Int J Angiol 2015; 24(03): 189-197
DOI: 10.1055/s-0035-1556075
Invited Review
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Ascending Aortic Proaneurysmal Genetic Mutations with Antiatherogenic Effects

Alexander Curtis
1   Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
Tanya Smith
1   Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
Bulat A. Ziganshin
1   Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
2   Department of Surgical Diseases No. 2, Kazan State Medical University, Kazan, Russia
John A. Elefteriades
1   Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
› Author Affiliations
Further Information

Publication History

Publication Date:
17 August 2015 (online)


Thoracic aortic aneurysms are common and are associated with a high morbidity and mortality. Despite this lethal diagnosis, there is an increasing body of evidence to suggest that the diagnosis of an aneurysm, specifically in the ascending thoracic aorta, may significantly reduce the risk of developing systemic atherosclerosis. Clinical observations in the operating room have shown pristine blood vessels in patients undergoing surgery for thoracic aortic aneurysms. There is now evidence that both the carotid intima-media thickness and arterial calcification, which are early and late signs of atherosclerosis respectively, are decreased in those with thoracic aortic aneurysms. These clinical studies are supported by molecular, genetic, and pharmacological evidence. Two principle mechanisms have been identified to explain the relationship of a proaneurysmal state conferring protection from atherosclerosis. These include an excess proteolytic balance of matrix metalloproteinase activity, leading to fragmentation of elastic lamellae and disordered collagen deposition. In addition, transforming growth factor β modulates vascular smooth muscle cells, extracellular matrix, and leukocytes. This confers protection from the initial plaque formation and, later provides stability to the plaque possibly through alteration of the types I and II transforming growth factor β receptor ratio. Furthermore, studies are now beginning to establish an important role for statins and estradiol in modulating these complex pathways. In the future, as our understanding of these complex mechanisms underlying aneurysmal protection against atherosclerosis increases, corresponding therapies may be developed to offer protection from atherosclerosis.

  • References

  • 1 Elefteriades JA. Beating a sudden killer. Sci Am 2005; 293 (2) 64-71
  • 2 Clouse WD, Hallett Jr JW, Schaff HV, Gayari MM, Ilstrup DM, Melton III LJ. Improved prognosis of thoracic aortic aneurysms: a population-based study. JAMA 1998; 280 (22) 1926-1929
  • 3 Clouse WD, Hallett Jr JW, Schaff HV , et al. Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture. Mayo Clin Proc 2004; 79 (2) 176-180
  • 4 Kuzmik GA, Sang AX, Elefteriades JA. Natural history of thoracic aortic aneurysms. J Vasc Surg 2012; 56 (2) 565-571
  • 5 Achneck H, Modi B, Shaw C , et al. Ascending thoracic aneurysms are associated with decreased systemic atherosclerosis. Chest 2005; 128 (3) 1580-1586
  • 6 Nakashima Y, Kurozumi T, Sueishi K, Tanaka K. Dissecting aneurysm: a clinicopathologic and histopathologic study of 111 autopsied cases. Hum Pathol 1990; 21 (3) 291-296
  • 7 Kojima S, Suwa S, Fujiwara Y , et al. Incidence and severity of coronary artery disease in patients with acute aortic dissection: comparison with abdominal aortic aneurysm and arteriosclerosis obliterans [in Japanese]. J Cardiol 2001; 37 (3) 165-171
  • 8 Kent KC, Zwolak RM, Egorova NN , et al. Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals. J Vasc Surg 2010; 52 (3) 539-548
  • 9 Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010; 55 (9) 841-857
  • 10 Kuzmik GA, Feldman M, Tranquilli M, Rizzo JA, Johnson M, Elefteriades JA. Concurrent intracranial and thoracic aortic aneurysms. Am J Cardiol 2010; 105 (3) 417-420
