Cardiovascular Manifestations of Marfan and Loeys-Dietz Syndrome

  • Florian S. SchoenhoffEmail author
  • Thierry P. Carrel


The last decade has seen an increasing awareness for patients with connective disorders and patients with Marfan syndrome (MFS) in particular. MFS has long been the only seriously considered differential diagnosis in young patients presenting with aortic aneurysms. The advent of multi-gene panel genetic testing and the discovery of new syndromic forms of connective tissue disorders such as Loeys-Dietz syndrome (LDS) as well as many forms of non-syndromic presentations have established thoracic aortic aneurysms as a genetically mediated disease. Although the spectrum has broadened, MFS still serves as a model for connective tissue disorders with vascular involvement. The vast majority of MFS patients develop aortic root aneurysms over time. Most MFS patients undergo root surgery in their early 30s. As patients with LDS patients may dissect below the accepted threshold for surgery in MFS patients, earlier intervention is recommended. The need for re-intervention in these patients is driven by a history of aortic dissection and prevention of dissection is of paramount importance.

MFS patients frequently exhibit anomalies of the mitral valve including thickening of the leaflets, excessive leaflet tissue but also structural deformations of the valvular and subvalvular apparatus. In children with a severe form of MFS, the mitral valve is the major cause of morbidity and mortality. Arterial tortuousity was one of the key features when LDS was initially described. Patients frequently present with marked tortuosity or even aneurysms of the supra-aortic branches. But the risk of rupture or dissection and the subsequent need for prophylactic intervention has not yet been determined. This chapter provides an overview of cardiovascular manifestations of MFS and LDS.


