Atherosclerosis 233 (2014) 104e112

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

Review

Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis Nikolaos Alexopoulos a, Demosthenes Katritsis a, Paolo Raggi b, c, * a

Cardiology Department, Athens Euroclinic, Athens, Greece Division of Cardiology, Department of Medicine, University of Alberta, Canada c Mazankowski Alberta Heart Institute, Edmonton, AB, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 October 2013 Received in revised form 16 December 2013 Accepted 16 December 2013 Available online 7 January 2014

The current epidemic of obesity with the associated increasing incidence of insulin resistance, diabetes mellitus and atherosclerosis affecting a large proportion of the North American and Western populations, has generated a strong interest in the potential role of visceral adipose tissue in the development of atherosclerosis and its complications. The intra-abdominal and epicardial space are two compartments that contain visceral adipose tissue with a similar embryological origin. These visceral fats are highly inflamed in obese patients, patients with the metabolic syndrome and in those with established coronary artery disease; additionally they are capable of secreting large quantities of pro-inflammatory cytokines and free fatty acids. There is accumulating evidence to support a direct involvement of these regional adipose tissue deposits in the development of atherosclerosis and its complicating events, as will be reviewed in this article. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Visceral adipose tissue Atherosclerosis Coronary artery disease

Contents 1. 2. 3. 4.

5. 6. 7.

Adipose tissue e a must have to survive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Adipose tissue: a friend or foe for your health? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Visceral adipose tissue classification (Figs. 1 and 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Visceral adipose tissue and atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 4.1. Abdominal (visceral) adipose tissue (Fig. 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.2. Epicardial adipose tissue (Fig. 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.3. Special populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.4. Perivascular adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Dynamic changes of visceral adipose tissue with pharmacological and non-pharmacological interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 Pathophysiological mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1. Adipose tissue e a must have to survive Adipose tissue is a type of connective tissue that plays important physiological roles in mammals. A 70 kg reference man has an * Corresponding author. Mazankowski Alberta Heart Institute, 8440-112 Street, Suite 4A7.050, Edmonton, AB T6G2B7, Canada. Tel.: þ1 780 407 4575; fax: þ1 780 407 7834. E-mail addresses: [email protected], [email protected] (P. Raggi). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.023

average of 15 kg of adipose tissue that corresponds to 21% of body mass. This percentage is higher in women, the elderly, and overweight subjects [1]. Not all deposits of adipose tissue in the human body are composed of the same type of fat. Human adipose tissue is classically characterized as white and brown, although more recently beige adipose tissue has also been described [2]. Brown adipose tissue is present in small quantities, in infants and in lean adults, and is mostly responsible for the production of heat when the body is exposed to cold temperatures. Beige adipose

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cells can generate heat when activated by a number of stimuli (cold, stress and treatment with TZDs for example), but are also capable of storing fat in the presence of energy surplus. The vast majority of human adipose tissue is of the white type; this type of fat is mainly located beneath the skin (subcutaneous adipose tissue), providing insulation from heat and cold, but also around internal organs (visceral adipose tissue), where it provides a sort of protective padding. White adipose tissue is metabolically active. Its main metabolic function is to store free fatty acids in the postprandial state, which are again released in the fasting state to provide a source of energy for the body. Thus, adipose tissue plays a role of paramount importance for both cardiac and skeletal muscles to function properly between meals. The vital role of adipose tissue is exemplified by the fact that total absence of adipose tissue, as it occurs in homozygous peroxisome proliferator-activated receptor gamma (PPAR-g) knot-out mice, is fatal [3]. 2. Adipose tissue: a friend or foe for your health? Obesity is accompanied by several adverse health effects such as hypertension, insulin resistance, franc diabetes, dyslipidemia and subclinical inflammation, all factors leading to atherosclerosis. Although adipocytes can increase in number (hyperplasia), they mostly grow in size (hypertrophy) accumulating lipids as body weight increases. In general, obesity results in a greater increase in visceral adipose tissue than in subcutaneous fat. However, it is well known that there is a “healthy obese phenotype” characterized by a greater accumulation of subcutaneous than visceral fat. These “healthy obese” subjects demonstrate a benign cardiometabolic profile. [4] Hence fat accumulation per-se cannot be considered the sole foe, and other factors are likely responsible for the poor cardiovascular outcome of obese patients. Epidemiological evidence collected over the last decade suggests a close link between visceral fat accumulation and atherosclerosis, and visceral adipose tissue has become the target of extensive research as the potential missing link between obesity and risk of cardiovascular events [5]. 3. Visceral adipose tissue classification (Figs. 1 and 2) The radiological classification of visceral adipose tissue is performed according to the body region where fat is deposited and it includes: intrathoracic (ITAT), intraabdominal (IAAT) and intrapelvic (IPAT) adipose tissue [1]. IAAT and IPAT are usually quantified together, as intraabdominopelvic (or abdominal) adipose tissue. Abdominal adipose tissue can be distinguished further into intraperitoneal and extraperitoneal adipose tissue (Fig. 1) [1]. For the

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purpose of this review intraabdominal adipose tissue will be described as VAT: visceral adipose tissue. ITAT is classified into epicardial adipose tissue (EAT), which is deposited directly on top of the myocardium and/or coronary arteries and beneath the visceral pericardium, and extrapericardial (or paracardial), which is deposited outside the parietal pericardium (Fig. 2). Additionally, small fat deposits can be found layered along the thoracic aorta. Together, epicardial, extrapericardial and periaortic fat constitute the ITAT. 4. Visceral adipose tissue and atherosclerosis Several studies explored the association of visceral adipose tissue with atherosclerosis; investigators used different methodologies for adipose tissue quantification and measured adipose tissue volume in different body regions. In the following paragraphs we will present some of the main findings according to the region where adipose tissue was quantified. Because there are discrepancies in the adipose tissue terminology used in the literature e for example the term “pericardial” adipose tissue has been used to describe all three adipose tissue compartments surrounding the heart (i.e. epicardial, extra-pericardial, and intrathoracic) e we will try to clarify which adipose tissue compartment was actually assessed. Finally, all data presented will regard visceral e not subcutaneous e adipose tissue. 4.1. Abdominal (visceral) adipose tissue (Fig. 1) In the literature intra-abdominal visceral adipose tissue is usually referred to as “visceral adipose tissue” (VAT). In the past several decades, numerous cross-sectional and retrospective studies suggested the existence of an association between VAT and atherosclerosis, although some suggested that the observed association disappeared after adjustment for traditional risk factors for cardiovascular disease (Table 1). In one of the first observations, nonobese men with coronary artery disease were shown to have larger VAT deposits than age- and BMI-matched controls [6]. Early findings from the Framingham Heart Study suggested that VAT volume, measured with computed tomography, was associated with prevalent cardiovascular disease, after adjusting for age, gender, body mass index and waist circumference. However, this association was attenuated after multivariable adjustment [7]. In a smaller study the association with coronary artery disease remained significant even after adjustment for risk factors [8]. In a cohort study, VAT was independently associated with carotid atherosclerosis in men, but not in women [9]. Finally, a small study in patients with known coronary artery disease showed that increased VAT volume was

Fig. 1. Abdominal axial computed tomography image at the level of the 4th lumbar vertebra (1A). In Fig. 1B, the subcutaneous adipose tissue is indicated by rust color arrows, the extra-peritoneal adipose tissue is highlighted in yellow and the intraperitoneal adipose tissue is indicated by blue arrows. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Fig. 2. Measurement of epicardial adipose tissue on non-contrast computed tomography. A and B. Single non-contrast axial images (two of a total of 36e40 contiguous slices) of the heart at an upper (A) and lower level (B) in the same heart. Fig. 2A shows calcium deposits in the left anterior descending coronary artery. C and D. In the same slices as A and B the epicardial adipose tissue below the visceral layer of the pericardium in highlighted in pink; the total epicardial adipose tissue volume is calculated as the sum of the epicardial adipose tissue area in each slice. E and F. In these images the pericardial adipose tissue (outside of the parietal pericardium) is highlighted in orange (E) and yellow (F). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

