© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Are Retinal Arteriolar Abnormalities Related to Atherosclerosis?
The Atherosclerosis Risk in Communities Study
From the Department of Ophthalmology and Visual Sciences (R.K., B.E.K.K., L.D.H.), University of Wisconsin Medical School, Madison; the Division of Epidemiology and Clinical Applications (A.R.S., L.S.C.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; the Collaborative Studies Coordinating Center (L.E.C.), Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill; and the Department of Public Health Sciences (G.E.), Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 N Walnut St, 460 WARF, Madison, WI 53705-2397. E-mail kleinr{at}epi.ophth.wisc.edu
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Abstract—The objective of this study was to describe associations of retinal arteriolar abnormalities with clinical and subclinical manifestations of atherosclerosis and a broad group of risk factors for vascular disease. A biracial population of 8772 adults (aged 48 to 72 years) living in 4 communities was examined from 1993 to 1995 were studied for that purpose. Retinal arteriovenous nicking and focal arteriolar narrowing were determined by light-box grading of a 45° fundus photograph by use of a standardized protocol. Diameters of arterioles and venules were measured in digitized photographs, and a summary arteriolar-to-venular ratio was derived as an index of generalized arteriolar narrowing. Focal arteriolar narrowing was associated only with hypertension. Generalized arteriolar narrowing was associated with carotid plaque but not with any other evidence of atherosclerosis, either clinical (cardiovascular disease or stroke) or subclinical (carotid or popliteal artery thickness or lower limb obstructive disease), or with plasma cholesterol. It was also associated with smoking, with inflammatory markers (white blood cell count, fibrinogen, and reduced albumin), and with the triglyceride and high density lipoprotein cholesterol changes associated with inflammation. Arteriovenous nicking was inconsistently associated with subclinical atherosclerosis. It was not associated with cardiovascular disease, stroke, or plasma cholesterol. Arteriovenous nicking was associated with markers of inflammation and vascular endothelial dysfunction (von Willebrand factor and factor VIII). Arteriolar narrowing and nicking appear to be related to hypertension and inflammatory factors. Nicking may also be related to endothelial dysfunction. Results suggest that these arteriolar changes are pathologically distinct from atherosclerosis. Including their measurement in population studies may permit evaluation of the independent contribution of arteriolar disease to various ischemic diseases of the heart, brain, and other organs.
Key Words: arteriosclerosis • atherosclerosis • epidemiology • inflammation • risk factors
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Introduction |
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Retinal arteriolar abnormalities (eg, focal and generalized narrowing and arteriovenous nicking) have long been recognized as being related to hypertension even in the absence of diabetes mellitus.1 2 3 4 5 6 They have also been described in persons without hypertension (or diabetes) and have then been attributed to other unspecified arteriosclerotic processes. Thus, although many studies have demonstrated the associations of hypertension with retinal arteriolar changes in people without diabetes, few have examined the associations of these arteriolar changes with other risk factors.2 7 8 9 10 11 12 13 14 The relationship of these arteriolar changes with atherosclerotic, inflammatory, and other pathogenic processes is largely unknown. In the present study, we describe the relationships of these arteriolar changes with clinical and subclinical manifestations of atherosclerosis and a broad group of risk factors for vascular disease, after controlling for hypertension in black and white nondiabetic participants in the Atherosclerosis Risk in Communities (ARIC) Study.
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Sample and Study Population
In 1987 to 1989, 15 792 women and men were examined. They had been selected as probability samples from 45- to 64-year-old residents of 4 US communities: Forsyth County, NC; the city of Jackson, Miss; suburbs of Minneapolis, Minn; and Washington County, Md.15 Only black residents were selected in Jackson, whereas residents were selected without regard to ethnicity in the other communities. Initial participation rates were 46% in Jackson and
65% in the other
communities. Survivors were reexamined in 1990 to 1992 and again in
1993 to 1995. Baseline differences between participants and
nonparticipants have been presented.16 17
A retinal photograph of 1 eye of each participant was taken at the
third examination, when the participants were aged 51 to 72
years.18 Of the 12 887 participants in the third
examination, 211 were excluded because they missed the second
examination; 38, because their race was neither black nor white; 1994,
because they had diabetes mellitus (defined as a fasting glucose level
140 mg/dL, nonfasting glucose level 200 mg/dL, or a history of or
treatment for diabetes); 133, because of missing blood pressure,
smoking, or cholesterol data; and 8, because of retinal
venous or arteriolar occlusion. Of the remaining 10 503 participants,
photographs were available for 10 354 persons. Of these, 1582
photographs could not be evaluated. Persons without gradable
photographs were older and, after adjusting for age, substantially more
likely to be black, to drink less alcohol, and to have higher Lp(a)
than those with gradable photographs (Table 1
).
