Korean Circ J.  2017 Sep;47(5):670-685. 10.4070/kcj.2017.0041.

Exploring the Crosstalk between Adipose Tissue and the Cardiovascular System

• Akoumianakis I
• Akawi N
• Antoniades C

• KMID: 2389598
• DOI: http://doi.org/10.4070/kcj.2017.0041

Abstract

Obesity is a clinical entity critically involved in the development and progression of cardiovascular disease (CVD), which is characterised by variable expansion of adipose tissue (AT) mass across the body as well as by phenotypic alterations in AT. AT is able to secrete a diverse spectrum of biologically active substances called adipocytokines, which reach the cardiovascular system via both endocrine and paracrine routes, potentially regulating a variety of physiological and pathophysiological responses in the vasculature and heart. Such responses include regulation of inflammation and oxidative stress as well as cell proliferation, migration and hypertrophy. Furthermore, clinical observations such as the "obesity paradox," namely the fact that moderately obese patients with CVD have favourable clinical outcome, strongly indicate that the biological "quality" of AT may be far more crucial than its overall mass in the regulation of CVD pathogenesis. In this work, we describe the anatomical and biological diversity of AT in health and metabolic disease; we next explore its association with CVD and, importantly, novel evidence for its dynamic crosstalk with the cardiovascular system, which could regulate CVD pathogenesis.

Keyword

Adipose tissue; Obesity; Cardiovascular disease; Oxidative stress

MeSH Terms

Adipokines
Adipose Tissue*
Biodiversity
Cardiovascular Diseases
Cardiovascular System*
Cell Proliferation
Heart
Humans
Hypertrophy
Inflammation
Metabolic Diseases
Obesity
Oxidative Stress
Adipokines

Figure

• 

  Figure 1 Overview of the interactions between AT and the cardiovascular system. AT is able to secrete a variety of biologically active molecules called adipocytokines which influence cardiovascular biology. Some of these adipocytokines (e.g., adiponectin, omentin) have overall protective effects on the heart and vasculature. In contrast, other adipocytokines (such as resistin, leptin, TNFα, and IL-6) promote inflammation and oxidative stress in the cardiovascular system, while facilitating myocardial injury and remodelling in the heart as well as endothelial dysfunction and VSMC proliferation in the vessels. The overall effect of AT on cardiovascular biology is determined by the balance between protective and detrimental adipocytokines, while anatomically different AT depots often have distinct secretomes. The cardiovascular system may be influenced by the endocrine effect of adipocytokines secreted in the systemic circulation by “remote” AT depots; in addition, the heart and vessels are in bidirectional interaction with AT depots directly surrounding them (i.e., EpAT and PVAT, respectively). This mutual paracrine crosstalk allows for EpAT and PVAT to directly influence cardiovascular biology while also acting as recipients of biological signals originating from the cardiovascular system. Further elucidation of the complex interactions between AT and the cardiovascular system may reveal new diagnostic, prognostic or therapeutic strategies against CVD. Arrows denote a positive (stimulatory) effect; lines with a straight horizontal end symbolize a negative (inhibitory) effect. AT = adipose tissue; CVD = cardiovascular disease; EpAT = epicardial AT; IL-6 = interleukin 6; PVAT = perivascular adipose tissue; RAAS = renin-angiotensin-aldosterone system; ScAT = subcutaneous adipose tissue; ThAT = thoracic adipose tisse; TNFα = tumour necrosis factor alpha; VSMC = vascular smooth muscle cell.

Reference

1. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983; 67:968–977.

2. Sowers JR. Obesity as a cardiovascular risk factor. Am J Med. 2003; 115:Suppl 8A. 37S–41S.

3. 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. 2013; 62:921–925.

4. Greif M, Becker A, von Ziegler F, et al. Pericardial adipose tissue determined by dual source CT is a risk factor for coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2009; 29:781–786.

5. McQuaid SE, Humphreys SM, Hodson L, Fielding BA, Karpe F, Frayn KN. Femoral adipose tissue may accumulate the fat that has been recycled as VLDL and nonesterified fatty acids. Diabetes. 2010; 59:2465–2473.

