Top

Published in:

01-11-2017

Epicardial adipose tissue as a metabolic transducer: role in heart failure and coronary artery disease

Authors: Vaibhav B. Patel, Saumya Shah, Subodh Verma, Gavin Y. Oudit

Published in: Heart Failure Reviews | Issue 6/2017

Abstract

Obesity and diabetes are strongly associated with metabolic and cardiovascular disorders including dyslipidemia, coronary artery disease, hypertension, and heart failure. Adipose tissue is identified as a complex endocrine organ, which by exerting a wide array of regulatory functions at the cellular, tissue and systemic levels can have profound effects on the cardiovascular system. Different terms including “epicardial,” “pericardial,” and “paracardial” have been used to describe adipose tissue deposits surrounding the heart. Epicardial adipose tissue (EAT) is a unique and multifaceted fat depot with local and systemic effects. The functional and anatomic proximity of EAT to the myocardium enables endocrine, paracrine, and vasocrine effects on the heart. EAT displays a large secretosome, which regulates physiological and pathophysiological processes in the heart. Perivascular adipose tissue (PVAT) secretes adipose-derived relaxing factor, which is a “cocktail” of cytokines, adipokines, microRNAs, and cellular mediators, with a potent effect on paracrine regulation of vascular tone, vascular smooth muscle cell proliferation, migration, atherosclerosis-susceptibility, and restenosis. Although there are various physiological functions of the EAT and PVAT, a phenotypic transformation can lead to a major pathogenic role in various cardiovascular diseases. The equilibrium between the physiological and pathophysiological properties of EAT is very delicate and susceptible to the influences of intrinsic and extrinsic factors. Various adipokines secreted from EAT and PVAT have a profound effect on the myocardium and coronary arteries; targeting these adipokines could be an important therapeutic approach to counteract cardiovascular disease.

Kenchaiah S, Sesso HD, Gaziano JM (2009) Body mass index and vigorous physical activity and the risk of heart failure among men. Circulation 119:44–52. doi:10.1161/CIRCULATIONAHA.108.807289 PubMedCrossRef

Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS (2002) Obesity and the risk of heart failure. N Engl J Med 347:305–313. doi:10.1056/NEJMoa020245 PubMedCrossRef

Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259. doi:10.1056/NEJMoa052256 PubMedCrossRef

Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128:1810–1852. doi:10.1161/CIR.0b013e31829e8807 PubMedCrossRef

Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847–853. doi:10.1038/nature05483 PubMedPubMedCentralCrossRef

Hassan M, Latif N, Yacoub M (2012) Adipose tissue: friend or foe? Nat Rev Cardiol 9:689–702. doi:10.1038/nrcardio.2012.148 PubMedCrossRef

Bjorndal B, Burri L, Staalesen V, Skorve J, Berge RK (2011) Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. J Obes 2011:490650. doi:10.1155/2011/490650 PubMedPubMedCentralCrossRef

Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444–E452. doi:10.1152/ajpendo.00691.2006 PubMedCrossRef

Nedergaard J, Cannon B (2013) How brown is brown fat? It depends where you look. Nat Med 19:540–541. doi:10.1038/nm.3187 PubMedCrossRef

10.

Iozzo P (2011) Myocardial, perivascular, and epicardial fat. Diabetes Care 34(Suppl 2):S371–S379. doi:10.2337/dc11-s250 PubMedPubMedCentralCrossRef

11.

Corradi D, Maestri R, Callegari S, Pastori P, Goldoni M, Luong TV, Bordi C (2004) The ventricular epicardial fat is related to the myocardial mass in normal, ischemic and hypertrophic hearts. Cardiovasc Pathol 13:313–316. doi:10.1016/j.carpath.2004.08.005 PubMedCrossRef

12.

Iacobellis G, Corradi D, Sharma AM (2005) Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2:536–543. doi:10.1038/ncpcardio0319 PubMedCrossRef

13.

Cherian S, Lopaschuk GD, Carvalho E (2012) 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. doi:10.1152/ajpendo.00061.2012 PubMedCrossRef

14.

Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY (2016) ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity. Diabetes 65:85–95. doi:10.2337/db15-0399 PubMedCrossRef

15.

Huang Cao ZF, Stoffel E, Cohen P (2017) Role of perivascular adipose tissue in vascular physiology and pathology. Hypertension 69:770–777. doi:10.1161/HYPERTENSIONAHA.116.08451 PubMedCrossRef

16.

Sacks HS, Fain JN (2007) Human epicardial adipose tissue: a review. Am Heart J 153:907–917. doi:10.1016/j.ahj.2007.03.019 PubMedCrossRef

17.

Talman AH, Psaltis PJ, Cameron JD, Meredith IT, Seneviratne SK, Wong DT (2014) Epicardial adipose tissue: far more than a fat depot. Cardiovasc Diagn Ther 4:416–429. doi:10.3978/j.issn.2223-3652.2014.11.05 PubMedPubMedCentral

18.

Marchington JM, Mattacks CA, Pond CM (1989) Adipose tissue in the mammalian heart and pericardium: structure, foetal development and biochemical properties. Comp Biochem Physiol B 94:225–232PubMedCrossRef

19.

