Use of Genetics for Personalized Management of Heritable Thoracic Aortic Disease: How Do We Get There?

Overview

Journal J Thorac Cardiovasc Surg

Specialties Cardiology & Vascular Diseases
General Surgery
Pulmonary Medicine

Date 2014 Sep 15

PMID 25218541

Citations 22

Authors

Dianna M Milewicz

Ellen S Regalado

Affiliations

Soon will be listed here.

Abstract

The major diseases affecting the thoracic aorta are aortic aneurysms and acute aortic dissections. Medical treatments can slow the enlargement of aneurysms, but the mainstay of treatment to prevent premature death resulting from dissection is surgical repair of the thoracic aortic aneurysm, which is typically recommended when the aortic diameter reaches 5.0 to 5.5 cm. Studies of patients with acute aortic dissections, however, indicate that as many as 60% of dissections occur at aortic diameters smaller than 5.5 cm. Clinical predictors are therefore needed to distinguish those at risk for dissection at an aortic diameter smaller than 5.0 cm and to determine the aortic diameter that justifies the risk of surgical repair to prevent an acute aortic dissection. Data from genetic studies during the past decade have established that mutations in specific genes can distinguish patients at risk for the disease and predict the risk of early dissection at diameters smaller than 5.0 cm. This information has the potential to optimize the timing of aortic surgery to prevent acute dissections.

Citing Articles

Systematic review of cardiovascular neurocristopathy-contemporary insights and future perspectives.

Soliman O, Acharya Y, Gilard M, Duffy G, Wijns W, Kannan V Front Cardiovasc Med. 2024; 11:1333265.

PMID: 38660479 PMC: 11040563. DOI: 10.3389/fcvm.2024.1333265.

Comprehensive review of aortic aneurysms, dissections, and cardiovascular complications in connective tissue disorders.

Elendu C, Amaechi D, Elendu T, Ibhiedu J, Torubiri A, Okoye O Medicine (Baltimore). 2023; 102(48):e36499.

PMID: 38050214 PMC: 10695548. DOI: 10.1097/MD.0000000000036499.

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection.

Tomida S, Ishima T, Sawaki D, Imai Y, Nagai R, Aizawa K Int J Mol Sci. 2023; 24(20).

PMID: 37894894 PMC: 10607035. DOI: 10.3390/ijms242015213.

Patterns of genetic mutations explored by systematic screening of patients with aortopathy and their family members.

Kim J, Yoo J, Kim H, Kim H, Kim D, Choo S JTCVS Open. 2023; 15:27-37.

PMID: 37808051 PMC: 10556810. DOI: 10.1016/j.xjon.2023.06.006.

Analysis of the genetic contribution to thoracic aortic aneurysm or dissection in a prospective cohort of patients with familial and sporadic cases in East China.

Duan Y, Xiong J, Lai Z, Zhong Y, Tian C, Du Z Orphanet J Rare Dis. 2023; 18(1):251.

PMID: 37644562 PMC: 10466872. DOI: 10.1186/s13023-023-02855-7.

References

Wang L, Guo D, Cao J, Gong L, Kamm K, Regalado E . Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010; 87(5):701-7. PMC: 2978973. DOI: 10.1016/j.ajhg.2010.10.006. View

Zhu L, Vranckx R, Khau Van Kien P, Lalande A, Boisset N, Mathieu F . Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006; 38(3):343-9. DOI: 10.1038/ng1721. View

Guo D, Pannu H, Tran-Fadulu V, Papke C, Yu R, Avidan N . Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007; 39(12):1488-93. DOI: 10.1038/ng.2007.6. View

Hiratzka L, Bakris G, Beckman J, Bersin R, Carr V, Casey Jr D . 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice.... Circulation. 2010; 121(13):e266-369. DOI: 10.1161/CIR.0b013e3181d4739e. View

Boileau C, Guo D, Hanna N, Regalado E, Detaint D, Gong L . TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012; 44(8):916-21. PMC: 4033668. DOI: 10.1038/ng.2348. View

Milewicz D, Michael K, Fisher N, Coselli J, Markello T, Biddinger A . Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation. 1996; 94(11):2708-11. DOI: 10.1161/01.cir.94.11.2708. View

Pannu H, Fadulu V, Chang J, Lafont A, Hasham S, Sparks E . Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. 2005; 112(4):513-20. DOI: 10.1161/CIRCULATIONAHA.105.537340. View

Tran-Fadulu V, Pannu H, Kim D, Vick 3rd G, Lonsford C, Lafont A . Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet. 2009; 46(9):607-13. DOI: 10.1136/jmg.2008.062844. View

Pyeritz R, MCKUSICK V . The Marfan syndrome: diagnosis and management. N Engl J Med. 1979; 300(14):772-7. DOI: 10.1056/NEJM197904053001406. View

10.

Guo D, Regalado E, Casteel D, Santos-Cortez R, Gong L, Kim J . Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet. 2013; 93(2):398-404. PMC: 3738837. DOI: 10.1016/j.ajhg.2013.06.019. View

11.

Munot P, Saunders D, Milewicz D, Regalado E, Ostergaard J, Braun K . A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012; 135(Pt 8):2506-14. PMC: 3407424. DOI: 10.1093/brain/aws172. View

12.

Albornoz G, Coady M, Roberts M, Davies R, Tranquilli M, Rizzo J . Familial thoracic aortic aneurysms and dissections--incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006; 82(4):1400-5. DOI: 10.1016/j.athoracsur.2006.04.098. View

13.

Iakoubova O, Tong C, Rowland C, Luke M, Garcia V, Catanese J . Genetic variants in FBN-1 and risk for thoracic aortic aneurysm and dissection. PLoS One. 2014; 9(4):e91437. PMC: 3990573. DOI: 10.1371/journal.pone.0091437. View

14.

Loeys B, Schwarze U, Holm T, Callewaert B, Thomas G, Pannu H . Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006; 355(8):788-98. DOI: 10.1056/NEJMoa055695. View

15.

LeMaire S, McDonald M, Guo D, Russell L, Miller 3rd C, Johnson R . Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat Genet. 2011; 43(10):996-1000. PMC: 3244938. DOI: 10.1038/ng.934. View

16.

Pape L, Tsai T, Isselbacher E, Oh J, OGara P, Evangelista A . Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007; 116(10):1120-7. DOI: 10.1161/CIRCULATIONAHA.107.702720. View

17.

Loscalzo M, Goh D, Loeys B, Kent K, Spevak P, Dietz H . Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A. 2007; 143A(17):1960-7. DOI: 10.1002/ajmg.a.31872. View

18.

Attias D, Stheneur C, Roy C, Collod-Beroud G, Detaint D, Faivre L . Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation. 2009; 120(25):2541-9. DOI: 10.1161/CIRCULATIONAHA.109.887042. View

19.

van de Laar I, Oldenburg R, Pals G, Roos-Hesselink J, de Graaf B, Verhagen J . Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011; 43(2):121-6. DOI: 10.1038/ng.744. View

20.

Milewicz D, Ostergaard J, Ala-Kokko L, Khan N, Grange D, Mendoza-Londono R . De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A. 2010; 152A(10):2437-43. PMC: 3573757. DOI: 10.1002/ajmg.a.33657. View