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New insights into the pathogenesis and treatment of arterial aneurysms and dissections

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Abstract

Aortic aneurysm and dissection (AAD) is a common cause of morbidity and death in the Western world. Over the last decade tremendous progress has been made in the identification of the genetic basis of aortic aneurysm syndromes. The study of rare monogenic syndromic forms of AAD can provide insights in the pathways underlying the more common nonsyndromic forms of AAD. In this paper, we describe the syndromic and nonsyndromic forms of aortic aneurysm and review the current knowledge of clinical presentation, genetic basis, pathogenesis, management, and new emerging treatment strategies.

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References and Recommended Reading

  1. Milewicz DM, Michael K, Fisher N, et al.: Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation 1996, 94:2708–2711.

    PubMed  CAS  Google Scholar 

  2. Roman MJ, Devereux RB, Kramer-Fox R, O’Loughlin J: Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol 1989, 64:507–512.

    Article  PubMed  CAS  Google Scholar 

  3. Johnston KW, Rutherford RB, Tilson MD, et al.: Suggested standards for reporting on arterial aneurysms. Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg 1991, 13:452–458.

    Article  PubMed  CAS  Google Scholar 

  4. Coady MA, Davies RR, Roberts M, et al.: Familial patterns of thoracic aortic aneurysms. Arch Surg 1999, 134:361–367.

    Article  PubMed  CAS  Google Scholar 

  5. De Paepe A, Devereux RB, Dietz HC, et al.: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996, 62:417–426.

    Article  PubMed  Google Scholar 

  6. Silverman DI, Burton KJ, Gray J, et al.: Life expectancy in the Marfan syndrome. Am J Cardiol 1995, 75:157–160.

    Article  PubMed  CAS  Google Scholar 

  7. Loeys B, De Backer J, Van Acker P, et al.: Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat 2004, 24:140–146.

    Article  PubMed  CAS  Google Scholar 

  8. Loeys B, Nuytinck L, Delvaux I, et al.: Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med 2001, 161:2447–2454.

    Article  PubMed  CAS  Google Scholar 

  9. Robinson PN, Arteaga-Solis E, Baldock C, et al.: The molecular genetics of Marfan syndrome and related disorders. J Med Genet 2006, 43:769–787.

    Article  PubMed  CAS  Google Scholar 

  10. Robinson PN, Godfrey M: The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 2000, 37:9–25.

    Article  PubMed  CAS  Google Scholar 

  11. Cohn RD, van Erp C, Habashi JP, et al.: Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 2007, 13:204–210.

    Article  PubMed  CAS  Google Scholar 

  12. Habashi JP, Judge DP, Holm TM, et al.: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006, 312:117–121.

    Article  PubMed  CAS  Google Scholar 

  13. Neptune ER, Frischmeyer PA, Arking DE, et al.: Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003, 33:407–411.

    Article  PubMed  CAS  Google Scholar 

  14. Mizuguchi T, Collod-Beroud G, Akiyama T, et al.: Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 2004, 36:855–860.

    Article  PubMed  CAS  Google Scholar 

  15. Loeys BL, Chen J, Neptune ER, et al.: A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005, 37:275–281.

    Article  PubMed  CAS  Google Scholar 

  16. Loeys BL, Schwarze U, Holm T, et al.: Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006, 355:788–798.

    Article  PubMed  CAS  Google Scholar 

  17. Williams JA, Loeys BL, Nwakanma LU, et al.: Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. Ann Thorac Surg 2007, 83:S757–S763; discussion S785–S790.

    Article  PubMed  Google Scholar 

  18. Wenstrup RJ, Meyer RA, Lyle JS, et al.: Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 2002, 4:112–117.

    Article  PubMed  Google Scholar 

  19. Malfait F, Symoens S, De Backer J, et al.: Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat 2007, 28:387–395.

    Article  PubMed  CAS  Google Scholar 

  20. Wenstrup RJ, Murad S, Pinnell SR: Ehlers-Danlos syndrome type VI: clinical manifestations of collagen lysyl hydroxylase deficiency. J Pediatr 1989, 115:405–409.

