Pathologic studies have demonstrated that disruption

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1 Risk Factors for Non-calcified Plaques in Asymptomatic Population Min Li, MD, Gang Sun, MD, Juan Ding, MD, Li Li, MD, Zhao-hui Peng, MD, Xiang-sen Jiang, MD Rationale and Objectives: The aims of this study were to assess the prevalence of noncalcified coronary plaques in asymptomatic patients and to investigate the risk factors. Materials and Methods: In this study, 584 patients were recruited prospectively. Patients were classified as having low, intermediate, or high pretest likelihoods of coronary artery disease according to the Morise score. Coronary computed tomographic angiography was performed in all patients using a 320 detector row dynamic-volume computed tomographic scanner. Imaging reconstruction was performed, and the postprocessed data were analyzed. Logistic regression analysis was used to evaluate the relationship between risk factors and the presence of noncalcified plaque. Results: Coronary computed tomographic angiography revealed noncalcified plaques in 38.3% of all patients (224 of 584). The prevalence of noncalcified plaques was significantly higher in patients with calcium scores > 0 (P <.001). Significant differences were found between the degrees of luminal stenosis among patients with low, intermediate, and high pretest likelihoods of coronary artery disease (P =.001), while the prevalence of noncalcified plaques did not differ with the Morise score (P =.08). Noncalcified plaque was associated with hypercholesterolemia (P =.02) and diabetes mellitus (P =.002). Age (P =.47), gender (P =.58), estrogen status (P =.55), smoking (P =.22), hypertension (P =.27), and family history (P =.09) did not differ between patients with and those without noncalcified plaques. Conclusions: Hypercholesterolemia and diabetes mellitus are high risk factors for the prevalence of noncalcified plaques for asymptomatic patients. Key Words: Computed tomography; angiography; coronary disease; plaque; risk factors. ªAUR, 2012 Pathologic studies have demonstrated that disruption or erosion of vulnerable plaques and subsequent thrombosis are among the most frequent causes of acute coronary syndromes (ACS) (1 3). Previous studies have proven that the composition of coronary plaques, rather than the degree of stenosis, is closely associated with the occurrence of ACS (2,4,5). Therefore, an assessment of plaque components and stability is critical for the clinical prevention of ACS. Although invasive coronary angiography (ICA) can provide a direct visualization of the plaque surface and intraluminal structures, it cannot distinguish the various components of plaques. Intravascular ultrasound has been proven to be an effective approach to detect the composition of plaques (6). However, ultrasound has been restrained from widespread clinical applications because of its complexity, expense, and invasiveness. In recent years, computed tomographic (CT) angiography (CTA) has been regarded as an emerging noninvasive technique for coronary plaque detection and evaluation. Although considered highly sensitive to calcification, CTA has also been found useful for evaluating noncalcified plaques (7). Previous studies using coronary CTA have confirmed the correlation between noncalcified components and the vulnerability of plaques (8 12). In some studies, noncalcified coronary plaques have also been demonstrated to be an important risk factor for ACS (12,13). Many risk factors, including age, gender, estrogen status, diabetes mellitus, hypertension, smoking, hypercholesterolemia, family history, and obesity, have proven to be correlated with the luminal stenosis of coronary artery disease (CAD) (14). Because pathologic studies have demonstrated that ACS are more likely to be associated with plaques without flow-limiting stenosis (2,4), detecting these plaques at an early asymptomatic stage is critical. In this study, we prospectively analyzed the CT findings of noncalcified coronary plaques in a group of asymptomatic patients. Our purposes were to study the prevalence of noncalcified coronary plaques in asymptomatic patients and to investigate the relative risk factors for ACS. Acad Radiol 2012; 19: From the Department of Medical Imaging, Jinan Military General Hospital, No 25, Shifan Road, Jinan , Shandong Province, China. Received March 3, 2011; accepted December 22, Address correspondence to: G.S. cjr.sungang@vip.163.com; and J.D. dingjuanx@163.com ªAUR, 2012 doi: /j.acra MATERIALS AND METHODS Study Population The study protocol, including the risk for exposure to radiation, was approved by the local ethics committee. Written 548