  • 11 de Groot E, Hovingh GK, Wiegman A , et al. Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation 2004; 109 (23) (Suppl. 01) III33-III38
  • 12 Hung A, Zafar M, Mukherjee S, Tranquilli M, Scoutt LM, Elefteriades JA. Carotid intima-media thickness provides evidence that ascending aortic aneurysm protects against systemic atherosclerosis. Cardiology 2012; 123 (2) 71-77
  • 13 Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115 (4) 459-467
  • 14 van de Luijtgaarden KM, Bakker EJ, Rouwet EV , et al. Aneurysmal disease is associated with lower carotid intima-media thickness than occlusive arterial disease. J Vasc Surg 2013; 57 (3) 642-647
  • 15 Chau K, Elefteriades JA. Ascending thoracic aortic aneurysms protect against myocardial infarctions. Int J Angiol 2014; 23 (3) 177-182
  • 16 Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000; 1477 (1-2) 267-283
  • 17 Ruddy JM, Jones JA, Stroud RE, Mukherjee R, Spinale FG, Ikonomidis JS. Differential effects of mechanical and biological stimuli on matrix metalloproteinase promoter activation in the thoracic aorta. Circulation 2009; 120 (11, Suppl): S262-S268
  • 18 Hanemaaijer R, Koolwijk P, Le Clercq L, de Vree WJ, van Hinsbergh VW. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. Biochem J 1993; 296 (Pt 3): 803-809
  • 19 Galis ZS, Muszynski M, Sukhova GK , et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res 1994; 75 (1) 181-189
  • 20 Mauviel A. Cytokine regulation of metalloproteinase gene expression. J Cell Biochem 1993; 53 (4) 288-295
  • 21 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17: 463-516
  • 22 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002; 90 (3) 251-262
  • 23 Johnson JL, George SJ, Newby AC, Jackson CL. Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc Natl Acad Sci U S A 2005; 102 (43) 15575-15580
  • 24 Ikonomidis JS, Gibson WC, Butler JE , et al. Effects of deletion of the tissue inhibitor of matrix metalloproteinases-1 gene on the progression of murine thoracic aortic aneurysms. Circulation 2004; 110 (11) (Suppl. 01) II268-II273
  • 25 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 (6) 2106-2110 , discussion 2110–2111
  • 26 Silence J, Collen D, Lijnen HR. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ Res 2002; 90 (8) 897-903
  • 27 Lemaître V, O'Byrne TK, Borczuk AC, Okada Y, Tall AR, D'Armiento J. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest 2001; 107 (10) 1227-1234
  • 28 Silence J, Lupu F, Collen D, Lijnen HR. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol 2001; 21 (9) 1440-1445
  • 29 Chau KH, Bender JR, Elefteriades JA. Silver lining in the dark cloud of aneurysm disease. Cardiology 2014; 128 (4) 327-332
  • 30 Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cardiac neural crest. Development 2000; 127 (8) 1607-1616
  • 31 Cheung C, Bernardo AS, Trotter MW, Pedersen RA, Sinha S. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol 2012; 30 (2) 165-173
  • 32 Gittenberger-de Groot AC, DeRuiter MC, Bergwerff M, Poelmann RE. Smooth muscle cell origin and its relation to heterogeneity in development and disease. Arterioscler Thromb Vasc Biol 1999; 19 (7) 1589-1594
  • 33 Schmoker JD, McPartland KJ, Fellinger EK , et al. Matrix metalloproteinase and tissue inhibitor expression in atherosclerotic and nonatherosclerotic thoracic aortic aneurysms. J Thorac Cardiovasc Surg 2007; 133 (1) 155-161
  • 34 Ruddy JM, Jones JA, Ikonomidis JS. Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin. Prog Cardiovasc Dis 2013; 56 (1) 68-73
  • 35 Bauer M, Pasic M, Meyer R , et al. Morphometric analysis of aortic media in patients with bicuspid and tricuspid aortic valve. Ann Thorac Surg 2002; 74 (1) 58-62
  • 36 Koullias GJ, Korkolis DP, Ravichandran P, Psyrri A, Hatzaras I, Elefteriades JA. Tissue microarray detection of matrix metalloproteinases, in diseased tricuspid and bicuspid aortic valves with or without pathology of the ascending aorta. Eur J Cardiothorac Surg 2004; 26 (6) 1098-1103
