Atherosclerosis 230 (2013) 177e184
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Review
Perivascular adipose tissue in the pathogenesis of cardiovascular diseaseq Hae-Young Lee a, Jean-Pierre Després b, Kwang Kon Koh c, * a
Division of Cardiology, Seoul National University College of Medicine, Seoul, Republic of Korea Quebec Heart and Lung Institute, Department of Kinesiology, Faculty of Medicine, Université Laval, Quebec, Canada c Division of Cardiology, Gachon University Gil Hospital, 1198 Kuwol-dong, Namdong-gu, Incheon 405-760, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 March 2013 Received in revised form 6 July 2013 Accepted 14 July 2013 Available online 27 July 2013
Adipose tissue, which has been considered mainly as a site of energy storage and mobilization, is found in many depots throughout the body. Adipose depots may have structural properties such as, for instance, the fat pads located in the hands and feet and the periorbital fat supporting the eyes. Adipose tissue also shows remarkable regional heterogeneity. For instance, substantial differences have been reported in the metabolic properties of visceral (intra-abdominal) vs. subcutaneous adipose depots. Visceral adipose tissue (VAT) has active endocrine and paracrine functions with the secretion of various pro-inflammatory chemokines potentially contributing to the progression of atherosclerosis related with obesity. In addition, adipose depots surrounding the heart, such as epicardial (EAT) and perivascular adipose tissues (PAT) may also exert important roles in the pathogenesis of cardiovascular disease beyond the contribution of VAT due to their close anatomic relationships with vascular structures and myocardium. The purpose of the present review is to outline the current understanding of the pathophysiological links between EAT, PAT and atherosclerotic cardiovascular disease. Also, we discuss the current investigative methods for PAT quantification and discuss the potential impact of PAT on cardiovascular risk prediction. Finally, potential clinical implications of these notions are discussed. Ó 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Perivascular adipose tissue Cardiovascular disease Risk factor
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .177 Imaging modalities to assess PAT quantity/quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .178 Paracrine and endocrine effects of PAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .179 Quantification of PAT in cardiovascular risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .180 Treatment to reduce PAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .182 Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .182 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .182 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
1. Introduction
q We delivered a part of this paper in the World Congress of Cardiology 2012 Scientific Meeting in April 21, Dubai, Arab Emirates. * Corresponding author. Tel.: þ82 32 460 3683; fax: þ82 32 460 3117. E-mail addresses:
[email protected],
[email protected] (K.K. Koh). 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.07.037
Adipose tissue/fat accumulation in the heart can be classified according to its anatomic location: 1- intramyocardial fat, which lies within the myocardium itself; 2- epicardial adipose tissue (EAT), which is located between the myocardium and the pericardium, directly in contact with the coronary arteries; 3- pericardial adipose tissue, which is located between the visceral and parietal pericardium; and 4- paracardial adipose tissue, which is intrathoracic fat
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located outside the pericardium (Fig. 1) [1,2]. Within the EAT, coronary perivascular adipose tissue (PAT) is defined as the fat surrounding coronary arteries. PAT may serve a supportive role by attenuating vascular tension, torsion and by providing insulation. In addition, PAT is widely accepted to play an endocrine and paracrine action maintaining vascular tone during healthy condition, but may contribute to the progression of obesity-associated atherosclerosis [3,4]. As there is no facial layer separating PAT from the vascular wall, adipocytes can infiltrate into the outer region of adventitia [5]. EAT differs from pericardial/paracardial adipose tissue in its embryonic origin and blood supply. Notably, EAT and the myocardium share the same microcirculation [6]. EAT has the same embryologic origin as omental and mesenteric adipose tissue, and thus is capable of comparable production of cytokines and adipokines as visceral adipose tissue (VAT), which