Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes.

Abstract

Alterations in retinal vascular caliber may reflect early subclinical microvascular dysfunction. In this study, we examined the association of retinal vascular caliber to incident retinopathy in young patients with type 1 diabetes.
This was a prospective cohort study of 645 initially retinopathy-free type 1 diabetic patients, aged 12-20 years. Participants had seven-field stereoscopic retinal photographs taken of both eyes at baseline and follow-up. Retinal vascular caliber was measured from baseline photographs using a computer-based program following a standardized protocol. Incident retinopathy was graded according to the modified Airlie House classification from follow-up photographs.
Over a median follow-up of 2.5 years, 274 participants developed retinopathy (14.8 per 100 person-years). After adjustments for age, sex, diabetes duration, glycemia, mean arterial blood pressure, BMI, and cholesterol levels, larger retinal arteriolar caliber (fourth versus first quartile) was associated with a more than threefold higher risk of retinopathy (hazard rate ratio 3.44 [95% CI 2.08-5.66]). Each SD increase in retinal arteriolar caliber was associated with a 46% increase in retinopathy risk (1.46 [1.22-1.74]). This association was stronger in female than in male participants. After similar adjustments, retinal venular caliber was not consistently associated with incident retinopathy.
Retinal arteriolar dilatation predicts retinopathy development in young patients with type 1 diabetes. Our data suggest that arteriolar dysfunction may play a critical role in the pathogenesis of early diabetic retinopathy and that computer-based retinal vascular caliber measurements may provide additional prognostic information regarding risk of diabetes microvascular complications.

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Retinal Arteriolar Dilation Predicts
Retinopathy in Adolescents With Type 1
Diabetes
NING CHEUNG, MBBS1,2
SOPHIE L. ROGERS, MEPI1
KIM C. DONAGHUE, MBBS, PHD3
ALICIA J. JENKINS, MBBS, MD4
GABRIELLA TIKELLIS, PHD5
TIEN YIN WONG, MBBS, PHD1,2,6
OBJECTIVE — Alterations in retinal vascular caliber may reflect early subclinical microvas-
cular dysfunction. In this study, we examined the association of retinal vascular caliber to
incident retinopathy in young patients with type 1 diabetes.
RESEARCH DESIGN AND METHODS — This was a prospective cohort study of 645
initially retinopathy-free type 1 diabetic patients, aged 12–20 years. Participants had seven-field
stereoscopic retinal photographs taken of both eyes at baseline and follow-up. Retinal vascular
caliber was measured from baseline photographs using a computer-based program following a
standardized protocol. Incident retinopathy was graded according to the modified Airlie House
classification from follow-up photographs.
RESULTS — Over a median follow-up of 2.5 years, 274 participants developed retinopathy
(14.8 per 100 person-years). After adjustments for age, sex, diabetes duration, glycemia, mean
arterialbloodpressure,BMI,andcholesterollevels,largerretinalarteriolarcaliber(fourthversus
first quartile) was associated with a more than threefold higher risk of retinopathy (hazard rate
ratio3.44[95%CI2.08–5.66]).EachSDincreaseinretinalarteriolarcaliberwasassociatedwith
a 46% increase in retinopathy risk (1.46 [1.22–1.74]). This association was stronger in female
than in male participants. After similar adjustments, retinal venular caliber was not consistently
associated with incident retinopathy.
CONCLUSIONS — Retinal arteriolar dilatation predicts retinopathy development in young
patientswithtype1diabetes.Ourdatasuggestthatarteriolardysfunctionmayplayacriticalrole
inthepathogenesisofearlydiabeticretinopathyandthatcomputer-basedretinalvascularcaliber
measurements may provide additional prognostic information regarding risk of diabetes micro-
vascular complications.
