Endocrine DOI 10.1007/s12020-013-0099-4
REVIEW
Epicardial adipose tissue in endocrine and metabolic diseases Gianluca Iacobellis
Received: 6 September 2013 / Accepted: 22 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Epicardial adipose tissue has recently emerged as new risk factor and active player in metabolic and cardiovascular diseases. Albeit its physiological and pathological roles are not completely understood, a body of evidence indicates that epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize, produce, and secrete bioactive molecules which are then transported into the adjacent myocardium through vasocrine and/or paracrine pathways. Based on these evidences, epicardial adipose tissue can be considered an endocrine organ. Epicardial fat is also thought to provide direct heating to the myocardium and protect the heart during unfavorable hemodynamic conditions, such as ischemia or hypoxia. Epicardial fat has been suggested to play an independent role in the development and progression of obesity- and diabetes-related cardiac abnormalities. Clinically, the thickness of epicardial fat can be easily and accurately measured. Epicardial fat thickness can serve as marker of visceral adiposity and visceral fat changes during weight loss interventions and treatments with drugs targeting the fat. The potential of modulating the epicardial fat with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. This review article will provide Endocrine’s reader with a focus on epicardial adipose tissue in endocrinology. Novel, established, but also speculative findings on epicardial fat will be discussed from the
G. Iacobellis (&) Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, 1400 NW 10th Ave, Dominion Tower Suite 805-807, Miami, FL 33136, USA e-mail: [email protected]
unexplored perspective of both clinical and basic Endocrinologist. Keywords Epicardial adipose tissue Epicardial fat Visceral adiposity Echocardiography
Introduction Epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize and secrete adipokines and bioactive factors that can reach out to the myocardium through vasocrine and/or paracrine pathways. Epicardial adipose tissue can be therefore considered an endocrine organ. As more novel and intriguing findings have been recently discovered, the interest into the epicardial fat is rapidly growing. This article wants to provide with an updated and comprehensive overview of the current notion concerning epicardial fat in the context of metabolic and endocrine disorders. Anatomy and embryology A brief introduction to the embryology and anatomy will help the reader in understanding most of the known or attributed properties of the human epicardial fat. The adipose tissue of the heart is divided into three layers: epicardial fat, the visceral layer, and pericardial fat, situated externally to the parietal layer of the pericardium [1–3]. Embryologically and anatomically, epicardial and pericardial fat are different [4]. Epicardial fat originates from the splanchnopleuric mesoderm, whereas pericardial fat originates from the primitive thoracic mesenchyme. Notably, epicardial evolves from brown adipose tissue [5]. Epicardial fat is supplied by branches of the coronary
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arteries, whereas pericardial fat is supplied by branches of noncoronary arteries. In the adult human heart, epicardial fat is more abundant in the atrioventricular and interventricular grooves. Epicardial fat can be further differentiated into myocardial and pericoronary epicardial fat [6]. Microscopically, epicardial fat is composed of mainly adipocytes, but it also contains nerve tissues, inflammatory, stromovascular, and immune cells [7]. Epicardial adipocytes are generally smaller than those located in subcutaneous and other visceral fat depots [8]. The highconsuming metabolism-preventing large lipid storage and the larger number of preadipocytes have been evoked to explain the smaller size of epicardial adipocytes [1, 2]. Remarkably, no muscle fascia divides epicardial fat and myocardium; therefore, the two tissues share the same microcirculation [2]. This allows a direct interaction and crosstalk between the epicardial fat and the myocardium. Physiology Under normal physiological conditions, epicardial fat could serve as a buffer, absorbing fatty acids and protecting the heart against high fatty acids levels and as pad-protecting abnormal curvature of the coronary arteries. It could also function as lipid storage and local energy source at times of high demand, channeling fatty acids to the myocardium, and as brown fat to defend the myocardium against hypothermia [1–4]. A role is controlling heart electrophysiology has been also suggested [1]. However, the physiological role of epicardial fat is still not being completely explored and understood. Epicardial fat as endocrine organ Epicardial adipose tissue can be considered an endocrine organ. It is a metabolically active organ and a source of several bioactive molecules that can influence the myocardium and coronary arteries [1–4]. Epicardial fat expresses and secretes a number of cytokines, pro- and anti-inflammatory adipokines, vasoactive factors, and growth factors [1, 2]. Whether epicardial fat exerts its function as paracrine, autocrine, or vasocrine organ will be briefly discussed in this article. Because of its anatomical proximity to the heart and the absence of fascial boundaries, epicardial adipose tissue may interact locally and modulate the myocardium and coronary arteries. Two major mechanisms of interaction between the myocardium and the epicardial fat, i.e., paracrine and vasocrine, have been suggested [4]. Paracrine release of cytokines from periadventitial epicardial fat could traverse the coronary wall by diffusion from outside-toinside. Given the dense inflammatory infiltrate within the human epicardial fat and its complex cellularity, it seems reasonable to suspect that cytokines are secreted by different
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cells. Adipokines secreted from epicardial adipocytes, stromal, and vascular cells may diffuse in interstitial fluid across the adventitia, media, and intima and then interact respectively with vasa vasorum, endothelial, and vascular smooth muscle cells of the coronary arteries. Alternatively, adipokines and free fatty acids (FFAs) might be released from epicardial tissue directly into vasa vasorum and be transported downstream into the arterial wall, in a vasocrine signaling mechanism [9]. Under pathological circumstances, epicardial fat releases factors that promote harmful coronary artery and myocardial changes. Epicardial fat as source of energy to the myocardium The myocardium uses and metabolizes FFAs from the coronary arterial blood, and FFA oxidation is responsible for about 50–70 % of the energy production of the heart. Epicardial adipose tissue has a greater capacity for FFAs release and uptake and lower rate of glucose utilization than any other visceral fat depot [10]. In fact, FFAs synthesis, rate of incorporation and breakdown are significantly higher in epicardial fat than in the other fat depots [10]. Hence, epicardial fat has been proposed to function as a buffer to protect the heart against exposure to excessively high levels of FFAs and to provide energy for the myocardium [1, 2]. Compared to subcutaneous adipose tissue, human epicardial fat appears to be rich in saturated fatty acids [11], such as myristic acid (14:0), palmitic acid (16:0), and stearic acid (18:0), whereas unsaturated fatty acids are lower. Given the absence of muscle fascia, FFAs are transported from the epicardial fat into the myocardium. FFAs could diffuse bidirectionally in interstitial fluid across concentration gradients. Epicardial adipose tissue might also secrete vasoactive products that regulate coronary arterial tone to then facilitate the FFAs influx. It is plausible that fatty acid-binding protein 4 participates in the intracellular transport of FFAs from the epicardial fat into the myocardium [12]. Epicardial adipose tissue as brown fat Brown adipose tissue generates heat in response to cold temperatures and activation of the autonomic nervous system. However, the role of brown fat in humans is unclear. Brown adipose tissue-specific gene uncoupling protein-1 (UCP-1) and other brown fat-related genes are all highly expressed in epicardial fat [13]. UCP-1 is significantly higher in human epicardial fat as compared to other fat depots, and basically undetectable in subcutaneous fat [13]. Clinically, a significant uptake of 18F-fluorodeoxyglucose (18F-FDG) by the heart suggested that brown adipose tissue may lie close to the heart, although it is more likely that the 18F-FDG signal actually comes from the
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myocardial tissue [14]. Although these recent findings are intriguing, the role of epicardial fat to serve as brown fat to the myocardium is far to be completely understood. Epicardial fat is thought to provide direct heating to the myocardium and protect the heart during a drop in core body temperature or during unfavorable hemodynamic conditions, such ischemia or hypoxia. This hypothesis may be supported by animal models. In fact, polar bears present large amounts of cardiac fat that can be used to store and supply energy to the myocardium during hibernation [9]. How and whether these observations can be translated to humans is unknown. Whether epicardial fat is a brown fat or it can function as brown fat-like depot is unclear and also topic of discussion. Very recently, small unilocular adipocytes without UCP-1 immunostaining have been described in epicardial fat, suggesting some histological similarities with those described in vitro in beige lineage adipocytes [15]. Epicardial fat and obesity Historically, obese individuals have been considered at higher cardiovascular risk than individuals with normal body weight. However, there is an almost univocal consensus in considering the visceral fat a stronger independent cardio-metabolic risk factor than overall obesity. Subjects with visceral fat accumulation are generally considered at higher risk for cardiovascular diseases than individuals with prevalent peripheral adiposity. The exact mechanisms that lead to a different anatomical fat accumulation in humans are still unclear. Different visceral fat depots seem to have different physiological and pathological properties. While most of the attention has been traditionally focused into the intraabdominal fat accumulation, epicardial adipose tissue has been only recently considered. Epicardial fat as marker of visceral fat It is certainly correct to state that obese subjects, both adults and children, present with higher epicardial fat than normoweight subjects [16]. However, a number of evidence indicates that epicardial fat should be considered primarily a marker of visceral adiposity. Epicardial fat thickness can be visualized and measured with standard two-dimensional echocardiography, as first proposed and validated by Iacobellis [17, 18] or with computed tomography techniques. Regardless of the measuring methodology, it has been well established that echocardiographic epicardial fat is actually a marker of visceral fat. Echocardiographic epicardial fat thickness is an independent predictor of visceral adiposity and weakly reflects the obesity degree as measured by body mass index (BMI). In
fact, echocardiographic epicardial fat strongly reflects the intraabdominal visceral fat as measured by magnetic resonance imaging and better than waist circumference does [16, 19]. Additionally, epicardial fat was associated with intramyocardial and intrahepatic fat accumulation, as measured by MR spectroscopy [20]. All together, this suggests that measuring epicardial fat provides a measure of visceral or better organ-specific adiposity.
