Purpose Fibroblast growth factor 23 (FGF23) is a main bone hormone responsible for the phosphate homeostasis. Moreover it is a good biomarker of chronic kidney disease. The only experimental report concerning FGF23 in the heart displayed its toxic effect on mice myocardium resulted in hypertrophy after intravenous injection of FGF23. However, there is no notification of FGF23 heart expression. Currently we observed that isolated neonatal as well as adult cardiomyocytes (CM) are able to produce FGF23 in stress conditions, but data in vivo are missing. Methods and Materials For this purpose we studied heart explants of 10 patients suffering from ischemic cardiomyopathy (ICM), 14 patients with dilated cardiomyopathy (DCM) and 12 patients with myocarditis (Myo). 2 healthy donor hearts (which were not used for transplantation) served as controls. In addition we used animal models: wild-type mice with myocardial infarction (WT-MI) induced by LAD ligation and transgenic mice with a cardiac restricted overexpression of monocyte chemotactic protein (MCP1) as a model of chronic inflammation. Results We firstly detected FGF23 positive CM in vivo. They were localized in diseased myocardium as isolated cells or in groups showing week or marked cross-striation. The number of FGF23 expressing CM was increased 14.8 fold in patients with ICM, 12.3 fold in DCM patients and 13.5 fold in patients with Myo in comparison with controls (p Conclusions For the first time we demonstrated FGF 23 expression in myocardium of patients with heart failure and in mice models. An increased activity of FGF23 and its receptor FGFR1c in stress conditions characterizes the FGF23 as a promising diagnostic and prognostic biomarker of cardiac pathology.

Aim: In this study we evaluated the use of rigid fixation technique using SternaLock® titanium plating (Biomet Microfixation, Jacksonville, FL, USA) for sternotomy closure in high risk patients for developing sternal wound infection.

Objectives: Proximal connectors may potentially be beneficial for patient outcome in off pump CABG. The PAS-Port System showed promising early patency rates in the pivotal clinical trial. For the first time the two anastomotic techniques were compared in a prospective randomized single center trial.

Objectives: Maturation of myeloid and plasmacytoid dendritic cells (DCs) produce IL-12 to induce T-cell activation to initiate the immune response. Therefore, in this study we monitored DCs in peripheral blood to compare the effects of different basis-immunosuppression in human heart transplanted (HTx) recipients: inhibitors of calcineurin (CNI, cyclosporine, tacrolimus) and of mTOR [sirolimus (SRL), everolimus (ERL)].

Objectives: Pharmacokinetic (PK) parameters like C2 have improved efficacy of immunosuppressive therapy. However, drug interactions, toxicities and individual differences to drug effects still remain challenging in the clinic. Therefore, this study was designed to assess PD effects of the combination CsA plus MMF on lymphocyte functions in peripheral blood of stable HTx using our established FACS assays.

A 35 year old male suffered from fever till 39degreesC and malaise since 6 months; infectious or neoplastic causes have been ruled out. Ultrasonography revealed a hypoechoic lesion of 75 mm diameter in the liver. The histologic examination of the needle biopsy showed an inflammatory process, and the final diagnosis was inflammatory pseudotumor. EBV specific LMP-1 protein was detected within the tumor immunohistochemically. A liver segment resection was performed, and the patient has been well and without fever since then for 18 months.Inflammatory pseudotumor is a rare but important differential diagnosis in cases of hypoechoic liver lesions associated by fever, if there is no abscess or malignancy. The diagnosis must be confirmed histologically, because imaging techniques cannot reliably classify the lesion.

O479 Aims: Therapeutic drug monitoring (TDM) in heart and lung transplanted (HTx, LTx) recipients for cyclosporine (CsA), tacrolimus (TRL) and sirolimus (SRL) relies on the daily measurements of blood concentrations (pharmacokinetic, PK) to maintain drug concentrations within their respective target ranges. However, the unknown absolute bioavailability and the interindividual variability regarding the biological effect are the limitations of TDM based on PK. Additional, drug therapy is influenced by interactions e.g. as the shared metabolism through the cytochrome P450 system for CsA, TRL and SRL. In earlier studies we have investigated the relationship of drug pharmacodynamics (PD) of lymphocyte function in whole blood with the drug PK to improve drug efficacy and safety. Methods: We assessed PD effects and PK in HTx and LTx recipients for two reasons: first, the conversion of CsA to TRL in patients with gingival hypertrophy (group I, 8 patients) and second, the conversion of CsA to SRL in patients with severe renal dysfunction (group II, 8 patients). 24 hours (group I) or 28 h (group II) after the last CsA dose (75 or 100mg) patients were treated with a fixed dosing regime: 6mg/BID TRL on days 1 and 2 (group I) or 6 mg/QD SRL on day 1 and 2 mg/QD SRL at days 2 and 3 (group II). Patients of both groups received mycophenolate mofetil/BID co-therapy with a dose range of 500-2500mg/day. Pharmacokinetic (PK) measurements of CsA, TRL were done by EMIT and for SRL by LC-MS/MS. PD effects of lymphocyte proliferation (PCNA) and activation (CD25, CD71, CD95, CD134, CD152, CD154) were analyzed by FACS. Results: Ctrough-values of PK and PD (%expression) on day-1 and -2 under TRL therapy (group I) or on day-1, -2 and -3 under SRL therapy (group II) were compared with Ctrough-values of PK and PD under CsA therapy (day-0), e.g. for 2 patients of each group: Group I: patient AI: day-0: CsA:141ng/ml; PCNA:8,4%; CD25:16%; day-1: TRL:7.2ng/ml; PCNA:2,8%; CD25:11,9%; day-2: TRL:14.3ng/ml; PCNA:2,1%; CD25:10,4%; patient BI: day-0: CsA:130ng/ml; PCNA:11%; CD25:5,3%; day-1: TRL:4ng/ml; PCNA:5,4%; CD25:8,4%; day-2: TRL:8ng/ml; PCNA:5,1%; CD25:3,9%. Group II: patient AII: CsA:125ng/ml; day-0: CD25:7%, CD95:15%; day 1: SRL:8.4μg/l; CD25:17%, CD95:11%; day-2: SRL:15.7μg/l, CD25:11%, CD95:14%, day-3: SRL:5.4μg/l, CD25:25%, CD95:14%; patient BII: day-0: CsA:118 ng/ml; CD25:9%, CD95:14%, day-1: SRL:4.3μg/l, CD25:6%, CD95:4%; day-2: SRL:11μg/l, CD25:8%, CD95:8%, day-3: SRL: 5.4μg/l, CD25:8%, CD95:5%. Conclusions: For the first time, the switch to TRL or SRL from CsA therapy in HTx and LTx was assessed by monitoring lymphocyte functions. The results of our studies showed that PK monitoring does not always predict the immunosuppressive effect actually achieved. Thus, indicating that TDM by assessing the PD effects will enhance the value of PK monitoring to achieve the goal of individualized immunosuppressive therapy to avoid drug toxicity and to enhance efficacy.

