Matrix Metalloproteinases in Ascending Aortic Aneurysms: Bicuspid versus Trileaflet Aortic Valves 1 Scott A. LeMaire, M.D.,* ,2 Xinwen Wang, M.D., Ph.D.,* Jonathan A. Wilks, B.A.,* Stacey A. Carter, B.A.,* Shixiang Wen, B.S.,* Taehee Won, M.D., Ph.D.,* Dominic Leonardelli, B.A.,* Gobind Anand,* Lori D. Conklin, M.D.,* Xing Li Wang, M.D., Ph.D.,* Robert W. Thompson, M.D.,† and Joseph S. Coselli, M.D.* *Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and The Methodist DeBakey Heart Center, Houston, Texas; and †Departments of Surgery (Section of Vascular Surgery), Radiology, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri Submitted for publication December 31, 2003 Background. Abnormal matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression contributes to the development of abdominal aortic aneurysms. Recent data suggest that MMP-2 and MMP-9 may also play a role in thoracic aortic disease. We sought to determine (1) whether ascending aortic aneurysms are associated with in- creased MMP expression and (2) whether aortic in- flammation and MMP expression differ between pa- tients with congenital bicuspid aortic valves (BAVs) and those with trileaflet aortic valves (TAVs). Materials and methods. Samples of ascending aortic aneurysms were obtained from 29 patients; 14 patients had BAVs and 15 had TAVs. Control ascending aorta was obtained from 14 organ donors or heart trans- plant recipients. Aortic histology and immunohisto- chemistry were performed to evaluate elastin degra- dation, inflammatory changes, and MMP-2 and MMP-9 expression. Aortic levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured using ELISA. Results. Aneurysms in the TAV patients exhibited marked inflammation, high CD68 expression, dimin- ished elastin content, increased MMP-9 expression, and normal MMP-2 levels. In contrast, BAV aneurysms were characterized by a relative lack of inflammation, preservation of elastin content, normal MMP-9 levels, and elevated MMP-2 expression. TIMP-1 and TIMP-2 levels were not significantly different among the three groups. Conclusions. Ascending aortic aneurysms exhibited increased MMP expression. The pattern of MMP ex- pression and the degree of inflammation, however, dif- fered between aneurysms associated with BAVs and those with TAVs. Variations in the molecular mecha- nisms underlying different types of thoracic aortic an- eurysms warrant further investigation. © 2004 Elsevier Inc. All rights reserved. Key Words: ascending aortic aneurysms; matrix met- alloproteinases; bicuspid aortic valves; medial degen- erative disease; gelatinase A; gelatinase B. INTRODUCTION The majority of research regarding the pathogenesis of ascending aortic dilatation has focused on aneu- rysms caused by Marfan syndrome (MFS) and other connective tissues disorders. The molecular mecha- nisms responsible for aneurysms in patients with other, far more common conditions—such as non- specific medial degenerative disease and congenital bi- cuspid aortic valve (BAV)—remain poorly understood. Recent studies have demonstrated that aneurysms as- sociated with BAVs exhibit striking histological and molecular differences compared to aneurysms in pa- tients with trileaflet aortic valves (TAVs), suggesting that different pathways are responsible for progressive aortic dilatation in these two groups [1– 4]. The therapeutic potential of protease inhibition makes matrix metalloproteinases (MMPs) attractive targets for investigation in these patients. Matrix met- alloproteinases are a family of zinc-dependent en- dopeptidases that are produced by leukocytes and 1 Presented in part at the 37th Annual Meeting of the Association for Academic Surgery, Sacramento, CA, November 13–15, 2003. 2 To whom correspondence and reprint requests should be ad- dressed at 6560 Fannin, Suite 1100, Houston, TX 77030. E-mail: slemaire@bcm.tmc.edu. Journal of Surgical Research 123, 40 – 48 (2005) doi:10.1016/j.jss.2004.06.007 40 0022-4804/05 $30.00 © 2004 Elsevier Inc. All rights reserved.