheral
resistance of the microcirculatory flow. In 2013, a
genome-wide association study in 18 722 unrelated
individuals of European ancestry identified one new
locus on chromosome 5 which harbor variants con-
vincingly associated with retinal arteriolar caliber.
The locus associated with retinal arteriolar caliber
on chromosome 5 spanned about 80 kb between
TMEM161B and MEF2C. Although, this study did
not manage to demonstrate associations between
the locus for retinal arteriolar and any macrovascu-
lar disease endpoints, including hypertension
maybe due to the limited power of the study to
detect associations with clinical outcomes [56].
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Ocular manifestations of systemic disease
A recent study using 24 000þ multiethnic
participants from 7 discovery cohorts and 5000þ
subjects of European ancestry reported 4 new loci
associated with central retinal venule diameter,
one of which is also associated with central retinal
arteriole diameter. The four single-nucleotide poly-
morphisms were rs7926971 in TEAD1, rs201259422
in TSPAN10, rs5442 in GNB3 and rs1800407 in
OCA2. The latter single-nucleotide polymorphism,
rs1800407, was also associated with central retinal
arteriole diameter. Regarding phenotype relations,
single-nucleotide polymorphism rs201255422 was
associated with both systolic and diastolic BPs [57].
The role of microRNAs (miRs) in hypertension
and in several hypertension-related pathologies
have been investigated by several studies [58].
In 2011, a study showed a miR signature in
plasma of patients with essential hypertension,
which differed from their healthy counterparts:
27 miRs were differentially expressed [59].
In another study, the interplay between miR-
155 expression, þ1166C polymorphism, and AT1R
protein expression was associated with the regula-
tion of BP [60].
Likewise, it’s been showed that the description
of a genetic variant in the 30 untranslated region
of vacuolar Hþ ATPase ATPV0A1 creates a miR-637-
binding motif related to hypertension risk by inter-
fering with the fine-tuning of several vasoactive
substances, including chromogranin A as precursor
of catestatin, an inhibitor of catecholamine
release [61].
In conclusion, genetic studies may elucidate
some aspects of hypertension pathophysiology
and its relation to end organ damage, though, it
needs to be affirmed that the contribution of arterial
hypertension itself to end-organ damage is multi-
factorial, and is a combination of genetic suscepti-
bility and environmental factors [58]. Further trials
are required to clarify the significance of genetic
factors in macrovascular disease endpoints, includ-
ing hypertension.
LATEST EPIDEMIOLOGICAL FEATURES
Some interesting aspects concerning hypertensive
ocular signs have emerged last years from epidemio-
logical studies.
There is good evidence that some signs,
particularly generalized retinal arteriolar narrowing,
may precede the development of hypertension [36].
In 2012, a meta-analysis of five cross-sectional
studies (including 19 633 subjects) showed that
arteriolar calibre decreased by 3.07 mm for every
10-mmHg increase in arterial BP. Furthermore, it
has been demonstrated that retinal artery narrowing
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is not only related to chronic exposure to hyperten-
sion, but might precede the development of hyper-
tension. In four longitudinal studies (6 247 adults)
with follow-up periods ranging from 3 to 7 years
consistently showed that generalized retinal arterio-
lar narrowing was associated with an increased risk
of incident hypertension [62].
Another more recent meta-analysis involving
six prospective cohort studies among 10 229
individuals provided a reliable demonstration and
confirmatory evidence that changes in retinal vas-
cular caliber, specifically retinal arteriolar narrowing
and venular widening, are associated with an
increased risk of hypertension, developing over
median follow-up periods of 2.9–10 years. The
associations persist in those with optimal BP at
baseline. On the basis of baseline and the follow-
up systolic BP (SBP) measurements, each 20-mm
decrease on retinal arteriolar caliber at baseline is
associated with a 1.12 mmHg greater increase in SBP
over 5 years [63].
These findings are consistent with the hypoth-
esis that generalized microvascular dysfunction,
seen in the retinal vasculature, precedes the onset
and development of hypertension and possibly
reflecting more widespread systemic peripheral
vasoconstriction.
Another interesting issue emerged from epide-
miologic studies is that the impact of elevated BP on
the retinal microcirculation occurs in early life.
In a study concerning very young children 4 to 5
years of age, higher SBP was associated with nar-
rower retinal arterioles and wider retinal venules
suggesting that elevated BP may affect the retinal
microvasculature from early childhood [64].
In another study of preschool-aged children
each 10 mmHg increase in SBP was associated with
a 1.70 mm narrower retinal arteriolar calibre. Accord-
ingly, SBP demonstrated inverse linear associations
with retinal arteriolar caliber, during early child-
hood suggesting that the influence of BP on small
vessels is continuous and commences early in
life [65].
