Comprehensive Physiology Wiley Online Library

Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat?

Full Article on Wiley Online Library


Epicardial adipose tissue (EAT) is a small but very biologically active ectopic fat depot that surrounds the heart. Given its rapid metabolism, thermogenic capacity, unique transcriptome, secretory profile, and simply measurability, epicardial fat has drawn increasing attention among researchers attempting to elucidate its putative role in health and cardiovascular diseases. The cellular crosstalk between epicardial adipocytes and cells of the vascular wall or myocytes is high and suggests a local role for this tissue. The balance between protective and proinflammatory/profibrotic cytokines, chemokines, and adipokines released by EAT seem to be a key element in atherogenesis and could represent a future therapeutic target. EAT amount has been found to predict clinical coronary outcomes. EAT can also modulate cardiac structure and function. Its amount has been associated with atrial fibrillation, coronary artery disease, and sleep apnea syndrome. Conversely, a beiging fat profile of EAT has been identified. In this review, we describe the current state of knowledge regarding the anatomy, physiology and pathophysiological role of EAT, and the factors more globally leading to ectopic fat development. We will also highlight the most recent findings on the origin of this ectopic tissue, and its association with cardiac diseases. © 2017 American Physiological Society. Compr Physiol 7:1051‐1082, 2017.

Figure 1. Figure 1. Layers of the heart and pericardium Scheme demonstrating epicardial fat between the visceral pericardium and myocardium, paracardial fat external to the parietal pericardium, and pericardial fat as the combination of epicardial and paracardial fat.
Figure 2. Figure 2. EAT among species—anterior and posterior heart photographic views in a 12‐months‐old rat (A), a 3‐months‐old swine (B), and a 50‐years‐old human (C).
Figure 3. Figure 3. The origin of EAT. Epicardial adipocytes derived from embryonic epicardial progenitors by ETFT. After myocardial infarction in adult animals, reactivation of ETFT enables new epicardial adipocytes formation from epicardium cells.
Figure 4. Figure 4. Main factors leading to ectopic fat deposition in humans. FFA: free fatty acids; ASCs: adipose stem stromal cells; T2D: type 2 diabetes; CAD: coronary artery disease; MHO: metabolically healthy obesity.
Figure 5. Figure 5. Echocardiography parasternal long axis view, thickness of paracardial and epicardial fat were measured on one anatomical point.
Figure 6. Figure 6. CT scans in axial views, without iodine injection and with cardiac synchronization in A and with iodine injection and cardiac synchronization in B, C, and D at different anatomical level. Pericardium was clearly depicted (white arrow) and allows the differentiation between epicardial fat (star in C) and paracardial fat (open arrow in C).
Figure 7. Figure 7. MR short axis cine sequences at the diastolic phase A, with contouring of the heart in B, contouring of the pericardium in C, and contouring of the pericardial fat in D; each surface was multiplicated by slice thickness to obtain volumes. This contouring was repeated on the whole stack of images covering the entire heart to be able to quantify total fat volume. Volume of epicardial fat was measured as = volume in C minus volume B), and paracardial fat (volume D minus volume C).
Figure 8. Figure 8. Atrial EAT and myocardium. (A) Sirius red sections, (B) Oil‐red‐O staining, and (C) Sirius red staining. At high magnification, adipocytes infiltration associated with important fibrosis within myocardium, impairing myocytes network, and (D) haematoxylin and eosin staining.
Figure 9. Figure 9. Role of epicardial fat in AF.
Figure 10. Figure 10. Role of epicardial fat in CAD.

Figure 1. Layers of the heart and pericardium Scheme demonstrating epicardial fat between the visceral pericardium and myocardium, paracardial fat external to the parietal pericardium, and pericardial fat as the combination of epicardial and paracardial fat.

Figure 2. EAT among species—anterior and posterior heart photographic views in a 12‐months‐old rat (A), a 3‐months‐old swine (B), and a 50‐years‐old human (C).

Figure 3. The origin of EAT. Epicardial adipocytes derived from embryonic epicardial progenitors by ETFT. After myocardial infarction in adult animals, reactivation of ETFT enables new epicardial adipocytes formation from epicardium cells.

Figure 4. Main factors leading to ectopic fat deposition in humans. FFA: free fatty acids; ASCs: adipose stem stromal cells; T2D: type 2 diabetes; CAD: coronary artery disease; MHO: metabolically healthy obesity.

Figure 5. Echocardiography parasternal long axis view, thickness of paracardial and epicardial fat were measured on one anatomical point.

Figure 6. CT scans in axial views, without iodine injection and with cardiac synchronization in A and with iodine injection and cardiac synchronization in B, C, and D at different anatomical level. Pericardium was clearly depicted (white arrow) and allows the differentiation between epicardial fat (star in C) and paracardial fat (open arrow in C).

Figure 7. MR short axis cine sequences at the diastolic phase A, with contouring of the heart in B, contouring of the pericardium in C, and contouring of the pericardial fat in D; each surface was multiplicated by slice thickness to obtain volumes. This contouring was repeated on the whole stack of images covering the entire heart to be able to quantify total fat volume. Volume of epicardial fat was measured as = volume in C minus volume B), and paracardial fat (volume D minus volume C).

Figure 8. Atrial EAT and myocardium. (A) Sirius red sections, (B) Oil‐red‐O staining, and (C) Sirius red staining. At high magnification, adipocytes infiltration associated with important fibrosis within myocardium, impairing myocytes network, and (D) haematoxylin and eosin staining.

Figure 9. Role of epicardial fat in AF.