6. Nishida C, Ko GT, Kumanyika S. Body fat distribution and noncommunicable diseases in populations: overview of the 2008 WHO Expert Consultation on Waist Circumference and Waist-Hip Ratio. Eur J Clin Nutr. 2010; 64:2–5.

7. Nagarajan V, Kohan L, Holland E, Keeley EC, Mazimba S. Obesity paradox in heart failure: a heavy matter. ESC Heart Fail. 2016; 3:227–234.

8. Park J, Ahmadi SF, Streja E, et al. Obesity paradox in end-stage kidney disease patients. Prog Cardiovasc Dis. 2014; 56:415–425.

9. Antonopoulos AS, Oikonomou EK, Antoniades C, Tousoulis D. From the BMI paradox to the obesity paradox: the obesity-mortality association in coronary heart disease. Obes Rev. 2016; 17:989–1000.

10. Akoumianakis I, Tarun A, Antoniades C. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. [Epub ahead of print]. Br J Pharmacol. 2016.

11. Fuster JJ, Ouchi N, Gokce N, Walsh K. Obesity-induced changes in adipose tissue microenvironment and their impact on cardiovascular disease. Circ Res. 2016; 118:1786–1807.

12. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol (Oxf). 2006; 64:355–365.

13. Saely CH, Geiger K, Drexel H. Brown versus white adipose tissue: a mini-review. Gerontology. 2012; 58:15–23.

14. Hassan M, Latif N, Yacoub M. Adipose tissue: friend or foe? Nat Rev Cardiol. 2012; 9:689–702.

15. Abraham TM, Pedley A, Massaro JM, Hoffmann U, Fox CS. Association between visceral and subcutaneous adipose depots and incident cardiovascular disease risk factors. Circulation. 2015; 132:1639–1647.

16. Marinou K, Hodson L, Vasan SK, et al. Structural and functional properties of deep abdominal subcutaneous adipose tissue explain its association with insulin resistance and cardiovascular risk in men. Diabetes Care. 2014; 37:821–829.

17. Jo J, Gavrilova O, Pack S, et al. Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLOS Comput Biol. 2009; 5:e1000324.

18. Laforest S, Labrecque J, Michaud A, Cianflone K, Tchernof A. Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction. Crit Rev Clin Lab Sci. 2015; 52:301–313.

19. Tanaka N, Takahashi S, Matsubara T, et al. Adipocyte-specific disruption of fat-specific protein 27 causes hepatosteatosis and insulin resistance in high-fat diet-fed mice. J Biol Chem. 2015; 290:3092–3105.

20. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84:277–359.

21. Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol. 2014; 10:24–36.

22. Tam CS, Lecoultre V, Ravussin E. Brown adipose tissue: mechanisms and potential therapeutic targets. Circulation. 2012; 125:2782–2791.

23. Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab. 2013; 305:E567–E572.

24. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013; 19:1252–1263.

25. Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest. 2017; 127:74–82.

26. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003; 112:1785–1788.

27. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010; 11:11–18.

28. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010; 316:129–139.

29. Molica F, Morel S, Kwak BR, Rohner-Jeanrenaud F, Steffens S. Adipokines at the crossroad between obesity and cardiovascular disease. Thromb Haemost. 2015; 113:553–566.

30. Margaritis M, Antonopoulos AS, Digby J, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013; 127:2209–2221.

31. Aghamohammadzadeh R, Withers S, Lynch F, Greenstein A, Malik R, Heagerty A. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target. Br J Pharmacol. 2012; 165:670–682.

32. Mazurek T, Opolski G. Pericoronary adipose tissue: a novel therapeutic target in obesity-related coronary atherosclerosis. J Am Coll Nutr. 2015; 34:244–254.

33. McAninch EA, Fonseca TL, Poggioli R, et al. Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease. Obesity (Silver Spring). 2015; 23:1267–1278.

34. Fitzgibbons TP, Czech MP. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc. 2014; 3:e000582.

35. Mazurek T, Kiliszek M, Kobylecka M, et al. Relation of proinflammatory activity of epicardial adipose tissue to the occurrence of atrial fibrillation. Am J Cardiol. 2014; 113:1505–1508.

36. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. 2003; 108:2460–2466.

