1. Heart transplantation (HTx) provides satisfactory long-term survival for patients with severe cardiomyopathy due to a variety of causes. Despite considerable advances and remarkable progress in the care of the heart transplant recipient and clinical management of acute rejection, patient survival is limited by cardiac allograft vasculopathy (CAV), acute cellular (ACR) and antibody-mediated rejection (AMR) with hemodynamic compromise. Biomarkers of endogenous tissue destruction (pregnancy-associated plasma protein A, PAPP-A), thrombosis (soluble CD40 ligand, sCD40L) and neoangiogenesis (placental growth factor, PlGF) may be significant risk factors for cardiovascular complications development in patients with ischemic heart disease as well as in heart transplant recipients. The study was aimed to determine the role of PAPP-A, sCD40L, and PlGF in development of CAV, severe ACR and acute AMR with graft failure in heart transplant recipients using a multivariate analysis. 76 heart transplant recipients (67 men, aged 34.4±12.3 years) were followed up to 120 months after the operation performed for dilated (48 patients, 63.2%) or ischemic (28 patients, 36.8%) cardiomyopathy. Immunosuppressive therapy included steroids, cyclosporine (46 patients, 60.5%) (or tacrolimus, 30 patients, 39.5%), and mycophenolate mofetil. Endpoints of the study were ACR (2R and more, 3 patients, 3.9%), AMR (4 patients, 5.3%), diagnosed by endomyocardial biopsy, and CAV (17 patients, 22.4%), verified by coronary angiography. Blood samples were obtained before HTx, in all cases with a period of fasting of at least eight hours, centrifuged for 15 min at 1450g after the extraction. All samples were analyzed under the same analytical conditions. Pretrasplant concentrations of PAPP-A, sCD40L, and PlGF were measured using ELISA. A measurement of pretransplant PAPP-A concentration as an independent factor might be useful to identify patients at high risk of the development of CAV, severe ACR and acute AMR with graft failure after heart transplantation. During follow-up, severe episodes of ACR or AMR, and CAV occurred in 24 patients (31.58%) at 7.5±10.2 months after HTx, and were detected more often in recipients with pretransplant PAPP-A, sCD40L, and PlGF levels above median: in 20 (38.5%) recipients with PAPP-A >11 mIU/l (vs. 4 pts, 16.6%), in 16 (34%) recipients with sCD40L >1.6 ng/ml (vs. 8 pts, 27.6%), and in 18 (34.6%) recipients with PlGF >12 pg/ml (vs. 6 pts, 25%). Cox regression analysis revealed that an independent, statistically significant risk factor for the development of CAV, severe episodes of ACR or AMR was PAPP-A level (HR 4.2, 95% CI:1.33;13.24, Chi-square 14.97, p=0.002) (Tabl.1.). Actuarial freedom from CAV, severe ACR and acute AMR with graft failure was significantly higher in patients with low pretransplant PAPP- A (Fig.1.), sCD40L (Fig.2.), or PlGF (Fig.3.) levels than in patients with their high levels (log-rank test p=0.0006, p=0.02, p=0.01 resp.). CovariatebSEP - valueExp(b)95% CI of Exp(b) PAPP-A1,43720,58760,01454,20891,3382 to 13,2376 sCD40L0,57360,48500,23701,77460,6892 to 4,5693 PlGF0,26250,55580,63671,30020,4398 to 3,8435 Relative Risk (95% CI) 120,5 4.27; 95% CI 1.61 to 11.31 р=0.0006 2.08; 95% CI 1.05 to 4.11 р=0.003 3 0,75 0,25 4 2.43; 95% CI 1.09 to 5.44 р=0.02 PAPP-A (> 11 mIU/l) sCD40L (> 1.6 ng/ml) PlGF (> 12 pg/ml) Among studied markers elevated pretransplant PAPP-A was associated with the highest risk of the development of CAV, severe episodes ACR or AMR after heart transplantation (Fig.4.). Comparison of predictive significance of soluble CD40 ligand, pregnancy-associated plasma protein A, and placental growth factor for graft failure development after heart transplantation. Shevchenko О.P. 1, Khalilulin T.A. 1, Shevchenko A.О. 2, Orlova O.V. 1, Mironkov B.L. 1, Kazakov E.N. 1, Kormer A.J. 1, Gautier S.V. 1 1-Federal Research Center of Transplantology and Artificial Organs named after Academician V.I.Shumakov, Moscow, Russia, 2 - Russian National Research Medical University named after N.I. Pirogov, Moscow, Russia Introduction Objectives Materials and methods Results Fig.1. Actuarial freedom from CAV, severe ACR and AMR in heart recipients with low and high PAPP-A levels. Fig.2. Actuarial freedom from CAV, severe ACR and AMR in heart recipients with low and high sCD40L levels. Presented at the 32 nd ISHLT Annual Meeting and Scientific Sessions, 18-21 April 2012, Prague, Czech Republic Results Fig.3. Actuarial freedom from CAV, severe ACR and AMR in heart recipients with low and high PlGF levels. Fig.4. Relative risk of the development of CAV, severe ACR and acute AMR with graft failure in heart recipients. Table 1. Multivariate analysis of the effects of PAPP-A, sCD40L, and PlGF on CAV, ACR and AMR development after HTx. Conclusion References 1. Hognestad A., Michelsen A., Brosstad F. et al. Plateled activation in heart transplant recipients. Clinical Transplantation. 2004:18:142-7. 2. Funayama A., Shishido Y., Netsu S. et al. Serum pregnancy-associated plasma protein A in Patients with heart failure. J.Card.Fail., 2011: 17(10):819-26 3. Labarrere C.A., Woods R., Hardin J.W. et al. Early prediction of cardiac allograft vasculopathy and heart transplant failure. Am.J.of Transpl., 2011:11(3):528-35 4. Lauzurica R., Pastor C., Bayes B. et al. Pretransplant pregnancy-associated plasma protein A as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events. Transplantation., 2005:80: 1441-6. 5. Schmauss D, Weis M. Cardiac allograft vasculopathy: Recent developments. Circulation 2008; 117: 2131–41. 6. Shevchenko O.P., Orlova O.V., Shevchenko A.O. et al. Pretransplant pregnancy-associated plasma protein A (PAPP-A) as a predictor of chronic graft vasculophaty and posttransplant cardiovascular events. 14th Congress of the European Society for Organ Transplantation, Paris, France, 30.08-02.09. 2009., P-157 PAPP-A < 11 mIU/l PAPP-A > 11 mIU/l sCD40L < 1.6 ng/ml sCD40L > 1.6 ng/ml PlGF < 12 pg/ml PlGF > 12 pg/ml