Impact of the reduction of calcineurin inhibitors on renal function in heart transplant patients: a systematic review and meta-analysis.

AIMS: Calcineurin inhibitors (CNIs) taken after heart transplantation lead to excellent short-term outcomes, but long-term use may cause chronic nephrotoxicity. Our aim was to identify, appraise, select and analyse all high-quality research evidence relevant to the question of the clinical impact of CNI-sparing strategies in heart transplant patients. METHODS: We carried out a systematic review and meta-analysis of randomized controlled trials on CNI reduction in heart transplant recipients. Primary outcomes were kidney function and acute rejection after 1 year. Secondary outcomes included graft loss, all-cause mortality and adverse events. RESULTS: Eight open-label studies were included, with 723 patients (four tested de novo CNI reduction and four maintenance CNI reduction). Calcineurin inhibitor reduction did not improve creatinine clearance at 12 months 5.46 [-1.17, 12.03] P = 0.32 I(2) = 65.4%. Acute rejection at 12 months (55/360 vs. 52/332), mortality (18/301 vs. 15/270) and adverse event rates (55/294 vs. 52/281) did not differ between the low-CNI and standard-CNI groups. There was significant benefit on creatinine clearance in patients with impaired renal function at 6 months [+12.23 (+5.26, +18.82) ml min(-1) , P = 0.0003] and at 12 months 4.63 [-4.55, 13.82] P = 0.32 I(2) = 75%. CONCLUSIONS: This meta-analysis did not demonstrate a favourable effect of CNI reduction on kidney function, but there was no increase in acute rejection. To provide a better analysis of the influence of CNI reduction patterns and associated treatments, a meta-analysis of individual patient data should be performed.

Ex Vivo Fluorescence Confocal Microscopy for Intraoperative Examinations of Lung Tumors as Alternative to Frozen Sections-A Proof-of-Concept Study.

BACKGROUND: Intraoperative frozen sections (FS) are frequently used to establish the diagnosis of lung cancer when preoperative examinations are not conclusive. The downside of FS is its resource-intensive nature and the risk of tissue depletion when small lesions are assessed. Ex vivo fluorescence confocal microscopy (FCM) is a novel microimaging method for loss-free examinations of native materials. We tested its suitability for the intraoperative diagnosis of lung tumors. METHODS: Samples from 59 lung resection specimens containing 45 carcinomas were examined in the FCM. The diagnostic performance in the evaluation of malignancy and histological typing of lung tumors was evaluated in comparison with FS and the final diagnosis. RESULTS: A total of 44/45 (98%) carcinomas were correctly identified as malignant in the FCM. A total of 33/44 (75%) carcinomas were correctly subtyped, which was comparable with the results of FS and conventional histology. Our tests documented the excellent visualization of cytological features of normal tissues and tumors. Compared to FS, FCM was technically less demanding and less personnel intensive. CONCLUSIONS: The ex vivo FCM is a fast, effective, and safe method for diagnosing and subtyping lung cancer and is, therefore, a promising alternative to FS. The method preserves the tissue without loss for subsequent examinations, which is an advantage in the diagnosis of small tumors and for biobanking.

Acute hemoptysis and pulmonary hemorrhage after judo as presentation of intralobar sequestration.

Intralobar sequestration (ILS) is a rare anomaly that is usually diagnosed with symptoms of cough, expectoration, or recurrent pneumonia in children. We experienced a case of an 11-year-old boy with massive hemoptysis after judo sports. He was admitted to hospital and intubated due to respiratory failure. His chest computed tomography (CT) scan which was performed without contrast agent revealed a large intrapulmonary hematoma or tumor, mimicking traumatic hemothorax. Due to blood loss and circulatory instability, emergency thoracotomy was performed and a massive intralobar hemorrhage due to a ruptured ILS artery was found. After lobectomy including resection of the ILS, the patient was stabilized and extubated. Aspergillus was detected in the resected lobe and postoperatively acute respiratory distress syndrome (ARDS) and invasive aspergillosis occurred and was treated specifically. However, the young patient was discharged home 3 weeks later. In young patients with hemoptysis and intrapulmonary hemorrhage after trauma, the possibility of ruptured ILS should be kept in mind. This report shows that ILS can have a dramatic course of disease, and for this reason a nonurgent resection should be considered in all patients when this diagnosis is made.

