Published online before print November 12, 2007, doi: 10.1161/HYPERTENSIONAHA.107.098343
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(Hypertension. 2008;51:119.)
© 2008 American Heart Association, Inc.
Original Articles |
Relationship Between Retinal Arteriolar Narrowing and Myocardial Perfusion
Multi-Ethnic Study of Atherosclerosis
From the Division of Preventive Medicine (L.W.), Department of Medicine, Brigham and Women’s Hospital, Boston, Mass; Center for Eye Research Australia (T.Y.W.), University of Melbourne, Melbourne, Australia; Singapore Eye Research Institute (T.Y.W.), National University of Singapore, Singapore; the Department of Epidemiology (A.R.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Md; the Department of Ophthalmology and Visual Sciences (R.K.), University of Wisconsin, School of Medicine and Public Health, Madison; the Division of Epidemiology and Community Health (A.R.F.), School of Public Health, and Department of Radiology (M.J-H.), School of Medicine, University of Minnesota, Minneapolis; and Advanced Imaging Research Center (M.J-H.), Oregon Health and Science University, Portland.
Correspondence to Lu Wang, Brigham and Women’s Hospital, 900 Commonwealth Ave East, Boston MA 02215. E-mail luwang{at}rics.bwh.harvard.edu
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Abstract |
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Retinal arteriolar narrowing is a marker of chronic hypertension. Myocardial perfusion reflects microvascular processes in the heart. The relationship between these 2 measures has not been studied previously and is examined in 212 men and women aged 45 to 84 years and free of cardiovascular disease diagnoses. Retinal caliber was measured through fundus photography and presented as central retinal arteriolar and venular caliber equivalents. Myocardial blood flow was measured using MRI during rest and adenosine-induced hyperemia. Among subjects with no coronary artery calcification (n=98), smaller retinal arteriolar caliber was associated with lower hyperemic myocardial blood flow and perfusion reserve (calculated as the ratio of hyperemic:resting blood flow). Mean hyperemic blood flow (3.43, 3.28, 3.26, and 3.09 mL/min per gram; Plinear=0.006) and mean perfusion reserve (3.52, 3.37, 3.19, and 3.10; Plinear=0.01) progressively decreased across decreasing quartiles of retinal arteriolar caliber. These associations remained significant after adjusting for age, gender, and race/ethnicity but were no longer significant after additionally adjusting for other cardiovascular risk factors. In contrast, among subjects with coronary calcification (n=114), retinal arteriolar caliber was not associated with hyperemic myocardial blood flow (Plinear=0.73) or perfusion reserve (Plinear=0.79). There were no associations between retinal venular caliber and perfusion measurements. We conclude that narrower retinal arterioles were associated with lower hyperemic myocardial blood flow and perfusion reserve in asymptomatic adults with no coronary calcification, which is partially mediated by traditional cardiovascular risk factors. This finding suggests that retinal arteriolar narrowing may serve as a marker of coronary microvascular disease.
Key Words: microvascular disease • retinal arteriolar narrowing • myocardial perfusion • coronary artery calcification • population study
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Introduction |
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Impairment of the coronary microcirculation may contribute to the risk of coronary heart disease (CHD) independent of obstructive stenosis in the epicardial arteries,1,2 particularly in persons with hypertension or other cardiovascular risk factors that have microvascular effects.3–5 Studies on coronary microvascular function and structure offer an opportunity to evaluate the role of microvascular processes in the development of CHD before clinical manifestation.
Retinal arterioles and venules measure 
150 to 250 µm. Retinal arteriolar narrowing is a marker of systemic microvascular damage from chronic hypertension.6–8 Previous studies reported that retinal arteriolar caliber is associated with risk of hypertension,9 left ventricular remodeling,10 and systemic biomarkers of inflammation and endothelial function11 but not with blood cholesterol levels.11 Retinal arteriolar narrowing has been further shown to predict clinical cardiovascular events, including CHD in women12 and stroke,13 independent of the traditional cardiovascular risk factors.
Myocardial perfusion is thought to reflect coronary vasoreactivity at the level of microcirculation when epicardial stenosis is absent.14 Abnormalities in myocardial blood flow (MBF) are associated with older age, higher blood pressure, higher fasting blood glucose, lower serum high-density lipoprotein (HDL) cholesterol,15 and coronary artery calcification (CAC)16 in asymptomatic subjects with no clinical cardiovascular disease. Reduced MBF in response to vasoactive stimuli is an independent predictor of incident coronary events, even in patients known to be at relatively low risk.17
Because retinal arteriolar narrowing and MBF abnormality both reflect impairment in microcirculation, we hypothesize that the 2 measurements may be related. In this study, we assessed the cross-sectional association between retinal microvascular caliber and MBF at rest or during hyperemia in middle-aged and older adults who had no clinical cardiovascular disease. We also explored the factors accounting for the relation between the microvascular measurements taken in 2 different circulatory beds.
