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Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease
Nutrition, Metabolism & Cardiovascular Diseases (2009) 19, 211e217
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease S. Eroglu*, L.E. Sade, A. Yildirir, U. Bal, S. Ozbicer, A.S. Ozgul, H. Bozbas, A. Aydinalp, H. Muderrisoglu Department of Cardiology, Baskent University Faculty of Medicine, 10.sok No:45, 06490 Bahcelievler, Ankara, Turkey Received 2 February 2008; received in revised form 27 March 2008; accepted 15 May 2008
KEYWORDS Epicardial adipose tissue; Echocardiography; Coronary artery disease
Abstract Background and aim: Epicardial adipose tissue (EAT), which is thought to be a component of visceral adiposity, is associated with the metabolic syndrome. We aimed to test the hypothesis that echocardiographic EAT thickness can be a marker for the presence and severity of coronary artery disease (CAD). Method and results: In all, 150 patients (100 patients with CAD and 50 patients with normal coronary arteries by diagnostic coronary angiography; 65 women, 85 men; mean age 55.7 7.4 years) were enrolled. EAT thickness was measured using 2-D echocardiographic parasternal long- and short-axis views. EAT thickness measurements were compared with angiographic findings. EAT thickness was significantly higher in patients with CAD in comparison to those with normal coronary arteries (6.9 1.5 mm vs. 4.4 0.8 mm; P < 0.001). Furthermore, EAT thickness increased with the severity of CAD (multivessel disease 7.4 1.2 mm vs. single vessel disease 5.7 1.7 mm; P < 0.001). Gensini’s score significantly correlated with EAT thickness (r Z 0.600, P < 0.001). EAT thickness of 5.2 mm had 85% sensitivity and 81% specificity (ROC area 0.914, P < 0.001, 95% CI [0.86e0.96]) for predicting CAD. Conclusion: EAT thickness, which is easily and non-invasively evaluated by transthoracic echocardiography, can be an adjunctive marker to classical risk factors for the prediction of CAD. ª 2008 Elsevier B.V. All rights reserved.
Introduction
* Corresponding author. Tel.: þ90 312 212 6868; fax: þ90 312 223 8697. E-mail address: [email protected] (S. Eroglu).
Visceral adiposity is fat deposition around internal organs. It is metabolically active and is an important risk factor for developing the metabolic syndrome (MS) [1e4]. Epicardial adipose tissue (EAT) is a component of visceral adiposity and mediates cardiac function and atherosclerosis via
0939-4753/$ - see front matter ª 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2008.05.002
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expression of several bioactive molecules [5,6]. Transthoracic echocardiography enables non-invasive assessment of EAT [4,7]. Several studies have addressed the association between EAT thickness and the severity of coronary artery disease (CAD) with conflicting results [8e10]. Thus, we aimed to test the hypothesis that echocardiographic EAT thickness could be a marker for the presence and severity of CAD.
plasma triglycerides: 150 mg/dL; (iii) plasma HDL cholesterol: <40 mg/dL in men and <50 mg/dL in women; (iv) systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg or the use of antihypertensive medicine; (v) plasma glucose 110 mg/dL or the use of antidiabetic medicine/insulin.
Methods
Echocardiographic examinations were performed using an Acuson Sequoia C-256 cardiac ultrasound machine (Acuson Corporation, CA, USA) with patients in the left lateral decubitus position. Echocardiograms were recorded on videotapes. EAT appears as an echo-lucent space between the linear echo-dense parietal pericardium and the right ventricular epicardium. Thus EAT thickness was measured as the vertical distance of this echo-lucent space as illustrated in Fig. 1 [7e10]. The second echo-lucent space above the parietal pericardium which is the mediastinal fat, was not included in the measurement of the EAT. EAT thickness was measured at end-diastole from parasternal long- and short-axis B mode still-frame images by two echocardiographers who were blinded to coronary angiography data. Parasternal long- and short-axis measurements were averaged to obtain the mean thickness. Left ventricular ejection fraction was measured using the modified Simpson method [12].
Patients who underwent coronary angiography due to chest pain and/or an abnormal stress test were enrolled. One hundred patients with CAD and 50 patients with normal coronary arteries were consecutively studied. The study complies with the declaration of Helsinki. All participants gave informed consent, and the Institutional Review Board of the University of Baskent approved the research protocol. Patients were excluded if they had abnormal images on transthoracic echocardiography, a history of coronary artery bypass graft surgery, chronic kidney disease, severe valvular disease, uncontrolled diabetes or hypertension. The day after coronary angiography, all patients underwent transthoracic echocardiography. Systolic and diastolic blood pressures were measured after 5 min of rest. Height, waist circumference, weight and body fat ratio (Tanita TBF 534, Japan) were measured during a fasting period. Body mass index was calculated as body weight divided by height squared. Blood samples were obtained during fasting, and levels of plasma glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and C-reactive protein (CRP) were measured. The metabolic syndrome was diagnosed according to NCEPATP III [11]. Thus, a participant had MS if he or she had three or more of the following: (i) abdominal obesity: waist circumference >102 cm in men and >88 cm in women; (ii)
Figure 1 tissue.
Transthoracic echocardiography
Coronary angiography data CAD was defined as stenosis 20% in any coronary artery. Stenosis between 20% and 50% was defined as minimal CAD; stenosis more than 50% was defined as significant CAD, otherwise as normal coronary arteries. Patients with slow flow in the absence of any discernible lesions were also excluded. Coronary angiograms were interpreted by two independent invasive cardiologists. Gensini’s score [13] was calculated for each patient.
