Atherosclerosis 237 (2014) 671e676
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Impact of abdominal and epicardial fat on the association between plasma adipocytokine levels and coronary atherosclerosis in nonobese patients Ken Harada a, *, Tetsuya Amano b, Takashi Kataoka a, Masahiro Takeshita a, Kazuhiro Harada a, Ayako Kunimura a, Yohei Takayama a, Norihiro Shinoda a, Bunichi Kato a, Tadayuki Uetani a, Masataka Kato a, Nobuyuki Marui a, Hideki Ishii c, Tatsuaki Matsubara d, Toyoaki Murohara c a
Department of Cardiology, Chubu Rosai Hospital, 10-6 1-Chome Komei, Minato-ku, Nagoya 455-8530, Japan Department of Cardiology, Aichi Medical University Hospital, 1-1 Nagakute, Aichi 480-1195, Japan c Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8560, Japan d Department of Internal Medicine, Aichi-Gakuin School of Dentistry, 2-11 Suemoridori, Chikusa-ku, Nagoya 464-8651, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 May 2014 Received in revised form 15 September 2014 Accepted 8 October 2014 Available online 18 October 2014
Objective: Ectopic fat accumulation is associated with coronary artery disease. Visceral adipose tissue has paracrine and systemic effects and is a source of adipocytokines. It has been implicated in the pathogenesis of coronary atherosclerosis; however, nothing is known about whether increases in epicardial fat have the same effect on coronary atherosclerosis as increases in abdominal visceral fat. Methods: We examined 216 consecutive patients suspected to have coronary artery disease. Individuals with acute coronary syndrome and inadequate computed tomography (CT) imaging were excluded. We enrolled 164 patients (65 ± 10 years old; 70% men; body mass index [BMI], 23.8 ± 3.6 kg/m2). The plasma concentrations of adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, and vascular endothelial growth factor were measured. The characteristics of coronary plaque, abdominal visceral fat area, and epicardial fat volume (EFV) were determined by 64-slice CT imaging. Results: EFV was greater in subjects with noncalcified plaque than in those with no plaque or with calcified plaque (126 ± 39 mL vs. 98 ± 34 mL and 97 ± 45 mL, respectively; P ¼ 0.010). EFV was significantly correlated with BMI, triglycerides, and the triglyceride/high-density lipoprotein cholesterol ratio (r ¼ 0.51, 0.19, and 0.20, respectively) but not with plasma levels of adipocytokines. The plasma adiponectin and IL-6 concentration was significantly correlated with abdominal visceral fat area in coronary plaque patients (r ¼ 0.49 and 0.20). Conclusions: In non-obese Japanese patients, epicardial fat may have unique mechanisms affecting the development of coronary atherosclerosis, which is different from abdominal visceral fat. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Epicardial fat volume Plasma adipocytokine level Coronary atherosclerotic plaque Abdominal visceral fat area 64-Slice computed tomography Non-obese
1. Introduction Fat mainly accumulates in subcutaneous depots, but sizeable amounts of visceral fat are also deposited in the abdomen, thorax, pancreas, and skeletal muscles as ectopic fat [1]. Ectopic fat accumulation is associated with an increased incidence of cardiovascular disease, mainly due to the release of adipocytokines that impair insulin signalling and promote endothelial dysfunction [2].
* Corresponding author. E-mail address: [email protected] (K. Harada). http://dx.doi.org/10.1016/j.atherosclerosis.2014.10.014 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
Compared to Caucasians, Japanese people have a greater amount of abdominal visceral fat relative to the abdominal subcutaneous fat [3]. In fact, many Japanese patients with acute coronary syndrome are non-obese [4], suggesting that the presence of ectopic fat may contribute to coronary artery disease. Adipose tissue is recognized as an active endocrine organ system that secretes adipocytokines, which are responsible for the local (autocrine and paracrine) and systemic regulation of numerous metabolic and inflammatory processes [5]. The circulating concentrations of adipocytokine are increased in overweight individuals with increased amounts of visceral fat [6]. The dysregulated secretion of adipocytokines triggers obesity-associated
672
K. Harada et al. / Atherosclerosis 237 (2014) 671e676
