General Thoracic and Cardiovascular Surgery

, Volume 67, Issue 1, pp 12–19 | Cite as

Is there a role for biomarkers in thoracic aortic aneurysm disease?

  • Damian Balmforth
  • Amer Harky
  • Benjamin Adams
  • John Yap
  • Alex Shipolini
  • Neil Roberts
  • Rakesh Uppal
  • Mohamad BashirEmail author
SPECIAL EDITION Controversies in Surgery for Thoracic Aorta


Thoracic aortic aneurysm (TAA) represents a major cause of mortality and morbidity in Western countries. The natural history of TAA is indolent, with patients usually being asymptomatic until a catastrophic event such as rupture or dissection ensues. As such, early diagnosis is crucial and the search is ongoing for a biomarker that can indicate the presence of TAA with sufficient accuracy to act as a screening tool. To date, no such marker has been developed for the diagnosis of non-familial or ‘sporadic’ TAA. However, our increased understanding of the pathogenesis of both familial and sporadic TAA has suggested potential candidates for diagnostic biomarkers. Many markers/pathways have been shown to have differential activity levels or expression in the aortic tissue of TAA. However, priority is given to markers that have shown differential levels in blood plasma, as blood tests represent the easiest route for mass screening for TAA. This review aims to evaluate the efficacy of clinical tests already in use in diagnosing TAA, explore novel proposed biomarkers and identify key areas of future interest.


Biomarkers Thoracic aorta Aneurysm Dissection 


Compliance with ethical standards

Conflict of interest

The authors do not wish to make any disclosures.