    Article  PubMed  CAS  Google Scholar 

  21. Szabo Z, Crepeau MW, Mitchell AL, et al.: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet 2006, 43:255–258.

    Article  PubMed  CAS  Google Scholar 

  22. Markova D, Zou Y, Ringpfeil F, et al.: Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet 2003, 72:998–1004.

    Article  PubMed  CAS  Google Scholar 

  23. Tassabehji M, Metcalfe K, Hurst J, et al.: An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa. Hum Mol Genet 1998, 7:1021–1028.

    Article  PubMed  CAS  Google Scholar 

  24. Hucthagowder V, Sausgruber N, Kim KH, et al.: Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet 2006, 78:1075–1080.

    Article  PubMed  CAS  Google Scholar 

  25. Loeys B, Van Maldergem L, Mortier G, et al.: Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet 2002, 11:2113–2118.

    Article  PubMed  CAS  Google Scholar 

  26. Wessels MW, Catsman-Berrevoets CE, Mancini GM, et al.: Three new families with arterial tortuosity syndrome. Am J Med Genet A 2004, 131:134–143.

    Article  PubMed  Google Scholar 

  27. Coucke PJ, Willaert A, Wessels MW, et al.: Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet 2006, 38:452–457.

    Article  PubMed  CAS  Google Scholar 

  28. Gupta PA, Wallis DD, Chin TO, et al.: FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly. J Med Genet 2004, 41:e56.

    Article  PubMed  CAS  Google Scholar 

  29. Lin AE, Lippe BM, Geffner ME, et al.: Aortic dilation, dissection, and rupture in patients with Turner syndrome. J Pediatr 1986, 109:820–826.

    Article  PubMed  CAS  Google Scholar 

  30. Power PD, Lewin MB, Hannibal MC, Glass IA: Aortic root dilatation is a rare complication of Noonan syndrome. Pediatr Cardiol 2006, 27:478–480.

    Article  PubMed  Google Scholar 

  31. Somlo S, Rutecki G, Giuffra LA, et al.: A kindred exhibiting cosegregation of an overlap connective tissue disorder and the chromosome 16 linked form of autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1993, 4:1371–1378.

    PubMed  CAS  Google Scholar 

  32. Larson EW, Edwards WD: Risk factors for aortic dissection: a necropsy study of 161 cases. Am J Cardiol 1984, 53:849–855.

    Article  PubMed  CAS  Google Scholar 

  33. Huntington K, Hunter AG, Chan KL: A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol 1997, 30:1809–1812.

    Article  PubMed  CAS  Google Scholar 

  34. Nkomo VT, Enriquez-Sarano M, Ammash NM, et al.: Bicuspid aortic valve associated with aortic dilatation: a community-based study. Arterioscler Thromb Vasc Biol 2003, 23:351–356.

    Article  PubMed  CAS  Google Scholar 

  35. Andelfinger G, Tapper AR, Welch RC, et al.: KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet 2002, 71:663–668.

    Article  PubMed  CAS  Google Scholar 

  36. Garg V, Muth AN, Ransom JF, et al.: Mutations in NOTCH1 cause aortic valve disease. Nature 2005, 437:270–274.

    Article  PubMed  CAS  Google Scholar 

  37. Martin LJ, Ramachandran V, Cripe LH, et al.: Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. 2007, 121:275–284.

    CAS  Google Scholar 

  38. Zhu L, Vranckx R, Khau Van Kien P, et al.: Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 2006, 38:343–349.

    Article  PubMed  CAS  Google Scholar 

  39. Biddinger A, Rocklin M, Coselli J, Milewicz DM: Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg 1997, 25:506–511.

    Article  PubMed  CAS  Google Scholar 

  40. Guo D, Hasham S, Kuang SQ, et al.: Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation 2001, 103:2461–2468.

    PubMed  CAS  Google Scholar 

  41. Kakko S, Raisanen T, Tamminen M, et al.: 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 2003, 126:106–113.

    Article  PubMed  CAS  Google Scholar 

  42. Vaughan CJ, Casey M, He J, et al.: Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation 2001, 103:2469–2475.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  44. Pannu H, Fadulu VT, Chang J, et al.: Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 2005, 112:513–520.

    Article  PubMed  CAS  Google Scholar 

  45. Ades L: Guidelines for the diagnosis and management of Marfan syndrome. Heart Lung Circ 2007, 16:28–30.

    Article  PubMed  Google Scholar 

  46. Milewicz DM, Dietz HC, Miller DC: Treatment of aortic disease in patients with Marfan syndrome. Circulation 2005, 111:e150–e157.