2 Academic Radiology, Vol 19, No 5, May 2012 RISK FACTORS FOR NON-CALCIFIED PLAQUES consent with information on the risk for radiation and iodine allergic reactions were obtained from all patients. Between September 2008 and July 2010, 1146 patients were prospectively enrolled in this study. The exclusion criteria were refusal or withdrawal of consent (n = 4), allergy to iodinated contrast agents (n = 6), renal insufficiency (creatinine > 120 mmol/l; n = 4), history of coronary artery bypass graft surgery and myocardial infarction (n = 126), nonanginal chest pain (n = 138), atypical angina (n = 154), and typical angina (n = 130). After the exclusion of 562 patients who met these criteria, the study population consisted of 584 patients (268 women, 316 men; mean age, years; age range, years). For these asymptomatic patients, the reasons for referral for CTA were as follows: screening (presence of one or more risk factors), evaluation of coronary arteries prior to high-risk major surgical operation, regional wall motion abnormalities on echocardiography, electrocardiographic evidence of ST-segment or T-wave changes, and clinical suspicion of valvular heart disease. Risk factors were recorded through a structured interview and/or existing medical record. Clinical data were collected, including patients age, gender, and estrogen status; the presence or absence of diabetes mellitus; hypercholesterolemia; current or prior cigarette smoking; hypertension; and a positive family history (age < 60 years) of coronary disease in a first-degree relative. Patients were also assessed for body mass index (BMI). Obesity was defined as a BMI > 27 kg/m 2. Hypertension was defined as a documented history of blood pressure >140/90 mm Hg or the use of antihypertensive medication. Hypercholesterolemia was defined as a total cholesterol level $ 5 mmol/l or treatment with medication (15). Estrogen status was considered positive if women were premenopausal or had missing or nonfunctioning ovaries and were on oral estrogen replacement therapy and negative if they were postmenopausal (ovaries missing or nonfunctioning) and not on estrogen replacement therapy (16). According to classification methods presented by Morise et al (14), patients were classified as having a low, intermediate, or high pretest likelihoods of stenotic CAD on the basis of age, gender, estrogen status, diabetes mellitus, hypertension, smoking, hypercholesterolemia, family history, and obesity. Classification of risks was carried out by a blinded observer who had no knowledge of the outcomes of CTA. CT Protocol All CT examinations were performed using a 320 detector row dynamic-volume CT scanner (Aquilion ONE; Toshiba Corporation, Nasu, Japan). The Agatston score was calculated on unenhanced images with a detection threshold of 130 Hounsfield units using semiautomated software (Vitrea II FX; Vital Images, Minnetonka, MN). In the absence of contraindications (hypotension, current use of nitrate medications, migraine sensitive to nitrates), 0.4 mg nitroglycerin was administered 2 minutes prior to scanning. The scanning range was set from the level of the tracheal bifurcation to the diaphragm to ensure entire heart coverage (scanning range coverage was cm). All scanning was carried out using detector collimation of mm. Other scanning parameters were varied according to BMI. For BMI < 18 kg/m 2, the tube voltage was 100 kv and the tube current was 350 ma; for BMI of 19 to 24 kg/m 2, the tube voltage was 100 kv and the tube current was 400 ma; and for BMI > 24 kg/m 2, the tube voltage was 120 kv and the tube current was 450 to 500 ma. With a gantry rotation of 350 ms, dynamic-volume computed tomography provided a temporal resolution of 175 ms. Beta-blockade was used to achieve a target heart rate of <65 beats/min. A target heart rate of <65 beats/min during scanning allowed a sufficiently long coronary artery rest period to complete scanning within a single heart beat. Reconstruction Method Image reconstruction was performed with a section thickness of 0.5 mm and an increment of 0.25 mm. The reconstructed field of view was adjusted to exactly encompass the heart ( mm). Images were reconstructed at 75% of the R-R interval. In case of insufficient image quality, additional reconstructions were performed in 2% steps of the R-R interval within the scanning window. All reconstructed images were transferred to an