Dabbah S, Komarov H, Marmor A, Assy N (2014) Epicardial fat, rather than pericardial fat, is independently associated with diastolic filling in subjects without apparent heart disease. Nutr Metab Cardiovasc Dis 24:877–882. doi:10.1016/j.numecd.2014.01.019 PubMedCrossRef

20.

Fain JN, Sacks HS, Bahouth SW, Tichansky DS, Madan AK, Cheema PS (2010) Human epicardial adipokine messenger RNAs: comparisons of their expression in substernal, subcutaneous, and omental fat. Metabolism 59:1379–1386. doi:10.1016/j.metabol.2009.12.027 PubMedCrossRef

21.

Iacobellis G (2009) Epicardial and pericardial fat: close, but very different. Obesity (Silver Spring) 17:625; author reply 626-627. doi:10.1038/oby.2008.575 CrossRef

22.

Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, Leonetti F (2003) Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res 11:304–310. doi:10.1038/oby.2003.45 PubMedCrossRef

23.

Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, Sarov-Blat L, O’Brien S, Keiper EA, Johnson AG, Martin J, Goldstein BJ, Shi Y (2003) Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108:2460–2466. doi:10.1161/01.CIR.0000099542.57313.C5 PubMedCrossRef

24.

Iacobellis G (2015) Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 11:363–371. doi:10.1038/nrendo.2015.58 PubMedCrossRef

25.

Bambace C, Telesca M, Zoico E, Sepe A, Olioso D, Rossi A, Corzato F, Di Francesco V, Mazzucco A, Santini F, Zamboni M (2011) Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc Pathol 20:e153–e156. doi:10.1016/j.carpath.2010.07.005 PubMedCrossRef

26.

Van Gaal LF, Mertens IL, De Block CE (2006) Mechanisms linking obesity with cardiovascular disease. Nature 444:875–880. doi:10.1038/nature05487 PubMedCrossRef

27.

Fontes-Carvalho R, Fontes-Oliveira M, Sampaio F, Mancio J, Bettencourt N, Teixeira M, Rocha Goncalves F, Gama V, Leite-Moreira A (2014) Influence of epicardial and visceral fat on left ventricular diastolic and systolic functions in patients after myocardial infarction. Am J Cardiol 114:1663–1669. doi:10.1016/j.amjcard.2014.08.037 PubMedCrossRef

28.

Fitzgibbons TP, Czech MP (2014) Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc 3:e000582. doi:10.1161/jaha.113.000582 PubMedPubMedCentralCrossRef

29.

Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129. doi:10.1152/physrev.00006.2004 PubMedCrossRef

30.

Marchington JM, Pond CM (1990) 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 14:1013–1022PubMed

31.

Iacobellis G, Bianco AC (2011) Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab 22:450–457. doi:10.1016/j.tem.2011.07.003 PubMedPubMedCentralCrossRef

32.

Burgeiro A, Fuhrmann A, Cherian S, Espinoza D, Jarak I, Carvalho RA, Loureiro M, Patricio M, Antunes M, Carvalho E (2016) 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. doi:10.1152/ajpendo.00384.2015 PubMedPubMedCentralCrossRef

33.

Pezeshkian M, Noori M, Najjarpour-Jabbari H, Abolfathi A, Darabi M, Darabi M, Shaaker M, Shahmohammadi G (2009) Fatty acid composition of epicardial and subcutaneous human adipose tissue. Metab Syndr Relat Disord 7:125–131PubMedCrossRef

34.

Carvalho E, Lopaschuk GD, Borsheim E, Burgeiro A (2016) Reply to Katlandur, Ozbek, and Keser. Am J Physiol Endocrinol Metab 310:E863. doi:10.1152/ajpendo.00113.2016 PubMedPubMedCentralCrossRef

35.

Dozio E, Vianello E, Briganti S, Fink B, Malavazos AE, Scognamiglio ET, Dogliotti G, Sigruener A, Schmitz G, Corsi Romanelli MM (2014) 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. doi:10.1016/j.ijcard.2014.04.045 PubMedCrossRef

36.

Sacks HS, Fain JN, Bahouth SW, Ojha S, Frontini A, Budge H, Cinti S, Symonds ME (2013) Adult epicardial fat exhibits beige features. J Clin Endocrinol Metab 98:E1448–E1455. doi:10.1210/jc.2013-1265 PubMedCrossRef

37.

Ojha S, Fainberg HP, Wilson V, Pelella G, Castellanos M, May ST, Lotto AA, Sacks H, Symonds ME, Budge H (2016) Gene pathway development in human epicardial adipose tissue during early life. JCI Insight 1:e87460. doi:10.1172/jci.insight.87460 PubMedPubMedCentralCrossRef

38.

Chechi K, Blanchard PG, Mathieu P, Deshaies Y, Richard D (2013) 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. doi:10.1016/j.ijcard.2012.06.008 PubMedCrossRef

39.

Aldiss P, Davies G, Woods R, Budge H, Sacks HS, Symonds ME (2017) ‘Browning’ the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk. Int J Cardiol 228:265–274. doi:10.1016/j.ijcard.2016.11.074 PubMedPubMedCentralCrossRef

40.

Thoonen R, Ernande L, Cheng J, Nagasaka Y, Yao V, Miranda-Bezerra A, Chen C, Chao W, Panagia M, Sosnovik DE, Puppala D, Armoundas AA, Hindle A, Bloch KD, Buys ES, Scherrer-Crosbie M (2015) Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy. J Mol Cell Cardiol 84:202–211. doi:10.1016/j.yjmcc.2015.05.002 PubMedPubMedCentralCrossRef

41.

Iacobellis G, Barbaro G (2008) The double role of epicardial adipose tissue as pro- and anti-inflammatory organ. Horm Metab Res 40:442–445. doi:10.1055/s-2008-1062724 PubMedCrossRef

42.

Wang W, McKinnie SM, Patel VB, Haddad G, Wang Z, Zhabyeyev P, Das SK, Basu R, McLean B, Kandalam V, Penninger JM, Kassiri Z, Vederas JC, Murray AG, Oudit GY (2013) Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic Apelin analogues. J Am Heart Assoc 2:e000249. doi:10.1161/JAHA.113.000249 PubMedPubMedCentral

43.

Li L, Zeng H, Chen JX (2012) Apelin-13 increases myocardial progenitor cells and improves repair postmyocardial infarction. Am J Physiol Heart Circ Physiol 303:H605–H618. doi:10.1152/ajpheart.00366.2012 PubMedPubMedCentralCrossRef

44.

Japp AG, Cruden NL, Barnes G, van Gemeren N, Mathews J, Adamson J, Johnston NR, Denvir MA, Megson IL, Flapan AD, Newby DE (2010) Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 121:1818–1827. doi:10.1161/CIRCULATIONAHA.109.911339 PubMedCrossRef

45.

Sato T, Suzuki T, Watanabe H, Kadowaki A, Fukamizu A, Liu PP, Kimura A, Ito H, Penninger JM, Imai Y, Kuba K (2013) Apelin is a positive regulator of ACE2 in failing hearts. J Clin Invest 123:5203–5211. doi:10.1172/JCI69608 PubMedPubMedCentralCrossRef

46.

Yao F, Lv YC, Zhang M, Xie W, Tan YL, Gong D, Cheng HP, Liu D, Li L, Liu XY, Zheng XL, Tang CK (2015) Apelin-13 impedes foam cell formation by activating Class III PI3K/Beclin-1-mediated autophagic pathway. Biochem Biophys Res Commun 466:637–643. doi:10.1016/j.bbrc.2015.09.045 PubMedCrossRef

47.

Alfarano C, Foussal C, Lairez O, Calise D, Attane C, Anesia R, Daviaud D, Wanecq E, Parini A, Valet P, Kunduzova O (2015) Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin. Int J Obes 39:312–320. doi:10.1038/ijo.2014.122 CrossRef

48.

Karmazyn M, Purdham DM, Rajapurohitam V, Zeidan A (2008) Signalling mechanisms underlying the metabolic and other effects of adipokines on the heart. Cardiovasc Res 79:279–286. doi:10.1093/cvr/cvn115 PubMedCrossRef

49.

Hui X, Lam KS, Vanhoutte PM, Xu A (2012) Adiponectin and cardiovascular health: an update. Br J Pharmacol 165:574–590. doi:10.1111/j.1476-5381.2011.01395.x PubMedPubMedCentralCrossRef

50.

Ouchi N, Walsh K (2008) A novel role for adiponectin in the regulation of inflammation. Arterioscler Thromb Vasc Biol 28:1219–1221. doi:10.1161/ATVBAHA.108.165068 PubMedCrossRef

51.

Ouchi N, Shibata R, Walsh K (2006) Targeting adiponectin for cardioprotection. Expert Opin Ther Targets 10:573–581. doi:10.1517/14728222.10.4.573 PubMedCrossRef

52.

Ouchi N, Shibata R, Walsh K (2006) Cardioprotection by adiponectin. Trends Cardiovasc Med 16:141–146. doi:10.1016/j.tcm.2006.03.001 PubMedPubMedCentralCrossRef

53.

Tao L, Gao E, Jiao X, Yuan Y, Li S, Christopher TA, Lopez BL, Koch W, Chan L, Goldstein BJ, Ma XL (2007) Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation 115:1408–1416. doi:10.1161/CIRCULATIONAHA.106.666941 PubMedCrossRef

54.

Cesari M, Pessina AC, Zanchetta M, De Toni R, Avogaro A, Pedon L, Dorigatti F, Maiolino G, Rossi GP (2006) Low plasma adiponectin is associated with coronary artery disease but not with hypertension in high-risk nondiabetic patients. J Intern Med 260:474–483. doi:10.1111/j.1365-2796.2006.01714.x PubMedCrossRef

55.

Dobrzynski E, Montanari D, Agata J, Zhu J, Chao J, Chao L (2002) Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 283:E1291–E1298. doi:10.1152/ajpendo.00147.2002 PubMedCrossRef

56.

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 (2012) Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction. Circulation 126:2324–2334. doi:10.1161/CIRCULATIONAHA.111.039586 PubMedCrossRef

57.

Niu J, Kolattukudy PE (2009) Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications. Clin Sci (Lond) 117:95–109. doi:10.1042/CS20080581 CrossRef

58.

Wollert KC, Drexler H (2001) The role of interleukin-6 in the failing heart. Heart Fail Rev 6:95–103PubMedCrossRef

59.

Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, Jang Y, Cho SY, Kim HS (2001) Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med 33:95–102. doi:10.1038/emm.2001.17 PubMedCrossRef

60.

Holmes MV, Simon T, Exeter HJ, Folkersen L, Asselbergs FW, Guardiola M, Cooper JA, Palmen J, Hubacek JA, Carruthers KF, Horne BD, Brunisholz KD, Mega JL, van Iperen EP, Li M, Leusink M, Trompet S, Verschuren JJ, Hovingh GK, Dehghan A, Nelson CP, Kotti S, Danchin N, Scholz M, Haase CL, Rothenbacher D, Swerdlow DI, Kuchenbaecker KB, Staines-Urias E, Goel A, van’t Hooft F, Gertow K, de Faire U, Panayiotou AG, Tremoli E, Baldassarre D, Veglia F, Holdt LM, Beutner F, Gansevoort RT, Navis GJ, Mateo Leach I, Breitling LP, Brenner H, Thiery J, Dallmeier D, Franco-Cereceda A, Boer JM, Stephens JW, Hofker MH, Tedgui A, Hofman A, Uitterlinden AG, Adamkova V, Pitha J, Onland-Moret NC, Cramer MJ, Nathoe HM, Spiering W, Klungel OH, Kumari M, Whincup PH, Morrow DA, Braund PS, Hall AS, Olsson AG, Doevendans PA, Trip MD, Tobin MD, Hamsten A, Watkins H, Koenig W, Nicolaides AN, Teupser D, Day IN, Carlquist JF, Gaunt TR, Ford I, Sattar N, Tsimikas S, Schwartz GG, Lawlor DA, Morris RW, Sandhu MS, Poledne R, Maitland-van der Zee AH, Khaw KT, Keating BJ, van der Harst P, Price JF, Mehta SR, Yusuf S, Witteman JC, Franco OH, Jukema JW, de Knijff P, Tybjaerg-Hansen A, Rader DJ, Farrall M, Samani NJ, Kivimaki M, Fox KA, Humphries SE, Anderson JL, Boekholdt SM, Palmer TM, Eriksson P, Pare G, Hingorani AD, Sabatine MS, Mallat Z, Casas JP, Talmud PJ (2013) Secretory phospholipase A(2)-IIA and cardiovascular disease: a Mendelian randomization study. J Am Coll Cardiol 62:1966–1976. doi:10.1016/j.jacc.2013.06.044 PubMedPubMedCentralCrossRef

61.

Higuchi Y, McTiernan CF, Frye CB, McGowan BS, Chan TO, Feldman AM (2004) Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alpha-induced cardiomyopathy. Circulation 109:1892–1897. doi:10.1161/01.CIR.0000124227.00670.AB PubMedCrossRef

62.

Meldrum DR, Dinarello CA, Cleveland JC Jr, Cain BS, Shames BD, Meng X, Harken AH (1998) Hydrogen peroxide induces tumor necrosis factor alpha-mediated cardiac injury by a P38 mitogen-activated protein kinase-dependent mechanism. Surgery 124:291–296 discussion 297PubMedCrossRef

63.

Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, Tilg H (2007) Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 178:1748–1758PubMedCrossRef

64.

Dahl TB, Yndestad A, Skjelland M, Oie E, Dahl A, Michelsen A, Damas JK, Tunheim SH, Ueland T, Smith C, Bendz B, Tonstad S, Gullestad L, Froland SS, Krohg-Sorensen K, Russell D, Aukrust P, Halvorsen B (2007) Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 115:972–980. doi:10.1161/CIRCULATIONAHA.106.665893 PubMedCrossRef

65.

Wang P, Xu TY, Guan YF, Su DF, Fan GR, Miao CY (2009) Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide. Cardiovasc Res 81:370–380. doi:10.1093/cvr/cvn288 PubMedCrossRef

66.

Van Berendoncks AM, Garnier A, Beckers P, Hoymans VY, Possemiers N, Fortin D, Martinet W, Van Hoof V, Vrints CJ, Ventura-Clapier R, Conraads VM (2010) Functional adiponectin resistance at the level of the skeletal muscle in mild to moderate chronic heart failure. Circ Heart Fail 3:185–194. doi:10.1161/CIRCHEARTFAILURE.109.885525 PubMedCrossRef

67.

Zhong JC, Zhang ZZ, Wang W, McKinnie SM, Vederas JC, Oudit GY (2016) Targeting the apelin pathway as a novel therapeutic approach for cardiovascular diseases. Biochim Biophys Acta. doi:10.1016/j.bbadis.2016.11.007

68.