Parasternal long- (A) and short-axis (B) transthoracic 2-dimensonal echocardiographic images of epicardial adipose
Epicardial adipose tissue and coronary artery disease
Statistical analyses Continuous variables are expressed as means SD. The t-test and ANOVA were used to assess differences among the groups. Categorical variables were compared with the chi-square test. The Pearson correlation analysis was used to determine the relationship between mean values. For the prediction of independent variables that are associated with CAD a multiple linear regression model including potential confounders was performed. The cut-off value of EAT thickness for predicting CAD with corresponding specificity and sensitivity was estimated by receiver operating characteristic (ROC) curve analysis. Well-known CAD risk factors were included in a logistic regression model of CAD. To assess the reproducibility of the echocardiographic measurements, EAT thickness was measured by two independent echocardiographers in 20 randomly
Table 1
213 selected patients and inter-observer correlation coefficients were calculated. In the same group of patients echocardiographic measurements were repeated 2 days later to calculate intra-observer correlation coefficients. Variabilities of measurements were also calculated as the mean of differences in measurements. A P value of less than 0.05 was considered statistically significant. SPSS software (Statistical Package for the Social Sciences, version 10.0, SSPS Inc., Chicago, IL, USA) was used for all statistical calculations.
Results There were 65 women and 85 men in the study population. The mean age was 55.7 7.4 years. The demographic and laboratory characteristics of the study groups are presented in Table 1.
Demographic, laboratory and echocardiographic characteristics of subjects by study groups
Variable
Normal coronary arteries (n Z 50)
Coronary artery Disease (n Z 100)
54.1 7.4 25/25 29.3 4.7 94.2 11.7 34.3 7.4 35
56.4 7.3 40/60 28.8 4.5 96.0 11.4 32.3 7.5 64
0.068 0.161 0.529 0.383 0.313 0.368
133.4 19.8 80.5 9.8
137.4 22.4 81.3 10.4
0.296 0.636
Laboratory findings Fasting plasma glucose (mg/dL) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) Hemoglobin (g/dl) CRP (mg/L)
97.2 12.2 203.7 37.2 122.6 33.9 48.0 13.4 156.0 99.2 14.4 1.6 3.5 2.7
103.2 18.7 189 38.5 117.6 30.9 43.6 11.5 171.9 93.2 14.5 1.4 5.0 4.3
0.073 0.068 0.386 0.063 0.359 0.699 0.068
Echocardiographic findings Ejection fraction (%) Left ventricle mass (g) EAT thickness PSLX (mm) EAT thickness PSSX (mm) Average EAT thickness (mm)
55.2 4.1 103.9 31.9 4.4 0.9 4.4 0.9 4.4 0.8
47.9 7.4 114.1 32.1 7.0 1.5 6.8 1.5 6.9 1.5
0.001 0.071 <0.001 <0.001 <0.001
Drugs Beta blockers (%) Calcium channel blockers (%) ACE inhibitors (%) AT II receptor blockers (%) Nitrates (%) Acetyl salicylic acid (%) Diuretics (%) Statins (%)
28 8 14 6 2 32 18 14
50 19 30 22 23 70 34 38
0.014 0.065 0.044 0.018 <0.001 <0.001 0.055 0.004
Demographic characteristics Age (years) Sex (female/male) BMI (kg/m2) Waist circumference (cm) Body fat ratio (%) Smoker (%) Blood pressure Systolic (mmHg) Diastolic (mmHg)
P value
ACE, angiotensin converting enzyme; AT, angiotensin; BMI, body mass index; CAD, coronary artery disease; CRP, C-reactive protein; EAT, epicardial adipose tissue thickness; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PSLX, parasternal long axis; PSSX, parasternal short axis.
214
Figure 2 Association between epicardial adipose tissue thickness and severity of coronary artery disease (CAD) (*P Z 0.005, minimal CADvs. normal; yP < 0.001, significant CADvs. minimal CAD; zP < 0.001, significant CADvs. normal).
Epicardial adipose tissue thickness and presence and severity of coronary artery disease
S. Eroglu et al. EAT was also thicker in patients with multivessel disease compared to those with single-vessel disease (7.1 1.4 mmvs. 5.7 1.7 mm). Gensini’s score was significantly correlated with EAT thickness (r Z 0.600, P < 0.001). ANOVA test showed the significant difference of Gensini’s score between the groups of EAT thickness quartile (Fig. 3). EAT thickness of 5.2 mm had an 85% sensitivity and an 81% specificity (ROC area 0.914, P < 0.001, 95% CI [0.86e 0.96]) for predicting CAD (Fig. 4). When patients were dichotomized according to the cut-off value of EAT thickness; male gender, diabetes mellitus, hypertension, smoking, MS, CAD incidences, CRP, triglycerides and creatinine levels, and waist circumference were increased and HDLcholesterol was decreased in patients with EAT thickness 5.2 mm in comparison to patients with EAT thickness <5.2 mm (Table 2). Diabetes mellitus, dyslipidemia and EAT thickness were found to be independent predictors of CAD in a multivariate regression model including well-known risk factors (Table 3).
