Atherosclerosis 237 (2014) 486e489

Contents lists available at ScienceDirect

Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Increased epicardial adipose tissue is associated with coronary artery disease and major adverse cardiovascular events Fereshteh Hajsadeghi*, Vahid Nabavi, Ajay Bhandari, Andrew Choi, Hunter Vincent, Ferdinand Flores, Matthew Budoff, Naser Ahmadi David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 December 2013 Received in revised form 17 August 2014 Accepted 22 September 2014 Available online 17 October 2014

Background: Increased-epicardial-adipose tissue (EAT) is associated with the presence and severity of subclinical-atherosclerosis. This study investigates the long-term clinical-outcome of subjects with and without increased-EAT. Methods: Two hundred and forty-five subjects, aged 61 ± 9 years and 34% women underwent clinically-indicated computed-tomography-angiography (CTA), and body-surfacearea adjusted EAT was measured and were followed prospectively. CTA-diagnosed coronary-arterydisease (CAD) was defined as obstructive (luminal-stenosis
50%), non-obstructive (luminal-stenosis: 1 e49%) and zero-obstruction. Major-adverse-cardiac-event (MACE) was defined as myocardial-infarction or cardiovascular-death. Results: EAT increased significantly from subjects with zero-obstructioncoronaries (93 ± 37 cm3/m2) to non-obstructive-CAD (132 ± 25 cm3/m2) to obstructive-CAD (145 ± 35 cm3/m2) (P ¼ 0.01). During the 48-month follow-up, the event-rate was 8.6% (21). The event free survival-rate decreased significantly from 99% in the lowest-quartile to 86.6% in the highestquartile of EAT. After adjustment for risk-factors, the hazard ratio of MACE was 1.4, 3.1 and 5.7 in lower mid-, upper mid- and highest-quartiles of EAT as compared to lowest-quartile of EAT (P < 0.05). Conclusion: Increased EAT is directly associated with CAD and predicts MACE independent of the age, gender and conventional-risk-factors. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Epicardial adipose tissue (EAT) Computed tomography angiography (CTA) Major adverse cardiac event (MACE) Coronary artery disease (CAD)

1. Introduction Increased regional fat distribution plays an important part in the development of an unfavorable metabolic and cardiovascular risk profile [1]. Epicardial adipose tissue (EAT) is associated with multiple markers of inflammation, vascular dysfunction and oxidative stress, atherosclerosis, the presence and extent of subclinical and clinical coronary atherosclerosis [2e4]. Furthermore EAT is associated with fatal and nonfatal coronary events in the general population independent of traditional cardiovascular risk factors [5,6]. This study investigates the long term clinical outcome of increased EAT measured by cardiac computed tomography (CT) in subjects without any prior documentation of coronary artery diseases (CAD), also compares the prognostic value of increased EAT and severity of CAD measured by CT over traditional risk factors

measured as Framingham risk score (FRS) in predicting major adverse cardiovascular events (MACE). 2. Methods Two hundred and forty five consecutive subjects with suspected CAD, aged 61 ± 9 years and 34% women, who underwent clinically indicated computed tomography angiography (CTA) in 2008e2009, were studied. After obtaining informed consent, the presence and severity of CAD as well as body surface area adjusted EAT was measured, and subjects were followed prospectively for median of 48-months. Subjects with irregular heart rates, allergies to contrast media, any prior documentation of CAD, liver disease, stroke, systemic inflammation, or impaired renal function were excluded. The study protocol and consent form were approved by the Institutional Review Board Committee at our institution. 2.1. Cardiac CTA

* Corresponding author. Greater Los Angeles VA Healthcare System, David Geffen School of Medicine at UCLA, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA. E-mail address: [email protected] (F. Hajsadeghi). http://dx.doi.org/10.1016/j.atherosclerosis.2014.09.037 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.

