EDITORIAL COMMENT
Early Growth Response Factor-1*
John A. Elefteriades, MD, FACC* and
Michael J. Collins, MD
Department of Surgery, Cardiothoracic Surgery, Yale University School of Medicine, New Haven, Connecticut
* Reprint requests and correspondence: Dr. John A. Elefteriades, Yale University School of Medicine, Cardiothoracic Surgery, Department of Surgery, 121 FMB, 333 Cedar Street, New Haven, Connecticut 06510 (Email: john.elefteriades{at}yale.edu).
Key Words: abdominal aortic aneurysm • thrombus • early growth response-1 • tissue factor
Aneurysm rupture is a potentially devastating complication of abdominal aortic aneurysms; however, the events leading to rupture remain unclear. It has been suggested that mural thrombus may play a role in this process (1). In this issue of the Journal, Shin et al. (2) examine the role of early growth response factor (Egr)-1 and tissue factor (TF) (a prothrombotic factor) in thrombus formation. In human aneurysmal tissue, they observe (using quantitative polymerase chain reaction and immunohistochemistry) increased amounts of Egr-1 and TF in the thrombus-covered wall compared with the thrombus-free wall. They show that in tissue culture, overexpression of Egr-1 results in TF up-regulation. Lastly, they confirm that overexpression of Egr-1 promotes thrombus formation in a mouse vena cava ligation model. The authors conclude that Egr-1 is up-regulated in the human thrombus-covered aneurysm wall and that Egr-1 may play an early role in thrombus formation and, potentially, aneurysm rupture.
The paper by Shin et al. (2) is an exceptional contribution, which really represents multiple studies in 1 beautifully integrated whole. The 3 components—the assay of Egr-1 in human aneurysm tissue, the tranfection cell culture, and the vena caval thrombosis observations—are beautifully planned and coordinated. The use of multiple models (cell culture, animal models, and aneurysmal human tissue) provides powerful evidence for the importance of Egr-1 in aneurysm pathogenesis. Each phase of the study has thoughtful, convincing control interventions, solidifying the importance of Egr-1 rather than other potential influences. However, it remains unclear whether differences in Egr-1 expression are primary forces or epiphenomena. The authors touch on this point in their Discussion section. Even if these are epiphenomena, the authors' observations still contribute to our understanding.
From the standpoint of a practicing aortic surgeon, it is important to emphasize that we see thrombus clinically only if there is significant dilation of a portion of the descending aorta. When the dilation is eccentric, the thrombus is limited to the most dilated portion, even if it affects only part of the circumference of the aorta. The surgeon understands this localization (rightly or not) as a consequence of slower flow in the eccentrically dilated portions of the aorta. It is well known that slow-flowing blood clots. Only the central portion of a severely dilated aorta has rapid, laminar flow. The authors touch on these anatomic and fluid dynamics issues in their Discussion section. It could well be that all changes in Egr-1 expression seen by the authors simply are downstream consequences of the basic principle that slow-flowing blood clots. This is, after all, the body's mechanism for sealing wounds. While the slow-flowing hypothesis could explain the thrombus, is there any way by which slow blood flow per se could lead directly to altered expression of Egr-1 in the aortic wall?
From a surgeon's viewpoint, it is important to also mention that thrombus is almost never seen in the ascending aorta, despite severe dilation (3). We have simplistically presumed that the ascending aorta is so thoroughly "washed" by blood flow that thrombus does not have a chance to form. Furthermore, a number of recent studies have demonstrated differences in gene expression between aneurysmal tissue in the abdominal aorta compared with that in the ascending aorta (4). These molecular studies, including the present report, combined with anatomic and pathological findings, suggest that aneurysms of the aorta may develop through different mechanisms in the ascending and descending/abdominal aortic segments.
The role of thrombus formation in abdominal aneurysm pathogenesis and rupture remains unclear. In the current report, the authors imply that—because of the involvement of Egr-1 in thrombosis and potentially in rupture—we might, therefore, want to stop thrombosis in an aneurysm. However, the potential benefit of this is not intuitively clear. Although embolization of thrombotic material does occasionally occur, this complication pales in comparison to catastrophic rupture in frequency and impact. Furthermore, while thrombus is often found at the site of rupture (5), there is no direct evidence that the thrombus promotes rupture. Is it not simply much more likely that thrombus and rupture both occur at the most dilated and mechanically weakened portion of the aortic wall?
Lastly, though the authors may have intended to use knowledge of the Egr-1 biology in monitoring an aneurysm patient's status and specific risk for rupture, this appears unlikely to be feasible at the present time. As with other molecular markers for aneurysm growth, any such application is limited by the simple fact that we cannot really biopsy the aortic wall sequentially in monitoring patients. This point highlights the need to identify systemic markers of aneurysm activity that can be assessed through peripheral blood drawing.
All in all, the authors provide a new perspective, centered around the phenomenon of localized thrombosis within aneurysms, which augments our understanding of the overall pathobiology of aneurysm disease.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Swedenborg J, Eriksson P. The intraluminal thrombus as a source of proteolytic activity Ann N Y Acad Sci 2006;1085:133-138.[CrossRef][Web of Science][Medline]2. Shin I-S, Kim J-M, Kim KL. Early growth response factor-1 is associated with intraluminal thrombus formation in human abdominal aortic aneurysm J Am Coll Cardiol 2009;53:792-799.[Abstract/Free Full Text] 3. Collins MJ, Dev V, Strauss BH, Fedak PW, Butany J. Variation in the histopathological features of patients with ascending aortic aneurysms: a study of 111 surgically excised cases J Clin Pathol 2008;61:519-523.[Abstract/Free Full Text] 4. Absi TS, Sundt 3rd TM, Tung WS, 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;126:344-357discussion 357.[Abstract/Free Full Text] 5. Simao da Silva E, Rodrigues AJ, Magalhaes Castro de Tolosa E, Rodrigues CJ, Villas Boas do Prado G, Nakamoto JC. Morphology and diameter of infrarenal aortic aneurysms: a prospective autopsy study Cardiovasc Surg 2000;8:526-532.[CrossRef][Web of Science][Medline]
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