Relationship of epicardial adipose tissue to clinical and biochemical features
Inter-observer and intra-observer correlation coefficients of EAT thickness measurements were found to be 0.96 and 0.94 respectively. Intra- and inter-observer variability of EAT thickness measurements yielded differences in repeat measurements that were very low (0.5 0.3 mm and 0.6 0.4 mm, respectively). The mean EAT thickness was 6.1 1.7 mm in the pooled data. EAT thickness was significantly increased in patients with CAD compared to patients with normal coronary arteries (6.9 1.5 mmvs. 4.4 0.8 mm; P < 0.001). Furthermore, EAT thickness increased significantly with the severity and extent of CAD. In patients with CAD, 20 had minimal CAD and 80 had significant CAD. The thickness of EAT was significantly increased in those with significant CAD in comparison to those with minimal CAD (7.3 1.2 mmvs. 5.4 1.5 mm; P < 0.001) (Fig. 2).
We further assessed the association between EAT and variables related to metabolic status. EAT thickness correlated with age (r Z 0.228, P Z 0.005), fasting glucose (r Z 0.186, P Z 0.044), HDL- cholesterol (r Z 0.203, P Z 0.045), triglycerides (r Z 0.232, P Z 0.001), CRP (r Z 0.232, P Z 0.017) and waist circumference (r Z 0.350, P < 0.001). In a multivariate linear regression analysis including all these variables only waist circumference was found to be an independent correlate of EAT (P Z 0.011, 95% CI [0.015e0.111]). We also compared EAT thicknesses in patients with and without MS. EAT thickness was significantly higher in patients with MS than it was in patients without MS (6.6 1.5 mmvs. 5.2 1.6 mm; P < 0.001). EAT thickness was highest in patients having both MS and CAD (Fig. 5).
Figure 3 An increasing trend in Gensini’s score was seen according to quartiles of epicardial adipose tissue thickness (*P < 0.01).
Figure 4 Receiver operating characteristic curve of the epicardial adipose tissue thickness in predicting angiographic coronary artery disease.
Epicardial adipose tissue and coronary artery disease
215
Table 2
Clinical and laboratory characteristics according to epicardial adipose tissue (EAT)
Variable
EAT thickness <5.2 mm (n Z 52)
EAT thickness 5.2 mm (n Z 98)
P value
Age (y) Men (%) BMI (kg/m2) Waist circumference (cm) Body fat ratio (%) Smoker (%) Hypertension (%) Diabetes mellitus (%) Coronary artery disease (%) Metabolic syndrome (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) CRP (mg/L) Creatinine (mg/dL)
54.5 7.3 18 28.8 4.5 91.2 10.9 33.8 7.4 24 30 10 15 22 206.5 35.5 115.2 31 48.6 11.1 138.2 77.9 3.4 2.7 0.84 0.20
55.8 7.3 82 28.5 4.7 96.8 11.3 32.1 6.3 76 70 90 85 78 187.5 37.2 127.3 32.8 42.1 12.6 181.1 83.7 5.1 4.5 0.99 0.24
0.381 <0.001 0.753 0.010 0.442 0.016 0.025 0.001 <0.001 0.001 0.027 0.054 0.011 0.021 0.028 0.001
BMI, body mass index; CRP, C-reactive protein; EAT, epicardial adipose tissue; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Epicardial adipose tissue according to gender and medications Although EAT thickness was higher in men than in women (6.5 1.6 mmvs. 5.5 1.8 mm; P < 0.001) in the pooled data, it was increased in patients with CAD compared to patients with normal coronary arteries in both genders (0 1.3 mmvs. 4.8 1.0 mm; P < 0.001, and 6.6 1.7 mmvs. 4.1 0.6 mm; P < 0.001, respectively). EAT was thicker in patients who were using calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, acetylsalicylic acid, nitrates and diuretics (P < 0.05). It was not different between patients who were using, or not using, b-blockers and statins (P not significant).
as an independent predictor of CAD among other wellknown risk factors. Two potential mechanisms for this association have been proposed: First, EAT is a component of visceral adiposity and is related to MS and cardiovascular risk factors [1e4]; secondly, EAT has paracrine and endocrine functions. It can secrete numerous bioactive molecules (adipokines) such as adiponectin, resistin and inflammatory cytokines (interleukin (IL)-1b, IL-6, tumor necrosis factor a) [5,6,14]. Sacks et al. pointed out the paracrine and vasocrine signaling effects of epicardial adipokines for the development of atherogenesis [15]. We believe that EAT thickness is part of active adipose tissue that mediates coronary circulation via secretion of inflammatory mediators and adipokines. It may thus be hypertrophied in the presence of atherosclerotic plaque. In addition, it may be related to cardiovascular risk factors and MS.
Discussion This study shows an association between EAT thickness and the presence and severity of CAD. EAT thickness emerged
Table 3 Multiple logistic regression analysis of coronary artery disease Risk factors Age (male 45, female 55 years) Hypertension Diabetes mellitus Dyslipidemia Smoking Family history of premature CAD EAT thickness 5.2 mm
Odds ratio (95% CI) 1.88 (0.77e4.584) 1.703 5.412 2.750 0.852 1.445
(0.857e3.385) (1.793e16.335) (1.322e5.710) (0.432e1.681) (0.726e2.879)
4.566 (2.688e7.756)
P value 0.161 0.129 0.003 0.007 0.644 0.295 0.000
CAD, coronary artery disease; EAT, epicardial adipose tissue.