    Article  PubMed  Google Scholar 

  47. Shores J, Berger KR, Murphy EA, Pyeritz RE: Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994, 330:1335–1341.

    Article  PubMed  CAS  Google Scholar 

  48. Kallenbach K, Baraki H, Khaladj N, et al.: Aortic valve-sparing operation in Marfan syndrome: what do we know after a decade? Ann Thorac Surg 2007, 83:S764–S768; discussion S785–S790.

    Article  PubMed  Google Scholar 

  49. Pepin M, Schwarze U, Superti-Furga A, Byers PH: Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000, 342:673–680.

    Article  PubMed  CAS  Google Scholar 

  50. Oderich GS, Panneton JM, Bower TC, et al.: The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg 2005, 42:98–106.

    Article  PubMed  Google Scholar 

  51. Ashton HA, Buxton MJ, Day NE, et al.: The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet 2002, 360:1531–1539.

    Article  PubMed  CAS  Google Scholar 

  52. Lederle FA, Johnson GR, Wilson SE, et al.: Prevalence and associations of abdominal aortic aneurysm detected through screening. Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study Group. Ann Intern Med 1997, 126:441–449.

    PubMed  CAS  Google Scholar 

  53. Verloes A, Sakalihasan N, Koulischer L, Limet R: Aneurysms of the abdominal aorta: familial and genetic aspects in three hundred thirteen pedigrees. J Vasc Surg 1995, 21:646–655.

    Article  PubMed  CAS  Google Scholar 

  54. Majumder PP, St Jean PL, Ferrell RE, et al.: On the inheritance of abdominal aortic aneurysm. Am J Hum Genet 1991, 48:164–170.

    PubMed  CAS  Google Scholar 

  55. Shibamura H, Olson JM, van Vlijmen-Van Keulen C, et al.: Genome scan for familial abdominal aortic aneurysm using sex and family history as covariates suggests genetic heterogeneity and identifies linkage to chromosome 19q13. Circulation 2004, 109:2103–2108.

    Article  PubMed  Google Scholar 

  56. Rossaak JI, Van Rij AM, Jones GT, Harris EL: Association of the 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor-1 with abdominal aortic aneurysms. J Vasc Surg 2000, 31:1026–1032.

    Article  PubMed  CAS  Google Scholar 

  57. Lederle FA, Johnson GR, Wilson SE, et al.: Yield of repeated screening for abdominal aortic aneurysm after a 4-year interval. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators. Arch Intern Med 2000, 160:1117–1121.

    Article  PubMed  CAS  Google Scholar 

  58. Lederle FA, Johnson GR, Wilson SE, et al.: Rupture rate of large abdominal aortic aneurysms in patients refusing or unfit for elective repair. JAMA 2002, 287:2968–2972.

    Article  PubMed  Google Scholar 

  59. Lederle FA, Wilson SE, Johnson GR, et al.: Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med 2002, 346:1437–1444.

    Article  PubMed  Google Scholar 

  60. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet 2005, 365:2179–2186.

  61. Duftner C, Seiler R, Dejaco C, et al.: Increasing evidence for immune-mediated processes and new therapeutic approaches in abdominal aortic aneurysms—a review. Ann N Y Acad Sci 2006, 1085:331–338.

    Article  PubMed  CAS  Google Scholar 

  62. Yoshimura K, Aoki H, Ikeda Y, et al.: Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med 2005, 11:1330–1338.

    Article  PubMed  CAS  Google Scholar 

  63. Yoshimura K, Aoki H, Ikeda Y, et al.: Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice. Ann N Y Acad Sci 2006, 1085:74–81.

    Article  PubMed  CAS  Google Scholar 

  64. Mosorin M, Juvonen J, Biancari F, et al.: Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: a randomized, double-blind, placebo-controlled pilot study. J Vasc Surg 2001, 34:606–610.

    Article  PubMed  CAS  Google Scholar 

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Callewaert, B.L., De Paepe, A.M. & Loeys, B.L. New insights into the pathogenesis and treatment of arterial aneurysms and dissections. Curr Cardio Risk Rep 1, 401–409 (2007). https://doi.org/10.1007/s12170-007-0066-9

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