  • 37 Ikonomidis JS, Jones JA, Barbour JR , et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with bicuspid or tricuspid aortic valves. J Thorac Cardiovasc Surg 2007; 133 (4) 1028-1036
  • 38 LeMaire SA, Wang X, Wilks JA , et al. Matrix metalloproteinases in ascending aortic aneurysms: bicuspid versus trileaflet aortic valves. J Surg Res 2005; 123 (1) 40-48
  • 39 Karakaya O, Barutcu I, Esen AM , et al. Relationship between circulating plasma matrix metalloproteinase-9 (gelatinase-B) concentration and aortic root dilatation. Am J Hypertens 2006; 19 (4) 361-365
  • 40 Ikonomidis JS, Ivey CR, Wheeler JB , et al. Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg 2013; 145 (5) 1326-1333
  • 41 Ikonomidis JS, Ruddy JM, Benton Jr SM , et al. Aortic dilatation with bicuspid aortic valves: cusp fusion correlates to matrix metalloproteinases and inhibitors. Ann Thorac Surg 2012; 93 (2) 457-463
  • 42 Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 1996; 271 (22) 13055-13060
  • 43 Lesauskaite V, Sinkunaite-Marsalkiene G, Tamosiunas A, Benetis R. Protective effects of angiotensin-converting enzyme I/I and matrix metalloproteinase-3 6A/6A polymorphisms on dilatative pathology within the ascending thoracic aorta. Eur J Cardiothorac Surg 2011; 40 (1) 23-27
  • 44 Ghilardi G, Biondi ML, DeMonti M, Turri O, Guagnellini E, Scorza R. Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke 2002; 33 (10) 2408-2412
  • 45 Rauramaa R, Väisänen SB, Luong LA , et al. Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20 (12) 2657-2662
  • 46 Gnasso A, Motti C, Irace C , et al. Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects. Arterioscler Thromb Vasc Biol 2000; 20 (6) 1600-1605
  • 47 Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995; 73 (3) 209-215
  • 48 Humphries SE, Luong LA, Talmud PJ , et al. The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study. Lopid Coronary Angiography Trial. Atherosclerosis 1998; 139 (1) 49-56
  • 49 Beyzade S, Zhang S, Wong YK, Day IN, Eriksson P, Ye S. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol 2003; 41 (12) 2130-2137
  • 50 Hirashiki A, Yamada Y, Murase Y , et al. Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors. J Am Coll Cardiol 2003; 42 (8) 1429-1437
  • 51 Abdul-Hussien H, Hanemaaijer R, Verheijen JH, van Bockel JH, Geelkerken RH, Lindeman JH. Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content. J Vasc Surg 2009; 49 (3) 741-749
  • 52 Grainger DJ, Kemp PR, Witchell CM, Weissberg PL, Metcalfe JC. Transforming growth factor beta decreases the rate of proliferation of rat vascular smooth muscle cells by extending the G2 phase of the cell cycle and delays the rise in cyclic AMP before entry into M phase. Biochem J 1994; 299 (Pt 1) 227-235
  • 53 Kojima S, Harpel PC, Rifkin DB. Lipoprotein (a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol 1991; 113 (6) 1439-1445
  • 54 Ignotz RA, Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 1986; 261 (9) 4337-4345
  • 55 Jiang X, Zeng HS, Guo Y, Zhou ZB, Tang BS, Li FK. The expression of matrix metalloproteinases-9, transforming growth factor-beta1 and transforming growth factor-beta receptor I in human atherosclerotic plaque and their relationship with plaque stability. Chin Med J (Engl) 2004; 117 (12) 1825-1829
  • 56 Cipollone F, Fazia M, Mincione G , et al. Increased expression of transforming growth factor-beta1 as a stabilizing factor in human atherosclerotic plaques. Stroke 2004; 35 (10) 2253-2257
  • 57 Li C, Mollahan P, Baguneid MS , et al. A comparative study of neovascularisation in atherosclerotic plaques using CD31, CD105 and TGF beta 1. Pathobiology 2006; 73 (4) 192-197
  • 58 Tsunawaki S, Sporn M, Ding A, Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature 1988; 334 (6179) 260-262