  1. 1.
    Olsson C, Thelin S, Stahle E, Ekbom A, Granath F. Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in a nationwide population-based study of more than 14,000 cases from 1987 to 2002. Circulation. 2006;114:2611–8.CrossRefGoogle Scholar
  2. 2.
    Wilson JMG, Jungner G. Principles and practice of screening for disease. Public health papers, No. 34. Geneva: World Health Organization; 1968. pp 26–7.Google Scholar
  3. 3.
    Ziganshin BA, Elefteriades JA. Guilt by association: a paradigm for detection of silent aortic disease. Ann Cardiothorac Surg. 2016;5:174 – 87.CrossRefGoogle Scholar
  4. 4.
    Black KM, Masuzawa A, Hagberg RC, Khabbaz KR, Trovato ME, Rettagliati VM, et al. Preliminary biomarkers for identification of human ascending thoracic aortic aneurysm. J Am Heart Assoc. 2013;2:e000138.CrossRefGoogle Scholar
  5. 5.
    Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol. 2010;55:841–57.CrossRefGoogle Scholar
  6. 6.
    Ramanath VS, Oh JK, Sundt TM 3rd, Eagle KA. Acute aortic syndromes and thoracic aortic aneurysm. Mayo Clin Proc. 2009;84:465–81.CrossRefGoogle Scholar
  7. 7.
    Trimarchi S, Sangiorgi G, Sang X, Rampoldi V, Suzuki T, Eagle KA, et al. In search of blood tests for thoracic aortic diseases. Ann Thorac Surg. 2010;90:1735–42.CrossRefGoogle Scholar
  8. 8.
    Golledge J, Tsao PS, Dalman RL, Norman PE. Circulating markers of abdominal aortic aneurysm presence and progression. Circulation. 2008;118:2382–92.CrossRefGoogle Scholar
  9. 9.
    Lippi G, Bonfanti L, Saccenti C, Cervellin G. Causes of elevated D-dimer in patients admitted to a large urban emergency department. Eur J Intern Med. 2014;25:45–8.CrossRefGoogle Scholar
  10. 10.
    Goldhaber SZ, Simons GR, Elliott CG, Haire WD, Toltzis R, Blacklow SC, et al. Quantitative plasma D-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism. JAMA. 1993;270:2819–22.CrossRefGoogle Scholar
  11. 11.
    Sidloff DA, Stather PW, Choke E, Bown MJ, Sayers RD. A systematic review and meta-analysis of the association between markers of hemostasis and abdominal aortic aneurysm presence and size. J Vasc Surg. 2014;59:528–35.CrossRefGoogle Scholar
  12. 12.
    Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Salerno Uriarte JA, et al. Diagnosis of acute aortic dissection by D-dimer: the international registry of acute aortic dissection substudy on biomarkers (IRAD-Bio) experience. Circulation. 2009;119:2702–7.CrossRefGoogle Scholar
  13. 13.
    Eggebrecht H, Naber CK, Bruch C, Kroger K, von Birgelen C, Schmermund A, et al. Value of plasma fibrin D-dimers for detection of acute aortic dissection. J Am Coll Cardiol. 2004;44:804–9.CrossRefGoogle Scholar
  14. 14.
    Yuan SM, Shi YH, Wang JJ, Lu FQ, Gao S. Elevated plasma D-dimer and hypersensitive C-reactive protein levels may indicate aortic disorders. Rev Bras Cir Cardiovasc. 2011;26:573 – 81.CrossRefGoogle Scholar
  15. 15.
    Lindholt JS, Jorgensen B, Shi GP, Henneberg EW. Relationships between activators and inhibitors of plasminogen, and the progression of small abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2003;25:546–51.CrossRefGoogle Scholar
  16. 16.
    Vainas T, Lubbers T, Stassen FR, Herngreen SB, van Dieijen-Visser MP, Bruggeman CA, et al. Serum C-reactive protein level is associated with abdominal aortic aneurysm size and may be produced by aneurysmal tissue. Circulation. 2003;107:1103–5.CrossRefGoogle Scholar
  17. 17.
    Elkind MS, Sciacca R, Boden-Albala B, Homma S, Di Tullio MR. Leukocyte count is associated with aortic arch plaque thickness. Stroke. 2002;33:2587–92.CrossRefGoogle Scholar
  18. 18.
    Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–26.CrossRefGoogle Scholar
  19. 19.
    Tribouilloy CM, Peltier M, Iannetta Peltier MC, Trojette F, Andrejak M, Lesbre JP. Plasma homocysteine and severity of thoracic aortic atherosclerosis. Chest. 2000;118:1685–9.CrossRefGoogle Scholar
  20. 20.
    Cao H, Hu X, Zhang Q, Li J, Wang J, Shao Y, et al. Homocysteine level and risk of abdominal aortic aneurysm: a meta-analysis. PLoS One. 2014;9:e85831.CrossRefGoogle Scholar
  21. 21.
    Sbarouni E, Georgiadou P, Analitis A, Chaidaroglou A, Marathias A, Degiannis D, et al. High homocysteine and low folate concentrations in acute aortic dissection. Int J Cardiol. 2013;168:463–6.CrossRefGoogle Scholar
  22. 22.
    Giusti B, Porciani MC, Brunelli T, Evangelisti L, Fedi S, Gensini GF, et al. Phenotypic variability of cardiovascular manifestations in Marfan Syndrome. Possible role of hyperhomocysteinemia and C677T MTHFR gene polymorphism. Eur Heart J. 2003;24:2038–45.CrossRefGoogle Scholar
  23. 23.
    Thota D, Zanoni S, Mells C, Auten JD. Acute, proximal aortic dissection with negative D-Dimer assay and normal portable chest radiograph: a case report. Mil Med. 2015;180:e164–7.CrossRefGoogle Scholar
  24. 24.
    Tsamis A, Krawiec JT, Vorp DA. Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review. J R Soc Interface. 2013;10:20121004.CrossRefGoogle Scholar
  25. 25.
    Toumpoulis IK, Oxford JT, Cowan DB, Anagnostopoulos CE, Rokkas CK, Chamogeorgakis TP, et al. Differential expression of collagen type V and XI alpha-1 in human ascending thoracic aortic aneurysms. Ann Thorac Surg. 2009;88:506–13.CrossRefGoogle Scholar
  26. 26.
    Arnaud L, Haroche J, Limal N, Toledano D, Gambotti L, Costedoat Chalumeau N, et al. Takayasu arteritis in France: a single-center retrospective study of 82 cases comparing white, North African, and black patients. Medicine (Baltimore). 2010;89:1–17.CrossRefGoogle Scholar
  27. 27.
    Wilson KA, Lindholt JS, Hoskins PR, Heickendorff L, Vammen S, Bradbury AW. The relationship between abdominal aortic aneurysm distensibility and serum markers of elastin and collagen metabolism. Eur J Vasc Endovasc Surg. 2001;21:175–8.CrossRefGoogle Scholar
  28. 28.
    Lindholt JS, Heickendorff L, Vammen S, Fasting H, Henneberg EW. Five-year results of elastin and collagen markers as predictive tools in the management of small abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2001;21:235–40.CrossRefGoogle Scholar
  29. 29.
    Ramirez F, Sakai LY. Biogenesis and function of fibrillin assemblies. Cell Tissue Res. 2010;339:71–82.CrossRefGoogle Scholar
  30. 30.
    Ramachandra CJ, Mehta A, Guo KW, Wong P, Tan JL, Shim W. Molecular pathogenesis of Marfan syndrome. Int J Cardiol. 2015;187:585 – 91.CrossRefGoogle Scholar
  31. 31.
    Marshall LM, Carlson EJ, O’Malley J, Snyder CK, Charbonneau NL, Hayflick SJ, et al. Thoracic aortic aneurysm frequency and dissection are associated with fibrillin-1 fragment concentrations in circulation. Circ Res. 2013;113:1159–68.CrossRefGoogle Scholar
  32. 32.
    Vine N, Powell JT. Metalloproteinases in degenerative aortic disease. Clin Sci (Lond). 1991;81:233–9.CrossRefGoogle Scholar
  33. 33.
    Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res. 1995;77:863–8.CrossRefGoogle Scholar
  34. 34.
    Rabkin SW. The role matrix metalloproteinases in the production of aortic aneurysm. Prog Mol Biol Transl Sci. 2017;147:239–65.CrossRefGoogle Scholar
  35. 35.
    Koullias GJ, Ravichandran P, Korkolis DP, Rimm DL, Elefteriades JA. Increased tissue microarray matrix metalloproteinase expression favors proteolysis in thoracic aortic aneurysms and dissections. Ann Thorac Surg. 2004;78:2106–10. (discussion 10–1).CrossRefGoogle Scholar
  36. 36.
    Sangiorgi G, Trimarchi S, Mauriello A, Righini P, Bossone E, Suzuki T, et al. Plasma levels of metalloproteinases-9 and -2 in the acute and subacute phases of type A and type B aortic dissection. J Cardiovasc Med (Hagerstown). 2006;7:307–15.CrossRefGoogle Scholar
  37. 37.
    Ikonomidis JS, Ivey CR, Wheeler JB, Akerman AW, Rice A, Patel RK, et al. Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg. 2013;145:1326–33.CrossRefGoogle Scholar
  38. 38.
    Lu H, Rateri DL, Cassis LA, Daugherty A. The role of the renin-angiotensin system in aortic aneurysmal diseases. Curr Hypertens Rep. 2008;10:99–106.CrossRefGoogle Scholar
  39. 39.
    Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312:117–21.CrossRefGoogle Scholar
  40. 40.
    Rateri DL, Davis FM, Balakrishnan A, Howatt DA, Moorleghen JJ, O’Connor WN, et al. Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms. Am J Pathol. 2014;184:2586–95.CrossRefGoogle Scholar
  41. 41.
    Huang LG, Liu DB, Wang HQ. Angiotensin-converting enzyme I/D polymorphism and aortic aneurysm risk: a meta-analysis. Interact Cardiovasc Thorac Surg. 2014;19:782–7.CrossRefGoogle Scholar
  42. 42.
