Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapy Insight: aortic aneurysm and dissection in Marfan's syndrome

Nature Clinical Practice Cardiovascular Medicine volume 1, pages 31–36 (2004)Cite this article

Abstract

Aortic dissection and aneurysm are common clinical problems with life-threatening consequences; they are also the hallmark of several genetic diseases, including Marfan's syndrome (MFS). In spite of clinical and surgical advances that have increased life expectancy for affected patients, cardiovascular manifestations remain significant contributors to morbidity and mortality in MFS. Dissecting aortic aneurysm in this disorder is accounted for by mutations in fibrillin-1, the major component of the microfibrils associated with elastin in the elastic fibers of the aortic media. Genetic studies of human patients and murine models have yielded invaluable insights into the pathophysiology of aneurysm formation and progression in MFS. They have also revealed a previously unappreciated role of microfibrils in regulating transforming growth factor and bone morphogenetic protein signaling. As a result, exciting new hypotheses have emerged regarding the pathogenesis of MFS, as well as opportunities to explore translational applications of this information that may be relevant to various manifestations of the disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Thompson RW et al. (2002) Abdominal aortic aneurysms: basic mechanisms and clinical implications. Curr Probl Surg 39: 110–232

    Article  Google Scholar 

  2. Pyeritz RE (1997) Marfan syndrome and other disorders of fibrillin. In Principles and Practice of Medical Genetics (3 vols), 1027–1066 (Eds DL Rimoin et al.) New York: Churchill Livingstone

    Google Scholar 

  3. Murdoch JL et al. (1972) Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 285: 804–808

    Article  Google Scholar 

  4. Silverman DI et al. (1995) Life expectancy in the Marfan syndrome. Am J Cardiol 75: 157–160

    Article  CAS  Google Scholar 

  5. Shores J et al. (1994) Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome. N Engl J Med 12: 1335–1341

    Article  Google Scholar 

  6. Salim MA et al. (1994) Effect of β-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome. Am J Cardiol 74: 629–633

    Article  CAS  Google Scholar 

  7. Haouzi A et al. (1997) Heterogeneous aortic response to acute β-adrenergic blockade in Marfan syndrome. Am Heart J 133: 60–63

    Article  CAS  Google Scholar 

  8. Rossi-Foulkes R et al. (1999) Phenotypic features and impact of β blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am J Cardiol 83: 1364–1368

    Article  CAS  Google Scholar 

  9. Rios AS et al. (1999) Effect of long-term β-blockade on aortic root compliance in patients with Marfan syndrome. Am Heart J 137: 1057–1061

    Article  CAS  Google Scholar 

  10. Morse RP et al. (1990) Diagnosis and management of infantile Marfan syndrome. Pediatrics 86: 888–895

    CAS  PubMed  Google Scholar 

  11. Bentall HH and DeBono AA (1968) A technique for complete replacement of the ascending aorta. Thorax 23: 338–339

    Article  CAS  Google Scholar 

  12. Gott VL et al. (1991) Composite graft repair of Marfan aneurysm of the ascending aorta: results in 100 patients. Ann Thorac Surg 52: 38–45

    Article  CAS  Google Scholar 

  13. David TE et al. (2001) Results of aortic valve-sparing operations. J Thorac Cardiovasc Surg 122: 39–46

    Article  CAS  Google Scholar 

  14. David TE et al. (2002) Aortic valve-sparing operations in patients with aneurysms of the aortic root or ascending aorta. Ann Thorac Surg 74: S1758–1761

    Article  Google Scholar 

  15. Karck et al. (2004) Aortic root surgery in Marfan syndrome: comparison of aortic valve-sparing reimplantation versus composite grafting. J Thorac Cardiovasc Surg 127: 391–398

    Article  Google Scholar 

  16. Cattaneo et al. (2004) Surgery for aortic root aneurysm in children: a 21-year experience in 50 patients. Ann Thorac Surg 77: 168–176

    Article  Google Scholar 

  17. Luciani et al. (2003) Fate of the aortic root late after Ross operation. Circulation 108 (Suppl 1): II61–II67

    PubMed  Google Scholar 

  18. Sisk HE et al. (1983) The Marfan syndrome in early childhood: analysis of 15 patients diagnosed at less than 4 years of age. Am J Cardiol 52: 353–358

    Article  CAS  Google Scholar 

  19. Gillinov AM et al. (1997) Cardiac operations in children with Marfan's syndrome: indications and results. Ann Thorac Surg 64: 1144–1145

    Article  Google Scholar 

  20. Silverman DI et al. (1995) Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival. J Am Coll Cardiol 26: 1062–1067

    Article  CAS  Google Scholar 

  21. Gott VL et al. (1999) Replacement of the aortic root in patients with Marfan's syndrome. N Engl J Med 340: 1307–1313

    Article  CAS  Google Scholar 

  22. Finkbohner R et al. (1995) Marfan syndrome: long-term survival and complications after aortic aneurysm repair. Circulation 91: 728–733