Beta blockers were administered for pulses greater than 65 bpm. A test IV bolus of 15 ml of contrast agent was followed by 20 ml of

F. Hajsadeghi et al. / Atherosclerosis 237 (2014) 486e489

normal saline flush at a rate of 4.5 ml/s. Using a dual-head power injector (Stellant, Medrad, Indianola, PA), a prospective ECG gated cardiac CT angiography was performed with a tri-phasic consecutive injection sequence beginning with 50 ml nonionic IV contrast material (Iopamidol 370; Bracco Diagnostics, Plainsboro, NJ) injected at a rate of 5.0 ml followed by 50 ml of a mixture of 60% contrast and normal saline and ended with a 50-ml flush of normal saline. Contrast was injected through an 18- to 20-gauge angiocatheter in an antecubital vein. Mean heart rate during the scan was 56 ± 3 bpm. 2.2. Data acquisition A snapshot pulse acquisitions axial ECG-Triggering mode with prospective gating using the 64- Multi-detector Computed Tomography (MDCT) Lightspeed VCT scanner (General Electric Healthcare Technologies, Milwaukee, WI) was used for all patients. Imaging was started 1 inch above the left main ostium and continued to 1 inch below the bottom of the heart. The following imaging and reconstruction parameters were applied: data acquisition collimation 0.625 mm  64 ¼ 4 cm; 120 kVp; 220e670 mAs; pitch 0.18e0.24 (depending on heart rate); rotation time 0.35 s; slice width 0.625 mm; matrix 512  512 and pixel size 0.39 mm2. ECG-triggered dose modulation with padding was applied in each case with 400e600 mA in 70e80% ReR interval. 2.3. CTA measurement EAT, adipose tissue inside the pericardial sac, was measured in axial images starting 15 mm above the superior extent of the left main coronary artery to the bottom of the heart. Volume Analysis software (GE Healthcare, Waukesha, WI) was used to discern EAT on the basis of a corresponding HU threshold of 190 to 30 HU (mean, 120 HU) [7]. EAT was measured by a semiautomatic segmentation technique in each slice with the above display settings. CTA diagnosed coronary artery disease (CAD) was defined as obstructive (luminal stenosis
50%), non-obstructive (luminal stenosis 1e49%) and zero-obstruction. Disease coronaries were defined as luminal stenosis
1. Two experienced computed tomography readers, blinded to each other, patient characteristics, treatment status, and outcome measured EAT as well as presence and severity of CAD. Mutual consensus was reached in cases of disagreement (n ¼ 3). Epidemiologic methods for follow-up included all those that ascertained of major adverse cardiac event (MACE) and outcome were blinded to CT status. The primary end point was the occurrence of myocardial infarction or cardiovascular death, which was verified by telephone interview follow-ups and primary physician verifications (i.e., 100% follow-up). As part of consent, all subjects were agreed to provide the contact information of their primary physician, themselves and minimum of 2 other authorized relatives/friends. All subjects had a primary physician. In case of lack of answer to phone calls or last physician visit>6-month at the time of ascertainment (n ¼ 15), the end points were verified by contacting authorized relatives/friends. 2.4. Statistical analysis Analyses were performed with SPSS version 21 (IBM SPSS, Inc., Chicago, Illinois). All continuous data are presented as mean ± SD, and all categorical data are reported as percentages or absolute numbers. KruskaleWallis tests and analysis-ofvariance tests were used to assess differences between groups. KaplaneMeier survival curves were constructed for quartiles of