Calcineurin inhibitor withdrawal and conversion to mycophenolate mofetil and steroids in cardiac transplant recipients with chronic renal failure: a word of caution.

BACKGROUND: Chronic renal failure (CRF) is a common complication of calcineurin inhibitor (CNI)-based immunosuppression following cardiac transplantation (HTx). The aim of this prospective study was to evaluate the impact of an immunosuppressive conversion from CNIs to mycophenolate mofetil (MMF) and steroids in cardiac transplant recipients with CRF on renal and cardiac graft function. METHODS: Since 1999, 12 HTx recipients (10 men; 58 +/- 3.6 yr of age; 8.7 +/- 4.2 yr after HTx) with CNI-based immunosuppression and a calculated creatinine clearance (CreaCl) <50 mL/min were included. Most patients (10/12) were on cyclosporine and two patients were on tacrolimus prior inclusion. MMF was started with 0.5 g/d and adjusted according to the target trough levels (2-4 ng/mL). Prednisone dosage was 0.4 mg/kg. Subsequently, CNIs were completely withdrawn. Acute rejection episodes were excluded one and three months after conversion by endomyocardial biopsy and by echocardiography every three months thereafter. RESULTS: After a mean follow-up of 20 +/- 16 months, CreaCl improved significantly: pre-conversion vs. post-conversion: 32.8 +/- 12.2 mg/dL vs. 42.8 +/- 21.14 mg/dL, p = 0.03. However, four acute rejection episodes occurred and patients were reconverted to CNIs. Additionally, six patients had a new onset of graft vessel disease (GVD) one yr after conversion. As a result of these adverse events, the study was stopped after inclusion of only 12 of the scheduled 30 patients. CONCLUSIONS: Conversion to MMF and steroids after HTx improves renal function, but increases the risk for recurrent rejection and GVD. Therefore, MMF and steroids should only be considered in patients with a markedly low risk for rejection.

Conversion to sirolimus and mycophenolate can attenuate the progression of bronchiolitis obliterans syndrome and improves renal function after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the major problem after lung and heart-lung transplantation (LTx/HLTx). Sirolimus (Sir) and Mycophenolate (MMF) showed a promising efficacy in the treatment of BOS in animal models. The first clinical experience in converting LTx/HLTx-recipients with BOS from calcineurin inhibitor-(CNI)-based immunosuppression to a Sir-MMF based immunosuppression is reported herein. METHODS: Six LTx- and five HLTx-recipients (eight men; 0.9 to 8 years after transplantation) with CNI-based immunosuppression (plus MMF) in whom BOS was diagnosed were included in the study. Mean patient age was 37+/-13 years (range 17-62 years). Sir was started with 6 mg and continued adjusted to according target trough levels (8-14 ng/ml). Subsequently, the CNIs were tapered down and finally stopped. Follow up included self determined pulmonary function tests, microbiological screening, chest radiographs, and laboratory studies RESULTS: Two acute rejection episodes occurred during the study period. The incidence of infection was 2.2+/-1.3 infections/patient-year after conversion. Mean FEV1 decreased after a mean follow up of 14.8+/-1.4 months: from 2.1+/-0.7 l prior conversion to 1.3+/-0.6l after conversion (P=0.03). However, graft function remained stable in three patients and progression of BOS slowed down in three patients. Overall, 2 of 10 patients died due to ongoing BOS while awaiting retransplantation CONCLUSIONS: After BOS was diagnosed, conversion to MMF and Sir stabilized graft function only in some of the converted patients. Therefore, earlier administration of Sir-based immunosuppression might be a more promising approach. Whether conversion to CNI-free immunosuppression can actually ameliorate the extent or progression of BOS has to be investigated in randomized trials.

Introduction of a flexible polymeric heart valve prosthesis with special design for mitral position.