independent workstation (Vitrea II FX). Multiplanar reconstruction (MPR), curveplanar reconstruction, and vessel analysis were performed on the workstation to assess plaques. CT Data Analysis Each study was assessed by two readers (with 6 and 7 years of experience in cardiovascular radiology), who were blinded to clinical information. Standard display settings with a window width of 800 Hounsfield units and window center of 250 Hounsfield units were used for this interpretation. A consensus reading was obtained for the presence, location, and type of plaque in each study using a 15-segment classification of the coronary tree, on the basis of the original American Heart Association classification (17). Noncalcified plaque was defined as plaque with a CT density less than the contrastenhanced coronary lumen but greater than the surrounding connective tissue. The degree of involved luminal stenosis was measured using the narrowest dimension of the lumen at the level of stenosis compared to normal luminal diameter distally. The measurement was done with electronic calipers on curve-planar reconstruction images. Segments were graded as follows: 0 = normal, I = minimal stenosis (1% 24%), II = mild stenosis (25% 49%), III = moderate stenosis (50% 74%), and IV = severe stenosis ($75%) (Fig 1). In three patients with technically limited coronary CT angiographic studies, five vessel segments could not be evaluated and were excluded from our analysis. 549

3 LI ET AL Academic Radiology, Vol 19, No 5, May 2012 Figure 1. Noncalcified plaques causing different grades of stenosis: (a) grade I, (b) grade II, (c) grade III, and (d) grade IV. Statistical Analysis Statistical analysis was performed using SPSS version 12 for Windows (SPSS, Inc, Chicago, IL). Quantitative variables are presented as mean standard deviation and categorical variables as frequencies or percentages. Consistency testing to evaluate interobserver reproducibility was carried out using k statistics. The difference in the prevalence of noncalcified plaques among patients with calcium scores of 0 and >0 was tested using the c 2 test. Univariate and multivariate logistic regression analysis were used to evaluate the relationship between risk factors and the presence of noncalcified plaque. Fisher s exact test was used to test the difference in stenosis among patients with low, intermediate, and high pretest likelihoods of CAD. Logistic regression analysis was performed to test the prevalence of noncalcified plaques in patients with low, intermediate, and high pretest likelihoods of CAD. RESULTS The average heart rate of the patients during scanning was beats/min (range, beats/min). The baseline characteristics of the patients are summarized in Table 1. A total of 270 of the 584 patients (46.2%) had calcium scores of 0. Noncalcified plaque was present in 38.3% of the patients (224 of 584), including 17.8% (48 of 270) of patients with calcium scores of 0 and 56.1% of patients (176 of 314) with positive calcium scores (>0) (Fig 2). The prevalence of noncalcified plaques was significantly higher in patients with calcium scores > 0 (P <.001). The Morise score was a good predictor for the presence of coronary stenosis (k = 0.81). Fisher s exact test showed that stenosis degree was significantly different between patients with low, intermediate, and high pretest likelihoods of CAD (P =.001; Fig 3). However, logistic regression analysis demonstrated that the prevalence of noncalcified plaque did not differ among patients with low, intermediate, and high pretest likelihoods of CAD (P =.08). By univariate logistic regression analysis, risk factors including gender, BMI, diabetes mellitus, hypertension, hypercholesterolemia, and smoking were found to be significantly related to noncalcified plaques. Age, family history, and estrogen status were not related to the prevalence of noncalcified plaques (Table 2). Multivariate logistic regression demonstrated that patients with noncalcified plaques were characterized significantly by hypercholesterolemia (P =.02) and the presence of diabetes mellitus (P =.002). For other factors, such as age (P =.47), gender (P =.58), estrogen status (P =.55), smoking (P =.22), hypertension (P =.27), and family history (P =.09), no differences were found between patients with and without noncalcified plaques (Table 2). Noncalcified plaques were found more commonly in patients with diabetes mellitus (49.7% [142 of 286]) than in patients without diabetes mellitus (27.5% [82 of 298]), and a higher proportion of noncalcified plaques were detected in patients with hypercholesterolemia (54.6% [178 of 326]) than those without hypercholesterolemia (29.5% [76 of 258]). 550

