Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
JOURNAL OF MAGNETIC RESONANCE IMAGING 14:698 –704 (2001) Original Research Arterial Wall MRI Characteristics Are Associated With Elevated Serum Markers of Inflammation in Humans Clifford R. Weiss, MD,1 Andrew E. Arai, MD,2 Minh N. Bui, MD,4 Kwabena O. Agyeman, MD,2 Myron A. Waclawiw, PhD,3 Robert S. Balaban, PhD,2 and Richard O. Cannon III, MD4* Inflammation contributes to atherosclerosis, but assessment in humans is largely restricted to measurement of markers in blood. We determined whether MRI properties of large arteries were associated with markers of inflammation in serum. Double inversion recovery, fast spin-echo images of the common carotid arteries and infrarenal aorta were obtained at 1.5 T both before and after gadolinium-DTPA (0.1 mmol/kg) in 52 subjects >40 years of age, 17 of whom had no risk factors for atherosclerosis and thus served as controls. Twenty-two study participants had increases in wall thickness (14), T2-weighted signal intensity (11), and/or contrast enhancement values (7) that were >2 standard deviations (SDs) from control group mean values. Ten subjects in this group had evidence of focal plaques in the carotids (5) and/or aorta (6). Compared with the remaining 30 subjects, these 22 had significantly higher levels of interleukin-6 (3.53 ⴞ 2.46 vs. 1.97 ⴞ 1.37 pg/mL, P ⴝ 0.004), C-reactive protein (0.56 ⴞ 0.98 vs. 0.30 ⴞ 0.52 mg/dL, P ⴝ 0.019), vascular cell adhesion molecule-1 (572 ⴞ 153 vs. 471 ⴞ 130 ng/mL, P ⴝ 0.012), and intercellular adhesion molecule-1 (244 ⴞ 80 vs. 202 ⴞ 45 ng/mL, P ⴝ 0.015), and nonsignificant differences in levels of E-selectin (46.1 ⴞ 18.9 vs. 42.3 ⴞ 11.3 ng/mL, P ⴝ 0.369). Thus, MRI characteristics of the aorta and carotid arteries were associated with elevated serum markers of inflammation, frequently in the absence of definite atheroma. MRI of large arteries may provide a new approach to investigate the contribution of inflammation to atherogenesis. J. Magn. Reson. Imaging 2001;14:698 –704. © 2001 Wiley-Liss, Inc. Index terms: inflammation; magnetic resonance imaging; atherosclerosis; cell adhesion molecules; hyperlipidemia INFLAMMATION IS BELIEVED to contribute importantly to the development and clinical expression of 1 Johns Hopkins University School of Medicine, Baltimore, Maryland. Laboratory of Caridac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. 3 Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. 4 Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. *Address reprint requests to: R.O.C., National Institutes of Health, Building 10, Room 7B-15, 10 Center Drive, MSC 1650, Bethesda, MD 20892-1650. E-mail: [email protected] Received April 4, 2001; Accepted August 16, 2001. 2 © 2001 Wiley-Liss, Inc. DOI 10.1002/jmri.10023 atherosclerosis (1–3), although evidence for this association in humans is derived largely from measures of surrogate markers of inflammation. In this regard, risk of future cardiovascular events has been found to correlate with serum markers of inflammation in large groups of patients with known or suspected coronary artery disease, as well as in apparently healthy subjects (4 –9). However, the sensitivity and specificity for any given serum level of a marker in defining the presence of active vascular inflammation is unknown. In this regard, many proposed markers of vascular inflammation may be elevated in chronic inflammatory conditions not associated with atherosclerosis (10). Also unknown is whether high levels of serum markers of inflammation may be present due to vascular inflammation preceding plaque development. Accordingly, techniques capable of demonstrating active arterial inflammation might identify individuals with significantly increased risk of developing atherosclerosis or acute coronary syndromes, and could prove useful in targeting aggressive therapies to reduce vascular inflammation. Prior magnetic resonance imaging (MRI) studies of human atherosclerosis have largely focused on plaque morphology and composition, which may be important in determining the risk of plaque rupture (11–15). However, MRI may also permit noninvasive demonstration of inflammation within the vessel wall, as suggested by experimental and clinical studies. Thus, MRI of sheep iliac arteries following implantation of Dacron-covered