Short-term angiopeptin therapy and the incidence of graft vessel disease after heart transplantation

Background: Graft vessel disease, the major limitation for long-term success after heart transplantation, is triggered by injury to the graft vessel endothelium, resulting in the expression of adhesion molecules, the migration of leukocytes into the graft, and the release of growth factors. Angiopeptin, a stable analog of somatostatin, is a growth-hormone inhibitor with additional anti-proliferative effects. We evaluated angiopeptin for prevention of graft vasculopathy after cardiac transplantation in the first prospective, randomized, double-blind, clinical trial. Methods: Thirty-one patients received treatment with either angiopeptin (n = 13) or placebo (n = 18). Patients were randomized according to the presence of hypercholesterolemia, recipient cytomegalovirus-antibody status, and donor age. All patients received standard triple-drug immunosuppression. Angiopeptin 1.5 mg or placebo was given subcutaneously immediately before surgery and twice a day after transplantation from Day 1 to Day 14. Furthermore, 1.5 mg was added to each liter of cardioplegic solution, 1.5 mg was given intravenously during surgery, and another 3 mg was given during the first 6 post-operative hours. During the first post-operative year, angiopeptin 1.5 mg or placebo was added to each treatment for acute rejection (twice a day subcutaneously). Baseline angiography was performed within the first 4 postoperative weeks and annually thereafter. Twenty-three patients each underwent an additional intracoronary ultrasound. Results: One- and 4-year survival rates were comparable: 85% and 85% for the group receiving angiopeptin, and 89% and 78% for the placebo group, respectively. One patient in the control group died of myocardial infarction caused by graft vessel disease. Although the mean number of rejection and infection episodes was similar, the overall incidence of newly occurring graft vessel disease after 2 and 4 years was greater in the control cohort: 9% vs 38% after 2 years and 27% vs 44% after 4 years (P = 0.183, 0.448). Comparison of the results of intracoronary ultrasound performed in a sub-group of patients confirmed that trend: the modified Stanford score, the mean intimal thickness, and the mean intimal index were lower in the angiopeptin group. Again, because of the relatively small number of patients available for evaluation, the difference did not reach statistical significance. Conclusions: Short-term peri-operative angiopeptin treatment along with additional injections during rejection episodes within the first year resulted in a marked decrease in graft vessel disease 2 and 4 years after heart transplantation. Based on our results, continuous, long-term application of slow-release angiopeptin could significantly decrease or even prevent graft vessel disease.