associated with the presence of multivessel rather than single vessel disease [10]. These findings are generally in line with other reports examining the association of VAT with surrogate markers of atherosclerosis, such as coronary artery calcium in various ethnic groups. For example, in a Japanese [11] and a Korean [12] population, VAT was significantly associated with coronary artery calcium even after adjustment for risk factors, whereas in a more recent study in African Americans, VAT was associated with coronary artery calcium only in univariate analyses [13]. In a mostly Caucasian population, this association was more pronounced among women than men [14]. In a recent report VAT was associated with the risk of progression of non-calcified coronary artery plaques in patients with coronary artery disease [15]. Additionally, increased amounts of VAT appeared to be associated with the presence of non-calcified coronary plaques with vulnerable features, such as positive remodeling, low CT density and spotty calcification [16]. These findings may provide clues to the association of VAT with future cardiovascular events. In fact, a few prospective studies have shed further light on the association of VAT with incident cardiovascular disease. In the Health, Aging and Body Composition Study VAT volume was an independent predictor of myocardial infarction in older women [17]. Data from the prospective long-term follow-up of the Framingham Heart Study showed that VAT was an independent predictor of incident cardiovascular disease [18]. 4.2. Epicardial adipose tissue (Fig. 2) Epicardial adipose tissue (EAT) has been extensively studied using different methodologies, such as echocardiography, computed tomography, and magnetic resonance imaging and several investigators reported its association with cardiovascular events. It is however important to note that there were substantial differences among the reports not only in the imaging methodology used and type of measurement made (i.e. epicardial adipose tissue thickness in single slices versus global or regional volume) but also in the terminology used to name the various types of

intrathoracic adipose tissue (see above). Strictly speaking “epicardial” adipose tissue is layered directly on the myocardium and confined below the visceral layer of the pericardium, whereas adipose tissue outside the pericardium should be referred to as extrapericardial or para-cardial. This differentiation is indeed appropriate since there are significant differences between epicardial and extrapericardial adipose tissue both for their embryological origin and their metabolic properties [19]. The sum of these adipose tissue compartments should be referred to as “intrathoracic” adipose tissue. The first investigators to examine the association of thoracic adipose tissue with coronary atherosclerosis measured pericardial visceral adipose tissue. In an early cross sectional study pericardial adipose tissue measured by CT was associated with the presence and extent of coronary artery disease on invasive angiography [20]. The association with coronary artery disease or coronary atherosclerosis was reported in several subsequent studies, measuring pericardial [21e23] and epicardial [24e34] adipose tissue. Notably, a few contrasting results have also been published: in one study the association was demonstrated only in patients with low body mass index [35]; other investigators who used echocardiography to measure EAT thickness failed to show any association with coronary artery disease [36], and in a Japanese study EAT was associated with coronary artery disease only in men but not in women [37]. Some have questioned whether the total volume of EAT or the volume of fat surrounding a specific coronary artery, for instance fat surrounding the left anterior descending coronary artery in the interventricular groove, is more closely associated with the development of coronary atherosclerosis [31,38]. In most studies, both pericardial [39e42] and epicardial [27,33,43] adipose tissue have been associated with the presence and extent of markers of atherosclerosis such as coronary artery calcium, although a few failed to show an association [44,45]. Employing coronary artery computed tomography angiography, several investigators demonstrated an association of EAT with coronary artery plaques exhibiting characteristics of instability and vulnerability such as low attenuation plaques, positive remodeling,

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Table 1 Representative list of studies investigating the association of visceral fat with cardiovascular disease. Author, year

Population

Type of study

Imaging technique

Main findings

Case control

CT

Cross-sectional

CT

Cross-sectional

CT

CAD patients had larger VAT than age- and BMI-matched controls VAT was associated with CV disease, but not in the fully adjusted model VAT was associated with CAD in the multivariate model VAT was independently associated with carotid atherosclerosis only in men VAT was associated with the presence of multivessel rather than single vessel CAD VAT was an independent predictor of the presence and extent of CAC

Abdominal (visceral) adipose tissue e VAT Nakamura, 1994 [6] 29 men with CAD (57  10 years) and 54 men without CAD (58  9 years) Mahabadi, 2009 [7] 1267 participants (46.2% men, 60  9 years) Marques, 2010 [8] 125 patients (57% men, 56  12 years) referred for CCTA Lear, 2007 [9] 794 participants (48.6% men, mean age 46.9, range 30e65 years Lee, 2010 [10] 90 men with CAD (47.7  0.6 years)

Cross-sectional

CT

Cross-sectional

CT

Ohashi, 2009 [11]

Cross-sectional

CT

Cross-sectional

CT

Choi, 2010 [12]

321 patients referred for CCTA (61.4% men, mean age 66, range 36e87 years) 1336 men (59  8 years)

Liu, 2012 [13]

2884 patients (35% men, mean age 60 years)

Cross-sectional

CT

Imai, 2012 [15]

320 patients with CAD (60% men, 63  11 years) 427 patients with known or suspected CAD (62.5% men, 67  11 years)