chronic inflammation and contributes to the development of cardiovascular atherosclerosis [7]. Epicardial fat, the local visceral adipose tissue of the heart, is deposited under the visceral layer of the pericardium and is thought to serve as a source of adipocytokines [8]. Given its close anatomic proximity to the coronary arteries, epicardial fat is considered an important factor in the development of cardiovascular disease. Excessive epicardial adipose tissue is thought to be directly responsible for inflammation of the adjacent coronary arteries and thus contributes to the pathogenesis of atherosclerosis [9]. However, the potential paracrine effects of adipocytokines produced by epicardial fat on myocardial metabolism and the role of these molecules in the pathogenesis of coronary artery disease remain unknown. Therefore, we evaluated the relationship between epicardial fat volume (EFV) and plasma adipocytokine concentrations and coronary atherosclerotic plaque (CAP). 2. Methods 2.1. Study patients Computed tomography (CT)-based coronary angiography was performed on 216 consecutive patients who visited the Nagoya University Hospital between January 2008 and February 2009 for evaluation of chest discomfort suggestive of coronary artery disease. Individuals with acute myocardial infarction, inadequate CT imaging due to atrial fibrillation, or renal insufficiency (serum creatinine, >1.5 mg/dL) were excluded, as were three patients who were undergoing chemotherapy for malignancy. Three patients had a history of percutaneous coronary intervention, and five had a history of coronary artery bypass graft surgery. None of the remaining patients showed evidence of known systemic inflammatory disease or had undergone surgery or experienced major trauma in the previous six months. Patients with coronary arteries with >50% luminal stenosis on CT angiography or those who could not be evaluated as a result of extensive calcification were referred for conventional coronary angiography. Thus, we performed the latter procedure on 57 patients. Of those, 20 underwent
percutaneous coronary intervention and five underwent coronary artery bypass graft surgery; these 25 patients were excluded from the study. Finally, we included 164 patients (mean age ± standard deviation [SD], 65 ± 10 years old; 70% men) in the study (Fig. 1). The study complied with the Declaration of Helsinki, was approved by the ethics review board of Nagoya University School of Medicine, and written informed consent was obtained from all patients prior to study enrolment. 2.2. Computed tomography angiography Coronary CT angiography was performed using a 64-slice CT scanner (Aquilion 64; Toshiba Medical Systems, Otawara, Japan). Patients with a resting heart rate of >70 beats/min received 50 mg of atenolol orally 60 min before the CT scan to avoid motion artefacts; for individuals with contraindications for ab-blocker or an unsatisfactory lowering of the heart rate, the scan was performed without atenolol. A 70-mL bolus of contrast agent was injected intravenously (3.5 mL/s) followed by a 20-mL saline flush at the same injection rate. When the signal in the ascending aorta achieved the predefined threshold of 150 Hounsfield units (HU), the scan was initiated automatically, and the entire volume of the heart was acquired during one breath-hold with simultaneous recording of the electrocardiogram (ECG). By using retrospective ECG gating, we routinely performed reconstructions at 75% of the ReR interval. If motion artefacts were present in these reconstructions, we selected a more optimal ECG phase to obtain a better image quality. The reconstructed CT image data were transferred to a computer workstation (ZIO M900; Amin, Tokyo, Japan) for subsequent processing. Cross-sectional and curved multiplanar reformation images were analysed by the workstation software, which detects plaque and vessel walls on CT images. 2.3. Computed tomography image analysis of epicardial fat, abdominal visceral fat, and coronary plaque Two experienced analysts measured EFV from CT images of the heart. EFV was defined as the total amount of adipose tissue
Fig. 1. Enrolment of patients. We enrolled 164 patients in the study, 111 of whom were diagnosed with CAP and assigned to seven categories on the basis of their coronary plaque morphology: A) only noncalcified plaque; B) only mixed plaque; C) only calcified plaque; D) noncalcified and mixed plaque; E) noncalcified and calcified plaque; F) mixed and calcified plaque; and G) noncalcified, mixed, and calcified plaque. AP, angina pectoris.
