Vascular tissue plasminogen activator and the development of coronary artery disease in heart-transplant recipients.

BACKGROUND

An aggressive and potentially fatal form of coronary artery disease may develop after cardiac transplantation. We studied the role of vascular tissue plasminogen activator (t-PA), the primary mediator of fibrinolysis, in the development of this problem.

METHODS

We studied 78 consecutive recipients of cardiac allografts over a five-year period, and we collected follow-up data over a mean (+/- SE) of 32.5 +/- 2.0 months. The patients were studied with ventricular function tests, serial endomyocardial biopsies (16.6 +/- 0.5 per patient), and annual coronary angiography. Measurements of t-PA and its inhibitor were performed immunocytochemically on unfixed cryostat sections of endomyocardial-biopsy specimens with the use of monoclonal antibodies to t-PA and its inhibitor.

RESULTS

In biopsy specimens obtained during the first three months of follow-up, 38 allografts had a normal distribution of t-PA in arteriolar smooth-muscle cells, whereas in 40 allografts there was depletion of t-PA that persisted in subsequent follow-up. Coronary artery disease developed during follow-up in 31 of 40 allografts (78 percent) with depletion of t-PA, but the disease developed in only 9 of the 38 allografts (24 percent) with normal t-PA levels (P < 0.001). Allografts with depletion of t-PA also had the t-PA inhibitor and were at greater risk for earlier and more severe disease than were allografts with normal arteriolar t-PA levels. Twelve patients whose allografts were depleted of t-PA either received a second transplant or died, whereas only one of the patients whose allografts had persistently normal t-PA levels died (P < 0.001).

CONCLUSIONS

These findings reveal an association between the depletion of t-PA from arteriolar smooth-muscle cells and the subsequent development of coronary artery disease and decreased graft survival. Although we cannot be certain about a cause-and-effect relation, our data suggest a possible role for deficient fibrinolysis in the development of coronary artery disease in transplanted human hearts.