Journal of Cardiovascular Translational Research

, Volume 4, Issue 6, pp 741–747

Mitral Valve Disease in Marfan Syndrome and Related Disorders

  • Daniel P. Judge
  • Rosanne Rouf
  • Jennifer Habashi
  • Harry C. Dietz


Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues. Myxomatous thickening and elongation of the mitral valve (MV) leaflets commonly occur in this condition. Investigation of murine models of this disease has led to improved understanding of the mechanisms that underlie many of the phenotypic features of MFS, including MV disease. Loeys–Dietz syndrome (LDS) is a related disorder due to heterozygous mutations in the genes encoding subunits of the TGFβ receptor, and it may also involve the MV leaflets with similar elongation and thickening of the MV leaflets. Although the genetic basis and pathogenesis of nonsyndromic MV prolapse has been elusive to date, insights derived from monogenic disorders like MFS and LDS can be informative with regard to novel gene discovery and investigation into the pathogenesis of MV disease. This manuscript will review the prevalence of MV disease in MFS, its pathogenic basis as determined in mice with Fbn1 mutations, and ongoing studies that seek to better understand MV disease in the context of fibrillin-1 deficiency or excessive TGFβ signaling.


Mitral valve Marfan TGF-beta 


  1. 1.
    Marfan, A.-B. (1896). Un cas de deformation congenitale des quarte membres plus prononcee aux extremites caracterisee par l'allongement des os avec un certain degre d'amincissement. Bulletins et Mémoires de la Société Médicale des Hôpitaux de Paris, 13, 220–226.Google Scholar
  2. 2.
    Marfan, A.-B. (1938). La dolichosténomélie [dolichomélie arachnodactylie]. Annals of Medicine, 44, 5–29.Google Scholar
  3. 3.
    Baer, R. W., Taussig, H. B., & Oppenheimer, E. H. (1943). Congenital aneurysmal dilatation of the aorta associated with arachnodactyly. Bulletin of the Johns Hopkins Hospital, 72, 309–317.Google Scholar
  4. 4.
    McKusick, V. A. (1955). The cardiovascular aspects of Marfan's syndrome. Circulation, 11, 321.PubMedGoogle Scholar
  5. 5.
    Bowers, D. (1969). Pathogenesis of primary abnormalities of the mitral valve in Marfan's syndrome. British Heart Journal, 31, 679–683.PubMedCrossRefGoogle Scholar
  6. 6.
    Loeys, B. L., Dietz, H. C., Braverman, A. C., et al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47, 476–485.PubMedCrossRefGoogle Scholar
  7. 7.
    De Paepe, A., Devereux, R. B., Dietz, H. C., Hennekam, R. C., & Pyeritz, R. E. (1996). Revised diagnostic criteria for the Marfan syndrome. American Journal of Medical Genetics, 62, 417–426.PubMedCrossRefGoogle Scholar
  8. 8.
    Barlow, J. B., & Bosman, C. K. (1966). Aneurysmal protrusion of the posterior leaflet of the mitral valve. An auscultatory-electrocardiographic syndrome. American Heart Journal, 71, 166–178.PubMedCrossRefGoogle Scholar
  9. 9.
    Bhudia, S. K., Troughton, R., Lam, B. K., et al. (2006). Mitral valve surgery in the adult Marfan syndrome patient. The Annals of Thoracic Surgery, 81, 843–848.PubMedCrossRefGoogle Scholar
  10. 10.
    Montgomery, R. A., Geraghty, M. T., Bull, E., et al. (1998). Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. American Journal of Human Genetics, 63, 1703–1711.PubMedCrossRefGoogle Scholar
  11. 11.
    Aalberts, J. J., Schuurman, A. G., Pals, G., et al. (2010). Recurrent and founder mutations in the Netherlands: extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation. Netherlands Heart Journal, 18, 85–89.PubMedCrossRefGoogle Scholar
  12. 12.
    Pyeritz, R. E., & Wappel, M. A. (1983). Mitral valve dysfunction in the Marfan syndrome. Clinical and echocardiographic study of prevalence and natural history. The American Journal of Medicine, 74, 797–807.PubMedCrossRefGoogle Scholar
  13. 13.
    Taub, C. C., Stoler, J. M., Perez-Sanz, T., et al. (2008). Mitral valve prolapse in Marfan syndrome: an old topic revisited. Echocardiography, 26(4), 357–364.PubMedCrossRefGoogle Scholar