stents showed both increased T2-weighted signal intensity and contrast enhancement of the arterial wall adjacent to the stent (16). At necropsy, vascular segments surrounding the prosthesis were found to be infiltrated with inflammatory cells, including macrophages, lymphocytes, granulocytes, and foreign body giant cells. Polyester-covered iliac artery stent implantation in 14 patients produced similar MRI findings in 11, while none of 20 patients who received conventional metallic stents or underwent balloon angioplasty of the iliac artery had these findings (17). MRI studies of intracranial vertebral and carotid arterial walls demonstrated contrast enhancement that correlated with age, and was hypothesized to be due to neovascularization associated with atherosclerotic plaques (18). Recently, pa- 698 Detection of Arterial Inflammation by MRI tients with clinically active Takayasu arteritis were reported to have aortic wall thickening with gadolinium contrast enhancement by MRI, associated with elevated levels of C-reactive protein (19). The purpose of this study was to determine whether MRI could identify features compatible with active inflammation in large arteries of middle-aged and older subjects, especially those with clinically established atherosclerosis or its risk factors. We hypothesized that arterial inflammation would cause increases in wall thickness, T2-weighted signal intensity, and/or arterial wall gadolinium contrast enhancement because of enhanced endothelial permeability with increased tissue water, cellular infiltration, and vasovasorum dilatation or neovascularization. Due to technical limitations in high-resolution coronary artery MRI, we chose to image large arteries commonly affected by atherosclerosis: the carotid arteries and the infrarenal aorta. Serum markers of inflammation were obtained to determine associations with the MRI characteristics of arterial walls that we considered to be potentially indicative of arterial wall inflammation. METHODS Study Population Fifty-two subjects ⱖ40 years of age (average age 56 years, range 40 –79 years) were included in the primary analysis of the study, representing a continuous series of subjects who completed the required MRI procedure. There were three predefined groups: 1) 10 men and seven women with no modifiable risk factors for atherosclerosis (all with LDL cholesterol ⱕ130 mg/dL, blood pressure ⬍140/90 mm Hg, fasting blood glucose ⬍120 mg/dL, and no smoking within the past 2 years) who served as controls for the determination of normal MRI parameters (mean value ⫾ 2 SD); 2) 13 men and five women with hypercholesterolemia (LDL cholesterol ⱖ 160 mg/dL), who had received no medications, hormone therapies, or antioxidant vitamins for at least 2 months prior to the study; and 3) 15 men and two women with angiographically defined coronary atherosclerosis (⬎70% luminal narrowing of at least one coronary artery at the time of diagnostic cardiac catheterization) with stable cardiac symptoms on appropriate medical management, including aspirin (16) and lipidlowering therapy (10). An additional group of 17 young adults between 25 and 30 years of age were studied for comparison with the older “control group” to assess the possibility of age-dependence of MRI features and serum markers of inflammation. No participant had known carotid disease, abdominal aortic aneurysm, systemic inflammatory disorder, or any contraindication to MRI. This protocol was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute, and all participants gave written informed consent. Laboratory Assays After an overnight fast except for water, blood was obtained from the antecubital vein. Serum aliquots were coded by a research nurse to blind laboratory personnel 699 as to subject identity, and were frozen at –70°C until processed as one batch for the following markers of inflammation: interleukin-6 (IL-6), E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) by enzyme-linked immunoassays (R&D Systems, Minneapolis, MN); and Creactive protein (CRP) by two-site chemiluminescent enzyme immunometric assay with a sensitivity of 0.01 mg/dL (Immulite, DPC, Los Angeles, CA). MRI of the Carotid Arteries and Aorta MRI was performed on a 1.5T General Electric CV/i scanner (Waukesha, WI) using a high-resolution, black