Figure 10. Role of epicardial fat in CAD.
 1.Abdesselam I, Dutour A, Kober F, Ancel P, Bege T, Darmon P, et al. Time Course of Change in Ectopic Fat Stores After Bariatric Surgery. J Am Coll Cardiol. Jan 5; 67(1): 117‐9, 2016.
 2.Adams DB, Narayan O, Munnur RK, Cameron JD, Wong DTL, Talman AH, et al. Ethnic differences in coronary plaque and epicardial fat volume quantified using computed tomography. Int J Cardiovasc Imaging. Sep 26; 2016.
 3.Addison O, Marcus RL, Lastayo PC, Ryan AS. Intermuscular fat: A review of the consequences and causes. Int J Endocrinol 2014: 309570, 2014.
 4.Ahmadi N, Nabavi V, Hajsadeghi F, Zeb I, Flores F, Ebrahimi R, Budoff M. Aged garlic extract with supplement is associated with increase in brown adipose, decrease in white adipose tissue and predict lack of progression in coronary atherosclerosis. Int J Cardiol 168: 2310‐2314, 2013.
 5.Al Chekakie MO, Welles CC, Metoyer R, Ibrahim A, Shapira AR, Cytron J, Santucci P, Wilber DJ, Akar JG. Pericardial fat is independently associated with human atrial fibrillation. J Am Coll Cardiol 56: 784‐788, 2010.
 6.Aldiss P, Davies G, Woods R, Budge H, Sacks HS, Symonds ME. “Browning” the cardiac and peri‐vascular adipose tissues to modulate cardiovascular risk. Int J Cardiol 228: 265‐274, 2017.
 7.Alligier M, Meugnier E, Debard C, Lambert‐Porcheron S, Chanseaume E, Sothier M, Loizon E, Hssain AA, Brozek J, Scoazec JYY, Morio B, Vidal H, Laville M. Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. J Clin Endocrinol Metab 97: 92, 2012.
 8.Apfaltrer P, Schindler A, Schoepf UJ, Nance JW, Tricarico F, Ebersberger U, et al. Comparison of epicardial fat volume by computed tomography in black versus white patients with acute chest pain. Am J Cardiol. Feb 1; 113(3): 422‐8, 2014.
 9.Atienza F, Calvo D, Almendral J, Zlochiver S, Grzeda KR, Martínez‐Alzamora N, González‐Torrecilla E, Arenal A, Fernández‐Avilés F, Berenfeld O. Mechanisms of fractionated electrograms formation in the posterior left atrium during paroxysmal atrial fibrillation in humans. J Am Coll Cardiol 57: 1081‐1092, 2011.
 10.Baba S, Jacene HA, Engles JM, Honda H, Wahl RL. CT Hounsfield units of brown adipose tissue increase with activation: Preclinical and clinical studies. J Nucl Med Off Publ Soc Nucl Med 51: 246‐250, 2010.
 11.Bachar GN, Dicker D, Kornowski R, Atar E. Epicardial adipose tissue as a predictor of coronary artery disease in asymptomatic subjects. Am J Cardiol 110: 534‐538, 2012.
 12.Baker AR, Harte AL, Howell N, Pritlove DC, Ranasinghe AM, da Silva NF, Youssef EM, Khunti K, Davies MJ, Bonser RS, Kumar S, Pagano D, McTernan PG. Epicardial adipose tissue as a source of nuclear factor‐kappaB and c‐Jun N‐terminal kinase mediated inflammation in patients with coronary artery disease. J Clin Endocrinol Metab 94: 261‐267, 2009.
 13.Bakkum MJ, Danad I, Romijn M a. J, Stuijfzand WJA, Leonora RM, Tulevski II, Somsen GA, Lammertsma AA, van Kuijk C, van Rossum AC, Raijmakers PG, Knaapen P. The impact of obesity on the relationship between epicardial adipose tissue, left ventricular mass and coronary microvascular function. Eur J Nucl Med Mol Imaging 42: 1562‐1573, 2015.
 14.Bambace C, Telesca M, Zoico E, Sepe A, Olioso D, Rossi A, Corzato F, Di Francesco V, Mazzucco A, Santini F, Zamboni M. Adiponectin gene expression and adipocyte diameter: A comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc Pathol 20: e153‐e156, 2011.
 15.Bapat SP, Myoung Suh J, Fang S, Liu S, Zhang Y, Cheng A, Zhou C, Liang Y, LeBlanc M, Liddle C, Atkins AR, Yu RT, Downes M, Evans RM, Zheng YC. Depletion of fat‐resident Treg cells prevents age‐associated insulin resistance. Nature 528: 137‐141, 2015.
 16.Barandier C, Montani J‐P, Yang Z. Mature adipocytes and perivascular adipose tissue stimulate vascular smooth muscle cell proliferation: Effects of aging and obesity. Am J Physiol Heart Circ Physiol 289: H1807‐H1813, 2005.
 17.Baroja‐Mazo A, Martín‐Sánchez F, Gomez AI, Martínez CM, Amores‐Iniesta J, Compan V, Barberà‐Cremades M, Yagüe J, Ruiz‐Ortiz E, Antón J, Buján S, Couillin I, Brough D, Arostegui JI, Pelegrín P. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15: 738‐748, 2014.
 18.Barone‐Rochette G, Vivodtzev I, Tamisier R, Rodière M, Ormezzano O, Baguet JP, Grangier A, Wuyam B, Levy P, Pépin JL. Left ventricular remodeling and epicardial fat volume in obese patients with severe obstructive sleep apnea treated by continuous positive airway pressure. Int J Cardiol 179: 218‐219, 2015.
 19.Bastarrika G, Broncano J, Schoepf UJ, Schwarz F, Lee YS, Abro JA, Costello P, Zwerner PL. Relationship between coronary artery disease and epicardial adipose tissue quantification at cardiac CT: Comparison between automatic volumetric measurement and manual bidimensional estimation. Acad Radiol 17: 727‐734, 2010.
 20.Batal O, Schoenhagen P, Shao M, Ayyad AE, Van Wagoner DR, Halliburton SS, Tchou PJ, Chung MK. Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol 3: 230‐236, 2010.
 21.Bellows CF, Zhang Y, Simmons PJ, Khalsa AS, Kolonin MG. Influence of BMI on level of circulating progenitor cells. Obes Silver Spring 19: 1722‐1726, 2011.
 22.Bidault G, Vatier C, Capeau J, Vigouroux C, Béréziat V. LMNA‐linked lipodystrophies: From altered fat distribution to cellular alterations. Biochem Soc Trans 39: 1752‐1757, 2011.
 23.Billon N, Dani C. Developmental origins of the adipocyte lineage: New insights from genetics and genomics studies. Stem Cell Rev 8: 55‐66, 2012.
 24.Bluher M. Adipose tissue dysfunction in obesity. Exp Clin Endocrinol Diabetes 117: 241‐250, 2009.
 25.Boixel C, Fontaine V, Rücker‐Martin C, Milliez P, Louedec L, Michel JB, Jacob MP, Hatem SN. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol 42: 336‐344, 2003.
 26.Bonapace S, Perseghin G, Molon G, Canali G, Bertolini L, Zoppini G, Barbieri E, Targher G. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 35: 389‐395, 2012.
 27.Bordicchia M, Liu D, Amri E‐Z, Ailhaud G, Dessì‐Fulgheri P, Zhang C, Takahashi N, Sarzani R, Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 122: 1022‐1036, 2012.
 28.Bourlier V, Sengenes C, Zakaroff‐Girard A, Decaunes P, Wdziekonski B, Galitzky J, Villageois P, Esteve D, Chiotasso P, Dani C, Bouloumie A. TGFbeta family members are key mediators in the induction of myofibroblast phenotype of human adipose tissue progenitor cells by macrophages. PLoS One 7: e31274, 2012.
 29.Bourlier V, Zakaroff‐Girard A, Miranville A, De Barros S, Maumus M, Sengenes C, Galitzky J, Lafontan M, Karpe F, Frayn KN, Bouloumie A. Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation 117: 806‐815, 2008.
 30.Brahimi‐Horn MC, Pouysségur J. Oxygen, a source of life and stress. FEBS Lett 581: 3582‐3591, 2007.
 31.Britton KA, Massaro JM, Murabito JM, Kreger BE, Hoffmann U, Fox CS. Body fat distribution, incident cardiovascular disease, cancer, and all‐cause mortality. J Am Coll Cardiol 62: 921‐925, 2013.
 32.Bruunsgaard H, Pedersen BK. Age‐related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23: 15‐39, 2003.
 33.Burgeiro A, Fuhrmann A, Cherian S, Espinoza D, Jarak I, Carvalho RA, Loureiro M, Patrício M, Antunes M, Carvalho E. Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes. Am J Physiol Endocrinol Metab 310: E550‐E564, 2016.
 34.Burstein B, Nattel S. Atrial fibrosis: Mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 51: 802‐809, 2008.
 35.Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kanderian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR. Ascorbate attenuates atrial pacing‐induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 89: E32‐E38, 2001.
 36.Cartwright MJ, Schlauch K, Lenburg ME, Tchkonia T, Pirtskhalava T, Cartwright A, Thomou T, Kirkland JL. Aging, depot origin, and preadipocyte gene expression. J Gerontol Biol Sci Med Sci 65: 242‐251, 2010.
 37.Castoldi A, Naffah de Souza C, Câmara NO, Moraes‐Vieira PM. The macrophage switch in obesity development. Front Immunol 6: 637, 2015.
 38.Cavalcante JL, Tamarappoo BK, Hachamovitch R, Kwon DH, Alraies MC, Halliburton S, Schoenhagen P, Dey D, Berman DS, Marwick TH. Association of epicardial fat, hypertension, subclinical coronary artery disease, and metabolic syndrome with left ventricular diastolic dysfunction. Am J Cardiol 110: 1793‐1798, 2012.
 39.Çetin S, Vural MG, Gündüz H, Akdemir R, Fırat H. Epicardial fat thickness regression with continuous positive airway pressure therapy in patients with obstructive sleep apnea: Assessment by two‐dimensional echocardiography. Wien Klin Wochenschr 128: 187‐192, 2016.
 40.Chao T‐F, Hung C‐L, Tsao H‐M, Lin Y‐J, Yun C‐H, Lai Y‐H, Chang S‐L, Lo L‐W, Hu Y‐F, Tuan T‐C, Chang H‐Y, Kuo J‐Y, Yeh H‐I, Wu T‐J, Hsieh M‐H, Yu W‐C, Chen S‐A. Epicardial adipose tissue thickness and ablation outcome of atrial fibrillation. PloS One 8: e74926, 2013.
 41.Chaowalit N, Lopez‐Jimenez F. Epicardial adipose tissue: Friendly companion or hazardous neighbour for adjacent coronary arteries? Eur Heart J 29: 695‐697, 2008.
 42.Chau Y‐Y, Bandiera R, Serrels A, Martínez‐Estrada OM, Qing W, Lee M, Slight J, Thornburn A, Berry R, McHaffie S, Stimson RH, Walker BR, Chapuli RM, Schedl A, Hastie N. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol 16: 367‐375, 2014.
 43.Chechi K, Blanchard P‐G, Mathieu P, Deshaies Y, Richard D. Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL‐cholesterol and triglycerides in patients with coronary artery disease. Int J Cardiol 167: 2264‐2270, 2013.
 44.Chechi K, Richard D. Thermogenic potential and physiological relevance of human epicardial adipose tissue. Int J Obes Suppl 5: S28‐S34, 2015.
 45.Cheng K‐H, Chu C‐S, Lee K‐T, Lin T‐H, Hsieh C‐C, Chiu C‐C, Voon W‐C, Sheu S‐H, Lai W‐T. Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease. Int J Obes 2005 32: 268‐274, 2008.
 46.Cheng VY, Dey D, Tamarappoo B, Nakazato R, Gransar H, Miranda‐Peats R, Ramesh A, Wong ND, Shaw LJ, Slomka PJ, Berman DS. Pericardial fat burden on ECG‐gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. JACC Cardiovasc Imaging 3: 352‐360, 2010.
 47.Cherian S, Lopaschuk GD, Carvalho E. Cellular cross‐talk between epicardial adipose tissue and myocardium in relation to the pathogenesis of cardiovascular disease. Am J Physiol Endocrinol Metab 303: E937‐E949, 2012.
 48.Cho K‐I, Kim B‐J, Cha T‐J, Heo J‐H, Kim H‐S, Lee J‐W. Impact of duration and dosage of statin treatment and epicardial fat thickness on the recurrence of atrial fibrillation after electrical cardioversion. Heart Vessels 30: 490‐497, 2015.
 49.Christopherson KW II, Cooper S, Broxmeyer HE. Cell surface peptidase CD26/DPPIV mediates G‐CSF mobilization of mouse progenitor cells. Blood 101: 4680‐4686, 2003.
 50.Cildir G, Akincilar SC, Tergaonkar V. Chronic adipose tissue inflammation: All immune cells on the stage. Trends Mol Med 19: 487‐500, 2013.
 51.Clement K, Basdevant A, Dutour A. Weight of pericardial fat on coronaropathy. Arterioscler Thromb Vasc Biol 29: 615‐616, 2009.
 52.Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence‐associated secretory phenotypes reveal cell‐nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6: 2853‐2868, 2008.
 53.Corradi D, Maestri R, Callegari S, Pastori P, Goldoni M, Luong TV, Bordi C. The ventricular epicardial fat is related to the myocardial mass in normal, ischemic and hypertrophic hearts. Cardiovasc Pathol 13: 313‐316, 2004.
 54.Coumel P. Paroxysmal atrial fibrillation: A disorder of autonomic tone? Eur Heart J 15 Suppl A: 9‐16, 1994.
 55.Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Pénicaud L, Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: Molecular and morphological characterization. J Cell Sci 103 (Pt 4): 931‐942, 1992.
 56.Creely SJ, McTernan PG, Kusminski CM, Fisher ff M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292: E740‐E747, 2007.
 57.Crendal E, Dutheil F, Naughton G, McDonald T, Obert P. Increased myocardial dysfunction, dyssynchrony, and epicardial fat across the lifespan in healthy males. BMC Cardiovasc Disord 14: 95, 2014.
 58.Cristobal‐Huerta A, Torrado‐Carvajal A, Malpica N, Luaces M, Hernandez‐Tamames JA. Automated quantification of epicardial adipose tissue in cardiac magnetic resonance imaging. Conf Proc Annu Int Conf IEEE Eng Med Biol Soc IEEE Eng Med Biol Soc Annu Conf 2015: 7308‐7311, 2015.
 59.Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng Y‐H, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360: 1509‐1517, 2009.
 60.Dabbah S, Komarov H, Marmor A, Assy N. Epicardial fat, rather than pericardial fat, is independently associated with diastolic filling in subjects without apparent heart disease. Nutr Metab Cardiovasc Dis NMCD 24: 877‐882, 2014.
 61.Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault I, Montastier E, Denis RG, Ancel P, Lacombe A, Ling Y, Allatif O, Cruciani‐Guglielmacci C, André S, Viguerie N, Poitou C, Stich V, Torcivia A, Foufelle F, Luquet S, Aron‐Wisnewsky J, Langin D, Clément K, Udalova IA, Venteclef N. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med 21(6): 610‐8, 2015.
 62.Dar A, Schajnovitz A, Lapid K, Kalinkovich A, Itkin T, Ludin A, Kao WM, Battista M, Tesio M, Kollet O, Cohen NN, Margalit R, Buss EC, Baleux F, Oishi S, Fujii N, Larochelle A, Dunbar CE, Broxmeyer HE, Frenette PS, Lapidot T. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4‐dependent SDF‐1 release from bone marrow stromal cells. Leukemia 25: 1286‐1296, 2011.
 63.Das M, Gabriely I, Barzilai N. Caloric restriction, body fat and ageing in experimental models. Obes Rev 5(1): 13‐9, 2004.
 64.Dean RT, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnea. Sleep 16: S15‐21‐22, 1993.
 65.Despres J‐P. Body fat distribution and risk of cardiovascular disease: An update. Circulation 126: 1301‐1313, 2012.
 66.Ding J, Hsu F‐C, Harris TB, Liu Y, Kritchevsky SB, Szklo M, Ouyang P, Espeland MA, Lohman KK, Criqui MH, Allison M, Bluemke DA, Carr JJ. The association of pericardial fat with incident coronary heart disease: The Multi‐Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 90: 499‐504, 2009.
 67.Divoux A, Clément K. Architecture and the extracellular matrix: The still unappreciated components of the adipose tissue. Obes Rev Off J Int Assoc Study Obes 12: 503, 2011.
 68.Djian P, Roncari AK, Hollenberg CH. Influence of anatomic site and age on the replication and differentiation of rat adipocyte precursors in culture. J Clin Invest 72: 1200‐1208, 1983.
 69.Doesch C, Haghi D, Flüchter S, Suselbeck T, Schoenberg SO, Michaely H, Borggrefe M, Papavassiliu T. Epicardial adipose tissue in patients with heart failure. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 12: 40, 2010.
 70.Doesch C, Suselbeck T, Leweling H, Fluechter S, Haghi D, Schoenberg SO, Borggrefe M, Papavassiliu T. Bioimpedance analysis parameters and epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with heart failure. Obes Silver Spring Md 18: 2326‐2332, 2010.
 71.Donato AJ, Henson GD, Hart CR, Layec G, Trinity JD, Bramwell CR, Enz RA, Morgan GR, Reihl KD, Hazra S. The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: Evidence of significant multisystem dysfunction. J Physiol 592: 4083‐4096, 2014.
 72.Döring Y, Pawig L, Weber C, Noels H. The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease. Front Physiol 5: 212, 2014.
 73.Douglas NJ, Polo O. Pathogenesis of obstructive sleep apnoea/hypopnoea syndrome. Lancet Lond Engl 344: 653‐655, 1994.
 74.Dozio E, Vianello E, Briganti S, Fink B, Malavazos AE, Scognamiglio ET, Dogliotti G, Sigrüener A, Schmitz G, Corsi Romanelli MM. Increased reactive oxygen species production in epicardial adipose tissues from coronary artery disease patients is associated with brown‐to‐white adipocyte trans‐differentiation. Int J Cardiol 174: 413‐414, 2014.
 75.Dutour A, Abdesselam I, Ancel P, Kober F, Mrad G, Darmon P, Ronsin O, Pradel V, Lesavre N, Martin JC, Jacquier A, Lefur Y, Bernard M, Gaborit B. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: A prospective randomised clinical trial using Magnetic Resonance Imaging and Spectroscopy. Diabetes Obes Metab 18(9): 882‐891, 2016.
 76.Dutour A, Achard V, Sell H, Naour N, Collart F, Gaborit B, Silaghi A, Eckel J, Alessi M‐C, Henegar C, Clément K. Secretory type II phospholipase A2 is produced and secreted by epicardial adipose tissue and overexpressed in patients with coronary artery disease. J Clin Endocrinol Metab 95: 963‐967, 2010.
 77.El Khoudary SR, Shin C, Masaki K, Miura K, Budoff M, Edmundowicz D, et al. Ectopic cardiovascular fat in middle‐aged men: effects of race/ethnicity, overall and central adiposity. The ERA JUMP study. Int J Obes. Mar 2005; 39(3): 488‐94, 2015.
 78.Enzi G, Gasparo M, Biondetti PR, Fiore D, Semisa M, Zurlo F. Subcutaneous and visceral fat distribution according to sex, age, and overweight, evaluated by computed tomography. Am J Clin Nutr 44: 739‐746, 1986.
 79.Fain JN, Sacks HS, Buehrer B, Bahouth SW, Garrett E, Wolf RY, Carter RA, Tichansky DS, Madan AK. Identification of omentin mRNA in human epicardial adipose tissue: Comparison to omentin in subcutaneous, internal mammary artery periadventitial and visceral abdominal depots. Int J Obes 2005 32: 810‐815, 2008.
 80.Ferraro GA, Mizuno H, Pallua N. Adipose stem cells: From bench to bedside. Stem Cells Int 2016: 6484038, 2016.
 81.Fontes‐Carvalho R, Fontes‐Oliveira M, Sampaio F, Mancio J, Bettencourt N, Teixeira M, Rocha Gonçalves F, Gama V, Leite‐Moreira A. Influence of epicardial and visceral fat on left ventricular diastolic and systolic functions in patients after myocardial infarction. Am J Cardiol 114: 1663‐1669, 2014.
 82.Fontes‐Carvalho R, Fontes‐Oliveira M, Sampaio F, Mancio J, Bettencourt N, Teixeira M, Rocha Gonçalves F, Gama V, Leite‐Moreira A. Influence of epicardial and visceral fat on left ventricular diastolic and systolic functions in patients after myocardial infarction. Am J Cardiol 114: 1663‐1669, 2014.
 83.Foster MT, Shi H, Seeley RJ, Woods SC. Removal of intra‐abdominal visceral adipose tissue improves glucose tolerance in rats: Role of hepatic triglyceride storage. Physiol Behav 104: 845‐854, 2011.
 84.Fox CS, White CC, Lohman K, Heard‐Costa N, Cohen P, Zhang Y, et al. Genome‐wide association of pericardial fat identifies a unique locus for ectopic fat. PLoS Genet 8(5): e1002705, 2012.
 85.Franssens BT, Nathoe HM, Leiner T, van der Graaf Y, Visseren FL, SMART study group. Relation between cardiovascular disease risk factors and epicardial adipose tissue density on cardiac computed tomography in patients at high risk of cardiovascular events. Eur J Prev Cardiol 24(6): 660‐670, 2017.
 86.Friedman DJ, Wang N, Meigs JB, Hoffmann U, Massaro JM, Fox CS, Magnani JW. Pericardial fat is associated with atrial conduction: The Framingham Heart Study. J Am Heart Assoc 3: e000477, 2014.
 87.Fukagawa NK, Kohrt WM. Loss of skeletal muscle mass with aging: Effect on glucose tolerance. J Gerontol A Biol Sci Med Sci 50 Spec No: 68‐72, 1995.
 88.Gaborit B, Abdesselam I, Dutour A. Epicardial fat: More than just an “epi” phenomenon? Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 45: 991‐1001, 2013.
 89.Gaborit B, Dutour A. Looking beyond ectopic fat amount: A SMART method to quantify epicardial adipose tissue density. Eur J Prev Cardiol 24(6): 657‐659, 2017.
 90.Gaborit B, Jacquier A, Kober F, Abdesselam I, Cuisset T, Boullu‐Ciocca S, Emungania O, Alessi M‐C, Clément K, Bernard M, Dutour A. 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.
 91.Gaborit B, Kober F, Jacquier A, Moro PJ, Cuisset T, Boullu S, Dadoun F, Alessi M‐C, Morange P, Clément K, Bernard M, Dutour A. Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: Relationship to metabolic profile, cardiac function and visceral fat. Int J Obes 36: 422‐430, 2012.
 92.Gaborit B, Kober F, Jacquier A, Moro PJ, Flavian A, Quilici J, Cuisset T, Simeoni U, Cozzone P, Alessi M‐C, Clément K, Bernard M, Dutour A. Epicardial fat volume is associated with coronary microvascular response in healthy subjects: a pilot study. Obes Silver Spring Md 20: 1200‐1205, 2012.
 93.Gaborit B, Venteclef N, Ancel P, Pelloux V, Gariboldi V, Leprince P, Amour J, Hatem SN, Jouve E, Dutour A, Clément K. Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri‐atrial, peri‐ventricular, or peri‐coronary location. Cardiovasc Res 108: 62‐73, 2015.
 94.Galant D, Gaborit B, Desgrouas C, Abdesselam I, Bernard M, Levy N, Merono F, Coirault C, Roll P, Lagarde A, Bonello‐Palot N, Bourgeois P, Dutour A, Badens C. A heterozygous ZMPSTE24 mutation associated with severe metabolic syndrome, ectopic fat accumulation, and dilated cardiomyopathy. Cells 5(2), pii: E21 2016.
 95.Garg SK, Delaney C, Shi H, Yung R. Changes in adipose tissue macrophages and T cells during aging. Crit Rev Immunol 34: 1‐14, 2014.
 96.Geiger K, Leiherer A, Muendlein A, Stark N, Geller‐Rhomberg S, Saely CH, Wabitsch M, Fraunberger P, Drexel H. Identification of hypoxia‐induced genes in human SGBS adipocytes by microarray analysis. PLoS One 6: e26465, 2011.
 97.Gil‐Ortega M, Fernandez‐Alfonso MS, Somoza B, Casteilla L, Sengenes C. Ex vivo microperfusion system of the adipose organ: A new approach to studying the mobilization of adipose cell populations. Int J Obes 38(9): 1255‐62, 2014.
 98.Gil‐Ortega M, Garidou L, Barreau C, Maumus M, Breasson L, Tavernier G, Garcia‐Prieto CF, Bouloumie A, Casteilla L, Sengenes C. Native adipose stromal cells egress from adipose tissue in vivo: Evidence during lymph node activation. Stem Cells 31: 1309‐1320, 2013.
 99.Gimble J, Guilak F. Adipose‐derived adult stem cells: Isolation, characterization, and differentiation potential. Cytotherapy 5: 362‐369, 2003.
 100.Gimble JM, Bunnell BA, Guilak F. Human adipose‐derived cells: An update on the transition to clinical translation. Regen Med 7: 225‐235, 2012.
 101.Gökdeniz T, Erkol A, Kalaycıoğlu E, Çağrı Aykan A, Gül İ, Boyacı F, Turan B, Ozkan M. Relation of epicardial fat thickness to subclinical right ventricular dysfunction assessed by strain and strain rate imaging in subjects with metabolic syndrome: A two‐dimensional speckle tracking echocardiography study. Echocardiogr Mt Kisco N 32: 248‐256, 2015.
 102.Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP, Konings E, Jocken JWE, Cajlakovic M, Ribitsch V, Clement K, Blaak EE. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 124: 67‐76, 2011.
 103.Gorter PM, de Vos AM, van der Graaf Y, Stella PR, Doevendans PA, Meijs MFL, Prokop M, Visseren FLJ. Relation of epicardial and pericoronary fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography. Am J Cardiol 102: 380‐385, 2008.
 104.Granér M, Nyman K, Siren R, Pentikäinen MO, Lundbom J, Hakkarainen A, Lauerma K, Lundbom N, Nieminen MS, Taskinen M‐R. Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease. Circ Cardiovasc Imaging 8(1) pii: e001979, 2014.
 105.Greif M, Becker A, von Ziegler F, Lebherz C, Lehrke M, Broedl UC, Tittus J, Parhofer K, Becker C, Reiser M, Knez A, Leber AW. Pericardial adipose tissue determined by dual source CT is a risk factor for coronary atherosclerosis. Arterioscler Thromb Vasc Biol 29: 781‐786, 2009.
 106.Greulich S, Chen WJY, Maxhera B, Rijzewijk LJ, van der Meer RW, Jonker JT, Mueller H, de Wiza DH, Floerke R‐R, Smiris K, Lamb HJ, de Roos A, Bax JJ, Romijn JA, Smit JWA, Akhyari P, Lichtenberg A, Eckel J, Diamant M, Ouwens DM. Cardioprotective properties of omentin‐1 in type 2 diabetes: Evidence from clinical and in vitro studies. PloS One 8: e59697, 2013.
 107.Greulich S, Maxhera B, Vandenplas G, de Wiza DH, Smiris K, Mueller H, Heinrichs J, Blumensatt M, Cuvelier C, Akhyari P, Ruige JB, Ouwens DM, Eckel J. Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction. Circulation 126: 2324‐2334, 2012.
 108.Greulich S, de Wiza DH, Preilowski S, Ding Z, Mueller H, Langin D, Jaquet K, Ouwens DM, Eckel J. Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function. J Cell Mol Med 15: 2399‐2410, 2011.
 109.Groves EM, Erande AS, Le C, Salcedo J, Hoang KC, Kumar S, Mohar DS, Saremi F, Im J, Agrawal Y, Nadeswaran P, Naderi N, Malik S. Comparison of epicardial adipose tissue volume and coronary artery disease severity in asymptomatic adults with versus without diabetes mellitus. Am J Cardiol 114: 686‐691, 2014.
 110.Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol 211: 144‐156, 2007.
 111.Guo SS, Zeller C, Chumlea WC, Siervogel RM. Aging, body composition, and lifestyle: The Fels Longitudinal Study. Am J Clin Nutr 70: 405‐411, 1999.
 112.Guo W, Pirtskhalava T, Tchkonia T, Xie W, Thomou T, Han J, Wang T, Wong S, Cartwright A, Hegardt FG, Corkey BE, Kirkland JL. Aging results in paradoxical susceptibility of fat cell progenitors to lipotoxicity. Am J Physiol Endocrinol Metab 292: E1041‐E1051, 2007.
 113.Gupta OT, Gupta RK. Visceral adipose tissue mesothelial cells: Living on the edge or just taking up space? Trends Endocrinol Metab TEM 26: 515‐523, 2015.
 114.Han JM, Wu D, Denroche HC, Yao Y, Verchere CB, Levings MK. IL‐33 reverses an obesity‐induced deficit in visceral adipose tissue ST2+ T regulatory cells and ameliorates adipose tissue inflammation and insulin resistance. J Immunol 194: 4777‐4783, 2015.
 115.Hassan M, Latif N, Yacoub M. Adipose tissue: Friend or foe? Nat Rev Cardiol 9: 689‐702, 2012.
 116.Hatem SN, Redheuil A, Gandjbakhch E. Cardiac adipose tissue and atrial fibrillation: The perils of adiposity. Cardiovasc Res 109: 502‐509, 2016.
 117.Hell MM, Ding X, Rubeaux M, Slomka P, Gransar H, Terzopoulos D, Hayes S, Marwan M, Achenbach S, Berman DS, Dey D. Epicardial adipose tissue volume but not density is an independent predictor for myocardial ischemia. J Cardiovasc Comput Tomogr 10: 141‐149, 2016.
 118.Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I, Guerre‐Millo M, Poitou C, Basdevant A, Stich V, Viguerie N, Langin D, Bedossa P, Zucker J‐DD, Clement KC. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 9(1): R14, 2008.
 119.Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 58: 248‐255, 2011.
 120.Hirata Y, Yamada H, Kusunose K, Iwase T, Nishio S, Hayashi S, Bando M, Amano R, Yamaguchi K, Soeki T, Wakatsuki T, Sata M. Clinical utility of measuring epicardial adipose tissue thickness with echocardiography using a high‐frequency linear probe in patients with coronary artery disease. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr 28: 1240‐1246.e1, 2015.
 121.Hocking SL, Stewart RL, Brandon AE, Suryana E, Stuart E, Baldwin EM, Kolumam GA, Modrusan Z, Junutula JR, Gunton JE, Medynskyj M, Blaber SP, Karsten E, Herbert BR, James DE, Cooney GJ, Swarbrick MM. Subcutaneous fat transplantation alleviates diet‐induced glucose intolerance and inflammation in mice. Diabetologia 58: 1587‐1600, 2015.
 122.Homsi R, Meier‐Schroers M, Gieseke J, Dabir D, Luetkens JA, Kuetting DL, Naehle CP, Marx C, Schild HH, Thomas DK, Sprinkart AM. 3D‐Dixon MRI based volumetry of peri‐ and epicardial fat. Int J Cardiovasc Imaging 32: 291‐299, 2016.
 123.Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease Cell 140(6): 900‐17, 2010.
 124.Hotamisligil GS, Arner P, Caro JF. Increased adipose tissue expression of tumor necrosis factor‐alpha in human obesity and insulin resistance. J Clin Invest 95(5): 2409‐15, 1995.
 125.Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor‐alpha: Direct role in obesity‐linked insulin resistance. Science 259: 87‐91, 1993.
 126.Hua N, Chen Z, Phinikaridou A, Pham T, Qiao Y, LaValley MP, Bigornia SJ, Ruth MR, Apovian CM, Ruberg FL, Hamilton JA. The influence of pericardial fat upon left ventricular function in obese females: Evidence of a site‐specific effect. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 16: 37, 2014.
 127.Iacobellis G. Relation of epicardial fat thickness to right ventricular cavity size in obese subjects. Am J Cardiol 104: 1601‐1602, 2009.
 128.Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 11: 363‐371, 2015.
 129.Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, Leonetti F. Epicardial fat from echocardiography: A new method for visceral adipose tissue prediction. Obes Res 11: 304‐310, 2003.
 130.Iacobellis G, Bianco AC. Epicardial adipose tissue: Emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab TEM 22: 450‐457, 2011.
 131.Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: Anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2: 536‐543, 2005.
 132.Iacobellis G, Leonetti F, Singh N, M Sharma A. Relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects. Int J Cardiol 115: 272‐273, 2007.
 133.Iacobellis G, Pistilli D, Gucciardo M, Leonetti F, Miraldi F, Brancaccio G, Gallo P, di Gioia CRT. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine 29: 251‐255, 2005.
 134.Iacobellis G, Pond CM, Sharma AM. Different “weight” of cardiac and general adiposity in predicting left ventricle morphology. Obes Silver Spring Md 14: 1679‐1684, 2006.
 135.Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F. Relation between epicardial adipose tissue and left ventricular mass. Am J Cardiol 94: 1084‐1087, 2004.
 136.Iacobellis G, Zaki MC, Garcia D, Willens HJ. Epicardial fat in atrial fibrillation and heart failure. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 46: 587‐590, 2014.
 137.Iozzo P. Myocardial, perivascular, and epicardial fat. Diabetes Care 34: S371‐S379, 2011.
 138.Iozzo P, Lautamaki R, Borra R, Lehto H‐R, Bucci M, Viljanen A, Parkka J, Lepomaki V, Maggio R, Parkkola R, Knuuti J, Nuutila P. Contribution of glucose tolerance and gender to cardiac adiposity. J Clin Endocrinol Metab 94: 4472‐4482, 2009.
 139.Ishikawa Y, Ishii T, Asuwa N, Masuda S. Absence of atherosclerosis evolution in the coronary arterial segment covered by myocardial tissue in cholesterol‐fed rabbits. Virchows Arch Int J Pathol 430: 163‐171, 1997.
 140.Ito T, Suzuki Y, Ehara M, Matsuo H, Teramoto T, Terashima M, Nasu K, Kinoshita Y, Tsuchikane E, Suzuki T, Kimura G. Impact of epicardial fat volume on coronary artery disease in symptomatic patients with a zero calcium score. Int J Cardiol 167: 2852‐2858, 2013.
 141.Iyengar P, Espina V, Williams TW, Lin Y, Berry D, Jelicks LA, Lee H, Temple K, Graves R, Pollard J, Chopra N, Russell RG, Sasisekharan R, Trock BJ, Lippman M, Calvert VS, Petricoin EF, Liotta L, Dadachova E, Pestell RG, Lisanti MP, Bonaldo P, Scherer PEC. Adipocyte‐derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115: 1163‐1176, 2005.
 142.Janik M, Hartlage G, Alexopoulos N, Mirzoyev Z, McLean DS, Arepalli CD, Chen Z, Stillman AE, Raggi P. Epicardial adipose tissue volume and coronary artery calcium to predict myocardial ischemia on positron emission tomography‐computed tomography studies. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol 17: 841‐847, 2010.
 143.Jing L, Binkley CM, Suever JD, Umasankar N, Haggerty CM, Rich J, Wehner GJ, Hamlet SM, Powell DK, Radulescu A, Kirchner HL, Epstein FH, Fornwalt BK. Cardiac remodeling and dysfunction in childhood obesity: A cardiovascular magnetic resonance study. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 18: 28, 2016.
 144.Johnson AR, Milner JJ, Makowski L. The inflammation highway: Metabolism accelerates inflammatory traffic in obesity. Immunol Rev 249: 218‐238, 2012.
 145.Kaisho T, Akira S. Toll‐like receptors as adjuvant receptors. Biochim Biophys Acta 1589: 1‐13, 2002.
 146.von Känel R, Loredo JS, Ancoli‐Israel S, Mills PJ, Natarajan L, Dimsdale JE. Association between polysomnographic measures of disrupted sleep and prothrombotic factors. Chest 131: 733‐739, 2007.
 147.Kankaanpää M, Lehto H‐R, Pärkkä JP, Komu M, Viljanen A, Ferrannini E, Knuuti J, Nuutila P, Parkkola R, Iozzo P. 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.
 148.Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: The Framingham study. N Engl J Med 306: 1018‐1022, 1982.
 149.Kaplan O, Kurtoglu E, Gozubuyuk G, Dogan C, Acar Z, EyupKoca F, Pekdemir H. Epicardial adipose tissue thickness in patients with chronic obstructive pulmonary disease having right ventricular systolic dysfunction. Eur Rev Med Pharmacol Sci 19: 2461‐2467, 2015.
 150.Karastergiou K, Evans I, Ogston N, Miheisi N, Nair D, Kaski J‐C, Jahangiri M, Mohamed‐Ali V. Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells. Arterioscler Thromb Vasc Biol 30: 1340‐1346, 2010.
 151.Karimabad MN, Hassanshahi G. Significance of CXCL12 in type 2 diabetes mellitus and its associated complications. Inflammation 38: 710‐717, 2015.
 152.Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LK, Frayn KN. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 51: 2467‐2473, 2002.
 153.Kato M, Roberts‐Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, Somers VK. Impairment of endothelium‐dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102: 2607‐2610, 2000.
 154.Keophiphath M, Achard V, Henegar C, Rouault C, Clément K, Lacasa D. Macrophage‐secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol 23: 11‐24, 2009.
 155.Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer PE. Metabolic dysregulation and adipose tissue fibrosis: Role of collagen VI. Mol Cell Biol 29: 1575‐1591, 2009.
 156.Kilicaslan B, Ozdogan O, Aydin M, Dursun H, Susam I, Ertas F. Increased epicardial fat thickness is associated with cardiac functional changes in healthy women. Tohoku J Exp Med 228: 119‐124, 2012.
 157.Kim KH, Song MJ, Chung J, Park H, Kim JB. Hypoxia inhibits adipocyte differentiation in a HDAC‐independent manner. Biochem Biophys Res Commun 333: 1178‐1184, 2005.
 158.Kirkland JL, Dobson DE. Preadipocyte function and aging: Links between age‐related changes in cell dynamics and altered fat tissue function. J Am Geriatr Soc 45: 959‐967, 1997.
 159.Kirkland JL, Hollenberg CH, Gillon WS. Age, anatomic site, and the replication and differentiation of adipocyte precursors. Am J Physiol 258: C206‐C210, 1990.
 160.Kitagawa T, Yamamoto H, Sentani K, Takahashi S, Tsushima H, Senoo A, Yasui W, Sueda T, Kihara Y. The relationship between inflammation and neoangiogenesis of epicardial adipose tissue and coronary atherosclerosis based on computed tomography analysis. Atherosclerosis 243: 293‐299, 2015.
 161.Kocyigit D, Gurses KM, Yalcin MU, Turk G, Evranos B, Yorgun H, Sahiner ML, Kaya EB, Hazirolan T, Tokgozoglu L, Oto MA, Ozer N, Aytemir K. Periatrial epicardial adipose tissue thickness is an independent predictor of atrial fibrillation recurrence after cryoballoon‐based pulmonary vein isolation. J Cardiovasc Comput Tomogr 9: 295‐302, 2015.
 162.Kolaparthy LK, Sanivarapu S, Moogla S, Kutcham RS. Adipose tissue—adequate, accessible regenerative material. Int J Stem Cells 8: 121‐127, 2015.
 163.Kostopoulos K, Alhanatis E, Pampoukas K, Georgiopoulos G, Zourla A, Panoutsopoulos A, Kallianos A, Velentza L, Zarogoulidis P, Trakada G. CPAP therapy induces favorable short‐term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea‐hypopnea syndrome (OSAHS). Sleep Breath Schlaf Atm 20: 483‐493, 2016.
 164.Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: Incidence, risk factors, and prognosis in the Manitoba Follow‐Up Study. Am J Med 98: 476‐484, 1995.
 165.Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E, Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols. Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 15: 91, 2013.
 166.Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA. IRF5 promotes inflammatory macrophage polarization and TH1‐TH17 responses. Nat Immunol 12: 231‐238, 2011.
 167.Krenning G, Zeisberg EM, Kalluri R. The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol 225: 631‐637, 2010.
 168.Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG. The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes. J Clin Endocrinol Metab 92: 270‐276, 2007.
 169.Kyle UG, Genton L, Hans D, Karsegard L, Slosman DO, Pichard C. Age‐related differences in fat‐free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. Eur J Clin Nutr 55: 663‐672, 2001.
 170.La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol 4: 371‐379, 2004.
 171.Langheim S, Dreas L, Veschini L, Maisano F, Foglieni C, Ferrarello S, Sinagra G, Zingone B, Alfieri O, Ferrero E, Maseri A, Ruotolo G. Increased expression and secretion of resistin in epicardial adipose tissue of patients with acute coronary syndrome. Am J Physiol Heart Circ Physiol 298: H746‐H753, 2010.
 172.Lansley SM, Searles RG, Hoi A, Thomas C, Moneta H, Herrick SE, Thompson PJ, Newman M, Sterrett GF, Prêle CM, Mutsaers SE. Mesothelial cell differentiation into osteoblast‐ and adipocyte‐like cells. J Cell Mol Med 15: 2095‐2105, 2011.
 173.Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood 106: 1901‐1910, 2005.
 174.Lapidot T, Kollet O. The essential roles of the chemokine SDF‐1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune‐deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 16: 1992‐2003, 2002.
 175.Lapidot T, Petit I. Current understanding of stem cell mobilization: The roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 30: 973‐981, 2002.
 176.Lau DH, Schotten U, Mahajan R, Antic NA, Hatem SN, Pathak RK, Hendriks JML, Kalman JM, Sanders P. Novel mechanisms in the pathogenesis of atrial fibrillation: Practical applications. Eur Heart J 37: 1573‐1581, 2016.
 177.Lee B‐C, Lee W‐J, Lo S‐C, Hsu H‐C, Chien K‐L, Chang Y‐C, Chen M‐F. The ratio of epicardial to body fat improves the prediction of coronary artery disease beyond calcium and Framingham risk scores. Int J Cardiovasc Imaging 32(Suppl 1): 117‐127, 2016.
 178.Levelt E, Pavlides M, Banerjee R, Mahmod M, Kelly C, Sellwood J, Ariga R, Thomas S, Francis J, Rodgers C, Clarke W, Sabharwal N, Antoniades C, Schneider J, Robson M, Clarke K, Karamitsos T, Rider O, Neubauer S. Ectopic and visceral fat deposition in lean and obese patients with type 2 diabetes. J Am Coll Cardiol 68(1): 53‐63, 2016.
 179.Levesque JP, Hendy J, Takamatsu Y, Williams B, Winkler IG, Simmons PJ. Mobilization by either cyclophosphamide or granulocyte colony‐stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp Hematol 30: 440‐449, 2002.
 180.Lim LP, Lau NC, Garrett‐Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769‐773, 2005.
 181.Lin H‐H, Lee J‐K, Yang C‐Y, Lien Y‐C, Huang J‐W, Wu C‐K. Accumulation of epicardial fat rather than visceral fat is an independent risk factor for left ventricular diastolic dysfunction in patients undergoing peritoneal dialysis. Cardiovasc Diabetol 12: 127, 2013.
 182.Lin Y‐K, Chen Y‐C, Chen J‐H, Chen S‐A, Chen Y‐J. Adipocytes modulate the electrophysiology of atrial myocytes: Implications in obesity‐induced atrial fibrillation. Basic Res Cardiol 107: 293, 2012.
 183.Liu Q, Chen D, Wang Y, Zhao X, Zheng Y. Cardiac autonomic nerve distribution and arrhythmia. Neural Regen Res 7: 2834‐2841, 2012.
 184.Liu Q, Huang X, Oh J‐H, Lin R‐Z, Duan S, Yu Y, Yang R, Qiu J, Melero‐Martin JM, Pu WT, Zhou B. Epicardium‐to‐fat transition in injured heart. Cell Res 24: 1367‐1369, 2014.
 185.Loader B, Stokic D, Riedl M, Hickmann S, Katzinger M, Willinger U, Luger A, Thurner S, Wick N. Combined analysis of audiologic performance and the plasma biomarker stromal cell‐derived factor 1a in type 2 diabetic patients. Otol Neurotol 29: 739‐744, 2008.
 186.Lombardi R, Dong J, Rodriguez G, Bell A, Leung TK, Schwartz RJ, Willerson JT, Brugada R, Marian AJ. Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circ Res 104: 1076‐1084, 2009.
 187.Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature 404: 652‐660, 2000.
 188.Lubrano C, Saponara M, Barbaro G, Specchia P, Addessi E, Costantini D, Tenuta M, Di Lorenzo G, Genovesi G, Donini LM, Lenzi A, Gnessi L. Relationships between body fat distribution, epicardial fat and obstructive sleep apnea in obese patients with and without metabolic syndrome. PloS One 7: e47059, 2012.
 189.Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175‐184, 2007.
 190.Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57: 3239‐3246, 2008.
 191.Lumeng CN, Liu J, Geletka L, Delaney C, Delproposto J, Desai A, Oatmen K, Martinez‐Santibanez G, Julius A, Garg S, Yung RL. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol 187: 6208‐6216, 2011.
 192.Maghbooli Z, Hossein‐Nezhad A. Transcriptome and molecular endocrinology aspects of epicardial adipose tissue in cardiovascular diseases: A systematic review and meta‐analysis of observational studies. BioMed Res Int 2015: 926567, 2015.
 193.Mahabadi AA, Berg MH, Lehmann N, Kälsch H, Bauer M, Kara K, Dragano N, Moebus S, Jöckel K‐H, Erbel R, Möhlenkamp S. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: The Heinz Nixdorf Recall Study. J Am Coll Cardiol 61: 1388‐1395, 2013.
 194.Mahabadi AA, Lehmann N, Kälsch H, Robens T, Bauer M, Dykun I, Budde T, Moebus S, Jöckel K‐H, Erbel R, Möhlenkamp S. Association of epicardial adipose tissue with progression of coronary artery calcification is more pronounced in the early phase of atherosclerosis: Results from the Heinz Nixdorf recall study. JACC Cardiovasc Imaging 7: 909‐916, 2014.
 195.Mahabadi AA, Massaro JM, Rosito GA, Levy D, Murabito JM, Wolf PA, O'Donnell CJ, Fox CS, Hoffmann U. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: The Framingham Heart Study. Eur Heart J 30: 850‐856, 2009.
 196.Mahajan R, Kuklik P, Grover S, Brooks AG, Wong CX, Sanders P, Selvanayagam JB. Cardiovascular magnetic resonance of total and atrial pericardial adipose tissue: A validation study and development of a 3 dimensional pericardial adipose tissue model. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 15: 73, 2013.
 197.Mahajan R, Lau DH, Brooks AG, Shipp NJ, Manavis J, Wood JPM, Finnie JW, Samuel CS, Royce SG, Twomey DJ, Thanigaimani S, Kalman JM, Sanders P. Electrophysiological, electroanatomical, and structural remodeling of the atria as consequences of sustained obesity. J Am Coll Cardiol 66: 1‐11, 2015.
 198.Mahfouz RA, Alzaiat A, Yousry A. Relationship of epicardial fat thickness with endothelial and cardiac functions in children with family history of type 2 diabetes mellitus. Echocardiogr Mt Kisco N 32: 28‐33, 2015.
 199.Main ML, Rao SC, O'Keefe JH. Trends in obesity and extreme obesity among US adults. JAMA 303: 1695; author reply 1695‐6, 2010.
 200.Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity‐related inflammation and insulin resistance: Cells, cytokines, and chemokines. ISRN Inflamm 2013: 139239, 2013.
 201.Malavazos AE, Di Leo G, Secchi F, Lupo EN, Dogliotti G, Coman C, Morricone L, Corsi MM, Sardanelli F, Iacobellis G. Relation of echocardiographic epicardial fat thickness and myocardial fat. Am J Cardiol 105: 1831‐1835, 2010.
 202.Marchington JM, Mattacks CA, Pond CM. Adipose tissue in the mammalian heart and pericardium: Structure, foetal development and biochemical properties. Comp Biochem Physiol B 94: 225‐232, 1989.
 203.Marchington JM, Pond CM. 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.
 204.Mariani S, Fiore D, Barbaro G, Basciani S, Saponara M, D'Arcangelo E, Ulisse S, Moretti C, Fabbri A, Gnessi L. Association of epicardial fat thickness with the severity of obstructive sleep apnea in obese patients. Int J Cardiol 167: 2244‐2249, 2013.
 205.Martínez‐Estrada OM, Lettice LA, Essafi A, Guadix JA, Slight J, Velecela V, Hall E, Reichmann J, Devenney PS, Hohenstein P, Hosen N, Hill RE, Muñoz‐Chapuli R, Hastie ND. Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E‐cadherin. Nat Genet 42: 89‐93, 2010.
 206.Masuda M, Mizuno H, Enchi Y, Minamiguchi H, Konishi S, Ohtani T, Yamaguchi O, Okuyama Y, Nanto S, Sakata Y. Abundant epicardial adipose tissue surrounding the left atrium predicts early rather than late recurrence of atrial fibrillation after catheter ablation. J Interv Card Electrophysiol Int J Arrhythm Pacing 44: 31‐37, 2015.
 207.Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Brönneke HS, Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA, Chawla A, Wunderlich FT, Brüning JCC. Signaling by IL‐6 promotes alternative activation of macrophages to limit endotoxemia and obesity‐associated resistance to insulin. Nat Immunol 15: 423‐430, 2014.
 208.Maumus M, Peyrafitte JA, D'Angelo R, Fournier‐Wirth C, Bouloumie A, Casteilla L, Sengenes C, Bourin P. Native human adipose stromal cells: Localization, morphology and phenotype. Int J Obes 35(9): 1141‐53, 2011.
 209.Maumus M, Sengenes C, Decaunes P, Zakaroff‐Girard A, Bourlier V, Lafontan M, Galitzky J, Bouloumie A. Evidence of in situ proliferation of adult adipose tissue‐derived progenitor cells: Influence of fat mass microenvironment and growth. J Clin Endocrinol Metab 93: 4098‐4106, 2008.
 210.Mazurek T. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108: 2460‐2466, 2003.
 211.Mazurek T, Kiliszek M, Kobylecka M, Skubisz‐Głuchowska J, Kochman J, Filipiak K, Królicki L, Opolski G. Relation of proinflammatory activity of epicardial adipose tissue to the occurrence of atrial fibrillation. Am J Cardiol 113: 1505‐1508, 2014.
 212.McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6: 483‐495, 2004.
 213.McClain J, Hsu F, Brown E, Burke G, Carr J, Harris T, et al. Pericardial adipose tissue and coronary artery calcification in the Multi‐ethnic Study of Atherosclerosis (MESA). Obes Silver Spring Md. May; 21(5): 1056‐63, 2013.
 214.McGavock JM, Victor RG, Unger RH, Szczepaniak LS, American College of Physicians and the American Physiological Society. Adiposity of the heart, revisited. Ann Intern Med 144: 517‐524, 2006.
 215.McKenney ML, Schultz KA, Boyd JH, Byrd JP, Alloosh M, Teague SD, Arce‐Esquivel AA, Fain JN, Laughlin MH, Sacks HS, others. Epicardial adipose excision slows the progression of porcine coronary atherosclerosis. J Cardiothorac Surg 9: 1, 2014.
 216.Meunier P, Aaron J, Edouard C, Vignon G. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin Orthop Relat Res 80: 147‐154, 1971.
 217.Mohar DS, Salcedo J, Hoang KC, Kumar S, Saremi F, Erande AS, Naderi N, Nadeswaran P, Le C, Malik S. Epicardial adipose tissue volume as a marker of coronary artery disease severity in patients with diabetes independent of coronary artery calcium: Findings from the CTRAD study. Diabetes Res Clin Pract 106: 228‐235, 2014.
 218.Moore MA, Hattori K, Heissig B, Shieh JH, Dias S, Crystal RG, Rafii S. Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector‐mediated elevation of serum levels of SDF‐1, VEGF, and angiopoietin‐1. Ann N Y Acad Sci 938: 36, 2001.
 219.Moraes‐Vieira P, Larocca RA, Bassi EJ, Peron JS, Andrade‐Oliveira V, Wasinski F, Araujo R, Thornley T, Quintana FJ, Basso AS, Strom TB, Câmara N. Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells. Eur J Immunol 44: 794‐806, 2014.
 220.Morin CL, Pagliassotti MJ, Windmiller D, Eckel RH. Adipose tissue‐derived tumor necrosis factor‐alpha activity is elevated in older rats. J Gerontol Biol Sci Med Sci 52: B190‐B195, 1997.
 221.Morley JE. The metabolic syndrome and aging. J Gerontol A Biol Sci Med Sci 59: 139‐142, 2004.
 222.Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H, Koyasu S. Innate production of T(H)2 cytokines by adipose tissue‐associated c‐Kit(+)Sca‐1(+) lymphoid cells. Nature 463: 540‐544, 2010.
 223.Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation. J Immunol 175: 6257‐6263, 2005.
 224.Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune T, Kofune M, Mano H, Sonoda K, Hirayama A. Association between epicardial adipose tissue volumes on 3‐dimensional reconstructed CT images and recurrence of atrial fibrillation after catheter ablation. Circ J Off J Jpn Circ Soc 75: 2559‐2565, 2011.
 225.Nakajima H, Nakajima HO, Salcher O, Dittiè AS, Dembowsky K, Jing S, Field LJ. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor‐beta(1) transgene in the heart. Circ Res 86: 571‐579, 2000.
 226.Nakanishi K, Fukuda S, Tanaka A, Otsuka K, Sakamoto M, Taguchi H, Yoshikawa J, Shimada K, Yoshiyama M. Peri‐atrial epicardial adipose tissue is associated with new‐onset nonvalvular atrial fibrillation. Circ J Off J Jpn Circ Soc 76: 2748‐2754, 2012.
 227.Nakazato R, Shmilovich H, Tamarappoo BK, Cheng VY, Slomka PJ, Berman DS, Dey D. Interscan reproducibility of computer‐aided epicardial and thoracic fat measurement from noncontrast cardiac CT. J Cardiovasc Comput Tomogr 5: 172‐179, 2011.
 228.Napolitano LC. The differentiation of white adipose cells. An electron microscope study. J Cell Biol 18: 663‐679, 1963.
 229.Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293: E444‐E452, 2007.
 230.Nelson AJ, Worthley MI, Psaltis PJ, Carbone A, Dundon BK, Duncan RF, Piantadosi C, Lau DH, Sanders P, Wittert GA, Worthley SG. Validation of cardiovascular magnetic resonance assessment of pericardial adipose tissue volume. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 11: 15, 2009.
 231.Nielsen MO, Kongsted AH, Thygesen MP, Strathe AB, Caddy S, Quistorff B, et al. Late gestation undernutrition can predispose for visceral adiposity by altering fat distribution patterns and increasing the preference for a high‐fat diet in early postnatal life. Br J Nutr. Jun; 109(11): 2098‐110, 2013.
 232.Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914‐920, 2009.
 233.Nishimura S, Manabe I, Takaki S, Nagasaki M, Otsu M, Yamashita H, Sugita J, Yoshimura K, Eto K, Komuro I, Kadowaki T, Nagai R. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab, pii: S1550‐4131(13)00386‐0, 2013.
 234.Nyman K, Granér M, Pentikäinen MO, Lundbom J, Hakkarainen A, Sirén R, Nieminen MS, Taskinen M‐R, Lundbom N, Lauerma K. Cardiac steatosis and left ventricular function in men with metabolic syndrome. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 15: 103, 2013.
 235.Oda S, Utsunomiya D, Funama Y, Yuki H, Kidoh M, Nakaura T, Takaoka H, Matsumura M, Katahira K, Noda K, Oshima S, Tokuyasu S, Yamashita Y. Effect of iterative reconstruction on variability and reproducibility of epicardial fat volume quantification by cardiac CT. J Cardiovasc Comput Tomogr 10: 150‐155, 2016.
 236.Ojha S, Fainberg HP, Wilson V, Pelella G, Castellanos M, May ST, Lotto AA, Sacks H, Symonds ME, Budge H. Gene pathway development in human epicardial adipose tissue during early life. JCI Insight 1: e87460, 2016.
 237.Olgin JE, Verheule S. Transgenic and knockout mouse models of atrial arrhythmias. Cardiovasc Res 54: 280‐286, 2002.
 238.O'Rourke RW, Meyer KA, Gaston G, White AE, Lumeng CN, Marks DL. Hexosamine biosynthesis is a possible mechanism underlying hypoxia's effects on lipid metabolism in human adipocytes. PLoS One 8: e71165, 2013.
 239.Otaki Y, Hell M, Slomka PJ, Schuhbaeck A, Gransar H, Huber B, Nakazato R, Germano G, Hayes SW, Thomson LEJ, Friedman JD, Achenbach S, Berman DS, Dey D. Relationship of epicardial fat volume from noncontrast CT with impaired myocardial flow reserve by positron emission tomography. J Cardiovasc Comput Tomogr 9: 303‐309, 2015.
 240.Ouwens DM, Sell H, Greulich S, Eckel J. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med 14: 2223‐2234, 2010.
 241.Palmer AK, Kirkland JL. Aging and adipose tissue: Potential interventions for diabetes and regenerative medicine. Exp Gerontol 86: 97‐105, 2016.
 242.Papathanassoglou E, El‐Haschimi K, Li XC, Matarese G, Strom T, Mantzoros C. Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J Immunol Baltim Md 1950 176: 7745‐7752, 2006.
 243.Parisi V, Rengo G, Perrone‐Filardi P, Pagano G, Femminella GD, Paolillo S, Petraglia L, Gambino G, Caruso A, Grimaldi MG, Baldascino F, Nolano M, Elia A, Cannavo A, De Bellis A, Coscioni E, Pellegrino T, Cuocolo A, Ferrara N, Leosco D. Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure. Circ Res 118: 1244‐1253, 2016.
 244.Park HE, Choi S‐Y, Kim M. Association of epicardial fat with left ventricular diastolic function in subjects with metabolic syndrome: Assessment using 2‐dimensional echocardiography. BMC Cardiovasc Disord 14: 3, 2014.
 245.Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY. ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet‐induced obesity. Diabetes 65: 85‐95, 2016.
 246.Patsouris D, Li P‐PP, Thapar D, Chapman J, Olefsky JM, Neels JGC. Ablation of CD11c‐positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8: 301‐309, 2008.
 247.Pawelec G. Hallmarks of human immunosenescence: Adaptation or dysregulation? Immun Ageing 9(1): 15, 2012.
 248.Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M, Tune JD. Epicardial perivascular adipose‐derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C‐beta pathway. Arterioscler Thromb Vasc Biol 30: 1711‐1717, 2010.
 249.Payne GA, Kohr MC, Tune JD. Epicardial perivascular adipose tissue as a therapeutic target in obesity‐related coronary artery disease. Br J Pharmacol 165: 659‐669, 2012.
 250.Pellegrinelli V, Carobbio S, Vidal‐Puig A. Adipose tissue plasticity: How fat depots respond differently to pathophysiological cues. Diabetologia 59: 1075‐1088, 2016.
 251.Perez LM, Pareja‐Galeano H, Sanchis‐Gomar F, Emanuele E, Lucia A, Galvez BG. “Adipaging”: Aging and obesity share biological hallmarks related to a dysfunctional adipose tissue. J Physiol (2016). doi: 10.1113/jp271691.
 252.Petrović V, Buzadzić B, Korać A, Vasilijević A, Janković A, Korać B. Free radical equilibrium in interscapular brown adipose tissue: Relationship between metabolic profile and antioxidative defense. Comp Biochem Physiol Toxicol Pharmacol CBP 142: 60‐65, 2006.
 253.Petta S, Argano C, Colomba D, Cammà C, Di Marco V, Cabibi D, Tuttolomondo A, Marchesini G, Pinto A, Licata G, Craxì A. Epicardial fat, cardiac geometry and cardiac function in patients with non‐alcoholic fatty liver disease: association with the severity of liver disease. J Hepatol 62: 928‐933, 2015.
 254.Pierdomenico SD, Pierdomenico AM, Cuccurullo F, Iacobellis G. Meta‐analysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome. Am J Cardiol. Jan 1; 111(1): 73‐8, 2013.
 255.Pinnick KE, Collins SC, Londos C, Gauguier D, Clark A, Fielding BA. Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition. Obes Silver Spring 16: 522‐530, 2008.
 256.Platonov PG. P‐wave morphology: Underlying mechanisms and clinical implications. Ann Noninvasive Electrocardiol Off J Int Soc Holter Noninvasive Electrocardiol Inc 17: 161‐169, 2012.
 257.Po SS, Nakagawa H, Jackman WM. Localization of left atrial ganglionated plexi in patients with atrial fibrillation. J Cardiovasc Electrophysiol 20: 1186‐1189, 2009.
 258.Prati F, Arbustini E, Labellarte A, Sommariva L, Pawlowski T, Manzoli A, Pagano A, Motolese M, Boccanelli A. Eccentric atherosclerotic plaques with positive remodelling have a pericardial distribution: a permissive role of epicardial fat? A three‐dimensional intravascular ultrasound study of left anterior descending artery lesions. Eur Heart J 24: 329‐336, 2003.
 259.Psychari SN, Rekleiti N, Papaioannou N, Varhalama E, Drakoulis C, Apostolou TS, Iliodromitis EK. Epicardial fat in nonalcoholic fatty liver disease: Properties and relationships with metabolic factors, cardiac structure, and cardiac function. Angiology 67: 41‐48, 2016.
 260.Rabkin SW. Epicardial fat: Properties, function and relationship to obesity. Obes Rev 8: 253‐261, 2007.
 261.Rabkin SW, Campbell H. Comparison of reducing epicardial fat by exercise, diet or bariatric surgery weight loss strategies: A systematic review and meta‐analysis. Obes Rev Off J Int Assoc Study Obes. May; 16(5): 406‐415, 2015.
 262.Rångemark C, Hedner JA, Carlson JT, Gleerup G, Winther K. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep 18: 188‐194, 1995.
 263.Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T‐cell infiltration. Int J Obes 32: 451‐463, 2008.
 264.Regazzetti C, Peraldi P, Gremeaux T, Najem‐Lendom R, Ben‐Sahra I, Cormont M, Bost F, Le Marchand‐Brustel Y, Tanti JF, Giorgetti‐Peraldi S. Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 58: 95‐103, 2009.
 265.Reggio S, Pellegrinelli V, Clément K, Tordjman J, Tordjman JC. Fibrosis as a cause or a consequence of white adipose tissue inflammation in obesity. Curr Obes Rep 2(1): 1‐9, 2013.
 266.Reiner L, Mazzoleni A, Rodriguez FL. Statistical analysis of the epicardial fat weight in human hearts. AMA Arch Pathol 60: 369‐373, 1955.
 267.Robicsek F, Thubrikar MJ. The freedom from atherosclerosis of intramyocardial coronary arteries: Reduction of mural stress—a key factor. Eur J Cardio‐Thorac Surg Off J Eur Assoc Cardio‐Thorac Surg 8: 228‐235, 1994.
 268.Rocha S. Gene regulation under low oxygen: Holding your breath for transcription. Trends Biochem Sci 32: 389‐397, 2007.
 269.Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell 135: 240‐249, 2008.
 270.Rodriguez‐Granillo GA, Carrascosa P, Deviggiano A, Capunay C, De Zan MC, Goldsmit A, Campisi R. Pericardial fat volume is related to atherosclerotic plaque burden rather than to lesion severity. Eur Heart J Cardiovasc Imaging (July 1, 2016). doi: 10.1093/ehjci/jew139.
 271.Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, O'Donnell CJ, Fox CS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community‐based sample: The Framingham Heart Study. Circulation 117: 605‐613, 2008.
 272.Sacks HS, Fain JN. Human epicardial adipose tissue: A review. Am Heart J 153: 907‐917, 2007.
 273.Sacks HS, Fain JN. Human epicardial fat: What is new and what is missing?: Epicardial fat review. Clin Exp Pharmacol Physiol 38: 879‐887, 2011.
 274.Sacks HS, Fain JN, Bahouth SW, Ojha S, Frontini A, Budge H, Cinti S, Symonds ME. Adult epicardial fat exhibits beige features. J Clin Endocrinol Metab 98: E1448‐E1455, 2013.
 275.Sacks HS, Fain JN, Cheema P, Bahouth SW, Garrett E, Wolf RY, Wolford D, Samaha J. 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.
 276.Sade LE, Eroglu S, Bozbaş H, Ozbiçer S, Hayran M, Haberal A, Müderrisoğlu H. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis 204: 580‐585, 2009.
 277.Salam N, Rane S, Das R, Faulkner M, Gund R, Kandpal U, Lewis V, Mattoo H, Prabhu S, Ranganathan V, Durdik J, George A, Rath S, Bal V. T cell ageing: Effects of age on development, survival & function. Indian J Med Res 138: 595‐608, 2013.
 278.Salami SS, Tucciarone M, Bess R, Kolluru A, Szpunar S, Rosman H, et al. Race and epicardial fat: the impact of anthropometric measurements, percent body fat and sex. Ethn Dis 23(3): 281‐5, 2013.
 279.Salgado‐Somoza A, Teijeira‐Fernández E, Fernández AL, González‐Juanatey JR, Eiras S. Proteomic analysis of epicardial and subcutaneous adipose tissue reveals differences in proteins involved in oxidative stress. Am J Physiol Heart Circ Physiol 299: H202‐H209, 2010.
 280.Sanchez‐Gurmaches J, Hung C‐MM, Guertin DAC. Emerging complexities in adipocyte origins and identity. Trends Cell Biol 26: 313‐326, 2016.
 281.Sawicka M, Janowska J, Chudek J. Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system. Int J Cardiol 222: 581‐589, 2016.
 282.Semenza GL. Targeting HIF‐1 for cancer therapy. Nat Rev Cancer 3: 721‐732, 2003.
 283.Sengenes C, Lolmede K, Zakaroff‐Girard A, Busse R, Bouloumie A. Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells. J Cell Physiol 205: 114‐122, 2005.
 284.Sengenes C, Miranville A, Maumus M, de Barros S, Busse R, Bouloumie A. Chemotaxis and differentiation of human adipose tissue CD34+/CD31− progenitor cells: Role of stromal derived factor‐1 released by adipose tissue capillary endothelial cells. Stem Cells 25: 2269‐2276, 2007.
 285.Shamsuzzaman ASM, Gersh BJ, Somers VK. Obstructive sleep apnea: Implications for cardiac and vascular disease. JAMA 290: 1906‐1914, 2003.
 286.Shimabukuro M, Hirata Y, Tabata M, Dagvasumberel M, Sato H, Kurobe H, Fukuda D, Soeki T, Kitagawa T, Takanashi S, Sata M. Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 33: 1077‐1084, 2013.
 287.Shimokawa H, Ito A, Fukumoto Y, Kadokami T, Nakaike R, Sakata M, Takayanagi T, Egashira K, Takeshita A. Chronic treatment with interleukin‐1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet‐derived growth factor. J Clin Invest 97: 769‐776, 1996.
 288.Shin SY, Yong HS, Lim HE, Na JO, Choi CU, Choi JI, Kim SH, Kim JW, Kim EJ, Park SW, Rha S‐W, Park CG, Seo HS, Oh DJ, Kim Y‐H. Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation. J Cardiovasc Electrophysiol 22: 647‐655, 2011.
 289.Sicari R, Sironi AM, Petz R, Frassi F, Chubuchny V, De Marchi D, Positano V, Lombardi M, Picano E, Gastaldelli A. Pericardial rather than epicardial fat is a cardiometabolic risk marker: An MRI vs echo study. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr 24: 1156‐1162, 2011.
 290.Sidossis L, Kajimura S. Brown and beige fat in humans: Thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 125: 478‐486, 2015.
 291.Silaghi A, Achard V, Paulmyer‐Lacroix O, Scridon T, Tassistro V, Duncea I, Clement K, Dutour A, Grino M. Expression of adrenomedullin in human epicardial adipose tissue: Role of coronary status. AJP Endocrinol Metab 293: E1443‐E1450, 2007.
 292.Silaghi A, Piercecchi‐Marti M‐D, Grino M, Leonetti G, Alessi MC, Clement K, Dadoun F, Dutour A. Epicardial adipose tissue extent: Relationship with age, body fat distribution, and coronaropathy. Obesity 16: 2424‐2430, 2008.
 293.Silver MA, Pick R, Brilla CG, Jalil JE, Janicki JS, Weber KT. Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: Two experimental models of myocardial fibrosis. Cardiovasc Res 24: 741‐747, 1990.
 294.Skurk T, Alberti‐Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92: 1023‐1033, 2007.
 295.Slawik M, Vidal‐Puig AJ. Lipotoxicity, overnutrition and energy metabolism in aging. Ageing Res Rev 5: 144‐164, 2006.
 296.Sohal RS, Orr WC. The redox stress hypothesis of aging. Free Radic Biol Med 52: 539‐555, 2012.
 297.Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96: 1897‐1904, 1995.
 298.Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, Young T, American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, American Heart Association Stroke Council, American Heart Association Council on Cardiovascular Nursing, American College of Cardiology Foundation. Sleep apnea and cardiovascular disease: an American Heart Association/american College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 118: 1080‐1111, 2008.
 299.Spach MS, Boineau JP. Microfibrosis produces electrical load variations due to loss of side‐to‐side cell connections: A major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol PACE 20: 397‐413, 1997.
 300.Spearman JV, Meinel FG, Schoepf UJ, Apfaltrer P, Silverman JR, Krazinski AW, Canstein C, De Cecco CN, Costello P, Geyer LL. Automated quantification of epicardial adipose tissue using CT angiography: Evaluation of a prototype software. Eur Radiol 24: 519‐526, 2014.
