Ann Thorac Surg 2009;88:513-514. doi:10.1016/j.athoracsur.2009.04.094
© 2009 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Invited Commentary
Ali Nsair, MD,
Katja Schenke-Layland, PhD, MS
Department of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, 675 Charles E. Young Dr S, MRL-3579, Los Angeles, CA 90095
(Email: kschenkelayland{at}mednet.ucla.edu).
The article by Toumpoulis and colleagues [1] addresses an important pathophysiologic question regarding the molecular mechanisms leading to degenerative ascending thoracic aortic aneurysms (ATAAs) in the nongenetic syndrome cases. With an incidence of 6 to 10 per 100,000, and being a disease that occurs mostly in the 6th and 7th decades of life, the incidence of ATAAs is going to increase dramatically in the next few years with our aging population. Currently there are no proven therapies to prevent or reverse the development of ATAAs. The only medical therapy that has been demonstrated to slow the progression of aneurysmal dilatation is treating these patients with beta blockers that act by decreasing left ventricular contractility (dp/dt) and shear stress on the aortic wall. Accordingly, Shores and colleagues [2] showed that the group treated with the beta blocker had a 73% slower rate of aortic dilatation and a lower mortality after the first 4 years of follow-up.
The present study [1] was elegantly presented and demonstrates a molecular mechanism for the possible pathways leading to these aneurysms. Collagen types V and 
1(XI) mRNA and protein expression levels were significantly increased within regions of cystic medial degenerative lesions in human ATAAs. The authors further showed a significant decrease in the protein levels of collagen types I and III, although mRNA expression levels were similar in ATAAs as compared with controls, which were also linearly correlated with the size of the aneurysms. The natural history of this disease is of continuous progression of the size of the aneurysm as the extracellular matrix (ECM) in the aortic wall weakens leading to eventual rupture if not intervened on. The 5-year risk of rupture was found to be 0% for aneurysms less than 40 mm when compared to 16 and 31% for aneurysms measuring 40 to 59 and 
60 mm, respectively [3]. The only option for treatment of critically dilated aneurysms is invasive intervention, whether it is surgical replacement of the involved aortic root and arch or endovascular stenting. Determining the triggers that set this cascade in motion, whether it is the oxidative stress of atherosclerosis, mechanical tension secondary to long-term uncontrolled hypertension, or other undetermined factors would be of importance. Furthermore, now that the molecular pathways of the pathogenesis of ATAAs has been more defined as demonstrated by Toumpoulis and colleagues [1], studying potential targets within this pathway to block the degradation of the ECM, as this is the end target that leads to eventual weakening of the aortic wall and aortic dissection, and its severe clinical consequences will be also critical. Early studies in animal models revealed a correlation between the rate of aneurysm rupture and an increase in matrix metalloproteinase (MMP) levels (2 and 9) [4]. Induction of local over-expression of tissue inhibitors of MMPs by retrovirally infecting smooth muscle cells locally prevented aneurysmal degeneration and rupture [4]. Therefore, this new understanding of the molecular mechanisms of development of ATAAs in humans will definitely aid in developing similar and novel therapeutics now that the pathway is more clearly delineated.
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References
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- Toumpoulis IK, Oxford JT, Cowan DB, et al. Differential expression of collagen type V and XI -1 in human ascending thoracic aortic aneurysms Ann Thorac Surg 2009;88:506-514.[Abstract/Free Full Text]
- Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta adrenergic blockade in Marfan's syndrome N Engl J Med 1994;330:1335-1385.[Medline]
- Clouse WD, Hallett JW, Schaff HV, Gayari MM, Ilstrup DM, Melton 3rd LJ. Improved prognosis of thoracic aortic aneurysms: a population-based study JAMA 1998;280:1926-1929.[Abstract/Free Full Text]
- Allaire E, Forough R, Clowes M, Starcher B, Clowes AW. Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model J Clin Invest 1998;102:1413-1420.[Medline]
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Differential Expression of Collagen Type V and XI -1 in Human Ascending Thoracic Aortic Aneurysms
- Ioannis K. Toumpoulis, Julia Thom Oxford, Douglas B. Cowan, Constantine E. Anagnostopoulos, Chris K. Rokkas, Themistocles P. Chamogeorgakis, Dimitrios C. Angouras, Richard J. Shemin, Mohamad Navab, Maria Ericsson, Micheline Federman, Sidney Levitsky, and James D. McCully
Ann. Thorac. Surg. 2009 88: 506-513.
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