Figure 5 Comparison of epicardial adipose tissue thickness according to the presence of the metabolic syndrome (MS) and coronary artery disease (CAD) (*P < 0.01; yP Z 0.039).
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Epicardial adipose tissue thickness by echocardiography and coronary artery disease
Differences of epicardial adipose tissue thickness according to race and sex
EAT thickness measurement by echocardiography was first validated by Iacobellis and associates [7]. These authors showed a significant correlation between magnetic resonance imaging and echocardiographic measurements of epicardial fat [7]. EAT thickness was also found to be related to the anthropometric and clinical parameters of MS [4]. The correlation between EAT thickness and the severity of CAD has been addressed previously [8,9]. However, the results of these studies are conflicting, as they did not assess patients with normal coronary arteries. Ahn et al. showed that EAT was thicker in subjects with CAD than those without CAD and that it might provide additional information for assessing CAD risk and predicting the extent and activity of CAD [10]. Our study is compatible with this. We found that EAT thickness was increased even in patients with minimal CAD compared with those with normal coronary arteries. Also, the thickness of EAT increased in parallel with the severity of CAD. In another study de Vos et al. showed, by cardiac computed tomography scan, that EAT is strongly associated with coronary calcification in healthy postmenopausal women [16]. Our study shows that EAT thickness is associated with the early stages of CAD and that it increases with the severity of CAD.
EAT thickness may be different according to race. In our pooled data mean EAT thickness was 6.1 mm which is consistent with some other studies. In a Japanese study [9] the mean EAT thickness was 6.3 mm; in a USA study [17] median values of EAT thickness were 9.5 mm in men and 7.5 mm in women, but in an another study from the USA [8] mean EAT thickness was 2.2 mm, as in a Korean study [10] with a mean EAT thickness of 3.2 mm. In addition we found that EAT was thicker in men than in women in the pooled data, and in controls. EAT thickness was significantly different between controls and patients with CAD in both genders. Iacobellis et al. [17] described similar differences between genders but Ahn et al. [10] did not find any difference of EAT thickness between men and women. Although EAT is less thick in women than in men, its thickness is still significantly increased in women with CAD as compared to those without CAD.
Epicardial adipose tissue and the metabolic syndrome Previous studies showed an association between EAT and MS [4,17]. Iacobellis et al. [17] found that EAT thickness was increased in subjects with MS. They stated that median values of EAT, 9.5 mm and 7.5 mm, should be considered the threshold values for high risk echocardiographic fat thickness in white men and women respectively. Our results support the findings that EAT is related to MS, but CAD has a stronger relationship with EAT thickness than MS. On the other hand, if CAD and MS coexist then EAT thickness is increased.
Relationship between EAT and clinical and biochemical features In our study, EAT thickness was correlated with age, waist circumference and levels of fasting glucose, triglycerides and CRP, and inversely correlated with HDL cholesterol. These findings are compatible with the findings of previous studies [4,8e10]. In our study, waist circumference was the only independent correlate of EAT thickness, supporting the view that EAT is a component of visceral adiposity and, probably, of the metabolic syndrome. EAT thickness was found to be an independent predictor of CAD in the multivariate regression model, including well-known risk factors such as age, hypertension, diabetes mellitus, smoking, dyslipidemia and a family history of premature CAD. These findings are compatible with those of Ahn et al. [10]. Therefore EAT is associated with both coronary risk factors and components of MS.
Limitations Evaluation of the effects of cardiovascular medications on EAT thickness was not within the scope of this study. Although EAT thickness was increased in patients who were on calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers, acetylsalicylic acid, nitrates and diuretics, this association was likely to be due to the severity of CAD in patients with increased EAT thickness. We did not evaluate insulin resistance in the study groups because our study population consisted of patients who underwent coronary angiography for classical indications and did not include patients with glucose metabolism abnormalities. EAT thickness evaluation could potentially be ameliorated by using 3D echocardiography.
Conclusion EAT thickness is related to the presence, severity and extent of CAD. EAT thickness therefore could serve as an easily measurable non-invasive adjunctive marker to classical risk factors for the prediction of CAD. Further studies are warranted to support our findings.
Acknowledgements The authors wish to thank Mrs. Vahide Simsek in the echocardiography laboratory for her devoted co-operation and the nutritionists for their measurements of total fat ratios.
References [1] Peiris AN, Sothmann MS, Hoffmann RG, Hennes MI, Wilson CR, Gustafson AB, et al. Adiposity, fat distribution, and cardiovascular risk. Ann Intern Med 1989;110:867e72. [2] Folsom AR, Kushi LH, Anderson KE, Mink PJ, Olson JE, Hong CP, et al. Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women’s Health Study. Arch Intern Med 2000;160:2117e28.
Epicardial adipose tissue and coronary artery disease [3] Rexrode KM, Buring JE, Manson JE. Abdominal and total adiposity and risk of coronary heart disease in men. Int J Obes Relat Metab Disord 2001;25:1047e56. [4] Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, 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;88:5163e8. [5] 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. [6] Baker AR, Silva NF, Quinn DW, Harte AL, Pagano D, Bonser RS, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006;5:1. [7] Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, et al. Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res 2003;11:304e10. [8] Chaowalit N, Somers VK, Pellikka PA, Rihal CS, LopezJimenez F. Subepicardial adipose tissue and the presence and severity of coronary artery disease. Atherosclerosis 2006;186:354e9. [9] Jeong JW, Jeong MH, Yun KH, Oh SK, Park EM, Kim YK, et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ J 2007;71:536e9.
