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Epicardial adipose tissue thickness is a predictor for plaque vulnerability in patients with significant coronary artery disease
Atherosclerosis 226 (2013) 134e139
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Epicardial adipose tissue thickness is a predictor for plaque vulnerability in patients with significant coronary artery disease Jin-Sun Park, So-Yeon Choi, Mingri Zheng, Hyoung-Mo Yang, Hong-Seok Lim, Byoung-Joo Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk, Joon-Han Shin* Department of Cardiology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 443-721, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 May 2012 Received in revised form 29 October 2012 Accepted 2 November 2012 Available online 15 November 2012
The aim of this study is to assess the relationship of epicardial adipose tissue (EAT) and plaque vulnerability. We consecutively enrolled 82 patients with coronary artery disease (CAD). A symptom-related vessel was imaged by virtual histology intravascular ultrasound (VH-IVUS). In 60 out of 82 patients, all three vessels were studied by VH-IVUS. EAT thickness was measured by echocardiography. All patients were divided into thick (3.5 mm) and thin EAT groups (<3.5 mm). VH-IVUS parameters were compared according to the EAT group. To evaluate the independent effect of EAT thickness on plaque vulnerability, a set of well-known CAD risk factors and EAT thickness were included in multiple linear regression models of VH-IVUS parameters which denotes plaque vulnerability. In a symptom-related vessel analysis, the thick EAT group had significantly more thin-cap fibroatheromas (TCFAs). In a symptom-related vessel analysis among 62 patients with unstable angina out of 82 patients, the thick EAT group had significantly more thin-cap fibroatheromas (TCFAs). In all three vessels analysis, the thick EAT group was associated with significantly larger total plaque volume, higher total plaque volume index, higher mean plaque burden, higher plaque volume indexes of the necrotic core (NC), and more total number of TCFAs than the thin EAT group. By multivariate analysis, total TCFAs of a symptom-related vessel, both in total population and in patients with unstable angina, and plaque volume index of the NC of all three vessels were independent factors associated with thick EAT. In multiple linear regression models of VH-IVUS parameters which means plaque vulnerability, EAT thickness was one of the independent factors. In the present study, the VH-IVUS parameters indicating vulnerable plaque were significantly related with the thickness of EAT. Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Epicardial adipose tissue Vulnerable plaque Virtual histology intravascular ultrasound Coronary artery atherosclerosis
1. Background Epicardial adipose tissue (EAT) is true visceral fat deposited around the heart, particularly around coronary vessels and mediates atherosclerosis via expression of several bioactive molecules [1,2]. EAT quantification has been demonstrated to correlate with the severity of coronary artery disease (CAD) and the extent of coronary artery atherosclerosis [3e6]. Although EAT may serve as a source of inflammation that can influence CAD activity, there are limited data regarding the association of EAT with the type of atherosclerotic plaque. We have reported that the thickness of EAT by echocardiography was significantly correlated with unstable presentation of CAD [3]. * Corresponding author. Tel.: þ82 31 219 5712; fax: þ82 31 219 5708. E-mail address: [email protected] (J.-H. Shin). 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.11.001
We hypothesized that the unstable presentation of CAD in patients with thick EAT might be related with plaque vulnerability. The aim of this study is to assess the relationship of EAT and plaque vulnerability using analysis of plaque components by virtual histology intravascular ultrasound (VH-IVUS) in patients with significant CAD. 2. Methods We consecutively enrolled 82 patients with angiographically significant CAD, who received successful coronary stenting. The medical records of all patients were retrospectively reviewed after informed consent of studied patients. As we intended to investigate the relationship between the histologic characteristics of plaque and EAT, we enrolled patients with angiographically significant CAD regardless of clinical presentation. As clinically stable angina is not necessarily associated with histologically stable atherosclerotic
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plaques [7,8] and a marker of inflammation or immune activation is occasionally raised in patients with stable angina according to disease activity [9], we enrolled patients with both stable angina and unstable angina. However, as inflammation within vulnerable coronary plaque is more closely related to unstable angina [10], we also tried to investigate the relationship between the histologic characteristics of plaque and EAT in patients with unstable angina. Upon quantitative analysis of the coronary angiograms, significant CAD was considered to be the presence of stenosis, 50% in diameter, of a major epicardial vessel. Revascularization was decided to be clinically indicated if there was >70% diameter stenosis on coronary angiography or >50% stenosis together with a positive stress test or ischemic symptoms. We tried to exclude the acute systemic inflammatory effect to avoid confounding the role of EAT. We excluded patients from the study if they had any of the following: active inflammation (such as infection or systemic autoimmune disease, often related to increased EAT [11,12]), a history of prior revascularization, heart failure, cardiomyopathy or acute myocardial infarction. Myocardial infarction was defined when there is a detection of rise in cardiac biomarkers (preferably troponin), with at least one value above the 99th percentile of the upper reference limit [13]. A symptom-related vessel was imaged by VH-IVUS before stent implantation in all patients. Symptom-related vessel was defined as the vessel with maximal stenosis (usually >70% diameter stenosis) by angiographic findings. If not localizable to a single symptomrelated vessel by angiographic findings, symptom-related vessel was defined according to pre-interventional IVUS findings in patients with multivessel disease. If there were several minimum lumen area (MLA) sites, the MLA site with the largest external elastic membrane cross sectional area was chosen as a symptomrelated lesion. A 20 MHz, 2.9 Fr IVUS imaging catheter (Eagle Eye, Volcano Corporation, Rancho Cordova, California, USA) was advanced as far distally as possible into the coronary artery after intracoronary administration of 100e200 mg nitroglycerine. Imaging was performed, paying attention to cover any evident atherosclerosis. Automated pullback was performed at a speed of 0.5 mm/s. During pull-back, the raw radiofrequency data were captured at the peak of the R waves for the reconstruction of a color-coded map by a VH data recorder (Volcano Corporation, Rancho Cordova, California, USA). Manual contour tracing of the lumen and the media-adventitia interface was performed by an experienced analyst who was unaware of the patients’ information. Volumetric data were generated using pcVH software (version 2.1, Volcano Corporation, Rancho Cordova, California, USA). The total plaque volume was automatically determined by the software, and the summation of measured cross sectional areas in all frames of the pullback region was based on Simpson’s rule. In 60 patients among the study population, all three major epicardial arteries were studied by VH-IVUS. VH-IVUS analysis classified the color-coded tissue into four major components as green (fibrous), yellow-green (fibrofatty), white (dense calcium), and red (necrotic core) [14e16]. Four plaque components were defined as follows: 1) fibrous: areas of densely packed collagen, 2) fibrofatty: fibrous tissue with lipid interspersed in collagen, 3) dense calcium: calcium deposits without adjacent necrosis, and 4) necrotic core: necrotic regions consisting of cholesterol clefts, foam cells, and microcalcifications [15]. Each plaque component was measured in every recorded frame. The total plaque volume of a symptom-related vessel was obtained, and the mean plaque burden was calculated as the total plaque volume of a symptom-related vessel divided by the total vessel volume of a symptom-related vessel 100. A plaque volume index of a symptom-related vessel was calculated as total plaque volume of a symptom-related vessel divided by vessel length. The plaque