will be further discussed in a later section [7]. Compared with subcutaneous adipose tissue (82e97% of total fat) and VAT (10e15% of total fat), PAT including EAT represents a very low proportion (0e3%) [8] of total body fat and its quantity correlates with VAT [9,10]. However, due to anatomical proximity, PAT could have a stronger influence on the cardiovascular system than what could be expected from its small absolute mass. Indeed, some investigators have suggested that PAT may be a risk marker of cardiovascular disease independent of traditional measures of obesity [11]. For instance, enlargement/dysfunction of PAT may generate a pro-inflammatory profile which could contribute to the formation of instable/fragile plaques prone to rupture and to atherothrombosis [12]. 2. Imaging modalities to assess PAT quantity/quality Adipose tissue can be measured by computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy, echocardiography, or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Among them, MRI and CT are considered as the gold standard methods [13]. In general, CT provides a more accurate quantification of adipose tissue due to its higher spatial resolution compared with MRI or ultrasound [14]. CT evaluation is highly reproducible and requires less scanning time than MRI. Although high cost and radiation exposure are substantial barriers to their widespread use, the overall radiation dose from CT evaluation can be minimized by limiting the number of axial images. EAT volume measurement by CT is performed by tracing regions of interest on short axis views
[2]. EAT volume can be calculated by adding up the traced areas which are measured from the apex of the heart to the center of the left atrium taking into account slice thickness and intersection gap between slices. Adipose tissue voxels are usually identified as contiguous 3D voxels of 190 to 30 Houndsfield Units. Perivascular coronary adipose tissue volume can be measured on axial views perpendicular to the surface of the heart [12]. Traditional CT evaluation method is 2D short-axis based, whereas 3D segmentation methods are under investigation, as recent findings have suggested a better resolution of EAT volume with the 3D approach [15]. However, there is a trade-off. Reducing the number of axial images to limit radiation dose will obviously result in a reduced 3D resolution. MRI is now privileged over CT for quantification of fat volume around the heart, because MRI can use multiple axes of asymmetric 3D cardiac structures. Furthermore, MRI can evaluate aortic stiffness and cardiac diastolic and systolic function simultaneously without specific manipulation. Recently, MR spectroscopy has been shown to be useful to assess myocardial triglyceride content [16]. Transthoracic echocardiography is also used for the estimation of epicardial fat thickness. In 60 healthy individuals covering a wide range of adiposity values, EAT thickness as measured by echocardiography was found to be well correlated with VAT as determined by MRI [9]. In addition, echocardiographic EAT thickness was significantly correlated with body mass index, waist circumference, obesity index, body fat percentage, systolic blood pressure, as well as with insulin, leptin and adiponectin levels in the obese population [17]. Although echocardiography provides a simple and convenient estimation of EAT thickness, it is difficult with this technique to discriminate epicardial from pericardial adipose tissue. Furthermore, due to the limitation of echocardiographic window, echocardiographic evaluation of epicardial fat thickness is usually limited to the lateral wall of the right ventricle in parasternal long-axis view. Because EAT is not uniformly distributed around the heart with individual differences in heart fat distribution, it is important to point out that echocardiographic evaluation cannot provide an accurate estimate of the total amount of EAT. FDG-PET combined with computed tomography is useful in evaluating adipose tissue inflammation as well as adipose tissue metabolism including brown and white adipose tissue ratio [18]. Lastly, in small animal models such as rodents, adiposity has been quantified by dual-energy X-ray Absorptiometry, weighing of abdominal and subcutaneous fat pads, micro-MRI, or multi-echo MR. Currently, micro-CT offers higher spatial resolutions and may
Fig. 1. Nomenclature of adipose tissue around the heart. This figure has been modified from a previous version published in Gorter et al. [2]. Quantification of epicardial and pericoronary adipose tissue using cardiac computed tomography. Reproduced with permission from the publisher.