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Methods
Participants underwent standardized evaluations at baseline and
at both follow-up examinations, including assessment of standard risk
factors for atherosclerotic diseases.19 Data collection
methods and variable definitions19 and the retinal
photography and its interpretation are described in detail
elsewhere.13 20 Briefly, a 45° retinal photograph
centered on the optic disk and macula was taken of 1 eye by use of an
automatically focusing camera. Pupillary dilation was achieved by
having the participant spend 5 minutes in a dark room (no
pharmacological agents were used). Photographic methods followed
written protocols. Image quality was monitored with periodic feedback
to the photographers. Photographs were evaluated at the Fundus
Photograph Reading Center in Madison, Wis. Trained graders, blinded to
subject identity, evaluated slides for focal arteriolar narrowing and
arteriovenous nicking. Diameters of retinal vessels were measured after
converting the photographs to digital images. All arterioles and
venules were measured in the area between 1/2 and 1 disk diameter from
the optic disk margin.
Definitions of Variables
Focal narrowing was recorded in each of 4 quadrants. Focal
narrowing was considered definite if an arteriole estimated to be
50 µm in diameter (1/3 of the diameter of a major vein at
the disk margin) had a constricted area of 
2/3 the width of proximal
and distal vessel segments. The maximum grade from the 4 quadrants
defined 2 end points: focal narrowing on the disk and outside the disk.
Both were categorized as definite versus questionable or absent.
Arteriovenous nicking was also categorized as definite versus
questionable or absent. It was considered to be present only if
seen in at least 1 of the temporal quadrants, because the superior and
inferior temporal vascular arcades each typically contain
at least 1 good example of arteriovenous crossing that can be examined
for nicking, whereas on the nasal side, arterioles and venules fanning
out from the disk may not display any major arteriovenous crossings
within the photograph. To quantify generalized narrowing as an
arteriolar-to-venular ratio (A/V ratio), measurements of individual
arterioles and venules were combined according to formulas developed by
Parr and Spears21 22 and Hubbard et al20 to
provide central equivalents. Arteriolar caliber measurements were
combined into the central retinal equivalent as the branch variant,
substituting branch measurements for any trunk arteriole 80
µm.
Methods used to measure blood pressure, smoking, diabetes, use of medications, and hemostatic variables are provided elsewhere.23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 In brief, resting blood pressure measurements, taken with a random-zero sphygmomanometer at baseline and both follow-up visits, were averaged.35 Mean arterial blood pressure was computed as 2/3 of the diastolic plus 1/3 of the systolic value. Smoking and diabetes history and use of medications for blood pressure and diabetes were obtained from examiner-administered questionnaires.29 31 Mean carotid and popliteal intima-media wall thickness was derived from standardized B-mode ultrasonograms.23 24 Carotid or popliteal plaques were identified if 2 of the following criteria were met: protrusion into the lumen with a rough arterial boundary, brighter echoes than adjacent boundaries, and thickness >1.5 mm.25 Prevalent coronary heart disease was defined as history of a physician-diagnosed heart attack, myocardial infarction by ECG, or cardiovascular surgery or coronary angioplasty.26 Plasma cholesterol and triglycerides were measured by enzymatic methods, and LDL cholesterol was calculated by the Friedewald formula (LDL cholesterol=total cholesterol-HDL cholesterol-(triglycerides/5).36 HDL cholesterol was measured by using dextran-magnesium precipitation.37 Platelet and white blood cell counts were measured by Coulter counter.34 37 Venous blood was drawn after an 8-hour fast for measuring fibrinogen, factor VIII, and von Willebrand factor (vWF) antigen. Fibrinogen was measured by thrombin-time titration; factor VIII activity, by clotting time with the use of factor VIII–deficient plasma; and vWF antigen, by ELISA kits.37 38 39 40 41
Reproducibility of ocular gradings has been presented
elsewhere.20 In brief, for the A/V ratio, reliability
coefficients were 0.84 for intragrader and 0.79 for intergrader repeat
measurements. The median of the absolute difference between the
original and replicate measurement was 0.03 each for intragrader and
for intergrader pairs. 