    Article  CAS  Google Scholar 

  23. Abraham PA et al. (1982) Marfan syndrome: demonstration of abnormal elastin in aorta. J Clin Invest 70: 1245–1252

    Article  CAS  Google Scholar 

  24. Dietz HC et al. (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352: 337–339

    Article  CAS  Google Scholar 

  25. Handford PA et al. (2000) Fibrillin: from domain structure to supramolecular assembly. Matrix Biol 19: 457–470

    Article  CAS  Google Scholar 

  26. Mizuguchi T et al. (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36: 855–860

    Article  CAS  Google Scholar 

  27. Putnam EA et al. (1995) Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 11: 456–458

    Article  CAS  Google Scholar 

  28. Sakai LY et al. (1986) Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 103: 2499–2509

    Article  CAS  Google Scholar 

  29. Isogai Z et al. (2003) Latent transforming growth factor β-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem 278: 2750–2757

    Article  CAS  Google Scholar 

  30. Rosenbloom J et al. (1993) Extracellular matrix 4: the elastic fiber. FASEB J 7: 1208–1218

    Article  CAS  Google Scholar 

  31. Brooke BS et al. (2003) Extracellular matrix in vascular morphogenesis and disease: structure versus signal. Trends Cell Biol 13: 51–56

    Article  CAS  Google Scholar 

  32. Faury G (2001) Function-structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibres. Pathol Biol 49: 310–325

    Article  CAS  Google Scholar 

  33. Collod-Beroud G et al. (2003) Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 22: 199–208

    Article  CAS  Google Scholar 

  34. Dietz HC and Mecham RP (2000) Mouse models of genetic diseases resulting from mutations in elastic fiber proteins. Matrix Biol 19: 481–488

    Article  CAS  Google Scholar 

  35. Pereira L et al. (1999) Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 96: 3819–3823

    Article  CAS  Google Scholar 

  36. Bunton TE et al. (2001) Phenotypic modulation of vascular smooth muscle cells contributes to elastolysis in a mouse model of Marfan syndrome. Circ Res 88: 37–43

    Article  CAS  Google Scholar 

  37. Pereira L et al. (1997) Targeting of the gene coding fibrillin-1 recapitulates the vascular phenotype of Marfan syndrome in the mouse. Nat Genet 17: 218–222

    Article  CAS  Google Scholar 

  38. Judge DP et al. (2004) Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 114: 172–181

    Article  CAS  Google Scholar 

  39. Ramirez F and Rifkin D (2003) Cell signaling events: a view from the matrix. Matrix Biol 22: 101–107

    Article  CAS  Google Scholar 

  40. Neptune ER et al. (2003) Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33: 407–411

    Article  CAS  Google Scholar 

  41. Annes JP et al. (2003) Making sense of latent TGF-β activation. J Cell Sci 142: 13–27

    Google Scholar 

  42. Arteaga-Solis E et al. (2001) Regulation of limb patterning by extracellular microfibrils. J Cell Biol 154: 275–281

    Article  CAS  Google Scholar 

  43. Sterner-Kock A et al. (2002) Disruption of the gene encoding the latent transforming growth factor-β binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev 16: 2264–2272

    Article  CAS  Google Scholar 

  44. Vaughan CJ et al. (2001) Identification of a chromosome 11q.23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogenous disorder. Circulation 103: 2469–2475

    Article  CAS  Google Scholar 

  45. Kako S et al. (2003) Candidate locus analysis of familial ascending aortic aneurysms and dissections confirms the linkage to the chromosome 5q13-14 in Finnish families. J Thorac Cardiovasc Surg 126: 106–113

    Article  Google Scholar 

  46. Hasham SN et al. (2003) Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24-25. Circulation 107: 3184–3190

    Article  Google Scholar 

Download references

Acknowledgements

Grants: NIH, Howard Hughes Medical Institute, and St Giles, Smilow, and National Marfan Foundations. Karen Johnson prepared the manuscript.

Author information

Authors and Affiliations

  1. Chief Scientific Officer and Director of the Laboratory of Genetics and Organogenesis, Hospital for Special Surgery, New York, NY, USA

    Francesco Ramirez

  2. the Victor A McKusick Professor of Department of Pediatrics, Medicine and Genetics, McKusick-Nathans Institute of Genetic Medicine and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD, USA

    Harry C Dietz

Authors
  1. Francesco Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harry C Dietz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Ramirez.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ramirez, F., Dietz, H. Therapy Insight: aortic aneurysm and dissection in Marfan's syndrome. Nat Rev Cardiol 1, 31–36 (2004). https://doi.org/10.1038/ncpcardio0020

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio0020

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing