Adrenal Secretome and Epicardial Adipose Tissue

  • Luigi Petramala
  • Antonio Concistrè
  • Gino Iannucci
  • Claudio LetiziaEmail author
Part of the Contemporary Cardiology book series (CONCARD)


Adrenal gland diseases, such as primary aldosteronism and Cushing’s syndrome, are associated with higher cardiovascular risk. Excessive production of aldosterone can lead to accumulation of epicardial adipose tissue (EAT), interfering with functional state. In fact, increased mineralocorticoid signaling is critically involved in the secretion of proinflammatory cytokines by EAT with consequent profibrotic cascade activation in the myocardium. In heart failure hyperaldosteronism is strictly related to increased visceral adiposity representing an interplay between EAT and cardiac remodeling. Therefore, obese patients with heart failure are particularly sensitive to mineralocorticoid receptor antagonists. On the other hand, interaction between EAT and aldosterone is also observed in primary aldosteronism. Furthermore, previous studies suggest an active role of the fat depot surrounding the adrenal gland—paracrine secretion of adipokines from the adipose tissue surrounding the adrenal neoplasia being hormonally active. Considering the EAT characteristics of visceral adipose tissue depot, as well as periadrenal fat, correlation has been found between EAT and cardiovascular changes in adrenal diseases such as Cushing syndrome and adrenal incidentaloma. Ultrasound measured EAT could be implemented in the routine assessment of patients with endocrine-caused hypertension.


Epicardial fat thickness Adrenal disease Hyperaldosteronism Hypercortisolism Adrenal incidentaloma 