BACKGROUND: Current heart valve prostheses are constructed mimicking the native aortic valve. Special hemodynamic characteristics of the mitral valve such as a nonaxial central inflow with creation of a left ventricular vortex have so far not been taken into account. A new polycarbonaturethane (PCU) bileaflet heart valve prosthesis with special design for the mitral position is introduced, and results of animal testing are presented. METHODS AND RESULTS: After in vitro testing, 7 PCU-prostheses and 7 commercial bioprostheses (Perimount, n=4; Mosaic, n=3) were implanted in mitral position into growing Jersey calves (age 3-5 months, weight 60-97 kg) for 20 weeks. 2-Dimensional echocardiography was performed after implantation and before sacrification. Autopsy included histologic, radiographic, and electron microscopic examination of the valves. In vitro durability was proven for >15 years. After implantation 2-dimensional-echocardiography showed no relevant gradient or regurgitation of any prosthesis. Clinical course of the animals with PCU valves was excellent. In contrast, 5 of 7 calves with bioprostheses were sacrificed after 1-9 weeks because of congestive heart failure. 2-Dimensional echocardiography of the PCU valves after 20 weeks showed mild leaflet thickening with trivial regurgitation; mean gradient was 8.1+/-5.0 mm Hg (weight: 160-170 kg). The explanted PCU prostheses revealed mild calcification and no structural degeneration. All of the Perimount bioprostheses were severely calcified and degenerated after 11+/-7 weeks. One Mosaic bioprosthesis was thrombosed after 1 week, and 2 showed severe and mild-to-moderate degeneration after 4 and 22 weeks, respectively. CONCLUSIONS: Polycarbonaturethane valve prostheses with special design for mitral position show excellent hemodynamic performance and durability in vivo. Calcification and structural changes are mild compared with bioprostheses. Controlled clinical studies are planned.

Impact of donor serum sodium levels on outcome after heart transplantation.

We investigated the impact of elevated donor serum sodium levels on outcome after heart transplantation in 336 consecutive heart transplantations. Mean donor serum sodium was 148.2+/-10.2 mmol/liter (range 116 to 180 mmol/liter). Recipients were divided into 4 groups with serum sodium levels of 141, 147 and 155 mmol/liter, resulting in sodium levels of: 133+/-6.1 mmol/liter for Quartile A; 144+/-4.2 mmol/liter for Quartile B; 151+/-4.3 mmol/liter for Quartile C; and 162+/-6.6 mmol/liter for Quartile D, respectively (mean+/- standard deviation). Mean occurrence of primary graft failure (PGF) was 3.6% with the following quartile breakdown: A, 3.6%; B, 4.8%; C, 3.6%; and D, 2.4% (p=non-significant [NS]). Mean 5-year survival was 81.32% with: A, 83.51%; B, 76.03%; C, 80.47%; and D, 85.25% (p=NS). Coronary allograft vasculopathy (CAV) occurred in 19% of patients with a quartile breakdown of: A, 16.5%; B, 21%; C, 20%; and D, 14.5% (p=NS). No impact of donor serum sodium levels was seen on early post-operative results or on long-term outcome, indicating that cardiac allografts from donors with elevated sodium levels may be transplanted successfully with favorable results.

Mechanical circulatory support in pediatric patients with the MEDOS assist device.

Mechanical circulatory support is successfully applied to patients with low cardiac output. The MEDOS-System provides pulsatile ventricular assistance for patients of all age groups, including neonates. We report our experience with seven consecutive pediatric patients with the MEDOS-VAD. The indication was bridge to transplantation in all patients. Mean age was 7.3 +/- 6.5 years (range 0.75-16.9 years) and mean weight was 26.3 +/- 21.7 kg (range 5.9-60 kg). Perioperative survival was 100%; complications occurred in six patients (86%; two cerebral embolism/bleeding, two rethoracotomy, two exchange of pump chamber due to thrombus formation after 4 and 9 days). Mean duration of support was 20.4 +/- 10.8 days (range 6-38 days). Bilirubin decreased from 3.5 +/- 2.6 mg/d to 2.1 +/- 1.2 mg/d. Hospital mortality was three of seven patients who did not receive an organ offer in time. All patients who underwent subsequent heart transplantation (four of seven patients; 57%) were discharged from the hospital. Mechanical circulatory support with the MEDOS-System can be performed successfully in pediatric patients of any age. Secondary organ functions improve under this pulsatile circulatory assistance. Hemorrhage and thromboembolic events are the most frequent complications.

Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure.

