Advertisement

Long-term danazol prophylaxis does not lead to increased carotid intima-media thickness in hereditary angioedema patients

  • Author Footnotes
    1 Authors contributed equally to the work presented in this manuscript.
    Róbert Szegedi
    Footnotes
    1 Authors contributed equally to the work presented in this manuscript.
    Affiliations
    Department of Neurology, Kútvölgyi Clinical Centre, Semmelweis University, Budapest, Hungary
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally to the work presented in this manuscript.
    Gábor Széplaki
    Footnotes
    1 Authors contributed equally to the work presented in this manuscript.
    Affiliations
    Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, H-1125 Budapest, Hungary
    Search for articles by this author
  • Lilian Varga
    Affiliations
    Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, H-1125 Budapest, Hungary
    Search for articles by this author
  • Zoltán Prohászka
    Affiliations
    Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, H-1125 Budapest, Hungary

    Research Group of Inflammation Biology and Immunogenomics, Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary
    Search for articles by this author
  • Zoltán Széplaki
    Affiliations
    Department of Neurology, Kútvölgyi Clinical Centre, Semmelweis University, Budapest, Hungary
    Search for articles by this author
  • István Karádi
    Affiliations
    Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, H-1125 Budapest, Hungary

    Research Group of Inflammation Biology and Immunogenomics, Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary
    Search for articles by this author
  • George Füst
    Affiliations
    Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, H-1125 Budapest, Hungary

    Research Group of Inflammation Biology and Immunogenomics, Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary
    Search for articles by this author
  • Henriette Farkas
    Correspondence
    Corresponding author. Tel.: +36 1 3251481; fax: +36 1 225 3899.
    Affiliations
    Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, H-1125 Budapest, Hungary
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally to the work presented in this manuscript.

      Abstract

      Background

      Hereditary angioedema (HAE) is characterized by episodic edematous attacks due to the deficiency of the C1-inhibitor (C1-INH). Recently, we have described that the long-term use of danazol affects lipid metabolism, resulting in decreased high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL) cholesterol levels, which might lead to accelerated, early atherosclerosis. Our aim in the present study was to investigate the impact of danazol treatment on the risk of atherosclerosis in HAE patients.

      Methods

      The prevalence of vascular disease, as well as carotid intima-media thickness (IMT) – an objective marker of atherosclerosis – was determined in 32 HAE patients undergoing danazol prophylaxis, and compared to 25 HAE patients without danazol treatment, as well as to 20 healthy controls. Distinct atherosclerosis risk profiles were determined in addition.

      Results

      HAE patients with danazol prophylaxis had higher body mass index (p = 0.0055 and 0.0020), creatinine (p = 0.0001 and 0.0130), alanine aminotransferase (p = 0.0298 and 0.0457), LDL (p = 0.0060 and <0.0001) and decreased HDL (p < 0.0001 and <0.0001) levels compared to both control groups. The prevalence of vascular diseases did not differ in the two patient groups. No significant differences were observed in mean (0.43 (0.37–0.50) mm vs. 0.40 (0.35–0.49) mm, p = 0.5465) carotid IMT values, when comparing patients with or without long-term danazol prophylaxis.

      Conclusions

      Thickening of IMT due to danazol use was not observed in HAE patients. We hypothesize that the functional deficiency of C1-INH might confer protection against atherosclerosis in these patients.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress. Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114:S51–131.

