Heart failure is the "Achilles heel" of cardiac surgical therapy. Being aware of this problem Prof. Mohr focused on therapeutic options and the possibilities when cardiac surgical therapy could be of benefit for our patients. He had this specific interest already during his early surgical career when he successfully established a new heart transplantation program in Göttingen in the years 1990 until 1994. During this time a frequent collaboration with Germany's largest transplantation center, the Heart and Diabetes Center in Bad Oeynhausen, Germany was established. In the consecutive years, several teams from Göttingen and later from Leipzig visited Bad Oeynhausen and learned from the large experience there. Based on this training a very successful patient support group was also formed at that time.

Before 2000, high urgency (HU) listing for heart transplantation (HTx) was only possible in cases of acute retransplantations; special urgency requests were limited to 15% of the listed patients. Since August 23, 2000, each center can submit for all patients fulfilling specific HU criteria unlimited, but audited HU requests to Eurotransplant. This study examines the impact of the preferential urgency allocation on transplantation outcome.

1Kidney Transplant Unit, Erasmus Medical Center, Rotterdam/NETHERLANDS, 2Eurotransplant, Leiden/NETHERLANDS, 3Kidney Transplantation, Room D-408, Erasmus Medical Center, Rotterdam/NETHERLANDS

Objectives: Severe mitral regurgitation (MR) is a frequent finding in end-stage cardiomyopathy. We analyzed the outcome after mitral valve (MV) surgery in this patient (pt) population.

Background: Recently, it has been realized that TH1/TH2 cytokine production offer the unique possibility to predict drug efficacy, However, there is still all incessant need to explore assay conditions and techniques of analyzing cytokines, which are specific and reliable for monitoring drug efficacy.Methods: in this study we used the multiplex bead array technique to detect cytokines of TH1/TH2 cells in whole blood of heart transplanted (HTx) recipients.Results: We found significantly different levels of cytokine expression in HTx recipients compared with cytokine levels in patients prior to HTx. Furthermore, particular cytokine levels were significanty decreased 2 h after drug dosing, compared with cytokine levels before dosing in mitogen-stimulated whole blood.Conclusions: Cytokine analysis with the multiplex array technique in mitogen-stimulated whole blood provides the possibility to predict immunosuppression. (c) 2006 International Society for Analytical Cytology.

We report two cases of pulmonary tuberculosis in heart transplant recipients: a 46-year-old man with pulmonary tuberculosis due to Mycobacterium tuberculosis and a 64-year-old man with nontuberculous mycobacterial infection with pulmonary infiltrates due to Mycobacterium xenopi. The time intervals from transplantation to diagnosis were 3 and 4 years, respectively. The patient with tuberculosis underwent standard treatment with isoniazid, rifampin, ethambutol, and pyrazinamide. The patient with the nontuberculous mycobacterial infection received treatment with clarithromycin and ciprofloxacin for 18 months in addition to rifampin for the first 3 months. Both patients responded well to treatment. No recurrences were observed during follow-up. The interactions between antibiotic treatment and cyclosporine therapy should be observed closely in organ transplant recipients, requiring frequent level determinations and dosing changes.

Objective. Conversion from cyclosporine (CsA) to tacrolimus (TRL) remains challenging in the daily routine due to individual variations in blood concentrations (pharmacokinetics, PK), pharmacodynamics (PD) and in interactions on plasma mycophenolic acid (MPA) concentrations. Therefore, we used our PD assays of lymphocyte function to monitor the conversion of CsA to TRL in heart (HTx) and lung (LTx) transplant recipients.Methods. Patients (six HTx, two LTx) were converted from CsA to TRL because of gingival hyperplasia. All patients were treated with 6 mg BID TRL 24 hours after the last CsA dose and received mycophenolate mofetil BID cotherapy. PK measurements of CsA, TRL, and MPA were done by EMIT. Expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and activation (CD25) was assessed by FACS.Results. TRL concentrations increased from day 1 to 3, but did not alter MPA concentrations, which were comparably high to MPA concentrations in combination with CsA (day 0). Compared to CsA therapy, increased TRL concentrations did not further inhibit PCNA expression, inhibited CD25 expression less on days 1 and 2 and equally high on day 3, but inhibited expression of IL-2 and TNF-alpha significantly higher on days 2 and 3 (P < .05).Conclusion. This study shows that monitoring PD of lymphocyte functions after conversion from CsA to TRL in HTx and LTx recipients revealed differences of inhibition of lymphocyte functions. Monitoring PD of lymphocyte function may provide insights in drug interactions of immunosuppressive combination therapy and may help to tailor immunosuppression to avoid toxicity and to enhance efficacy.