  14. 14.
    Detaint, D., Faivre, L., Collod-Beroud, G., et al. (2010). Cardiovascular manifestations in men and women carrying a FBN1 mutation. European Heart Journal, 31, 2223–2229.PubMedCrossRefGoogle Scholar
  15. 15.
    Morse, R. P., Rockenmacher, S., Pyeritz, R. E., et al. (1990). Diagnosis and management of infantile Marfan syndrome. Pediatrics, 86, 888–895.PubMedGoogle Scholar
  16. 16.
    Sisk, H. E., Zahka, K. G., & Pyeritz, R. E. (1983). The Marfan syndrome in early childhood: analysis of 15 patients diagnosed at less than 4 years of age. The American Journal of Cardiology, 52, 353–358.PubMedCrossRefGoogle Scholar
  17. 17.
    Faivre, L., Masurel-Paulet, A., Collod-Beroud, G., et al. (2009). Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations. Pediatrics, 123, 391–398.PubMedCrossRefGoogle Scholar
  18. 18.
    Freed, L. A., Levy, D., Levine, R. A., et al. (1999). Prevalence and clinical outcome of mitral-valve prolapse. The New England Journal of Medicine, 341, 1–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Levine, R., Triulzi, M., Harrigan, P., & Weyman, A. (1987). The relationship of mitral annular shape to the diagnosis of mitral valve prolapse. Circulation, 75, 756–767.PubMedCrossRefGoogle Scholar
  20. 20.
    Disse, S., Abergel, E., Berrebi, A., et al. (1999). Mapping of a first locus for autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2-p12.1. American Journal of Human Genetics, 65, 1242–1251.PubMedCrossRefGoogle Scholar
  21. 21.
    Freed, L. A., Acierno, J. S., Jr., Dai, D., et al. (2003). A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4. American Journal of Human Genetics, 72, 1551–1559.PubMedCrossRefGoogle Scholar
  22. 22.
    Nesta, F., Leyne, M., Yosefy, C., et al. (2005). New locus for autosomal dominant mitral valve prolapse on chromosome 13: clinical insights from genetic studies. Circulation, 112, 2022–2030.PubMedCrossRefGoogle Scholar
  23. 23.
    Shi, Y., & Massague, J. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 113, 685–700.PubMedCrossRefGoogle Scholar
  24. 24.
    Massam-Wu, T., Chiu, M., Choudhury, R., et al. (2010). Assembly of fibrillin microfibrils governs extracellular deposition of latent TGF beta. Journal of Cell Science, 123, 3006–3018.PubMedCrossRefGoogle Scholar
  25. 25.
    Isogai, Z., Ono, R. N., Ushiro, S., et al. (2003). Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. Journal of Biological Chemistry, 278, 2750–2757.PubMedCrossRefGoogle Scholar
  26. 26.
    Judge, D. P., Biery, N. J., Keene, D. R., et al. (2004). Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. The Journal of Clinical Investigation, 114, 172–181.PubMedGoogle Scholar
  27. 27.
    Ng, C. M., Cheng, A., Myers, L. A., et al. (2004). TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. The Journal of Clinical Investigation, 114, 1586–1592.PubMedGoogle Scholar
  28. 28.
    Neptune, E. R., Frischmeyer, P. A., Arking, D. E., et al. (2003). Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nature Genetics, 33, 407–411.PubMedCrossRefGoogle Scholar
  29. 29.
    Habashi, J. P., Judge, D. P., Holm, T. M., et al. (2006). Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science, 312, 117–121.PubMedCrossRefGoogle Scholar
  30. 30.
    Cohn, R. D., van Erp, C., Habashi, J. P., et al. (2007). Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nature Medicine, 13, 204–210.PubMedCrossRefGoogle Scholar
  31. 31.
    Jones, K. B., Myers, L., Judge, D. P., Kirby, P. A., Dietz, H. C., & Sponseller, P. D. (2005). Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome. Spine, 30, 291–293.PubMedCrossRefGoogle Scholar
  32. 32.
    Rodriguez-Vita, J., Sanchez-Lopez, E., Esteban, V., Ruperez, M., Egido, J., & Ruiz-Ortega, M. (2005). Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism. Circulation, 111, 2509–2517.PubMedCrossRefGoogle Scholar
  33. 33.