iCAMs play a critical role in mediating allograft recognition and rejection, leading to leukocyte attachment to graft endothelium and transendothelial migration into the myocardium. This process is a crucial step in the development of transplant vasculopathy (TVP). We investigated the effect of CSA, FK506 and MMF on ICAM-1, VCAM-1, PECAM-1 and P-Selectin expression, the resulting leukocyte infiltration and neointimal proliferation of arteries after cardiac transplantation in rats. 340 transplantations were performed (Lewis to Fisher), animals were divided into 4 groups: CSA 3mg/kg/d (n 74), MMF 40mg/kg/d (n 96), FK506 0.3mg/kg/d (n 96) and Control (no therapy, n 74). 3–4 animals of each group were sacri-ficed in intervals of 1–4 days up to day 60. Using immunohistochemistry we investigated quote, intensity and geometric distribution of ICAM-1, VCAM-1, PECAM and P-Selectin staining. We analysed the accumulation of leukocytes (CD4, CD8, CD11a, CD18, VLA4) in the perivascular space (pvs) of arteries. TVP in coronary arteries was expressed as mean vessel occlusion (mvo). In controls staining parameters of iCAMs, leukocyte accumulation and mvo rapidly increased and were reduced by all drugs compared to controls. We found significant correlations between staining parameters, infiltration of leukocytes and mvo. MMF was superior to CSA and FK506 in reducing TVP, leukocyte attachment, infiltration, and iCAMs expression, except VCAM-1 expression and VLA4 infiltration being significantly higher in MMF treated animals compared to CSA or FK506. The only difference between the calcineurin inhibitors was a further reduction of VCAM-1 expression and VLA4 leukocyte infiltration by FK506. Although MMF had no significant effect on VCAM-1/VLA4 mechanisms, it reduced the development of TVP significantly compared to calcineurin inhibitors. This effect was due to the reduction of ICAM-1, PECAM-1 and P-Selectin expression that correlates with the infiltration of leukocytes into the pvs of arteries.

Objectives: Deep sternal wound infection (DSWI) remains a serious complication after cardiac surgery. Previously body mass index (BMI) >30 (odds ratio (OR) 1.5), diabetes (OR 2.1), the use of single (OR 2.8) and bilateral internal thoracic arteries (ITA) (OR 12.5) were identified as risk factors for DSWI in a multivariate logistic regression model. Based on these results, our routine practice of ITA harvesting was changed from a pedicled to a skeletonized technique. The purpose of this study was to compare both techniques in the same institution.

Background: The interaction of lymphocyte function-associated antigen-1 (LFA-1)-positive host leukocytes with intercellular adhesion molecule-1 (ICAM-1) on graft endothelium may play a key role in allograft recognition, triggering the development of transplant vasculopathy (TVP). We investigated the correlation between TVP and ICAM-1 expression and accumulation of LFA-1-positive leukocytes in the perivascular space (PVS) of arteries under different immunosuppressive drugs.Methods: After cardiac transplantation (Lewis to Fisher) animals were randomized 4 groups: cyclosporine (CsA), 3 mg/kg/day (n = 74); mycophenolate mofetil (MMF), 40 mg/kg/day (n = 96); FK 506, 0.3 mg/kg/day (n = 96); and control, no therapy (n = 74). Three or 4 animals from each group were harvested at intervals of 1 to 4 days within the study period of 60 days. Using immunohistochemistry,LFA-1 -positive leukocytes were analyzed in intra- and epicardial arteries. ICAM-1 expression was scored histologically. TVP was assessed by digitizing morphometry and expressed as mean vascular occlusion.Results: Accumulation of LFA-1-positive leukocytes in the PVS of arteries and the myocardium correlated with expression of ICAM-1 on graft endothelium. The severity of TVP in arteries correlated with the accumulation of LFA-1-positive leukocytes in PVS. All immunosuppressive drugs significantly reduced ICAM-1 expression, LFA-1 accumulation and extent of TVP, compared with controls. In MMF-treated animals, we also found a significant reduction of ICAM-1 expression, LFA-1 accumulation and extent of TVP compared with the groups treated with CsA and FK 506 (P < 0.005).Conclusion: These data support an essential role of LFA-1/ICAM-1 interaction in the genesis of TVP that may be abrogated, especially by the use of MMF. Copyright (C) 2004 by the International Society for Heart and Lung Transplantation.