4 Academic Radiology, Vol 19, No 5, May 2012 RISK FACTORS FOR NON-CALCIFIED PLAQUES TABLE 1. Baseline Characteristics of the Study Patients (n = 584) Variable Value Age (y) Men/women 316/268 Average body mass index (kg/m 2 ) Diabetes mellitus 286 (49.0%) Hypertension 278 (47.6%) Hypercholesterolemia 326 (55.8%) Family history of CAD 316 (54.1%) Female estrogen status (positive/negative) 138/130 Smoking 212 (36.3%) Pretest likelihood of CAD Low 204 (34.9%) Intermediate 300 (51.4%) High 80 (13.7%) CAD, coronary artery disease. Data are expressed as mean standard deviation or as number (percentage). Figure 3. Distribution of luminal stenosis classified by different pretest likelihood of coronary artery disease. There was significantly difference of luminal stenosis among patients with low, intermediate, and high pretest likelihoods of coronary artery disease (P =.001). Figure 2. Distribution of coronary computed tomographic angiographic findings. Noncalcified plaques, alone or in combination with calcifications in other segments, were detected in 38.3% patients. DISCUSSION Autopsy studies have shown that atherosclerotic lesions are frequently found in asymptomatic individuals (18). Strong et al (19) found that plaques existed in 47.4% of the young adults in their study. Previous studies have reported about 22.9% to 29.8% of noncalcified plaques in different study populations using coronary CTA (9,20). Our study showed that noncalcified coronary plaques was detected in a higher percentage, 38.3%. This difference may be explained by the improved ability of dynamic-volume computed tomography to image coronary plaques (9,21,22). Coronary stenosis with myocardial ischemia and ACS are two distinct disease processes related to the presence of CAD. Myocardial ischemia (stable angina) is related to stenosis from stable plaque, while ACS are related to rupture of vulnerable plaque. The present study evaluated risk factors associated with different plaque types, calcified versus noncalcified, that may be associated with the concept of vulnerable plaque and ACS. Although the Framingham risk score is commonly used to estimate the risk for a cardiovascular event, the Morise score was chosen for this study because our goal was to assess the plaque morphology rather than patient outcomes. Several studies have indicated that the Morise score can be applied to classify patients into groups of low, medium, and high risk for stenotic CAD (14,23), which has been proven to be an effective reference index to predict the degree of the stenosis of lumen (14). Our study also confirmed that the Morise score was associated with narrower luminal stenosis. However, it was not capable of classifying the risk for prevalence of noncalcified plaques. Clinically, the risk for a heart attack or stroke in a patient can be assessed by comprehensive analysis of all risk factors. However, the cardiovascular risk factors for vulnerable patients not only influence vulnerable plaques but also act on vulnerable vessels and myocardium (24). The aim of our study was to investigate the risk factors for prevalence and stenosis for noncalcified plaques, which were believed to be associated with vulnerable plaques (8 12). A previous study on arterial specimens demonstrated that men had 551

5 LI ET AL Academic Radiology, Vol 19, No 5, May 2012 TABLE 2. Univariate and Multivariate Logistic Regression Demonstrating Associations of Risk Factors with Presence of Noncalcified Plaque Univariate Logistic Regression Multivariate Logistic Regression Variable OR 95% CI P OR 95% CI P Age Gender Body mass index Diabetes mellitus < Hypertension Hypercholesterolemia Family history Estrogen status Smoking CI, confidence interval; OR, odds ratio. a significantly greater stenosis than women, and stenosis was also found to be correlated positively with age (25). On the other hand, lipid lesion distribution in blood vessels was similar and independent of age or sex. Similarly, although smokers are found to experience acute coronary events earlier than nonsmokers, histomorphometric analysis showed no significant correlation between smoking and fatty streaks (25). Previous studies have demonstrated that smoking is a risk factor to accelerate lesions (25,26). Therefore, different risk factors may act on different stages of development of atherosclerotic plaques (25). Our results showed that the prevalence of