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  • Review Article
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Abdominal aortic aneurysm: update on pathogenesis and medical treatments

Nature Reviews Cardiology volume 16, pages 225–242 (2019)Cite this article

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Abstract

Abdominal aortic aneurysm (AAA) rupture is an important cause of death in adults. Currently, the only treatment for AAA is open or endovascular surgical repair. In most parts of the developed world, AAAs can be identified at an early stage as a result of incidental imaging and screening programmes. Randomized clinical trials have demonstrated that early elective surgical repair of these small AAAs is not beneficial, and an unmet clinical need exists to develop medical therapies for small AAAs that limit or prevent the progressive expansion and rupture of the aneurysm. A large amount of research is currently being performed to increase the understanding of AAA pathogenesis and ultimately lead to the development of medical therapies, such as drug-based and cell-based strategies for this disease. This Review summarizes the latest research findings and current theories on AAA pathogenesis, including discussion of the pros and cons of current rodent models of AAA, and highlights potential medical therapies for AAA, summarizing previous, ongoing and potential clinical trials of medical interventions for small AAAs. This expanding volume of research on AAA is expected to result in a range of novel medical therapies for AAA within the next decade.

Key points

  • Currently, no drug therapy is available for abdominal aortic aneurysm (AAA), which drives a substantial interest in the pathogenesis of this condition.

  • Most previous studies in animals and humans indicate a major role of chronic aortic inflammation in AAA pathogenesis.

  • Evidence suggests that inherited and haemodynamic factors also have an important role in AAA pathogenesis.

  • Atherosclerosis might be important in the development of some AAAs.

  • Clinical trials of drug therapies for AAA have all had negative results; reports of ongoing trials are expected over the next 2 years.

  • Alternative design methods for future clinical trials on AAA drugs should be considered.

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Fig. 1: Potential effects of inflammation in AAA pathogenesis.
Fig. 2: Potential role of excessive positive remodelling in AAA pathogenesis.
Fig. 3: Examples of different AAA phenotypes.
Fig. 4: Schematic overview of the TGFβ pathway.

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References

  1. Golledge, J., Muller, J., Daugherty, A. & Norman, P. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler. Thromb. Vasc. Biol. 26, 2605–2613 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Lederle, F. A. et al. Prevalence and associations of abdominal aortic aneurysm detected through screening. Ann. Intern. Med. 126, 441–449 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Svensjö, S. et al. Low prevalence of abdominal aortic aneurysm among 65-year-old swedish men indicates a change in the epidemiology of the disease. Circulation 124, 1118–1123 (2011).

    Article  PubMed  Google Scholar 

  4. Oliver-Williams, C. et al. Lessons learned about prevalence and growth rates of abdominal aortic aneurysms from a 25-year ultrasound population screening programme. Br. J. Surg. 105, 68–74 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Singh, K., Bønaa, K. H., Jacobsen, B. K., Bjørk, L. & Solberg, S. Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study: the Tromsø study. Am. J. Epidemiol. 154, 236–244 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Jamrozik, K. et al. Screening for abdominal aortic aneurysm: lessons from a population-based study. Med. J. Aust. 173, 345–350 (2000).

    CAS  PubMed  Google Scholar 

  7. Tang, W. et al. Lifetime risk and risk factors for abdominal aortic aneurysm in a 24-year prospective study: the ARIC study (atherosclerosis risk in communities). Arterioscler. Thromb. Vasc. Biol. 36, 2468–2477 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gianfagna, F. et al. Prevalence of abdominal aortic aneurysms in the general population and in subgroups at high cardiovascular risk in Italy: results of the RoCAV population based study. Eur. J. Vasc. Endovasc. Surg. 55, 633–639 (2018).

    Article  PubMed  Google Scholar 

  9. Sweeting, M. J. et al. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br. J. Surg. 99, 655–665 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Lederle, F. A. The rise and fall of abdominal aortic aneurysm. Circulation 124, 1097–1099 (2011).

    Article  PubMed  Google Scholar 

  11. Ulug, P. et al. Meta-analysis of the current prevalence of screen-detected abdominal aortic aneurysm in women. Br. J. Surg. 103, 1097–1104 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Sampson, U. K. A. et al. Estimation of global and regional incidence and prevalence of abdominal aortic aneurysms 1990 to 2010. Glob. Heart 9, 159–170 (2014).

    Article  PubMed  Google Scholar 

  13. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117–171 (2013).

    Google Scholar 

  14. Sampson, U. K. A. et al. Global and regional burden of aortic dissection and aneurysms: mortality trends in 21 world regions, 1990 to 2010. Glob. Heart 9, 171–180 (2014).

    Article  PubMed  Google Scholar 

  15. Powell, J. T. et al. Final 12-year follow-up of surgery versus surveillance in the UK small aneurysm trial. Br. J. Surg. 94, 702–708 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Lederle, F. A. et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N. Engl. J. Med. 346, 1437–1444 (2002).

    Article  PubMed  Google Scholar 

  17. Parkinson, F. et al. Rupture rates of untreated large abdominal aortic aneurysms in patients unfit for elective repair. J. Vasc. Surg. 61, 1606–1612 (2015).

    Article  PubMed  Google Scholar 

  18. Lederle, F. A. et al. Rupture rate of large abdominal aortic aneurysms in patients refusing or unfit for elective repair. JAMA 287, 2968–2972 (2002).