UNLABELLED Pharmacokinetic (PK) parameters like C2h have improved efficacy of immunosuppressive therapy. However, drug interactions, toxicities, and individual differences to drug effects still remain challenging. Therefore, this study was designed to assess pharmacodynamic (PD) effects of the combination cyclosporin (CsA) plus mycophenolate mofetil (MMF) on lymphocyte functions in peripheral blood of stable heart transplant recipients (HTx) using our established FACS assays. METHODS Blood from 25 HTx patients was drawn before (C0h) and 2 hours after dosing (C2h). CsA and mycophenolic acid (MPA) concentrations were measured by EMIT. FACS assessed expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and T-cell activation (CD25, CD95). RESULTS Evening doses of CsA (25/50/75 or 100 mg) and MMF (250/500 or 1000 mg) produced C0h levels as follows: CsA, 162 +/- 12 ng/mL; MPA, 1.7 +/- 0.2 mg/L. Morning doses of CsA (50/75 or 100 mg) and MMF (250/500/1000 or 1500 mg) produced C2h-levels as follows: CsA, 589 +/- 56 ng/mL and MPA, 7.4 +/- 1.3 mg/L. PD effects at C0h/C2h (% expression +/- SEM, all P < .05) were IL-2, 18 +/- 3/10 +/- 2; TNF-alpha, 12 +/- 2/7 +/- 1; PCNA, 8 +/- 1/5 +/- 1; CD25, 26 +/- 4/13 +/- 2; CD95, 23 +/- 4/11 +/- 2). Correlations (r2) at time point C2h between inhibition of lymphocyte functions (PD) with drug concentrations (PK) and with drug doses were CsA-PK, 0.71 to 0.91; MMF-PK, 0.55 to 0.76; CsA-dose, 0.73 to 0.87; MMF-dose, 0.61 to 0.80. CONCLUSION For the first time, the immunosuppressive effects of the combination CsA plus MMF were quantified in whole blood of human HTx at different time points. PD assays may offer the opportunity to optimize clinical immunosuppressive drug therapy.

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.

Dynamic cardiomyoplasty has been performed in over 1000 patients worldwide but due to limited success the procedure was never been adopted as an alternative approach for the surgical therapy of heart failure. However, observations in these patients showed that the nonstimulated or fibrotic transformed latissimus dorsi by itself led to an improvement of heart failure symptoms. These findings stimulated animal experiments with so-called passive cardiomyoplasty devices. In several animal models, the progression of heart failure could be stopped, and even reversed remodeling could be demonstrated. Several different devices have been developed and tested in animal models. The Acorn CorCap™ has already passed a successful clinical feasibility study. However, the final evaluation of two multicenter trials has to be awaited to assess the future role of this device in the treatment of heart failure.

n Zusammenfassung Die dynamische Kardiomyoplastie, die weltweit bei über 1000 Patienten durchgeführt wurde, hat sich auf Grund der Komplexität und der zum Teil nicht überzeugenden Resultate klinisch nicht durchsetzen können. Im Rahmen der experimentellen Untersuchung von dynamischen Kardiomyoplastieverfahren konnte gezeigt werden, dass allein die passive Unterstützung des Herzens mit dem nicht stimulierten oder sogar fibrosierten Latissimus dorsi zu einer Verbesserung der Hämodynamik führte. Diese Beobachtungen bildeten die Grundlage für tierexperimentelle Untersuchungen im Herzinsuffizienzmodell mit allein passiven Unterstützungssystemen. In diesen Experimenten konnte eindeutig eine Progression der Ventrikeldilatation verhindert werden, in einigen Tiermodellen ein reversed remodelling nachgewiesen werden. Verschiedene Systeme aus unterschiedlichen Materialien wurden konstruiert, deren klinische Erprobung bevorsteht. Am weitesten fortgeschritten ist die Entwicklung des CSD (Cardiac support device (CorCap), Acorn Inc.). Ermutigende Ergebnisse aus der initialen Erprobung haben zu der Durchführung von 2 großen Multi-Center-Studien geführt, deren abschließende Auswertung unmittelbar bevorsteht. Gegenwärtig hat die passive Kardiomyoplastie in der Herzinsuffizienztherapie einen experimentellen Charakter. n Schlüsselwörter Kardiomyoplastie – Herzinsuffizienz – Übersichtsarbeit

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.

Dynamic cardiomyoplasty has been performed in over 1000 patients worldwide but due to limited success the procedure was never been adopted as an alternative approach for the surgical therapy of heart failure. However, observations in these patients showed that the nonstimulated or fibrotic transformed latissimus dorsi by itself led to an improvement of heart failure symptoms. These findings stimulated animal experiments with so-called passive cardiomyoplasty devices. In several animal models, the progression of heart failure could be stopped, and even reversed remodeling could be demonstrated. Several different devices have been developed and tested in animal models. The Acorn CorCap has already passed a successful clinical feasibility study. However, the final evaluation of two multicenter trials has to be awaited to assess the future role of this device in the treatment of heart failure.