Diabetes Care 31:1842–1846, 2008
C
(1). Identifying high-risk patients early is
thekeytoallowtimelyimplementationof
effective interventions to prevent this di-
abetes microvascular complication. How-
ever, clinically useful predictors of
retinopathy risk in young patients with
type 1 diabetes remain limited.
hildren and adolescents with type 1
diabetes have a significant lifetime
risk of blindness from retinopathy
There is emerging evidence that
quantitative measurement of retinal vas-
cular caliber may provide prognostic in-
formation regarding the risk of diabetes
microvascular complications, including
retinopathy (2–7). Studies in older adult
populations have shown that wider reti-
nal arterioles are associated with the inci-
dence and progression of diabetic
retinopathy (3,4,7). These findings are
consistent with experimental work that
indicates a role of retinal arteriolar dys-
function, reflected as vasodilatation, in
thepathogenesisofearlydiabeticretinop-
athy (3,7–9). According to the laws of
Starling and Laplace, retinal arteriolar di-
latation may increase capillary pressure
and lead to capillary wall dilatation (mi-
croaneurysm), leakage (edema), and rup-
ture (hemorrhage), which are all classical
signs of diabetic retinopathy (3,9).
However, most previous studies were
conducted in older patients with type 2
diabetes, in whom residual confounding
from coexisting metabolic diseases and
retinopathy risk factors (e.g., hyperten-
sion, insulin resistance, and dyslipide-
mia) is difficult to fully account for. The
valueofmeasuringretinalvascularcaliber
changes in younger patients with type 1
diabetes for retinopathy risk prediction is
less clear, with only a small retrospective
case-controlstudytodate(10).Inthecur-
rent study, we examined prospectively
the association of retinal vascular caliber
with incident retinopathy risk in a cohort
of children and adolescents with type 1
diabetes.
RESEARCH DESIGN AND
METHODS— This is a prospective
cohort study of children and adolescents
with type 1 diabetes, aged 12–20 years
old, managed at The Children’s Hospital
at Westmead in Sydney, Australia. De-
tailed characteristics of this cohort have
been reported in previous publications
(11–15). Children and adolescents with
type 1 diabetes, referred by their physi-
cians, were assessed for complications in
our clinics. Complications were assessed
duringa2-hvisitthatconsistedofclinical
assessment by an endocrinologist; an-
thropometry, blood pressure measure-
ment, and pubertal staging; screening for
retinopathy, nephropathy, and neuropa-
thy; and A1C and biochemical analyses,
as described previously (11–15). For this
report, 650 eligible patients who had ret-
inalphotographs,whohadnoevidenceof
diabetic retinopathy at baseline between
1990and2002,andwhoreturnedforfol-
low-up examination were included. Of
these, we excluded those with photo-
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From the1Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia; the2Royal
Victorian Eye and Ear Hospital, Melbourne, Australia;3The Children’s Hospital at Westmead, University
of Sydney, Westmead, Australia; the4Department of Medicine, St. Vincent’s Hospital, University of
Melbourne, Melbourne, Australia; the5Baker Heart Research Institute, Melbourne, Australia; and the
6Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
Corresponding author: Dr. Ning Cheung, dannycheung@hotmail.com.
Received 26 January 2008 and accepted 26 May 2008.
Published ahead of print at http://care.diabetesjournals.org on 3 June 2008. DOI: 10.2337/dc08-0189.
© 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
P a t h o p h y s i o l o g y / C o m p l i c a t i o n s
O R I G I N A LA R T I C L E
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graphs of insufficient quality for retinal
vascular caliber measurements (n ? 5),
leaving 645 participants for the current
analysis. The excluded patients did not
differ significantly from the included
patients in any of the characteristics
shown in Table 1.
Retinal photography and assessment
Retinal photography was performed ac-
cording to a standardized protocol, as de-
tailed elsewhere (11–15). In brief, seven-
field stereoscopic retinal photographs
were taken of both eyes after pupil dila-
tion. Diabetic retinopathy was graded
from these photographs by an ophthal-
mologist, masked to participants’ charac-
teristics,accordingtotheEarlyTreatment
Diabetic Retinopathy (ETDRS) adapta-
tion of the modified Airlie House classifi-
cation. Incident retinopathy was defined
asETDRSlevel21(minimalnonprolifera-
tive diabetic retinopathy) or greater after
at least 1 year of follow-up visits and at
least two clinic visits. The overall agree-
ment based on 30% of photographs
graded independently by another oph-
thalmologist,alsomaskedtosubjectchar-
acteristics, was high (weighted k ? 0.80)
(10).