487

CT measured EAT and compared using the log-rank test. Multivariate Cox regression analyses were employed to assess the relation of increased EAT with MACE. The hazard ratio of MACE was calculated with: a) each quartile increase in EAT as compared to lowest EAT quartile, and b) each standard deviation increase in EAT (40 cm3/m2) before and after adjustment for age, gender, smoking status, diabetes mellitus, hypertension, hypercholesterolemia, family history of premature CAD, presence and severity of CTA diagnosed CAD. Receiver operating characteristic (ROC) curves were constructed, and the area under the ROC curve (AUC) was calculated to predict the ability of each model (FRS, EAT (continues data), CTA diagnosed CAD and combination) to predict MACE. The likelihood ratio statistic tests the significance of the addition of each variable to predict MACE; assessing independent prognostic value of models. 3. Results Table 1ashows that there is no significant differences in age, gender, prevalence of hypertension, hyperlipidemia, diabetes mellitus, family history of premature CAD and smoking across quartiles of EAT (P > 0.05). The prevalence of diseased coronaries, but not obstructive CAD, increased with each quartile increase of EAT (P < 0.05). EAT increased significantly from subjects with zeroobstruction coronaries (93 ± 37 cm3/m2) to non-obstructive CAD (132 ± 25 cm3/m2) to obstructive CAD (145 ± 35 cm3/m2) (P ¼ 0.01) that was more robust in subjects with MACE as compared to those without MACE (Fig. 1a). During the median of 48 month follow-ups, the event rate was 8.6% (21). The event free survival rate decreased significantly from 99% in the lowest quartile of EAT to 86.6% in the highest quartile of EAT (p ¼ 0.001). Table 1breveals that after adjustment for risk factors, the hazard ratio of MACE was 1.4(95%CI 1.2e4.2), 3.1(95%CI 1.4e6.9) and 5.7(95%CI 1.6e9.8) in lower mid, upper mid and highest quartiles of EAT as compared to lowest quartile of EAT (P < 0.05). Similarly, the hazard ratio of MACE increased 2.23 (95%CI 1.5e3.3) folds with each standard deviation increase in EAT (p < 0.05). The area under ROC curve to predict MACE was 0.60 (95%CI 0.52e0.68), 0.73 (95%CI 0.58e0.86, p ¼ 0.0001) for each 10 cm3/m2 increase in EAT, 0.72 (95%CI 0.61e0.74, p ¼ 0.0001) for presence and severity of CTA diagnosed CAD, and 0.87 (95%CI 0.81e0.89, p ¼ 0.0001) for the combination of increased EAT and CTA diagnosed CAD. The likelihood ratio test revealed EAT predicts MACE

Table 1a Clinical characteristics of studied subjects across quartiles of epicardial adipose tissue. Model

Lowest Q Lower mid EAT n ¼ 62 Q EAT n ¼ 61

Upper mid Q EAT n ¼ 61

Highest Q P EAT n ¼ 61 value

Age Gender Diabetes mellitus Hypertension Hypercholesterolemia Family history of CHD Smoker Diseased coronaries Obstructive CAD MACE (%)

63 ± 10 73% 17% 21% 27% 58% 3% 40% 12% 1%

64 ± 10 76% 21% 35% 26% 65% 8% 69% 21% 11.4%

64 ± 14 79% 18% 28% 44% 62% 5% 71% 21% 13.4%

63 ± 12 73% 21% 20% 32% 46% 5% 63% 16% 3.3%

Q: quartile. MACE: major adverse cardiovascular events. CAD: coronary artery disease. CHD: coronary heart disease. Diseased Coronaries: coronary artery obstruction of 1e99%.

0.8 0.9 0.9 0.2 0.4 0.9 0.7 0.01 0.2 0.001

488

F. Hajsadeghi et al. / Atherosclerosis 237 (2014) 486e489

Fig. 1. a. The relation epicardial adipose tissue with presence and severity of coronary artery disease in subjects with and without major adverse cardiovascular events. b. The ROC curve models of conventional risk factors, epicardial adipose tissue, CTA diagnosed CTA and combination of EAT and CAT in prediction of major adverse cardiovascular events.

over risk factors. Also combination of EAT and CTA diagnosed CAD improved area under curve to predict MACE more robust that each alone (p < 0.05) (Fig. 1b). 4. Discussion The current study demonstrates that: 1) increased epicardial adipose tissue (EAT) is associated with coronary atherosclerosis, 2) increased EAT predicts long term major adverse cardiovascular events independent of age, gender, conventional risk factors and CTA diagnosed CAD, and 3) addition of EAT to CTA diagnosed CAD significantly improves prognostication of future MACE. EAT is composed of perivascular visceral adipocytes which modulate insulin sensitivity and cellular function in an autocrine or paracrine manner while attracting macrophages to the depot, further exacerbating inflammation and adipocyte dysfunction [8,9]. Previous