    Lacro, R. V., Dietz, H. C., Wruck, L. M., et al. (2007). Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. American Heart Journal, 154, 624–631.PubMedCrossRefGoogle Scholar
  34. 34.
    Helin, K., Stoll, M., Meffert, S., Stroth, U., & Unger, T. (1997). The role of angiotensin receptors in cardiovascular diseases. Annals of Medicine, 29, 23–29.PubMedCrossRefGoogle Scholar
  35. 35.
    Shafiq, M. M., Menon, D. V., & Victor, R. G. (2008). Oral direct renin inhibition: premise, promise, and potential limitations of a new antihypertensive drug. The American Journal of Medicine, 121, 265–271.PubMedCrossRefGoogle Scholar
  36. 36.
    Pitt, B., Poole-Wilson, P. A., Segal, R., et al. (2000). Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet, 355, 1582–1587.PubMedCrossRefGoogle Scholar
  37. 37.
    Barnett, A. H., Bain, S. C., Bouter, P., et al. (2004). Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. The New England Journal of Medicine, 351, 1952–1961.PubMedCrossRefGoogle Scholar
  38. 38.
    Jones, E. S., Black, M. J., & Widdop, R. E. (2004). Angiotensin AT2 receptor contributes to cardiovascular remodelling of aged rats during chronic AT1 receptor blockade. Journal of Molecular and Cellular Cardiology, 37, 1023–1030.PubMedCrossRefGoogle Scholar
  39. 39.
    Daugherty, A., Manning, M. W., & Cassis, L. A. (2001). Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. British Journal of Pharmacology, 134, 865–870.PubMedCrossRefGoogle Scholar
  40. 40.
    Nagashima, H., Sakomura, Y., Aoka, Y., et al. (2001). Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan's syndrome. Circulation, 104, I282–I287.PubMedCrossRefGoogle Scholar
  41. 41.
    Nagashima, H., Uto, K., Sakomura, Y., et al. (2002). An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. Journal of Vascular Surgery, 36, 818–823.PubMedGoogle Scholar
  42. 42.
    Habashi, J. P., Doyle, J. J., Holm, T. M., et al. (2011). Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science, 332, 361–365.PubMedCrossRefGoogle Scholar
  43. 43.
    Siragy, H. M., Inagami, T., Ichiki, T., & Carey, R. M. (1999). Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proceedings of the National Academy of Sciences of the United States of America, 96, 6506–6510.PubMedCrossRefGoogle Scholar
  44. 44.
    Gu, X., & Masters, K. S. (2009). Role of the MAPK/ERK pathway in valvular interstitial cell calcification. American Journal of Physiology—Heart and Circulatory Physiology, 296, H1748–H1757.PubMedCrossRefGoogle Scholar
  45. 45.
    Xu, J., Jian, B., Chu, R., et al. (2002). Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. American Journal of Pathology, 161, 2209–2218.PubMedCrossRefGoogle Scholar
  46. 46.
    Loeys, B. L., Chen, J., Neptune, E. R., et al. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics, 37, 275–281.PubMedCrossRefGoogle Scholar
  47. 47.
    Loeys, B. L., Schwarze, U., Holm, T., et al. (2006). Aneurysm syndromes caused by mutations in the TGF-beta receptor. The New England Journal of Medicine, 355, 788–798.PubMedCrossRefGoogle Scholar
  48. 48.
    Attias, D., Stheneur, C., Roy, C., et al. (2009). Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation, 120, 2541–2549.PubMedCrossRefGoogle Scholar
  49. 49.
    van de Laar, I. M., Oldenburg, R. A., Pals, G., et al. (2011). Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nature Genetics, 43, 121–126.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Daniel P. Judge
    • 1
    • 2
  • Rosanne Rouf
    • 1
  • Jennifer Habashi
    • 3
    • 4
  • Harry C. Dietz
    • 4
    • 5
  1. 1.Division of CardiologyJohns Hopkins UniversityBaltimoreUSA
  2. 2.Université Paris-DescartesSorbonne Paris CitéParisFrance
  3. 3.Division of Pediatric CardiologyJohns Hopkins UniversityBaltimoreUSA
  4. 4.McKusick-Nathans Institute of Genetic MedicineJohns Hopkins UniversityBaltimoreUSA
  5. 5.Howard Hughes Medical InstituteChevy ChaseUSA

Personalised recommendations