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volume index of each plaque component was calculated. Each plaque component was also expressed as a percentage of the total plaque volume. Thin-cap fibroatheroma (TCFA) was defined as a necrotic core 10% of plaque area without evident overlying fibrous tissue in the presence of 40% plaque burden in at least three consecutive frames [16]. The numbers of TCFAs were calculated in a symptom-related vessel. Also, total plaque volume, mean plaque burden and plaque volume indexes, percentage of each plaque component and the numbers of TCFAs were obtained in 60 patients by analyzing all three major epicardial arteries. Two-dimensional transthoracic echocardiography was performed within 1 week, either after or before undergoing VH-IVUS. Recordings of three cycles of the two-dimensional parasternal long-axis were obtained. We enlarged images for better visualization and accurate measurement of EAT thickness. EAT thickness was measured on the free wall of the right ventricle (RV) in the still image of a two-dimensional echocardiography at end diastole on the parasternal long-axis view. We preferred the area above the RV to measure EAT thickness, as this area is recognized as having the thickest EAT layer. In addition, the parasternal long-axis view allows the most accurate measurement of EAT thickness with optimal cursor beam orientation. The anterior echo-lucent space between the linear echo-dense parietal pericardium and the RV epicardium was considered to be EAT. We measured the thickest point of EAT in each cycle. The average value of the EAT thickness was calculated. All patients were divided into two groups: thick EAT group, EAT 3.5 mm (n ¼ 37) and thin EAT group, EAT <3.5 mm (n ¼ 45). The median value of EAT thickness in patients with unstable presentation of CAD was 3.5 mm in our previous studies [3,17]. We chose 3.5 mm, the median value of EAT thickness in patients with significant CAD, derived from these previous studies, as the cut off value, instead of the median value of EAT thickness in the present study population. While the present study population consists of relatively small number, more than 500 patients were enrolled in our previous studies. The cut off value, 3.5 mm, derived from these studies might be a more reasonable standard than the median EAT value of the present study. We compared the characteristics of patients in the thick EAT group to those in the thin EAT group. VHIVUS analyses were compared according to the EAT groups (Fig. 1). Volumetric VH-IVUS analyses and the total number of TCFA of symptom-related vessel of all study populations were compared according to the EAT groups. Volumetric VH-IVUS analyses and the total number of TCFAs of symptom-related vessel of patients with unstable angina were compared according to the EAT groups (thick EAT group ¼ 28, thin EAT group ¼ 34). Volumetric VH-IVUS analyses and the total number of TCFAs of all three major epicardial arteries of 60 patients were compared according to the EAT groups (thick EAT group ¼ 21, thin EAT group ¼ 39). The SPSS 13.0 (SPSS inc., Chicago, Illinois, USA) statistical software package was used for all calculations. Data are shown as the mean standard deviation for continuous variables and as percentages for categorical variables. Comparisons were conducted by unpaired Student’s t test. Multiple stepwise logistic regression analysis was performed to assess independent VH-IVUS parameters that were related to thick EAT. To evaluate the independent effect of EAT thickness on plaque vulnerability, a set of well-known CAD risk factors and EAT thickness were included in multiple linear regression models of VH-IVUS parameters which denotes plaque vulnerability. A p value < 0.05 was considered statistically significant. 3. Results The median and mean standard deviation EAT thickness of the study population were 2.8 mm and 3.4 2.2 mm, respectively. The
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Fig. 1. Examples of plaque components in patients with (A) epicardial adipose tissue 3.5 mm and in those with (B) epicardial adipose tissue <3.5 mm. VH-IVUS analysis classified the color-coded tissue into four major components as green (fibrous), yellow-green (fibrofatty), white (dense calcium), and red (necrotic core).
mean age of the study population was 59 10 years old. Clinical characteristics according to the group of EAT thickness are summarized in Table 1. Thirty-seven patients (45%) were included in the thick EAT group and the others were included in the thin EAT group (45 patients, 55%). Compared to the thin EAT group, subjects in the thick EAT group had a significantly higher level of body mass index and higher rates of diabetes, dyslipidemia, and metabolic syndrome. The results of volumetric VH-IVUS findings and the total TCFA numbers of a symptom-related vessel according to EAT groups are listed in Table 2. The thick EAT group had significantly more total TCFA compared to thin EAT group (p ¼ 0.003). The thick EAT group
Table 1 Baseline characteristics according to the group of epicardial adipose tissue thickness. Variables
EAT 3.5 mm (n ¼ 37)
EAT <3.5 mm (n ¼ 45)
Age (years) Men BMI (kg/m2) Body weight (kg) Unstable angina Hypertension Diabetes mellitus Dyslipidemia Metabolic syndrome Smoker EAT (mm)
58 10 20 (54%) 26.03 3.69 67.9 11.3 28 (76%) 23 (62%) 15 (41%) 11 (30%) 15 (41%) 13 (35%) 5.4 1.4 (median 5.3)
59 11 0.445 24 (53%) 0.949 24.16 2.87 0.013 66.3 10.7 0.498 34 (76%) 0.99 27 (60%) 0.725 9 (20%) 0.039 5 (11%) 0.037 1 (2%) <0.001 15 (34%) 0.853 1.6 0.8 (median 1.7) <0.001
p value
Continuous variables are expressed as the mean standard deviation and categorical values as absolute (percentage) values. EAT: epicardial adipose tissue; BMI: body mass index.
tended to have more total plaque volume compared to the thin EAT group (p ¼ 0.077). There was no significant statistical difference in volume index and mean percentage of each plaque component between the two groups. By multivariate analysis of the VH-IVUS parameters, the total number of TCFAs of the symptom-related vessel was an independent factor associated with thick EAT. Sixty-two patients out of 82 were diagnosed as unstable angina. Among these patients, the results of volumetric VH-IVUS findings and the total TCFA numbers of a symptom-related vessel according to EAT groups are listed in Table 3. The thick EAT group had significantly more total TCFA compared to thin EAT group (p < 0.001). The thick EAT group tended to have more total plaque volume compared to the thin EAT group (p ¼ 0.073). There was no significant statistical difference in volume index and mean percentage of each plaque component between the two groups. By multivariate analysis of the VH-IVUS parameters among patients with unstable angina, the total number of TCFAs of the symptomrelated vessel was an independent factor associated with thick EAT. In Table 4, volumetric VH-IVUS analyses and the total number of TCFAs of all three major epicardial arteries of 60 patients were compared according to the EAT groups. Twenty-one patients (35%) were included in the thick EAT group. The thin EAT group consisted of 39 patients (65%). The mean age of 60 patients was 59 9 years. The thick EAT group had significantly larger total plaque volume, higher total plaque volume index, higher mean plaque burden and more total number of TCFAs compared to the thin EAT group (p ¼ 0.01, 0.001, <0.001 and 0.031, respectively). Analysis of volume index of each plaque component showed significantly higher plaque volume index of the necrotic core in the thick EAT group compared to the thin EAT group (p ¼ 0.004). The thick EAT group
J.-S. Park et al. / Atherosclerosis 226 (2013) 134e139 Table 2 Symptom-related vessel analysis. Variables
Table 4 Analysis of all three major epicardial vessels. EAT 3.5 mm (n ¼ 37)
EAT <3.5 mm (n ¼ 45)
Volumetric VH-IVUS analyses 482.1 280.9 352.55 165.2 Plaque volume (mm3) Total length (mm) 65.6 23 56.7 18.6 7.1 2.7 6.2 1.7 Plaque volume index (mm3/mm) Mean plaque burden (%) 47.6 7 46.9 7.1 Volume index of each plaque component (mm3/mm) Necrotic core 0.5 1.5 0.4 0.3 Dense calcium 0.7 0.6 0.5 0.4 Fibrous 2.2 1.2 1.8 0.9 Fibrofatty 0.5 0.5 0.5 0.5 Mean percentage of each plaque component (%) Necrotic core (%) 9.5 5.8 8.4 8.3 Dense calcium (%) 17 9 14.7 8.3 Fibrous (%) 60.9 10.1 60.7 10 Fibrofatty (%) 12.6 7.8 15.9 9.3 Qualitative VH-IVUS analysis Total TCFA (n) 1.2 0.9 0.6 0.9 Variables
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Odds ratio (95% CI)
Multiple regression analysis of epicardial adipose tissue Total TCFA (n) 1.393 (1.009e1.924)
p value
Variables
EAT 3.5 mm (n ¼ 21)
EAT <3.5 mm (n ¼ 39)
p value
0.003
Volumetric VH-IVUS analyses 1360.1 492.1 1048.5 398.2 0.01 Plaque volume (mm3) Total length (mm) 189.6 44 179.8 47.2 0.436 7.1 1.7 5.8 1.3 0.001 Plaque volume index (mm3/mm) Mean plaque burden (%) 45.4 6 38.5 8.1 <0.001 Volume index of each plaque component (mm3/mm) Necrotic core 0.6 0.4 0.3 0.2 0.004 Dense calcium 0.4 0.3 0.2 0.3 0.05 Fibrous 2.3 0.9 1.8 1.9 0.235 Fibrofatty 0.5 0.4 0.4 0.4 0.355 Mean percentage of each plaque component (%) Necrotic core 16.1 6.1 12.3 6.5 0.072 Dense calcium 9.7 5.2 7.0 5.6 0.086 Fibrous 62.0 6.5 63.6 7.8 0.219 Fibrofatty 12.3 7.4 17.0 8.0 0.052 Qualitative VH-IVUS analysis Total TCFA (n) 3.3 2.2 2.1 1.6 0.031
p value
Variables
0.044
Multiple regression analysis of epicardial adipose tissue Volume index of necrotic core (mm3/mm) 31.229 (3.091e315.546) 0.004
0.077 0.151 0.193 0.73 0.649 0.11 0.257 0.936 0.596 0.37 0.942 0.198
Odds ratio (95% CI)
p value
Continuous variables are expressed as the mean standard deviation. EAT: epicardial adipose tissue; TCFA: thin-cap fibroatheroma; CI: confidence interval.