Epicardial fat and the obese heart Recent evidence showed that obesity leads not only to increased fat depots in classical adipose tissue locations, but also to significant ectopic lipid accumulation and infiltration within and around other tissues and internal organs. Ectopic fat deposition may occur within the heart and affects its function. However, nonadipocytes and cardiomyocytes have a very limited capacity to store excess fat. Consequently, if they are exposed to high levels of plasma lipids, as usually occurs in obesity, they may undergo steatosis and loss of function, ultimately resulting in cardiac lipotoxicity. Visceral adiposity induces fatty infiltration of the myocardium by different mechanisms. An infiltration of adipocytes from the epicardial adipose tissue to the myocardium has been suggested and corroborated by clinical studies [21]. Imaging studies showed an independent and significant relation of epicardial fat, as measured with echocardiography, and intramyocardial lipid content, as measured by proton magnetic resonance spectroscopy [20]. Myocardial lipid content increases with the degree of adiposity and may contribute to the adverse structural and functional cardiac adaptations seen in obese persons. Clinically, epicardial fat has been associated with cardiac changes, commonly observed in obese subjects. In fact, increased epicardial fat has been associated with increased left ventricular mass and abnormal right ventricle geometry, as detected by echocardiography [22, 23]. Echocardiographic findings were in agreement with autoptic studies. Mechanical and biomolecular mechanisms have been evoked to explain these correlations. Increased epicardial fat by adding to the mass of the ventricles may increase the work of pumping. Increased left ventricular mass in morbidly obese subjects could be due to a direct effect of excess epicardial fat. Increase in epicardial fat was also significantly correlated with enlarged atria and impaired right and left ventricular diastolic filling in morbidly obese subjects [2]. Epicardial fat may directly contribute to impair diastolic function in subjects with increased visceral adiposity. A mechanical obstacle to diastolic filling due to the excessive epicardial fat can explain these findings.
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Effects of weight loss on epicardial fat Substantial and sustainable weight loss is the primary goal to reduce cardiometabolic risk in obese subjects. Nevertheless, whether the fat loss during weight loss interventions is uniform across body fat compartments is still unclear. Whether the proportion changes in overall and visceral adiposity can be different is partially unanswered. Visceral fat reduction is associated with a significant improvement of the cardiometabolic profile. However, it is presently unknown how much visceral adipose tissue loss is needed to induce favorable cardiac changes. In the phase of rapid weight loss after laparoscopic bariatric surgery, a preferential mobilization of visceral abdominal fat, as compared with total and subcutaneous adiposity, was observed. However, this preferential visceral fat reduction seems to occur only in those patients presenting higher levels of visceral fat deposition at baseline. Easy and reliable markers of visceral adiposity may therefore provide a more complete understanding of metabolic risk associated with variation in fat distribution. To answer, at least partially, this interesting question, epicardial fat served as therapeutic target during weight loss interventions. Epicardial fat has shown to significantly reduce after very low calorie diet, bariatric surgery, and moderate aerobic exercise [24–26], although postbariatric surgery results are not univocal [27]. Interestingly, echocardiographic epicardial fat has been reported to significantly and quickly decrease after a very low calorie diet in morbidly obese subjects. Changes in epicardial fat thickness were significantly higher than changes in BMI and waist circumference -32 % versus -23 % versus -19 % after the very low calorie diet program [24]. Changes in epicardial fat thickness were consensually and independently associated with the improvement in cardiac parameters in these subjects. Epicardial fat reduces with exercise in humans, but its inflammatory response to aerobic exercise seems to be variable in experimental models [26]. Epicardial fat and diabetes The role of visceral fat in the development and worsening of type 2 diabetes has been extensively studied. Nevertheless, an exclusive relation of epicardial fat with type 2 diabetes has been only recently evaluated. In particular, the potential of epicardial fat thickness in predicting glucose abnormalities was the object of interest. Epicardial fat thickness was measured in nondiabetic Caucasian subjects who underwent routine transthoracic echocardiogram [28]. Study subjects were designated as having normal fasting glucose and impaired fasting glucose (IFG) (fasting glucose between 100 and \126 mg/dl). Epicardial fat thickness was significantly higher in subjects with IFG and
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resulted in the best correlate of fasting glucose. Epicardial fat thickness was found higher in type 2 diabetic subjects with subclinical atherosclerosis [29]. The higher increase of trans and conjugated fatty acids in epicardial adipose tissue may contribute to atherosclerosis development and progression in diabetic patients [30]. However, larger studies will be required to establish an independent correlative or predictive role of epicardial fat in type 2 diabetes. Insulin resistance is another key component of type 2 diabetes. Epicardial fat thickness was associated with indices of insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, in obese subjects [31]. It was also related to surrogate markers of insulin resistance, as well as fasting insulin and Homeostatic Model Assessment –Insulin resistance (HOMA-IR) index in a nondiabetic adult population [31], prepubertal, and early pubertal children [32]. Different cut-off values of epicardial fat thickness for prediction of insulin resistance have been proposed [16]. Ethnicity and gender can explain the variability of epicardial fat thickness values and the differences among studies [33, 34]. The highest values of epicardial fat thickness were found in subjects presenting with large intraabdominal fat and severe insulin resistance [16]. While clinical data seem to provide quite robust evidences, epicardial fat expression of emerging adipokines linking type 2 diabetes [35] to insulin resistance will have to be evaluated. Diabetes is often associated with a peculiar and unique cardiomyopathy, although the causes are probably multifactorial and mechanisms are still being partially unclear. A recent experimental study conducted on rat cardiomyocytes showed that secretory profile of epicardial fat may contribute to the pathogenesis of diabetes mellitus-related cardiomyopathy [36]. While a relationship of a visceral fat depot with type 2 diabetes seems to be intuitive and somehow expected, the role of excessive visceral adiposity in subjects with type 1 diabetes has been only recently suggested [37]. In fact, very recent evidences pointed out a possible correlation between visceral fat and type 1 diabetes. One single study showed a relation of epicardial fat with central obesity in type 1 diabetic subjects [38]. Given its rapid metabolism and its simple objective measurability, epicardial fat can serve as target for pharmaceutical agents commonly used in both type 1 and type 2 diabetes. The effect on the epicardial fat mass and function by medications which are known to modulate the adipose tissue, such as statins and thiazolidinediones, has been evaluated. Interestingly, epicardial fat thickness reduced in diabetic subjects treated with atorvastatin in comparison with those who received simvastatin and ezetimibe [39]. Consistently, atorvastatin therapy induced a reduction of
