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(Circulation. 2002;105:1955.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Myocardial Ischemic Injury After Heart Transplantation Is Associated With Upregulation of Vitronectin Receptor (_vß₃), Activation of the Matrix Metalloproteinase Induction System, and Subsequent Development of Coronary Vasculopathy

Mohamad H. Yamani, MD; E. Murat Tuzcu, MD; Randall C. Starling, MD MPH; Norman B. Ratliff, MD; Yang Yu, BS; D. Geoffrey Vince, PhD; Kimerly Powell, PhD; Daniel Cook, PhD; Patrick McCarthy, MD; James B. Young, MD

From the Departments of Cardiovascular Medicine (M.H.Y., E.M.T., R.C.S., Y.Y., J.B.Y.), Anatomic Pathology (N.B.R.), Biomedical Engineering (D.G.V., K.P.), and Cardiothoracic Surgery (P.M.), and the Allogen Laboratory (D.C.) and Kaufman Center for Heart Failure (M.H.Y., E.M.T., R.C.S., Y.Y., J.B.Y., P.M.), Cleveland Clinic Foundation, Ohio.

Correspondence to Mohamad H. Yamani, MD, Cleveland Clinic Foundation, Cardiology, F25, 9500 Euclid Ave, Cleveland, OH 44195. E-mail yamanim{at}ccf.org

Background— Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin _vß₃) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models.

Methods and Results— Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for _vß₃, tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of _vß₃ (3.2-fold, P<0.001), tissue factor (2.5-fold, P<0.001), and EMMPRIN (1.9-fold, P=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24±1.8% versus 14±1.1%, P<0.001) and zymographic activity of MMP-2 (1.4-fold, P<0.001), MMP-3 (1.2-fold, P<0.001), and MMP-9 (1.3-fold, P=0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54±0.1 versus 0.26±0.06 mm; P=0.031).

Conclusions— Myocardial ischemic injury after cardiac transplantation is associated with upregulation of _vß₃, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.

Key Words: glycoproteins • metalloproteinases • transplantation • ultrasonics

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