blood, ECG-gated, double inversion recovery, fast spin echo pulse sequence (20). Common carotid arteries and the infrarenal aorta were imaged in this protocol because of the predilection for atherosclerosis, and because the laminar nature of the blood flow in these regions minimizes intraluminal signal associated with eddy currents in the vessel. Imaging of the carotid arteries was performed using a dual 3-inch surface coil phased array with a 16 –18-cm field of view (FOV) (256 ⫻ 256 matrix) and 2-mm slices. The average number of pixels per carotid ROI was 14 ⫾ 7 (range 8 –72), with pixel dimensions of 0.63 ⫻ 0.63 mm, and an acquisition time of 32 heartbeats. Imaging of the aorta was performed using a four-element cardiac phased array coil with a 24-cm FOV (256 ⫻ 128 matrix) and 4-mm slices. The average number of pixels per aortic ROI was 13 ⫾ 6 (range 4 –35), with pixel dimensions of 0.94 ⫻ 1.88 mm, and an acquisition time of 16 heartbeats. All imaging was ECG-gated (32 echos every other heartbeat). Fat saturation was used on all images analyzed quantitatively. Carotid imaging was performed 5–10 minutes after contrast (gadolinium DTPA 0.1 mmol/kg I.V.), and aortic imaging occurred 10 –25 minutes after contrast. Proton density-weighted images (baseline) with echo time (TE) ⫽ 5 msec were compared with T2-weighted images (TE ⫽ 60 msec) (Fig. 1), and gadolinium contrast-enhanced images (TE ⫽ 5 msec) (Fig. 2). The same prescan values were used within a subject to minimize signal intensity changes from scan to scan as well as pre- and postcontrast. Further, interscan variability was minimized by immobilization of the patient’s head within a cradle apparatus, and by securing surface coils to the neck with a clamp device and to the abdomen with Velcro straps. The inversion time was empirically adjusted to minimize the blood pool signal. Data Analysis Two representative imaging planes were chosen for analysis from each vessel out of the five to seven planes acquired. If focal wall thickening was seen, such a slice was preferentially selected. Otherwise, vessels with optimal contrast from the surrounding tissue were used to facilitate generating regions of interest (ROIs). The inner and outer borders of the vessel wall were drawn on the baseline scan with the assistance of a semiautomated edge detection tool. ROIs were copied onto images from different acquisitions at the same location 700 Weiss et al. Figure 1. a and b: Baseline and T2-weighted images of a normal-appearing left carotid artery based on (a) the proton density-weighted scan. b: The T2-weighted image has a 48% decrease in signal intensity from the baseline image. c and d: A normal-appearing right carotid artery based on the (c) proton density-weighted scan. d: The T2-weighted image shows a 32% decrease in signal intensity from the baseline image. The window and level are the same for each patient. and modified, if needed, to account for minor registration differences. Once defined, the wall was divided into eight equal segments which were analyzed for 1) wall thickness, measured from the baseline series (TE ⫽ 5 msec with fat saturation); 2) T2-weighted signal intensity, measured as percent change in signal intensity between the baseline and the TE ⫽ 60 msec series; and 3) postcontrast signal enhancement, measured as percent change in signal intensity between the baseline and the TE ⫽ 5 msec postcontrast series. MRI studies were analyzed by an experienced reader who was blinded to the diagnoses of study participants and the results of serum assays. Interobserver variability of the fundamental measurements was performed on 20 carotid arteries and 10 aortas using computer-assisted image analysis, as described in the Methods section. Thus, with eight sectors per vessel, 20 arteries, three image acquisitions methods per vessel, two different wall thickness methods, an area measurement, and signal intensity measurements, a total of 2880 measurements were compared between two observers unaware of the results obtained by the other. The correlation between two observers’ measurements of carotid wall thickness was y ⫽ 0.93x ⫹ 0.00, r ⫽ 0.88. In the comparison studies, the average carotid wall thickness was 1.71 ⫾ 0.49 mm. Bland-Altman analysis showed a small bias in absolute wall thickness determination. The difference in