217 [10] Ahn SG, Lim HS, Joe DY, Kang SJ, Choi BJ, Choi SY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 2008;94:1e6. [11] Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143e421. [12] Otto CM. Left and right ventricular systolic function. In: Otto CM, editor. Textbook of clinical echocardiography. 3rd ed. Philadelphia: Elsevier Saunders; 2004. p. 131e65. [13] Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606. [14] Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460e6. [15] Sacks HS, Fain JN. Human epicardial adipose tissue: a review. Am Heart J 2007;153:907e17. [16] de Vos AM, Prokop M, Roos CJ, Meijs MF, van der Schouw YT, Rutten A, et al. Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post-menopausal women. Eur Heart J 2008;29(6): 777e83. [17] Iacobellis G, Willens HJ, Barbaro G, Sharma AM. Threshold values of high-risk echocardiographic epicardial fat thickness. Obesity (Silver Spring) 2008 [Epub ahead of print].
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease S. Eroglu*, L.E. Sade, A. Yildirir, U. Bal, S. Ozbicer, A.S. Ozgul, H. Bozbas, A. Aydinalp, H. Muderrisoglu Department of Cardiology, Baskent University Faculty of Medicine, 10.sok No:45, 06490 Bahcelievler, Ankara, Turkey Received 2 February 2008; received in revised form 27 March 2008; accepted 15 May 2008
KEYWORDS Epicardial adipose tissue; Echocardiography; Coronary artery disease
Abstract Background and aim: Epicardial adipose tissue (EAT), which is thought to be a component of visceral adiposity, is associated with the metabolic syndrome. We aimed to test the hypothesis that echocardiographic EAT thickness can be a marker for the presence and severity of coronary artery disease (CAD). Method and results: In all, 150 patients (100 patients with CAD and 50 patients with normal coronary arteries by diagnostic coronary angiography; 65 women, 85 men; mean age 55.7 7.4 years) were enrolled. EAT thickness was measured using 2-D echocardiographic parasternal long- and short-axis views. EAT thickness measurements were compared with angiographic findings. EAT thickness was significantly higher in patients with CAD in comparison to those with normal coronary arteries (6.9 1.5 mm vs. 4.4 0.8 mm; P < 0.001). Furthermore, EAT thickness increased with the severity of CAD (multivessel disease 7.4 1.2 mm vs. single vessel disease 5.7 1.7 mm; P < 0.001). Gensini’s score significantly correlated with EAT thickness (r Z 0.600, P < 0.001). EAT thickness of 5.2 mm had 85% sensitivity and 81% specificity (ROC area 0.914, P < 0.001, 95% CI [0.86e0.96]) for predicting CAD. Conclusion: EAT thickness, which is easily and non-invasively evaluated by transthoracic echocardiography, can be an adjunctive marker to classical risk factors for the prediction of CAD. ª 2008 Elsevier B.V. All rights reserved.
Introduction
* Corresponding author. Tel.: þ90 312 212 6868; fax: þ90 312 223 8697. E-mail address: [email protected] (S. Eroglu).
Visceral adiposity is fat deposition around internal organs. It is metabolically active and is an important risk factor for developing the metabolic syndrome (MS) [1e4]. Epicardial adipose tissue (EAT) is a component of visceral adiposity and mediates cardiac function and atherosclerosis via
0939-4753/$ - see front matter ª 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2008.05.002
212
S. Eroglu et al.
expression of several bioactive molecules [5,6]. Transthoracic echocardiography enables non-invasive assessment of EAT [4,7]. Several studies have addressed the association between EAT thickness and the severity of coronary artery disease (CAD) with conflicting results [8e10]. Thus, we aimed to test the hypothesis that echocardiographic EAT thickness could be a marker for the presence and severity of CAD.
plasma triglycerides: 150 mg/dL; (iii) plasma HDL cholesterol: <40 mg/dL in men and <50 mg/dL in women; (iv) systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg or the use of antihypertensive medicine; (v) plasma glucose 110 mg/dL or the use of antidiabetic medicine/insulin.
Methods
Echocardiographic examinations were performed using an Acuson Sequoia C-256 cardiac ultrasound machine (Acuson Corporation, CA, USA) with patients in the left lateral decubitus position. Echocardiograms were recorded on videotapes. EAT appears as an echo-lucent space between the linear echo-dense parietal pericardium and the right ventricular epicardium. Thus EAT thickness was measured as the vertical distance of this echo-lucent space as illustrated in Fig. 1 [7e10]. The second echo-lucent space above the parietal pericardium which is the mediastinal fat, was not included in the measurement of the EAT. EAT thickness was measured at end-diastole from parasternal long- and short-axis B mode still-frame images by two echocardiographers who were blinded to coronary angiography data. Parasternal long- and short-axis measurements were averaged to obtain the mean thickness. Left ventricular ejection fraction was measured using the modified Simpson method [12].