Prospective longitudinal Cross-sectional

CT

Ohashi, 2010 [16]

Nicklas, 2004 [17]

CT

VAT was an independent predictor of the presence of moderate-to-severe CAC VAT was positively associated with CAC in ageesex-adjusted models, but the association was diminished with multivariable adjustment VAT was associated with progression of non-calcified plaque VAT was associated with the presence of non-calcified coronary plaques with vulnerable features VAT was an independent predictor of myocardial infarction (only in women) VAT was an independent predictor of incident cardiovascular disease

2503 participants (44.6% men, age 70e79 years) Britton, 2013 [18] 3086 participants (51% men, 50  10 years) Pericardial (PAT) and epicardial (EAT) adipose tissue Tagushi, 2001 [20] 251 men, 59.3  7.5 years

Cross-sectional

CT

Ding, 2008 [39]

Cross-sectional

CT

Cross-sectional

CT

PAT was associated with the presence and extend of CAD PAT was independently associated with calcified coronary plaque PAT was independently associated with CAC

Cross-sectional

CT

PAT was independently associated with CAC

Cross-sectional

CT

Cross-sectional

CT

Cross-sectional

CT

Intrathoracic adipose tissue was independently associated with CAC EAT was independently associated with the presence of CAD EAT was independently associated with CAC

Cross-sectional

CT

Cross-sectional

CT

Cross-sectional

CT

Liu, 2010 [40] Divers, 2010 [41] Huang, 2012 [42] Bachar, 2012 [27] Yun, 2012 [43] Alexopoulos, 2010 [33] Schlett, 2012 [26]

Rajani, 2013 [32]

159 participants (50% men, mean 64.3 years) 1414 participants (35% men, 58  11 years) 422 patients with DM2 (36% men, 56.5  9.6 years) 650 women (52.9  2.6 years) 190 patients (85% men, 56.5  9.2 years) 719 patients (74.4% men, 48  8 years) 214 patients (50% men, 54  14 years) 358 patients with chest pain (62% men, median [IQR] age 51 [45,59] years) 402 patients (56% men, median age 66, range 23e92 years)

Prospective longitudinal Prospective longitudinal

CT CT

EAT was independently associated with the presence of mixed or non-calcified plaque EAT was independently associated with the presence of coronary plaques with high-risk features EAT was independently associated with the presence of significant stenosis and of coronary plaques with high-risk features EAT was independently associated with the presence of non-calcified plaques and of coronary plaques with high-risk features EAT was independently associated with the presence of coronary plaques with high-risk features (IVUS) EAT was independently associated with the presence of thin-capped fibroatheroma (OCT) EAT was increased to ACS patients compared to controls

Oka, 2012 [46]

357 patients (64% men, 66  11 years)

Cross-sectional

CT

Park, 2013 [47]

82 PCI patients (54% men, 59  10 years)

Cross-sectional

Echo

Ito, 2012 [48]

117 PCI patients (82% men, mean age 66 years) 80 ACS patients (77% men, 65  12 years) and 90 controls (64% men, 62  11 years) 45 patients with ischemia in MPI and 52 controls (52% men, 61  14 years) 73 patients with ischemia in MPI (90% men, 60  10 years) and 146 controls (90% men, 59  9 years) 65 women with chest pain and no stenosis (mean age 56 years) 107 stable chest pain patients (60% men, mean age 63 years)

Cross-sectional

CT

Case control

CT

Case control

CT

EAT was an independent predictor of myocardial ischemia

Case control

CT

EAT was an independent predictor of myocardial ischemia

Cross-sectional

Echo

Cross-sectional

CT

EAT was an independent predictor of microvascular dysfunction EAT was an independent predictor of microvascular dysfunction

Harada, 2011 [49]

Janik, 2010 [50]

Tamarappoo, 2010 [52]

Sade, 2009 [53] Bucci, 2011 [54]

(continued on next page)

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Table 1 (continued ) Author, year

Population

Type of study

Imaging technique

Main findings

Otaki, 2011 [55]

212 patients with zero CAC score at baseline (53% men, mean age 57 years) 162 intermediate risk subjects (68% male, mean age 60 years) 333 DM2 patients (62% men, median [IQR] age 54 [47,60] years) 226 healthy subjects (51% men, 52  9 years) 4093 participants (47% men, 59.4  7.8 years) 760 acute chest pain patients (40.2% men, 54.4  13.7 years) 1119 participants (46.6% men, age 45e84)