        • Frank M.M.
        Hereditary angioedema: the clinical syndrome and its management in the United States.
        Immunol Allergy Clin N Am. 2006; 26: 653-668
        • Bowen T.
        • Cicardi M.
        • Farkas H.
        • et al.
        Canadian 2003 international consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema.
        J Allergy Clin Immunol. 2004; 114: 629-637
        • Gelfand J.A.
        • Sherins R.J.
        • Alling D.W.
        • et al.
        Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities.
        N Engl J Med. 1976; 295: 1444-1448
        • Farkas H.
        • Gyeney L.
        • Gidofalvy E.
        • et al.
        The efficacy of short-term danazol prophylaxis in hereditary angioedema patients undergoing maxillofacial and dental procedures.
        J Oral Maxillofac Surg. 1999; 57: 404-408
        • Cicardi M.
        • Castelli R.
        • Zingale L.C.
        • et al.
        Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients.
        J Allergy Clin Immunol. 1997; 99: 194-196
        • Széplaki G.
        • Varga L.
        • Valentin S.
        • et al.
        Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema.
        J Allergy Clin Immunol. 2005; 115: 864-869
        • Eckardstein A.
        • Wu F.C.
        Testosterone atherosclerosis.
        Growth Horm IGF Res. 2003; 13: S72-S84
        • Oksjoki R.
        • Kovanen P.T.
        • Pentikainen M.O.
        Role of complement activation in atherosclerosis.
        Curr Opin Lipidol. 2003; 14: 477-482
        • Simon A.
        • Gariepy J.
        • Chironi G.
        • et al.
        Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk.
        J Hypertens. 2002; 20: 159-169
        • Ter Avest E.
        • Stalenhoef A.F.
        • de Graaf J.
        What is the role of non-invasive measurements of atherosclerosis in individual cardiovascular risk prediction?.
        Clin Sci (Lond). 2007; 112: 507-516
        • Brooks R.
        EuroQol: the current state of play.
        Health Policy. 1996; 37: 53-72
        • Howard G.
        • Burke G.L.
        • Evans G.W.
        • et al.
        Relations of intimal-medial thickness among sites within the carotid artery as evaluated by B-mode ultrasound. ARIC Investigators. Atherosclerosis Risk in Communities.
        Stroke. 1994; 25: 1581-1587
        • Széplaki G.
        • Prohászka Z.
        • Duba J.
        • et al.
        Association of high serum concentration of the third component of complement (C3) with pre-existing severe coronary artery disease and new vascular events in women.
        Atherosclerosis. 2004; 177: 383-389
        • Chambless L.E.
        • Folsom A.R.
        • Clegg L.X.
        • et al.
        Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study.
        Am J Epidemiol. 2000; 151: 478-487
        • Graner M.
        • Varpula M.
        • Kahri J.
        • et al.
        Association of carotid intima-media thickness with angiographic severity and extent of coronary artery disease.
        Am J Cardiol. 2006; 97: 624-629
        • Lorenz M.W.
        • von Kegler S.
        • Steinmetz H.
        • et al.
        Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS).
        Stroke. 2006; 37: 87-92
        • Alagona C.
        • Soro A.
        • Westerbacka J.
        • et al.
        Low HDL cholesterol concentration is associated with increased intima-media thickness independent of arterial stiffness in healthy subjects from families with low HDL cholesterol.
        Eur J Clin Invest. 2003; 33: 457-463
        • Ridker P.M.
        • Genest J.
        • Libby P.
        Risk factors for atherosclerotic disease.
        in: Braunwald E. Zipes D.P. Libby P. Heart disease: a textbook of cardiovascular medicine. WB Saunders, Philadelphia2001: 1010-1040
        • Ross R.
        Atherosclerosis is an inflammatory disease.
        Am Heart J. 1999; 138: S419-S420
        • Vapaatalo H.
        • Mervaala E.
        Clinically important factors influencing endothelial function.
        Med Sci Monit. 2001; 7: 1075-1085
        • Buono C.
        • Come C.E.
        • Witztum J.L.
        • et al.
        Influence of C3 deficiency on atherosclerosis.
        Circulation. 2002; 105: 3025-3031
        • Schunkert H.
        Obesity and target organ damage: the heart.
        Int J Obes Relat Metab Disord. 2002; 26: S15-S20
        • Schindhelm R.K.
        • Dekker J.M.
        • Nijpels G.
        • et al.
        Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study.
        Atherosclerosis. 2007; 191: 391-396
        • Culleton B.F.
        • Larson M.G.
        • Wilson P.W.
        • et al.
        Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.
        Kidney Int. 1999; 56: 2214-2219
        • Assmann G.
        • Gotto Jr., A.M.
        HDL cholesterol and protective factors in atherosclerosis.
        Circulation. 2004; 109: III8-III14
        • Nussberger J.
        • Cugno M.
        • Amstutz C.
        • et al.
        Plasma bradykinin in angio-oedema.
        Lancet. 1998; 351: 1693-1697
        • Cruden N.L.
        • Newby D.E.
        Clots, kinins and coronaries.
        Atherosclerosis. 2005; 183: 189-198
        • Curzen N.P.
        • Fox K.M.
        Do ACE inhibitors modulate atherosclerosis?.
        Eur Heart J. 1997; 18: 1530-1535
        • Zuraw B.L.
        Novel therapies for hereditary angioedema.
        Immunol Allergy Clin N Am. 2006; 26: 691-708