    Article  PubMed  Google Scholar 

  19. Chaikof, E. L. et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J. Vasc. Surg. 67, 2–77.e2 (2018).

    Article  PubMed  Google Scholar 

  20. Moll, F. L. et al. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur. J. Vasc. Endovasc. Surg. 41, S1–S58 (2011).

  21. Cao, P. et al. Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial. Eur. J. Vasc. Endovasc. Surg. 41, 13–25 (2010).

    Article  PubMed  Google Scholar 

  22. Ouriel, K., Clair, D. G., Kent, K. C. & Zarins, C. K. & PIVOTAL Investigators. Endovascular repair compared with surveillance for patients with small abdominal aortic aneurysms. J. Vasc. Surg. 51, 1081–1087 (2010).

    Article  PubMed  Google Scholar 

  23. IMPROVE Trial Investigators. Comparative clinical effectiveness and cost effectiveness of endovascular strategy v open repair for ruptured abdominal aortic aneurysm: three year results of the IMPROVE randomised trial. BMJ 359, j4859 (2017).

    Article  PubMed Central  Google Scholar 

  24. Powell, J. T. et al. Meta-analysis of individual-patient data from EVAR-1, DREAM, OVER and ACE trials comparing outcomes of endovascular or open repair for abdominal aortic aneurysm over 5 Years. J. Vasc. Surg. 65, 1539–1540 (2017).

    Article  Google Scholar 

  25. Michel, M. et al. A study of the cost-effectiveness of fenestrated/branched EVAR compared with open surgery for patients with complex aortic aneurysms at 2 years. Eur. J. Vasc. Endovasc. Surg. 56, 15–21 (2018).

    Article  PubMed  Google Scholar 

  26. Sweeting, M. J., Patel, R., Powell, J. T., Greenhalgh, R. M. & EVAR Trial Investigators. Endovascular repair of abdominal aortic aneurysm in patients physically ineligible for open repair: very long-term follow-up in the EVAR-2 randomized controlled trial. Ann. Surg. 266, 713–719 (2017).

    Article  PubMed  Google Scholar 

  27. Buck, D. B., Van Herwaarden, J. A., Schermerhorn, M. L. & Moll, F. L. Endovascular treatment of abdominal aortic aneurysms. Nat. Rev. Cardiol. 11, 112–123 (2014).

    Article  PubMed  Google Scholar 

  28. Filardo, G., Powell, J. T., Martinez, M. A., Martinez, M. A. & Ballard, D. J. Surgery for small asymptomatic abdominal aortic aneurysms. Cochrane Database Syst. Rev. 3, CD001835 (2015).

    Google Scholar 

  29. Kokje, V. B. C., Hamming, J. F. & Lindeman, J. H. N. Pharmaceutical management of small abdominal aortic aneurysms: a systematic review of the clinical evidence. Eur. J. Vasc. Endovasc. Surg. 50, 702–713 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Rughani, G., Robertson, L. & Clarke, M. Medical treatment for small abdominal aortic aneurysms. Cochrane Database Syst. Rev. 9, CD009536 (2012).

    Google Scholar 

  31. Golledge, J. & Norman, P. E. Current status of medical management for abdominal aortic aneurysm. Atherosclerosis 217, 57–63 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. The UK Small Aneurysm Trial Participants. Health service costs and quality of life for early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 352, 1656–1660 (1998).

    Article  Google Scholar 

  33. Daugherty, A., Manning, M. W. & Cassis, L. A. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J. Clin. Invest. 105, 1605–1612 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alsiraj, Y. et al. Female mice with an XY sex chromosome complement develop severe angiotensin II–induced abdominal aortic aneurysms. Circulation 135, 379–391 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, S. et al. Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo. Nat. Med. 18, 902–910 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rateri, D. L. et al. Prolonged infusion of angiotensin II in apoE−/− mice promotes macrophage recruitment with continued expansion of abdominal aortic aneurysm. Am. J. Pathol. 179, 1542–1548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rush, C. et al. Whole genome expression analysis within the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic aneurysm. BMC Genomics 10, 298–298 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Trachet, B. et al. Angiotensin II infusion into ApoE(−/−) mice: a model for aortic dissection rather than abdominal aortic aneurysm? Cardiovasc. Res. 113, 1230–1242 (2007).

    Article  CAS  Google Scholar 

  39. Trachet, B. et al. Ascending aortic aneurysm in angiotensin II–infused mice: formation, progression, and the role of focal dissections. Arterioscler. Thromb. Vasc. Biol. 36, 673–681 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Moran, C. S. et al. Resveratrol inhibits growth of experimental abdominal aortic aneurysm associated with upregulation of angiotensin-converting enzyme 2. Arterioscler. Thromb. Vasc. Biol. 37, 2195–2195 (2017).

    Article  CAS  PubMed  Google Scholar 

  41. Yu, M., Chen, C., Cao, Y. & Qi, R. Inhibitory effects of doxycycline on the onset and progression of abdominal aortic aneurysm and its related mechanisms. Eur. J. Pharmacol. 811, 101–109 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Busch, A. et al. Extra- and intraluminal elastase induce morphologically distinct abdominal aortic aneurysms in mice and thus represent specific subtypes of human disease. J. Vasc. Res. 53, 49–57 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Johnston, W. F. et al. Aromatase is required for female abdominal aortic aneurysm protection. J. Vasc. Surg. 61, 1565–1574 (2015).

