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Valvular heart disease induced by drugs

William H Gaasch, MD
Gerard P Aurigemma, MD
Section Editor
Catherine M Otto, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


Valvular abnormalities have been described in association with anorectic drugs and with ergot derivatives including drugs used for treatment or prophylaxis of migraine, particularly ergotamine and methysergide, and drugs used in the treatment of Parkinson disease, particularly pergolide and cabergoline [1]. Use of 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy) may also induce valve disease. The common pathogenetic link is increased serotonin activity.


The echocardiographic and pathologic features of the valve disease seen in patients with drug-induced valvular disease are similar to those occurring in carcinoid heart valve disease [2]. (See "Carcinoid heart disease".)

The link between these two conditions appears to be serotonin, a neurotransmitter that is elevated in serum and plasma of most patients with carcinoid heart valve disease [3]. As noted above, fenfluramine and dexfenfluramine augment serotonergic activity, while phentermine may contribute to the fenfluramine valvulopathy by interfering with the pulmonary clearance of serotonin.

Serotonin is also thought to play a role in the valve disease associated with ergot derivatives ergotamine [4], methysergide [5], and the dopamine agonists pergolide and cabergoline [6-8]. These drugs are structurally similar to serotonin and are thought to produce valve disease by stimulation of serotonin (5-HT 2B) receptors [6,9,10]. (See 'Parkinson disease' below.)

Serotonin stimulates fibroblast growth and fibrogenesis, which appears to underlie the valve disease seen in patients with carcinoid and anorectic drug and ergot derivative related heart valve disease. More direct evidence for a central role of serotonin comes from studies in animals:

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Literature review current through: Nov 2017. | This topic last updated: Jul 29, 2015.
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  1. Bhattacharyya S, Schapira AH, Mikhailidis DP, Davar J. Drug-induced fibrotic valvular heart disease. Lancet 2009; 374:577.
  2. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993; 87:1188.
  3. Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995; 92:790.
  4. Hendrikx M, Van Dorpe J, Flameng W, Daenen W. Aortic and mitral valve disease induced by ergotamine therapy for migraine: a case report and review of the literature. J Heart Valve Dis 1996; 5:235.
  5. Bana DS, MacNeal PS, LeCompte PM, et al. Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J 1974; 88:640.
  6. Waller EA, Kaplan J, Heckman MG. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2005; 80:1016.
  7. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007; 356:29.
  8. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007; 356:39.
  9. Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000; 102:2836.
  10. Roth BL. Drugs and valvular heart disease. N Engl J Med 2007; 356:6.
  11. Gustafsson BI, Tømmerås K, Nordrum I, et al. Long-term serotonin administration induces heart valve disease in rats. Circulation 2005; 111:1517.
  12. Mekontso-Dessap A, Brouri F, Pascal O, et al. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation 2006; 113:81.
  13. Mast ST, Gersing KR, Anstrom KJ, et al. Association between selective serotonin-reuptake inhibitor therapy and heart valve regurgitation. Am J Cardiol 2001; 87:989.
  14. Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Engl J Med 1997; 337:396.
  15. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337:581.
  16. Graham DJ, Green L. Further cases of valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337:635.
  17. Langreth R. Critics claim diet clinics misuse obesity drugs. Wall Street Journal. March 31, 1997;B8.
  18. Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med 1998; 339:725.
  19. Khan MA, Herzog CA, St Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998; 339:713.
  20. Jick H, Vasilakis C, Weinrauch LA, et al. A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med 1998; 339:719.
  21. Shively BK, Roldan CA, Gill EA, et al. Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation 1999; 100:2161.
  22. Gardin JM, Schumacher D, Constantine G, et al. Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. JAMA 2000; 283:1703.
  23. Burger AJ, Sherman HB, Charlamb MJ, et al. Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months. J Am Coll Cardiol 1999; 34:1153.
  24. Singh JP, Evans JC, Levy D, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999; 83:897.
  25. Caccitolo JA, Connolly HM, Rubenson DS, et al. Operation for anorexigen-associated valvular heart disease. J Thorac Cardiovasc Surg 2001; 122:656.
  26. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 guideline for the clinical application of echocardiography www.acc.org/qualityandscience/clinical/statements.htm (Accessed on August 24, 2006).
  27. Klein AL, Burstow DJ, Tajik AJ, et al. Age-related prevalence of valvular regurgitation in normal subjects: a comprehensive color flow examination of 118 volunteers. J Am Soc Echocardiogr 1990; 3:54.
  28. Centers for Disease Control and Prevention (CDC). Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997; 46:1061.
  29. Teramae CY, Connolly HM, Grogan M, Miller FA Jr. Diet drug-related cardiac valve disease: the Mayo Clinic echocardiographic laboratory experience. Mayo Clin Proc 2000; 75:456.
  30. Dahl CF, Allen MR, Urie PM, Hopkins PN. Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med 2008; 6:34.
  31. Weissman NJ, Panza JA, Tighe JF, Gwynne JT. Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134:267.
  32. Gardin JM, Weissman NJ, Leung C, et al. Clinical and echocardiographic follow-up of patients previously treated with dexfenfluramine or phentermine/fenfluramine. JAMA 2001; 286:2011.
  33. Mast ST, Jollis JG, Ryan T, et al. The progression of fenfluramine-associated valvular heart disease assessed by echocardiography. Ann Intern Med 2001; 134:261.
  34. Klein AL, Griffin BP, Grimm RA, et al. Natural history of valvular regurgitation using side-by-side echocardiographic analysis in anorexigen-treated subjects. Am J Cardiol 2005; 96:1711.
  35. Graham JR. Cardiac and pulmonary fibrosis during methysergide therapy for headache. Am J Med Sci 1967; 254:1.
  36. Misch KA. Development of heart valve lesions during methysergide therapy. Br Med J 1974; 2:365.
  37. Redfield MM, Nicholson WJ, Edwards WD, Tajik AJ. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med 1992; 117:50.
  38. Wilke A, Hesse H, Hufnagel G, Maisch B. Mitral, aortic and tricuspid valvular heart disease associated with ergotamine therapy for migraine. Eur Heart J 1997; 18:701.
  39. Martínez Quintana E, Llorens León R, Redondo Martínez E, et al. [Valvular heart disease associated with ergotamine]. Rev Esp Cardiol 2005; 58:97.
  40. Flowers CM, Racoosin JA, Lu SL, Beitz JG. The US Food and Drug Administration's registry of patients with pergolide-associated valvular heart disease. Mayo Clin Proc 2003; 78:730.
  41. Pritchett AM, Morrison JF, Edwards WD, et al. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002; 77:1280.
  42. Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004; 363:1179.
  43. Baseman DG, O'Suilleabhain PE, Reimold SC, et al. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology 2004; 63:301.
  44. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease. Lancet Neurol 2007; 6:826.
  45. US Food and Drug Administration. FDA announces voluntary withdrawal of pergolide products (March 29, 2007). http://www.fda.gov/newsevents/newsroom/pressannouncements/2007/ucm108877.htm (Accessed on August 01, 2012).
  46. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol 2003; 63:1223.
  47. Droogmans S, Cosyns B, D'haenen H, et al. Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease. Am J Cardiol 2007; 100:1442.
  48. Roldan CA, Gill EA, Shively BK. Prevalence and diagnostic value of precordial murmurs for valvular regurgitation in obese patients treated with dexfenfluramine. Am J Cardiol 2000; 86:535.