H.-Y. Lee et al. / Atherosclerosis 230 (2013) 177e184
be the best suited imaging modality for small animals [19]. For example, dual-energy X-ray Absorptiometry may greatly overestimate total fat mass when compared with micro-CT due to poor image resolution [20]. The imaging modalities frequently used for the evaluation of PAT are summarized in Table 1. 3. Paracrine and endocrine effects of PAT PAT is a source of endocrine and paracrine cytokines, substrates, and adipokines. PAT mainly consists of adipocytes and tissue macrophages, both of which have secretory capacities. Whereas visceral adipose tissue, liver fat and skeletal fat volumes affect global cardiometabolic risk profile, PAT may rather contribute to cardiovascular risk largely through paracrine actions to the local organs by direct diffusion [21,22]. The accumulation of lipids in visceral organs such as liver and muscles alters glucose and insulin metabolism, and thus modulates insulin resistance [23]. Although intrahepatic fat and intramuscular fat have a volume that is much smaller than VAT, they may have important systemic effects that contribute to metabolic abnormalities. However, the relative importance of these various fat depots and their contributions to systemic metabolic derangements remain unclear, and is an active area of investigation. In contrast to the ectopic fat depots with predominantly systemic metabolic effects, fat depots surrounding the heart and blood vessels and within the renal sinus are postulated to have primarily local effects. Increasing body weight may directly influence the heart by at least 2 mechanisms: 1- accumulation of adipose tissue surrounding the heart and coronary arteries; 2- lipid accumulation within cardiomyocytes. Obesity appears to reduce the physiological effect of PAT on smooth muscle migration. These derangements in the function of PAT appear to be related to infiltration of the adipose tissue by macrophages and upregulation of inflammatory adipokines. Epicardial fat harvested at the time of coronary artery bypass surgery was found to have higher levels of pro-inflammatory mediators in comparison with subcutaneous fat. Renal sinus fat has been postulated to affect kidney function by compressing blood vessels as they exit the kidney. Renal sinus fat was found to be associated with both hypertension and chronic kidney disease even after adjustment for cardiovascular risk factors, including VAT (Fig. 2) [22]. In 1987, the expression of the angiotensinogen gene in rat periaortic adipocytes was first reported by in situ hybridization [24]. In 1991, PAT, harvested from thoracic aorta of male Sprague-Dawley rats, was reported to play an important role in both norepinephrine clearance and release [25]. In 2002, “adventitium-derived relaxing factor” (ADRF) was found in adipocytes isolated from adult Sprague-Dawley rats [26]. Of note, endovascular injury upregulated pro-inflammatory adipocytokines and down-regulated adiponectin within PAT in models of mouse femoral artery wire injury [27]. There is still controversy as to whether or not PAT
Table 1 Clinically applicable imaging modalities for evaluation of perivascular and epicardial adipose tissue. Methods
Ultrasound
CT
MRI
MR spectroscopy
PET
Cost Specificity Accuracy Functional evaluation Reproducibility Quantitative assessment Qualitative assessment Radiation exposure Metabolism assessment
þ þþ þ þþ þ
þþ þþþ þþþ þþ þ þ
þþþ þþþ þþþ þþ þþþ þþ þ
þþþ þþþ þ þþþ þþ þ
þþþ þþ þ þþþ þ þ
179
should be considered as a white or brown adipose tissue. Although the expression of brown adipocyte-related genes such as uncoupling protein 1 is higher in PAT than in subcutaneous adipocytes, the absolute levels are 1000-fold lower compared to brown adipocytes [5]. These results suggest that human PAT is mainly composed of white rather than brown adipocytes. Recently, Chechi et al. reported brown adipose tissue gene expression in EAT which correlated with high-density lipoproteincholesterol and triglycerides in patients with coronary heart disease [28]. Thus, in addition to protecting the heart from hypothermia, variation in brown adipose tissue content/properties in EAT could have metabolic consequences. It has therefore been suggested the brown adipose tissue content/activity of EAT could be a factor modulating the balance between pro/anti-atherogenic (and inflammatory) properties of EAT. These findings open new perspectives in our understanding of the morphology/metabolism of EAT/PAT as a regulator of CAD risk and as a possible therapeutic target. In the non-obese state, PAT regulates