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Methods |
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Study Subjects
Subjects were recruited from participants in the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based prospective cohort study of subclinical cardiovascular disease and its progression. Study design and participant characteristics of MESA have been described in detail elsewhere.18 In brief, 6814 men and women from 4 ethnic origins, aged 45 to 84 years and free from clinically diagnosed cardiovascular disease based on self-reported information, were enrolled from 6 US field centers. The baseline examination took place between July 2000 and September 2002, followed by a second examination from August 2002 to January 2004. Each cohort member at the MESA Minnesota Field Center (n=1066) was introduced to a perfusion study. Of these, 234 agreed to participate. This subcohort was 45 to 84 years old and composed of 57% men and 57% whites (remainder Hispanics). Subjects who participated in the perfusion study were comparable to those who did not on most standard CHD risk factors but had a smaller body mass index (28.9 versus 29.6 kg/m2) and a lower prevalence of hypertension (27% versus 36%). The perfusion study was approved by the institutional review board at the University of Minnesota, and the study procedures followed were in accordance with institutional guidelines. All of the study subjects provided informed consent.
MRI and Quantification of MBF
Cardiac magnetic resonance (CMR) imaging was performed with a 1.5-T clinical magnetic resonance scanner (Sonata, Siemens Medical Systems). Participants were positioned supine. A flexible 4-element phased-array coil was placed over the heart, with 2 elements of a spine array coil serving as posterior antennae. T1-weighted images of 2 to 3 sections (sections thickness: 8 mm) in a short axis were acquired with a fast ECG-triggered gradient echo sequence during each heartbeat, for a total of 50 heartbeats. Starting at the third or fourth heartbeat, a gadolinium-diethyltriaminepentaacetic acid bolus (Magnevist, Berlex) of 0.04 mmol/kg of body weight was administered with a power injector through an antecubital vein at a rate of 7 mL/s followed by a saline flush of 15 mL at the same rate. First perfusion scan was performed during rest. A second scan followed 15 minutes later during maximal vasodilation induced by intravenous infusion of adenosine: 0.14 mg/kg per minute for 3 minutes before scanning and continuing after magnetic resonance contrast injection until acquisition of the first 10 to 15 images.
The observers who analyzed CMR images were blinded to participants’ characteristics. Signal intensity curves were generated for 8 transmural myocardial sectors with a CMR image analysis program (MASS CMR analysis software, Leiden University). Signal intensity curves represent the change of mean signal intensity as a function of time, corrected for baseline signal- and coil-sensitivity variations. In accordance with the central volume principle,19 MBF was estimated from the initial amplitude of the myocardial impulse response by deconvolution analysis of the signal intensity curves. MBF estimated by the method used in this study had an excellent linear correlation (R2=0.995; slope: 0.96; intercept: 0.06) with the measurements from radioisotope labeled microspheres,20 which is regarded as the reference method for quantification of MBF. Perfusion reserve (PR) is calculated as the ratio of MBF during hyperemia to that at rest. MBF measurements are reported in the present study as the global average over 8 myocardial segments and 2 to 3 sections.
Retinal Photography and Measurement of Retinal Vascular Caliber
Fundus photography was performed during the second MESA examination at all of the MESA field centers using a standardized protocol.21 Participants were seated in a darkened room. Both eyes of each participant were photographed using a 45°, 6.3-megapixel digital nonmydriatic camera. Two photographic fields were taken of each eye; the first centered on the optic disc (field 1), and the second centered on the fovea (field 2). Images were sent from the field centers to University of Wisconsin for measurement of the retinal vascular caliber and assessment of other retinal pathology. A total of 224 of the 234 participants of the perfusion study had retinal photographs that were suitable for measurement of the retinal vascular caliber, 0.5 to 33.0 months (mean: 9.0 months) after the perfusion scanning.