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computed tomography-measured epicardial fat in hyperlipidemic postmenopausal women, as very recently reported [40]. The effect of atorvastatin on epicardial fat was independent of lipid lowering or coronary artery disease progression. In this context, it is certainly notable that epicardial fat overexpression of lipoprotein receptors such as low-density lipoprotein receptor-related protein 1 and very low-density lipoprotein receptor has been recently suggested to play a role in changes of lipid metabolism commonly associated with type 2 diabetes mellitus [41]. Thiazolidinediones were also targeted to the epicardial fat. Notably, epicardial fat inflammatory secretome improved with pioglitazone treatment [42]. In fact, treatment with pioglitazone in type 2 diabetic patients was associated with reductions in expression of interleukin-1b and other proinflammatory genes in epicardial fat [42]. Interestingly, a recent study reveals that peroxisome proliferator–activated receptor-c (PPAR-c) agonist can induce a rapid browning of the epicardial fat in experimental models [43]. Rosiglitazone treatment caused a significant upregulation of PPARc coactivator 1 alpha (PGC1-a), a key precursor of brown fat, in epicardial adipocytes of Zucker rats. In the past few years, new diabetic medications, such as glucagon like peptide-1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors, rapidly emerged. Of note, dipeptidyl peptidase-4 inhibitor treatment increased the levels of PGC-1 and UCPs in brown adipose tissue in mice with diet-induced obesity [44]. Future and more numerous studies looking at the effect of GLP-1 analogs and DPP4 inhibitors on the epicardial fat seem to be warranted. Epicardial fat thickness and metabolic syndrome Several clinical studies showed the relationship of echocardiographic epicardial fat thickness and metabolic syndrome. Epicardial fat thickness is usually significantly higher in subjects with metabolic syndrome than in subjects without metabolic syndrome [19]. When cardio-metabolic parameters are considered separately, epicardial fat is independently associated with blood pressure, low density lipoprotein cholesterol, fasting glucose, and inflammatory markers. A recent meta analysis conducted on nine studies showed that thickness was significantly higher in patients with metabolic syndrome than in those without [45]. Moreover, the meta analysis reported a significant variability of epicardial fat with ethnicity, with a greater difference in Caucasian subjects than in other ethnic groups. Different cut-off points of high-risk epicardial fat thickness for the prediction of metabolic syndrome have been proposed [16]. In a large observational study, receiver operating characteristics analysis showed that epicardial fat thickness values of 9.5 and 7.5 mm maximize the
sensitivity and specificity to predict the metabolic syndrome in men and women, respectively. Nevertheless, different epicardial fat values predicting the risk of developing metabolic syndrome have been reported in different ethnic and age groups. A larger and multiethnic population-based study would probably be necessary to establish high-risk epicardial fat thickness values. It could be hypothesized that higher epicardial fat might be implicated in the pathophysiology of metabolic syndrome, because it produces a number of factors that influence insulin sensitivity, inflammation, and visceral adiposity. However, it is probably more plausible that higher epicardial fat may serve as an objective and reproducible indicator of excessive visceral fat accumulation, the role of which in metabolic syndrome has been well described. Epicardial fat and other endocrine disorders The clinical use of epicardial fat thickness in endocrine disorders involving directly or indirectly the visceral adiposity will be briefly discussed here. Epicardial fat and adrenal incidentaloma It has been recently shown that epicardial fat thickness, as measured with echocardiography, was higher in subjects with adrenal incidentaloma when compared to healthy controls [46]. Additionally, epicardial fat thickness correlated with cardiac changes regardless of the presence of hypercortisolism. The clinical significance and management adrenal incidentalomas is object of recent debate. Recent data indicate that patients diagnosed with adrenal incidentaloma present with higher cardiovascular risk. Given that most of subjects with adrenal incidentaloma or mild Cushing’s syndrome are often asymptomatic for cardiovascular disease, the predictive role of epicardial fat thickness in detecting early cardiac changes would be of importance and deserve further studies. Epicardial fat and growth hormone deficiency Growth hormone deficiency (GHD) syndrome is characterized by an abnormal body fat distribution and increased visceral fat accumulation. Consequently, this syndrome is associated with an increased morbidity and mortality for cardiovascular diseases. Interestingly, significant reduction in epicardial fat thickness after recombinant human GH (rhGH) replacement therapy has been reported in both adolescents [47] and adults with GHD syndrome [48]. At baseline, subjects with adult-onset GHD syndrome showed higher epicardial fat thickness than controls, suggesting a higher visceral fat accumulation in these patients. Echocardiographic epicardial fat thickness significantly decreased
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internal organs, including the endocrine glands. Given that epicardial fat can be easily measured, its assessment may be an additional tool for the clinical endocrinologist too. Its measurement can serve as marker of visceral adiposity and rapid visceral fat changes during weight loss and pharmacological interventions targeting the adipose tissue. The potential of modulating the epicardial fat to its physiological functions with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. Conflict of interest
The author declares no conflict of interest.
References Fig. 1 Roles and clinical applications of epicardial adipose tissue in endocrinology. This graphic summarizes and depicts some features of the epicardial fat that are relevant in endocrine and metabolic diseases such as its biochemical and functional characteristics of an endocrine organ, its genetic and functional profile of brown fat, its role in the pathophysiology of obesity and diabetes-related cardiac changes, its function as marker of visceral fat and visceral fat changes during weight loss interventions, and its responsiveness to pharmacological agents targeting the fat
after short-term rhGH replacement therapy, whereas, neither waist circumference nor BMI showed significant changes during the replacement treatment [48]. Epicardial fat thickness may have potential to serve as rapid and sensitive marker of visceral fat reduction also during rhGH replacement treatment. Epicardial fat and polycystic ovary syndrome Patients with polycystic ovary syndrome commonly present with abdominal obesity and visceral adiposity. Epicardial fat thickness was higher in these patients than in controls [49]. Epicardial fat thickness was also correlated with markers of insulin resistance in patients with polycystic ovary syndrome [50].
Conclusions Epicardial fat displays some features that are relevant in endocrinology (Fig. 1). Epicardial adipose tissue is a unique fat depot with biochemical and functional characteristics of an endocrine organ. Given its peculiar anatomic location, its secretome is transported directly into the myocardium through paracrine and/or vasocrine mechanisms. These features may be of interest and object of research for the basic scientist committed to understand the complex interplay between the adipose tissue and the other
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1. G. Iacobellis, A.C. Bianco, Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trend. Endocrinol. Metab. 22, 450–457 (2011) 2. G. Iacobellis, D. Corradi, A.M. Sharma, Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat. Clin. Pract. Cardiovasc. Med. 2, 536–543 (2005) 3. P. Iozzo, Myocardial, perivascular, and epicardial fat. Diabetes Care 34(Suppl 2), S371–S379 (2011) 4. G. Iacobellis, Epicardial and pericardial fat: close, but very different. Obesity 17, 625 (2009) 5. J.M. Marchington, C.A. Mattacks, C.M. Pond, Adipose tissue in the mammalian heart and pericardium; structure, foetal development and biochemical properties. Comp. Biochem. Physiol. 94B, 225–232 (1989) 6. H.S. Sacks, J.N. Fain, Human epicardial adipose tissue: a review. Am. Heart J. 153, 907–917 (2007) 7. T. Mazurek, L. Zhang, A. Zalewski, J.D. Mannion, J.T. Diehl, H. Arafat, Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108, 2460–2466 (2003) 8. C. Bambace, M. Telesca, E. Zoico, A. Sepe, D. Olioso, A. Rossi, F. Corzato, V. Di Francesco, A. Mazzucco, F. Santini, M. Zamboni, Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc. Pathol. 20(5), 153–156 (2010) 9. J.S. Judkin, E. Eringa, C.D.A. Stehouwer, ‘‘Vasocrine signalling’’ from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 365, 1817–1820 (2005) 10. J.M. Marchington, C.M. Pond, Site-specific properties of pericardial and epicardial adipose tissue. The effects of insulin and high-fat feeding on lipogenesis and the incorporation of fatty acids in vitro. Int. J. Obes. 14, 1013–1022 (1990) 11. M. Pezeshkian, M. Noori, H. Najjarpour-Jabbari, A. Abolfathi, M. Darabi, M. Darabi, M. Shaaker, G. Shahmohammadi, Fatty acid composition of epicardial and subcutaneous human adipose tissue. Metab. Syndr. Relat. Disord. 7, 125–131 (2009) 12. B. Vural, F. Atalar, C. Ciftci, A. Demirkan, B. Susleyici-Duman, D. Gunay, Presence of fatty-acid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovasc. Pathol. 17, 392–398 (2008) 13. H.S. Sacks, J.N. Fain, B. Holman, P. Cheema, A. Chary, F. Parks, Uncoupling protein-1 and related mRNAs in human epicardial and other adipose tissues: epicardial fat functioning as brown fat. J. Clin. Endocrinol. Metab. 94, 3611–3615 (2009) 14. A.M. Cypess, S. Lehman, G. Williams, I. Tal, D. Rodman, A.B. Goldfine, F.C. Kuo, E.L. Palmer, Y.H. Tseng, A. Doria, G.M.