Case control

CT

Baseline EAT and EAT change were not associated with CAC progression

Case control

CT

Prospective longitudinal Prospective longitudinal Prospective longitudinal Prospective longitudinal Case-cohort

CT

CT

Increase in EAT during follow-up was associated with greater progression of CAC EAT was an independent predictor of baseline CAC and CAC progression EAT was an independent predictor of cardiovascular events EAT was an independent predictor of coronary events EAT was an independent predictor of cardiovascular events PAT was an independent predictor of future CV disease

Cross-sectional

CT

Cross-sectional

CT

Cross-sectional

CT

Nakanishi, 2011 [45] Yerramasu, 2012 [56] Shmilovich, 2011 [57] Mahabadi, 2013 [58] Forouzandeh, 2013 [59] Ding, 2009 [21] Perivascular adipose tissue Lehman, 2010 [72] Britton, 2012 [73]

Fox, 2010 [74]

1067 participants (43.9% men, 59  9 years) 3246 (52% men, 51.1  10.4 years)

1205 participants (46.3% men, 65.9  8.9 years)

CT CT CT

Thoracic periaortic adipose tissue was independently associated with CAC Thoracic periaortic adipose tissue was independently associated with the presence of CV disease Thoracic periaortic adipose tissue was independently associated with the presence of peripheral arterial disease

ACS, acute coronary syndrome; BMI, body mass index; CAC, coronary artery calcium; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; CT, computed tomography; CV, cardiovascular; DM2, diabetes mellitus type 2; Echo, echocardiography; IQR, interquartile range; IVUS, intravascular ultrasound; MPI, myocardial perfusion imaging; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; VAT, visceral adipose tissue.

and spotty calcification. Alexopoulos et al. were the first to show that the larger the EAT volume the higher the prevalence of noncalcified plaques or plaques containing a mixture (Fig. 3) of calcium and areas of low attenuation (purportedly a lipid rich core) [33]. Further evidence of the association was provided in subsequent studies showing a positive relationship of EAT with features of plaque vulnerability [26,32,34,46]. This association was also confirmed using intravascular ultrasound [47], optical coherence tomography [48], and in patients with acute coronary syndromes [49]. One further piece of evidence linking EAT to coronary artery disease is the higher incidence of inducible myocardial ischemia on functional stress testing as the EAT volume increases [50e52]. Of interest, larger volumes of EAT have also been linked with reduced coronary flow reserve both in women with chest pain and

angiographically normal coronary arteries [53], and in patients with stable chest pain with or without macroscopic coronary artery disease [54]. In the latter group, only epicardial but not extrapericardial adipose tissue was predictive of an abnormal hyperemic flow response to adenosine stimulation [54], a reminder of the different clinical relevance of these visceral adipose tissue compartments. The results of these studies suggest that EAT is associated with endothelial dysfunction even before development of obstructive coronary artery disease. All of the above mentioned studies reported the association of EAT with atherosclerosis in cross-section analyses. Interesting pathophysiological information can be garnered from studies exploring the development and/or progression of atherosclerosis during follow-up in patients where EAT volume was measured at baseline. In 106 low-risk patients without subclinical

