Myocardial Ischemic Injury After Heart Transplantation Is Associated With Upregulation of Vitronectin Receptor (α v β 3 ), Activation of the Matrix Metalloproteinase Induction System, and Subsequent Development of Coronary Vasculopathy

Abstract

Background — Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin α v β 3 ) 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 α v β 3 , 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 α v β 3 (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 α v β 3 , tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.