Continuous variables are expressed as the mean standard deviation. EAT: epicardial adipose tissue; TCFA: thin-cap fibroatheroma; CI: confidence interval.
tended to have higher volume index of dense calcium than the thin EAT group (p ¼ 0.05). Comparing the percentages of each plaque component, the thick EAT group tended to have higher mean percentage of the necrotic core and dense calcium and lower mean percentage of fibrofatty plaque compared to the thin EAT group (p ¼ 0.072, 0.086 and 0.052, respectively). By multivariate analysis of the volumetric VH-IVUS parameters of all three major epicardial arteries, the plaque volume indexes of the necrotic core was an independent factor associated with thick EAT. In a multiple linear regression model of total TCFAs of symptom-related vessel, EAT thickness and diabetes mellitus were independent factors (p ¼ 0.043 and 0.035, respectively, Table 5). In a multiple linear regression model of total TCFAs of symptom-related vessel in patients with unstable angina, EAT thickness was independent
factors (p ¼ 0.041, Table 5). In a multiple linear regression model of volume index of the necrotic core of all three major epicardial vessels, EAT thickness and metabolic syndrome were independent factors (p ¼ 0.005 and <0.001, respectively, Table 6).
Table 3 Symptom-related vessel analysis in patients with unstable angina. Variables
EAT 3.5 mm (n ¼ 28)
EAT <3.5 mm (n ¼ 34)
p value
Volumetric VH-IVUS analyses 519.92 301.9 374.55 175.4 0.073 Plaque volume (mm3) Total length (mm) 66.5 23.2 58.3 18.4 0.237 7.5 2.7 6.3 1.7 0.133 Plaque volume index (mm3/mm) Mean plaque burden (%) 48.7 7 47.7 6.8 0.662 Volume index of each plaque component (mm3/mm) Necrotic core 0.7 1.8 0.4 0.3 0.59 Dense calcium 0.8 0.6 0.5 0.3 0.066 Fibrous 2.3 1.2 1.9 0.8 0.249 Fibrofatty 0.5 0.5 0.5 0.4 0.963 Mean percentage of each plaque component (%) Necrotic core (%) 9.9 5.8 7.1 6.5 0.191 Dense calcium (%) 18.2 8.8 13.5 7.2 0.092 Fibrous (%) 59.6 9.3 62.7 9.1 0.319 Fibrofatty (%) 12.4 8.4 16.4 8 0.152 Qualitative VH-IVUS analysis Total TCFA (n) 1.2 0.9 0.4 0.6 <0.001 Variables
Odds ratio (95% CI)
Multiple regression analysis of epicardial adipose tissue Total TCFA (n) 2.485 (1.047e5.896)
p value 0.039
Continuous variables are expressed as the mean standard deviation. EAT: epicardial adipose tissue; TCFA: thin-cap fibroatheroma; CI: confidence interval.
4. Discussion In our previous study, the thickness of EAT by echocardiography was significantly correlated with unstable presentation of CAD [3]. Although we suggested that EAT might serve as a source of inflammation that could influence CAD activity, very few data are available regarding the relationship between EAT and plaque vulnerability. Recently a report that EAT was associated with the development of coronary atherosclerosis and with the most potentially dangerous types of plaques was published [18]. They demonstrated that the presence and extent of a non-calcified component, one of the features of vulnerable plaque, measured in an atherosclerotic plaque using computed tomography (CT), were correlated with EAT volume. Although CT scan provides an accurate and reproducible method for the quantitative assessment of total plaque and calcified plaque [19], the CT scan technique may not be sufficient to clearly discriminate the necrotic core from other
Table 5 Multiple linear regression analysis of total TCFAs of symptom-related vessel. Variables Total population BMI (kg/m2) Diabetes mellitus Dyslipidemia Metabolic syndrome EAT thickness Patients with unstable angina BMI (kg/m2) Diabetes mellitus Dyslipidemia Metabolic syndrome EAT thickness
B (95% CI)
p value
0.011 0.539 0.021 0.373 0.106
(1.754e1.687) (0.04e1.038) (0.552e0.594) (0.159e0.905) (0.004e0.208)
0.969 0.035 0.941 0.165 0.043
0.014 0.359 0.352 0.161 0.646
(0.083e0.111) (0.248e0.966) (1.062e0.358) (1.062e0.358) (0.028e1.264)
0.772 0.238 0.322 0.579 0.041
EAT: epicardial adipose tissue; BMI: body mass index; TCFA: thin-cap fibroatheroma; CI: confidence interval.
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Table 6 Multiple linear regression analysis of volume index of necrotic core of all three major epicardial vessels. Variables
B (95% CI)
p value
BMI (kg/m2) Diabetes mellitus Dyslipidemia Metabolic syndrome EAT thickness
0.123 0.027 0.384 3.137 3.504
0.106 0.961 0.08 <0.001 0.005
(0.027e0.274) (1.076e1.130) (0.866e1.633) (1.797e4.476) (2.297e5.346)
EAT: epicardial adipose tissue; BMI: body mass index; CI: confidence interval.
plaque components [20]. Hence, we used VH-IVUS to subclassify the plaque components in an atherosclerotic plaque. Many studies using VH-IVUS have analyzed plaque composition at target lesions or non-obstructive lesions, but not from the entire coronary arterial tree. As EAT might affect the entire coronary tree, we decided on volumetric analysis of the whole plaque burden from the entire coronary arterial tree and a symptom-related vessel. The analysis of a symptom-related vessel might demonstrate the present risk for coronary events. The analysis of all three major epicardial vessels might demonstrate the potentials for future coronary events. The volumetric VH-IVUS analysis of the whole plaque burden used in the present study might be more representative than focal plaque analysis for assessing the relationship of EAT and plaque vulnerability. Owing to the anatomical characteristics of EAT, EAT may have a local proatherosclerotic effect on the underlying coronary arteries [21]. The preference for an epicardial distribution of atherosclerotic lesions implicates a role for the local proatherosclerotic effect of EAT [22]. Several biomolecular studies in humans have shown that EAT is metabolically active and an important source of inflammatory mediators [1,2,23]. The presence of inflammatory mediators in EAT surrounding coronary arteries could lead to amplification of vascular inflammation, plaque instability via apoptosis, and neovascularization [22]. In the present study, EAT thickness by echocardiography was closely related with plaque volume indexes of the necrotic core of three vessels in patients with significant CAD. The necrotic core has currently become the surrogate for assessing the vulnerability of plaque [24]. The necrotic core is composed of free cholesterol, cholesterol crystals, and cholesterol esters derived from lipids that have infiltrated the arterial wall and also lipids derived from the death, by apoptosis or necrosis, of foam cells, mostly macrophages [25]. The necrotic core tends to be the most thrombogenic part of the plaque in part due to direct platelet activating effects of oxidized lipids [26]. Volumetric VH-IVUS analysis of each plaque component showed significantly higher plaque volume indexes of relatively unstable plaque components, such as the necrotic core and dense calcium, of all three vessels in the thick EAT group. Although the relationship between dense calcium and plaque vulnerability is controversial, dense calcium has been reported to be common in plaque rupture [27]. The mean percentage of relatively stable components of plaques, such as fibrous and fibrofatty, of all three vessels tended to be lower in the thick EAT group. The structural components of a fibrous plaque include matrix molecules like collagen, elastin and proteoglycans, and derived smooth muscle cells [25]. The fibrofatty plaque is a mixed plaque composed of fibrous plaque and lipids that have infiltrated the arterial wall. These plaque components prevent plaque rupture by protecting the deeper components of the plaque from contact with circulating blood. Decrease of these components is generally considered a sign of vulnerability. These VH-IVUS analyses of all three vessels might imply that thick EAT is correlated with the potential for future coronary events due to plaque vulnerability. In the symptom-related vessel, EAT was significantly correlated with the number of TCFAs. The TCFA is the most common type of