Patients who underwent coronary angiography due to chest pain and/or an abnormal stress test were enrolled. One hundred patients with CAD and 50 patients with normal coronary arteries were consecutively studied. The study complies with the declaration of Helsinki. All participants gave informed consent, and the Institutional Review Board of the University of Baskent approved the research protocol. Patients were excluded if they had abnormal images on transthoracic echocardiography, a history of coronary artery bypass graft surgery, chronic kidney disease, severe valvular disease, uncontrolled diabetes or hypertension. The day after coronary angiography, all patients underwent transthoracic echocardiography. Systolic and diastolic blood pressures were measured after 5 min of rest. Height, waist circumference, weight and body fat ratio (Tanita TBF 534, Japan) were measured during a fasting period. Body mass index was calculated as body weight divided by height squared. Blood samples were obtained during fasting, and levels of plasma glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and C-reactive protein (CRP) were measured. The metabolic syndrome was diagnosed according to NCEPATP III [11]. Thus, a participant had MS if he or she had three or more of the following: (i) abdominal obesity: waist circumference >102 cm in men and >88 cm in women; (ii)
Figure 1 tissue.
Transthoracic echocardiography
Coronary angiography data CAD was defined as stenosis 20% in any coronary artery. Stenosis between 20% and 50% was defined as minimal CAD; stenosis more than 50% was defined as significant CAD, otherwise as normal coronary arteries. Patients with slow flow in the absence of any discernible lesions were also excluded. Coronary angiograms were interpreted by two independent invasive cardiologists. Gensini’s score [13] was calculated for each patient.
Parasternal long- (A) and short-axis (B) transthoracic 2-dimensonal echocardiographic images of epicardial adipose
Epicardial adipose tissue and coronary artery disease
Statistical analyses Continuous variables are expressed as means SD. The t-test and ANOVA were used to assess differences among the groups. Categorical variables were compared with the chi-square test. The Pearson correlation analysis was used to determine the relationship between mean values. For the prediction of independent variables that are associated with CAD a multiple linear regression model including potential confounders was performed. The cut-off value of EAT thickness for predicting CAD with corresponding specificity and sensitivity was estimated by receiver operating characteristic (ROC) curve analysis. Well-known CAD risk factors were included in a logistic regression model of CAD. To assess the reproducibility of the echocardiographic measurements, EAT thickness was measured by two independent echocardiographers in 20 randomly
Table 1
213 selected patients and inter-observer correlation coefficients were calculated. In the same group of patients echocardiographic measurements were repeated 2 days later to calculate intra-observer correlation coefficients. Variabilities of measurements were also calculated as the mean of differences in measurements. A P value of less than 0.05 was considered statistically significant. SPSS software (Statistical Package for the Social Sciences, version 10.0, SSPS Inc., Chicago, IL, USA) was used for all statistical calculations.
Results There were 65 women and 85 men in the study population. The mean age was 55.7 7.4 years. The demographic and laboratory characteristics of the study groups are presented in Table 1.
Demographic, laboratory and echocardiographic characteristics of subjects by study groups
Variable
Normal coronary arteries (n Z 50)
Coronary artery Disease (n Z 100)
54.1 7.4 25/25 29.3 4.7 94.2 11.7 34.3 7.4 35
56.4 7.3 40/60 28.8 4.5 96.0 11.4 32.3 7.5 64
0.068 0.161 0.529 0.383 0.313 0.368
133.4 19.8 80.5 9.8
137.4 22.4 81.3 10.4
0.296 0.636
Laboratory findings Fasting plasma glucose (mg/dL) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) Hemoglobin (g/dl) CRP (mg/L)
97.2 12.2 203.7 37.2 122.6 33.9 48.0 13.4 156.0 99.2 14.4 1.6 3.5 2.7
103.2 18.7 189 38.5 117.6 30.9 43.6 11.5 171.9 93.2 14.5 1.4 5.0 4.3
0.073 0.068 0.386 0.063 0.359 0.699 0.068
Echocardiographic findings Ejection fraction (%) Left ventricle mass (g) EAT thickness PSLX (mm) EAT thickness PSSX (mm) Average EAT thickness (mm)
55.2 4.1 103.9 31.9 4.4 0.9 4.4 0.9 4.4 0.8
47.9 7.4 114.1 32.1 7.0 1.5 6.8 1.5 6.9 1.5
0.001 0.071 <0.001 <0.001 <0.001
Drugs Beta blockers (%) Calcium channel blockers (%) ACE inhibitors (%) AT II receptor blockers (%) Nitrates (%) Acetyl salicylic acid (%) Diuretics (%) Statins (%)
28 8 14 6 2 32 18 14
50 19 30 22 23 70 34 38
0.014 0.065 0.044 0.018 <0.001 <0.001 0.055 0.004
Demographic characteristics Age (years) Sex (female/male) BMI (kg/m2) Waist circumference (cm) Body fat ratio (%) Smoker (%) Blood pressure Systolic (mmHg) Diastolic (mmHg)
P value
ACE, angiotensin converting enzyme; AT, angiotensin; BMI, body mass index; CAD, coronary artery disease; CRP, C-reactive protein; EAT, epicardial adipose tissue thickness; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PSLX, parasternal long axis; PSSX, parasternal short axis.
214
Figure 2 Association between epicardial adipose tissue thickness and severity of coronary artery disease (CAD) (*P Z 0.005, minimal CADvs. normal; yP < 0.001, significant CADvs. minimal CAD; zP < 0.001, significant CADvs. normal).