37. Yudkin JS, Eringa E, Stehouwer CD. “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet. 2005; 365:1817–1820.

38. Iacobellis G, Bianco AC. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab. 2011; 22:450–457.

39. Antoniades C, Antonopoulos AS, Tousoulis D, Stefanadis C. Adiponectin: from obesity to cardiovascular disease. Obes Rev. 2009; 10:269–279.

40. Woodward L, Akoumianakis I, Antoniades C. Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease. [Epub ahead of print]. Br J Pharmacol. 2016.

41. Kobashi C, Urakaze M, Kishida M, et al. Adiponectin inhibits endothelial synthesis of interleukin-8. Circ Res. 2005; 97:1245–1252.

42. Ouedraogo R, Gong Y, Berzins B, et al. Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest. 2007; 117:1718–1726.

43. Kobayashi H, Ouchi N, Kihara S, et al. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res. 2004; 94:e27–e31.

44. Antonopoulos AS, Margaritis M, Coutinho P, et al. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes. 2015; 64:2207–2219.

45. Antonopoulos AS, Margaritis M, Verheule S, et al. Mutual regulation of epicardial adipose tissue and myocardial redox state by PPAR-γ/adiponectin signalling. Circ Res. 2016; 118:842–855.

46. Shibata R, Sato K, Pimentel DR, et al. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med. 2005; 11:1096–1103.

47. Essick EE, Wilson RM, Pimentel DR, et al. Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes. PLoS One. 2013; 8:e68697.

48. Joki Y, Ohashi K, Yuasa D, et al. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochem Biophys Res Commun. 2015; 459:124–130.

49. Antonopoulos AS, Margaritis M, Coutinho P, et al. Reciprocal effects of systemic inflammation and brain natriuretic peptide on adiponectin biosynthesis in adipose tissue of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 2014; 34:2151–2159.

50. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000; 62:413–437.

51. Sweeney G. Cardiovascular effects of leptin. Nat Rev Cardiol. 2010; 7:22–29.

52. Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: response to therapeutic interventions. Circulation. 2008; 117:3238–3249.

53. Tümer N, Erdös B, Matheny M, Cudykier I, Scarpace PJ. Leptin antagonist reverses hypertension caused by leptin overexpression, but fails to normalize obesity-related hypertension. J Hypertens. 2007; 25:2471–2478.

54. Zuo G, Du X, Zheng L, Wang C, Wang K, Li Y. The role of leptin in the ventricular remodeling process and its mechanism. Int J Clin Exp Med. 2015; 8:5553–5558.

55. Martínez-Martínez E, Jurado-López R, Valero-Muñoz M, et al. Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity. J Hypertens. 2014; 32:1104–1114.

56. Yan W, Zhang H, Liu P, et al. Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol. 2013; 108:329.

57. Smith CC, Mocanu MM, Davidson SM, Wynne AM, Simpkin JC, Yellon DM. Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. Br J Pharmacol. 2006; 149:5–13.

58. Lee S, Lee HC, Kwon YW, et al. Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell Metab. 2014; 19:484–497.

59. Langheim S, Dreas L, Veschini L, et al. Increased expression and secretion of resistin in epicardial adipose tissue of patients with acute coronary syndrome. Am J Physiol Heart Circ Physiol. 2010; 298:H746–H753.

60. Jung HS, Park KH, Cho YM, et al. Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res. 2006; 69:76–85.

61. Muse ED, Feldman DI, Blaha MJ, et al. The association of resistin with cardiovascular disease in the Multi-ethnic Study of Atherosclerosis. Atherosclerosis. 2015; 239:101–108.

62. He Y, Bai XJ, Li FX, et al. Resistin may be an independent predictor of subclinical atherosclerosis formale smokers. Biomarkers. 2017; 22:291–295.

63. Gencer B, Auer R, de Rekeneire N, et al. Association between resistin levels and cardiovascular disease events in older adults: the health, aging and body composition study. Atherosclerosis. 2016; 245:181–186.

64. Kang S, Chemaly ER, Hajjar RJ, Lebeche D. Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem. 2011; 286:18465–18473.