BACKGROUND: Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil [MMF] and sirolimus [Sir]) treatment on renal function. METHODS AND RESULTS: Thirty-one HTx patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine greater than 1.9 mg/dL were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Mean patient age was 50+/-14 (range 19-74) years. Conversion was started with 6 mg Sir, continued with 2 mg, and the dose was adjusted to achieve target trough levels between 8 and 14 ng/mL. MMF was continued with trough level adjusted (1.5-4 microg/mL). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up (first and every 3 months after conversion) included endomyocardial biopsies, echocardiography, and laboratory studies. Survival was 90% after a mean follow-up of 13+/-95 months. No acute rejection episode was detected during the study period. Renal function improved significantly after conversion: creatinine preconversion vs. postconversion: 3.14+/-0.76 mg/dL vs. 2.14+/-0.83 mg/dL, P =0.001. Cystatin preconversion vs. postconversion: 2.95+/-1.06 mg/L vs. 2.02+/-1.1 mg/L, P =0.01. In three patients, hemodialysis therapy was stopped completely after conversion. Graft function remained stable. Fractional shortening preconversion vs. postconversion: 36.9+/-6% vs. 36.4+/-6%. There were no serious adverse events. One patient had to be excluded because of noncompliance. CONCLUSIONS: Conversion from CNI-based immunosuppression to MMF and Sir in HTx patients with chronic renal failure was safe, preserved graft function, and improved renal function.

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.

Sirolimus and mycophenolate mofetil as calcineurin inhibitor-free immunosuppression in a cardiac transplant patient with chronic renal failure.

Chronic renal failure triggered by calcineurin inhibitor (CNI)-based immunosuppression is a common complication after cardiac transplantation. Sirolimus and mycophenolate mofetil (MMF) are 2 newer immunosuppressive agents with no documented nephrotoxic side effects. This case report describes a patient with ongoing chronic renal failure 10 months after cardiac transplantation on cyclosporine-based immunosuppressive therapy. Conversion of the immunosuppressive regimen from cyclosporine to sirolimus and MMF resulted in freedom from acute rejection, excellent cardiac graft function and consistently improved renal function. This case illustrates the beneficial potential of sirolimus and MMF as CNI-free and safe long-term immunosuppression in a patient with chronic renal failure after heart transplantation.

Myosplint implant and shape-change procedure: intra- and peri-operative safety and feasibility.

BACKGROUND: In patients with dilated cardiomyopathy (DCM), the heart enlarges, leading to a corresponding increase in ventricular wall stress. To reduce the stress, transventricular tension members (Myosplint, Myocor, Inc.) were implanted to change the left ventricle (LV) effective radius and to reduce the LV wall stress by 20%. We conducted this study to evaluate the intra- and peri-operative safety and feasibility of LV-shape change therapy. METHODS: In 7 patients, all diagnosed with DCM, Myosplints were implanted. New York Heart Association class ranged from III-IV, and LV end-diastolic diameter ranged from 70 to 102 mm. Mitral valve regurgitation was classified as mild in 3 and moderate in 4 cases. Four patients underwent mitral valve annuloplasty. RESULTS: We observed no significant device-related complications, such as thromboembolism, bleeding, device instability, or vascular damage, at 90 days. Early indications in a small patient population demonstrate some improvements in clinical parameters. CONCLUSIONS: From this initial experience, one may conclude that placement of the Myosplint devices can be safely performed without early, significant adverse events. In patients with significant mitral valve incompetence, concomitant mitral valve repair is indicated to realize the full benefit of the procedure. This study also suggests that Myosplints can be safely implanted in combination with mitral valve repair. The long-term effect of each procedure on cardiac function and survival will require further evaluation.

Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression.

A prospective, pilot trial was started to evaluate the effect of a sirolimus-based immunosuppressive regimen on acute and chronic rejection in de novo lung transplant patients. Primary lung transplant (LTx) recipients received a sirolimus- and tacrolimus-based immunosuppressive therapy immediately after transplantation. Both immunosuppressants were administered with trough level adjusted, while steroid administration was minimized. Four patients were enrolled (2 single-lung transplants, 1 double-lung transplant, 1 heart-lung transplant) in the study. Mean ischemia time was 387 +/- 92 minutes. Acute rejection (at least Grade A1 ISHLT) was detected in 1 patient. Incidence of infection was 0.6 infection per 100 patient-days (3 Aspergillus infections). Until hospital discharge mean sirolimus trough level was 6.2 +/- 1.2 ng/ml. Depending upon mean sirolimus trough levels of each patient, severe wound-healing complications were seen in 3 patients, resulting in bronchial airway dehiscence in 2 patients with lethal outcome in 1 patient. As a result of these complications, we revised the study design after inclusion of only 4 patients: Sirolimus administration is now started after completion of bronchial wound-healing. Sirolimus-based immunosuppressive therapy administered immediately after lung transplantation seems to be associated with severe wound-healing complications of the bronchial anastomosis.

Fas/FasL and perforin/granzyme pathway in acute rejection and diffuse alveolar damage after allogeneic lung transplantation-a human biopsy study.

Acute rejection and diffuse alveolar damage are major problems during the early time after transplantation. Against this background, lung biopsies after allogeneic lung transplantation were studied using immunohistochemistry. Biopsies with acute rejection, diffuse alveolar damage and morphological inconspicuous biopsies were chosen. The objectives of this study were to ascertain: (a) if and how CD4 and CD8 T cells contribute to allograft rejection and diffuse alveolar damage, (b) whether there is a correlation of the chemoattractant regulated on activation normal T cells (RANTES) with the mononuclear infiltrate and (c) whether perforin/granzyme and Fas/FasL pathways contribute to lung injury after lung transplantation. Our results show that CD4(+) and CD8(+) T cells were increased in biopsies with acute rejection and, to a minor extent, also in biopsies with diffuse alveolar damage due to reperfusion injury. RANTES expression of T cells was increased in biopsies with acute rejection. Perforin seemed to have a dual role in the alloimmune response. In one regard, it had a cytolytic function in the acute rejection process, and, in contrast, it may be responsible for downregulating both CD4- and CD8-mediated alloimmune responses. The FasL/Fas pathway is not only important for induction of apoptosis during rejection but is also a mechanism of lung injury in the development of diffuse alveolar damage.

Renal recovery after conversion to a calcineurin inhibitor-free immunosuppression in late cardiac transplant recipients.

OBJECTIVE: Calcineurin inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this prospective study was to evaluate the safety and efficacy of a completely CNI-free immunosuppressive regimen [mycophenolate mofetil (MMF) and sirolimus (Sir)] in HTx-recipients with late post-transplant renal impairment. METHODS: Since 2001, 30 HTx-patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine >1.9 mg/dl were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Conversion was started with 6 mg Sir or 500 mg MMF according to the pre-existing regimen and was continued with the dose adjusted to achieve target trough levels between 8 and 14 ng/ml (Sir) or 1.5 and 4 microg/ml (mycophenolate). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up included endomyocardial biopsies, echocardiography and laboratory studies. Additionally, every HTx-patient treated at our centre between 1996 and 2001 due to chronic renal failure without immunosuppressive conversion and fulfilling the inclusion criteria were retrospectively analysed and acted as control group. RESULTS: Patient demographics and 1-year survival [93 (conversion) vs 90% (control)] were compared. No acute rejection episode was detected in either group. Renal function improved significantly in the conversion group (creatinine: 3.18+/-0.71 vs 2.22+/-0.79 mg/dl, P=0.001; cystatin pre- vs post-conversion: 2.95+/-1.06 vs 2.02+/-1.1 mg/l, P=0.01). In three patients haemodialysis therapy was stopped completely after conversion. In the control group renal impairment was deteriorating, creatinine increased from 2.44+/-0.8 to 3.28+/-1 mg/dl (P=0.01). In 10 out of 33 patients chronic haemodialysis had to be initiated within 1 year. Although side effects of CNI-free immunosuppression were common (76%), no patient had to be excluded due to adverse effects. CONCLUSIONS: Conversion from CNI-based immunosuppression to MMF and Sir in HTx-patients with chronic renal failure was safe, preserved graft function and improved renal function.

Introduction of a flexible polymeric heart valve prosthesis with special design for aortic position.