    Li Y, Hu J, Qian H, Gu J, Meng W, Zhang EY. Novel findings: Expression of angiotensin-converting enzyme and angiotensin-converting enzyme 2 in thoracic aortic dissection and aneurysm. J Renin Angiotensin Aldosterone Syst. 2015;16:1130–4.CrossRefGoogle Scholar
  43. 43.
    Liew CC, Ma J, Tang HC, Zheng R, Dempsey AA. The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Clin Med. 2006;147:126–32.CrossRefGoogle Scholar
  44. 44.
    Coady MA, Davies RR, Roberts M, Goldstein LJ, Rogalski MJ, Rizzo JA, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg. 1999;134:361–7.CrossRefGoogle Scholar
  45. 45.
    Milewicz DM, Regalado E. Heritable Thoracic Aortic Disease Overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC et al, editors. GeneReviews(R). Seattle: University of Washington; 1993. (GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved).Google Scholar
  46. 46.
    Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. 2005;112:513–20.CrossRefGoogle Scholar
  47. 47.
    Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y, Presley C, et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16:2453–62.CrossRefGoogle Scholar
  48. 48.
    Renard M, Callewaert B, Baetens M, Campens L, MacDermot K, Fryns JP, et al. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFbeta signaling in FTAAD. Int J Cardiol. 2013;165:314–21.CrossRefGoogle Scholar
  49. 49.
    Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488–93.CrossRefGoogle Scholar
  50. 50.
    Kim JH, Na CY, Choi SY, Kim HW, Du Kim Y, Kwon JB, et al. Integration of gene-expression profiles and pathway analysis in ascending thoracic aortic aneurysms. Ann Vasc Surg. 2010;24:538–49.CrossRefGoogle Scholar
  51. 51.
    Sakai H, Suzuki S, Mizuguchi T, Imoto K, Yamashita Y, Doi H, et al. Rapid detection of gene mutations responsible for non-syndromic aortic aneurysm and dissection using two different methods: resequencing microarray technology and next-generation sequencing. Hum Genet. 2012;131:591–9.CrossRefGoogle Scholar
  52. 52.
    Absi TS, Sundt TM 3rd, Tung WS, Moon M, Lee JK, Damiano RR Jr, et al. Altered patterns of gene expression distinguishing ascending aortic aneurysms from abdominal aortic aneurysms: complementary DNA expression profiling in the molecular characterization of aortic disease. J Thorac Cardiovasc Surg. 2003;126:344–57 (discission 57).CrossRefGoogle Scholar
  53. 53.
    Isselbacher EM, Lino Cardenas CL, Lindsay ME. Hereditary influence in thoracic aortic aneurysm and dissection. Circulation. 2016;133:2516–28.CrossRefGoogle Scholar
  54. 54.
    LeMaire SA, McDonald ML, Guo DC, Russell L, Miller CC 3rd, Johnson RJ, et al. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat Genet. 2011;43:996–1000.CrossRefGoogle Scholar
  55. 55.
    Gillis E, Van Laer L, Loeys BL. Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-beta signaling and vascular smooth muscle cell contractility. Circ Res. 2013;113:327–40.CrossRefGoogle Scholar
  56. 56.
    Suzuki T, Trimarchi S, Sawaki D, Grassi V, Costa E, Rampoldi V, et al. Circulating transforming growth factor-beta levels in acute aortic dissection. J Am Coll Cardiol. 2011;58:775.CrossRefGoogle Scholar
  57. 57.
    Li T, Lv Z, Jing JJ, Yang J, Yuan Y. Matrix metalloproteinase family polymorphisms and the risk of aortic aneurysmal diseases: a systematic review and meta-analysis. Clin Genet. 2017.
  58. 58.
    Wang Y, Barbacioru CC, Shiffman D, Balasubramanian S, Iakoubova O, Tranquilli M, et al. Gene expression signature in peripheral blood detects thoracic aortic aneurysm. PLoS One. 2007;2:e1050.CrossRefGoogle Scholar
  59. 59.
    Kim HW, Stansfield BK. Genetic and epigenetic regulation of aortic aneurysms. BioMed Res Int. 2017;2017:7268521.Google Scholar

Copyright information

© The Japanese Association for Thoracic Surgery 2017

Authors and Affiliations

  • Damian Balmforth
    • 1
    • 2
  • Amer Harky
    • 1
  • Benjamin Adams
    • 1
  • John Yap
    • 1
  • Alex Shipolini
    • 1
  • Neil Roberts
    • 1
  • Rakesh Uppal
    • 1
    • 2
  • Mohamad Bashir
    • 1
    Email author
  1. 1.Department of Cardiac Surgery, Barts Heart CentreSt Bartholomew’s HospitalLondonUK
  2. 2.William Harvey Research InstituteLondonUK

Personalised recommendations