Fig. 3. Coronary computed tomography angiography. A] Curved multiplanar reformatted image of the left anterior descending coronary artery demonstrating an area in the proximal portion of the vessel with a mixture of calcification and low attenuation (i.e. lipid rich) plaque. B] Same image as A; the yellow arrows are pointing at the calcified plaque in the longitudinal and cross-sectional image (small insert) of the vessel and the dashed lines delineate the areas with low-attenuation plaques. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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atherosclerosis (zero calcium score) the baseline volume of EAT and its change over time were not associated with accumulation of coronary artery calcium after a median follow-up of 4 years [55], although a significant association was described by some of the same investigators in patients with moderate amounts of coronary calcium at baseline [45] and in diabetic patients [56]. More importantly, EAT has emerged as an independent predictor of incident cardiovascular events both in apparently healthy individuals [57,58] and in patients with acute chest pain [59]. Ding et al. also reported that pericardial adipose tissue is a predictor of incident cardiovascular events in the Framingham Heart Study [21]. 4.3. Special populations In patients receiving hemodialysis, a population at extremely elevated cardiovascular risk and high incidence of arterial calcifications [60], EAT was shown to be associated with coronary artery calcium [61], and be an independent predictor of mortality [62]. The association of EAT with coronary atherosclerosis and cardiometabolic risk has been observed in other populations at high cardiovascular risk such as HIV infected patients receiving antiretroviral therapy (ART) [63], and patients with rheumatologic disorders [64,65]. Guaraldi et al. [63] conducted a cross-sectional study of 836 young HIV patients (average age 47  8 year/old) treated with chronic ART and found an association of EAT with traditional cardiovascular risk factors, subclinical atherosclerosis, as well as central and mixed form lipodystrophy phenotypes, cumulative exposure to ART and the CD4 cell count. The latter observation is of interest and suggests that the prolonged use of ART may induce the proliferation of functionally abnormal CD4 (and/or CD8) lymphocytes with potentially pro-inflammatory and proatherogenic activity. In a retrospective observation Orlando et al. demonstrated that epicardial adipose tissue was independently associated with risk of cardiovascular events in 583 HIVþ men [66]. Finally, the progression of CAC in 240 HIVþ patients paralleled the increase in EAT volume during an average follow-up of 18 months and EAT increase was again associated with CD4 recovery after ART [67]. Young patients affected by chronic rheumatological disorders are known to have a substantial increase in risk of atherosclerotic events [68,69]. Lipson et al. [64] reported an increased volume of EAT in 162 patients (average age 40  12 year/old) affected by systemic lupus erythematosus (SLE) compared to 86 age and sex matched controls; they further reported an association of EAT volume with cumulative corticosteroid use in SLE patients. The long-term use of corticosteroids may induce changes in the adipose tissue composition that could potentially cause destabilization of atherosclerotic plaques [70], and it can also induce secretion of coagulation and vasoconstrictor factors (specifically endothelin-1), impair the removal of cholesterol from the vessel wall and induce hypertension [71]. In a recent publication, Ormseth et al. reported a close association of EAT with features of the metabolic syndrome, smoking, HOMA, serum triglyceride and homocysteine levels but not corticosteroid use in 162 patients affected by rheumatoid arthritis [65]. 4.4. Perivascular adipose tissue After having examined visceral adipose tissue in various body regions, attention was more recently directed to the association of perivascular adipose tissue in peripheral vascular territories with atherosclerosis; to a certain extent EAT may also be considered a perivascular fat, since it is layered directly on the coronary arteries adventitia without fascial interposition. A few reports have been published on the significance of periaortic adipose tissue. Data from

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the Framingham Heart Study indicate that this type of visceral fat is independently associated with coronary artery calcification [72], and with increased prevalence of cardiovascular disease even in the presence of normal amounts of visceral adipose tissue [73]. Furthermore, an association has been described between periaortic adipose tissue and peripheral arterial disease [74]. In a welldesigned experimental mouse study, transplantation of visceral adipose tissue immediately adjacent to the common carotid artery but not subcutaneous adipose tissue resulted in accelerated regional atherosclerosis [75]. 5. Dynamic changes of visceral adipose tissue with pharmacological and non-pharmacological interventions Interventional and observational studies have addressed the dynamic changes of visceral adipose tissue under different conditions. Weight loss was very effective in reducing abdominal VAT [76] and slightly less efficacious in reducing EAT [77,78]. In one study, the regression of EAT volume was accompanied by a reduction in the serum level of the pro-inflammatory CD40 ligand [75]. Bariatric surgery in morbidly obese patients restored the anticontractile activity of perivascular adipose tissue observed in lean adults along with measurable improvements in insulin sensitivity, reduction in inflammatory cytokines and systolic blood pressure [79]. Treatment with ezetimibe reduced VAT volume and increased serum adiponectin levels in patients with the metabolic syndrome [80]. Finally, intensive lipid-lowering therapy with statins resulted in greater decreases in EAT (3% per year) compared to moderate lipid-lowering therapy (0.9% per year) in postmenopausal women [81]. 6. Pathophysiological mechanisms The exact mechanisms by which visceral adipose tissue predisposes to atherosclerosis development are unknown, although several plausible mechanisms may be involved in this process. Large VAT volumes have been repeatedly associated with the presence of traditional cardiovascular risk factors, such as hyperlipidemia, arterial hypertension and diabetes mellitus or impaired glucose tolerance and the presence of the metabolic syndrome [82]. The endocrine, metabolic, and inflammatory activities of VAT appear to play a systemic role [83,84]. A local, paracrin effect may be primarily involved in the proatherogenic activity of EAT and perivascular adipose tissue where no fascia separates the adipose tissue from the adventitia of the arteries. This may allow direct access of humoral and cellular inflammatory mediators to the adventitia of the vessel wall with proliferation of vasa vasorum and growth of subendothelial atherosclerotic deposits [84]. In the EAT of patients with established coronary artery disease there is a pathological increase in the expression of inflammatory humoral mediators and their messenger RNA along with a dense infiltration of inflammatory cells; such changes are not observed in the subcutaneous tissue of the same patients [85e89]. The inflammatoryproatherogenic milieu is more accentuated in patients with acute coronary syndromes than in patients with stable coronary artery disease [89,90]. Adipocytes are capable of secreting numerous adipocytokines that can affect metabolic, inflammatory and vascular pathways; some of them, plasminogen activator inhibitor type-1 (PAI-1), tumor necrosis factor-a, interleukin 1 and 6, monocyte chemo-attractant protein 1 (MCP-1), angiotensin II, and cholesteryl ester transfer protein, are also produced in other tissues, and have systemic as well as local pro-inflammatory activities and can reduce the insulin sensitivity of adipocytes [91]. Others, like adiponectin, leptin, and resistin, are preferentially or specifically produced and secreted by adipocytes [92e94]. There appears