    Article  PubMed  Google Scholar 

  44. Bergoeing, M. P. et al. Cigarette smoking increases aortic dilatation without affecting matrix metalloproteinase-9 and -12 expression in a modified mouse model of aneurysm formation. J. Vasc. Surg. 45, 1217–1227 (2007).

    Article  PubMed  Google Scholar 

  45. Steinmetz, E. F. et al. Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice. Ann. Surg. 241, 92–101 (2005).

    PubMed  PubMed Central  Google Scholar 

  46. Busch, A. et al. Four surgical modifications to the classic elastase perfusion aneurysm model enable haemodynamic alterations and extended elastase perfusion. Eur. J. Vasc. Endovasc. Surg. 56, 102–109 (2018).

    Article  PubMed  Google Scholar 

  47. Wang, Y., Krishna, S. & Golledge, J. The calcium chloride-induced rodent model of abdominal aortic aneurysm. Atherosclerosis 226, 29–39 (2012).

    Article  PubMed  CAS  Google Scholar 

  48. Wang, Y. et al. Influence of apolipoprotein E, age and aortic site on calcium phosphate induced abdominal aortic aneurysm in mice. Atherosclerosis 235, 204–212 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Franck, G. et al. Reestablishment of the endothelial lining by endothelial cell therapy stabilizes experimental abdominal aortic aneurysms. Circulation 127, 1877–1887 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Schneider, F. et al. Bone marrow mesenchymal stem cells stabilize already-formed aortic aneurysms more efficiently than vascular smooth muscle cells in a rat model. Eur. J. Vasc. Endovasc. Surg. 45, 666–672 (2003).

    Article  Google Scholar 

  51. Coscas, R. et al. Exploring antibody-dependent adaptive immunity against aortic extracellular matrix components in experimental aortic aneurysms. J. Vasc. Surg. 138, 1551–1568 (2018).

    Article  PubMed  Google Scholar 

  52. Lu, G. et al. A novel chronic advanced stage abdominal aortic aneurysm murine model. J. Vasc. Surg. 66, 232–242 (2016).

    Article  Google Scholar 

  53. Lareyre, F. et al. TGFβ (transforming growth factor-β) blockade induces a human-like disease in a nondissecting mouse model of abdominal aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 37, 2171–2171 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Riber, S. S. et al. Induction of autoimmune abdominal aortic aneurysm in pigs — a novel large animal model. Ann. Med. Surg. 20, 26–31 (2017).

    Article  Google Scholar 

  55. Sénémaud, J. et al. Translational relevance and recent advances of animal models of abdominal aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 37, 401–410 (2017).

    Article  PubMed  CAS  Google Scholar 

  56. Marinov, G. R. et al. Can the infusion of elastase in the abdominal aorta of the Yucatán miniature swine consistently produce experimental aneurysms? J. Invest. Surg. 10, 129–150 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Wanhainen, A., Mani, K. & Golledge, J. Surrogate markers of abdominal aortic aneurysm progression. Arterioscler. Thromb. Vasc. Biol. 36, 236–244 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Golledge, J., Norman, P. E., Murphy, M. P. & Dalman, R. L. Challenges and opportunities in limiting abdominal aortic aneurysm growth. J. Vasc. Surg. 65, 225–233 (2016).

    Article  PubMed  Google Scholar 

  59. Walker, D. I., Bloor, K., Williams, G. & Gillie, I. Inflammatory aneurysms of the abdominal aorta. Br. J. Surg. 59, 609–614 (1972).

    Article  CAS  PubMed  Google Scholar 

  60. Spin, J. M. et al. Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm. Physiol. Genomics 43, 993–1003 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Uchida, H. A. et al. Total lymphocyte deficiency attenuates AngII-induced atherosclerosis in males but not abdominal aortic aneurysms in apoE deficient mice. Atherosclerosis 211, 399–403 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Furusho, A. et al. Involvement of B cells, immunoglobulins, and syk in the pathogenesis of abdominal aortic aneurysm. J. Am. Heart Assoc. 7, 1–16 (2018).

    Article  CAS  Google Scholar 

  63. Meher, A. K. et al. B2 cells suppress experimental abdominal aortic aneurysms. Am. J. Pathol. 184, 3130–3141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schaheen, B. et al. B cell depletion promotes aortic infiltration of immunosuppressive cells and is protective of experimental aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 36, 2191–2202 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yodoi, K. et al. Foxp3+ regulatory T cells play a protective role in angiotensin II–induced aortic aneurysm formation in mice. Hypertension 65, 889–895 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Ait-Oufella, H. et al. Natural regulatory T cells limit angiotensin II–induced aneurysm formation and rupture in mice. Arterioscler. Thromb. Vasc. Biol. 33, 2374–2379 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Hayashi, T. et al. Ultraviolet B exposure inhibits angiotensin II–induced abdominal aortic aneurysm formation in mice by expanding CD4+Foxp3+ regulatory T cells. J. Am. Heart Assoc. 6, 1–13 (2017).