Patel VB, Basu R, Oudit GY (2016) ACE2/Ang 1-7 axis: a critical regulator of epicardial adipose tissue inflammation and cardiac dysfunction in obesity. Adipocyte 5:306–311. doi:10.1080/21623945.2015.1131881 PubMedPubMedCentralCrossRef

69.

Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184. doi:10.1172/JCI29881 PubMedPubMedCentralCrossRef

70.

Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309. doi:10.1016/j.cmet.2008.08.015 PubMedPubMedCentralCrossRef

71.

Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614. doi:10.1038/39335 PubMedCrossRef

72.

Abd-Elrahman KS, Colinas O, Walsh EJ, Zhu HL, Campbell CM, Walsh MP, Cole WC (2017) Abnormal myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization contribute to impaired myogenic regulation of cerebral arterial diameter in the type 2 diabetic Goto-Kakizaki rat. J Cereb Blood Flow Metab 37:227–240. doi:10.1177/0271678X15622463 PubMedCrossRef

73.

Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia-Martin R, Grinspoon SK, Gorden P, Kahn CR (2017) Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–455. doi:10.1038/nature21365 PubMedPubMedCentralCrossRef

74.

Mittelbrunn M, Sanchez-Madrid F (2012) Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol 13:328–335. doi:10.1038/nrm3335 PubMedPubMedCentral

75.

Sahoo S, Emanueli C (2016) Exosomes in diabetic cardiomyopathy: the next-generation therapeutic targets? Diabetes 65:2829–2831. doi:10.2337/dbi16-0041 PubMedPubMedCentralCrossRef

76.

Fan D, Creemers EE, Kassiri Z (2014) Matrix as an interstitial transport system. Circ Res 114:889–902. doi:10.1161/CIRCRESAHA.114.302335 PubMedCrossRef

77.

Lin, Chun TH, Kang L (2016) Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem Pharmacol 119:8–16. doi:10.1016/j.bcp.2016.05.005 PubMedPubMedCentralCrossRef

78.

Wong JC, Krueger KC, Costa MJ, Aggarwal A, Du H, McLaughlin TL, Feldman BJ (2016) A glucocorticoid- and diet-responsive pathway toggles adipocyte precursor cell activity in vivo. Sci Signal 9:ra103. doi:10.1126/scisignal.aag0487 PubMedCrossRef

79.

Jiang DS, Zeng HL, Li R, Huo B, Su YS, Fang J, Yang Q, Liu LG, Hu M, Cheng C, Zhu XH, Yi X, Wei X (2017) Aberrant Epicardial adipose tissue extracellular matrix remodeling in patients with severe ischemic cardiomyopathy: insight from comparative quantitative proteomics. Sci Rep 7:43787. doi:10.1038/srep43787 PubMedPubMedCentralCrossRef

80.

Xia N, Li H (2016) The role of perivascular adipose tissue in obesity-induced vascular dysfunction. Br J Pharmacol. doi:10.1111/bph.13650

81.

Ayala-Lopez N, Watts SW (2016) New actions of an old friend: perivascular adipose tissue’s adrenergic mechanisms. Br J Pharmacol. doi:10.1111/bph.13663

82.

Soltis EE, Cassis LA (1991) Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin Exp Hypertens A 13:277–296PubMed

83.

Lohn M, Dubrovska G, Lauterbach B, Luft FC, Gollasch M, Sharma AM (2002) Periadventitial fat releases a vascular relaxing factor. FASEB J 16:1057–1063. doi:10.1096/fj.02-0024com PubMedCrossRef

84.

Lee RM, Bader M, Alenina N, Santos RA, Gao YJ, Lu C (2011) Mas receptors in modulating relaxation induced by perivascular adipose tissue. Life Sci 89:467–472. doi:10.1016/j.lfs.2011.07.016 PubMedCrossRef

85.

Bertaso AG, Bertol D, Duncan BB, Foppa M (2013) Epicardial fat: definition, measurements and systematic review of main outcomes. Arq Bras Cardiol 101:e18–e28. doi:10.5935/abc.20130138 PubMedPubMedCentral

86.

Iacobellis G, Willens HJ, Barbaro G, Sharma AM (2008) Threshold values of high-risk echocardiographic epicardial fat thickness. Obesity (Silver Spring) 16:887–892. doi:10.1038/oby.2008.6 CrossRef

87.

Nakazato R, Shmilovich H, Tamarappoo BK, Cheng VY, Slomka PJ, Berman DS, Dey D (2011) Interscan reproducibility of computer-aided epicardial and thoracic fat measurement from noncontrast cardiac CT. J Cardiovasc Comput Tomogr 5:172–179. doi:10.1016/j.jcct.2011.03.009 PubMedPubMedCentralCrossRef

88.

Gronemeyer SA, Steen RG, Kauffman WM, Reddick WE, Glass JO (2000) Fast adipose tissue (FAT) assessment by MRI. Magn Reson Imaging 18:815–818PubMedCrossRef

89.

Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887. doi:10.1038/nature05488 PubMedCrossRef

90.