  • 59 Argmann CA, Van Den Diepstraten CH, Sawyez CG , et al. Transforming growth factor-beta1 inhibits macrophage cholesteryl ester accumulation induced by native and oxidized VLDL remnants. Arterioscler Thromb Vasc Biol 2001; 21 (12) 2011-2018
  • 60 Mallat Z, Gojova A, Marchiol-Fournigault C , et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001; 89 (10) 930-934
  • 61 McCaffrey TA, Consigli S, Du B , et al. Decreased type II/type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-beta1. J Clin Invest 1995; 96 (6) 2667-2675
  • 62 Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol 2004; 24 (3) 399-404
  • 63 Koch W, Hoppmann P, Mueller JC, Schömig A, Kastrati A. Association of transforming growth factor-beta1 gene polymorphisms with myocardial infarction in patients with angiographically proven coronary heart disease. Arterioscler Thromb Vasc Biol 2006; 26 (5) 1114-1119
  • 64 Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y. Association of a T29—>C polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 2000; 101 (24) 2783-2787
  • 65 Najar RA, Ghaderian SM, Panah AS. Association of transforming growth factor-β1 gene polymorphisms with genetic susceptibility to acute myocardial infarction. Am J Med Sci 2011; 342 (5) 365-370
  • 66 Rodríguez-Vita J, Sánchez-Galán E, Santamaría B , et al. Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation. PLoS ONE 2008; 3 (12) e3959
  • 67 Vecerova L, Strasky Z, Rathouska J , et al. Activation of TGF-β receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice. J Atheroscler Thromb 2012; 19 (2) 115-126
  • 68 Gourdy P, Schambourg A, Filipe C , et al. Transforming growth factor activity is a key determinant for the effect of estradiol on fatty streak deposit in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol 2007; 27 (10) 2214-2221
  • 69 Annabi B, Shédid D, Ghosn P , et al. Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms. J Vasc Surg 2002; 35 (3) 539-546
  • 70 Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994; 94 (6) 2493-2503
  • 71 Müller A, Krämer SD, Meletta R , et al. Gene expression levels of matrix metalloproteinases in human atherosclerotic plaques and evaluation of radiolabeled inhibitors as imaging agents for plaque vulnerability. Nucl Med Biol 2014; 41 (7) 562-569
  • 72 Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002; 110 (5) 625-632
  • 73 Davis V, Persidskaia R, Baca-Regen L , et al. Matrix metalloproteinase-2 production and its binding to the matrix are increased in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 1998; 18 (10) 1625-1633
  • 74 Jones JA, Ruddy JM, Bouges S , et al. Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model. Am J Physiol Heart Circ Physiol 2010; 299 (1) H114-H124
  • 75 Fontaine V, Jacob MP, Houard X , et al. Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am J Pathol 2002; 161 (5) 1701-1710
  • 76 Pradhan-Palikhe P, Vikatmaa P, Lajunen T , et al. Elevated MMP-8 and decreased myeloperoxidase concentrations associate significantly with the risk for peripheral atherosclerosis disease and abdominal aortic aneurysm. Scand J Immunol 2010; 72 (2) 150-157
  • 77 Ikonomidis JS, Barbour JR, Amani Z , et al. Effects of deletion of the matrix metalloproteinase 9 gene on development of murine thoracic aortic aneurysms. Circulation 2005; 112 (9, Suppl): I242-I248
  • 78 Kim SC, Singh M, Huang J , et al. Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 1997; 41 (3) 642-666 , discussion 646–647
  • 79 Tromp G, Gatalica Z, Skunca M , et al. Elevated expression of matrix metalloproteinase-13 in abdominal aortic aneurysms. Ann Vasc Surg 2004; 18 (4) 414-420
  • 80 Deguchi JO, Aikawa E, Libby P , et al. Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. Circulation 2005; 112 (17) 2708-2715
  • 81 Bruno G, Todor R, Lewis I, Chyatte D. Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 1998; 89 (3) 431-440