Retinalvascularcaliberwasmeasured
using a computer-based program follow-
ing a previously validated protocol
(16,17). For each photograph, all arte-
rioles and venules coursing through an
area one-half to one disc diameter from
the optic disc margin were measured and
summarized as the central retinal arterio-
lar and venular equivalents, using formu-
las described elsewhere (16,17). These
equivalents represented the average of
projected calibers for the central retinal
vessels. For this study, retinal vascular
caliberintherighteyewasmeasured.Left
eye measurements were performed when
photographsoftherighteyewereungrad-
able. Retinal vascular caliber measure-
ments have been shown to be highly
correlated between the right and left eye
(16). Reproducibility data have been re-
ported previously, with intra- and inter-
grader intraclass correlation coefficients
ranging from 0.78 to 0.99 (16–18).
Risk factors and definitions
Participants underwent standardized in-
terviews, clinical examinations, and labo-
ratory investigations at baseline and
follow-up visits (11–15). Pubertal stage
was assessed by an endocrinologist ac-
cording to the Tanner stage classification
(14). BMI was calculated as weight in ki-
logramsdividedbythesquareofheightin
meters. Blood pressure was measured in
the seated position with a sphygmoma-
nometer using the appropriate cuff size
after 5 min of rest. Mean arterial blood
pressure was calculated as one-third of
the systolic plus two-thirds of the dia-
stolic blood pressure. Venous blood was
obtained for measurement of A1C and to-
tal cholesterol levels. Albumin excretion
rate was also measured at baseline and
determined from three consecutive timed
overnight urine collections. Microalbu-
minuriawasdefinedasalbuminexcretion
rate ?20 ?g/min (15).
Statistical analysis
Crude incidence rates were calculated per
100person-years.Manyparticipantcharac-
teristicsofinterestwerefoundtobenotnor-
mally distributed, and thus nonparametric
statistics were applied as appropriate. Dif-
ferencesbetweenthosewhodidanddidnot
develop retinopathy were assessed using
Wilcoxon rank-sum and ?2tests. We used
Cox proportional hazards regression to de-
termine the hazard ratio (HR) for retinopa-
thy in relation to retinal arteriolar and
venular calibers, initially adjusting for age
and sex and additionally for diabetes dura-
tion, A1C, Tanner pubertal stage, mean ar-
terial blood pressure, BMI, and total
cholesterol levels. All covariates were mea-
sured at the baseline visit. Both arteriolar
andvenularcalibersweremodeledsimulta-
neously. Supplementary analysis adjusted
further for log(albumin excretion rate), al-
though the data for this measure were lim-
ited to 60% of participants. We also
performed the above analyses stratified by
sex.AllanalyseswereperformedwithInter-
cooled Stata 9.2 for Windows (StataCorp,
College Station, TX).
RESULTS— Table 1 shows baseline
characteristics of our study population by
Table 1—Baseline characteristics of participants, by incident retinopathy status
CharacteristicsAll No retinopathy Retinopathy
P value
n
Age (years)
Sex (% male)
Diabetes duration (years)
BMI (kg/m2)
Mean arterial blood pressure (mmHg)
A1C (%)
Albumin excretion rate (?g/min)
Microalbuminuria present
Total cholesterol (mmol/l)
Tanner pubertal stage
1
2
3
4
5
Retinal arteriolar caliber (?m)
Retinal venular caliber (?m)
Data are medians (interquartile range) or proportions. P values relate to Wilcoxon rank-sum or ?2test for difference between those who did and did not develop
retinopathy during follow-up.