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to be substantial differences between EAT and VAT as far as the ability to secrete adipocytokines. Chen et al., [95] reported that the concentration of TNF-alpha, IL-6, visfatin and leptin was elevated in both VAT and EAT of patients with established coronary artery disease, and adiponectin levels were suppressed in both. However, the overexpression of noxious cytokines and the under-expression of adiponectin were significantly greater in the VAT than EAT of these patients. Additionally, the adipocytes in the epicardial location are smaller than those found in all other fat depots and a larger size adipocyte is believed to be able to secrete larger amounts of cytokines [96,97]. Whether this is an indication that VAT has a greater propensity to induce atherosclerosis development than EAT is unknown at this time. Several other factors, however, may render EAT proatherogenic. EAT appears to have a higher turn-over (uptake and secretion) of free fatty acids (FFA) than other visceral fat deposits, although VAT is also capable of secreting large quantities of FFA [98]. Additionally, increased lipolysis and increased concentration of saturated FA with lower concentrations of unsaturated FA have been demonstrated in EAT compared to other fat deposits [99]. Hence a combination of local and systemic mechanisms is most likely responsible for the pro-atherogenic effects of visceral adipose tissues [22,43,100]. 7. Conclusion Visceral adipose tissues (intra-abdominal and intra-thoracic) are metabolically active and are the source of humoral and cellular inflammation in obese patients and patients with established coronary artery disease. Whether the inflammation in these tissues predisposes to the development of arterial disease or is the consequence of such process is still speculative. However, the role of cellular inflammation in particular is increasingly being recognized in other cardiovascular disease states such as hypertension where it seems to have a substantial promoter role [101,102]. Both types of visceral adipose tissues have been linked with prevalent and incident atherosclerotic events and with numerous markers of sub-clinical atherosclerosis, often independent of other cardiovascular risk factors. Regression has been noted with both pharmacological and non-pharmacological interventions, but its clinical significance remains uncertain. Both intra-abdominal and intrathoracic adipose tissues can be easily measured with CT, but can also be assessed with MRI and echocardiography in the specific case of epicardial fat. Given the predictive power of these new markers of risk, it may be appropriate to start noting and reporting information regarding visceral fat deposits in the numerous noninvasive imaging tests acquired daily in patients at risk of developing cardiovascular disease. Acknowledgments This work was supported in part by a grant from the Stavros Niarchos Foundation (Nikolaos Alexopoulos, MD). References [1] Shen W, Wang Z, Punyanita M, et al. Adipose tissue quantification by imaging methods: a proposed classification. Obes Res 2003;11(1):5e16. [2] Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 2013;27(3):234e50. [3] Barak Y, Nelson MC, Ong ES, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999;4(4):585e95. [4] Despres JP. Body fat distribution and risk of cardiovascular disease: an update. Circulation 2012;126(10):1301e13. [5] Raggi P, Alakija P. Epicardial adipose tissue: a long-overlooked marker of risk of cardiovascular disease. Atherosclerosis 2013;229(1):32e3. [6] Nakamura T, Tokunaga K, Shimomura I, et al. Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men. Atherosclerosis 1994;107(2):239e46.

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