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CLINICAL STUDY: HEART TRANSPLANT

The role of vitronectin receptor (vß3) and tissue factor in the pathogenesis of transplant coronary vasculopathy

Mohamad H. Yamani, MD^*||,*, Carolina S. Masri, MD^*||, Norman B. Ratliff, MD, Meredith Bond, PhD, Randall C. Starling, MD, MPH, FACC^*||, E. Murat Tuzcu, MD^*, Patrick M. McCarthy, MD^|| and James B. Young, MD, FACC^*||

^* Department of Cardiology, Learner Research Institute, Cleveland, Ohio, USA
Department of Anatomic Pathology, Learner Research Institute, Cleveland, Ohio, USA
Department of Molecular Cardiology, Learner Research Institute, Cleveland, Ohio, USA
Department of Cardiothoracic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^|| Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Manuscript received May 4, 2001; revised manuscript received November 28, 2001, accepted December 12, 2001.

^* Reprint requests and correspondence: Dr. Mohamad H Yamani, Cleveland Clinic Foundation, Cardiology, F25, Heart Failure/Transplant Section, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
yamanim{at}ccf.org

OBJECTIVES: This study was undertaken to test the hypothesis that transplant coronary vasculopathy (CV) is associated with increased myocardial protein expression of both tissue factor (TF) and integrin vß3.

BACKGROUND: The vitronectin receptor (integrin vß3) and TF have recently been found to play a key role in apoptotic cell death and vascular endothelial cell injury.

METHODS: A total of 77 heart transplant recipients underwent simultaneous endomyocardial biopsy and intravascular ultrasound (IVUS) at one year of transplant. Patients with pre-existing donor coronary atherosclerosis (n = 35) or with acute rejection (grade >1A, n = 10) at the time of the IVUS were excluded from the analysis. The remaining 32 patients constitute the cohort of the present study. A computerized biopsy score was derived based on the duration and severity of cellular rejection. Both TF and vß3 expression in the heart biopsy specimens were evaluated by immunoperoxidase histochemistry and Western blot analysis.

RESULTS: Patients with CV (n = 24) had increased expression of vß3 (2.7-fold, p = 0.003) and TF (7.9-fold, p = 0.04) compared with patients without evidence of vasculopathy (n = 8). In the absence of myocardial fibrosis, vß3 expression correlated significantly with the cellular rejection score (r = 0.58, p = 0.02).

CONCLUSIONS: Transplant vasculopathy is associated with increased expression of both TF and vß3. The significant correlation of vß3 with cellular rejection suggests an important role for this integrin in serving as a mechanistic link between cellular rejection and vasculopathy.

Abbreviations and Acronyms   GAPDH   CMIT   coronary maximal intimal thickness   CV   coronary vasculopathy   GAPDH   glyceraldehyde-3-phosphate dehydrogenase   IVUS   intravascular ultrasound   TF   tissue factor   VSMC   vascular smooth muscle cell

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