K. Harada et al. / Atherosclerosis 237 (2014) 671e676
between the surface of the heart and the visceral layer of the pericardium. The measurements were performed on short-axis views of 3-mm-thick slices. The stack of short-axis views began at the apex immediately below the fibrous pericardium and extended to the centre of the left atrium. An epicardial area was measured by tracing a single region of interest semiautomatically, and the epicardial fat in the section obtained at each level was determined. A density range of 190 to 30 HU was used to isolate the adipose tissue [10]. Fat was distinguished from other tissues by using volume analysis software (Supplementary Fig. 1). The interobserver variability for the quantification of EFV was 1 mm2 that was located either within the coronary artery lumen or adjacent to the lumen, which could be distinguished from the surrounding pericardial tissue, epicardial fat, or the vessel lumen itself. We defined CAP as the presence of visible plaque in the coronary arteries on CT angiography. Noncalcified coronary plaque was defined as a low-density mass that was located within the vessel wall, which was clearly distinguishable from the contrast-enhanced coronary lumen and the surrounding pericardial tissue. Calcified plaque was defined as a lesion composed exclusively of material with a CT density greater than that of the contrast-enhanced coronary lumen. The plaque types were evaluated by visual assessment.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Impact of abdominal and epicardial fat on the association between plasma adipocytokine levels and coronary atherosclerosis in nonobese patients Ken Harada a, *, Tetsuya Amano b, Takashi Kataoka a, Masahiro Takeshita a, Kazuhiro Harada a, Ayako Kunimura a, Yohei Takayama a, Norihiro Shinoda a, Bunichi Kato a, Tadayuki Uetani a, Masataka Kato a, Nobuyuki Marui a, Hideki Ishii c, Tatsuaki Matsubara d, Toyoaki Murohara c a
Department of Cardiology, Chubu Rosai Hospital, 10-6 1-Chome Komei, Minato-ku, Nagoya 455-8530, Japan Department of Cardiology, Aichi Medical University Hospital, 1-1 Nagakute, Aichi 480-1195, Japan c Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8560, Japan d Department of Internal Medicine, Aichi-Gakuin School of Dentistry, 2-11 Suemoridori, Chikusa-ku, Nagoya 464-8651, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 May 2014 Received in revised form 15 September 2014 Accepted 8 October 2014 Available online 18 October 2014
Objective: Ectopic fat accumulation is associated with coronary artery disease. Visceral adipose tissue has paracrine and systemic effects and is a source of adipocytokines. It has been implicated in the pathogenesis of coronary atherosclerosis; however, nothing is known about whether increases in epicardial fat have the same effect on coronary atherosclerosis as increases in abdominal visceral fat. Methods: We examined 216 consecutive patients suspected to have coronary artery disease. Individuals with acute coronary syndrome and inadequate computed tomography (CT) imaging were excluded. We enrolled 164 patients (65 ± 10 years old; 70% men; body mass index [BMI], 23.8 ± 3.6 kg/m2). The plasma concentrations of adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, and vascular endothelial growth factor were measured. The characteristics of coronary plaque, abdominal visceral fat area, and epicardial fat volume (EFV) were determined by 64-slice CT imaging. Results: EFV was greater in subjects with noncalcified plaque than in those with no plaque or with calcified plaque (126 ± 39 mL vs. 98 ± 34 mL and 97 ± 45 mL, respectively; P ¼ 0.010). EFV was significantly correlated with BMI, triglycerides, and the triglyceride/high-density lipoprotein cholesterol ratio (r ¼ 0.51, 0.19, and 0.20, respectively) but not with plasma levels of adipocytokines. The plasma adiponectin and IL-6 concentration was significantly correlated with abdominal visceral fat area in coronary plaque patients (r ¼ 0.49 and 0.20). Conclusions: In non-obese Japanese patients, epicardial fat may have unique mechanisms affecting the development of coronary atherosclerosis, which is different from abdominal visceral fat. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Epicardial fat volume Plasma adipocytokine level Coronary atherosclerotic plaque Abdominal visceral fat area 64-Slice computed tomography Non-obese
1. Introduction Fat mainly accumulates in subcutaneous depots, but sizeable amounts of visceral fat are also deposited in the abdomen, thorax, pancreas, and skeletal muscles as ectopic fat [1]. Ectopic fat accumulation is associated with an increased incidence of cardiovascular disease, mainly due to the release of adipocytokines that impair insulin signalling and promote endothelial dysfunction [2].
* Corresponding author. E-mail address: [email protected] (K. Harada). http://dx.doi.org/10.1016/j.atherosclerosis.2014.10.014 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
Compared to Caucasians, Japanese people have a greater amount of abdominal visceral fat relative to the abdominal subcutaneous fat [3]. In fact, many Japanese patients with acute coronary syndrome are non-obese [4], suggesting that the presence of ectopic fat may contribute to coronary artery disease. Adipose tissue is recognized as an active endocrine organ system that secretes adipocytokines, which are responsible for the local (autocrine and paracrine) and systemic regulation of numerous metabolic and inflammatory processes [5]. The circulating concentrations of adipocytokine are increased in overweight individuals with increased amounts of visceral fat [6]. The dysregulated secretion of adipocytokines triggers obesity-associated
672
K. Harada et al. / Atherosclerosis 237 (2014) 671e676