Retinal vascular caliber was measured using a computer-based program (IVAN, University of Wisconsin). Trained graders who performed these measurements were masked to participant characteristics. For this study, field 1 photographs in the right eye were selected for measurement. If retinal vascular caliber could not be measured in the right eye, the photograph of left eye was chosen as an alternative. For each photograph, all of the retinal arterioles and venules coursing through an area one-half to 1-disc diameter from the optic disc margin were measured and summarized as the average central retinal arteriolar "equivalents" (CRAE) and venular equivalents (CRVE), using formulas developed by Hubbard et al22 and later modified by Knudtson et al.23 These equivalents are projected calibers for the central retinal vessels, measured away from the optic disc. The intragrader and intergrader intraclass correlation coefficients of retinal vascular measurements ranged from 0.78 to 0.99.22,24
Measurement of Coronary Risk Factors and CAC
Assessment of other coronary risk profiles was based on information collected at the MESA baseline clinic exams. Body mass index was calculated from measured height and weight. Current smoking was defined as smoking cigarettes within the past 30 days. Resting seated blood pressure was measured 3 times using an automated oscillometric sphygmomanometer (DINAMAP PRO 100), and the average of the last 2 measurements was used for analysis. Hypertension was defined as systolic blood pressure 
140 mm Hg, diastolic blood pressure 90 mm Hg, self-reported history of hypertension, or current use of antihypertensive medications. Blood samples were obtained from participants after 8 hours of fasting and analyzed at a central laboratory for glucose, total cholesterol, low-density lipoprotein, and HDL cholesterol. Diabetes mellitus was defined as fasting glucose 126 mg/dL or the use of diabetes medications. Impaired fasting glucose was defined as fasting glucose 110 to 125 mg/dL with no treatment of diabetes.
CAC was measured at the MESA Minnesota Field center using a 4-detector row computed tomography scanner (Volume Zoom, Siemens). During a single breath hold, prospectively ECG-triggered scans were acquired at 50% of each R-R interval, covering 4 simultaneous 2.5-mm sections for each cardiac cycle. Each subject was scanned twice consecutively and over a phantom with known calcium content. Scans were read centrally at the Harbor-University of California Los Angeles Research and Education Institute. Agatston calcification score25 was calculated as a product of the area of calcified plaque multiplied by a coefficient rated 1 through 4 on the basis of peak calcium density in the identified deposit. Total calcification score was the sum of the scores of individual lesions. The agreement for the presence of CAC on the consecutive scans for the same participant was high (
=0.92). The intraclass correlation coefficients for readings of the CAC amount performed by the same or by different readers were >0.99. The average of 2 CAC scores was used for analysis.
Statistical Analysis
Statistical analysis was performed using SAS software version 8 (SAS Institute). Participants were excluded from statistical analysis if they had missing values on perfusion measurements (n=5) or retinal vascular calibers (n=10) or if they took caffeine within 12 hours before CMR scanning (n=7). A total of 212 subjects remained for analysis after exclusions. With generally normal distributions, perfusion measurements and retinal vascular equivalents were all presented as mean±SD. In our study, we chose to analyze the relationship of myocardial perfusion with retinal vascular equivalents (CRAE and CRVE) separately instead of their ratio as in some previous studies.12 This was because CRAE and CRVE have different predictors26,27 and associate with CHD and stroke differently,12,13 and, therefore, the ratio is difficult to interpret.26,28 Retinal vascular equivalents and MBF were compared across categories of demographic factors and coronary risk factors using ANOVA. Linear regression was used to estimate the difference in perfusion measurements predicted by 1 unit change in retinal vascular equivalents. The initial model did not adjust for any covariates; model 1 adjusted for age, gender, and race/ethnicity, and model 2 additionally adjusted for traditional CHD risk factors including cigarette smoking, hypertension status, systolic blood pressure, diabetes status, fasting blood glucose, low-density lipoprotein cholesterol, HDL cholesterol, and body mass index. Curvilinear trends were tested by including quadratic terms in the model. To account for confounding effects, models for CRAE also adjusted for CRVE and vice versa. All of the linear models were further stratifying by CAC level, an indicator of overall atherosclerosis burden in epicardial arteries. Based on the results of linear regression analysis, the mean values of hyperemic MBF and PR were compared across quartiles of CRAE using ANOVA, stratified on CHD risk factor status (age of 45 to 64 years versus 65 years, gender of women versus men, hypertension yes versus no, and diabetes or impaired fasting glucose yes versus no). All of the interactions were tested using the Wald 
2 test.
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Results |
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The mean±SD of perfusion measurements and retinal vascular calibers were shown across participant characteristics in Table 1. Generally consistent with findings from the entire MESA cohort, CRAE was inversely associated with age and systolic and diastolic blood pressure and positively associated with cigarette smoking; CRVE was inversely associated with age, white ethnicity, and serum HDL cholesterol and positively associated with cigarette smoking and fasting blood glucose. Meanwhile, resting MBF was not associated with most individual CHD risk factors except for gender and serum HDL cholesterol; hyperemic MBF was inversely associated with older age, male gender, higher blood pressure, lower serum HDL cholesterol, and possibly with higher fasting blood glucose.