645371274
13.5 (12.8–14.9)
45.6
4.7 (3.2–7.4)
21.0 (19.2–23.5)
83.3 (80.0–88.3)
8.4 (7.7–9.3)
4.4 (3.3–6.9)
13.7 (12.9–15.1)
45.8
3.9 (2.8–6.5)
21.4 (19.6–23.9)
83.3 (80–88.3)
8.2 (7.5–9.1)
4.5 (3.2–8.0)
13.3 (12.6–14.6)
45.3
5.6 (3.9–8.9)
20.6 (18.8–23.0)
83.3 (80–88.3)
8.6 (7.8–9.5)
4.2 (3.4–6.2)
?0.001
0.886
?0.001
0.001
0.411
0.005
0.348
0.269
0.866
0.038
2.5 3.21.4
4.3 (3.7–4.8) 4.2 (3.8–4.8)4.3 (3.7–4.8)
5.7
13.3
14.2
25.3
41.5
4.2
11.0
12.9
25.6
46.3
7.5
16.2
15.8
24.9
35.6
170.51 (157.35–182.86)
246.60 (232.22–263.53)
165.98 (153.07–178.67)
245.41 (231.19–260.70)
176.11 (163.50–187.43)
249.86 (233.76–267.12)
?0.001
0.019
Cheung and Associates
DIABETES CARE, VOLUME 31, NUMBER 9, SEPTEMBER 2008
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Page 3

incident retinopathy status. Participants
who developed retinopathy had longer
duration of diabetes, lower BMI, higher
A1C, lower pubertal stage, and larger ret-
inal arteriolar and venular caliber than
those who did not develop retinopathy.
Over a median follow-up of 2.5 years
(interquartile range of 1.4–3.9 years),
274 participants developed retinopathy,
an incidence of 14.8 per 100 person-
years. Table 2 shows that after adjust-
ments for age, sex, diabetes duration,
A1C, mean arterial blood pressure, pu-
bertal stage, BMI, and cholesterol levels,
larger retinal arteriolar caliber was associ-
ated with higher risk of incident retinop-
athy. Compared with participants with
arteriolar caliber in the lowest quartile,
those with arteriolar caliber in the highest
quartile had a nearly 31⁄2-fold higher risk
of retinopathy (HR 3.44 [95% CI 2.08–
5.66]). For each SD increase in retinal ar-
teriolar caliber, there was a 46% increase
in retinopathy risk (1.46 [1.22–1.74]). In
supplementary analysis, we further ad-
justed for renal function in participants
with albumin excretion rate measured at
baseline (60%). The association of larger
retinal arteriolar caliber and diabetic reti-
nopathy remained and appeared to be
even stronger (2.23 [1.74–2.85] for each
SD increase in retinal arteriolar caliber;
8.18 [3.97–16.87] for highest compared
with lowest quartile of retinal arteriolar
caliber). Retinal venular caliber was not
associated with incident retinopathy.
In analyses stratified by sex, the asso-
ciation between larger retinal arteriolar
caliber and incident retinopathy risk was
stronger in female than in male partici-
pants (HR 4.39 [95% CI 2.34–8.23] for
female and 2.44 [1.09–5.45] for male
participantsinthehighestcomparedwith
the lowest quartile of arteriolar caliber)
(Table 3). However, there was no statisti-
callysignificantinteraction(P?0.10)for
sex.Participants’characteristicsbysexare
summarized in supplemental Table 1
(available in an online appendix at http://
dx.doi.org/10.2337/dc08-0189). In gen-
eral, female participants differed signi-
Table 2—Association of retinal vascular caliber and incident diabetic retinopathy
n
Incidence
(per 100 person-years)
Model 1 HR
(95% CI)
P value
Model 2 HR
(95% CI)
P value
Retinal arteriolar caliber
Per SD increase, 18.90 ?m
Quartile 1, ?157.2 ?m
Quartile 2, 157.3–170.5 ?m
Quartile 3, 170.51–182.85 ?m
Quartile 4, ?182.86 ?m
Ptrend
Retinal venular caliber
Per SD increase, 22.63 ?m
Quartile 1, ?232.2 ?m
Quartile 2, 232.2–246.59 ?m
Quartile 3, 246.6–263.5 ?m
Quartile 4, ?263.5 ?m
Ptrend
Model 1 HR adjusted for age and sex. Model 2 HR adjusted for model 1 covariates plus diabetes duration, A1C, mean arterial blood pressure, Tanner pubertal stage,
BMI, and total cholesterol. Models for arteriolar caliber were adjusted for venular caliber and vice versa.