 301.Spearman JV, Renker M, Schoepf UJ, Krazinski AW, Herbert TL, De Cecco CN, Nietert PJ, Meinel FG. Prognostic value of epicardial fat volume measurements by computed tomography: A systematic review of the literature. Eur Radiol 25: 3372‐3381, 2015.
 302.Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol 30: 647‐675, 2012.
 303.Starr ME, Evers BM, Saito H. Age‐associated increase in cytokine production during systemic inflammation: Adipose tissue as a major source of IL‐6. J Gerontol Biol Sci Med Sci 64: 723‐730, 2009.
 304.Stojanovska J, Kazerooni EA, Sinno M, Gross BH, Watcharotone K, Patel S, Jacobson JA, Oral H. Increased epicardial fat is independently associated with the presence and chronicity of atrial fibrillation and radiofrequency ablation outcome. Eur Radiol 25: 2298‐2309, 2015.
 305.Suárez AG, Hornero F, Berjano EJ. Mathematical modeling of epicardial RF ablation of atrial tissue with overlying epicardial fat. Open Biomed Eng J 4: 47‐55, 2010.
 306.Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest 121: 2094‐2101, 2011.
 307.Sun K, Tordjman J, Clément K, Scherer PEC. Fibrosis and adipose tissue dysfunction. Cell Metab 18: 470‐477, 2013.
 308.Sun L, Liu C, Xu X, Ying Z, Maiseyeu A, Wang A, et al. Ambient fine particulate matter and ozone exposures induce inflammation in epicardial and perirenal adipose tissues in rats fed a high fructose diet. Part Fibre Toxicol 10: 43, 2013.
 309.Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev 79: 215‐262, 1999.
 310.Takahashi K, Okumura Y, Watanabe I, Nagashima K, Sonoda K, Sasaki N, Kogawa R, Iso K, Kurokawa S, Ohkubo K, Nakai T, Nakahara S, Hori Y, Nikaido M, Hirayama A. Anatomical proximity between ganglionated plexi and epicardial adipose tissue in the left atrium: implication for 3D reconstructed epicardial adipose tissue‐based ablation. J Interv Card Electrophysiol 47(2): 203‐212, 2016.
 311.Takahashi Y, Sanders P, Jaïs P, Hocini M, Dubois R, Rotter M, Rostock T, Nalliah CJ, Sacher F, Clémenty J, Haïssaguerre M. Organization of frequency spectra of atrial fibrillation: Relevance to radiofrequency catheter ablation. J Cardiovasc Electrophysiol 17: 382‐388, 2006.
 312.Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, Saito Y, Nagai R, Sata M. Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res 105: 906‐911, 2009.
 313.Takaoka M, Suzuki H, Shioda S, Sekikawa K, Saito Y, Nagai R, Sata M. Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue. Arterioscler Thromb Vasc Biol 30: 1576‐1582, 2010.
 314.Tamarappoo B, Dey D, Shmilovich H, Nakazato R, Gransar H, Cheng VY, Friedman JD, Hayes SW, Thomson LEJ, Slomka PJ, Rozanski A, Berman DS. Increased pericardial fat volume measured from noncontrast CT predicts myocardial ischemia by SPECT. JACC Cardiovasc Imaging 3: 1104‐1112, 2010.
 315.Tanami Y, Jinzaki M, Kishi S, Matheson M, Vavere AL, Rochitte CE, Dewey M, Chen MY, Clouse ME, Cox C, Kuribayashi S, Lima JAC, Arbab‐Zadeh A. Lack of association between epicardial fat volume and extent of coronary artery calcification, severity of coronary artery disease, or presence of myocardial perfusion abnormalities in a diverse, symptomatic patient population: Results from the CORE320 multicenter study. Circ Cardiovasc Imaging 8: e002676, 2015.
 316.Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM. White fat progenitor cells reside in the adipose vasculature. Science 322: 583‐586, 2008.
 317.Tansey DK, Aly Z, Sheppard MN. Fat in the right ventricle of the normal heart. Histopathology 46: 98‐104, 2005.
 318.Tchkonia T, Morbeck DE, Zglinicki T, Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell 9: 667‐684, 2010.
 319.Tchkonia T, Pirtskhalava T, Thomou T, Cartwright MJ, Wise B, Karagiannides I, Shpilman A, Lash TL, Becherer JD, Kirkland JL. Increased TNFalpha and CCAAT/enhancer‐binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis. Am J Physiol Endocrinol Metab 293: E1810‐E1819, 2007.
 320.Tedrow UB, Conen D, Ridker PM, Cook NR, Koplan BA, Manson JE, Buring JE, Albert CM. The long‐ and short‐term impact of elevated body mass index on the risk of new atrial fibrillation the WHS (women's health study). J Am Coll Cardiol 55: 2319‐2327, 2010.
 321.Thanassoulis G, Massaro JM, O'Donnell CJ, Hoffmann U, Levy D, Ellinor PT, Wang TJ, Schnabel RB, Vasan RS, Fox CS, Benjamin EJ. Pericardial fat is associated with prevalent atrial fibrillation: The Framingham Heart Study. Circ Arrhythm Electrophysiol 3: 345‐350, 2010.
 322.Thomas EL, Fitzpatrick JA, Malik SJ, Taylor‐Robinson SD, Bell JD. Whole body fat: Content and distribution. Prog Nucl Magn Reson Spectrosc 73: 56‐80, 2013.
 323.Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Dement WC. Hemodynamics in sleep‐induced apnea. Studies during wakefulness and sleep. Ann Intern Med 85: 714‐719, 1976.
 324.Tran K‐V, Gealekman O, Frontini A, Zingaretti MC, Morroni M, Giordano A, Smorlesi A, Perugini J, De Matteis R, Sbarbati A, Corvera S, Cinti S. The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab 15: 222‐229, 2012.
 325.Trayhurn P. Hypoxia and adipocyte physiology: Implications for adipose tissue dysfunction in obesity. Annu Rev Nutr 34: 207‐236, 2014.
 326.Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: A basis for the dysregulation of tissue function in obesity? Br J Nutr 100: 227‐35, 2008.
 327.Tsao H‐M, Hu W‐C, Wu M‐H, Tai C‐T, Lin Y‐J, Chang S‐L, Lo L‐W, Hu Y‐F, Tuan T‐C, Wu T‐J, Sheu M‐H, Chang C‐Y, Chen S‐A. Quantitative analysis of quantity and distribution of epicardial adipose tissue surrounding the left atrium in patients with atrial fibrillation and effect of recurrence after ablation. Am J Cardiol 107: 1498‐1503, 2011.
 328.Unger RH, Scherer PEC. Gluttony, sloth and the metabolic syndrome: A roadmap to lipotoxicity. Trends Endocrinol Metab TEM 21: 345‐352, 2010.
 329.Vacca M, Di Eusanio M, Cariello M, Graziano G, D'Amore S, Petridis FD, D'orazio A, Salvatore L, Tamburro A, Folesani G, Rutigliano D, Pellegrini F, Sabbà C, Palasciano G, Di Bartolomeo R, Moschetta A. Integrative miRNA and whole‐genome analyses of epicardial adipose tissue in patients with coronary atherosclerosis. Cardiovasc Res 109: 228‐239, 2016.
 330.Vague J. The degree of masculine differentiation of obesities: A factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 4: 20‐34, 1956.
 331.Venteclef N, Guglielmi V, Balse E, Gaborit B, Cotillard A, Atassi F, Amour J, Leprince P, Dutour A, Clément K, Hatem SN. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo‐fibrokines. Eur Heart J 36: 795‐805a, 2015.
 332.Virtue S, Vidal‐Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome—an allostatic perspective. Biochim Biophys Acta 1801: 338‐349, 2010. Vos AM, Prokop M, Roos CJ, Meijs MFL, van der Schouw YT, Rutten A, Gorter PM, Cramer M‐J, Doevendans PA, Rensing BJ, Bartelink M‐L, Velthuis BK, Mosterd A, Bots ML. Peri‐coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post‐menopausal women. Eur Heart J 29: 777‐783, 2008.
 334.Vural B, Atalar F, Ciftci C, Demirkan A, Susleyici‐Duman B, Gunay D, Akpinar B, Sagbas E, Ozbek U, Buyukdevrim AS. Presence of fatty‐acid‐binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovasc Pathol Off J Soc Cardiovasc Pathol 17: 392‐398, 2008.
 335.Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity—results of a meta‐analysis. Am Heart J 155: 310‐315, 2008.
 336.Wang TJ, Parise H, Levy D, D'Agostino RB, Wolf PA, Vasan RS, Benjamin EJ. Obesity and the risk of new‐onset atrial fibrillation. JAMA 292: 2471‐2477, 2004.
 337.Watanabe K, Kishino T, Sano J, Ariga T, Okuyama S, Mori H, Matsushima S, Ohtsuka K, Ohnishi H, Watanabe T. Relationship between epicardial adipose tissue thickness and early impairment of left ventricular systolic function in patients with preserved ejection fraction. Heart Vessels 31: 1010‐1015, 2016.
 338.Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796‐1808, 2003.
 339.Wenger DS, Kawut SM, Ding J, Bluemke DA, Hough CL, Kronmal RA, Lima JA, Leary PJ. Pericardial fat and right ventricular morphology: The Multi‐Ethnic Study of Atherosclerosis‐ Right Ventricle Study (MESA‐RV). PloS One 11: e0157654, 2016.
 340.Wensveen FM, Valentić S, Šestan M, Turk Wensveen T, Polić B. The “Big Bang” in obese fat: Events initiating obesity‐induced adipose tissue inflammation. Eur J Immunol 45: 2446‐2456, 2015.
 341.Wernstedt Asterholm I, Tao C, Morley TS, Wang QA, Delgado‐Lopez F, Wang ZV, Scherer PEC. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 20: 103‐118, 2014.
 342.Willens HJ, Gómez‐Marín O, Chirinos JA, Goldberg R, Lowery MH, Iacobellis G. Comparison of epicardial and pericardial fat thickness assessed by echocardiography in African American and non‐Hispanic White men: a pilot study. Ethn Dis 18(3): 311‐6, 2008.
 343.Wolf P, Winhofer Y, Smajis S, Jankovic D, Anderwald C‐H, Trattnig S, Luger A, Krebs M, Krššák M. Pericardial—rather than intramyocardial fat is independently associated with left ventricular systolic heart function in metabolically healthy humans. PloS One 11: e0151301, 2016.
 344.Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke J Cereb Circ 22: 983‐988, 1991.
 345.Wong CX, Abed HS, Molaee P, Nelson AJ, Brooks AG, Sharma G, Leong DP, Lau DH, Middeldorp ME, Roberts‐Thomson KC, Wittert GA, Abhayaratna WP, Worthley SG, Sanders P. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 57: 1745‐1751, 2011.
 346.Wood IS, Stezhka T, Trayhurn P. Modulation of adipokine production, glucose uptake and lactate release in human adipocytes by small changes in oxygen tension. Pflugers Arch 462: 469‐477, 2011.
 347.Wu F‐Z, Chou K‐J, Huang Y‐L, Wu M‐T. The relation of location‐specific epicardial adipose tissue thickness and obstructive coronary artery disease: Systemic review and meta‐analysis of observational studies. BMC Cardiovasc Disord 14: 62, 2014.
 348.Wu F‐Z, Huang Y‐L, Wang Y‐C, Lin H‐S, Chen C‐S, Ju Y‐J, Chiou K‐R, Cheng C‐C, Wu M‐T. Impact of location of epicardial adipose tissue, measured by coronary artery calcium‐scoring computed tomography on obstructive coronary artery disease. Am J Cardiol 112: 943‐949, 2013.
 349.Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang A‐H, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150: 366‐376, 2012.
 350.Wystrychowski W, Patlolla B, Zhuge Y, Neofytou E, Robbins RC, Beygui RE. Multipotency and cardiomyogenic potential of human adipose‐derived stem cells from epicardium, pericardium, and omentum. Stem Cell Res Ther 7: 84, 2016.
 351.Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity‐related insulin resistance. J Clin Invest 112: 1821‐1830, 2003.
 352.Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4: e12997, 2015.
 353.Yamaguchi Y, Cavallero S, Patterson M, Shen H, Xu J, Kumar SR, Sucov HM. Adipogenesis and epicardial adipose tissue: A novel fate of the epicardium induced by mesenchymal transformation and PPARγ activation. Proc Natl Acad Sci U S A 112: 2070‐2075, 2015.
 354.Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293: E1118‐E1128, 2007.
 355.Ye JC. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes 2005 33: 54‐66, 2009.
 356.Yerramasu A, Dey D, Venuraju S, Anand DV, Atwal S, Corder R, Berman DS, Lahiri A. Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub‐clinical coronary atherosclerosis. Atherosclerosis 220: 223‐230, 2012.
 357.Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J. Role of hypoxia in obesity‐induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab 296: E333‐E342, 2009.
 358.Yudkin JS, Eringa E, Stehouwer CDA. “Vasocrine” signalling from perivascular fat: A mechanism linking insulin resistance to vascular disease. Lancet Lond Engl 365: 1817‐1820, 2005.
 359.Zangi L, Oliveira MS, Ye LY, Ma Q, Sultana N, Hadas Y, Chepurko E, Später D, Zhou B, Chew WL, Ebina W, Abrial M, Wang Q‐D, Pu WT, Chien KR. Insulin‐like growth factor 1 receptor‐dependent pathway drives epicardial adipose tissue formation after myocardial injury. Circulation 135: 59‐72, 2017.
 360.Zghaib T, Ipek EG, Zahid S, Balouch MA, Misra S, Ashikaga H, Berger RD, Marine JE, Spragg DD, Zimmerman SL, Zipunnikov V, Trayanova N, Calkins H, Nazarian S. Association of left atrial epicardial adipose tissue with electrogram bipolar voltage and fractionation: Electrophysiologic substrates for atrial fibrillation. Heart Rhythm 13(12): 2333‐2339, 2016.
 361.Zhang H, Pu W, Liu Q, He L, Huang X, Tian X, Zhang L, Nie Y, Hu S, Lui KO, Zhou B. Endocardium contributes to cardiac fat. Circ Res 118: 254‐265, 2016.
 362.Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: Implications for cell‐based therapies. Tissue Eng 7: 211‐228, 2001.