Epicardial adipose tissue thickness and presence and severity of coronary artery disease
S. Eroglu et al. EAT was also thicker in patients with multivessel disease compared to those with single-vessel disease (7.1 1.4 mmvs. 5.7 1.7 mm). Gensini’s score was significantly correlated with EAT thickness (r Z 0.600, P < 0.001). ANOVA test showed the significant difference of Gensini’s score between the groups of EAT thickness quartile (Fig. 3). EAT thickness of 5.2 mm had an 85% sensitivity and an 81% specificity (ROC area 0.914, P < 0.001, 95% CI [0.86e 0.96]) for predicting CAD (Fig. 4). When patients were dichotomized according to the cut-off value of EAT thickness; male gender, diabetes mellitus, hypertension, smoking, MS, CAD incidences, CRP, triglycerides and creatinine levels, and waist circumference were increased and HDLcholesterol was decreased in patients with EAT thickness 5.2 mm in comparison to patients with EAT thickness <5.2 mm (Table 2). Diabetes mellitus, dyslipidemia and EAT thickness were found to be independent predictors of CAD in a multivariate regression model including well-known risk factors (Table 3).
Relationship of epicardial adipose tissue to clinical and biochemical features
Inter-observer and intra-observer correlation coefficients of EAT thickness measurements were found to be 0.96 and 0.94 respectively. Intra- and inter-observer variability of EAT thickness measurements yielded differences in repeat measurements that were very low (0.5 0.3 mm and 0.6 0.4 mm, respectively). The mean EAT thickness was 6.1 1.7 mm in the pooled data. EAT thickness was significantly increased in patients with CAD compared to patients with normal coronary arteries (6.9 1.5 mmvs. 4.4 0.8 mm; P < 0.001). Furthermore, EAT thickness increased significantly with the severity and extent of CAD. In patients with CAD, 20 had minimal CAD and 80 had significant CAD. The thickness of EAT was significantly increased in those with significant CAD in comparison to those with minimal CAD (7.3 1.2 mmvs. 5.4 1.5 mm; P < 0.001) (Fig. 2).
We further assessed the association between EAT and variables related to metabolic status. EAT thickness correlated with age (r Z 0.228, P Z 0.005), fasting glucose (r Z 0.186, P Z 0.044), HDL- cholesterol (r Z 0.203, P Z 0.045), triglycerides (r Z 0.232, P Z 0.001), CRP (r Z 0.232, P Z 0.017) and waist circumference (r Z 0.350, P < 0.001). In a multivariate linear regression analysis including all these variables only waist circumference was found to be an independent correlate of EAT (P Z 0.011, 95% CI [0.015e0.111]). We also compared EAT thicknesses in patients with and without MS. EAT thickness was significantly higher in patients with MS than it was in patients without MS (6.6 1.5 mmvs. 5.2 1.6 mm; P < 0.001). EAT thickness was highest in patients having both MS and CAD (Fig. 5).
Figure 3 An increasing trend in Gensini’s score was seen according to quartiles of epicardial adipose tissue thickness (*P < 0.01).
Figure 4 Receiver operating characteristic curve of the epicardial adipose tissue thickness in predicting angiographic coronary artery disease.
Epicardial adipose tissue and coronary artery disease
215
Table 2
Clinical and laboratory characteristics according to epicardial adipose tissue (EAT)
Variable
EAT thickness <5.2 mm (n Z 52)
EAT thickness 5.2 mm (n Z 98)
P value
Age (y) Men (%) BMI (kg/m2) Waist circumference (cm) Body fat ratio (%) Smoker (%) Hypertension (%) Diabetes mellitus (%) Coronary artery disease (%) Metabolic syndrome (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) CRP (mg/L) Creatinine (mg/dL)
54.5 7.3 18 28.8 4.5 91.2 10.9 33.8 7.4 24 30 10 15 22 206.5 35.5 115.2 31 48.6 11.1 138.2 77.9 3.4 2.7 0.84 0.20
55.8 7.3 82 28.5 4.7 96.8 11.3 32.1 6.3 76 70 90 85 78 187.5 37.2 127.3 32.8 42.1 12.6 181.1 83.7 5.1 4.5 0.99 0.24
0.381 <0.001 0.753 0.010 0.442 0.016 0.025 0.001 <0.001 0.001 0.027 0.054 0.011 0.021 0.028 0.001
BMI, body mass index; CRP, C-reactive protein; EAT, epicardial adipose tissue; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Epicardial adipose tissue according to gender and medications Although EAT thickness was higher in men than in women (6.5 1.6 mmvs. 5.5 1.8 mm; P < 0.001) in the pooled data, it was increased in patients with CAD compared to patients with normal coronary arteries in both genders (0 1.3 mmvs. 4.8 1.0 mm; P < 0.001, and 6.6 1.7 mmvs. 4.1 0.6 mm; P < 0.001, respectively). EAT was thicker in patients who were using calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, acetylsalicylic acid, nitrates and diuretics (P < 0.05). It was not different between patients who were using, or not using, b-blockers and statins (P not significant).
as an independent predictor of CAD among other wellknown risk factors. Two potential mechanisms for this association have been proposed: First, EAT is a component of visceral adiposity and is related to MS and cardiovascular risk factors [1e4]; secondly, EAT has paracrine and endocrine functions. It can secrete numerous bioactive molecules (adipokines) such as adiponectin, resistin and inflammatory cytokines (interleukin (IL)-1b, IL-6, tumor necrosis factor a) [5,6,14]. Sacks et al. pointed out the paracrine and vasocrine signaling effects of epicardial adipokines for the development of atherogenesis [15]. We believe that EAT thickness is part of active adipose tissue that mediates coronary circulation via secretion of inflammatory mediators and adipokines. It may thus be hypertrophied in the presence of atherosclerotic plaque. In addition, it may be related to cardiovascular risk factors and MS.