65. Rothwell SE, Richards AM, Pemberton CJ. Resistin worsens cardiac ischaemia-reperfusion injury. Biochem Biophys Res Commun. 2006; 349:400–407.

66. Chemaly ER, Hadri L, Zhang S, et al. Long-term in vivo resistin overexpression induces myocardial dysfunction and remodeling in rats. J Mol Cell Cardiol. 2011; 51:144–155.

67. Laurikka A, Vuolteenaho K, Toikkanen V, et al. Adipocytokine resistin correlates with oxidative stress and myocardial injury in patients undergoing cardiac surgery. Eur J Cardiothorac Surg. 2014; 46:729–736.

68. Takeishi Y, Niizeki T, Arimoto T, et al. Serum resistin is associated with high risk in patients with congestive heart failure--a novel link between metabolic signals and heart failure. Circ J. 2007; 71:460–464.

69. Tan BK, Adya R, Randeva HS. Omentin: a novel link between inflammation, diabesity, and cardiovascular disease. Trends Cardiovasc Med. 2010; 20:143–148.

70. Kazama K, Okada M, Yamawaki H. A novel adipocytokine, omentin, inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell migration through antioxidative mechanism. Am J Physiol Heart Circ Physiol. 2014; 306:H1714–H1719.

71. Yamawaki H, Kuramoto J, Kameshima S, Usui T, Okada M, Hara Y. Omentin, a novel adipocytokine inhibits TNF-induced vascular inflammation in human endothelial cells. Biochem Biophys Res Commun. 2011; 408:339–343.

72. Ohashi K, Shibata R, Murohara T, Ouchi N. Role of anti-inflammatory adipokines in obesity-related diseases. Trends Endocrinol Metab. 2014; 25:348–355.

73. Uemura Y, Shibata R, Kanemura N, et al. Adipose-derived protein omentin prevents neointimal formation after arterial injury. FASEB J. 2015; 29:141–151.

74. Kazama K, Okada M, Yamawaki H. Adipocytokine, omentin inhibits doxorubicin-induced H9c2 cardiomyoblasts apoptosis through the inhibition of mitochondrial reactive oxygen species. Biochem Biophys Res Commun. 2015; 457:602–607.

75. Kataoka Y, Shibata R, Ohashi K, et al. Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. J Am Coll Cardiol. 2014; 63:2722–2733.

76. Harada K, Shibata R, Ouchi N, et al. Increased expression of the adipocytokine omentin in the epicardial adipose tissue of coronary artery disease patients. Atherosclerosis. 2016; 251:299–304.

77. Saely CH, Leiherer A, Muendlein A, et al. High plasma omentin predicts cardiovascular events independently from the presence and extent of angiographically determined atherosclerosis. Atherosclerosis. 2016; 244:38–43.

78. Narumi T, Watanabe T, Kadowaki S, et al. Impact of serum omentin-1 levels on cardiac prognosis in patients with heart failure. Cardiovasc Diabetol. 2014; 13:84.

79. Romacho T, Sánchez-Ferrer CF, Peiró C. Visfatin/Nampt: an adipokine with cardiovascular impact. Mediators Inflamm. 2013; 2013:946427.

80. Formentini L, Moroni F, Chiarugi A. Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo. Biochem Pharmacol. 2009; 77:1612–1620.

81. Vallejo S, Romacho T, Angulo J, et al. Visfatin impairs endothelium-dependent relaxation in rat and human mesenteric microvessels through nicotinamide phosphoribosyltransferase activity. PLoS One. 2011; 6:e27299.

82. Li B, Zhao Y, Liu H, et al. Visfatin destabilizes atherosclerotic plaques in apolipoprotein E-deficient mice. PLoS One. 2016; 11:e0148273.

83. Lovren F, Pan Y, Shukla PC, et al. Visfatin activates eNOS via Akt and MAP kinases and improves endothelial cell function and angiogenesis in vitro and in vivo: translational implications for atherosclerosis. Am J Physiol Endocrinol Metab. 2009; 296:E1440–E1449.

84. Yamawaki H, Hara N, Okada M, Hara Y. Visfatin causes endothelium-dependent relaxation in isolated blood vessels. Biochem Biophys Res Commun. 2009; 383:503–508.