wall thickness between the two observers averaged 0.25 ⫾ 0.28 mm, which represents approximately one-third of a pixel and about 15% of the arterial wall thickness. The coefficient of variation between the two observers’ measurement of wall thickness was 14%. The average carotid arterial wall signal intensity in a sector was 949 ⫾ 328 (arbitrary units (AU)) on baseline studies (TE ⫽ 5 msec), 572 ⫾ 232 AU on T2-weighted images, and 1086 ⫾ 375 AU on postcontrast images. The difference in signal intensity measurements between the two observers averaged 52 ⫾ 54 AU for TE ⫽ 5 msec images, 50 ⫾ 55 AU for T2-weighted images, and 50 ⫾ 50 AU on postcontrast images. This translates to coefficients of variation of 5%, 8%, and 4% for baseline, T2-weighted, and postcontrast images, respectively. The contrast enhancement measurements for carotid arteries correlated well between observers (y ⫽ 0.99x ⫹ 0.01, r ⫽ 0.81) and there was no systematic bias between observers on Bland-Altman analysis. For contrast enhancement that averaged 0.17 ⫾ 0.11, the average difference in contrast enhancement between observers was 0.01 ⫾ 0.08. T2-weighted measurements also correlated well between observers (y ⫽ 1.14x – 0.08, r ⫽ 0.93) and there was no systematic bias between observers on Bland-Altman analysis. For T2weighted measurements that averaged 0.39 ⫾ 0.07, the average difference in contrast enhancement between observers was 0.02 ⫾ 0.03. Aortic measurements showed similar trends. Detection of Arterial Inflammation by MRI 701 Figure 2. a: A normal-appearing right carotid artery. Compared with (a) the baseline proton density-weighted image, (b) infusion of gadolinium contrast increased signal intensity by 15%. c: A left carotid artery with focal plaque. Gadolinium caused a 32% increase in signal intensity not only in the plaque (arrows), but also in (d) the adjacent arterial wall. Postcontrast enhancement of the veins (anterior to the carotid artery) was seen in subjects from all groups, and may represent an artifact of low velocity blood flow (25). We have seen similar venous effects in normal volunteers after contrast, which were eliminated by repositioning the surface coil off the surface of the neck. Since the black blood contrast is accomplished by a combination of flow, inversion recovery timing, and the fast spin echo readout, the low pressure and lower flow of veins may be more susceptible to the effects of light pressure on the neck surface than the arteries. The window and level before and after contrast are the same for each patient. For each parameter measured on each subject, an average value for each vessel and the most abnormal segment value were determined for each of the three MRI features. Subjects who had a value greater than 2 SDs from the control group mean directionally anticipated for inflammation (increased wall thickness, increased T2-weighted signal intensity (lower percent change in signal intensity from baseline), and postcontrast signal enhancement (greater percent change in signal intensity from baseline)) for at least one parameter were designated as having an MRI study compatible with inflammation. Based on these criteria, study participants were then divided into two groups: those with an abnormal MRI study, and those with entirely normal MRI studies. Levels of serum markers of inflammation in these two groups were compared using the two-tailed, unpaired t-test for normally distributed data, and the nonparametric Mann-Whitney test for non-normal data. P ⬍ 0.05 was accepted as indicating statistical significance. RESULTS MRI data for carotid artery and aorta wall thickness, T2-weighted signal intensity, and postcontrast signal intensity for the 17 subjects ⱖ40 years of age who had no risk factors for atherosclerosis and served as controls are provided in Table 1. Of the total cohort of 52 subjects ⱖ40 years of age, 22 subjects had values for these imaging characteristics of the carotid arteries and/or aorta that were greater than two SDs from the control group mean in the direction compatible with inflammation: 14 had increased wall thickness (of Table 1 MRI Data for Control Group ⱖ40 Years of Age Thickness (mm) Average Maximum T2-weighted signal intensity (percent below baseline) Average Maximum Post-contrast signal intensity (percent above baseline) Average