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15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Kolodny, Kahn CR Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009) H.S. Sacks, J.N. Fain, S.W. Bahouth, S. Ojha, A. Frontini, H. Budge, S. Cinti, M.E. Symonds, Adult epicardial fat exhibits beige features. J. Clin. Endocrinol. Metab. 98(9), 1448–1455 (2013) G. Iacobellis, H.J. Willens, G. Barbaro, A.M. Sharma, Threshold values of high-risk echocardiographic epicardial fat thickness. Obesity (Silver Spring) 16, 887–892 (2008) G. Iacobellis, H.J. Willens, Echocardiographic epicardial fat: a review of research and clinical applications. J. Am. Soc. Echocardiogr. 22, 1311–1319 (2009) G. Iacobellis, F. Assael, M.C. Ribaudo, A. Zappaterreno, G. Alessi, U. Di Mario, F. Leonetti, Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes. Res. 11, 304–310 (2003) G. Iacobellis, M.C. Ribaudo, F. Assael, E. Vecci, C. Tiberti, A. Zappaterreno, U. Di Mario, Leonetti F Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J. Clin. Endocrinol. Metab. 388, 5163–5168 (2003) A.E. Malavazos, G. Di Leo, F. Secchi, E.N. Lupo, G. Dogliotti, C. Coman, L. Morricone, M.M. Corsi, F. Sardanelli, G. Iacobellis, Relation of echocardiographic epicardial fat thickness and myocardial fat. Am. J. Cardiol. 105, 1831–1835 (2010) M. Kankaanpa¨a¨, H.R. Lehto, J.P. Pa¨rkka¨, M. Komu, A. Viljanen, E. Ferrannini, J. Knuuti, P. Nuutila, R. Parkkola, P. Iozzo, Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J. Clin. Endocrinol. Metab. 91, 4689–4695 (2006) G. Iacobellis, M.C. Ribaudo, A. Zappaterreno, C.V. Iannucci, F. Leonetti, Relation between epicardial adipose tissue and left ventricular mass. Am. J. Cardiol. 94, 1084–1087 (2004) G. Iacobellis, Relation of epicardial fat thickness to right ventricular cavity size in obese subjects. Am. J. Cardiol. 104, 1601–1602 (2009) G. Iacobellis, N. Singh, S. Wharton, A.M. Sharma, Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity 16, 1693–1697 (2008) H.J. Willens, P. Byers, J.A. Chirinos, E. Labrador, J.M. Hare, E. de Marchena, Effects of weight loss after bariatric surgery on epicardial fat measured using echocardiography. Am. J. Cardiol. 99, 1242–1245 (2007) M.K. Kim, T. Tomita, M.J. Kim, H. Sasai, S. Maeda, K. Tanaka, Aerobic exercise training reduces epicardial fat in obese men. J. Appl. Physiol. 106, 5–11 (2009) B. Gaborit, A. Jacquier, F. Kober, I. Abdesselam, T. Cuisset, S. Boullu-Ciocca, O. Emungania, M.C. Alessi, K. Cle´ment, M. Bernard, A. Dutour, Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. J. Am. Coll. Cardiol. 60, 1381–1389 (2012) G. Iacobellis, G. Barbaro, Gerstein HC Relationship of epicardial fat thickness and fasting glucose. Int. J. Cardiol. 128, 424–426 (2008) M. Cetin, M. Cakici, M. Polat, A. Suner, C. Zencir, I. Ardic, Relation of epicardial fat thickness with carotid intima-media thickness in patients with type 2 diabetes mellitus. Int. J. Endocrinol. 2013, 769175 (2013) M. Pezeshkian, M.R. Mahtabipour, Epicardial and subcutaneous adipose tissue Fatty acids profiles in diabetic and non-diabetic patients candidate for coronary artery bypass graft. Bioimpacts 3, 83–89 (2013) G. Iacobellis, F. Leonetti, Epicardial adipose tissue and insulin resistance in obese subjects. J. Clin. Endocrinol. Metab. 90, 6300–6302 (2005)
32. M. Manco, A. Morandi, M. Marigliano, F. Rigotti, R. Manfredi, C. Maffeis, Epicardial fat, abdominal adiposity and insulin resistance in obese pre-pubertal and early pubertal children. Atherosclerosis 226, 490–495 (2013) 33. H.J. Willens, O. Go´mez-Marı´n, J.A. Chirinos, R. Goldberg, M.H. Lowery, G. Iacobellis, Comparison of epicardial and pericardial fat thickness assessed by echocardiography in African American and non-hispanic white men: a pilot study. Ethn. Dis. 18, 311–316 (2008) 34. S.S. Salami, M. Tucciarone, R. Bess, A. Kolluru, S. Szpunar, H. Rosman, G. Cohen, Race and epicardial fat: the impact of anthropometric measurements, percent body fat and sex. Ethn. Dis. 23, 281–285 (2013) 35. M. Bluher, Vaspin in obesity and diabetes: pathophysiological and clinical significance. Endocrine 41, 176–182 (2012) 36. S. Greulich, B. Maxhera, G. Vandenplas, D.H. de Wiza, K. Smiris, H. Mueller, J. Heinrichs, M. Blumensatt, C. Cuvelier, P. Akhyari, J.B. Ruige, D.M. Ouwens, J. Eckel, Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction. Circulation 126, 2324–2334 (2012) ¨ zben, D. Yavuz, O. Deyneli, H. Aydın, O ¨ . Tarcin, 37. D. Yazıcı, B. O S. Akalın, Epicardial adipose tissue thickness in type 1 diabetic patients. Endocrine 40, 250–255 (2011) 38. D.P. Momesso, I. Bussade, M.A. Epifanio, C.D. Schettino, L.A. Russo, R. Kupfer, Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome. Diabetes Res. Clin. Pract. 91, 47–53 (2011) 39. J.H. Park, Y.S. Park, Y.J. Kim, I.S. Lee, J.H. Kim, J.H. Lee et al., Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: comparison of atorvastatin with simvastatin/ezetimibe. J. Cardiovasc. Ultrasound. 18, 121–126 (2010) 40. N. Alexopoulos, B.H. Melek, C.D. Arepalli, G.R. Hartlage, Z. Chen, S. Kim, A.E. Stillman, P. Raggi, Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (Beyond Endorsed Lipid Lowering with EBT Scanning). J. Am. Coll. Cardiol. 61, 1956–1961 (2013) 41. L. Nasarre, O. Juan-Babot, P. Gastelurrutia, A. Llucia-Valldeperas, L. Badimon, A. Bayes-Genis, V. Llorente-Corte´s, Low density lipoprotein receptor-related protein 1 is upregulated in epicardial fat from type 2 diabetes mellitus patients and correlates with glucose and triglyceride plasma levels. Acta Diabetol. (2012) 42. H.S. Sacks, J.N. Fain, P. Cheema, S.W. Bahouth, E. Garrett, R.Y. Wolf, Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone. Diabetes Care 34, 730–733 (2011) 43. E. Distel, G. Penot, T. Cadoudal, I. Balguy, S. Durant, C. Benelli, Early induction of a brown-like phenotype by rosiglitazone in the epicardial adipose tissue of fatty Zucker rats. Biochimie 94, 1660–1667 (2012) 44. T. Shimasaki, T. Masaki, K. Mitsutomi, D. Ueno, K. Gotoh, S. Chiba, T. Kakuma, Yoshimatsu H The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity. PLoS One 8, e63626 (2013) 45. S.D. Pierdomenico, A.M. Pierdomenico, F. Cuccurullo, G. Iacobellis, Metaanalysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome. Am. J. Cardiol. 15, 1234–1236 (2012) 46. G. Iacobellis, L. Petramala, G. Barbaro, A.Y. Kargi, V. Serra, L. Zinnamosca, L. Colangelo, C. Marinelli, A. Ciardi, G. De Toma, C. Letizia, Epicardial fat thickness and left ventricular mass in
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Endocrine subjects with adrenal incidentaloma. Endocrine 44(2), 532–536 (2013) 47. R. Lanes, A. Soros, K. Flores, P. Gunczler, E. Carrillo, J. Bandel, Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters. J. Clin. Endocrinol. Metab. 90, 3978–3982 (2005) 48. E. Ferrante, A.E. Malavazos, C. Giavoli, F. Ermetici, C. Coman, S. Bergamaschi, E. Profka, S. Briganti, C.L. Ronchi, E. Passeri, S. Corbetta, A.G. Lania, A. Spada, G. Iacobellis, B. Ambrosi, P. Beck-Peccoz, Epicardial fat thickness significantly decreases after short-term growth hormone (GH) replacement therapy in
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adults with GH deficiency. Nutr. Metab. Cardiovasc. Dis. 23, 459–465 (2013) 49. S. Borruel, E. Ferna´ndez-Dura´n, M. Alpan˜e´s, D. Martı´, F. Alvarez-Blasco, M. Luque-Ramı´rez, H.F. Escobar-Morreale, Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J. Clin. Endocrinol. Metab. 98, 1254–1263 (2013) 50. E. Cakir, M. Dog˘an, O. Topaloglu, M. Ozbek, E. Cakal, M.G. Vural, E. Yeter, T. Delibasi, Subclinical atherosclerosis and hyperandrogenemia are independent risk factors for increased epicardial fat thickness in patients with PCOS and idiopathic hirsutism. Atherosclerosis 226, 291–295 (2013)
REVIEW
Epicardial adipose tissue in endocrine and metabolic diseases Gianluca Iacobellis
Received: 6 September 2013 / Accepted: 22 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Epicardial adipose tissue has recently emerged as new risk factor and active player in metabolic and cardiovascular diseases. Albeit its physiological and pathological roles are not completely understood, a body of evidence indicates that epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize, produce, and secrete bioactive molecules which are then transported into the adjacent myocardium through vasocrine and/or paracrine pathways. Based on these evidences, epicardial adipose tissue can be considered an endocrine organ. Epicardial fat is also thought to provide direct heating to the myocardium and protect the heart during unfavorable hemodynamic conditions, such as ischemia or hypoxia. Epicardial fat has been suggested to play an independent role in the development and progression of obesity- and diabetes-related cardiac abnormalities. Clinically, the thickness of epicardial fat can be easily and accurately measured. Epicardial fat thickness can serve as marker of visceral adiposity and visceral fat changes during weight loss interventions and treatments with drugs targeting the fat. The potential of modulating the epicardial fat with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. This review article will provide Endocrine’s reader with a focus on epicardial adipose tissue in endocrinology. Novel, established, but also speculative findings on epicardial fat will be discussed from the
G. Iacobellis (&) Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, 1400 NW 10th Ave, Dominion Tower Suite 805-807, Miami, FL 33136, USA e-mail: [email protected]
unexplored perspective of both clinical and basic Endocrinologist. Keywords Epicardial adipose tissue Epicardial fat Visceral adiposity Echocardiography