Discussion This study shows an association between EAT thickness and the presence and severity of CAD. EAT thickness emerged
Table 3 Multiple logistic regression analysis of coronary artery disease Risk factors Age (male 45, female 55 years) Hypertension Diabetes mellitus Dyslipidemia Smoking Family history of premature CAD EAT thickness 5.2 mm
Odds ratio (95% CI) 1.88 (0.77e4.584) 1.703 5.412 2.750 0.852 1.445
(0.857e3.385) (1.793e16.335) (1.322e5.710) (0.432e1.681) (0.726e2.879)
4.566 (2.688e7.756)
P value 0.161 0.129 0.003 0.007 0.644 0.295 0.000
CAD, coronary artery disease; EAT, epicardial adipose tissue.
Figure 5 Comparison of epicardial adipose tissue thickness according to the presence of the metabolic syndrome (MS) and coronary artery disease (CAD) (*P < 0.01; yP Z 0.039).
216
S. Eroglu et al.
Epicardial adipose tissue thickness by echocardiography and coronary artery disease
Differences of epicardial adipose tissue thickness according to race and sex
EAT thickness measurement by echocardiography was first validated by Iacobellis and associates [7]. These authors showed a significant correlation between magnetic resonance imaging and echocardiographic measurements of epicardial fat [7]. EAT thickness was also found to be related to the anthropometric and clinical parameters of MS [4]. The correlation between EAT thickness and the severity of CAD has been addressed previously [8,9]. However, the results of these studies are conflicting, as they did not assess patients with normal coronary arteries. Ahn et al. showed that EAT was thicker in subjects with CAD than those without CAD and that it might provide additional information for assessing CAD risk and predicting the extent and activity of CAD [10]. Our study is compatible with this. We found that EAT thickness was increased even in patients with minimal CAD compared with those with normal coronary arteries. Also, the thickness of EAT increased in parallel with the severity of CAD. In another study de Vos et al. showed, by cardiac computed tomography scan, that EAT is strongly associated with coronary calcification in healthy postmenopausal women [16]. Our study shows that EAT thickness is associated with the early stages of CAD and that it increases with the severity of CAD.
EAT thickness may be different according to race. In our pooled data mean EAT thickness was 6.1 mm which is consistent with some other studies. In a Japanese study [9] the mean EAT thickness was 6.3 mm; in a USA study [17] median values of EAT thickness were 9.5 mm in men and 7.5 mm in women, but in an another study from the USA [8] mean EAT thickness was 2.2 mm, as in a Korean study [10] with a mean EAT thickness of 3.2 mm. In addition we found that EAT was thicker in men than in women in the pooled data, and in controls. EAT thickness was significantly different between controls and patients with CAD in both genders. Iacobellis et al. [17] described similar differences between genders but Ahn et al. [10] did not find any difference of EAT thickness between men and women. Although EAT is less thick in women than in men, its thickness is still significantly increased in women with CAD as compared to those without CAD.
Epicardial adipose tissue and the metabolic syndrome Previous studies showed an association between EAT and MS [4,17]. Iacobellis et al. [17] found that EAT thickness was increased in subjects with MS. They stated that median values of EAT, 9.5 mm and 7.5 mm, should be considered the threshold values for high risk echocardiographic fat thickness in white men and women respectively. Our results support the findings that EAT is related to MS, but CAD has a stronger relationship with EAT thickness than MS. On the other hand, if CAD and MS coexist then EAT thickness is increased.
Relationship between EAT and clinical and biochemical features In our study, EAT thickness was correlated with age, waist circumference and levels of fasting glucose, triglycerides and CRP, and inversely correlated with HDL cholesterol. These findings are compatible with the findings of previous studies [4,8e10]. In our study, waist circumference was the only independent correlate of EAT thickness, supporting the view that EAT is a component of visceral adiposity and, probably, of the metabolic syndrome. EAT thickness was found to be an independent predictor of CAD in the multivariate regression model, including well-known risk factors such as age, hypertension, diabetes mellitus, smoking, dyslipidemia and a family history of premature CAD. These findings are compatible with those of Ahn et al. [10]. Therefore EAT is associated with both coronary risk factors and components of MS.
Limitations Evaluation of the effects of cardiovascular medications on EAT thickness was not within the scope of this study. Although EAT thickness was increased in patients who were on calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers, acetylsalicylic acid, nitrates and diuretics, this association was likely to be due to the severity of CAD in patients with increased EAT thickness. We did not evaluate insulin resistance in the study groups because our study population consisted of patients who underwent coronary angiography for classical indications and did not include patients with glucose metabolism abnormalities. EAT thickness evaluation could potentially be ameliorated by using 3D echocardiography.
Conclusion EAT thickness is related to the presence, severity and extent of CAD. EAT thickness therefore could serve as an easily measurable non-invasive adjunctive marker to classical risk factors for the prediction of CAD. Further studies are warranted to support our findings.
Acknowledgements The authors wish to thank Mrs. Vahide Simsek in the echocardiography laboratory for her devoted co-operation and the nutritionists for their measurements of total fat ratios.
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