vascular responsiveness. Ex vivo studies in organ chamber assays using rat aorta or porcine coronary artery indicate that vasoconstriction is blunted when PAT remains intact, suggesting the existence of a still unidentified ADRF [25,26]. In the healthy lean state, adiponectin and ADRF are released by perivascular fat to decrease contractile responses to vasoconstrictive agents, thus exerting a protective anti-hypertensive function via the control of vasodilation [29,30]. Moreover, resident macrophages harvested from lean mice increase the release of the antiinflammatory cytokine, interleukin-10, which is markedly reduces in high-fat fed mice [31]. Another important vascular relaxing factor is adrenomedullin. Adrenomedullin levels in the coronary artery were reported to be lower in coronary artery disease (CAD) patients than in non-CAD patients who underwent valve replacement surgery and epicardial fat adrenomedullin gene and protein expression were also found to be down-regulated in CAD subjects [32]. The possible contribution of perivascular adipocytes to the regulation of vascular tone and remodeling is important because of the current obesity, diabetic and hypertensive epidemic [33]. Although PAT may play a beneficial role in the non-obese state, PAT could promote vascular dysfunction and atherosclerosis in the setting of metabolic derangement [29]. In metabolic and cardiovascular disease states, PAT expands, becomes hypoxic and dysfunctional, and recruits phagocytic cells [34,35]. The changes in adipocyte size and increase in macrophage and T cell infiltration reduce the production of protective adipokines and rather increase the production of detrimental adipokines such as leptin, resistin, chemerin, vaspin, interleukin-6, or tumor necrosis factor-a (TNF-a) both in human adipose tissue and in ob/ob mice [35,36]. These molecules can directly diffuse into the myocardial tissue and vessel walls, altering the balance between vasodilatory molecules such as nitric oxide and vasoconstricting molecules [1]. For example, TNF-a and interleukin-6 have been shown to reduce the vasodilatory response of healthy blood vessels, which is similar to the obese phenotype [29]. PAT was also found to be negatively correlated with post-ischemic increase in blood flow [37]. Small arteries from the visceral adipose tissue of obese patients are characterized by an increased TNF- a production, which reduces NO availability by promoting superoxide generation [38]. Recently, aorta harvested from obese mice, which were surrounded by PAT, exhibited decreases of lysyl oxidase activity and cross-linked elastin, and increases of elastin fragmentation [39]. In vitro studies revealed that the conditioned medium from PAT of ob/ob mice attenuated lysyl oxidase activity. In contrary, inhibition of lysyl oxidase in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity, suggesting the role of PAT in vascular stiffness.
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Fig. 2. Model proposed by Britton and Fox to classify ectopic fat depots and their potential systemic and local effects [22]. Reproduced with permission from the publisher.
Serum levels of various pro-inflammatory cytokines are increased in obese people with high levels of VAT, suggesting their possible involvement in obesity-associated cardiovascular complications [40e 42]. Adiponectin protein expression in EAT has been shown to be lower in patients with CAD compared to non-CAD patients [43]. Conversely, samples of PAT from CAD patients showed increased expression of inflammatory cytokines relative to subcutaneous fat [44]. Pericardial, perimuscular, perivascular, orbital, and paraosseal adipose depots also have lipolytic and inflammatory activities via dysregulated local secretion of vasoactive and inflammatory factors. Pathogenic PAT may directly contribute to atherosclerosis through an “outside to inside” inflammatory atherogenic “signal” conveyed through vasa vasora [45]. The concentrations of TNF-a, interleukin-6, visfatin and leptin in supernatants of incubated EAT from CAD patients were found to be higher than in those from patients without CAD [46]. Interestingly, obese individuals with reduced adipose tissue inflammation markers such as inflamed macrophage having crown-like structures show lower matrix metalloproteinase-9, leptin, low density lipoprotein and C-reactive protein concentrations than obese individuals with high adipose tissue inflammation markers, suggesting two phenotypes within obesity [47]. Perivascular adipocytes exhibit reduced differentiation, showing dramatically lower expression of adipocytic differentiation related genes than subcutaneous and visceral regions. Morphological appearance of perivascular adipocytes was less than half the diameter of their subcutaneous and visceral counterparts, suggesting that perivascular adipocytes exist in a more primitive adipocytic state [5,48]. On the other hand, inflammatory gene expression was significantly higher, whereas anti-inflammatory adipokines were markedly reduced in perivascular adipose tissue [5]. Proinflammatory PAT might link metabolic signals to inflammation in the blood vessel wall [5]. Dysfunctional PAT can stimulate smooth muscle cell proliferation and the progression of atherosclerosis, which is enhanced in aged Wistar-Kyoto rats and in high-fat, dietinduced obese Zucker rats [49]. Resistin secretion was reported to be increased in EAT from CAD patients, acting as a chemotactic stimulus to macrophage recruitment [50]. Interleukin-8 and monocyte chemoattractant protein-1 also appear to mediate the migration of granulocytes, monocytes and activated T cells [35]. However, there is little possibility that obesity induces phenotypic change of perivascular adipocyte. Rather, local hypoxia by rapid expansion of adipocyte overwhelming vascular development might trigger
inflammatory response. Local hypoxia, not phenotypic change of adipocyte, might be key mechanism amplifying obesity-related inflammatory response from the pro-inflammatory perivascular adipocyte. Similarly, both pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages have been reported to be increased in EAT of CAD patients. However, the ratio of M1/M2 was found to be significantly increased by systemic recruitment of M1 macrophage, suggesting a shift toward a pro-inflammatory state [51]. Expression of pro-inflammatory cytokines was positively correlated whereas expression of anti-inflammatory cytokines was negatively correlated with the ratio of M1/M2 macrophages in EAT of CAD patients. By contrast, there was no significant difference in macrophage infiltration and cytokine expression in subcutaneous adipose tissue between CAD and non-CAD groups [52]. Inflammatory macrophages may express platelet-derived growth factor in adipose tissue to facilitate leaky and unstable capillary formation [34]. Plaque neoangiogenesis is associated closely with plaque progression, intraplaque hemorrhage, and rupture [53]. Those effects of PAT are summarized in Fig. 3. Also, paracrine and endocrine effects of PAT are summarized in Table 2. Finally, although adipocytes of PAT and EAT have been reported to be smaller in size than subcutaneous adipocytes, the magnitude of the individual variation in PAT/EAT fat cell size has not been documented, nor has the putative associations between morphological differences in PAT/EAT vs. cardiometabolic risk profile/CAD. This represents another important area of investigation for the future. 4. Quantification of PAT in cardiovascular risk assessment Intramyocardial lipid accumulation represents a manifestation of ectopic fat storage in individuals with impaired glucose tolerance and type-2 diabetes mellitus [54]. Furthermore, PAT has been proposed as important ectopic lipid markers of cardiovascular risk [55]. Indeed, PAT has been shown to be negatively correlated with insulin sensitivity and the post-ischemic increase in blood flow, which was independent of age, sex, VAT, liver fat, body mass index and of other cardiovascular risk factors [37]. Similarly, in the Framingham heart study, pericardial adipose tissue has been associated with higher triglycerides, lower high-density lipoprotein, hypertension, impaired fasting glucose, diabetes mellitus and metabolic syndrome after multivariate adjustment including body mass index and waist circumference [56]. However, these associations did not persist after
H.-Y. Lee et al. / Atherosclerosis 230 (2013) 177e184
Metabolic disease
Healthy, lean body
Resting adipocyte
181
Resident macrophage
Adiponectin
Adipocyte expansion
Interleukin-8 Resistin MCP-1
Hypoxia Dysfunction
Adipocyte derived Relaxing factor (unidentified)
Interleukin-10
Macrophage, T cell recruitment Leptin TNF-α Visfatin Interleukin-6
Mintenance of vasodilating response
Antiinflammation
Vasoconstriction
SMC proliferation Inflammation Plaque rupture
CAD, hypertension
Fig. 3. Schematic diagram summarizing the difference of perivascular adipose tissue between healthy lean individuals and obese patients. TNF-a, Tumor necrosis factor-a; MCP-1, Monocyte chemoattractant protein-1; SMC, Smooth muscle cell; CAD, Coronary artery disease.