Introduction Epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize and secrete adipokines and bioactive factors that can reach out to the myocardium through vasocrine and/or paracrine pathways. Epicardial adipose tissue can be therefore considered an endocrine organ. As more novel and intriguing findings have been recently discovered, the interest into the epicardial fat is rapidly growing. This article wants to provide with an updated and comprehensive overview of the current notion concerning epicardial fat in the context of metabolic and endocrine disorders. Anatomy and embryology A brief introduction to the embryology and anatomy will help the reader in understanding most of the known or attributed properties of the human epicardial fat. The adipose tissue of the heart is divided into three layers: epicardial fat, the visceral layer, and pericardial fat, situated externally to the parietal layer of the pericardium [1–3]. Embryologically and anatomically, epicardial and pericardial fat are different [4]. Epicardial fat originates from the splanchnopleuric mesoderm, whereas pericardial fat originates from the primitive thoracic mesenchyme. Notably, epicardial evolves from brown adipose tissue [5]. Epicardial fat is supplied by branches of the coronary
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arteries, whereas pericardial fat is supplied by branches of noncoronary arteries. In the adult human heart, epicardial fat is more abundant in the atrioventricular and interventricular grooves. Epicardial fat can be further differentiated into myocardial and pericoronary epicardial fat [6]. Microscopically, epicardial fat is composed of mainly adipocytes, but it also contains nerve tissues, inflammatory, stromovascular, and immune cells [7]. Epicardial adipocytes are generally smaller than those located in subcutaneous and other visceral fat depots [8]. The highconsuming metabolism-preventing large lipid storage and the larger number of preadipocytes have been evoked to explain the smaller size of epicardial adipocytes [1, 2]. Remarkably, no muscle fascia divides epicardial fat and myocardium; therefore, the two tissues share the same microcirculation [2]. This allows a direct interaction and crosstalk between the epicardial fat and the myocardium. Physiology Under normal physiological conditions, epicardial fat could serve as a buffer, absorbing fatty acids and protecting the heart against high fatty acids levels and as pad-protecting abnormal curvature of the coronary arteries. It could also function as lipid storage and local energy source at times of high demand, channeling fatty acids to the myocardium, and as brown fat to defend the myocardium against hypothermia [1–4]. A role is controlling heart electrophysiology has been also suggested [1]. However, the physiological role of epicardial fat is still not being completely explored and understood. Epicardial fat as endocrine organ Epicardial adipose tissue can be considered an endocrine organ. It is a metabolically active organ and a source of several bioactive molecules that can influence the myocardium and coronary arteries [1–4]. Epicardial fat expresses and secretes a number of cytokines, pro- and anti-inflammatory adipokines, vasoactive factors, and growth factors [1, 2]. Whether epicardial fat exerts its function as paracrine, autocrine, or vasocrine organ will be briefly discussed in this article. Because of its anatomical proximity to the heart and the absence of fascial boundaries, epicardial adipose tissue may interact locally and modulate the myocardium and coronary arteries. Two major mechanisms of interaction between the myocardium and the epicardial fat, i.e., paracrine and vasocrine, have been suggested [4]. Paracrine release of cytokines from periadventitial epicardial fat could traverse the coronary wall by diffusion from outside-toinside. Given the dense inflammatory infiltrate within the human epicardial fat and its complex cellularity, it seems reasonable to suspect that cytokines are secreted by different
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cells. Adipokines secreted from epicardial adipocytes, stromal, and vascular cells may diffuse in interstitial fluid across the adventitia, media, and intima and then interact respectively with vasa vasorum, endothelial, and vascular smooth muscle cells of the coronary arteries. Alternatively, adipokines and free fatty acids (FFAs) might be released from epicardial tissue directly into vasa vasorum and be transported downstream into the arterial wall, in a vasocrine signaling mechanism [9]. Under pathological circumstances, epicardial fat releases factors that promote harmful coronary artery and myocardial changes. Epicardial fat as source of energy to the myocardium The myocardium uses and metabolizes FFAs from the coronary arterial blood, and FFA oxidation is responsible for about 50–70 % of the energy production of the heart. Epicardial adipose tissue has a greater capacity for FFAs release and uptake and lower rate of glucose utilization than any other visceral fat depot [10]. In fact, FFAs synthesis, rate of incorporation and breakdown are significantly higher in epicardial fat than in the other fat depots [10]. Hence, epicardial fat has been proposed to function as a buffer to protect the heart against exposure to excessively high levels of FFAs and to provide energy for the myocardium [1, 2]. Compared to subcutaneous adipose tissue, human epicardial fat appears to be rich in saturated fatty acids [11], such as myristic acid (14:0), palmitic acid (16:0), and stearic acid (18:0), whereas unsaturated fatty acids are lower. Given the absence of muscle fascia, FFAs are transported from the epicardial fat into the myocardium. FFAs could diffuse bidirectionally in interstitial fluid across concentration gradients. Epicardial adipose tissue might also secrete vasoactive products that regulate coronary arterial tone to then facilitate the FFAs influx. It is plausible that fatty acid-binding protein 4 participates in the intracellular transport of FFAs from the epicardial fat into the myocardium [12]. Epicardial adipose tissue as brown fat Brown adipose tissue generates heat in response to cold temperatures and activation of the autonomic nervous system. However, the role of brown fat in humans is unclear. Brown adipose tissue-specific gene uncoupling protein-1 (UCP-1) and other brown fat-related genes are all highly expressed in epicardial fat [13]. UCP-1 is significantly higher in human epicardial fat as compared to other fat depots, and basically undetectable in subcutaneous fat [13]. Clinically, a significant uptake of 18F-fluorodeoxyglucose (18F-FDG) by the heart suggested that brown adipose tissue may lie close to the heart, although it is more likely that the 18F-FDG signal actually comes from the
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myocardial tissue [14]. Although these recent findings are intriguing, the role of epicardial fat to serve as brown fat to the myocardium is far to be completely understood. Epicardial fat is thought to provide direct heating to the myocardium and protect the heart during a drop in core body temperature or during unfavorable hemodynamic conditions, such ischemia or hypoxia. This hypothesis may be supported by animal models. In fact, polar bears present large amounts of cardiac fat that can be used to store and supply energy to the myocardium during hibernation [9]. How and whether these observations can be translated to humans is unknown. Whether epicardial fat is a brown fat or it can function as brown fat-like depot is unclear and also topic of discussion. Very recently, small unilocular adipocytes without UCP-1 immunostaining have been described in epicardial fat, suggesting some histological similarities with those described in vitro in beige lineage adipocytes [15]. Epicardial fat and obesity Historically, obese individuals have been considered at higher cardiovascular risk than individuals with normal body weight. However, there is an almost univocal consensus in considering the visceral fat a stronger independent cardio-metabolic risk factor than overall obesity. Subjects with visceral fat accumulation are generally considered at higher risk for cardiovascular diseases than individuals with prevalent peripheral adiposity. The exact mechanisms that lead to a different anatomical fat accumulation in humans are still unclear. Different visceral fat depots seem to have different physiological and pathological properties. While most of the attention has been traditionally focused into the intraabdominal fat accumulation, epicardial adipose tissue has been only recently considered. Epicardial fat as marker of visceral fat It is certainly correct to state that obese subjects, both adults and children, present with higher epicardial fat than normoweight subjects [16]. However, a number of evidence indicates that epicardial fat should be considered primarily a marker of visceral adiposity. Epicardial fat thickness can be visualized and measured with standard two-dimensional echocardiography, as first proposed and validated by Iacobellis [17, 18] or with computed tomography techniques. Regardless of the measuring methodology, it has been well established that echocardiographic epicardial fat is actually a marker of visceral fat. Echocardiographic epicardial fat thickness is an independent predictor of visceral adiposity and weakly reflects the obesity degree as measured by body mass index (BMI). In
fact, echocardiographic epicardial fat strongly reflects the intraabdominal visceral fat as measured by magnetic resonance imaging and better than waist circumference does [16, 19]. Additionally, epicardial fat was associated with intramyocardial and intrahepatic fat accumulation, as measured by MR spectroscopy [20]. All together, this suggests that measuring epicardial fat provides a measure of visceral or better organ-specific adiposity.
Epicardial fat and the obese heart Recent evidence showed that obesity leads not only to increased fat depots in classical adipose tissue locations, but also to significant ectopic lipid accumulation and infiltration within and around other tissues and internal organs. Ectopic fat deposition may occur within the heart and affects its function. However, nonadipocytes and cardiomyocytes have a very limited capacity to store excess fat. Consequently, if they are exposed to high levels of plasma lipids, as usually occurs in obesity, they may undergo steatosis and loss of function, ultimately resulting in cardiac lipotoxicity. Visceral adiposity induces fatty infiltration of the myocardium by different mechanisms. An infiltration of adipocytes from the epicardial adipose tissue to the myocardium has been suggested and corroborated by clinical studies [21]. Imaging studies showed an independent and significant relation of epicardial fat, as measured with echocardiography, and intramyocardial lipid content, as measured by proton magnetic resonance spectroscopy [20]. Myocardial lipid content increases with the degree of adiposity and may contribute to the adverse structural and functional cardiac adaptations seen in obese persons. Clinically, epicardial fat has been associated with cardiac changes, commonly observed in obese subjects. In fact, increased epicardial fat has been associated with increased left ventricular mass and abnormal right ventricle geometry, as detected by echocardiography [22, 23]. Echocardiographic findings were in agreement with autoptic studies. Mechanical and biomolecular mechanisms have been evoked to explain these correlations. Increased epicardial fat by adding to the mass of the ventricles may increase the work of pumping. Increased left ventricular mass in morbidly obese subjects could be due to a direct effect of excess epicardial fat. Increase in epicardial fat was also significantly correlated with enlarged atria and impaired right and left ventricular diastolic filling in morbidly obese subjects [2]. Epicardial fat may directly contribute to impair diastolic function in subjects with increased visceral adiposity. A mechanical obstacle to diastolic filling due to the excessive epicardial fat can explain these findings.
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Effects of weight loss on epicardial fat Substantial and sustainable weight loss is the primary goal to reduce cardiometabolic risk in obese subjects. Nevertheless, whether the fat loss during weight loss interventions is uniform across body fat compartments is still unclear. Whether the proportion changes in overall and visceral adiposity can be different is partially unanswered. Visceral fat reduction is associated with a significant improvement of the cardiometabolic profile. However, it is presently unknown how much visceral adipose tissue loss is needed to induce favorable cardiac changes. In the phase of rapid weight loss after laparoscopic bariatric surgery, a preferential mobilization of visceral abdominal fat, as compared with total and subcutaneous adiposity, was observed. However, this preferential visceral fat reduction seems to occur only in those patients presenting higher levels of visceral fat deposition at baseline. Easy and reliable markers of visceral adiposity may therefore provide a more complete understanding of metabolic risk associated with variation in fat distribution. To answer, at least partially, this interesting question, epicardial fat served as therapeutic target during weight loss interventions. Epicardial fat has shown to significantly reduce after very low calorie diet, bariatric surgery, and moderate aerobic exercise [24–26], although postbariatric surgery results are not univocal [27]. Interestingly, echocardiographic epicardial fat has been reported to significantly and quickly decrease after a very low calorie diet in morbidly obese subjects. Changes in epicardial fat thickness were significantly higher than changes in BMI and waist circumference -32 % versus -23 % versus -19 % after the very low calorie diet program [24]. Changes in epicardial fat thickness were consensually and independently associated with the improvement in cardiac parameters in these subjects. Epicardial fat reduces with exercise in humans, but its inflammatory response to aerobic exercise seems to be variable in experimental models [26]. Epicardial fat and diabetes The role of visceral fat in the development and worsening of type 2 diabetes has been extensively studied. Nevertheless, an exclusive relation of epicardial fat with type 2 diabetes has been only recently evaluated. In particular, the potential of epicardial fat thickness in predicting glucose abnormalities was the object of interest. Epicardial fat thickness was measured in nondiabetic Caucasian subjects who underwent routine transthoracic echocardiogram [28]. Study subjects were designated as having normal fasting glucose and impaired fasting glucose (IFG) (fasting glucose between 100 and \126 mg/dl). Epicardial fat thickness was significantly higher in subjects with IFG and
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resulted in the best correlate of fasting glucose. Epicardial fat thickness was found higher in type 2 diabetic subjects with subclinical atherosclerosis [29]. The higher increase of trans and conjugated fatty acids in epicardial adipose tissue may contribute to atherosclerosis development and progression in diabetic patients [30]. However, larger studies will be required to establish an independent correlative or predictive role of epicardial fat in type 2 diabetes. Insulin resistance is another key component of type 2 diabetes. Epicardial fat thickness was associated with indices of insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, in obese subjects [31]. It was also related to surrogate markers of insulin resistance, as well as fasting insulin and Homeostatic Model Assessment –Insulin resistance (HOMA-IR) index in a nondiabetic adult population [31], prepubertal, and early pubertal children [32]. Different cut-off values of epicardial fat thickness for prediction of insulin resistance have been proposed [16]. Ethnicity and gender can explain the variability of epicardial fat thickness values and the differences among studies [33, 34]. The highest values of epicardial fat thickness were found in subjects presenting with large intraabdominal fat and severe insulin resistance [16]. While clinical data seem to provide quite robust evidences, epicardial fat expression of emerging adipokines linking type 2 diabetes [35] to insulin resistance will have to be evaluated. Diabetes is often associated with a peculiar and unique cardiomyopathy, although the causes are probably multifactorial and mechanisms are still being partially unclear. A recent experimental study conducted on rat cardiomyocytes showed that secretory profile of epicardial fat may contribute to the pathogenesis of diabetes mellitus-related cardiomyopathy [36]. While a relationship of a visceral fat depot with type 2 diabetes seems to be intuitive and somehow expected, the role of excessive visceral adiposity in subjects with type 1 diabetes has been only recently suggested [37]. In fact, very recent evidences pointed out a possible correlation between visceral fat and type 1 diabetes. One single study showed a relation of epicardial fat with central obesity in type 1 diabetic subjects [38]. Given its rapid metabolism and its simple objective measurability, epicardial fat can serve as target for pharmaceutical agents commonly used in both type 1 and type 2 diabetes. The effect on the epicardial fat mass and function by medications which are known to modulate the adipose tissue, such as statins and thiazolidinediones, has been evaluated. Interestingly, epicardial fat thickness reduced in diabetic subjects treated with atorvastatin in comparison with those who received simvastatin and ezetimibe [39]. Consistently, atorvastatin therapy induced a reduction of
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computed tomography-measured epicardial fat in hyperlipidemic postmenopausal women, as very recently reported [40]. The effect of atorvastatin on epicardial fat was independent of lipid lowering or coronary artery disease progression. In this context, it is certainly notable that epicardial fat overexpression of lipoprotein receptors such as low-density lipoprotein receptor-related protein 1 and very low-density lipoprotein receptor has been recently suggested to play a role in changes of lipid metabolism commonly associated with type 2 diabetes mellitus [41]. Thiazolidinediones were also targeted to the epicardial fat. Notably, epicardial fat inflammatory secretome improved with pioglitazone treatment [42]. In fact, treatment with pioglitazone in type 2 diabetic patients was associated with reductions in expression of interleukin-1b and other proinflammatory genes in epicardial fat [42]. Interestingly, a recent study reveals that peroxisome proliferator–activated receptor-c (PPAR-c) agonist can induce a rapid browning of the epicardial fat in experimental models [43]. Rosiglitazone treatment caused a significant upregulation of PPARc coactivator 1 alpha (PGC1-a), a key precursor of brown fat, in epicardial adipocytes of Zucker rats. In the past few years, new diabetic medications, such as glucagon like peptide-1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors, rapidly emerged. Of note, dipeptidyl peptidase-4 inhibitor treatment increased the levels of PGC-1 and UCPs in brown adipose tissue in mice with diet-induced obesity [44]. Future and more numerous studies looking at the effect of GLP-1 analogs and DPP4 inhibitors on the epicardial fat seem to be warranted. Epicardial fat thickness and metabolic syndrome Several clinical studies showed the relationship of echocardiographic epicardial fat thickness and metabolic syndrome. Epicardial fat thickness is usually significantly higher in subjects with metabolic syndrome than in subjects without metabolic syndrome [19]. When cardio-metabolic parameters are considered separately, epicardial fat is independently associated with blood pressure, low density lipoprotein cholesterol, fasting glucose, and inflammatory markers. A recent meta analysis conducted on nine studies showed that thickness was significantly higher in patients with metabolic syndrome than in those without [45]. Moreover, the meta analysis reported a significant variability of epicardial fat with ethnicity, with a greater difference in Caucasian subjects than in other ethnic groups. Different cut-off points of high-risk epicardial fat thickness for the prediction of metabolic syndrome have been proposed [16]. In a large observational study, receiver operating characteristics analysis showed that epicardial fat thickness values of 9.5 and 7.5 mm maximize the
sensitivity and specificity to predict the metabolic syndrome in men and women, respectively. Nevertheless, different epicardial fat values predicting the risk of developing metabolic syndrome have been reported in different ethnic and age groups. A larger and multiethnic population-based study would probably be necessary to establish high-risk epicardial fat thickness values. It could be hypothesized that higher epicardial fat might be implicated in the pathophysiology of metabolic syndrome, because it produces a number of factors that influence insulin sensitivity, inflammation, and visceral adiposity. However, it is probably more plausible that higher epicardial fat may serve as an objective and reproducible indicator of excessive visceral fat accumulation, the role of which in metabolic syndrome has been well described. Epicardial fat and other endocrine disorders The clinical use of epicardial fat thickness in endocrine disorders involving directly or indirectly the visceral adiposity will be briefly discussed here. Epicardial fat and adrenal incidentaloma It has been recently shown that epicardial fat thickness, as measured with echocardiography, was higher in subjects with adrenal incidentaloma when compared to healthy controls [46]. Additionally, epicardial fat thickness correlated with cardiac changes regardless of the presence of hypercortisolism. The clinical significance and management adrenal incidentalomas is object of recent debate. Recent data indicate that patients diagnosed with adrenal incidentaloma present with higher cardiovascular risk. Given that most of subjects with adrenal incidentaloma or mild Cushing’s syndrome are often asymptomatic for cardiovascular disease, the predictive role of epicardial fat thickness in detecting early cardiac changes would be of importance and deserve further studies. Epicardial fat and growth hormone deficiency Growth hormone deficiency (GHD) syndrome is characterized by an abnormal body fat distribution and increased visceral fat accumulation. Consequently, this syndrome is associated with an increased morbidity and mortality for cardiovascular diseases. Interestingly, significant reduction in epicardial fat thickness after recombinant human GH (rhGH) replacement therapy has been reported in both adolescents [47] and adults with GHD syndrome [48]. At baseline, subjects with adult-onset GHD syndrome showed higher epicardial fat thickness than controls, suggesting a higher visceral fat accumulation in these patients. Echocardiographic epicardial fat thickness significantly decreased
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internal organs, including the endocrine glands. Given that epicardial fat can be easily measured, its assessment may be an additional tool for the clinical endocrinologist too. Its measurement can serve as marker of visceral adiposity and rapid visceral fat changes during weight loss and pharmacological interventions targeting the adipose tissue. The potential of modulating the epicardial fat to its physiological functions with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. Conflict of interest
The author declares no conflict of interest.
References Fig. 1 Roles and clinical applications of epicardial adipose tissue in endocrinology. This graphic summarizes and depicts some features of the epicardial fat that are relevant in endocrine and metabolic diseases such as its biochemical and functional characteristics of an endocrine organ, its genetic and functional profile of brown fat, its role in the pathophysiology of obesity and diabetes-related cardiac changes, its function as marker of visceral fat and visceral fat changes during weight loss interventions, and its responsiveness to pharmacological agents targeting the fat
after short-term rhGH replacement therapy, whereas, neither waist circumference nor BMI showed significant changes during the replacement treatment [48]. Epicardial fat thickness may have potential to serve as rapid and sensitive marker of visceral fat reduction also during rhGH replacement treatment. Epicardial fat and polycystic ovary syndrome Patients with polycystic ovary syndrome commonly present with abdominal obesity and visceral adiposity. Epicardial fat thickness was higher in these patients than in controls [49]. Epicardial fat thickness was also correlated with markers of insulin resistance in patients with polycystic ovary syndrome [50].
Conclusions Epicardial fat displays some features that are relevant in endocrinology (Fig. 1). Epicardial adipose tissue is a unique fat depot with biochemical and functional characteristics of an endocrine organ. Given its peculiar anatomic location, its secretome is transported directly into the myocardium through paracrine and/or vasocrine mechanisms. These features may be of interest and object of research for the basic scientist committed to understand the complex interplay between the adipose tissue and the other
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1. G. Iacobellis, A.C. Bianco, Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trend. Endocrinol. Metab. 22, 450–457 (2011) 2. G. Iacobellis, D. Corradi, A.M. Sharma, Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat. Clin. Pract. Cardiovasc. Med. 2, 536–543 (2005) 3. P. Iozzo, Myocardial, perivascular, and epicardial fat. Diabetes Care 34(Suppl 2), S371–S379 (2011) 4. G. Iacobellis, Epicardial and pericardial fat: close, but very different. Obesity 17, 625 (2009) 5. J.M. Marchington, C.A. Mattacks, C.M. Pond, Adipose tissue in the mammalian heart and pericardium; structure, foetal development and biochemical properties. Comp. Biochem. Physiol. 94B, 225–232 (1989) 6. H.S. Sacks, J.N. Fain, Human epicardial adipose tissue: a review. Am. Heart J. 153, 907–917 (2007) 7. T. Mazurek, L. Zhang, A. Zalewski, J.D. Mannion, J.T. Diehl, H. Arafat, Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108, 2460–2466 (2003) 8. C. Bambace, M. Telesca, E. Zoico, A. Sepe, D. Olioso, A. Rossi, F. Corzato, V. Di Francesco, A. Mazzucco, F. Santini, M. Zamboni, Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc. Pathol. 20(5), 153–156 (2010) 9. J.S. Judkin, E. Eringa, C.D.A. Stehouwer, ‘‘Vasocrine signalling’’ from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 365, 1817–1820 (2005) 10. J.M. Marchington, C.M. Pond, Site-specific properties of pericardial and epicardial adipose tissue. The effects of insulin and high-fat feeding on lipogenesis and the incorporation of fatty acids in vitro. Int. J. Obes. 14, 1013–1022 (1990) 11. M. Pezeshkian, M. Noori, H. Najjarpour-Jabbari, A. Abolfathi, M. Darabi, M. Darabi, M. Shaaker, G. Shahmohammadi, Fatty acid composition of epicardial and subcutaneous human adipose tissue. Metab. Syndr. Relat. Disord. 7, 125–131 (2009) 12. B. Vural, F. Atalar, C. Ciftci, A. Demirkan, B. Susleyici-Duman, D. Gunay, Presence of fatty-acid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovasc. Pathol. 17, 392–398 (2008) 13. H.S. Sacks, J.N. Fain, B. Holman, P. Cheema, A. Chary, F. Parks, Uncoupling protein-1 and related mRNAs in human epicardial and other adipose tissues: epicardial fat functioning as brown fat. J. Clin. Endocrinol. Metab. 94, 3611–3615 (2009) 14. A.M. Cypess, S. Lehman, G. Williams, I. Tal, D. Rodman, A.B. Goldfine, F.C. Kuo, E.L. Palmer, Y.H. Tseng, A. Doria, G.M.
