TIME-COURSE OF CORONARY ENDOTHELIAL DYSFUNCTION IN ACUTE UNTREATED REJECTION AFTER HETEROTOPIC HEART-TRANSPLANTATION

Background: Endothelial dysfunction is one of the early events leading to atherosclerosis. It occurs early after orthotopic heart transplant ation and precedes the appearance of accelerated graft coronary artery disease believed to stem from chronic rejection of the endothelium. A cute rejection may contribute to the development of graft vasculopathy . Methods: To assess the time course and specific mechanisms of corona ry endothelial dysfunction in acute untreated rejection, a swine model of retroperitoneal heterotopic heart transplantation was used. Large white swine (age 10 +/- 2 weeks, weight 25 +/- 5 kg) were serum-typed for class I antigen of the swine leukocyte antigen system and selected to ensure a similar degree of incompatibility. Donor hearts were pres erved with normothermic blood cardioplegia and regional hypothermia; t he mean ischemic time was 64 +/- 15 minutes. Myocardial contractility decreased from day 5 (normal) to day 14 (weak), but electrical activit y was preserved. All coronary arteries were patent, and International Society for Heart and Lung Transplantation grade 4 rejection was prese nt in all hearts beyond 5 days. The endothelial function of epicardial coronary arterial rings of native and transplanted hearts was studied in organ chambers filled with modified Krebs-Ringer bicarbonate solut ion and compared 1, 5, 9, and 14 days after transplantation. Results: Maximal endothelium-independent relaxations were unaffected at all sta ges. Endothelium-dependent relaxations to serotonin and alpha(2)-adren ergic agonist UK 14304 (which activate receptors coupled to Gi-protein s) and to sodium fluoride (a direct G-protein activator) deteriorated progressively over time. At 14 days maximal relaxations to the calcium ionophore A23187, adenosine diphosphate, and bradykinin were also red uced, but to a lesser degree than those to serotonin and sodium fluori de. Histomorphometric studies of the allograft coronary artery rings s howed progressive intimal hyperplasia from day 5 to day 14, with an in crease in the incidence from 29% +/- 8.3% to 61.5% +/- 12%. Conclusion s: These studies show that endothelial dysfunction in untreated acute rejection after heart transplantation develops beyond 5 days and initi ally involves G-proteins; the dysfunction worsens over time to finally affect all endothelial mechanisms and vascular smooth muscle. The pro gression of the associated intimal hyperplasia parallels the alteratio n in endothelial function, suggesting a permissive role of the dysfunc tion in the development of this acute form of coronary graft vasculopa thy.