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Table 2 showed the results of linear regression of myocardial perfusion measurements on central retinal vascular equivalents. Before adjusting for covariates, smaller CRAE was associated with lower hyperemic MBF and PR but not associated with resting MBF. A 1-µm decrease in CRAE was associated with a decrease of 0.0088 mL/min per gram in hyperemic MBF (P=0.04) and a decrease of 0.0092 in PR (P=0.05). After adjusting for age, gender, and race/ethnicity, these associations were substantially attenuated and no longer significant. When the linear regression was stratified by levels of CAC, the relations between CRAE and hyperemic MBF and PR significantly differed by the presence or absence of CAC (P for interaction <0.05). Among subjects with no CAC (Agatston CAC score=0), smaller CRAE was strongly associated with lower hyperemic MBF (regression coefficient β=0.017; P=0.006) and PR (regression coefficient β=0.017; P=0.01). The associations remained significant after adjusting for age, gender, and race/ethnicity (β=0.013 and P=0.03 for hyperemic MBF; β=0.017 and P=0.02 for PR) but were further attenuated and no longer significant after additionally adjusting for other traditional CHD risk factors (β=0.0069 and P=0.28 for hyperemic MBF; β=0.0080 and P=0.26 for PR). Among subjects with CAC (Agatston CAC score >0), however, there were no significant associations between perfusion measurements and CRAE in any model. CRVE was not associated with any perfusion measurements in the entire sample or in subsamples stratified by levels of CAC.
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The Figure further showed the mean hyperemic MBF and PR across quartiles of CRAE, stratified by levels of CAC. Among subjects with Agatston CAC scores of 0, mean hyperemic MBF (3.43, 3.28, 3.26, and 3.09 mL/min per gram; P for trend=0.006) and mean PR (3.52, 3.37, 3.19, and 3.10; P for trend=0.01) progressively decreased across decreasing quartiles of CRAE. In contrast, among subjects with Agatston CAC scores >0, mean hyperemic MBF and mean PR across quartiles of CRAE were not significantly different. The associations between CRAE and hyperemic MBF and PR did not differ by other CHD risk factors (Table 3). The trends of mean hyperemic MBF and PR across quartiles of CRAE were similar in women versus in men, in subjects with versus those without hypertension, and in subjects with versus those without diabetes/impaired fasting glucose (all P for interactions >0.05). Among subjects aged 45 to 64 years but not those aged 65 years, mean hyperemic MBF (3.24, 3.16, 2.98, and 3.16 mL/min per gram; P for trend=0.03) and PR (3.33, 3.24, 3.02, and 3.14; P for trend=0.02) tended to decrease across descending quartiles of CRAE. However, this difference by age group was not statistically significant.
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Discussion |
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In the present study, we examined cross-sectional associations between myocardial perfusion in the coronary circulation and microvascular caliber in the retinal circulation among 212 middle-aged and older adults with no clinical cardiovascular disease. Among subjects with no evidence of CAC, we found an association between smaller retinal arteriolar caliber and lower hyperemic MBF and PR after adjusting for age, gender, and race/ethnicity. This association was attenuated and no longer significant after further adjusting for other CHD risk factors, suggesting that the association was partially mediated by traditional cardiovascular risk factors. Among subjects with CAC, in contrast, no association between perfusion measurements and retinal arteriolar caliber was found.
Coronary microvascular processes may be altered in the absence of significant atherosclerosis in epicardial arteries, and these microvascular alterations may be independently implicated in the development of CHD event.1,2 CHD risk factors, such as hypertension and diabetes, but not hypercholesterolemia, have demonstrated noteworthy microvascular effects.3–5 Although there are a number of methods available to assess microvascular structure and function, they are mostly highly specialized and invasive. Retinal photography offers a unique opportunity to noninvasively evaluate the human microvasculature in vivo. Retinal arteriolar narrowing is a marker for chronic hypertensive end-organ effects elsewhere in the body.6,7 Previous studies show that retinal arteriolar narrowing, histopathologically resulting from intimal thickening, medial hyperplasia, hyalinization, and sclerosis,29 is strongly associated with both current and past blood pressure levels9 and predicts the risk of CHD12 and stroke13 independent of traditional cardiovascular risk factors.
