Published Online
on September 15, 2003

A more recent version of this article appeared on October 7, 2003

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Submitted on May 12, 2003
Revised on June 30, 2003
Accepted on July 2, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: Yamanim{at}ccf.org.

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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