645
161
161
160
163
274 cases
8.5
13.5
15.3
22.5
1.43 (1.23–1.66)
Reference
1.72 (1.15–2.58)
1.94 (1.29–2.92)
3.13 (2.01–4.86)
?0.001
?0.001 1.46 (1.22–1.74)
Reference
1.75 (1.11–2.75)
1.82 (1.15–2.89)
3.44 (2.08–5.66)
?0.001
?0.001
0.009
0.001
?0.001
0.017
0.010
?0.001
643
160
161
161
161
272 cases
12.8
11.7
16.3
18.3
0.89 (0.77–1.04)
Reference
0.81 (0.56–1.17)
0.98 (0.68–1.42)
0.94 (0.63–1.40)
0.975
0.1340.82 (0.69–0.98)
Reference
0.75 (0.50–1.13)
0.91 (0.60–1.37)
0.78 (0.50–1.23)
0.457
0.028
0.255
0.922
0.757
0.165
0.640
0.281
Table 3—Association of retinal arteriolar caliber and incident diabetic retinopathy in young females and male patients
Retinal arteriolar caliber
n
Incidence
(per 100 person-years)
Model 1 HR
(95% CI)
P value
Model 2 HR
(95% CI)
P value
Female
Per SD increase, 18.7 ?m
Quartile 1, ?160.0 ?m
Quartile 2, 160.0–172.1 ?m
Quartile 3, 172.2–183.5 ?m
Quartile 4, ?183.5 ?m
Ptrend
Male
Per SD increase, 19.0 ?m
Quartile 1, ?154.8 ?m
Quartile 2, 154.8–168.8 ?m
Quartile 3, 168.9–181.7 ?m
Quartile 4, ?181.7 ?m
Ptrend
Model 1 HR adjusted for age. Model 2 HR adjusted for age, diabetes duration, A1C, mean arterial blood pressure, Tanner pubertal stage, BMI, and total cholesterol.
Models for arteriolar caliber were adjusted for venular caliber and vice versa.
351 14.6
1.61 (1.32–1.96)
Reference
1.45 (0.83–2.54)
2.40 (1.39–4.17)
3.80 (2.12–6.81)
?0.001
?0.0011.82 (1.45–2.28)
Reference
1.39 (0.77–2.54)
2.39 (1.30–4.39)
4.39 (2.34–8.23)
?0.001
?0.001
87
88
88
88
8.33
11.22
16.58
23.51
0.187
0.002
?0.001
0.276
0.005
?0.001
29414.9
1.25 (1.00–1.56)
Reference
2.01 (1.11–3.65)
1.76 (0.95–3.24)
2.42 (1.25–4.67)
0.026
0.0501.12 (0.85–1.48)
Reference
2.12 (1.04–4.31)
1.71 (0.83–3.53)
2.44 (1.09–5.45)
0.088
0.424
73
74
72
75
8.36
16.32
14.84
20.76
0.021
0.072
0.008
0.039
0.148
0.030
Retinal arteriolar caliber and retinopathy risk
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ficantly from male participants in that
they were further through puberty and
had higher cholesterol levels, higher BMI,
and larger retinal arteriolar and venular
calibers.
CONCLUSIONS — Our study shows
that larger retinal arteriolar caliber pre-
dicts a higher risk of incident retinopathy
inyoungindividualswithtype1diabetes,
independent of diabetes duration, blood
pressure, glycemic control, and other risk
factors. This finding is consistent with
previous population-based studies in
olderadultswithdiabetes.IntheWiscon-
sin Epidemiological Study of Diabetic
Retinopathy, the investigators reported
an association of larger retinal arteriolar
caliberwith4-yearprogressionofdiabetic
retinopathy (relative risk 2.04 [95% CI
1.20–3.47]) in type 1 diabetes and with
10-year incident retinopathy risk in type
2 diabetes (odds ratio 1.78 [95% CI
1.06–3.00])(3,4).Thesefindingsarefur-
ther reinforced by data from the Austra-
lian Diabetes Obesity and Lifestyle Study
of predominantly type 2 diabetic adults
(7). Our study now extends these obser-
vationstoyoungchildrenandadolescents
with type 1 diabetes and findings from
our previous retrospective case-control
study (10).
