, Volume 18, Issue 1, pp 135–141 | Cite as

Soluble TNFα-receptor 1 as a predictor of coronary calcifications in patients after long-term cure of Cushing’s syndrome

  • María-José Barahona
  • Eugenia Resmini
  • David Viladés
  • José-Manuel Fernández-Real
  • Wifredo Ricart
  • José-María Moreno-Navarrete
  • Guillem Pons-Lladó
  • Rubén Leta
  • Susan M. Webb



Increased cardiovascular (CV) risk persists in Cushing’s syndrome (CS), despite remission of hypercortisolism. The aim of this study was to evaluate prevalence of coronary artery disease in CS patients and its correlation with classical CV risk factors and inflammatory markers.


Cardiac multidetector computed tomography (MDCT) was performed in 41 patients (7 men, 31 of pituitary origin, 29 cured, mean age: 48.6 ± 13 years), using 64-slice Toshiba Aquilion systems. Coronary atherosclerotic plaques were detected and coronary calcifications quantified by the Agatston score (AS). Clinical and biochemical parameters were correlated with the AS to identify possible surrogate markers of coronary disease. Normal values for clinical and biochemical parameters were obtained from a gender- and age-matched normal reference population (n = 82).


CS patients with calcifications (AS > 0) (N = 13, 32 %) had higher levels of sTNF-R1, homocysteine, triglycerides, blood pressure and body mass index than patients without calcifications (AS = 0) and those of normal reference population. Both groups of CS patients (AS > 0 and AS = 0) had elevated trunk fat mass and IL-6 compared to reference values. Patients with AS > 0 had less adiponectin and higher insulin, HOMA and fibrinogen than those found in normal reference population. sTNF-R1 correlated positively with AS and remained significant after adjusting for confounding factors. The same result was observed when we considered only cured CS patients.


In our cohort of CS patients sTNF-R1 was a predictor of coronary calcifications. Since MDCT is an expensive technique not readily available in daily clinical practice, increased sTNF-R1 could be a marker of CV risk even in cured CS.