statistics were higher for focal arteriolar
narrowing elsewhere and arteriovenous nicking (0.4 to 0.6) than for
focal narrowing at the disk (0.3 to 0.4).
Statistical Methods
CIs for crude prevalence and means estimates were based on
normal approximations. Adjusted means and prevalences and their CIs
were calculated by ANCOVA,42 from linear and logistic
regression, respectively. Odds ratios (ORs) for retinal abnormalities
were calculated from logistic regression,43 adjusting for
age, sex, race, use of antihypertensive medication at visit 3, and mean
arterial blood pressure averaged over visits 1 to 3.
Differences between quartiles were tested by using a Wald
2 test43 to determine whether the
coefficients were zero for dummy variables representing
the 3 upper quartiles.
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Results |
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Focal narrowing and arteriovenous nicking prevalence consistently increased with age (Table 2
). Controlling for age and race, A/V
ratios were lower (P<0.001, Table 3) in men than in women. Controlling for
age, race, and sex, mean arterial blood pressure averaged
over 3 visits was significantly associated with A/V ratio, focal
narrowing at the disk and elsewhere, and arteriovenous nicking. ORs per
10 mm Hg blood pressure were 1.25 for arteriovenous nicking, 1.7
for focal narrowing on the disk, and 2.0 for focal narrowing
elsewhere.13 20 As previously reported, a lower A/V
ratio was strongly associated with blood pressure measured 3 and 6
years previously (P<0.001 for each sex) after adjusting for
current blood pressure.13
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After adjustment for age, race, sex, use of blood pressure
medications at visit 3, and the mean arterial blood
pressure average over a 6-year period, focal narrowing of arterioles at
the disk was associated with only a higher ankle-brachial blood
pressure ratio (fourth versus first quadrant, OR 1.35, 95% CI 1.04 to
1.77), and focal narrowing of arterioles elsewhere was associated with
higher ankle-brachial blood pressure (fourth versus first quadrant
range OR 1.34, 95% CI 1.04 to 1.72), presence of carotid artery plaque
(OR 1.39, 95% CI 1.11 to 1.74), and lower serum
cholesterol (OR 0.69, 95% CI 0.54 to 0.89). Associations
of population characteristics with A/V ratio and arteriovenous nicking
are presented in Tables 4 and 5, respectively, adjusted for age, race,
sex, use of blood pressure medications at visit 3, and the mean
arterial blood pressure averaged over a 6-year period. A
lower mean A/V ratio was associated with carotid plaque, lower HDL
cholesterol (P=0.08), higher plasma
triglycerides, lower serum albumin, higher
hematocrit and leukocyte and platelet counts, greater body mass
index, being a former or current smoker, cigarette pack-years, alcohol
consumption, higher fibrinogen levels, and lower vWF and factor VIII
levels (Table 4).
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Retinal arteriovenous nicking was associated with popliteal artery
plaque, greater body mass index, higher leukocyte count and hematocrit,
lower platelet count and serum albumin, being a current or
former smoker, pack-years, and higher factor VIII level (Table 5
). It was also associated, but of only borderline significance
(0.05<P<0.10), with increased carotid and popliteal
intima-media thickness, lower HDL cholesterol, and higher
fibrinogen and vWF levels.
