Editorial Commentary
Hypertensive Retinopathy
A Window to Vascular Remodeling in Arterial Hypertension
Roland E. Schmieder
A t the end of the 19th century, hypertensive retinopathy
was first described by Markus Gunn in hypertensive
patients with renal disease. Nearly 50 years later, Keith and
colleagues documented the prognostic value of funduscopic
abnormalities in hypertensive patients and categorized hyper-
tensive nephropathy into 4 groups of increasing severity that
since then have been taught in medical university schools. In
1966, the ophthalmoscopic changes were confirmed to be
predictive of death in patients with essential hypertension.1,2
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The usefulness of the classification system and its rele-
vance to current clinical practice, however, have been ques-
tioned repeatedly.3 The direct ophthalmoscopic examination
has been shown to be unreliable, with high rates of interob-
server (20% to 40%) and intraobserver (10% to 33%)
variability.4 The criticism refers to stages 1 and 2 of the
Keith-Wagner-Barker classification. Only hemorrhages and
exudates can be reliably assessed in retinal photographs. A
systematic review identified 6 studies that provided data on
interobserver agreement for hypertensive retinopathy using
retinal photographs.3 In these studies interobserver agreement
was modest and fair for focal arterial narrowing and arterio-
venous nicking, good for the arteriovenous ratio, and excel-
lent only for hemorrhages and exudates. Most current guide-
lines for the management of arterial hypertension, therefore,
do not recommend funduscopy as a routine diagnostic test,
but advanced retinopathy (hemorrhages, exudates, or papill-
edema) is accepted as a factor influencing prognosis in
hypertensive patients.5
Hypertensive retinopathy is generally considered to be a
marker and/or predictor of vascular disease and death. Be-
cause the retinal and cerebrovascular circulations share com-
mon anatomic, physiological, histological, and embryological
features, it is not surprising that hypertensive retinopathy is
strongly related to stroke or lacunar infarctions. In a 3-year
population-based cohort study with atherosclerotic risk, exu-
dates (cotton-wool spots), retinal hemorrhages, and microan-
eurysms were associated with a 2-fold to 4-fold higher risk of
incident stroke, cognitive decline, white matter lesions, cere-
bral atrophy, and stroke mortality.1 Signs of microvascular
changes (arteriovenous nicking, generalized or focal arterio-
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Department of Nephrology and Hypertension, University
Hospital, Erlangen, Germany.
Correspondence to Roland E. Schmieder, Department of Nephrology
and Hypertension, University Hospital, Krankenhausstra␤e 12, 91054
Erlangen, Germany. E-mail roland.schmieder@rzmail.uni-erlangen.de
(Hypertension. 2008;51:43-44.)
© 2007 American Heart Association, Inc.
Hypertension is available at http://hypertension.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.107.100230
43
lar narrowing, and arteriovenous ratio) were weaker but still
significantly related to incident stroke. Further population-
based longitudinal studies reported consistently that signs of
hypertensive retinopathy, in particular, if advanced, were
related to a 2-fold to 3-fold increase in the risk of fatal and
nonfatal stokes independent of cardiovascular risk factors.1
Inconsistent results were reported for the association of
hypertensive retinopathy and coronary heart disease, although
an increased risk of coronary events was observed in women
but not in men.6 This gender-related observation may reflect
the higher risk of coronary microvascular disease among
women than in men.
In this issue of Hypertension the relationship between
retinal arteriolar narrowing and myocardial perfusion was
analyzed in 234 participants free from clinically diagnosed
cardiovascular disease based on self-reported information.7
Myocardial perfusion reserve measured after maximal vaso-
dilation with adenosine reflects microvascular changes in the
coronary circulation and may contribute to the risk of
coronary heart disease in hypertensive patients independent
of obstructive stenosis in epicardial arteries. The major
finding of this cross-sectional analysis is that decreased
myocardial perfusion reserve was associated with narrower
retinal arterioles.7 This association was independent from
age, gender, and ethnicity but not from cardiovascular risk
factors and was only observed in patients without coronary
calcifications. Because macrovascular coronary artery disease
was not excluded by coronary angiography, it remains unre-
solved whether patients with coronary calcification being
indicative for epicardial stenosis suffered from coronary
macrovascular artery disease. Nevertheless, the study clearly
indicates that retinal arterioles that can be examined nonin-