  1. 1.
    Fitzgibbons TP, Kogan S, Aouadi M, Hendricks GM, Straubhaar J, Czech MP. Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation. Am J Physiol Heart Circ Physiol. 2011;301:H1425–37.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Teijeira-Fernandez E, Eiras S, Salgado Somoza A, Gonzalez-Juanatey JR. Baseline epicardial adipose tissue adiponectin levels predict cardiovascular outcomes: a long-term follow-up study. Cytokine. 2012;60:674–80.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    van Dam AD, Boon MR, Berbée JFP, Rensen PCN, van Harmelen V. Targeting white, brown and perivascular adipose tissue in atherosclerosis development. Eur J Pharmacol. 2017;816:82–92.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Cheng KH, Chu CS, Lee KT, Lin TH, Hsieh CC, Chiu CC, et al. Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease. Int J Obes. 2008;32:268–74.CrossRefGoogle Scholar
  5. 5.
    Gruzdeva OV, Akbasheva OE, Dyleva YA, Antonova LV, Matveeva VG, Uchasova EG, et al. Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary heart disease. Bull Exp Biol Med. 2017;163:608–11.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH, Garg R. Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab. 2007;92:4472–5.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Iacobellis G, Petramala L, Marinelli C, Calvieri C, Zinnamosca L, Concistrè A, et al. Epicardial fat thickness and primary aldosteronism. Horm Metab Res. 2016;48:238–41.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wu C, Zhang H, Zhang J, Xie C, Fan C, Zhang H, et al. Inflammation and fibrosis in perirenal adipose tissue of patients with aldosterone-producing adenoma. Endocrinology. 2018;159:227–37.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Essick EE, Sam F. Cardiac hypertrophy and fibrosis in the metabolic syndrome: a role for aldosterone and the mineralocorticoid receptor. Int J Hypertens. 2011;2011:346985.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Olivier A, Pitt B, Girerd N, Lamiral Z, Machu JL, McMurray JJ, et al. Effect of eplerenone in patients with heart failure and reduced ejection fraction: potential effect modification by abdominal obesity. Insight from the EMPHASIS-HF trial. Eur J Heart Fail. 2017;19:1186–97.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Wada T, Ishikawa A, Watanabe E, Nakamura Y, Aruga Y, Hasegawa H, et al. Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance. J Endocrinol. 2017;235:179–91.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045–50.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, PAPY Study Investigators, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–300.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med. 2013;64:233–47.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008;168:80–5.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243–8.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Iacobellis G, Petramala L, Cotesta D, Pergolini M, Zinnamosca L, Cianci R, et al. Adipokines and cardiometabolic profile in primary hyperaldosteronism. J Clin Endocrinol Metab. 2010;95:2391–8.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Pallauf A, German Conn’s Registry-Else Kröner-Fresenius-Hyperaldosteronism Registry, et al. Observational study mortality in treated primary aldosteronism: the German Conn’s registry. Hypertension. 2012;60:618–24.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Rossi GP, Sacchetto A, Visentin P, Canali C, Graniero GR, Palatini P, Pessina AC. Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension. 1996;27:1039–45.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, et al. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension. 2013;62:62–9.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Young M, Fullerton M, Dilley R, Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest. 1994;93:2578–83.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension. 2013;62:331–6.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A, et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab. 2013;98:4826–33.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Muiesan ML, Rizzoni D, Salvetti M, Porteri E, Monteduro C, Guelfi D, et al. Structural changes in small resistance arteries and left ventricular geometry in patients with primary and secondary hypertension. J Hypertens. 2002;20:1439–44.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Reil JC, Hohl M, Selejan S, Lipp P, Drautz F, Kazakow A, et al. Aldosterone promotes atrial fibrillation. Eur Heart J. 2012;33:2098–108.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Fischer E, Adolf C, Pallauf A, Then C, Bidlingmaier M, Beuschlein F, et al. Aldosterone excess impairs first phase insulin secretion in primary aldosteronism. J Clin Endocrinol Metab. 2013;98:2513–20.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Chen W, Li F, He C, Zhu Y, Tan W. Elevated prevalence of abnormal glucose metabolism in patients with primary aldosteronism: a meta-analysis. Ir J Med Sci. 2014;183:283–91.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Matrozova J, Steichen O, Amar L, Zacharieva S, Jeunemaitre X, Plouin PF. Fasting plasma glucose and serum lipids in patients with primary aldosteronism: a controlled cross-sectional study. Hypertension. 2009;53:605–10.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Mosso LM, Carvajal CA, Maiz A, Ortiz EH, Castillo CR, Artigas RA, Fardella CE. A possible association between primary aldosteronism and a lower beta-cell function. J Hypertens. 2007;25:2125–30.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Goodfriend TL, Egan B, Stepniakowski K, Ball DL. Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. Hypertension. 1995;25:30–6.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Hanslik G, Wallaschofski H, Dietz A, Riester A, Reincke M, Allolio B, Participants of the German Conn’s Registry, et al. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn’s Registry. Eur J Endocrinol. 2015;173:665–75.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Fallo F, Pilon C, Urbanet R. Primary aldosteronism and metabolic syndrome. Horm Metab Res. 2012;44:208–14.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Hannemann A, Meisinger C, Bidlingmaier M, Döring A, Thorand B, Heier M, et al. Association of plasma aldosterone with the metabolic syndrome in two German populations. Eur J Endocrinol. 2011;164:751–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150:776–83.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med. 2005;2:536–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Iacobellis G, Bianco AC. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab. 2011;22:450–7.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab. 2003;88:5163–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Letizia C, Petramala L, Di Gioia CR, Chiappetta C, Zinnamosca L, Marinelli C, et al. Leptin and adiponectin mRNA expression from the adipose tissue surrounding the adrenal neoplasia. J Clin Endocrinol Metab. 2015;100:E101–4.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Iacobellis G, Petramala L, Barbaro G, Kargi AY, Serra V, Zinnamosca L, et al. Epicardial fat thickness and left ventricular mass in subjects with adrenal incidentaloma. Endocrine. 2013;44:532–6.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Iacobellis G, Willens HJ. Echocardiographic epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr. 2009;22:1311–9.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Malavazos AE, Di Leo G, Secchi F, Lupo EN, Dogliotti G, Coman C, et al. Relation of echocardiographic epicardial fat thickness and myocardial fat. Am J Cardiol. 2010;105:1831–5.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Kremen J, Dolinkova M, Krajickova J, Blaha J, Anderlova K, Lacinova Z, et al. Increased subcutaneous and epicardial adipose tissue production of proin-flammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab. 2006;91:4620–7.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Iacobellis G, Leonetti F. Epicardial adipose tissue and insulin resistance in obese subjects. J Clin Endocrinol Metab. 2005;90:6300–2.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Lubrano C, Saponara M, Barbaro G, Specchia P, Addessi E, Costantini D, et al. Relationships between body fat distribution, epicardial fat and obstructive sleep apnea in obese patients with and without metabolic syndrome. PLoS One. 2012;7:e47059.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Blumensatt M, Fahlbusch P, Hilgers R, Bekaert M, Herzfeld de Wiza D, Akhyari P, et al. Secretory products from epicardial adipose tissue from patients with type 2 diabetes impair mitochondrial β-oxidation in cardiomyocytes via activation of the cardiac renin-angiotensin system and induction of miR-208a. Basic Res Cardiol. 2017;112:2.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Blumensatt M, Greulich S, Herzfeld de Wiza D, Mueller H, Maxhera B, Rabelink MJ, et al. Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143. Cardiovasc Res. 2013;100:201–10.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57:660–71.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Diniz GP, Takano AP, Barreto-Chaves ML. MiRNA-208a and miRNA-208b are triggered in thyroid hormone-induced cardiac hypertrophy - role of type 1 angiotensin II receptor (AT1R) on miRNA-208a/alpha-MHC modulation. Mol Cell Endocrinol. 2013;374:117–24.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Goossens GH. The renin-angiotensin system in the pathophysiology of type 2 diabetes. Obes Facts. 2012;5:611–24.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Davenport C, Liew A, Doherty B, Win HH, Misran H, Hanna S, et al. The prevalence of adrenal incidentaloma in routine clinical practice. Endocrine. 2011;40:80–3.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85:637–44.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Rossi R, Tauchmanova L, Di Luciano A, Martino M, Battista C, Del Viscovo L, et al. Mild Cushing’s syndrome in patients with adrenal incidentaloma: clinical and biochemical features. J Clin Endocrinol Metab. 2000;85:1440–8.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Terzolo M, Osella G, Alì A, Borretta G, Cesario F, Paccotti P, Angeli A. Mild Cushing’s syndrome in adrenal incidentaloma. Clin Endocrinol. 1998;48:89–97.CrossRefGoogle Scholar
  54. 54.
    Vassiliadi DA, Tsagarakis S. Subclinical hypercortisolism: debatable or visible on the lightbox? Endocrine. 2012;42:7–8.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Giordano R, Guaraldi F, Berardelli R, Karamouzis I, D’Angelo V, Marinazzo E, et al. Glucose metabolism in patients with subclinical Cushing’s syndrome. Endocrine. 2012;41:415–23.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Ermetici F, Dall’Asta C, Malavazos AE, Morricone L, Dall’Asta C, Corsi MM, Ambrosi B. Echocardiographic alterations in patients with non-functioning adrenal incidentaloma. J Endocrinol Investig. 2008;31:573–7.CrossRefGoogle Scholar
  57. 57.
    Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab. 2010;95:4106–13.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Bujawansa S, Bowen-Jones D. Low investigation rate for adrenal incidentalomas. Endocrine. 2011;40:134–6.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Bassareo PP, Fanos V, Zaffanello M, Mercuro G. Early markers of cardiovascular dysfunction in young girls affected by Cushing’s syndrome before and after successful cure. J Pediatr Endocrinol Metab. 2010;23:627–35.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Luigi Petramala
    • 1
  • Antonio Concistrè
    • 1
  • Gino Iannucci
    • 1
  • Claudio Letizia
    • 1
    Email author
  1. 1.Secondary Arterial Hypertension Unit, Department of Translational and Precision Medicine“Sapienza” University of RomeRomeItaly

Personalised recommendations