Because arteriovenous nicking and A/V ratios were related to a number of acute-phase reactants, we reran models for these 2 end points in current nonsmokers (n=7242), adjusting for the same covariates as before. The direction of the associations of leukocyte count, fibrinogen, factor VIII, vWF, serum albumin, and HDL cholesterol with arteriovenous nicking and A/V ratio remained similar to that found for the whole cohort, although some associations were no longer significant (data not shown).
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Discussion |
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Previous reports have consistently shown strong associations between hypertension and the retinal abnormalities examined in the present study.2 7 8 9 10 11 12 13 Therefore, we adjusted all of our models for blood pressure. To reduce residual blood pressure confounding, we adjusted for the average of blood pressure measured at all 3 visits and the use of antihypertensive medications. We report that the arteriolar abnormalities differ in their associations with atherosclerosis and its risk factors.
Generalized arteriolar narrowing has been considered an early sign of hypertension.2 4 5 6 44 45 As previously reported in the ARIC Study, a lower A/V ratio was strongly associated with blood pressure measured 3 and 6 years previously (P<0.001 in each sex) after adjusting for present blood pressure.13 This suggests that generalized narrowing is a persistent or structural effect of elevated blood pressure. After adjusting for present and previous blood pressure and medications, the A/V ratio was not associated with any clinical or subclinical indicators of atherosclerosis, except carotid plaque. Its association with carotid plaque might be a local effect of disease in the carotid artery rather than evidence of extension of the same pathogenic process. Furthermore, plasma cholesterol, which is strongly related to atherosclerotic carotid disease in the ARIC Study,36 showed no substantial or significant association with the A/V ratio.
However, retinal arteriolar narrowing shares many other risk factors with atherosclerosis. These include blood pressure, of course, and, we now report, smoking, which is an inflammatory stimulus, and measures of the acute-phase inflammatory response, namely, elevated white cells, platelets, fibrinogen, and reduced albumin.46 47 Associations with inflammatory markers were seen even in nonsmoking participants. Inflammation may explain why a low A/V ratio was associated with body mass index, because cytokines causing the innate inflammatory response may originate in adipose tissue,48 and with elevated triglycerides and reduced HDL cholesterol, because this lipid pattern is characteristic of the inflammatory response.
We have no explanation for the association of arteriolar narrowing with low vWF and factor VIII levels. Elevated vWF levels are believed to reflect functional or structural changes in the vascular endothelium.49 50 Factor VIII levels are correlated with vWF levels (r=0.73),51 because they circulate together as a complex, and elevated vWF and factor VIII levels were associated with coronary heart disease incidence in the ARIC Study.37
There are no other data with which to compare ARIC findings because of our unique approach used to measure the A/V ratio. However, in the Gothenburg Study (Svardsudd et al9 ), generalized narrowing, based on clinical ophthalmoscopy, was associated with higher plasma cholesterol and smoking.
Understanding the pathogenesis of a low A/V ratio is important because it may explain, in part, the pathogenesis of some strokes. The A/V ratio was strongly and independently associated with small MRI-determined cerebral infarctions in hypertensive ARIC participants (OR 3.71, 95% CI 1.58 to 8.72 comparing the lowest with highest quintile of the A/V ratio; L.S.C., unpublished data, 1997). A case-control study in Japan showed generalized arteriolar narrowing associated with hemorrhagic and thrombotic stroke.52
It has long been hypothesized that hypertension, but not arteriosclerosis, is important in the pathogenesis of focal retinal arteriolar narrowing.45 In the ARIC Study, the pattern of associations did not suggest that focal narrowing is related to atherosclerosis. Focal narrowing was either not associated or was significantly inversely associated with plasma cholesterol. There are few data from other studies that show associations of factors other than hypertension with focal narrowing.53 The population-based Beaver Dam Eye Study (Klein et al12 ) showed hypertension associated with increased 5-year incidence of focal narrowing (relative risk, 2.3 in men and 1.6 in women), but after adjusting for hypertension, narrowing was unrelated to plasma total or HDL cholesterol, platelet or white blood cell counts, hematocrit, serum albumin, smoking status, or history of cardiovascular disease (R.K., unpublished data, 1998).