vasively and the coronary microcirculation reveal similar
abnormalities at an early stage of vascular injury.
In accordance, microvascular changes of small arteries that
were taken from subcutaneous fat tissue were related to
coronary flow reserve and predictive of cardiovascular
events.8 In essential hypertension, vascular remodeling oc-
curs early in small arteries with a lumen diameter of 100 to
350 ␮m of which the sizes are similar to the diameter of
retinal arterioles. Vascular changes in small arteries may be
of a structural (remodeling) or functional (vasoconstriction)
nature. In hypertensive patients, endothelium dysfunction has
been documented in systemic, coronary, renal, and retinal
circulations.9 Structural changes, ie, remodeling of the micro-
vascular wall, lead either to eutrophic (rearrangement of
smooth muscle cells, more common in mild-to-moderate
hypertension) or hypertrophic remodeling, but both reveal an
increased wall:lumen ratio.10 With eutrophic remodeling
there is no cell hypertrophy, and vessels have the same
 44 Hypertension January 2008
Figure. Assessment of wall:lumen ratio of retinal arterioles.12
number of smooth muscle cells, but they are restructured
around a smaller vessel lumen and diameter.
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Increased wall:lumen ratios of subcutaneous small arteries
have been found to predict cardiovascular events in hyper-
tensive patients and in a more heterogeneous cohort including
those with secondary hypertension and diabetes.11 Similarly,
arteriolar narrowing in the retinal circulation corresponding
with the eutrophic remodeling indicates microvascular
changes in the coronary circulation7 and predicts cardiovas-
cular mortality.1,6 However, none of these prospective studies
examined or adjusted the results for other indicators of
hypertensive organ damage, such as left ventricular hypertro-
phy, microalbuminuria, intima-media thickness of carotid
arteries, or pulse wave velocity. This lack of inclusion of
other measures of target organ damage limits the value of
evaluating hypertensive retinopathy in hypertension (unless
in hypertensive emergency), because the added value is
uncertain.3 So far, all of these trials just measured the
diameter of the arterioles and/or venules to calculate the
arteriovenous ratio. Scanning laser Doppler flowmetry and
automatic full-field perfusion imaging analysis enable us now
to assess not only the diameter of arterioles but also the
wall:lumen ratio increasing the explanatory power of this
approach (Figure).12
Vascular injuries to small arteries may occur early in the
development of hypertension and may even precede hyper-
tension.10 Narrowing of the retinal arterials has been found to
predict the risk of hypertension in normotensive subjects and
of incident severe hypertension.1,3 However, the sensitivity of
retinal abnormalities associated with hypertension is low (low
positive predictive value), and half of the people without
hypertensive retinopathy still have hypertension (low nega-
tive predictive value). Moreover, only middle-aged and older
people were included in the prospective trials, although the
association among hypertensive retinopathy, blood pressure,
and risk of cardiovascular disease is stronger in younger
populations.3 By introducing new tools to assess the remod-
eling of retinal arterioles noninvasively (ie, wall:lumen ratio),
early vascular changes in the retinal circulation can be
analyzed more precisely, and limitations and inconsistencies
of studies might be resolved.12
Thus, based on our current knowledge, the added value of
funduscopy even after introducing photographs and comput-
erized analysis is disappointingly modest. The prospective
studies are hampered by the fact that none of the trials have
included concurrent measures of hypertensive organ damage.
Thus, the precise role and cost-effectiveness calculations of
funduscopy cannot be derived. New opportunities to deter-
mine vascular changes earlier and more concisely are on the
horizon and may offer a new view on the diagnostic and
predictive values of hypertensive retinopathy in arterial
hypertension.
Source of Funding
This work was supported by a grant of the Deutsche Forschungsge-
meinschaft (KFO 106-2).
Disclosures
None.
References
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3. van den Born BJ, Hulsman CA, Hoekstra JB, Schlingemann RO, van
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tension: systematic review. BMJ. 2005;331:73.
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 Hypertensive Retinopathy: A Window to Vascular Remodeling in Arterial Hypertension
Roland E. Schmieder

Hypertension. 2008;51:43-44; originally published online November 12, 2007;

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doi: 10.1161/HYPERTENSIONAHA.107.100230
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563

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