    Article  Google Scholar 

  68. Zhou, Y. et al. Regulatory T cells in human and angiotensin II-induced mouse abdominal aortic aneurysms. Cardiovasc. Res. 107, 98–107 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Meng, X. et al. Regulatory T cells prevent angiotensin II–induced abdominal aortic aneurysm in apolipoprotein E knockout mice. Hypertension 64, 875–882 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. van Puijvelde, G. et al. CD1d deficiency inhibits the development of abdominal aortic aneurysms in LDL receptor deficient mice. PLOS ONE 13, e0190962 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Zhang, S. et al. Deficiency of γδT cells protects against abdominal aortic aneurysms by regulating phosphoinositide 3-kinase/AKT signalling. J. Vasc. Surg. 67, 899–908 (2016).

    Article  PubMed  Google Scholar 

  72. Tsuruda, T. et al. Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ. Res. 102, 1368–1377 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Wang, J. et al. IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms. EMBO Mol. Med. 6, 952–969 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Eliason, J. L. et al. Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation. Circulation 112, 232–240 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Meng, X. et al. Regulatory T cells in cardiovascular diseases. Nat. Rev. Cardiol. 13, 167–179 (2015).

    Article  PubMed  CAS  Google Scholar 

  76. Zhang, J. et al. Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation. Circ. Res. 108, 1316–1327 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sun, J. et al. Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation. Circulation 120, 973–982 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu, C. et al. Allergic lung inflammation aggravates angiotensin II–induced abdominal aortic aneurysms in mice. Arterioscler. Thromb. Vasc. Biol. 36, 69–77 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Koole, D. et al. Osteoprotegerin is associated with aneurysm diameter and proteolysis in abdominal aortic aneurysm disease. Arterioscler. Thromb. Vasc. Biol. 32, 1497–1504 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Golledge, A. L. V., Walker, P., Norman, P. E. & Golledge, J. A systematic review of studies examining inflammation associated cytokines in human abdominal aortic aneurysm samples. Dis. Markers 26, 181–188 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lindeman, J. H. N., Rabelink, T. J. & Van Bockel, J. H. Immunosuppression and the abdominal aortic aneurysm: Doctor Jekyll or Mister Hyde? Circulation 124, 463–465 (2011).

    Article  Google Scholar 

  82. Biros, E. et al. Differential gene expression in human abdominal aortic aneurysm and aortic occlusive disease. Oncotarget 6, 12984–12996 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Biros, E. et al. Differential gene expression in the proximal neck of human abdominal aortic aneurysm. Atherosclerosis 233, 211–218 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Forester, N. D., Cruickshank, S. M., Scott, D. J. A. & Carding, S. R. Functional characterization of T cells in abdominal aortic aneurysms. Immunology 115, 262–270 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lu, S. et al. Aneurysmal lesions of patients with abdominal aortic aneurysm contain clonally expanded t cells. J. Immunol. 192, 4897–4912 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yin, M. et al. Deficient CD4+CD25+ T regulatory cell function in patients with abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 30, 1825–1831 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Golledge, J., Tsao, P. S., Dalman, R. L. & Norman, P. E. Circulating markers of abdominal aortic aneurysm presence and progression. Circulation 118, 2382–2392 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Harrison, S. et al. Interleukin-6 receptor pathways in abdominal aortic aneurysm. Eur. Heart J. 34, 3707–3716 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Brittenden, J. et al. Aortic wall inflammation predicts abdominal aortic aneurysm expansion, rupture, and need for surgical repair. Circulation 136, 787–797 (2017).

    Article  Google Scholar 

  90. Tajima, Y. et al. Oral steroid use and abdominal aortic aneurysm expansion — positive association. Circ. J. 81, 1774–1782 (2017).

    Article  PubMed  Google Scholar 

  91. Sillesen, H. et al. Randomized clinical trial of mast cell inhibition in patients with a medium-sized abdominal aortic aneurysm. Br. J. Surg. 102, 894–901 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Arnoud Meijer, C. et al. Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial. Ann. Intern. Med. 159, 815–823 (2013).

    Article  PubMed  Google Scholar 

  93. Lindeman, J. H. N., Abdul-Hussien, H., Van Bockel, J. H., Wolterbeek, R. & Kleemann, R. Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm doxycycline selectively depletes aortic wall neutrophils and cytotoxic t cells. Circulation 119, 2209–2216 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Golledge, J. & Norman, P. E. Atherosclerosis and abdominal aortic aneurysm: cause, response, or common risk factors? Arterioscler. Thromb. Vasc. Biol. 30, 1075–1077 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ward, M. R., Pasterkamp, G., Yeung, A. C. & Borst, C. Arterial remodeling: mechanisms and clinical implications. Circulation 102, 1186–1191 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Kasashima, S. et al. Upregulated interleukins (IL-6, IL-10, and IL-13) in immunoglobulin G4-related aortic aneurysm patients. J. Vasc. Surg. 67, 1248–1262 (2017).

    Article  PubMed  Google Scholar 

  97. Moran, C. S. et al. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis. Sci. Rep. 7, 1–12 (2017).

    Article  CAS  Google Scholar 

  98. Krishna, S. M. et al. Wnt signaling pathway inhibitor sclerostin inhibits angiotensin II–induced aortic aneurysm and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 37, 553–566 (2017).

    Article  CAS  PubMed  Google Scholar 

  99. Umebayashi, R. et al. Cilostazol attenuates angiotensin II-induced abdominal aortic aneurysms but not atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 38, 903–912 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Dale, M. A. et al. Background differences in baseline and stimulated MMP levels influence abdominal aortic aneurysm susceptibility. Atherosclerosis 243, 621–629 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yao, L. et al. Association of carotid atherosclerosis and stiffness with abdominal aortic aneurysm: the atherosclerosis risk in communities (ARIC) study. Atherosclerosis 270, 110–116 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Matthews, E. O. et al. Meta-analysis of the association between peripheral artery disease and growth of abdominal aortic aneurysms. J. Vasc. Surg. 67, 674–674 (2018).