vulnerable plaque and the precursor of plaque rupture [28,29]. The TCFA is most frequently observed in patients dying of acute plaque rupture [29]. This VH-IVUS analysis of a symptom-related vessel might implicate that thick EAT is correlated with current risk of coronary plaque rupture. The present study suggests that thickened EAT is a predictor of both current and future plaque vulnerability. There are several limitations to the present study. First, EAT thickness by echocardiography does not exactly represent the amount of total EAT. Even though echocardiography is not the optimal methods for quantification of EAT, our previous study showed that EAT thickness measured by echocardiography has a good correlation with the total area of EAT measured by CT scan representing the total EAT volume [30]. The EAT thickness measured by echocardiography showed a strong positive correlation with the total abdominal visceral adipose tissue (VAT) volume measured by magnetic resonance imaging (MRI). Echocardiographic EAT could be applied as an easy and reliable imaging indicator of VAT and cardiovascular risk [31]. As echocardiography is frequently performed in high risk cardiac patients, EAT thickness measured by echocardiography may be readily available at no extra cost. Magnetic resonance imaging is not widely available, is more costly and cannot be used on patients with implanted pacemakers or defibrillators, and CT scan involves radiation exposure. Since echocardiography costs less and is more widely used than these other methods, EAT thickness by echocardiography is an easy and reliable indicators of EAT without radiation exposure in clinical setting [3,31]. Second, there are still controversies regarding the reliability of VH-IVUS. A recent comparison of VH-IVUS versus a model of porcine atherosclerosis found no correlation in the assessment of the necrotic core [32]. However, pathological correlations of VH-IVUS versus ex vivo coronary arteries and directional coronary atherectomy specimens have been demonstrated [15,33]. Third, the present study is cross sectional study. Although the ability of VH-IVUS to identify plaque anatomy and composition is potentially a powerful method of predicting subsequent patient outcome [34], the longitudinal study about the clinical outcomes according to EAT thickness is needed for demonstrating that EAT might imply the potential for future coronary events. Forth, the population of the present study included both unstable angina and stable angina. Although we intended to demonstrate the relationship of EAT and histologic plaque characteristics, unstable angina and stable angina had different clinical manifestations. However, clinically stable angina is not necessarily associated with histologically stable atherosclerotic plaques [7,8] and a marker of inflammation or immune activation is occasionally raised in patients with stable angina according to disease activity [9]. The present study might demonstrate the relationship between the histologically vulnerable plaque and EAT regardless of clinical manifestations. The present study demonstrated that the EAT thickness by echocardiography is related with plaque vulnerability in patients with significant CAD. The EAT thickness might provide additional information for predicting the activity of CAD. These findings suggested that a more intensive treatment for vulnerable plaque might be needed for patients of CAD with thick EAT. Disclosures None. Acknowledgments We express our gratitude to Seung-Soo Sheen, MD in Ajou University School of Medicine, Section of Clinical Epidemiology and Biostatistics, Regional Clinical Trial Center for help with statistical analysis.
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References [1] Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2005;2:536e43. [2] Baker AR, Silva NF, Quinn DW, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006;5:1. [3] Ahn SG, Lim HS, Joe DY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 2008;94:e7. [4] Eroglu S, Sade LE, Yildirir A, et al. Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease. Nutr Metab Cardiovasc Dis 2009;19(3):211e7. [5] Djaberi R, Schuijf JD, van Werkhoven JM, Nucifora G, Jukema JW, Bax JJ. Relation of epicardial adipose tissue to coronary atherosclerosis. Am J Cardiol 2008;102:1602e7. [6] Gorter PM, de Vos AM, van der Graaf Y, et al. Relation of epicardial and pericardial fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography. Am J Cardiol 2008;102:380e5. [7] van der Wal AC, Becker AE, Koch KT, et al. Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques. Heart 1996;76(4):312e6. [8] Hermens JA, van Houwelingen GK, de Man FH, Louwerenburg HW, von Birgelen C. Thrombus aspiration in a series of patients with stable or unstable angina pectoris and lesion-site thrombus formation. Neth Heart J 2010;18(9): 423e9. [9] Garcia-Moll X, Cole D, Zouridakis E, Kaski JC. Increased serum neopterin: a marker of coronary artery disease activity in women. Heart 2000;83(3): 346e50. [10] Arbustini E, Dal Bello B, Morbini P, et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999;82(3):269e72. [11] Lo J, Abbara S, Rocha-Filho JA, Shturman L, Wei J, Grinspoon SK. Increased epicardial adipose tissue volume in HIV-infected men and relationships to body composition and metabolic parameters. AIDS 2010;24(13):2127e30. [12] Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med 1975;58(2):243e64. [13] Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116(22):2634e53. [14] Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106:2200e6. [15] Nasu K, Tsuchikane E, Katoh O, et al. Accuracy of in vivo coronary plaque morphology assessment: a validation study of in vivo virtual histology compared with in vitro histopathology. J Am Coll Cardiol 2006;47:2405e12. [16] Rodriguez-Granillo GA, García-García HM, Mc Fadden EP, et al. In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol 2005;46:2038e42. [17] Park JS, Ahn SG, Hwang JW, et al. Impact of body mass index on the relationship of epicardial adipose tissue to metabolic syndrome and coronary artery disease in an Asian population. Cardiovasc Diabetol 2010;9:29.
139
[18] Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P. Epicardial adipose tissue and coronary artery plaque characteristics. Atherosclerosis 2010;210(1):150e4. [19] Knollmann F, Ducke F, Krist L, et al. Quantification of atherosclerotic coronary plaque components by submillimeter computed tomography. Int J Cardiovasc Imaging 2008;24(3):301e10. [20] Choi BJ, Kang DK, Tahk SJ, et al. Comparison of 64-slice multidetector computed tomography with spectral analysis of intravascular ultrasound backscatter signals for characterizations of noncalcified coronary arterial plaques. Am J Cardiol 2008;102(8):988e93. [21] Mahabadi AA, Reinsch N, Lehmann N, et al. Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. Atherosclerosis 2010;211(1):195e9. [22] Prati F, Arbustini E, Labellarte A, et al. Eccentric atherosclerotic plaques with positive remodeling have a pericardial distribution: a permissive role of epicardial fat? Eur Heart J 2003;24(4):291e3. [23] Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460e6. [24] Zheng M, Choi SY, Tahk SJ, et al. The relationship between volumetric plaque components and classical cardiovascular risk factors and the metabolic syndrome a 3-vessel coronary artery virtual histology-intravascular ultrasound analysis. JACC Cardiovasc Interv 2011;4(5):503e10. [25] Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009; 23(1):31e40. [26] Fernández-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 1994;23(7):1562e9. [27] Burke AP, Taylor A, Farb A, Malcom GT, Virmani R. Coronary calcification: insights from sudden coronary death victims. Z Kardiol 2000;89(Suppl. 2):49e53. [28] Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesion. Atheroscler Thromb Vasc Biol 2000;20(5):1262e75. [29] Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006;18(47):C13e8. [30] Hwang JW, Choi UJ, Ahn SG, et al. Echocardiographic plains reflecting total amount of epicardial adipose tissue as risk factor of coronary artery disease. J Cardiovasc Ultrasound 2008;16(1):17e22. [31] Iacobellis G, Ribaudo MC, Assael F, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003;88(11):5163e8. [32] Thim T, Hagensen MK, Wallace-Bradley D, et al. Unreliable assessment of necrotic core by virtual histology intravascular ultrasound in porcine coronary artery disease. Circ Cardiovasc Imaging 2010;3(4):384e91. [33] Nair A, Margolis MP, Kuban BD, Vince DG. Automated coronary plaque characterisation with intravascular ultrasound backscatter: ex vivo validation. EuroIntervention 2007;3(1):113e20. [34] Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VHIVUS in Vulnerable Atherosclerosis) Study. JACC Cardiovasc Imaging 2011; 4(8):894e901.