Aneurysm Dissection Fibrillin-1 Loeys-Dietz syndrome Marfan syndrome 


  1. 1.
    Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collée M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Cameron DE, Alejo DE, Patel ND, Nwakanma LU, Weiss ES, Vricella LA, Dietz HC, Spevak PJ, Williams JA, Bethea BT, Fitton TP, Gott VL. Aortic root replacement in 372 Marfan patients: evolution of operative repair over 30 years. Ann Thorac Surg. 2009;87:1344–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwöger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ, ESC Committee for Practice Guidelines. ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;35:2873–926.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease. Circulation. 2010;121:266–369.Google Scholar
  7. 7.
    Williams JA, Loeys BL, Nwakanma LU, Dietz HC, Spevak PJ, Patel ND, François K, DeBacker J, Gott VL, Vricella LA, Cameron DE. Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. Ann Thorac Surg. 2007;83:S757–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Patel ND, Arnaoutakis GJ, George TJ, Allen JG, Alejo DE, Dietz HC, Cameron DE, Vricella LA. Valve-sparing aortic root replacement in Loeys-Dietz syndrome. Ann Thorac Surg. 2011;92:556–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Schoenhoff FS, Mueller C, Czerny M, Matyas G, Kadner A, Schmidli J, Carrel T. Outcome of aortic surgery in patients with Loeys-Dietz syndrome primarily treated as having Marfan syndrome. Eur J Cardiothorac Surg. 2014;46:444–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Attias D, Stheneur C, Roy C, Collod-Béroud G, Detaint D, Faivre L, Delrue MA, Cohen L, Francannet C, Béroud C, Claustres M, Iserin F, Khau Van Kien P, Lacombe D, Le Merrer M, Lyonnet S, Odent S, Plauchu H, Rio M, Rossi A, Sidi D, Steg PG, Ravaud P, Boileau C, Jondeau G. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation. 2009;120:2541–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Rienhoff HY Jr, Yeo CY, Morissette R, Khrebtukova I, Melnick J, Luo S, Leng N, Kim YJ, Schroth G, Westwick J, Vogel H, McDonnell N, Hall JG, Whitman M. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am J Med Genet A. 2013;161:2040–6.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Wischmeijer A, Van Laer L, Tortora G, Bolar NA, Van Camp G, Fransen E, Peeters N, Di Bartolomeo R, Pacini D, Gargiulo G, Turci S, Bonvicini M, Mariucci E, Lovato L, Brusori S, Ritelli M, Colombi M, Garavelli L, Seri M, Loeys BL. Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. Am J Med Genet A. 2013;161:1028–35.CrossRefGoogle Scholar
  13. 13.
    Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, Bjeda D, Oswald G, Elias AF, Levy HP, Anderlid BM, Yang MH, Bongers EM, Timmermans J, Braverman AC, Canham N, Mortier GR, Brunner HG, Byers PH, Van Eyk J, Van Laer L, Dietz HC, Loeys BL. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44:922–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Finkbohner R, Johnston D, Crawford ES, Coselli J, Milewicz DM. Marfan syndrome. Long-term survival and complications after aortic aneurysm repair. Circulation. 1995;91:728–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, Dietz HC, Vricella LA, Cameron DE. Long-term outcomes of aortic root operations for Marfan syndrome: a comparison of Bentall versus aortic valve-sparing procedures. J Thorac Cardiovasc Surg. 2016;151:330–6.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    David TE, Armstrong S, Maganti M, Colman J, Bradley TJ. Long-term results of aortic valve-sparing operations in patients with Marfan syndrome. J Thorac Cardiovasc Surg. 2009;138:859–64.PubMedCrossRefGoogle Scholar
  17. 17.
    Coselli JS, Volguina IV, LeMaire SA, Sundt TM, Connolly HM, Stephens EH, Schaff HV, Milewicz DM, Vricella LA, Dietz HC, Minard CG, Miller DC, Aortic Valve Operative Outcomes in Marfan Patients Study Group. Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: a prospective, multicenter, comparative study. J Thorac Cardiovasc Surg. 2014;147:1758–66.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Schoenhoff FS, Langhammer B, Wustmann K, Reineke D, Kadner A, Carrel T. Decision-making in aortic root surgery in Marfan syndrome: bleeding, thromboembolism and risk of reintervention after valve-sparing or mechanical aortic root replacement. Eur J Cardiothorac Surg. 2015;48:931–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Benedetto U, Melina G, Takkenberg JJ, Roscitano A, Angeloni E, Sinatra R. Surgical management of aortic root disease in Marfan syndrome: a systematic review and meta-analysis. Heart. 2011;97:955–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Gott VL, Greene PS, Alejo DE, Cameron DE, Naftel DC, Miller DC, Gillinov AM, Laschinger JC, Pyeritz RE. Replacement of the aortic root in patients with Marfan’s syndrome. N Engl J Med. 1999;340:1307–13.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Milewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients with Marfan syndrome. Circulation. 2005;111:150–7.CrossRefGoogle Scholar
  22. 22.
    Schoenhoff FS, Jungi S, Czerny M, Roost E, Reineke D, Matyas G, Steinmann B, Schmidli J, Kadner A, Carrel T. Acute aortic dissection determines the fate of initially untreated aortic segments in Marfan syndrome. Circulation. 2013;16:1569–75.CrossRefGoogle Scholar
  23. 23.
    Sun L, Li M, Zhu J, Liu Y, Chang Q, Zheng J, Qi R. Surgery for patients with Marfan syndrome with type A dissection involving the aortic arch using total arch replacement combined with stented elephant trunk implantation: the acute versus the chronic. J Thorac Cardiovasc Surg. 2011;142:e85–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Nordon IM, Hinchliffe RJ, Holt PJ, Morgan R, Jahangiri M, Loftus IM, Thompson MM. Endovascular management of chronic aortic dissection in patients with Marfan syndrome. J Vasc Surg. 2009;50:987–91.PubMedCrossRefGoogle Scholar