adjustment for VAT. PAT was also reported to be associated with coronary artery calcification in post-menopausal women [57]. Although many studies have reported that PAT quantity is correlated with risk factors of CAD [58e60], the causal relation between PAT and CAD cannot be established at this time because the amount of VAT, which is well known to secrete various inflammatory cytokines [61], is increased in most patients with high levels of PAT. Therefore, adjustment for VAT is important, considering that VAT can act as a strong confounding variable in the relation between PAT and CAD. In this regard, the impact of different ectopic Table 2 Paracrine and endocrine effect of PAT. Paracrine and endocrine effects
Secreting condition
Reference
Non-obese Non-obese
[24] [26]
Down-regulated in CAD
[27]
Neurohormonal regulation Angiotensinogen Angiotensin-II
Non-obese Non-obese
[24] [24]
Anti-inflammatory mediator release Interleukin-10
Non-obese
[30]
Inflammatory mediator release Leptin Resistin Tumor necrosis factor-alpha (TNF-a) Interleukin-6 Visfatin Chemerin Vaspin Matrix metalloproteinase-9 (MMP-9) C-reactive protein (CRP)
Obese, Obese, Obese, Obese, Obese, Obese, Obese, Obese Obese
[34,45,46] [34] [34,45] [34,45] [34,45] [35] [35] [46] [46]
Maintenance of vascular tone Adiponectin Adipocyte-derived relaxing factors (unidentified) Adrenomedullin
Chemotaxis of pro-inflammatory cells Resistin Interleukin-8 Monocyte chemoattractant protein-1 (MCP-1)
CAD CAD CAD
CAD CAD CAD CAD CAD CAD CAD
[49] [49] [49]
lipid depots on metabolic dysfunction and cardiovascular disease risk estimated by Framingham score was examined [62]. It was found that after controlling for gender and body mass index by multivariable analysis, VAT but not PAT could discriminate cardiovascular disease risk profile. VAT is a much larger depot than PAT. On that basis, VAT is a stronger correlate of most metabolic risk factors than PAT whereas it is still debated whether PAT and pericardial adipose tissue could make additional paracrine effect to the adjacent cardiovascular systems. Nonetheless, because pericardial, perimuscular, perivascular, orbital, and paraosseal adipose tissue depots have lipolytic and inflammatory activities, pericardial and perivascular adiposopathy may have direct pathogenic effects on the myocardium, coronary arteries, and peripheral vessels via dysregulated local secretion of vasoactive and inflammatory factors. PAT may exert potent local toxic effect on the vasculature due to close proximity to the arteries and, also directly contribute to atherosclerosis through an “outside to inside” inflammatory atherogenic model through vasa vasora [63]. Absence of atherosclerosis in coronary artery segments with myocardial bridges where epicardial fat did not cover coronary artery suggest a causal relation between PAT and atherosclerosis [64]. Many reports have suggested that PAT might exert toxic ‘vasocrine’ effects independent of VAT. In 1205 participants from the Framingham Heart Study Offspring cohort, periaortic fat was associated with clinical spectrum of atherosclerosis from low ankle-brachial index to peripheral arterial diseases in multivariable logistic regression after adjusting for body mass index or VAT [65]. This data suggest that perivascular adipose tissue may play an independent role in the pathogenesis of arterial stiffness and insulin resistance by direct vascular effects influencing muscular blood flow. Furthermore, in the same cohort, pericardial adipose tissue was reported to be associated with coronary artery calcification even after multivariable and VAT adjustment [56]. The correlation between EAT and coronary calcification was also observed in other cohorts although no adjustment for VAT had been performed [59,60]. Furthermore, EAT volume had a stronger correlation with CAD than VAT in both obese and non-obese population [11]. Pericardial adipose tissue has also been found to be an independent risk factor of CAD assessed by MDCT. Patients with atherosclerotic
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lesions have significantly larger volume of pericardial adipose tissue than patients without atherosclerosis. In a multivariate regression analysis adjusting for age, gender and body mass index, subjects with more pericardial fat had a higher risk for significant (>50%) stenosis of coronary vessels. In the MESA cohort, pericardial adipose tissue was associated with carotid artery stiffness even after adjusting for body mass index and waist circumference [66]. In another study, EAT was significantly correlated with arterial stiffness measured by cardio-ankle vascular index. EAT showed an independent association with arterial stiffness after adjustment for several variables including VAT [67]. In addition to their vasocrine effect, EAT and PAT could also be related to cardiac function. Subjects with increased ectopic adipose tissue including VAT and PAT had impaired cardiac systolic [68] and diastolic function [69]. Because cardiac lipotoxicity could be involved in the development of cardiomyopathy, the association of epicardial and intramyocardial fat with cardiomyopathy was studied. Incidence of cardiomyopathy was found to be higher in an animal model of obesity [70] and also in patients with impaired glucose and fatty acid metabolism [71]. The associations of pericardial adipose tissue with measures of cardiac structure and function, and clinical cardiovascular disease, have been investigated. Pericardial adipose tissue volume assessed by MDCT was found to be positively associated with MRI measured left atrial size in men [72]. Subsequent work supported these findings by demonstrating a positive association between pericardial adipose tissue and prevalent atrial fibrillation [73]. Although some studies have suggested a link between abdominal obesity and the risk of stroke [74] or aortic stenosis [75], no data are currently available on the potential associations between PAT and these clinical outcomes. It has been suggested that the importance of the relative contribution of all adipose and ectopic lipid depots (including EAT and PAT) to complications may depend upon the outcome considered [55]. For instance, it is likely that insulin resistance may be more closely driven by VAT, liver fat and muscle fat content, whereas it is possible that excess PAT/EAT may be associated with metabolic derangements contributing to generate instable coronary plaques from prone to rupture, leading to an acute coronary syndrome. 