    Article  Google Scholar 

  103. Takagi, H. & Umemoto, T. & ALICE Group. Association of peripheral artery disease with abdominal aortic aneurysm growth. J. Vasc. Surg. 64, 506–513 (2016).

    Article  PubMed  Google Scholar 

  104. Brady, A. R. et al. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. Circulation 110, 16–21 (2014).

    Article  Google Scholar 

  105. Michel, J. et al. Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc. Res. 90, 18–27 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Owens, I. et al. Platelet inhibitors reduce rupture in a mouse model of established abdominal aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 35, 2032–2041 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dai, J., Louedec, L., Philippe, M., Michel, J. B. & Houard, X. Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model. J. Vasc. Surg. 49, 719–727 (2009).

    Article  PubMed  Google Scholar 

  108. Fontaine, V. et al. Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am. J. Pathol. 161, 1701–1710 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Golledge, J., Wolanski, P., Parr, A. & Buttner, P. Measurement and determinants of infrarenal aortic thrombus volume. Eur. Radiol. 18, 1987–1994 (2008).

    Article  PubMed  Google Scholar 

  110. Nguyen, V. L. et al. Abdominal aortic aneurysms with high thrombus signal intensity on magnetic resonance imaging are associated with high growth rate. Eur. J. Vasc. Endovasc. Surg. 48, 676–684 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Behr-Rasmussen, C., Grøndal, N., Bramsen, M. B., Thomsen, M. D. & Lindholt, J. S. Mural thrombus and the progression of abdominal aortic aneurysms: a large population-based prospective cohort study. Eur. J. Vasc. Endovasc. Surg. 48, 301–307 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Parr, A. et al. Thrombus volume is associated with cardiovascular events and aneurysm growth in patients who have abdominal aortic aneurysms. J. Vasc. Surg. 53, 28–35 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lindholt, J. S., Jørgensen, B., Fasting, H. & Henneberg, E. W. Plasma levels of plasmin-antiplasmin-complexes are predictive for small abdominal aortic aneurysms expanding to operation-recommendable sizes. J. Vasc. Surg. 34, 611–615 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Golledge, J., Muller, R., Clancy, P., McCann, M. & Norman, P. E. Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm. Eur. Heart J. 32, 354–364 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Vega de Ceniga, M. et al. Assessment of biomarkers and predictive model for short-term prospective abdominal aortic aneurysm growth — a pilot study. Ann. Vasc. Surg. 28, 1642–1648 (2014).

    Article  PubMed  Google Scholar 

  116. Arzani, A., Suh, G., Dalman, R. L. & Shadden, S. C. A. A longitudinal comparison of hemodynamics and intraluminal thrombus deposition in abdominal aortic aneurysms. Am. J. Physiol. Heart Circ. Physiol. 307, H1786–H1795 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Golledge, J. et al. Thrombus volume is similar in patients with ruptured and intact abdominal aortic aneurysms. J. Vasc. Surg. 59, 315–320 (2014).

    Article  PubMed  Google Scholar 

  118. Speelman, L. et al. The mechanical role of thrombus on the growth rate of an abdominal aortic aneurysm. J. Vasc. Surg. 51, 19–26 (2010).

    Article  PubMed  Google Scholar 

  119. Dong, S. L. et al. Aneurysm of the anomalous splenic artery arising from superior mesenteric artery treated by coil embolization: a report of two cases and literature review. Ann. Vasc. Surg. 48, 251.e5–251.e10 (2018).

    Article  Google Scholar 

  120. Salata, K. et al. Statins reduce abdominal aortic aneurysm growth, rupture, and perioperative mortality: a sys tematic review and meta-analysis. J. Am. Heart Assoc. 7, e008657 (2018).

  121. Joergensen, T. M. M. et al. High heritability of liability to abdominal aortic aneurysms: a population based twin study. Eur. J. Vasc. Endovasc. Surg. 52, 41–46 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Golledge, J. & Kuivaniemi, H. Genetics of abdominal aortic aneurysm. Curr. Opin. Cardiol. 28, 290–296 (2013).

    Article  PubMed  Google Scholar 

  123. Raffort, J., Lareyre, F., Clement, M. & Mallat, Z. Micro-RNAs in abdominal aortic aneurysms: insights from animal models and relevance to human disease. Cardiovasc. Res. 110, 165–177 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Golledge, J., Biros, E., Bingley, J., Iyer, V. & Krishna, S. M. Epigenetics and peripheral artery disease. Curr. Atheroscler. Rep. 18, 1–9 (2016).

    Article  CAS  Google Scholar 

  125. Maegdefessel, L. et al. MiR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat. Commun. 5, 5214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zampetaki, A. et al. Role of miR-195 in aortic aneurysmal disease. Circ. Res. 115, 857–866 (2014).

    Article  CAS  PubMed  Google Scholar 

  127. Kim, C. W. et al. Prevention of abdominal aortic aneurysm by anti–microRNA-712 or anti–microRNA-205 in angiotensin II–infused mice. Arterioscler. Thromb. Vasc. Biol. 34, 1412–1421 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Maegdefessel, L. et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci. Transl Med. 4, 122–134 (2012).