Maximum Data ⫽ mean ⫾ SD. Carotid arteries Infrarenal aorta 1.5 ⫾ 0.2 1.8 ⫾ 0.3 2.4 ⫾ 0.4 2.9 ⫾ 0.7 42 ⫾ 6 10 ⫾ 17 30 ⫾ 10 3 ⫾ 23 13 ⫾ 12 56 ⫾ 29 19 ⫾ 14 68 ⫾ 41 702 Weiss et al. Figure 3. Bar graphs show levels of serum markers of inflammation in 22 subjects with abnormal MRI compared with 30 subjects with normal MRI vascular studies. IL-6 ⫽ interleukin-6, CRP ⫽ C-reactive protein, ICAM-1 ⫽ intercellular adhesion molecule-1, and VCAM-1 ⫽ vascular cell adhesion molecule-1. Data ⫽ mean ⫾ SEM. whom seven also had increased T2-weighted signal intensity and two had increased postcontrast signal intensity) and eight had normal wall thickness, but increased T2-weighted signal intensity (3), increased postcontrast signal intensity (4), or a combination of these findings (1). Seven subjects had abnormal carotid MRI studies with normal aorta MRI studies, 10 had abnormal aorta but normal carotid MRI studies, and five had abnormal MRI studies of both the carotids and the aorta. Ten subjects had evidence of focal plaque in the carotids (5) and/or aorta (6). Of these 22 subjects with abnormal MRI studies, 13 had coronary artery disease, five had hypercholesterolemia, and four were from the healthy control group. Conversely, 30 subjects, including four patients with coronary artery disease, 13 hypercholesterolemic subjects, and 13 healthy controls, had values for these imaging characteristics that fell within 2 SDs of the control group means for all parameters measured. The 22 subjects with abnormal MRI studies had significantly higher levels of IL-6, CRP VCAM-1, and ICAM-1, and nonsignificantly higher levels of E-selectin, compared with the 30 subjects whose MRI values fell within 2 SDs of the control group means (Fig. 3). For IL-6, CRP, VCAM-1, and ICAM-1, the 14 subjects with increased wall thickness alone had significantly higher levels of these markers compared with the 30 subjects with normal MRI studies. The eight subjects with normal wall thickness but increased T2-weighted and/or postcontrast signal intensities tended to have intermediate values (Fig. 4). The abnormal MRI group was older than the normal MRI group (58.6 ⫾ 11.0; range 41–76 years vs. 53.2 ⫾ 8.1; range 41–79 years, P ⫽ 0.048). There was no dif- ference in sex distribution between the abnormal MRI (18 men, four women) vs. the normal MRI group (22 men, eight women; P ⫽ 0.51 by Fisher’s Exact test). There were no significant differences between these two groups for the following lipid levels: total cholesterol (198 ⫾ 40 vs. 212 ⫾ 53 mg/dL), LDL cholesterol (126 ⫾ 35 vs. 137 ⫾ 46 mg/dL), HDL cholesterol (44 ⫾ 10 vs. 51 ⫾ 24 mg/dL), and triglycerides (174 ⫾ 160 vs. 153 ⫾ 76 mg/dL) (all P ⬎ 0.20). Compared with the 17 control subjects ⱖ40 years of age, the 17 young adults 25–30 years of age had significantly thinner carotid arteries and aortas (Table 2). The carotids showed significantly greater reduction in T2weighted signal intensity from the baseline proton density-weighted scans, and the aorta showed significantly less increase in signal intensity following gadolinium contrast infusion. The 17 young adults also had lower levels of many of the markers of inflammation measured in this study: IL-6 (1.58 ⫾ 0.69 vs. 2.19 ⫾ 1.20 pg/mL, P ⫽ 0.082), CRP (0.17 ⫾ 0.10 vs. 0.41 ⫾ 0.70 mg/dL, P ⫽ 0.309), E-selectin (33.4 ⫾ 10 vs. 41.2 ⫾ 12.0 ng/mL, P ⫽ 0.055), ICAM-1 (168 ⫾ 38 vs. 203 ⫾ 53 ng/mL, P ⫽ 0.033), VCAM-1 (480 ⫾ 137 vs. 499 ⫾ 115 ng/mL, P ⫽ 0.670). DISCUSSION Histologic studies in humans provide strong evidence that not only is inflammation present in atherosclerotic disease, but it may also be a powerful measure of the degree of activity of the atherosclerotic process due to its association with plaque rupture and acute coronary syndromes (1–3). However, vascular inflammation may contribute importantly to atherogenesis prior to the de- Detection of Arterial Inflammation by MRI 703 Figure 4. Bar graphs show levels of serum markers of inflammation in 14 subjects with increased wall thickness (1WT), eight subjects with normal wall thickness but increased postcontrast signal intensity and/or T2-weighted (1Gd/T2), and 30 subjects with normal MRI studies. Data ⫽ mean ⫾ SEM. One-way analysis of variance was performed on each data set, with post-hoc significance identified above the bars. Abbreviations are the same