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(Circulation. 2003;108:1724.)
© 2003 American Heart Association, Inc.

Clinical Investigations

Donor Spontaneous Intracerebral Hemorrhage Is Associated With Systemic Activation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 and Subsequent Development of Coronary Vasculopathy in the Heart Transplant Recipient

Mohamad H. Yamani, MD; Randall C. Starling, MD, MPH; Daniel J. Cook, PhD; E. Murat Tuzcu, MD; Ashraf Abdo, MD; Philip Paul, PhD; Kimerly Powell, PhD; Norman B. Ratliff, MD; Yang Yu; Patrick M. McCarthy, MD; James B. Young, MD

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

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

Received May 12, 2003; revision received June 30, 2003; accepted July 2, 2003.

Abstract

Background— Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy.

Methods and Results— We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69).

Conclusions— This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.

Key Words: metalloproteinases • hemorrhage • transplantation

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