    Article  CAS  Google Scholar 

  129. Maegdefessel, L. et al. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J. Clin. Invest. 122, 497–506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Leeper, N. J. et al. Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler. Thromb. Vasc. Biol. 33, 1–10 (2013).

    Article  CAS  Google Scholar 

  131. Li, D. Y. et al. H19 induces abdominal aortic aneurysm development and progression. Circulation 138, 1551–1568 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Pahl, M. C. et al. MicroRNA expression signature in human abdominal aortic aneurysms. BMC Med. Genomics 5, 25–25 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zhang, W. et al. Plasma microRNAs serve as potential biomarkers for abdominal aortic aneurysm. Clin. Biochem. 48, 988–992 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Iyer, V., Rowbotham, S., Biros, E., Bingley, J. & Golledge, J. A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms. Atherosclerosis 261, 78–89 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. Jones, G. T. et al. Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci. Circ. Res. 120, 341–353 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Harrison, S. et al. Genetic association of lipids and lipid drug targets with abdominal aortic aneurysm: a meta-analysis. JAMA Cardiol. 3, 26–33 (2018).

    Article  PubMed  Google Scholar 

  137. Bäck, M. et al. Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovasc. Res. 99, 232–241 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Raaz, U. et al. Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development. Circulation 131, 1783–1795 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Sughimoto, K. et al. Effects of arterial blood flow on walls of the abdominal aorta: distributions of wall shear stress and oscillatory shear index determined by phase-contrast magnetic resonance imaging. Heart Vessels 31, 1168–1175 (2016).

    Article  PubMed  Google Scholar 

  140. Nchimi, A. et al. Multifactorial relationship between 18F-fluoro-deoxy-glucose positron emission tomography signaling and biomechanical properties in unruptured aortic aneurysms. Circ. Cardiovasc. Imaging 7, 82–91 (2014).

    Article  PubMed  Google Scholar 

  141. Khosla, S. et al. Meta-analysis of peak wall stress in ruptured, symptomatic and intact abdominal aortic aneurysms. Br. J. Surg. 101, 1350–1357 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Fillinger, M. F., Marra, S. P., Raghavan, M. L. & Kennedy, F. E. Prediction of rupture risk in abdominal aortic aneurysm during observation: wall stress versus diameter. J. Vasc. Surg. 37, 724–732 (2003).

    Article  PubMed  Google Scholar 

  143. The Propranolol Aneurysm Trial Investigators. Propranolol for small abdominal aortic aneurysms: results of a randomized trial. J. Vasc. Surg. 35, 72–79 (2002).

    Article  Google Scholar 

  144. Bicknell, C. et al. An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomized placebo-controlled trial (AARDVARK). Eur. Heart J. 37, 3213–3221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Pinchbeck, J. L. et al. A randomized placebo-controlled trial assessing the effect of 24 weeks fenofibrate therapy on circulating markers of abdominal aortic aneurysm: outcomes from the FAME-2 trial. J. Am. Heart Assoc. 7, e009866 (2018).

    Article  PubMed  Google Scholar 

  146. Morris, D. R. et al. Telmisartan in the management of abdominal aortic aneurysm (TEDY): the study protocol for a randomized controlled trial. Trials 16, 274 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02070653 (2018).

  148. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02225756 (2015).

  149. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01904981 (2014).

  150. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01756833 (2017).

  151. Xiong, J., Wu, Z., Chen, C., Wei, Y. & Guo, W. Association between diabetes and prevalence and growth rate of abdominal aortic aneurysms: a meta-analysis. Int. J. Cardiol. 221, 484–495 (2016).

    Article  PubMed  Google Scholar 

  152. Golledge, J. et al. Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte-matrix interactions. Eur. Heart J. 29, 665–672 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Dattani, N., Sayers, R. D. & Bown, M. J. Diabetes mellitus and abdominal aortic aneurysms: a review of the mechanisms underlying the negative relationship. Diab. Vasc. Dis. Res. 15, 367–374 (2018).

    Article  PubMed  Google Scholar 

  154. Kubota, Y., Folsom, A. R., Pankow, J. S., Wagenknecht, L. E. & Tang, W. Diabetes-related factors and abdominal aortic aneurysm events: the atherosclerotic risk in communities study. Ann. Epidemiol. 28, 102–106 (2018).

    Article  PubMed  Google Scholar 

  155. Le, M. T. Q., Jamrozik, K., Davis, T. M. E. & Norman, P. E. Negative association between infra-renal aortic diameter and glycaemia: the Health in Men study. Eur. J. Vasc. Endovasc. Surg. 33, 599–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Kristensen, K. L., Dahl, M., Rasmussen, L. M. & Lindholt, J. S. Glycated hemoglobin is associated with the growth rate of abdominal aortic aneurysms: a substudy from the VIVA (Viborg vascular) randomized screening trial. Arterioscler. Thromb. Vasc. Biol. 37, 730–736 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Morris, D. R. et al. The association of blood glucose and diabetes with peripheral arterial disease involving different vascular territories: results from 628 246 people who attended vascular screening. Eur. Heart J. 38, 654 (2017).