as for Fig. 3. velopment of established plaque. Using MRI features we hypothesized to be consistent with inflammatory processes in the vessel wall, we were able to stratify the study population into two groups, with the abnormal vascular MRI group having higher levels of serum markers of inflammation than the group with normal MRI studies. Intriguingly, abnormal MRI studies were frequently not associated with MRI detection of actual atherosclerotic plaque in the vessels imaged, and were found in four of 17 control subjects. These findings suggest that arterial inflammation may precede development of plaque, and that this process may occur in subjects without conventional risk factors for atherosclerosis. In this regard, epidemiological studies suggest that only approximately one-half the excess risk of atherosclerotic events, such as myocardial infarction, Table 2 MRI Data for Young Adults 25–30 Years of Age Wall thickness Average Maximum T2-weighted signal intensity (percent below baseline) Average Maximum Post-contrast signal intensity (percent above baseline) Average Maximum Carotid arteries Infrarenal aorta 1.2 ⫾ 0.1** 1.6 ⫾ 0.2** 2.2 ⫾ 0.3 2.5 ⫾ 0.4* 47 ⫾ 6* 12 ⫾ 16 34 ⫾ 8 11 ⫾ 20 13 ⫾ 14 71 ⫾ 48 7 ⫾ 17* 59 ⫾ 32 Data ⫽ mean ⫾ SD. *P ⬍ .05, **P ⬍ 0.01 vs. control group ⱖ40 years of age (Table 1). in apparently healthy populations is accountable by conventional risk factors, including hypercholesterolemia (21). Accordingly, alternative risk factors for atherosclerosis, such as serum markers of inflammation (6 –9), are under investigation as potentially sensitive markers of atherosclerosis risk. Of note, the majority of patients with established coronary artery disease had MRI evidence of arterial inflammation despite the use of medications (aspirin and lipid-lowering therapies) associated with reduced risk of future cardiovascular events (22). Our studies extend the observations of Rohde et al. (23), who reported significant correlations between ICAM-1 and VCAM-1 levels, and carotid intimal-medial thickness measured by 2D ultrasound. Our study suggests that MRI provides a more complete tissue characterization of the vessel wall which may permit the identification of inflammation, even in the absence of increased wall thickness. In this regard, eight of 22 subjects with abnormal MRI scans had increased T2weighted signal intensity and/or gadolinium contrast enhancement in the absence of increased wall thickness, and had levels of several markers of inflammation intermediate to those of the 14 subjects with increased wall thickness and the 30 subjects with normal MRI studies. This observation raises the possibility that T2weighted and contrast-enhanced properties of MRI may identify arterial inflammation at an earlier stage than is manifested by increased thickness of the arterial wall. Limitations of Study An important limitation of this study is the absence of tissue from carotid arteries or aortae of our subjects for 704 histological demonstration of the presence or absence of inflammation. Wasserman et al. (24) recently reported that gadolinium enhancement of carotid arteries by MRI was associated with fibrocellular tissue in atherosclerotic plaque during subsequent microscopic analysis following endarterectomy. Correlational studies of MRI and histopathology in animal models of atherosclerosis may be useful in further validating the capability of MRI to identify active vascular inflammation. A second limitation of our study is that differences in MRI characteristics and in levels of serum markers of inflammation between the normal and abnormal vascular MRI groups could have resulted in part from differences in age, although the range of ages was the same for the two groups. Due to the importance of age as a determinant of atherosclerosis risk, any method that detects pathophysiological features of atherosclerosis (i.e., inflammation) is expected to have an association with age. Of interest, the mean IL-6 value for the abnormal MRI group in our study falls in the highest quartile of IL-6 values in the Physicians’ Health Study, using the same commercial assay, in whom a greater than twofold risk of future myocardial infarction was reported compared with men whose IL-6 values fell within the lowest quartile (9). In this regard, MRI characteristics of large