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Epicardial adipose tissue thickness is a predictor for plaque vulnerability in patients with significant coronary artery disease Jin-Sun Park, So-Yeon Choi, Mingri Zheng, Hyoung-Mo Yang, Hong-Seok Lim, Byoung-Joo Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk, Joon-Han Shin* Department of Cardiology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 443-721, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 May 2012 Received in revised form 29 October 2012 Accepted 2 November 2012 Available online 15 November 2012
The aim of this study is to assess the relationship of epicardial adipose tissue (EAT) and plaque vulnerability. We consecutively enrolled 82 patients with coronary artery disease (CAD). A symptom-related vessel was imaged by virtual histology intravascular ultrasound (VH-IVUS). In 60 out of 82 patients, all three vessels were studied by VH-IVUS. EAT thickness was measured by echocardiography. All patients were divided into thick (3.5 mm) and thin EAT groups (<3.5 mm). VH-IVUS parameters were compared according to the EAT group. To evaluate the independent effect of EAT thickness on plaque vulnerability, a set of well-known CAD risk factors and EAT thickness were included in multiple linear regression models of VH-IVUS parameters which denotes plaque vulnerability. In a symptom-related vessel analysis, the thick EAT group had significantly more thin-cap fibroatheromas (TCFAs). In a symptom-related vessel analysis among 62 patients with unstable angina out of 82 patients, the thick EAT group had significantly more thin-cap fibroatheromas (TCFAs). In all three vessels analysis, the thick EAT group was associated with significantly larger total plaque volume, higher total plaque volume index, higher mean plaque burden, higher plaque volume indexes of the necrotic core (NC), and more total number of TCFAs than the thin EAT group. By multivariate analysis, total TCFAs of a symptom-related vessel, both in total population and in patients with unstable angina, and plaque volume index of the NC of all three vessels were independent factors associated with thick EAT. In multiple linear regression models of VH-IVUS parameters which means plaque vulnerability, EAT thickness was one of the independent factors. In the present study, the VH-IVUS parameters indicating vulnerable plaque were significantly related with the thickness of EAT. Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Epicardial adipose tissue Vulnerable plaque Virtual histology intravascular ultrasound Coronary artery atherosclerosis
1. Background Epicardial adipose tissue (EAT) is true visceral fat deposited around the heart, particularly around coronary vessels and mediates atherosclerosis via expression of several bioactive molecules [1,2]. EAT quantification has been demonstrated to correlate with the severity of coronary artery disease (CAD) and the extent of coronary artery atherosclerosis [3e6]. Although EAT may serve as a source of inflammation that can influence CAD activity, there are limited data regarding the association of EAT with the type of atherosclerotic plaque. We have reported that the thickness of EAT by echocardiography was significantly correlated with unstable presentation of CAD [3]. * Corresponding author. Tel.: þ82 31 219 5712; fax: þ82 31 219 5708. E-mail address: [email protected] (J.-H. Shin). 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.11.001
We hypothesized that the unstable presentation of CAD in patients with thick EAT might be related with plaque vulnerability. The aim of this study is to assess the relationship of EAT and plaque vulnerability using analysis of plaque components by virtual histology intravascular ultrasound (VH-IVUS) in patients with significant CAD. 2. Methods We consecutively enrolled 82 patients with angiographically significant CAD, who received successful coronary stenting. The medical records of all patients were retrospectively reviewed after informed consent of studied patients. As we intended to investigate the relationship between the histologic characteristics of plaque and EAT, we enrolled patients with angiographically significant CAD regardless of clinical presentation. As clinically stable angina is not necessarily associated with histologically stable atherosclerotic
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plaques [7,8] and a marker of inflammation or immune activation is occasionally raised in patients with stable angina according to disease activity [9], we enrolled patients with both stable angina and unstable angina. However, as inflammation within vulnerable coronary plaque is more closely related to unstable angina [10], we also tried to investigate the relationship between the histologic characteristics of plaque and EAT in patients with unstable angina. Upon quantitative analysis of the coronary angiograms, significant CAD was considered to be the presence of stenosis, 50% in diameter, of a major epicardial vessel. Revascularization was decided to be clinically indicated if there was >70% diameter stenosis on coronary angiography or >50% stenosis together with a positive stress test or ischemic symptoms. We tried to exclude the acute systemic inflammatory effect to avoid confounding the role of EAT. We excluded patients from the study if they had any of the following: active inflammation (such as infection or systemic autoimmune disease, often related to increased EAT [11,12]), a history of prior revascularization, heart failure, cardiomyopathy or acute myocardial infarction. Myocardial infarction was defined when there is a detection of rise in cardiac biomarkers (preferably troponin), with at least one value above the 99th percentile of the upper reference limit [13]. A symptom-related vessel was imaged by VH-IVUS before stent implantation in all patients. Symptom-related vessel was defined as the vessel with maximal stenosis (usually >70% diameter stenosis) by angiographic findings. If not localizable to a single symptomrelated vessel by angiographic findings, symptom-related vessel was defined according to pre-interventional IVUS findings in patients with multivessel disease. If there were several minimum lumen area (MLA) sites, the MLA site with the largest external elastic membrane cross sectional area was chosen as a symptomrelated lesion. A 20 MHz, 2.9 Fr IVUS imaging catheter (Eagle Eye, Volcano Corporation, Rancho Cordova, California, USA) was advanced as far distally as possible into the coronary artery after intracoronary administration of 100e200 mg nitroglycerine. Imaging was performed, paying attention to cover any evident atherosclerosis. Automated pullback was performed at a speed of 0.5 mm/s. During pull-back, the raw radiofrequency data were captured at the peak of the R waves for the reconstruction of a color-coded map by a VH data recorder (Volcano Corporation, Rancho Cordova, California, USA). Manual contour tracing of the lumen and the media-adventitia interface was performed by an experienced analyst who was unaware of the patients’ information. Volumetric data were generated using pcVH software (version 2.1, Volcano Corporation, Rancho Cordova, California, USA). The total plaque volume was automatically determined by the software, and the summation of measured cross sectional areas in all frames of the pullback region was based on Simpson’s rule. In 60 patients among the study population, all three major epicardial arteries were studied by VH-IVUS. VH-IVUS analysis classified the color-coded tissue into four major components as green (fibrous), yellow-green (fibrofatty), white (dense calcium), and red (necrotic core) [14e16]. Four plaque components were defined as follows: 1) fibrous: areas of densely packed collagen, 2) fibrofatty: fibrous tissue with lipid interspersed in collagen, 3) dense calcium: calcium deposits without adjacent necrosis, and 4) necrotic core: necrotic regions consisting of cholesterol clefts, foam cells, and microcalcifications [15]. Each plaque component was measured in every recorded frame. The total plaque volume of a symptom-related vessel was obtained, and the mean plaque burden was calculated as the total plaque volume of a symptom-related vessel divided by the total vessel volume of a symptom-related vessel 100. A plaque volume index of a symptom-related vessel was calculated as total plaque volume of a symptom-related vessel divided by vessel length. The plaque