    Google Scholar 

  158. Vasamsetti, S. B. et al. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes 64, 2028–2041 (2015).

    Article  CAS  PubMed  Google Scholar 

  159. Fujimura, N. et al. Metformin treatment status and abdominal aortic aneurysm disease progression. J. Vasc. Surg. 64, 46–54 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Miyama, N. et al. Hyperglycemia limits experimental aortic aneurysm progression. J. Vasc. Surg. 52, 975–983 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Golledge, J. et al. Association between metformin prescription and growth rates of abdominal aortic aneurysms: metformin and growth rate of abdominal aortic aneurysm. Br. J. Surg. 104, 1486–1493 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Itoga, N. K. et al. Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population. J. Vasc. Surg. https://doi.org/10.1016/j.jvs.2018.06.194 (2018).

    Article  PubMed  Google Scholar 

  163. Golledge, J. et al. Metformin prescription is associated with a reduction in the combined incidence of surgical repair and rupture related mortality in patients with abdominal aortic aneurysm. Eur. J. Vasc. Endovasc. Surg. https://doi.org/10.1016/j.ejvs.2018.07.035 (2018).

    Article  PubMed  Google Scholar 

  164. Kristensen, K. L., Pottegård, A., Hallas, J., Rasmussen, L. M. & Lindholt, J. S. Metformin treatment does not affect the risk of ruptured abdominal aortic aneurysms. J. Vasc. Surg. 66, 768–774 (2017).

    Article  PubMed  Google Scholar 

  165. Hinchliffe, R. J. Metformin and abdominal aortic aneurysm. Eur. J. Vasc. Endovasc. Surg. 54, 679–680 (2017).

    Article  PubMed  Google Scholar 

  166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03507413 (2018).

  167. Hosoyama, K. et al. Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types. J. Thorac. Cardiovasc. Surg. 155, 2301–2313 (2018).

    Article  PubMed  Google Scholar 

  168. Xie, J. et al. Human adipose-derived stem cells suppress elastase-induced murine abdominal aortic inflammation and aneurysm expansion through paracrine factors. Cell Transplant. 26, 173–189 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Blose, K. J. et al. Periadventitial adipose-derived stem cell treatment halts elastase-induced abdominal aortic aneurysm progression. Regen. Med. 9, 733–741 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sharma, A. K. et al. Mesenchymal stem cells attenuate NADPH oxidase-dependent high mobility group box 1 production and inhibit abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 36, 908–918 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Davis, J. P. et al. Attenuation of aortic aneurysms with stem cells from different genders. J. Surg. Res. 199, 249–258 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Yamawaki-Ogata, A. et al. Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model. Eur. J. Cardiothorac. Surg. 45, 156–165 (2014).

    Article  Google Scholar 

  173. Fu, X. et al. Intravenous administration of mesenchymal stem cells prevents angiotensin II-induced aortic aneurysm formation in apolipoprotein E-deficient mouse. J. Transl Med. 11, 175–175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Hashizume, R., Yamawaki-Ogata, A., Ueda, Y., Wagner, W. R. & Narita, Y. Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice. J. Vasc. Surg. 54, 1743–1752 (2011).

    Article  PubMed  Google Scholar 

  175. Park, H. S. et al. Potential role of vascular smooth muscle cell-like progenitor cell therapy in the suppression of experimental abdominal aortic aneurysms. Biochem. Biophys. Res. Commun. 431, 326–331 (2013).

    Article  CAS  PubMed  Google Scholar 

  176. Sharma, A. K. et al. Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment. Circulation 126, S38–S45 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Swaminathan, G. et al. Pro-elastogenic effects of bone marrow mesenchymal stem cell-derived smooth muscle cells on cultured aneurysmal smooth muscle cells: stem cell induced elastogenesis by aneurysmal smooth muscle cells. J. Tissue Eng. Regen. Med. 11, 679–693 (2017).

    Article  CAS  PubMed  Google Scholar 

  178. Wang, S. K. et al. Rationale and design of the ARREST trial investigating mesenchymal stem cells in the treatment of small abdominal aortic aneurysm. Ann. Vasc. Surg. 47, 230–237 (2018).

    Article  PubMed  Google Scholar 

  179. Schepers, D. et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum. Mutat. 39, 621–634 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Milewicz, D. M., Prakash, S. K. & Ramirez, F. Therapeutics targeting drivers of thoracic aortic aneurysms and acute aortic dissections: insights from predisposing genes and mouse models. Annu. Rev. Med. 68, 51–67 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Mallat, Z., Ait-Oufella, H. & Tedgui, A. The pathogenic transforming growth factor-beta overdrive hypothesis in aortic aneurysms and dissections: a mirage? Circ. Res. 120, 1718–1720 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Daugherty, A., Chen, Z., Sawada, H., Rateri, D. L. & Sheppard, M. B. Transforming growth factor-β in thoracic aortic aneurysms: good, bad, or irrelevant? J. Am. Heart Assoc. 6, e005221 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. Angelov, S. N. et al. TGF-β (transforming growth factor-β) signaling protects the thoracic and abdominal aorta from angiotensin II-induced pathology by distinct mechanisms. Arterioscler. Thromb. Vasc. Biol. 37, 2102 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Chen, X. et al. TGF-β neutralization enhances angii-induced aortic rupture and aneurysm in both thoracic and abdominal regions. PLOS ONE 11, e0153811 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Wang, Y. et al. TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J. Clin. Invest. 120, 422–432 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Zhang, P. et al. Smad4 deficiency in smooth muscle cells initiates the formation of aortic aneurysm. Circ. Res. 118, 388–399 (2016).