Assessment of myocardial perfusion was originally designed to determine the hemodynamic effect of stenosis in epicardial arteries. In the absence of significant stenosis, however, MBF is largely controlled at the level of coronary resistance vessels (arterioles with a luminal diameter of <100 µm14) and, thus, reflects the vasoreactivity of microcirculation. Animal studies30,31 and human angiography data32,33 have supported the view that microvascular dysfunction contributes to the abnormalities in MBF in coronary artery segments with no significant epicardial stenosis. Clinical studies using noninvasive imaging techniques showed that MBF is often abnormal in individuals with CHD risk factors or angina but with no evidence of epicardial stenosis.34–37 Among 222 MESA Minnesota Field center participants, MBF during adenosine-induced hyperemia and PR were strongly and inversely associated with CHD risk factor burden,15 which provides additional evidence that microvascular dysfunction may occur in asymptomatic subjects, possibly caused by the microvascular effect of several CHD risk factors.
Although myocardial perfusion and retinal vascular caliber both reflect changes in the microcirculation, data are lacking on the associations between these 2 measurements. To our knowledge, our study is the first study relating perfusion measurements and retinal vascular caliber among individuals with no clinical cardiovascular disease. In the total study population, we found that narrower retinal arterioles were associated with lower hyperemic MBF and PR, but the overall associations appear to be largely explained by the associations with age, gender, and race/ethnicity. These associations were similar across strata of many CHD risk factors but were significantly different by levels of CAC. A stronger association was found among subjects with no CAC, where stenotic epicardial atherosclerosis is presumed absent and MBF is largely controlled by coronary arterioles. The significant associations between smaller retinal arteriolar caliber and lower hyperemic MBF and PR indicate that microvascular changes in the coronary and retinal circulations may share the same pathogenic process. The associations become nonsignificant after adjusting for known CHD risk factors, suggesting that the microvascular pathogenic process in different circulatory beds is affected by common risk factors. These data are supported by previous studies showing a relationship between coronary flow reserve and microvascular structure in subcutaneous fat tissue38 and that vascular structure in subcutaneous small arteries predicts cardiovascular events.39 The contribution of microcirculation to myocardial perfusion is substantially limited in the presence of atherosclerosis, presumably because significant upstream stenoses restrict MBF downstream or because endothelial dysfunction in epicardial arteries attenuates flow-dependent vasodilation. As a result, myocardial perfusion is no longer an accurate indicator of coronary microvascular function but instead demonstrating the hemodynamic significance of epicardial lesions among subjects with substantial coronary atherosclerosis. The lack of associations between perfusion measurements and retinal vascular caliber in subjects with CAC is in agreement with this conception.
Several potential limitations of this study deserve comment. First, because there was a mean of 9 months (maximum: 33 months) of lag time between myocardial perfusion and retinal photography measurements, we must assume that vascular disease does not progress substantially in asymptomatic participants within such a time period to consider our analysis reflecting a cross-sectional association. Second, because our study subjects did not undergo coronary angiography, we cannot verify whether those with an Agatston score >0 truly had obstructive atherosclerotic lesions or evaluate the lesion severity. Third, we cannot rule out the possibility that hyperemic MBF response was blunted in cases where adenosine was prematurely terminated because of atrial-ventricular block (n=43). However, previous studies with intracoronary administration of adenosine report that, after stopping the adenosine infusion, coronary blood flow will stay close to its peak for a plateau phase,40 which is sufficiently long for a valid estimation of hyperemic MBF.41 Sensitivity analyses excluding subjects with atrial-ventricular block also obtained similar results. Finally, because there are potentially several sources of variation in the qualification of retinal vascular caliber,42 a lack of multiple measurements in the same individual may introduce random variability and limit the value of a single retinal vascular caliber measurement as a predictor of myocardial perfusion.
Perspectives
Our study in middle-aged and older adults with no clinical cardiovascular disease showed associations between narrower retinal arterioles and lower hyperemic MBF and PR among subjects with no CAC, who presumably had little if any epicardial atherosclerosis. The association was independent of age, gender, and race/ethnicity but was attenuated by other CHD risk factors, suggesting an association partially mediated by common risk factors. Our study suggests that retinal arteriolar narrowing may serve as a marker of the extent of coronary microvascular disease. Future studies with follow-up data are needed to assess the relative predictive value of myocardial perfusion and retinal vascular caliber for CHD event risk.
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Acknowledgments |
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Sources of Funding
This work was supported by grant R01 HL-65580 and contracts N01-HC-95159 through N01-HC-95169 (Multi-Ethnic Study of Atherosclerosis) from the National Heart, Lung, and Blood Institute at the National Institutes of Health.
Disclosures
None.
Received July 24, 2007; first decision August 9, 2007; accepted October 16, 2007.
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