chronic inflammation and contributes to the development of cardiovascular atherosclerosis [7]. Epicardial fat, the local visceral adipose tissue of the heart, is deposited under the visceral layer of the pericardium and is thought to serve as a source of adipocytokines [8]. Given its close anatomic proximity to the coronary arteries, epicardial fat is considered an important factor in the development of cardiovascular disease. Excessive epicardial adipose tissue is thought to be directly responsible for inflammation of the adjacent coronary arteries and thus contributes to the pathogenesis of atherosclerosis [9]. However, the potential paracrine effects of adipocytokines produced by epicardial fat on myocardial metabolism and the role of these molecules in the pathogenesis of coronary artery disease remain unknown. Therefore, we evaluated the relationship between epicardial fat volume (EFV) and plasma adipocytokine concentrations and coronary atherosclerotic plaque (CAP). 2. Methods 2.1. Study patients Computed tomography (CT)-based coronary angiography was performed on 216 consecutive patients who visited the Nagoya University Hospital between January 2008 and February 2009 for evaluation of chest discomfort suggestive of coronary artery disease. Individuals with acute myocardial infarction, inadequate CT imaging due to atrial fibrillation, or renal insufficiency (serum creatinine, >1.5 mg/dL) were excluded, as were three patients who were undergoing chemotherapy for malignancy. Three patients had a history of percutaneous coronary intervention, and five had a history of coronary artery bypass graft surgery. None of the remaining patients showed evidence of known systemic inflammatory disease or had undergone surgery or experienced major trauma in the previous six months. Patients with coronary arteries with >50% luminal stenosis on CT angiography or those who could not be evaluated as a result of extensive calcification were referred for conventional coronary angiography. Thus, we performed the latter procedure on 57 patients. Of those, 20 underwent
percutaneous coronary intervention and five underwent coronary artery bypass graft surgery; these 25 patients were excluded from the study. Finally, we included 164 patients (mean age ± standard deviation [SD], 65 ± 10 years old; 70% men) in the study (Fig. 1). The study complied with the Declaration of Helsinki, was approved by the ethics review board of Nagoya University School of Medicine, and written informed consent was obtained from all patients prior to study enrolment. 2.2. Computed tomography angiography Coronary CT angiography was performed using a 64-slice CT scanner (Aquilion 64; Toshiba Medical Systems, Otawara, Japan). Patients with a resting heart rate of >70 beats/min received 50 mg of atenolol orally 60 min before the CT scan to avoid motion artefacts; for individuals with contraindications for ab-blocker or an unsatisfactory lowering of the heart rate, the scan was performed without atenolol. A 70-mL bolus of contrast agent was injected intravenously (3.5 mL/s) followed by a 20-mL saline flush at the same injection rate. When the signal in the ascending aorta achieved the predefined threshold of 150 Hounsfield units (HU), the scan was initiated automatically, and the entire volume of the heart was acquired during one breath-hold with simultaneous recording of the electrocardiogram (ECG). By using retrospective ECG gating, we routinely performed reconstructions at 75% of the ReR interval. If motion artefacts were present in these reconstructions, we selected a more optimal ECG phase to obtain a better image quality. The reconstructed CT image data were transferred to a computer workstation (ZIO M900; Amin, Tokyo, Japan) for subsequent processing. Cross-sectional and curved multiplanar reformation images were analysed by the workstation software, which detects plaque and vessel walls on CT images. 2.3. Computed tomography image analysis of epicardial fat, abdominal visceral fat, and coronary plaque Two experienced analysts measured EFV from CT images of the heart. EFV was defined as the total amount of adipose tissue
Fig. 1. Enrolment of patients. We enrolled 164 patients in the study, 111 of whom were diagnosed with CAP and assigned to seven categories on the basis of their coronary plaque morphology: A) only noncalcified plaque; B) only mixed plaque; C) only calcified plaque; D) noncalcified and mixed plaque; E) noncalcified and calcified plaque; F) mixed and calcified plaque; and G) noncalcified, mixed, and calcified plaque. AP, angina pectoris.
K. Harada et al. / Atherosclerosis 237 (2014) 671e676
between the surface of the heart and the visceral layer of the pericardium. The measurements were performed on short-axis views of 3-mm-thick slices. The stack of short-axis views began at the apex immediately below the fibrous pericardium and extended to the centre of the left atrium. An epicardial area was measured by tracing a single region of interest semiautomatically, and the epicardial fat in the section obtained at each level was determined. A density range of 190 to 30 HU was used to isolate the adipose tissue [10]. Fat was distinguished from other tissues by using volume analysis software (Supplementary Fig. 1). The interobserver variability for the quantification of EFV was 1 mm2 that was located either within the coronary artery lumen or adjacent to the lumen, which could be distinguished from the surrounding pericardial tissue, epicardial fat, or the vessel lumen itself. We defined CAP as the presence of visible plaque in the coronary arteries on CT angiography. Noncalcified coronary plaque was defined as a low-density mass that was located within the vessel wall, which was clearly distinguishable from the contrast-enhanced coronary lumen and the surrounding pericardial tissue. Calcified plaque was defined as a lesion composed exclusively of material with a CT density greater than that of the contrast-enhanced coronary lumen. The plaque types were evaluated by visual assessment.