studies showed that increased epicardial adipose tissue is directly associated with vascular stiffness, increased inflammation and insulin resistance which increased the risk of plaque instability, arterial thrombosis, presence and severity of atherosclerosis measured by coronary artery calcium (CAC) [10]. Previous studies revealed that EAT is associated with fatal and nonfatal coronary events in the general population independent of traditional cardiovascular risk factors [5,6]. The current study reconfirms previous studies [5] that increased EAT is an independent risk factor for MACE in subjects without known coronary artery disease, and for the first time reported the superior prognostication value of EAT over traditional risk factors to identify at risk individuals as well as significant improvement in prediction of MACE by addition of EAT to the presence and severity of CTA diagnosed CAD. This highlights the potential role for EAT measurement is risk stratifications of at risk individuals.

F. Hajsadeghi et al. / Atherosclerosis 237 (2014) 486e489 Table 1b The hazard ratio (95% CI) of major adverse cardiovascular events across (top) quartiles of epicardial adipose tissue and each standard deviation increase of EAT. Model

Lowest Q EAT

Lower mid Q EAT Upper mid Q EAT Highest Q EAT

Unadjusted MACE 1.0 (Ref)

1.7 (1.4e3.1), 4.9(1.9e6.2), 7.9(2.4e12.6), p ¼ 0.01 p ¼ 0.001 p ¼ 0.001 Adjusted for age and gender MACE 1.0 (Ref) 1.5 (1.3e3.9), 4.2(1.3e5.4), 7.3(2.1e12.9), p ¼ 0.01 p ¼ 0.001 p ¼ 0.001 Adjusted for age, gender, diabetes mellitus, hypertension, hypercholesterolemia, family history of premature CAD, presence and severity of CTA diagnosed CAD MACE 1.0 (Ref) 1.4 (1.2e4.2), 3.1(1.4e6.9), 5.7(1.6e9.8), p ¼ 0.03 p ¼ 0.008 p ¼ 0.001 Model

Hazard ratio of death (95%CI) with each standard deviation increase in EAT

Unadjusted MACE 2.32 (1.62e3.31), p < 0.001 Adjusted for age and gender MACE 2.31 (1.55e3.44), p ¼ 0.001 Adjusted for age, gender, diabetes mellitus, hypertension, hypercholesterolemia, family history of premature CAD, presence and severity of CTA diagnosed CAD MACE 2.23 (1.51e3.32), p ¼ 0.001 Q: quartile. EAT (Mean: 110 cm3/m2, SD: 40 cm3/m2).

5. Conclusion Increased epicardial adipose tissue is directly associated with coronary artery disease and predicts MACE independent of the age, gender and conventional risk factors. Our findings highlights the

489

important role of EAT measurement in risk stratification and identification of at risk individuals for MACE. Conflict of interest None. References [1] Young P, Arch JR, Ashwell M. Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett. 1984;167:10e4. [2] Fain JN, Madan AK, Hiler ML, et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004;145:2273e82. [3] Taguchi R, Takasu J, Itani Y, et al. Pericardial fat accumulation in men as a risk factor for coronary artery disease. Atherosclerosis 2001;157:203e9. [4] Jeong JW, Jeong MH, Yun KH, et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ. J. 2007;71:536e9. [5] Mahabadi AA, Berg MH, Lehmann N, et al. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf recall study. J. Am. Coll. Cardiol. 2013;61: 1388e95. [6] Ding J, Hsu FC, Harris TB, et al. The association of pericardial fat with incident coronary heart disease: the multi-ethnic study of atherosclerosis (MESA). Am. J. Clin. Nutr. 2009;90:499e504. [7] Ahmadi N, Nabavi V, Yang E, et al. Increased epicardial, pericardial, and subcutaneous adipose tissue is associated with the presence and severity of coronary artery calcium. Acad. Radiol. 2010;17:1518e24. [8] Chatterjee TK, Stoll LL, Denning GM, et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ. Res. 2009;104: 541e9. [9] Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 2005;96:939e49. [10] de Vos AM, Prokop M, Roos CJ, et al. Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in postmenopausal women. Eur. heart J. 2008;29:777e83.