noncalcified plaques was characterized only by hypercholesterolemia and diabetes mellitus. Although age, gender, estrogen status, smoking, hypertension, and family history were associated with the luminal stenosis (14), these factors did not lead to a higher prevalence of noncalcified plaques. Unlike stenotic CAD, the composition of plaques, rather than the degree of the stenosis, was the major cause of ACS (2,4,5). Thus, the prevalence of noncalcified plaques is important for the risk assessment of ACS. Pathobiologic and epidemiologic studies have shown that hypercholesterolemia is significantly associated with vulnerable plaques, which suggests that more attention should be paid to hypercholesterolemia at an early stage to reduce the likelihood of ACS (27,28). A number of studies have also confirmed the effect of diabetes on vulnerable plaques and ACS (29,30). Rosamond et al (31) proposed that patients with diabetes may have more myocardial infarction and cardiac death than those without diabetes. Scognamiglio et al (32) suggested that patients with diabetes should undergo ICA for screening regardless of the existence of other risk factors. Detection of these plaques in an asymptomatic stage would probably improve risk stratification of these patients. However, most of the vessels with noncalcified plaques had mild stenosis. Thus, ICA might underestimate the risk for plaque, particularly when there is compensatory positive remodeling for the involved artery. In addition, ICA is an invasive examination and cannot distinguish among the components of plaques. CTA could be a better modality to detect the presence as well as the severity of noncalcified plaques in an asymptomatic stage. The results showed that the prevalence of noncalcified plaques was higher for calcium scores > 0. Coronary artery calcium scoring has been used for decades. Despite its recognized limitations, it is currently regarded as an effective method for the prediction of stenotic lesions (33,34). Recent studies have found that calcium scoring was also correlated with ACS (35,36). However, autopsy has shown that vulnerable plaques were predominantly noncalcified plaques (3). The potential reason may be that for calcium scores > 0, a vessel with a higher calcium score has a greater noncalcified plaque burden instead of exclusive calcified plaque. A recent study using intravascular ultrasound also confirmed that patients with high calcium scores had more vulnerable plaque components (37). Some studies indicated that a noncalcified plaque burden was a better predictor of myocardial ischemia than calcium score and degree of stenosis (38,39). However, whether the identification of noncalcified plaques provides additional information for risk stratification is yet to be evaluated. Several limitations need to be addressed. First, vessel segments that could not be evaluated were assumed to be normal. Therefore, the prevalence of noncalcified plaques may have been underestimated. Second, because the subjects in our study were asymptomatic patients, the results were not compared to those of intravascular ultrasound, which was not available and acceptable for many of asymptomatic patients. Also, it is well known that there is overlap in the attenuation ranges of fibrous and lipid-rich plaques. Thus, noncalcified plaques cannot be diagnosed directly as vulnerable plaques. However, the characteristics of noncalcified plaques can be used as an indirect tool for risk stratification of ACS (8 13,38). The relationship between the outcome and the characteristics of noncalcified plaques in a large-scale group needs to be identified by further investigation. In further studies, spectral computed tomography combined with a gold high-density lipoprotein nanoparticle contrast agent can be used as a better alternative to provide 552

6 Academic Radiology, Vol 19, No 5, May 2012 RISK FACTORS FOR NON-CALCIFIED PLAQUES more information about the diagnosis of vulnerable plaques and risk stratification of ACS (40). In conclusion, for asymptomatic patients, hypercholesterolemia and diabetes mellitus are high-risk factors related to the prevalence of noncalcified plaques. REFERENCES 1. Mizuno K, Satomura K, Miyamoto A, et al. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992; 326: Falk E, Shah P, Fuster V. Coronary plaque disruption. Circulation 1995; 92: Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol 1995; 15: Kelly P, Bhatt DL. Identification of vulnerable plaque the quest continues. 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