Cushing’s syndrome Atherosclerosis Adipokines Coronary calcifications 



Supported by a Grant from the Spanish Health Ministry, Fondo de Investigación Sanitaria 05/0448. The Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filipella M, Di Somma C, Lombardi G, Colao A (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 88:2527–2533PubMedCrossRefGoogle Scholar
  2. 2.
    Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filipella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G (1999) Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J Clin Endocrinol Metab 84:2664–2672PubMedGoogle Scholar
  3. 3.
    Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G (2004) High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines. Clin Endocrinol 61:768–777CrossRefGoogle Scholar
  4. 4.
    Pivonello R, Faggiano A, Lombardi G, Colao A (2005) The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. Endocrinol Metab Clin North Am 34:327–339PubMedCrossRefGoogle Scholar
  5. 5.
    Barahona MJ, Sucunza N, Resmini E, Fernández-Real JM, Ricart W, Moreno-Navarrete JM, Puig T, Farrerons J, Webb SM (2009) Persistent body fat mass and inflammatory marker increases after long-term cure of Cushing’s syndrome. J Clin Endocrinol Metab 94:3365–3371PubMedCrossRefGoogle Scholar
  6. 6.
    Fallo F, Famoso G, Capizzi D, Sonino N, Dassie F, Maffei P, Martini C, Paoletta A, Iliceto S, Tona F (2013) Coronary microvascular function in patients with Cushing’s syndrome. Endocrine 43:206–213PubMedCrossRefGoogle Scholar
  7. 7.
    Neary NM, Booker OJ, Abel BS, Matta JR, Muldoon N, Sinaii N, Pettigrew RI, Nieman LK, Gharib AM (2013) Hypercortisolism is associated with increased coronary arterial atherosclerosis: analysis of noninvasive coronary angiography using multidetector computerized tomography. J Clin Endocrinol Metab 98:2045–2052PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Barahona MJ, Resmini E, Viladés D, Pons-Lladó G, Leta R, Puig T, Webb SM (2013) Coronary artery disease detected by multislice computed tomography in patients alter long-term cure of Cushing’s syndrome. J Clin Endocrinol Metab 98:1093–1099PubMedCrossRefGoogle Scholar
  9. 9.
    Thilo C, Standl E, Knez A, Reiser M, Steinbeck G, Haberl R, Schnell O (2004) Coronary calcification in long-term type 1 diabetic patients—a study with multi slice spiral computed tomography. Exp Clin Endocrinol Diabetes 112:561–565PubMedCrossRefGoogle Scholar
  10. 10.
    Becker A, Knez A, Leber A, Boekstegers P, Steinbeck G (2004) Diabetes mellitus type 2: coronary calcifications as a predictor of coronary artery disease. Herz 29:488–495PubMedCrossRefGoogle Scholar
  11. 11.
    Cannavo S, Almoto B, Cavalli G, Squadrito S, Romanello G, Vigo MT, Fiumara F, Benvenga S, Trimarchi F (2006) Acromegaly and coronary disease: an integrated evaluation of conventional coronary risk factors and coronary calcifications detected by computed tomography. J Clin Endocrinol Metab 91:3766–3772PubMedCrossRefGoogle Scholar
  12. 12.
    Bogazzi F, Battolla L, Spinelli C, Rossi G, Gavioli S, Di Bello V, Cosci C, Sardella C, Volterrani D, Talini E, Pepe P, Falaschi F, Mariani G, Martino E (2007) Risk factors for development of coronary heart disease in patients with acromegaly: a 5-year prospective study. J Clin Endocrinol Metab 92:4271–4277PubMedCrossRefGoogle Scholar
  13. 13.
    Civilibal M, Caliskan S, Adaletli I, Oflaz H, Sever L, Candan C, Canpolat N, Kasapcopur O, Kuruoglu S, Arisoy N (2006) Coronary artery calcifications in children with end-stage renal disease. Pediatr Nephrol 21:1426–1433PubMedCrossRefGoogle Scholar
  14. 14.
    Fernández-Real JM, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J, Richart C (1998) Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes 47:1757–1762PubMedCrossRefGoogle Scholar
  15. 15.
    Santaniemi M, Kesäbuenu YA, Ukkola O (2006) Low plasma adiponectin concentration is an indicator of the metabolic syndrome. Eur J Endocrinol 155:745–750PubMedCrossRefGoogle Scholar
  16. 16.
    Frystyk J, Berne C, Berglund L, Jensevik K, Flyvbjerg A, Zethelius B (2007) Serum adiponectin is a predictor of coronary heart disease: a population-based 10-year follow-up study in elderly men. J Clin Endocrinol Metab 92:571–576PubMedCrossRefGoogle Scholar
  17. 17.
    Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M (2003) Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 108:2317–2322PubMedCrossRefGoogle Scholar
  18. 18.
    Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, Curhan GC, Rifai N, Cannuscio CC, Stampfer MJ, Rimm EB (2004) Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 351:2599–2610PubMedCrossRefGoogle Scholar
  19. 19.
    Taylor AJ, Cerqueira M, Hodgson JM, Mark D, Min J, O’Gara P, Rubin GD (2010) Appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation appropriate use criteria task force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 56:1864–1894PubMedCrossRefGoogle Scholar
  20. 20.
    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827–832PubMedCrossRefGoogle Scholar
  21. 21.
    Leta R, Carreras F, Alomar X, Monell J, García-Picart J, Augé JM, Salvador A, Pons-Lladó G (2004) Non-invasive coronary angiography with 16 multidetector-row spiral computed tomography: a comparative study with invasive coronary angiography. Rev Esp Cardiol 57:217–224PubMedCrossRefGoogle Scholar
  22. 22.
    Church TS, Levine BD, McGuire DK, LaMonte MJ, FitzGerald SJ, Cheng YJ, Kimball TE, Blair SN, Gibbons LW, Nichaman MZ (2007) Coronary artery calcium score, risk factors, and incident coronary heart disease events. Atherosclerosis 190:224–231PubMedCrossRefGoogle Scholar
  23. 23.
    Keelan PC, Bielak LF, Ashai K, Jamjoum LS, Denktas AE, Rumberger JA, Sheedy PF, Peyser PA, Schwartz RS (2001) Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation 104:412–417PubMedCrossRefGoogle Scholar
  24. 24.
    Kondos GT, Hoff JA, Sevrukov A, Daviglus ML, Garside DB, Devries SS, Chomka EV, Liu K (2003) Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5,635 initially asymptomatic low- to intermediate-risk adults. Circulation 107:2571–2576PubMedCrossRefGoogle Scholar
  25. 25.
    Sarwar A, Shaw LJ, Shapiro MD, Blankstein R, Hoffmann U, Cury RC, Abbara S, Brady TJ, Budoff MJ, Blumenthal RS, Nasir K (2009) Diagnostic and prognostic value of absence of coronary artery calcification. J Am Coll Cardiol Img 2:675–688CrossRefGoogle Scholar
  26. 26.
    Svenungsson E, Gunnarsson I, Fei GZ, Lundberg IE, Klareskog L, Frostegard J (2003) Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum 48:2533–2540PubMedCrossRefGoogle Scholar
  27. 27.
    Al-Aly Z (2008) Arterial calcification: a tumor necrosis factor-alpha mediated vascular Wnt-opathy. Transl Res 151:233–239PubMedCrossRefGoogle Scholar
  28. 28.
    Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJW, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS, for the CONFIRM Investigators (2011) Age and sex-related differences in all cause mortality risk based on coronary computed tomography angiography findings. Results from the international multicenter CONFIRM (coronary CT angiography evaluation for clinical outcomes: an international multicenter registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 58:849–860PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • María-José Barahona
    • 1
    • 3
  • Eugenia Resmini
    • 2
    • 3
  • David Viladés
    • 4
  • José-Manuel Fernández-Real
    • 5
  • Wifredo Ricart
    • 5
  • José-María Moreno-Navarrete
    • 5
  • Guillem Pons-Lladó
    • 4
  • Rubén Leta
    • 4
  • Susan M. Webb
    • 2
    • 3
  1. 1.Department of EndocrinologyHospital Universitari Mútua de TerrassaTerrassaSpain
  2. 2.Departments of Endocrinology and MedicineHospital Sant Pau, Universitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747)Instituto de Salud Carlos IIIMadridSpain
  4. 4.Cardiology DepartmentHospital Sant Pau, Universitat Autònoma de BarcelonaBarcelonaSpain
  5. 5.Endocrinology DepartmentInstitut d’Investigació Biomèdica de Girona (IDIBGI) and CIBER Fisiopatologia de la Obesidad y Nutrición CB06/03/010, Hospital Josep TruetaGironaSpain

Personalised recommendations