Lovren F, Teoh H, Verma S (2015) Obesity and atherosclerosis: mechanistic insights. Can J Cardiol 31:177–183. doi:10.1016/j.cjca.2014.11.031 PubMedCrossRef

91.

Garcia-Labbe D, Ruka E, Bertrand OF, Voisine P, Costerousse O, Poirier P (2015) Obesity and coronary artery disease: evaluation and treatment. Can J Cardiol 31:184–194. doi:10.1016/j.cjca.2014.12.008 PubMedCrossRef

92.

Gupta PP, Fonarow GC, Horwich TB (2015) Obesity and the obesity paradox in heart failure. Can J Cardiol 31:195–202. doi:10.1016/j.cjca.2014.08.004 PubMedCrossRef

93.

Lee JJ, Pedley A, Hoffmann U, Massaro JM, Fox CS (2016) Association of changes in abdominal fat quantity and quality with incident cardiovascular disease risk factors. J Am Coll Cardiol 68:1509–1521. doi:10.1016/j.jacc.2016.06.067 PubMedPubMedCentralCrossRef

94.

Nazare JA, Smith J, Borel AL, Aschner P, Barter P, Van Gaal L, Tan CE, Wittchen HU, Matsuzawa Y, Kadowaki T, Ross R, Brulle-Wohlhueter C, Almeras N, Haffner SM, Balkau B, Despres JP, Investigators IMI (2015) Usefulness of measuring both body mass index and waist circumference for the estimation of visceral adiposity and related cardiometabolic risk profile (from the INSPIRE ME IAA study). Am J Cardiol 115:307–315. doi:10.1016/j.amjcard.2014.10.039 PubMedCrossRef

95.

Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE (1995) The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 98:476–484. doi:10.1016/S0002-9343(99)80348-9 PubMedCrossRef

96.

Nattel S (2017) Atrial fibrillation and body composition: is it fat or lean that ultimately determines the risk? J Am Coll Cardiol 69:2498–2501. doi:10.1016/j.jacc.2017.03.566 PubMedCrossRef

97.

Hatem SN (2014) Is epicardial adipose tissue an epiphenomenon or a new player in the pathophysiology of atrial fibrillation? Arch Cardiovasc Dis 107:349–352. doi:10.1016/j.acvd.2014.06.002 PubMedCrossRef

98.

Hatem SN, Sanders P (2014) Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res 102:205–213. doi:10.1093/cvr/cvu045 PubMedCrossRef

99.

Cabrera-Rego JO, Iacobellis G, Castillo-Herrera JA, Valiente-Mustelier J, Gandarilla-Sarmientos JC, Marin-Julia SM, Navarrete-Cabrera J (2014) Epicardial fat thickness correlates with carotid intima-media thickness, arterial stiffness, and cardiac geometry in children and adolescents. Pediatr Cardiol 35:450–456. doi:10.1007/s00246-013-0799-9 PubMedCrossRef

100.

Nakanishi R, Rajani R, Cheng VY, Gransar H, Nakazato R, Shmilovich H, Otaki Y, Hayes SW, Thomson LE, Friedman JD, Slomka PJ, Berman DS, Dey D (2011) Increase in epicardial fat volume is associated with greater coronary artery calcification progression in subjects at intermediate risk by coronary calcium score: a serial study using non-contrast cardiac CT. Atherosclerosis 218:363–368. doi:10.1016/j.atherosclerosis.2011.07.093 PubMedCrossRef

101.

Tonbul HZ, Turkmen K, Kayikcioglu H, Ozbek O, Kayrak M, Biyik Z (2011) Epicardial adipose tissue and coronary artery calcification in diabetic and nondiabetic end-stage renal disease patients. Ren Fail 33:770–775. doi:10.3109/0886022x.2011.599913 PubMedCrossRef

102.

Natale F, Tedesco MA, Mocerino R, de Simone V, Di Marco GM, Aronne L, Credendino M, Siniscalchi C, Calabro P, Cotrufo M, Calabro R (2009) Visceral adiposity and arterial stiffness: echocardiographic epicardial fat thickness reflects, better than waist circumference, carotid arterial stiffness in a large population of hypertensives. Eur J Echocardiogr 10:549–555. doi:10.1093/ejechocard/jep002 PubMedCrossRef

103.

Venteclef N, Guglielmi V, Balse E, Gaborit B, Cotillard A, Atassi F, Amour J, Leprince P, Dutour A, Clement K, Hatem SN (2015) Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J 36:795–805a. doi:10.1093/eurheartj/eht099 PubMedCrossRef

104.

Ahn SG, Lim HS, Joe DY, Kang SJ, Choi BJ, Choi SY, Yoon MH, Hwang GS, Tahk SJ, Shin JH (2008) Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 94:e7. doi:10.1136/hrt.2007.118471 PubMedCrossRef

105.

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 (2016) Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure. Circ Res 118:1244–1253. doi:10.1161/CIRCRESAHA.115.307765 PubMedCrossRef

106.

Obokata M, Reddy YN, Pislaru SV, Melenovsky V, Borlaug BA (2017) Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. doi:10.1161/CIRCULATIONAHA.116.026807

107.