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volume index of each plaque component was calculated. Each plaque component was also expressed as a percentage of the total plaque volume. Thin-cap fibroatheroma (TCFA) was defined as a necrotic core 10% of plaque area without evident overlying fibrous tissue in the presence of 40% plaque burden in at least three consecutive frames [16]. The numbers of TCFAs were calculated in a symptom-related vessel. Also, total plaque volume, mean plaque burden and plaque volume indexes, percentage of each plaque component and the numbers of TCFAs were obtained in 60 patients by analyzing all three major epicardial arteries. Two-dimensional transthoracic echocardiography was performed within 1 week, either after or before undergoing VH-IVUS. Recordings of three cycles of the two-dimensional parasternal long-axis were obtained. We enlarged images for better visualization and accurate measurement of EAT thickness. EAT thickness was measured on the free wall of the right ventricle (RV) in the still image of a two-dimensional echocardiography at end diastole on the parasternal long-axis view. We preferred the area above the RV to measure EAT thickness, as this area is recognized as having the thickest EAT layer. In addition, the parasternal long-axis view allows the most accurate measurement of EAT thickness with optimal cursor beam orientation. The anterior echo-lucent space between the linear echo-dense parietal pericardium and the RV epicardium was considered to be EAT. We measured the thickest point of EAT in each cycle. The average value of the EAT thickness was calculated. All patients were divided into two groups: thick EAT group, EAT 3.5 mm (n ¼ 37) and thin EAT group, EAT <3.5 mm (n ¼ 45). The median value of EAT thickness in patients with unstable presentation of CAD was 3.5 mm in our previous studies [3,17]. We chose 3.5 mm, the median value of EAT thickness in patients with significant CAD, derived from these previous studies, as the cut off value, instead of the median value of EAT thickness in the present study population. While the present study population consists of relatively small number, more than 500 patients were enrolled in our previous studies. The cut off value, 3.5 mm, derived from these studies might be a more reasonable standard than the median EAT value of the present study. We compared the characteristics of patients in the thick EAT group to those in the thin EAT group. VHIVUS analyses were compared according to the EAT groups (Fig. 1). Volumetric VH-IVUS analyses and the total number of TCFA of symptom-related vessel of all study populations were compared according to the EAT groups. Volumetric VH-IVUS analyses and the total number of TCFAs of symptom-related vessel of patients with unstable angina were compared according to the EAT groups (thick EAT group ¼ 28, thin EAT group ¼ 34). Volumetric VH-IVUS analyses and the total number of TCFAs of all three major epicardial arteries of 60 patients were compared according to the EAT groups (thick EAT group ¼ 21, thin EAT group ¼ 39). The SPSS 13.0 (SPSS inc., Chicago, Illinois, USA) statistical software package was used for all calculations. Data are shown as the mean standard deviation for continuous variables and as percentages for categorical variables. Comparisons were conducted by unpaired Student’s t test. Multiple stepwise logistic regression analysis was performed to assess independent VH-IVUS parameters that were related to thick EAT. To evaluate the independent effect of EAT thickness on plaque vulnerability, a set of well-known CAD risk factors and EAT thickness were included in multiple linear regression models of VH-IVUS parameters which denotes plaque vulnerability. A p value < 0.05 was considered statistically significant. 3. Results The median and mean standard deviation EAT thickness of the study population were 2.8 mm and 3.4 2.2 mm, respectively. The
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J.-S. Park et al. / Atherosclerosis 226 (2013) 134e139
Fig. 1. Examples of plaque components in patients with (A) epicardial adipose tissue 3.5 mm and in those with (B) epicardial adipose tissue <3.5 mm. VH-IVUS analysis classified the color-coded tissue into four major components as green (fibrous), yellow-green (fibrofatty), white (dense calcium), and red (necrotic core).
mean age of the study population was 59 10 years old. Clinical characteristics according to the group of EAT thickness are summarized in Table 1. Thirty-seven patients (45%) were included in the thick EAT group and the others were included in the thin EAT group (45 patients, 55%). Compared to the thin EAT group, subjects in the thick EAT group had a significantly higher level of body mass index and higher rates of diabetes, dyslipidemia, and metabolic syndrome. The results of volumetric VH-IVUS findings and the total TCFA numbers of a symptom-related vessel according to EAT groups are listed in Table 2. The thick EAT group had significantly more total TCFA compared to thin EAT group (p ¼ 0.003). The thick EAT group
Table 1 Baseline characteristics according to the group of epicardial adipose tissue thickness. Variables
EAT 3.5 mm (n ¼ 37)
EAT <3.5 mm (n ¼ 45)
Age (years) Men BMI (kg/m2) Body weight (kg) Unstable angina Hypertension Diabetes mellitus Dyslipidemia Metabolic syndrome Smoker EAT (mm)
58 10 20 (54%) 26.03 3.69 67.9 11.3 28 (76%) 23 (62%) 15 (41%) 11 (30%) 15 (41%) 13 (35%) 5.4 1.4 (median 5.3)
59 11 0.445 24 (53%) 0.949 24.16 2.87 0.013 66.3 10.7 0.498 34 (76%) 0.99 27 (60%) 0.725 9 (20%) 0.039 5 (11%) 0.037 1 (2%) <0.001 15 (34%) 0.853 1.6 0.8 (median 1.7) <0.001
p value
Continuous variables are expressed as the mean standard deviation and categorical values as absolute (percentage) values. EAT: epicardial adipose tissue; BMI: body mass index.
tended to have more total plaque volume compared to the thin EAT group (p ¼ 0.077). There was no significant statistical difference in volume index and mean percentage of each plaque component between the two groups. By multivariate analysis of the VH-IVUS parameters, the total number of TCFAs of the symptom-related vessel was an independent factor associated with thick EAT. Sixty-two patients out of 82 were diagnosed as unstable angina. Among these patients, the results of volumetric VH-IVUS findings and the total TCFA numbers of a symptom-related vessel according to EAT groups are listed in Table 3. The thick EAT group had significantly more total TCFA compared to thin EAT group (p < 0.001). The thick EAT group tended to have more total plaque volume compared to the thin EAT group (p ¼ 0.073). There was no significant statistical difference in volume index and mean percentage of each plaque component between the two groups. By multivariate analysis of the VH-IVUS parameters among patients with unstable angina, the total number of TCFAs of the symptomrelated vessel was an independent factor associated with thick EAT. In Table 4, volumetric VH-IVUS analyses and the total number of TCFAs of all three major epicardial arteries of 60 patients were compared according to the EAT groups. Twenty-one patients (35%) were included in the thick EAT group. The thin EAT group consisted of 39 patients (65%). The mean age of 60 patients was 59 9 years. The thick EAT group had significantly larger total plaque volume, higher total plaque volume index, higher mean plaque burden and more total number of TCFAs compared to the thin EAT group (p ¼ 0.01, 0.001, <0.001 and 0.031, respectively). Analysis of volume index of each plaque component showed significantly higher plaque volume index of the necrotic core in the thick EAT group compared to the thin EAT group (p ¼ 0.004). The thick EAT group
J.-S. Park et al. / Atherosclerosis 226 (2013) 134e139 Table 2 Symptom-related vessel analysis. Variables
Table 4 Analysis of all three major epicardial vessels. EAT 3.5 mm (n ¼ 37)
EAT <3.5 mm (n ¼ 45)
Volumetric VH-IVUS analyses 482.1 280.9 352.55 165.2 Plaque volume (mm3) Total length (mm) 65.6 23 56.7 18.6 7.1 2.7 6.2 1.7 Plaque volume index (mm3/mm) Mean plaque burden (%) 47.6 7 46.9 7.1 Volume index of each plaque component (mm3/mm) Necrotic core 0.5 1.5 0.4 0.3 Dense calcium 0.7 0.6 0.5 0.4 Fibrous 2.2 1.2 1.8 0.9 Fibrofatty 0.5 0.5 0.5 0.5 Mean percentage of each plaque component (%) Necrotic core (%) 9.5 5.8 8.4 8.3 Dense calcium (%) 17 9 14.7 8.3 Fibrous (%) 60.9 10.1 60.7 10 Fibrofatty (%) 12.6 7.8 15.9 9.3 Qualitative VH-IVUS analysis Total TCFA (n) 1.2 0.9 0.6 0.9 Variables
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Odds ratio (95% CI)
Multiple regression analysis of epicardial adipose tissue Total TCFA (n) 1.393 (1.009e1.924)
p value
Variables
EAT 3.5 mm (n ¼ 21)
EAT <3.5 mm (n ¼ 39)
p value
0.003
Volumetric VH-IVUS analyses 1360.1 492.1 1048.5 398.2 0.01 Plaque volume (mm3) Total length (mm) 189.6 44 179.8 47.2 0.436 7.1 1.7 5.8 1.3 0.001 Plaque volume index (mm3/mm) Mean plaque burden (%) 45.4 6 38.5 8.1 <0.001 Volume index of each plaque component (mm3/mm) Necrotic core 0.6 0.4 0.3 0.2 0.004 Dense calcium 0.4 0.3 0.2 0.3 0.05 Fibrous 2.3 0.9 1.8 1.9 0.235 Fibrofatty 0.5 0.4 0.4 0.4 0.355 Mean percentage of each plaque component (%) Necrotic core 16.1 6.1 12.3 6.5 0.072 Dense calcium 9.7 5.2 7.0 5.6 0.086 Fibrous 62.0 6.5 63.6 7.8 0.219 Fibrofatty 12.3 7.4 17.0 8.0 0.052 Qualitative VH-IVUS analysis Total TCFA (n) 3.3 2.2 2.1 1.6 0.031
p value
Variables
0.044
Multiple regression analysis of epicardial adipose tissue Volume index of necrotic core (mm3/mm) 31.229 (3.091e315.546) 0.004
0.077 0.151 0.193 0.73 0.649 0.11 0.257 0.936 0.596 0.37 0.942 0.198
Odds ratio (95% CI)
p value
Continuous variables are expressed as the mean standard deviation. EAT: epicardial adipose tissue; TCFA: thin-cap fibroatheroma; CI: confidence interval.