arteries may convey prognostic significance, although comparison of this testing with more easily performed serum markers of inflammation will require a much larger series of subjects followed prospectively for development of cardiovascular events. We conclude that MRI characteristics of vascular inflammation in large vessels are associated with increases in serum markers of inflammation. This occurred even in healthy middle-aged and older subjects without modifiable risk factors for atherosclerosis, and frequently in the absence of adjacent plaque. Accordingly, MRI of large arteries may provide a new approach to investigate the contribution of inflammation to atherogenesis. ACKNOWLEDGMENTS We thank Samuel Hou, M.S., Arnon Blum, M.D., Gyorgy Csako, M.D., William H. Schenke, B.A., Londa Hathaway, R.N., Karen Bove-Bettis, M.R.T, and Bruce Wasserman, M.D., for their invaluable assistance in the conduct of this study, and Judith Taylor for typing the manuscript. Clifford R. Weiss was a Fellow in the Clinical Research Training Program of the National Institutes of Health. REFERENCES 1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–126. 2. Davies MJ, Gordon JL, Gearing AJ, et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 1993;171:223–229. 3. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844 –2850. Weiss et al. 4. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994;331:417– 424. 5. Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in myocardial infarction. J Am Coll Cardiol 1998;31: 1460 –1465. 6. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998;97:2007–2011. 7. Ridker PM Hennekens CH, Roitman-Johnson B, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998;351:88 –92. 8. Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731–733. 9. Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentrations of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–1772. 10. Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today 1994;15:81– 88. 11. Pohost GM, Fuisz AR. From the microscope to the clinic: MR assessment of atherosclerotic plaque. Circulation 1998;98:1477–1478. 12. Yuan C, Beach KW, Smith Jr LH, et al. Measurement of atherosclerotic carotid plaque size in vivo using high resolution magnetic resonance imaging. Circulation 1998;98:2666 –2671. 13. Toussaint JF, Southern JF, Fuster V, et al. T2-weighted contrast for NMR characterization of human atherosclerosis. Arterioscler Thromb Vasc Biol 1995;15:1533–1542. 14. Toussaint JF, LaMuraglia GM, Southern JF, et al. Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo. Circulation 1996;94: 932–938. 15. Shinnar M, Fallon JT, Wehrli S, et al. The diagnostic accuracy of ex vivo MRI for human atherosclerotic plaque characterization. Arterioscler Thromb Vasc Biol 1999;19:2756 –2761. 16. Schurmann K, Vorwerk D, Bucker A, et al. Perigraft inflammation due to Dacron-covered stent-grafts in sheep iliac arteries: correlation of MR imaging and histopathologic findings. Radiology 1997; 204:757–763. 17. Kellner W, Kuffer G, Pfluger T, et al. MR imaging of soft-tissue changes after percutaneous transluminal angioplasty and stent placement. Radiology 1997;202:327–331. 18. Aoki S, Shirouzu I, Sasaki Y, et al. Enhancement of the intracranial arterial wall at MR imaging: relationship to cerebral atherosclerosis. Radiology 1995;194:477– 481. 19. Choe YH, Kim DK, Koh EM, et al. Takayasu arteritis: diagnosis with MR imaging and MR angiography in acute and chronic active stages. J Magn Reson Imaging 1999;10:751–757. 20. Simonetti OP, Finn JP, White RD, et al. “Black blood” T2-weighted inversion-recovery MR imaging of the heart. Radiology 1996;199: 49 –57. 21. Manson JE, Tosteson H, Ridker PM, et al. Current concepts: primary prevention of myocardial infarction. N Engl J Med 1992;326: 1406 –1416. 22. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 1999;99:2829 –2848. 23. Rohde LE, Lee RT, Rivero J, et al. Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 1998;18:1765–1770. 24. Wasserman BA, Smith WI, Trout III HH, et al. Morphologic characterization of carotid artery atherosclerosis by in vivo gadolinium enhanced double oblique MR imaging: initial results. Radiology (in press). 25. NessAiver M. All you really need to know about MRI physics. Baltimore: Simply Physics; 1997; Chapter 8:1-3; Chapter 9:1-16.