5. Treatment to reduce PAT It is well documented that weight loss can induce reductions in all ectopic fat depots [55]. Therefore, weight reduction can significantly reduce EAT mass [76]. Indeed, EISNER (Early Identification of Subclinical Atherosclerosis using Non-invasive Imaging Research) Registry showed close correlation between weight reduction and epicardial fat volume reduction and also weight gain and epicardial fat increase [77]. Interestingly, EAT reduction during weight loss is generally larger than the decrease in common indices of body fatness and the reduced EAT adiposity has been reported to be maintained despite regain in body weight and VAT [76,78]. On the contrary, weight reduction by bariatric surgery showed superior effect on VAT reduction compared with epicardial and intramyocardial fat reduction [79]. Difference in patients’ characteristics could contribute to explain these heterogeneous responses. Pharmacologic agents such as peroxisome proliferator activated receptor-g agonist may reduce epicardial fat thickness. However, human studies are controversial. Pioglitazone treatment decreased the secretion of inflammatory markers [80], but pericardial fat volume was reported to be increased after pioglitazone treatment [81]. Another promising result came from HMG-CoA reductase inhibitors. In the substudy of the BELLES Trial (Beyond Endorsed Lipid Lowering with EBT Scanning), statin therapy, especially high dose, appears to induce EAT regression in hyperlipidemic postmenopausal women [82]. Although the absolute reduction of EAT
by statin is small (3.38% for 1 year in the BELLES trial) [82], statin therapy might be effective in reducing inflammatory response from PAT [83] and replenish adiponectin production beyond PAT volume reducing effect [84]. Ezetimibe alone or with statin was also found effective in visceral adipose tissue regression of VAT and increase in adiponectin in the absence of weight changes [85,86]. These results are preliminary and further intervention studies are needed. The effect of agents potentially affecting total and regional adiposity indices on myocardial lipids as well as on epi-, peri and paracardial adipose tissue will require further studies. From the robust data available on the importance of various ectopic fat depots including PAT on cardiometabolic risk and various cardiovascular outcomes, it is clear that proper consideration for the effects of various pharmacotherapies and of lifestyle interventions on these important adipose/fat depots will have to be given in the future clinical trials. 6. Perspective Although our understanding of PAT has increased substantially, studies conducted have left us with many unanswered questions. Epidemiological studies have demonstrated associations between unique fat depots and cardiovascular disease. Further work will be needed to confirm whether causal relations drive these associations. From their known metabolic properties, PAT and EAT may exert a protecting role of vascular function in healthy subjects. However, their expansion in obesity and in patients with features of the metabolic syndrome may lead to the development of a prothrombotic and pro-inflammatory profile. Although PAT quantity is reported to be correlated with risk factors and metabolic complications, PAT mass is also correlated with the amount of VAT and with the size of other important ectopic lipid depots (liver, muscles, etc.). Therefore, the specific contribution of PAT to the development of cardiometabolic diseases remains to be established. However, due to its proximity to the vascular structure and the heart, inflammatory processes in an enlarged PAT depot may directly contribute to cardiovascular complications. Therefore, there may be different effects of adipose tissue at different locations and arteries. Technological advances in imaging techniques combined with in vitro work will allow us to answer these questions. Modulation of PAT size/activity in response to lifestyle intervention or selective pharmacotherapies may represent relevant approaches to manage the cardiovascular complications associated with cardiometabolic disorders such as metabolic syndrome, obesity, and diabetes mellitus. However, there is currently no consensus on the specific effect of PAT loss on clinical outcomes and these studies are already warranted. Meanwhile, the renewed interest for the fat tissue covering the heart and within it represents a fascinating and rapidly evolving field with tremendous implications in clinical and preventive cardiology. Acknowledgment This study was partly supported by grants from established investigator award (2010-1), Gachon University Gil Medical Center (K.K. Koh). Disclosures None. References [1] Iozzo P. Myocardial, perivascular, and epicardial fat. Diabetes Care 2011 May;34(Suppl. 2):S371e9 [Review].
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