  25. 25.
    Bachet J, Larrazet F, Goudot B, Dreyfus G, Folliguet T, Laborde F, Guilmet D. When should the aortic arch be replaced in Marfan patients? Ann Thorac Surg. 2007;83:S774–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Schoenhoff F, Kadner A, Czerny M, Jungi S, Meszaros K, Schmidli J, Carrel T. Should aortic arch replacement be performed during initial surgery for aortic root aneurysm in patients with Marfan syndrome? Eur J Cardiothorac Surg. 2013;44:346–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Rylski B, Bavaria JE, Beyersdorf F, Branchetti E, Desai ND, Milewski RK, Szeto WY, Vallabhajosyula P, Siepe M, Kari FA. Type A aortic dissection in Marfan syndrome: extent of initial surgery determines long-term outcome. Circulation. 2014;129:1381–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Mimoun L, Detaint D, Hamroun D, Arnoult F, Delorme G, Gautier M, Milleron O, Meuleman C, Raoux F, Boileau C, Vahanian A, Jondeau G. Dissection in Marfan syndrome: the importance of the descending aorta. Eur Heart J. 2011;32:443–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Girdauskas E, Kuntze T, Borger MA, Falk V, Mohr FW. Distal aortic reinterventions after root surgery in Marfan patients. Ann Thorac Surg. 2008;86:1815–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Schoenhoff FS, Alejo D, Black JH, Crawford TC, Dietz HC, Grimm JC, Magruder JT, Patel ND, Vricella LA, Young A, Carrel TP, Cameron DE. The Griepp paper – management of the aortic arch in Loeys-Dietz syndrome. AATS aortic symposium 2016, New York City.Google Scholar
  31. 31.
    Pyeritz RE, Gasner C. The Marfan syndrome. 5th ed. Houston, TX: Baylor College of Medicine; 2001.Google Scholar
  32. 32.
    Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366:1965–76.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Judge DP, Rouf R, Habashi J, Dietz HC. Mitral valve disease in Marfan syndrome and related disorders. J Cardiovasc Transl Res. 2011;4:741–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Durbin AD, Gotlieb AI. Advances towards understanding heart valve response to injury. Cardiovasc Pathol. 2002;11:69–77.PubMedCrossRefGoogle Scholar
  35. 35.
    Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D, Gabrielson KL, Hausladen JM, Mecham RP, Judge DP, Dietz HC. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004;114:1586–92.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Geirsson A, Singh M, Ali R, Abbas H, Li W, Sanchez JA, Hashim S, Tellides G. Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers. Circulation. 2012;126:S189–97.PubMedCrossRefGoogle Scholar
  37. 37.
    Morse RP, Rockenmacher S, Pyeritz RE, Sanders SP, Bieber FR, Lin A, MacLeod P, Hall B, Graham JM Jr. Diagnosis and management of infantile Marfan syndrome. Pediatrics. 1990;86:888–95.PubMedGoogle Scholar
  38. 38.
    Sisk HE, Zahka KG, Pyeritz RE. The Marfan syndrome in early childhood: analysis of 15 patients diagnosed at less than 4 years of age. Am J Cardiol. 1983;52:353–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Krohg-Sørensen K, Lingaas PS, Lundblad R, Seem E, Paus B, Geiran OR. Cardiovascular surgery in Loeys-Dietz syndrome types 1–4. Eur J Cardiothorac Surg. 2017;52:1125–31.PubMedCrossRefGoogle Scholar
  40. 40.
    Pyeritz R, Wappel M. Mitral valve dysfunction in the Marfan syndrome. Clinical and echocardiographic study of prevalence and natural history. Am J Med. 1983;74:797–807.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Taub CC, Stoler JM, Perez-Sanz T, Chu J, Isselbacher EM, Picard MH, Weyman AE. Mitral valve prolapse in Marfan syndrome: an old topic revisited. Echocardiography. 2009;26:357–64.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Fuzellier JF, Chauvaud SM, Fornes P, Berrebi AJ, Lajos PS, Bruneval P, Carpentier AF. Surgical management of mitral regurgitation associated with Marfan’s syndrome. Ann Thorac Surg. 1998;66:68–72.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Jouan J, Berrebi A, Chauvaud S, Menasché P, Carpentier A, Fabiani JN. Mitral valve reconstruction in Barlow disease: long-term echographic results and implications for surgical management. J Thorac Cardiovasc Surg. 2012;143:S17–20.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Rybczynski M, Treede H, Sheikhzadeh S, Groene EF, Bernhardt AM, Hillebrand M, Mir TS, Kühne K, Koschyk D, Robinson PN, Berger J, Reichenspurner H, Meinertz T, von Kodolitsch Y. Predictors of outcome of mitral valve prolapse in patients with the Marfan syndrome. Am J Cardiol. 2011;107:268–74.PubMedCrossRefGoogle Scholar
  45. 45.
    Gillinov AM, Hulyalkar A, Cameron DE, Cho PW, Greene PS, Reitz BA, Pyeritz RE, Gott VL. Mitral valve operation in patients with the Marfan syndrome. J Thorac Cardiovasc Surg. 1994;107:724–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Meijboom LJ, Timmermans J, van Tintelen JP, Nollen GJ, De Backer J, van den Berg MP, Boers GH, Mulder BJ. Evaluation of left ventricular dimensions and function in Marfan’s syndrome without significant valvular regurgitation. Am J Cardiol. 2005;95:795–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Hetzer R, Siegel G, Delmo Walter EM. Cardiomyopathy in Marfan syndrome. Eur J Cardiothorac Surg. 2016;49:561–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Rodrigues VJ, Elsayed S, Loeys BL, Dietz HC, Yousem DM. Neuroradiologic manifestations of Loeys-Dietz syndrome type 1. AJNR Am J Neuroradiol. 2009;30:1614–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim ST, Brinjikji W, Kallmes DF. Prevalence of intracranial aneurysms in patients with connective tissue diseases: a retrospective study. AJNR Am J Neuroradiol. 2016;37:1422–6.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Cardiovascular SurgeryUniversity Hospital BernBernSwitzerland

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