Teaching Material

B. Gaborit, C. Sengenes, P. Ancel, A. Jacquier, A. Dutour. Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat? Compr Physiol 7 2017, 1051-1082.

Didactic Synopsis

EAT is an ectopic fat depot located between myocardium and the visceral pericardium with no fascia separating the tissues, allowing local interaction and cellular cross-talk between myocytes and adipocytes

  • Given the lack of standard terminology, it is necessary to make a distinction between epicardial and pericardial fat to avoid confusion in the use of terms. The pericardial fat refers to the combination of epicardial fat and paracardial fat (located on the external surface of the parietal pericardium)
  • Imaging techniques such as echocardiography, computed tomography or magnetic resonance imaging are necessary to study EAT distribution in humans
  • Very little amount of EAT is found in rodents compared to humans
  • EAT displays high rate of fatty acids metabolism (lipogenesis and lipolysis), thermogenic (beiging features), and mechanical properties (protective framework for cardiac autonomic nerves and vessels)
  • Compared to visceral fat, EAT is likely to have predominant local effects
  • EAT secretes numerous bioactive factors including adipokines, fibrokines, growth factors, and cytokines that could either be protective or harmful depending on the local microenvironment
  • Human EAT has a unique transcriptome enriched in genes implicated in extracellular matrix remodeling, inflammation, immune signaling, beiging, thrombosis and apoptosis pathways
  • Epicardial adipocytes have a mesothelial origin and derive mainly from epicardium. Cells originating from the Wt1+ mesothelial lineage, can differentiate into EAT and this “epicardium-to-fat transition” fate could be reactivated after myocardial infarction
  • Factors leading to cardiac ectopic fat deposition may include dysfunctional subcutaneous adipose tissue, fibrosis, inflammation, hypoxia, and aging
  • Periatrial EAT has a specific transcriptomic signature and its amount is associated with atrial fibrillation
  • EAT is likely to play a role in the pathogenesis of cardiovascular disease and coronary artery disease
  • EAT amount is a strong independent predictor of future coronary events
  • EAT is increased in obesity, type 2 diabetes, hypertension, metabolic syndrome, nonalcoholic fatty liver disease, and obstructive sleep apnea (OSA)

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: a variety of terms including “epicardial,” “pericardial,” “paracardial,” and “intrathoracic” have been used in the literature to describe ectopic fat depots in proximity to the heart or within mediastinum. The use of these terms appears to be a point of confusion, as there is varied use of definitions. Of particular confusion is the term used to define the adipose tissue located within the pericardial sac, between myocardium and visceral pericardium. This has previously been described in the literature as “pericardial fat,” while other groups have referred it as “epicardial fat.” As illustrated in Figure 1, the most accurate term for the adipose tissue fully enclosed in the pericardial sac that directly surrounds myocardium and coronary arteries is EAT. Pericardial fat (PeriF) refers to paracardial fat (ParaF) plus all adipose tissue located internal to the parietal pericardium. PeriF=ParaF+EAT.

Figure 2. This figure illustrates the relative amount of epicardial adipose tissue among species. Humans and swine have much more EAT than rodents.

Figure 3. This figure illustrates the origin of epicardial adipose tissue. Epicardial adipocytes have a mesothelial origin and derive mainly from epicardium. Cells originating from the (Wilms’ tumor gene Wt1) Wt1+ mesothelial lineage, can differentiate into EAT and this epicardium-to-fat transition (ETFT) fate can be reactivated after myocardial infarction.

Figure 4. This figure illustrates the mechanisms driving the development of ectopic fat deposition and its consequences. In an obesogenic environment and chronic positive energy balance, the ability of subcutaneous adipose tissue (SAT) to expand, and to store the free fatty acids in excess is crucial in preventing the accumulation of fat in ectopic sites, and the development of obesity complications. Healthy SAT and gynoid obesity are associated with a protective phenotype with less ectopic fat and metabolically healthy obesity, while dysfunctional SAT and android obesity are associated with more visceral fat and ectopic fat accumulation with an increased risk of type 2 diabetes, metabolic syndrome and coronary artery disease (CAD). Inflammation or profibrotic processes, hypoxia, and aging could also contribute to ectopic fat development. Mobilization and release of adipose progenitors adipose-derived stem/stromal cells (ASCs) into the circulation and their further infiltration into non adipose tissues leading to ectopic adipocyte formation also cannot be excluded.

Figures 5 to 7. These figures illustrate imaging techniques for EAT quantification. MRI remains the standard reference for adipose tissue quantification. The major advantage of this technique is its excellent spatial resolution and possible distinction between paracardial and epicardial fat. The major limitation of echocardiography is its 2D approach (thickness measurement). The major limitation of computed tomography remains its radiation exposure.

Figure 8. This figure illustrates microscopic images of human atrial epicardial adipose tissue and myocardium. One can observe fatty infiltration of myocardium with EAT, that is, direct adipocytes infiltration into the underlying atrial myocardium, associated with fibrosis. Such direct adipocytes infiltration separating myocytes are supposed to induce remodeled atrial substrate, and lead to conduction defects (conduction slowing or inhomogeneity).

Figure 9. This figure summarizes the possible mechanisms that could link EAT with atrial fibrillation. EAT expansion-induced mechanical stress, direct adipocyte infiltration within atrial myocardium, inflammation, oxidative stress, and EAT producing adipofibrokines are thought to participate in structural and electrical remodeling of the atria, and in cardiac autonomous system activation, hence promoting arrhythmogenesis.

Figure 10. This figures illustrates a transversal and longitudinal view of EAT surrounding a coronary artery. As there is no fascia separating EAT from the vessel wall, free fatty acids or proinflammatory cytokines produced by EAT could diffuse passively or in vasa vasorum through the arterial wall and participate in the early stages of atherosclerosis plaque formation (endothelial dysfunction, ROS production, oxidized LDL uptake, monocyte transmigration, smooth muscle cells proliferation, macrophages transformation into foam cells). An imbalance between antiatherogenic, and harmful adipocytokines secreted by EAT could initiate inflammation in the intima. Innate immunity can be activated via the toll-like receptors (TLRs), which recognize antigens such as lipopolysaccharide (LPS). Activation of TLRs leads to the translocation of NFκB into the adipocyte nucleus to initiate the transcription and the release of proinfammatory molecules such as IL-6, TNF-α, and resistin. NLRP3 inflammasome is a sensor in the nod-like receptor family of the innate immune cell system that activates caspase-1, and mediates the processing and release of IL-1β by the adipocyte, and thereby has a central role in the EAT-induced inflammatory response.




Related Articles:

Brown and Beige Adipose Tissues in Health and Disease
Role of Perivascular Adipose Tissue in Health and Disease

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Bénédicte Gaborit, Coralie Sengenes, Patricia Ancel, Alexis Jacquier, Anne Dutour. Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat?. Compr Physiol 2017, 7: 1051-1082. doi: 10.1002/cphy.c160034