Our study supports the hypothesis
that retinal arteriolar dilatation is a phys-
iological indicator of diabetes-related ret-
inal microvascular dysfunction (3,9).
Arteriolar dilatation is a sign of impaired
arteriolar autoregulation, which has been
suggested to play a pivotal role in the ini-
tiation and progression of diabetic reti-
nopathy (8). Experimental studies show
that an increase in retinal blood flow and
associated arteriolar dilatation are fre-
quently found in the retinas of diabetic
patients, reflecting underlying arteriolar
autoregulatory dysfunction (8). This
could be due to hyperglycemia-mediated
endothelin-1 resistance and calcium in-
flux channel inhibition in smooth muscle
cells. Such processes could impair retinal
arteriolar constriction and also augment
retinal arteriolar dilatory response by re-
ducing oxygen tension from retinal capil-
lary nonperfusion (8). In contrast, retinal
venular dilatation may represent a later
sign of established diabetic retinopathy,
explaining the lack of associations with
incidentretinopathyriskinourstudyand
others (3,5,7,10), although there is evi-
dence of associations with the prevalence
and progression of retinopathy in older
adults with type 2 diabetes (4,19,20).
Our data also suggest a possible sex
difference in the association of retinal ar-
teriolar caliber with retinopathy risk. To
the best of our knowledge, this aspect has
not been examined in previous studies.
The reasons for this observation are not
apparent. Although epidemiological
studies offer inconsistent evidence that
the risk of diabetic retinopathy differs by
sex, it has long been hypothesized that
women are more susceptible to microvas-
culardiseasedevelopmentthanmen(21).
Moreover, hormonal changes associated
with puberty have been suggested to con-
tributetothedevelopmentofdiabeticret-
inopathy (14,22–24). Because these
changes are different for boys and girls,
theymayprovideanothersourceofexpla-
nation for our finding of an apparent sex
difference (e.g., vasodilatory effects of es-
trogen and progesterone). However, it is
important to note that we did not find a
statistically significant interaction with
sex. Thus, additional studies are needed
to confirm and further elucidate the im-
portance of this observation.
Strengthsofourstudyincludeitspro-
spectivedesign,quantitativeevaluationof
retinal vascular caliber, and standardized
assessment of diabetic retinopathy using
stereoscopic seven-field retinal photo-
graphs. Potential limitations may merit
consideration. First, the generally short
periodoffollow-up(3years)mayresultin
some misclassifications, as some partici-
pants could potentially still develop reti-
nopathy after the end of follow-up.
Second, there may be limited generaliz-
ability of our findings to the general com-
munity, as our study population was
derivedfromatertiaryhospital-basedset-
ting. Our results might have been biased
toward exceptionally good endocrinolog-
ical and ophthalmological monitoring,
and mild retinopathy or no retinopathy
could be over-represented relative to the
generaldiabeticpopulation.Forexample,
we had no cases of proliferative retinopa-
thy in our population. However, in Aus-
tralia, most individuals with type 1
diabetes are seen at a tertiary referral cen-
ter (11,12). Finally, findings from our
stratified analyses should be interpreted
with caution, as there might be power
concerns after stratification.
In summary, our study shows that
retinal arteriolar dilatation, measured
quantitatively from retinal photographs,
isaclinicalpredictoroffutureretinopathy
riskinchildrenandadolescentswithtype
1 diabetes, independent of standard risk
factors. Further research and develop-
ments in computer-based techniques to
analyze retinal vascular changes may un-
cover insights into early microvascular
diseaseandopennewavenuestoimprove
risk stratification of retinopathy in young
people with diabetes.
Acknowledgments— This study was sup-
ported by National Health and Medical Re-
search Council Grant 475605 (T.Y.W.,
K.C.D., A.J.J., and G.T.). Additional support
was obtained from a Juvenile Diabetes Re-
search Foundation Travel Grant (N.C.).
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