Vianello E, Dozio E, Arnaboldi F, Marazzi MG, Martinelli C, Lamont J, Tacchini L, Sigruner A, Schmitz G, Corsi Romanelli MM (2016) Epicardial adipocyte hypertrophy: association with M1-polarization and toll-like receptor pathways in coronary artery disease patients. Nutr Metab Cardiovasc Dis 26:246–253. doi:10.1016/j.numecd.2015.12.005 PubMedCrossRef

108.

Smith HL, Willius FA (1933) Adiposity of the heart: a clinical and pathologic study of one hundred and thirty-six obese patients. Arch Intern Med 52:911–931. doi:10.1001/archinte.1933.00160060085007 CrossRef

109.

Malavazos AE, Di Leo G, Secchi F, Lupo EN, Dogliotti G, Coman C, Morricone L, Corsi MM, Sardanelli F, Iacobellis G (2010) Relation of echocardiographic epicardial fat thickness and myocardial fat. Am J Cardiol 105:1831–1835. doi:10.1016/j.amjcard.2010.01.368 PubMedCrossRef

110.

Palanivel R, Vu V, Park M, Fang X, Sweeney G (2008) Differential impact of adipokines derived from primary adipocytes of wild-type versus streptozotocin-induced diabetic rats on glucose and fatty acid metabolism in cardiomyocytes. J Endocrinol 199:389–397. doi:10.1677/JOE-08-0336 PubMedCrossRef

111.

Lamounier-Zepter V, Ehrhart-Bornstein M, Karczewski P, Haase H, Bornstein SR, Morano I (2006) Human adipocytes attenuate cardiomyocyte contraction: characterization of an adipocyte-derived negative inotropic activity. FASEB J 20:1653–1659. doi:10.1096/fj.05-5436com PubMedCrossRef

112.

Ouwens DM, Sell H, Greulich S, Eckel J (2010) The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med 14:2223–2234. doi:10.1111/j.1582-4934.2010.01141.x PubMedPubMedCentralCrossRef

113.

Vural B, Atalar F, Ciftci C, Demirkan A, Susleyici-Duman B, Gunay D, Akpinar B, Sagbas E, Ozbek U, Buyukdevrim AS (2008) Presence of fatty-acid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovasc Pathol 17:392–398. doi:10.1016/j.carpath.2008.02.006 PubMedCrossRef

114.

Eroglu S, Sade LE, Yildirir A, Bal U, Ozbicer S, Ozgul AS, Bozbas H, Aydinalp A, Muderrisoglu H (2009) Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease. Nutr Metab Cardiovasc Dis 19:211–217. doi:10.1016/j.numecd.2008.05.002 PubMedCrossRef

115.

Tanindi A, Erkan AF, Ekici B (2015) Epicardial adipose tissue thickness can be used to predict major adverse cardiac events. Coron Artery Dis 26:686–691. doi:10.1097/mca.0000000000000296 PubMedCrossRef

116.

Doesch C, Haghi D, Fluchter S, Suselbeck T, Schoenberg SO, Michaely H, Borggrefe M, Papavassiliu T (2010) Epicardial adipose tissue in patients with heart failure. J Cardiovasc Magn Reson 12:40. doi:10.1186/1532-429X-12-40 PubMedPubMedCentralCrossRef

117.

Doesch C, Streitner F, Bellm S, Suselbeck T, Haghi D, Heggemann F, Schoenberg SO, Michaely H, Borggrefe M, Papavassiliu T (2013) Epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with heart failure due to dilated cardiomyopathy. Obesity (Silver Spring) 21:E253–E261. doi:10.1002/oby.20149 CrossRef

118.

Mori J, Patel VB, Abo Alrob O, Basu R, Altamimi T, Desaulniers J, Wagg CS, Kassiri Z, Lopaschuk GD, Oudit GY (2014) Angiotensin 1-7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation. Circ Heart Fail 7:327–339. doi:10.1161/circheartfailure.113.000672 PubMedCrossRef

119.

Mori J, Patel VB, Ramprasath T, Alrob OA, DesAulniers J, Scholey JW, Lopaschuk GD, Oudit GY (2014) Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity. Am J Physiol Renal Physiol 306:F812–F821. doi:10.1152/ajprenal.00655.2013 PubMedCrossRef

120.

Tasci I, Dogru T, Naharci I, Erdem G, Yilmaz MI, Sonmez A, Bingol N, Kilic S, Bingol S, Erikci S (2007) Plasma apelin is lower in patients with elevated LDL-cholesterol. Exp Clin Endocrinol Diabetes 115:428–432. doi:10.1055/s-2007-971067 PubMedCrossRef

121.

Pang H, Han B, Li ZY, Fu Q (2015) Identification of molecular markers in patients with hypertensive heart disease accompanied with coronary artery disease. Genet Mol Res 14:93–100. doi:10.4238/2015.January.15.12 PubMedCrossRef

122.

Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, Llorens-Cortes C, Hazra S, Murray AG, Vederas JC, Oudit GY (2016) Angiotensin-converting enzyme 2 metabolizes and partially inactivates Pyr-apelin-13 and apelin-17: physiological effects in the cardiovascular system. Hypertension 68:365–377. doi:10.1161/HYPERTENSIONAHA.115.06892 PubMedCrossRef

123.

Gaborit B, Venteclef N, Ancel P, Pelloux V, Gariboldi V, Leprince P, Amour J, Hatem SN, Jouve E, Dutour A, Clement K (2015) 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. doi:10.1093/cvr/cvv208 PubMedCrossRef

124.

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 (2009) 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. doi:10.1210/jc.2007-2579 PubMedCrossRef

125.

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 (2011) Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 58:248–255. doi:10.1016/j.jacc.2011.01.048 PubMedCrossRef

126.

Iacobellis G, di Gioia CR, Cotesta D, Petramala L, Travaglini C, De Santis V, Vitale D, Tritapepe L, Letizia C (2009) Epicardial adipose tissue adiponectin expression is related to intracoronary adiponectin levels. Horm Metab Res 41:227–231. doi:10.1055/s-0028-1100412 PubMedCrossRef

127.

Teijeira-Fernandez E, Eiras S, Shamagian LG, Somoza AS, Delgado C, Gonzalez-Juanatey JR (2011) Lower epicardial adipose tissue adiponectin in patients with metabolic syndrome. Cytokine 54:185–190. doi:10.1016/j.cyto.2011.01.016 PubMedCrossRef

128.

Iacobellis G, di Gioia CR, Di Vito M, Petramala L, Cotesta D, De Santis V, Vitale D, Tritapepe L, Letizia C (2009) Epicardial adipose tissue and intracoronary adrenomedullin levels in coronary artery disease. Horm Metab Res 41:855–860. doi:10.1055/s-0029-1231081 PubMedCrossRef

129.

Sawicka M, Janowska J, Chudek J (2016) Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system. Int J Cardiol 222:581–589. doi:10.1016/j.ijcard.2016.07.054 PubMedCrossRef

130.

Kelly KR, Navaneethan SD, Solomon TP, Haus JM, Cook M, Barkoukis H, Kirwan JP (2014) Lifestyle-induced decrease in fat mass improves adiponectin secretion in obese adults. Med Sci Sports Exerc 46:920–926. doi:10.1249/MSS.0000000000000200 PubMedPubMedCentralCrossRef

131.

Kim MK, Tomita T, Kim MJ, Sasai H, Maeda S (1985) Tanaka K (2009) Aerobic exercise training reduces epicardial fat in obese men. J Appl Physiol 106:5–11. doi:10.1152/japplphysiol.90756.2008 CrossRef

132.

Rabkin SW, Campbell H (2015) Comparison of reducing epicardial fat by exercise, diet or bariatric surgery weight loss strategies: a systematic review and meta-analysis. Obes Rev 16:406–415. doi:10.1111/obr.12270 PubMedCrossRef

133.

Alexopoulos N, Melek BH, Arepalli CD, Hartlage GR, Chen Z, Kim S, Stillman AE, Raggi P (2013) Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (Beyond Endorsed Lipid Lowering with EBT Scanning). J Am Coll Cardiol 61:1956–1961. doi:10.1016/j.jacc.2012.12.051 PubMedCrossRef

134.

Iacobellis G, Mohseni M, Bianco SD, Banga PK (2017) Liraglutide causes large and rapid epicardial fat reduction. Obesity (Silver Spring) 25:311–316. doi:10.1002/oby.21718 CrossRef

135.

Verma S, Lovren F, Pan Y, Yanagawa B, Deb S, Karkhanis R, Quan A, Teoh H, Feder-Elituv R, Moussa F, Souza DS, Fremes SE (2014) Pedicled no-touch saphenous vein graft harvest limits vascular smooth muscle cell activation: the PATENT saphenous vein graft study. Eur J Cardiothorac Surg 45:717–725. doi:10.1093/ejcts/ezt560 PubMedCrossRef

Title: Epicardial adipose tissue as a metabolic transducer: role in heart failure and coronary artery disease
Authors: Vaibhav B. Patel
Saumya Shah
Subodh Verma
Gavin Y. Oudit
Publication date: 01-11-2017
Publisher: Springer US
Published in: Heart Failure Reviews / Issue 6/2017
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI: https://doi.org/10.1007/s10741-017-9644-1

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Epicardial adipose tissue as a metabolic transducer: role in heart failure and coronary artery disease

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2017

Effect of renin-angiotensin system inhibitors on mortality in heart failure with preserved ejection fraction: a meta-analysis of observational cohort and randomized controlled studies

Pathophysiology of acute heart failure syndrome: a knowledge gap

Readmission rate after ultrafiltration in acute decompensated heart failure: a systematic review and meta-analysis

Effects of exercise training on anabolic and catabolic markers in patients with chronic heart failure: a systematic review

Left ventricular ejection fraction as therapeutic target: is it the ideal marker?

Angiogenic growth factors in myocardial infarction: a critical appraisal

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page