VASCULAR TISSUE-PLASMINOGEN ACTIVATOR AND THE DEVELOPMENT OF CORONARY-ARTERY DISEASE IN HEART-TRANSPLANT RECIPIENTS

Background. An aggressive and potentially fatal form of coronary arter y disease may develop after cardiac transplantation. We studied the ro le of vascular tissue plasminogen activator (t-PA), the primary mediat or of fibrinolysis, in the development of this problem. Methods. We st udied 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 perf ormed immunocytochemically on unfixed cryostat sections of endomyocard ial-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 ther e was depletion of t-PA that persisted in subsequent follow-up. Corona ry artery disease developed during follow-up in 31 of 40 allografts (7 8 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 tPA also had the t-PA inhibitor and were at greater risk for earlier and more severe disease than were allograf ts with normal arteriolar t-PA levels. Twelve patients whose allograft s were depleted of t-PA either received a second transplant or died, w hereas only one of the patients whose allografts had persistently norm al t-PA levels died (P<0.001). Conclusions. These findings reveal an a ssociation between the depletion of t-PA from arteriolar smooth-muscle cells and the subsequent development of coronary artery disease and d ecreased graft survival. Although we cannot be certain about a cause-a nd-effect relation, our data suggest a possible role for deficient fib rinolysis in the development of coronary artery disease in transplante d human hearts.