Another noteworthy issue emerged from
epidemiologic studies is that retinal venular
diameter, not traditionally considered part of the
spectrum of hypertensive retinopathy signs, may
convey additional information regarding the state
of the retinal vasculature and systemic health [6].
A meta-analysis in 2014 [63] confirmed findings
in several studies [35–37,66], which have reported
an association between retinal venular widening
and incident hypertension. Retinal venular widen-
ing has been hypothesized to be a general marker of
retinal ischemia and hypoperfusion secondary to
microvascular rarefaction. The ensuing reduction
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in blood vessels can cause a significant increase in
peripheral vascular resistance and can exacerbate
an initial increase in blood flow or pressure. In
addition, retinal venular widening may reflect endo-
thelial dysfunction [1] and thereby increase leuko-
cyte adhesion, which, in turn, is involved in
microvascular remodeling [67]. However, retinal
venular widening may have pleiotropic associations
with cardiovascular risk factors and diseases, but not
be a specific biomarker for hypertension [63].
The significance of retinal venular dilation in
association to hypertension should be further
evaluated.
Hypertensive retinopathy signs and risk of
end-organ damage
The retina is the one place in the body where the
physician can actually directly inspect the body’s
microvasculature, the tissue most directly at risk
from hypertension [68].
Cerebral microvascular disease
Retinal and cerebral small vessels share similar
embryological origin, anatomical features, and
physiological properties; thus the easily accessible
evaluation of retinal vasculature has been
considered a window on the brain [68,69].
Retinopathy was shown to be predictive of
cerebrovascular-related deaths. The presence of
retinopathy phenotype in association to increased
BP could identify patients at higher risk of fatal
stroke [70].
Additionally, cross-sectional studies demon-
strated a correlation between retinal microvascular
changes and dementia, cognitive impairment, and
brain imaging abnormalities [69].
Ong et al. [4] studied 2907 participants in the
Atherosclerosis Risk in Communities Study, who
were free of diabetes mellitus, stroke, or coronary
artery disease at baseline, and were followed for
13 years. They found that even among patients
who were well controlled on antihypertensive
medication, moderate/severe retinopathy carried a
nearly three-fold increase in the risk of stroke.
Retinal signs of hypertensive retinopathy that
include arteriovenous (AV) nicking, focal arteriolar
narrowing, and any retinopathy as well as its
components were associated with leukoaraiosis
progression and brain microvascular disease [71].
Other studies further demonstrated that specific
hypertensive retinopathy signs might allow further
refinement and subtyping of stroke.
In a multicenter study of patients with
acute stroke, different hypertensive retinopathy
signs were associated with specific stroke subtypes.
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Hypertension and the eye Konstantinidis and Guex-Crosier
For example, retinal arteriolar narrowing was associ-
ated with lacunar stroke, while retinal hemorrhages
were linked with cerebral hemorrhages [72].
Other studies showed that copper wiring and
silver wiring predict atherosclerotic cerebral infarc-
tion [73], whereas signs of hypertensive arteriolar
disease predict lacunar infarction [74].
In the Rotterdam study [75], larger retinal ven-
ular caliber is associated with an increased risk for
stroke in the general population and, in particular,
with an increased risk for intracerebral hemorrhage.
If retinal microvascular changes precede
progression of cerebral microvascular disease, this
might indicate a point at which preventive thera-
pies, for example, aimed at control of hypertension
might be implemented which could even lead to
reduction in brain microvascular disease. Future
studies might evaluate the utility of retinal screen-
ing as an indicator of a need for more aggressive
vascular risk factor control [71].
Cardiovascular disease
The presence of hypertensive retinopathy signs is
associated with multiple markers of subclinical athe-
rosclerotic diseases, including coronary artery calci-
fication, aortic stiffness, LV hypertrophy, and
carotid intima-media thickness [6].
Retinopathy signs were associated with cardio-
vascular disease including increased coronary heart
disease risk [76] and congestive heart failure [77].
Presence and severity of retinopathy were also
associated with increased risk of development
of cardiovascular disease in patients with chronic
kidney disease [78].
Furthermore, another study showed that in the
presence of chronic kidney disease, retinopathy is a
strong predictor of mortality [79].
In another note, the capacity of retinal arterioles
to dilate in response to flicker light was demon-
strated as an independent predictor of the presence
of coronary artery disease and may suggests that
retinal microvascular endothelial dysfunction is a
marker for underlying coronary artery disease [80].
In conclusion, the presence of hypertensive
retinopathy may convey additional prognostic
information on the risk of cardiovascular disease
and may alert for preventive systemic therapies.
CONCLUSION
Hypertension has widespread effects on the ocular
vasculature. The presence of hypertensive retinop-
athy may convey additional prognostic information
on the risk of end-organ damage and may alert for
urgent systemic management or even preventive
systemic therapies. Further development of retinal
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