Endocrine
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Kolodny, Kahn CR Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009) H.S. Sacks, J.N. Fain, S.W. Bahouth, S. Ojha, A. Frontini, H. Budge, S. Cinti, M.E. Symonds, Adult epicardial fat exhibits beige features. J. Clin. Endocrinol. Metab. 98(9), 1448–1455 (2013) G. Iacobellis, H.J. Willens, G. Barbaro, A.M. Sharma, Threshold values of high-risk echocardiographic epicardial fat thickness. Obesity (Silver Spring) 16, 887–892 (2008) G. Iacobellis, H.J. Willens, Echocardiographic epicardial fat: a review of research and clinical applications. J. Am. Soc. Echocardiogr. 22, 1311–1319 (2009) G. Iacobellis, F. Assael, M.C. Ribaudo, A. Zappaterreno, G. Alessi, U. Di Mario, F. Leonetti, Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes. Res. 11, 304–310 (2003) G. Iacobellis, M.C. Ribaudo, F. Assael, E. Vecci, C. Tiberti, A. Zappaterreno, U. Di Mario, Leonetti F Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J. Clin. Endocrinol. Metab. 388, 5163–5168 (2003) A.E. Malavazos, G. Di Leo, F. Secchi, E.N. Lupo, G. Dogliotti, C. Coman, L. Morricone, M.M. Corsi, F. Sardanelli, G. Iacobellis, Relation of echocardiographic epicardial fat thickness and myocardial fat. Am. J. Cardiol. 105, 1831–1835 (2010) M. Kankaanpa¨a¨, H.R. Lehto, J.P. Pa¨rkka¨, M. Komu, A. Viljanen, E. Ferrannini, J. Knuuti, P. Nuutila, R. Parkkola, P. Iozzo, Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J. Clin. Endocrinol. Metab. 91, 4689–4695 (2006) G. Iacobellis, M.C. Ribaudo, A. Zappaterreno, C.V. Iannucci, F. Leonetti, Relation between epicardial adipose tissue and left ventricular mass. Am. J. Cardiol. 94, 1084–1087 (2004) G. Iacobellis, Relation of epicardial fat thickness to right ventricular cavity size in obese subjects. Am. J. Cardiol. 104, 1601–1602 (2009) G. Iacobellis, N. Singh, S. Wharton, A.M. Sharma, Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity 16, 1693–1697 (2008) H.J. Willens, P. Byers, J.A. Chirinos, E. Labrador, J.M. Hare, E. de Marchena, Effects of weight loss after bariatric surgery on epicardial fat measured using echocardiography. Am. J. Cardiol. 99, 1242–1245 (2007) M.K. Kim, T. Tomita, M.J. Kim, H. Sasai, S. Maeda, K. Tanaka, Aerobic exercise training reduces epicardial fat in obese men. J. Appl. Physiol. 106, 5–11 (2009) B. Gaborit, A. Jacquier, F. Kober, I. Abdesselam, T. Cuisset, S. Boullu-Ciocca, O. Emungania, M.C. Alessi, K. Cle´ment, M. Bernard, A. Dutour, Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. J. Am. Coll. Cardiol. 60, 1381–1389 (2012) G. Iacobellis, G. Barbaro, Gerstein HC Relationship of epicardial fat thickness and fasting glucose. Int. J. Cardiol. 128, 424–426 (2008) M. Cetin, M. Cakici, M. Polat, A. Suner, C. Zencir, I. Ardic, Relation of epicardial fat thickness with carotid intima-media thickness in patients with type 2 diabetes mellitus. Int. J. Endocrinol. 2013, 769175 (2013) M. Pezeshkian, M.R. Mahtabipour, Epicardial and subcutaneous adipose tissue Fatty acids profiles in diabetic and non-diabetic patients candidate for coronary artery bypass graft. Bioimpacts 3, 83–89 (2013) G. Iacobellis, F. Leonetti, Epicardial adipose tissue and insulin resistance in obese subjects. J. Clin. Endocrinol. Metab. 90, 6300–6302 (2005)
32. M. Manco, A. Morandi, M. Marigliano, F. Rigotti, R. Manfredi, C. Maffeis, Epicardial fat, abdominal adiposity and insulin resistance in obese pre-pubertal and early pubertal children. Atherosclerosis 226, 490–495 (2013) 33. H.J. Willens, O. Go´mez-Marı´n, J.A. Chirinos, R. Goldberg, M.H. Lowery, G. Iacobellis, Comparison of epicardial and pericardial fat thickness assessed by echocardiography in African American and non-hispanic white men: a pilot study. Ethn. Dis. 18, 311–316 (2008) 34. S.S. Salami, M. Tucciarone, R. Bess, A. Kolluru, S. Szpunar, H. Rosman, G. Cohen, Race and epicardial fat: the impact of anthropometric measurements, percent body fat and sex. Ethn. Dis. 23, 281–285 (2013) 35. M. Bluher, Vaspin in obesity and diabetes: pathophysiological and clinical significance. Endocrine 41, 176–182 (2012) 36. S. Greulich, B. Maxhera, G. Vandenplas, D.H. de Wiza, K. Smiris, H. Mueller, J. Heinrichs, M. Blumensatt, C. Cuvelier, P. Akhyari, J.B. Ruige, D.M. Ouwens, J. Eckel, Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction. Circulation 126, 2324–2334 (2012) ¨ zben, D. Yavuz, O. Deyneli, H. Aydın, O ¨ . Tarcin, 37. D. Yazıcı, B. O S. Akalın, Epicardial adipose tissue thickness in type 1 diabetic patients. Endocrine 40, 250–255 (2011) 38. D.P. Momesso, I. Bussade, M.A. Epifanio, C.D. Schettino, L.A. Russo, R. Kupfer, Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome. Diabetes Res. Clin. Pract. 91, 47–53 (2011) 39. J.H. Park, Y.S. Park, Y.J. Kim, I.S. Lee, J.H. Kim, J.H. Lee et al., Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: comparison of atorvastatin with simvastatin/ezetimibe. J. Cardiovasc. Ultrasound. 18, 121–126 (2010) 40. N. Alexopoulos, B.H. Melek, C.D. Arepalli, G.R. Hartlage, Z. Chen, S. Kim, A.E. Stillman, P. Raggi, Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (Beyond Endorsed Lipid Lowering with EBT Scanning). J. Am. Coll. Cardiol. 61, 1956–1961 (2013) 41. L. Nasarre, O. Juan-Babot, P. Gastelurrutia, A. Llucia-Valldeperas, L. Badimon, A. Bayes-Genis, V. Llorente-Corte´s, Low density lipoprotein receptor-related protein 1 is upregulated in epicardial fat from type 2 diabetes mellitus patients and correlates with glucose and triglyceride plasma levels. Acta Diabetol. (2012) 42. H.S. Sacks, J.N. Fain, P. Cheema, S.W. Bahouth, E. Garrett, R.Y. Wolf, Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone. Diabetes Care 34, 730–733 (2011) 43. E. Distel, G. Penot, T. Cadoudal, I. Balguy, S. Durant, C. Benelli, Early induction of a brown-like phenotype by rosiglitazone in the epicardial adipose tissue of fatty Zucker rats. Biochimie 94, 1660–1667 (2012) 44. T. Shimasaki, T. Masaki, K. Mitsutomi, D. Ueno, K. Gotoh, S. Chiba, T. Kakuma, Yoshimatsu H The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity. PLoS One 8, e63626 (2013) 45. S.D. Pierdomenico, A.M. Pierdomenico, F. Cuccurullo, G. Iacobellis, Metaanalysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome. Am. J. Cardiol. 15, 1234–1236 (2012) 46. G. Iacobellis, L. Petramala, G. Barbaro, A.Y. Kargi, V. Serra, L. Zinnamosca, L. Colangelo, C. Marinelli, A. Ciardi, G. De Toma, C. Letizia, Epicardial fat thickness and left ventricular mass in
123
Endocrine subjects with adrenal incidentaloma. Endocrine 44(2), 532–536 (2013) 47. R. Lanes, A. Soros, K. Flores, P. Gunczler, E. Carrillo, J. Bandel, Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters. J. Clin. Endocrinol. Metab. 90, 3978–3982 (2005) 48. E. Ferrante, A.E. Malavazos, C. Giavoli, F. Ermetici, C. Coman, S. Bergamaschi, E. Profka, S. Briganti, C.L. Ronchi, E. Passeri, S. Corbetta, A.G. Lania, A. Spada, G. Iacobellis, B. Ambrosi, P. Beck-Peccoz, Epicardial fat thickness significantly decreases after short-term growth hormone (GH) replacement therapy in
123
adults with GH deficiency. Nutr. Metab. Cardiovasc. Dis. 23, 459–465 (2013) 49. S. Borruel, E. Ferna´ndez-Dura´n, M. Alpan˜e´s, D. Martı´, F. Alvarez-Blasco, M. Luque-Ramı´rez, H.F. Escobar-Morreale, Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J. Clin. Endocrinol. Metab. 98, 1254–1263 (2013) 50. E. Cakir, M. Dog˘an, O. Topaloglu, M. Ozbek, E. Cakal, M.G. Vural, E. Yeter, T. Delibasi, Subclinical atherosclerosis and hyperandrogenemia are independent risk factors for increased epicardial fat thickness in patients with PCOS and idiopathic hirsutism. Atherosclerosis 226, 291–295 (2013)