    Article  CAS  PubMed  Google Scholar 

  187. Gao, F. et al. Disruption of TGF-β signaling in smooth muscle cell prevents elastase-induced abdominal aortic aneurysm. Biochem. Biophys. Res. Commun. 454, 137–143 (2014).

    Article  CAS  PubMed  Google Scholar 

  188. Li, W. et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J. Clin. Invest. 124, 755–767 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Yang, P. et al. Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events. Sci. Rep. 6, 35444 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Hu, J. H. et al. Postnatal deletion of the type II transforming growth factor-β receptor in smooth muscle cells causes severe aortopathy in mice. Arterioscler. Thromb. Vasc. Biol. 35, 2647–2656 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Wei, H. et al. Aortopathy in a mouse model of marfan syndrome is not mediated by altered transforming growth factor β signaling. J. Am. Heart Assoc. 6, e004968 (2017).

    PubMed  PubMed Central  Google Scholar 

  192. van der Pluijm, I. et al. Defective connective tissue remodeling in Smad3 mice leads to accelerated aneurysmal growth through disturbed downstream TGF-β signaling. EBioMedicine 12, 280–294 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Dai, X. et al. SMAD3 deficiency promotes vessel wall remodeling, collagen fiber reorganization and leukocyte infiltration in an inflammatory abdominal aortic aneurysm mouse model. Sci. Rep. 5, 10180 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Da Ros, F. et al. Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling. Immunity 47, 959–973 (2017).

    Article  PubMed  CAS  Google Scholar 

  195. Krishna, S. et al. High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice. Clin. Sci. 131, 1261–1281 (2017).

    Article  CAS  PubMed  Google Scholar 

  196. Liu, Z. et al. Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm. Circ. Res. 117, 129–141 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Krishna, S. M. et al. A peptide antagonist of thrombospondin-1 promotes abdominal aortic aneurysm progression in the angiotensin II–infused apolipoprotein-E–deficient mouse. Arterioscler. Thromb. Vasc. Biol. 35, 389–398 (2015).

    Article  CAS  PubMed  Google Scholar 

  198. Kojima, Y. et al. Proefferocytic therapy promotes transforming growth factor-beta signaling and prevents aneurysm formation. Circulation 137, 750–753 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Li, J. et al. Diabetes reduces severity of aortic aneurysms depending on the presence of cell division autoantigen 1 (CDA1). Diabetes 67, 755–768 (2018).

    Article  CAS  PubMed  Google Scholar 

  200. Dai, J. et al. Long term stabilization of expanding aortic aneurysms by a short course of cyclosporine a through transforming growth factor-beta induction. PLOS ONE 6, e28903 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Wang, Y., Krishna, S., Walker, P. J., Norman, P. & Golledge, J. Transforming growth factor-β and abdominal aortic aneurysms. Cardiovasc. Pathol. 22, 126–132 (2013).

    Article  PubMed  CAS  Google Scholar 

  202. Kim, M. et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum. Gene Ther. Clin. Dev. 29, 48–59 (2018).

    Article  CAS  PubMed  Google Scholar 

  203. Takeda, N. et al. TGF-β signaling-related genes and thoracic aortic aneurysms and dissections. Int. J. Mol. Sci. 19, E2125 (2018).

    Article  PubMed  CAS  Google Scholar 

  204. Golledge, J. et al. The novel association of the chemokine CCL22 with abdominal aortic aneurysm. Am. J. Pathol. 176, 2098–2106 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Jacomelli, J., Summers, L., Stevenson, A., Lees, T. & Earnshaw, J. J. Inequalities in abdominal aortic aneurysm screening in England: effects of social deprivation and ethnicity. Eur. J. Vasc. Endovasc. Surg. 53, 837–843 (2017).

    Article  CAS  PubMed  Google Scholar 

  206. Baxter, B. T. et al. Non-invasive treatment of abdominal aortic aneurysm clinical trial (N-TA3CT): design of a phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm. Contemp. Clin. Trials 48, 91–98 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank Evan Mathews (James Cook University, Australia) for help with preparing figure 3 before submission; Anne-Marie Hill and Alexandra Golledge (James Cook University, Australia) for help with the references, other figures and proof reading; and the researchers from the Queensland Research Centre for Peripheral Vascular Disease, especially Joseph Moxon, Corey Moran, Dylan Morris and Smriti Krishna, for their ongoing research on AAA pathogenesis, which has contributed towards the insight included in this Review. Finally, I apologise to scientists whose research could not be included in this Review due to space limitations. The author’s research was supported by grants from the National Health and Medical Research Council (1098717, 1079369 and 1022752), Townsville Hospital and Health Service Study, Education and Research Trust Fund and Queensland Government. J.G. holds a Practitioner Fellowship from the National Health and Medical Research Council (1117601) and a Senior Clinical Research Fellowship from the Queensland Government.

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Nature Reviews Cardiology thanks G.-P. Shi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia

    Jonathan Golledge

  2. Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia

    Jonathan Golledge

  3. Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia

    Jonathan Golledge

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J.G. is employed by a public hospital (The Townsville Hospital, Australia) and university (James Cook University, Australia) as a professor of vascular surgery.

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Golledge, J. Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol 16, 225–242 (2019). https://doi.org/10.1038/s41569-018-0114-9

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