Focal narrowing was associated with higher ankle-brachial index values in the ARIC Study. Atherosclerosis, on the other hand, is marked by a low ankle-brachial index.54 A possible explanation of this finding is that high peripheral pressures can occur when the pulse wave is reflected back toward the heart, and this might occur in the ankle with arteriolar constriction in the foot. This is plausible, because it suggests only that arteriolar constriction in the foot may be associated with arteriolar constriction in the retina.
Unlike generalized arteriolar narrowing, arteriovenous nicking showed a few associations with macroarterial disease. It was significantly associated with popliteal plaque, and its associations with popliteal and carotid thickening were positive, although only of borderline significance. However, nicking was not associated with carotid plaque, ankle-brachial index, or coronary or stroke prevalence. The association of arteriovenous nicking with plasma cholesterol, although not significant, was inverse, thus clearly distinguishing nicking from manifestations of atherosclerosis.
Like the A/V ratio, arteriovenous nicking was significantly associated with smoking, obesity, elevated white cell count and fibrinogen and hematocrit levels, and reduced serum albumin levels. However, the borderline associations for fibrinogen and the white cell count make the evidence of an inflammatory component to arteriovenous nicking less compelling than for the A/V ratio. In contrast, arteriovenous nicking, unlike the A/V ratio, was associated with elevated vWF and factor VIII, suggesting that factors related to endothelial function may have a unique role in the etiology of nicking.
The findings in the ARIC Study are consistent with the significant association of smoking, but not cholesterol, with arteriovenous nicking in the Gothenburg Study.9 In the Beaver Dam Eye Study,12 smoking was associated with the incidence of arteriovenous nicking. Regardless of its pathogenesis, arteriovenous nicking has been found to be associated with cardiovascular morbidity and mortality,52 55 56 particularly stroke.52 In the ARIC Study, arteriovenous nicking was independently associated with MRI-determined cerebral infarcts in persons with hypertension (OR 2.59, 95% CI 1.55 to 4.31; L.S.C., unpublished data, 1997).
Caution must be observed in interpreting the findings described in the present study, because analyses were cross-sectional. Care must be exercised in judging the significance of the associations reported, because a large sample size increases the statistical power for detecting associations of a small magnitude. For a number of risk factors, A/V ratio differences were <0.02. The prognostic implications of differences of this magnitude remain to be determined. Finally, as shown by our reproducibility statistics, there may have been errors in identifying arteriovenous nicking.
In summary, findings from the ARIC Study suggest that the pathogenesis of retinal arteriolar changes (focal narrowing, A/V ratio, and arteriovenous nicking) differ. All 3 are strongly related to hypertension but not to cholesterol level. Inflammatory factors may contribute to nicking and generalized narrowing, and vascular endothelial dysfunction may contribute to nicking. Atherosclerosis, a disease of larger arteries, is a major cause of coronary heart disease and many strokes. Arteriolar nicking and generalized narrowing, which we now see occurring independently of atherosclerosis, might provide independent prediction for ischemic diseases of the heart, brain, and other organs (eg, heart failure, small strokes, and cognitive decline). The standardized methods now available for measuring arteriolar changes facilitate their inclusion in population studies designed to address these questions.
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Acknowledgments |
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This research was supported by National Institutes of Health grant EYO6594 (R. Klein, B.E.K. Klein) and HL-59259 (R. Klein, B.E.K. Klein); in part, by the Research to Prevent Blindness (R. Klein, Senior Scientific Investigator Award); and by contracts NO1-HC-55015, NO1-HC-55018, NO1-HC-55019, NO1-HC-55020, NO1-HC-55021, and NO1-HC-35125 from National Heart, Lung, and Blood Institute. The authors acknowledge the valuable contributions made by the ARIC staff at the collaborating institutions: the University of Wisconsin, Madison; the University of North Carolina, Chapel Hill; the University of Mississippi Medical Center, Jackson; the University of Minnesota, Minneapolis; the Johns Hopkins University, Baltimore, Md; and the University of North Carolina Coordinating Center, Chapel Hill.
Received November 29, 1999; accepted March 17, 2000.
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