Continuous variables are expressed as the mean standard deviation. EAT: epicardial adipose tissue; TCFA: thin-cap fibroatheroma; CI: confidence interval.
tended to have higher volume index of dense calcium than the thin EAT group (p ¼ 0.05). Comparing the percentages of each plaque component, the thick EAT group tended to have higher mean percentage of the necrotic core and dense calcium and lower mean percentage of fibrofatty plaque compared to the thin EAT group (p ¼ 0.072, 0.086 and 0.052, respectively). By multivariate analysis of the volumetric VH-IVUS parameters of all three major epicardial arteries, the plaque volume indexes of the necrotic core was an independent factor associated with thick EAT. In a multiple linear regression model of total TCFAs of symptom-related vessel, EAT thickness and diabetes mellitus were independent factors (p ¼ 0.043 and 0.035, respectively, Table 5). In a multiple linear regression model of total TCFAs of symptom-related vessel in patients with unstable angina, EAT thickness was independent
factors (p ¼ 0.041, Table 5). In a multiple linear regression model of volume index of the necrotic core of all three major epicardial vessels, EAT thickness and metabolic syndrome were independent factors (p ¼ 0.005 and <0.001, respectively, Table 6).
Table 3 Symptom-related vessel analysis in patients with unstable angina. Variables
EAT 3.5 mm (n ¼ 28)
EAT <3.5 mm (n ¼ 34)
p value
Volumetric VH-IVUS analyses 519.92 301.9 374.55 175.4 0.073 Plaque volume (mm3) Total length (mm) 66.5 23.2 58.3 18.4 0.237 7.5 2.7 6.3 1.7 0.133 Plaque volume index (mm3/mm) Mean plaque burden (%) 48.7 7 47.7 6.8 0.662 Volume index of each plaque component (mm3/mm) Necrotic core 0.7 1.8 0.4 0.3 0.59 Dense calcium 0.8 0.6 0.5 0.3 0.066 Fibrous 2.3 1.2 1.9 0.8 0.249 Fibrofatty 0.5 0.5 0.5 0.4 0.963 Mean percentage of each plaque component (%) Necrotic core (%) 9.9 5.8 7.1 6.5 0.191 Dense calcium (%) 18.2 8.8 13.5 7.2 0.092 Fibrous (%) 59.6 9.3 62.7 9.1 0.319 Fibrofatty (%) 12.4 8.4 16.4 8 0.152 Qualitative VH-IVUS analysis Total TCFA (n) 1.2 0.9 0.4 0.6 <0.001 Variables
Odds ratio (95% CI)
Multiple regression analysis of epicardial adipose tissue Total TCFA (n) 2.485 (1.047e5.896)
p value 0.039
Continuous variables are expressed as the mean standard deviation. EAT: epicardial adipose tissue; TCFA: thin-cap fibroatheroma; CI: confidence interval.
4. Discussion In our previous study, the thickness of EAT by echocardiography was significantly correlated with unstable presentation of CAD [3]. Although we suggested that EAT might serve as a source of inflammation that could influence CAD activity, very few data are available regarding the relationship between EAT and plaque vulnerability. Recently a report that EAT was associated with the development of coronary atherosclerosis and with the most potentially dangerous types of plaques was published [18]. They demonstrated that the presence and extent of a non-calcified component, one of the features of vulnerable plaque, measured in an atherosclerotic plaque using computed tomography (CT), were correlated with EAT volume. Although CT scan provides an accurate and reproducible method for the quantitative assessment of total plaque and calcified plaque [19], the CT scan technique may not be sufficient to clearly discriminate the necrotic core from other
Table 5 Multiple linear regression analysis of total TCFAs of symptom-related vessel. Variables Total population BMI (kg/m2) Diabetes mellitus Dyslipidemia Metabolic syndrome EAT thickness Patients with unstable angina BMI (kg/m2) Diabetes mellitus Dyslipidemia Metabolic syndrome EAT thickness
B (95% CI)
p value
0.011 0.539 0.021 0.373 0.106
(1.754e1.687) (0.04e1.038) (0.552e0.594) (0.159e0.905) (0.004e0.208)
0.969 0.035 0.941 0.165 0.043
0.014 0.359 0.352 0.161 0.646
(0.083e0.111) (0.248e0.966) (1.062e0.358) (1.062e0.358) (0.028e1.264)
0.772 0.238 0.322 0.579 0.041
EAT: epicardial adipose tissue; BMI: body mass index; TCFA: thin-cap fibroatheroma; CI: confidence interval.
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J.-S. Park et al. / Atherosclerosis 226 (2013) 134e139
Table 6 Multiple linear regression analysis of volume index of necrotic core of all three major epicardial vessels. Variables
B (95% CI)
p value
BMI (kg/m2) Diabetes mellitus Dyslipidemia Metabolic syndrome EAT thickness
0.123 0.027 0.384 3.137 3.504
0.106 0.961 0.08 <0.001 0.005
(0.027e0.274) (1.076e1.130) (0.866e1.633) (1.797e4.476) (2.297e5.346)
EAT: epicardial adipose tissue; BMI: body mass index; CI: confidence interval.
plaque components [20]. Hence, we used VH-IVUS to subclassify the plaque components in an atherosclerotic plaque. Many studies using VH-IVUS have analyzed plaque composition at target lesions or non-obstructive lesions, but not from the entire coronary arterial tree. As EAT might affect the entire coronary tree, we decided on volumetric analysis of the whole plaque burden from the entire coronary arterial tree and a symptom-related vessel. The analysis of a symptom-related vessel might demonstrate the present risk for coronary events. The analysis of all three major epicardial vessels might demonstrate the potentials for future coronary events. The volumetric VH-IVUS analysis of the whole plaque burden used in the present study might be more representative than focal plaque analysis for assessing the relationship of EAT and plaque vulnerability. Owing to the anatomical characteristics of EAT, EAT may have a local proatherosclerotic effect on the underlying coronary arteries [21]. The preference for an epicardial distribution of atherosclerotic lesions implicates a role for the local proatherosclerotic effect of EAT [22]. Several biomolecular studies in humans have shown that EAT is metabolically active and an important source of inflammatory mediators [1,2,23]. The presence of inflammatory mediators in EAT surrounding coronary arteries could lead to amplification of vascular inflammation, plaque instability via apoptosis, and neovascularization [22]. In the present study, EAT thickness by echocardiography was closely related with plaque volume indexes of the necrotic core of three vessels in patients with significant CAD. The necrotic core has currently become the surrogate for assessing the vulnerability of plaque [24]. The necrotic core is composed of free cholesterol, cholesterol crystals, and cholesterol esters derived from lipids that have infiltrated the arterial wall and also lipids derived from the death, by apoptosis or necrosis, of foam cells, mostly macrophages [25]. The necrotic core tends to be the most thrombogenic part of the plaque in part due to direct platelet activating effects of oxidized lipids [26]. Volumetric VH-IVUS analysis of each plaque component showed significantly higher plaque volume indexes of relatively unstable plaque components, such as the necrotic core and dense calcium, of all three vessels in the thick EAT group. Although the relationship between dense calcium and plaque vulnerability is controversial, dense calcium has been reported to be common in plaque rupture [27]. The mean percentage of relatively stable components of plaques, such as fibrous and fibrofatty, of all three vessels tended to be lower in the thick EAT group. The structural components of a fibrous plaque include matrix molecules like collagen, elastin and proteoglycans, and derived smooth muscle cells [25]. The fibrofatty plaque is a mixed plaque composed of fibrous plaque and lipids that have infiltrated the arterial wall. These plaque components prevent plaque rupture by protecting the deeper components of the plaque from contact with circulating blood. Decrease of these components is generally considered a sign of vulnerability. These VH-IVUS analyses of all three vessels might imply that thick EAT is correlated with the potential for future coronary events due to plaque vulnerability. In the symptom-related vessel, EAT was significantly correlated with the number of TCFAs. The TCFA is the most common type of
