Skip to main content

Advertisement

SpringerLink
Log in

Mitral Valve Disease in Marfan Syndrome and Related Disorders

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  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. Marfan, A.-B. (1938). La dolichosténomélie [dolichomélie arachnodactylie]. Annals of Medicine, 44, 5–29.

    Google Scholar 

  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. McKusick, V. A. (1955). The cardiovascular aspects of Marfan's syndrome. Circulation, 11, 321.

    PubMed  CAS  Google Scholar 

  5. Bowers, D. (1969). Pathogenesis of primary abnormalities of the mitral valve in Marfan's syndrome. British Heart Journal, 31, 679–683.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  15. Morse, R. P., Rockenmacher, S., Pyeritz, R. E., et al. (1990). Diagnosis and management of infantile Marfan syndrome. Pediatrics, 86, 888–895.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  23. Shi, Y., & Massague, J. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 113, 685–700.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge support from the Fondation Leducq, the W.W. Smith Charitable Trust, the Smilow Center for Marfan Syndrome Research, the National Marfan Foundation, the Howard Hughes Medical Institute, and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Cardiology, Johns Hopkins University, Ross 1049 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Daniel P. Judge & Rosanne Rouf

  2. Université Paris-Descartes, Sorbonne Paris Cité, Paris, France

    Daniel P. Judge

  3. Division of Pediatric Cardiology, Johns Hopkins University, Baltimore, MD, USA

    Jennifer Habashi

  4. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    Jennifer Habashi & Harry C. Dietz

  5. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Harry C. Dietz

Authors
  1. Daniel P. Judge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosanne Rouf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer Habashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harry C. Dietz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel P. Judge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Judge, D.P., Rouf, R., Habashi, J. et al. Mitral Valve Disease in Marfan Syndrome and Related Disorders. J. of Cardiovasc. Trans. Res. 4, 741–747 (2011). https://doi.org/10.1007/s12265-011-9314-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-011-9314-y

Keywords

Search

Navigation