85. Xiao J, Sun B, Li M, Wu Y, Sun XB. A novel adipocytokine visfatin protects against H(2)O(2) -induced myocardial apoptosis: a missing link between obesity and cardiovascular disease. J Cell Physiol. 2013; 228:495–501.

86. Lim SY, Davidson SM, Paramanathan AJ, Smith CC, Yellon DM, Hausenloy DJ. The novel adipocytokine visfatin exerts direct cardioprotective effects. J Cell Mol Med. 2008; 12:1395–1403.

87. Chang YH, Chang DM, Lin KC, Shin SJ, Lee YJ. Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: a meta-analysis and systemic review. Diabetes Metab Res Rev. 2011; 27:515–527.

88. Vanhoutte PM. Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ J. 2009; 73:595–601.

89. Dahl TB, Yndestad A, Skjelland M, et al. Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation. 2007; 115:972–980.

90. Hung WC, Yu TH, Hsu CC, et al. Plasma visfatin levels are associated with major adverse cardiovascular events in patients with acute ST-elevation myocardial infarction. Clin Invest Med. 2015; 38:E100–E109.

91. McKellar GE, McCarey DW, Sattar N, McInnes IB. Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol. 2009; 6:410–417.

92. Hartman J, Frishman WH. Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev. 2014; 22:147–151.

93. Ntaios G, Gatselis NK, Makaritsis K, Dalekos GN. Adipokines as mediators of endothelial function and atherosclerosis. Atherosclerosis. 2013; 227:216–221.

94. Hamid T, Guo SZ, Kingery JR, Xiang X, Dawn B, Prabhu SD. Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc Res. 2011; 89:129–138.

95. Sun M, Chen M, Dawood F, et al. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation. 2007; 115:1398–1407.

96. Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res. 2004; 94:1543–1553.

97. Hürlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002; 106:2184–2187.

98. Wong M, Oakley SP, Young L, et al. Infliximab improves vascular stiffness in patients with rheumatoid arthritis. Ann Rheum Dis. 2009; 68:1277–1284.

99. Kume K, Amano K, Yamada S, Hatta K, Ohta H, Kuwaba N. Tocilizumab monotherapy reduces arterial stiffness as effectively as etanercept or adalimumab monotherapy in rheumatoid arthritis: an open-label randomized controlled trial. J Rheumatol. 2011; 38:2169–2171.

100. Greenberg JD, Furer V, Farkouh ME. Cardiovascular safety of biologic therapies for the treatment of RA. Nat Rev Rheumatol. 2011; 8:13–21.

101. Marcus Y, Shefer G, Stern N. Adipose tissue renin-angiotensin-aldosterone system (RAAS) and progression of insulin resistance. Mol Cell Endocrinol. 2013; 378:1–14.

102. Pacurari M, Kafoury R, Tchounwou PB, Ndebele K. The Renin-angiotensin-aldosterone system in vascular inflammation and remodeling. Int J Inflamm. 2014; 2014:689360.

103. Cooper SA, Whaley-Connell A, Habibi J, et al. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol. 2007; 293:H2009–H2023.

104. Ellmers LJ, Rademaker MT, Charles CJ, Yandle TG, Richards AM. (Pro)renin receptor blockade ameliorates cardiac injury and remodeling and improves function after myocardial infarction. J Card Fail. 2016; 22:64–72.

105. Nguyen Dinh Cat A, Antunes TT, Callera GE, et al. Adipocyte-specific mineralocorticoid receptor overexpression in mice is associated with metabolic syndrome and vascular dysfunction: role of redox-sensitive PKG-1 and Rho kinase. Diabetes. 2016; 65:2392–2403.

106. von Lueder TG, Krum H. RAAS inhibitors and cardiovascular protection in large scale trials. Cardiovasc Drugs Ther. 2013; 27:171–179.

107. Venteclef N, Guglielmi V, Balse E, et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J. 2015; 36:795–805a.

108. Hatem SN, Sanders P. Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res. 2014; 102:205–213.

109. Thanassoulis G, Massaro JM, O'Donnell CJ, et al. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol. 2010; 3:345–350.

110. Reilly SN, Jayaram R, Nahar K, et al. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation. 2011; 124:1107–1117.