vulnerable plaque and the precursor of plaque rupture [28,29]. The TCFA is most frequently observed in patients dying of acute plaque rupture [29]. This VH-IVUS analysis of a symptom-related vessel might implicate that thick EAT is correlated with current risk of coronary plaque rupture. The present study suggests that thickened EAT is a predictor of both current and future plaque vulnerability. There are several limitations to the present study. First, EAT thickness by echocardiography does not exactly represent the amount of total EAT. Even though echocardiography is not the optimal methods for quantification of EAT, our previous study showed that EAT thickness measured by echocardiography has a good correlation with the total area of EAT measured by CT scan representing the total EAT volume [30]. The EAT thickness measured by echocardiography showed a strong positive correlation with the total abdominal visceral adipose tissue (VAT) volume measured by magnetic resonance imaging (MRI). Echocardiographic EAT could be applied as an easy and reliable imaging indicator of VAT and cardiovascular risk [31]. As echocardiography is frequently performed in high risk cardiac patients, EAT thickness measured by echocardiography may be readily available at no extra cost. Magnetic resonance imaging is not widely available, is more costly and cannot be used on patients with implanted pacemakers or defibrillators, and CT scan involves radiation exposure. Since echocardiography costs less and is more widely used than these other methods, EAT thickness by echocardiography is an easy and reliable indicators of EAT without radiation exposure in clinical setting [3,31]. Second, there are still controversies regarding the reliability of VH-IVUS. A recent comparison of VH-IVUS versus a model of porcine atherosclerosis found no correlation in the assessment of the necrotic core [32]. However, pathological correlations of VH-IVUS versus ex vivo coronary arteries and directional coronary atherectomy specimens have been demonstrated [15,33]. Third, the present study is cross sectional study. Although the ability of VH-IVUS to identify plaque anatomy and composition is potentially a powerful method of predicting subsequent patient outcome [34], the longitudinal study about the clinical outcomes according to EAT thickness is needed for demonstrating that EAT might imply the potential for future coronary events. Forth, the population of the present study included both unstable angina and stable angina. Although we intended to demonstrate the relationship of EAT and histologic plaque characteristics, unstable angina and stable angina had different clinical manifestations. However, clinically stable angina is not necessarily associated with histologically stable atherosclerotic plaques [7,8] and a marker of inflammation or immune activation is occasionally raised in patients with stable angina according to disease activity [9]. The present study might demonstrate the relationship between the histologically vulnerable plaque and EAT regardless of clinical manifestations. The present study demonstrated that the EAT thickness by echocardiography is related with plaque vulnerability in patients with significant CAD. The EAT thickness might provide additional information for predicting the activity of CAD. These findings suggested that a more intensive treatment for vulnerable plaque might be needed for patients of CAD with thick EAT. Disclosures None. Acknowledgments We express our gratitude to Seung-Soo Sheen, MD in Ajou University School of Medicine, Section of Clinical Epidemiology and Biostatistics, Regional Clinical Trial Center for help with statistical analysis.
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References [1] Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2005;2:536e43. [2] Baker AR, Silva NF, Quinn DW, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006;5:1. [3] Ahn SG, Lim HS, Joe DY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 2008;94:e7. [4] Eroglu S, Sade LE, Yildirir A, et al. Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease. Nutr Metab Cardiovasc Dis 2009;19(3):211e7. [5] Djaberi R, Schuijf JD, van Werkhoven JM, Nucifora G, Jukema JW, Bax JJ. Relation of epicardial adipose tissue to coronary atherosclerosis. Am J Cardiol 2008;102:1602e7. [6] Gorter PM, de Vos AM, van der Graaf Y, et al. Relation of epicardial and pericardial fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography. Am J Cardiol 2008;102:380e5. [7] van der Wal AC, Becker AE, Koch KT, et al. Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques. Heart 1996;76(4):312e6. [8] Hermens JA, van Houwelingen GK, de Man FH, Louwerenburg HW, von Birgelen C. Thrombus aspiration in a series of patients with stable or unstable angina pectoris and lesion-site thrombus formation. Neth Heart J 2010;18(9): 423e9. [9] Garcia-Moll X, Cole D, Zouridakis E, Kaski JC. Increased serum neopterin: a marker of coronary artery disease activity in women. Heart 2000;83(3): 346e50. [10] Arbustini E, Dal Bello B, Morbini P, et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999;82(3):269e72. [11] Lo J, Abbara S, Rocha-Filho JA, Shturman L, Wei J, Grinspoon SK. Increased epicardial adipose tissue volume in HIV-infected men and relationships to body composition and metabolic parameters. AIDS 2010;24(13):2127e30. [12] Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med 1975;58(2):243e64. [13] Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116(22):2634e53. [14] Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106:2200e6. [15] Nasu K, Tsuchikane E, Katoh O, et al. Accuracy of in vivo coronary plaque morphology assessment: a validation study of in vivo virtual histology compared with in vitro histopathology. J Am Coll Cardiol 2006;47:2405e12. [16] Rodriguez-Granillo GA, García-García HM, Mc Fadden EP, et al. In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol 2005;46:2038e42. [17] Park JS, Ahn SG, Hwang JW, et al. Impact of body mass index on the relationship of epicardial adipose tissue to metabolic syndrome and coronary artery disease in an Asian population. Cardiovasc Diabetol 2010;9:29.
139
[18] Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P. Epicardial adipose tissue and coronary artery plaque characteristics. Atherosclerosis 2010;210(1):150e4. [19] Knollmann F, Ducke F, Krist L, et al. Quantification of atherosclerotic coronary plaque components by submillimeter computed tomography. Int J Cardiovasc Imaging 2008;24(3):301e10. [20] Choi BJ, Kang DK, Tahk SJ, et al. Comparison of 64-slice multidetector computed tomography with spectral analysis of intravascular ultrasound backscatter signals for characterizations of noncalcified coronary arterial plaques. Am J Cardiol 2008;102(8):988e93. [21] Mahabadi AA, Reinsch N, Lehmann N, et al. Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. Atherosclerosis 2010;211(1):195e9. [22] Prati F, Arbustini E, Labellarte A, et al. Eccentric atherosclerotic plaques with positive remodeling have a pericardial distribution: a permissive role of epicardial fat? Eur Heart J 2003;24(4):291e3. [23] Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460e6. [24] Zheng M, Choi SY, Tahk SJ, et al. The relationship between volumetric plaque components and classical cardiovascular risk factors and the metabolic syndrome a 3-vessel coronary artery virtual histology-intravascular ultrasound analysis. JACC Cardiovasc Interv 2011;4(5):503e10. [25] Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009; 23(1):31e40. [26] Fernández-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 1994;23(7):1562e9. [27] Burke AP, Taylor A, Farb A, Malcom GT, Virmani R. Coronary calcification: insights from sudden coronary death victims. Z Kardiol 2000;89(Suppl. 2):49e53. [28] Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesion. Atheroscler Thromb Vasc Biol 2000;20(5):1262e75. [29] Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006;18(47):C13e8. [30] Hwang JW, Choi UJ, Ahn SG, et al. Echocardiographic plains reflecting total amount of epicardial adipose tissue as risk factor of coronary artery disease. J Cardiovasc Ultrasound 2008;16(1):17e22. [31] Iacobellis G, Ribaudo MC, Assael F, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003;88(11):5163e8. [32] Thim T, Hagensen MK, Wallace-Bradley D, et al. Unreliable assessment of necrotic core by virtual histology intravascular ultrasound in porcine coronary artery disease. Circ Cardiovasc Imaging 2010;3(4):384e91. [33] Nair A, Margolis MP, Kuban BD, Vince DG. Automated coronary plaque characterisation with intravascular ultrasound backscatter: ex vivo validation. EuroIntervention 2007;3(1):113e20. [34] Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VHIVUS in Vulnerable Atherosclerosis) Study. JACC Cardiovasc Imaging 2011; 4(8):894e901.