OBJECTIVE: Current prosthetic heart valves necessitate permanent anticoagulation or have limited durability and impaired hemodynamic performance compared to natural valves. Recently a polymeric valve prostheses with special design for mitral position demonstrated excellent in vitro and in vivo results with improved durability and no need for permanent anticoagulation. In this study, a respective flexible polymeric aortic valve is presented and in vitro and in vivo results are reported. METHODS: The aortic prosthesis (ADIAM lifescience AG, Erkelenz, Germany) is entirely made of polycarbonaturethane. The tri-leaflet flexible prosthesis mimicks the natural aortic valve and has a diminished pressure loss and reduced stress and strain peaks at the commissures. The valve underwent long-term in vitro testing and in vivo-testing in a growing calve animal model (20 weeks, 7 aortic valves) and was compared to two different commercial bioprostheses. RESULTS: The polymeric aortic heart valve substitute demonstrated excellent in vitro and in vivo hemodynamics. Five/seven animals with aortic PCU-prostheses had an excellent clinical long-term course. The explanted valves showed a variable degree of calcification. Two of the seven animals died at 27 and 77 days due to pannus overgrowth causing severe LVOTO without degeneration of the valve itself. Both animals with commercial bioprostheses had to be sacrificed because of congestive heart failure related to structural degeneration of the bioprosthesis after 10 and 30 days of implantation. There was no increased thrombogenity of the PCU valves compared to bioprostheses. CONCLUSION: The new flexible polymeric aortic valve prosthesis is superior to current bioprostheses in animal testing.

New flexible polymeric heart valve prostheses for the mitral and aortic positions.

OBJECTIVE: Current prosthetic heart valves necessitate permanent anticoagulation or have limited durability and impaired hemodynamic performance compared with natural valves. We report in vivo and in vitro results with new polymeric valve prostheses that have a special design for the mitral and aortic positions. The aims are improved durability and elimination of the need for permanent anticoagulation. METHODS: The mitral and aortic prostheses (Adiam Life Science, Erkelenz, Germany) are made entirely of polycarbonate urethane (PCU). The bileaflet asymmetric mitral valve mimics natural, nonaxial inflow, which creates a left ventricular vortex, saving energy for systolic ejection of blood. The trileaflet aortic prosthesis has diminished pressure loss and reduced stress and strain peaks at the commissures. The valves were subjected to long-term in vitro testing and in vivo testing in a growing calf model (20 weeks; 7 mitral and 7 aortic valves) with comparison with 2 commercial bioprostheses (7 mitral, 2 aortic). Two-dimensional echocardiography was performed after implantation and prior to sacrifice with autopsy and valve examination. RESULTS: In vitro durability of the PCU valves was proved up to 20 years. In vivo durability and hemodynamics were superior to those of all bioprostheses. Survival of PCU valves versus bioprostheses was 7 versus 2 mitral valves and 5 versus 0 aortic valves, respectively. Two animals with PCU aortic valves died of pannus overgrowth that caused severe left ventricular outflow tract obstruction without changes in the valves. Degeneration and calcification were mild (mitral) and moderate (aortic) in PCU valves but were severe in biological valves. There was no increased thrombogenicity of the PCU valves compared with bioprostheses. CONCLUSION: The new flexible polymeric aortic and mitral valve prostheses were superior to current bioprostheses in animal testing.

Ten-year results of a randomized trial comparing tacrolimus versus cyclosporine a in combination with mycophenolate mofetil after heart transplantation.

BACKGROUND: Long-term results of prospective randomized trials comparing triple immunosuppressive strategies combining tacrolimus (TAC) or cyclosporine A (CsA) with mycophenolate mofetil (MMF) and steroids after heart transplantation (HTX) are rarely published. Therefore, we collected long-term follow-up data of an intervention cohort 10 years after randomization. METHODS: Ten-year follow-up data of 60 patients included in a prospective, randomized trial between 1998 and 2000 were analyzed as intention-to-treat (TAC-MMF n=30; CsA-MMF n=30). Baseline characteristics were well balanced. Cardiac allograft vasculopathy (CAV) was graduated in accordance with the new ISHLT classification. RESULTS: Survival at 1, 5, and 10 years was 96.7%, 80.0%, and 66.7% for TAC-MMF and 90.0%, 83.3%, and 80.0% for CsA-MMF (P=ns). Freedom from acute rejection (AR) was significantly higher in TAC-MMF versus CsA-MMF (65.5% vs. 21.7%, log-rank 8.3, P=0.004). Freedom from ISHLT≥CAV1 after 5 and 10 years was in TAC-MMF 64.0% and 45.8%, and in CsA-MMF 36.0% (log-rank 3.0, P=0.085) and 8.0% (log-rank 9.0, P=0.003). No difference in long-term results for freedom from coronary angioplasty or stenting, renal dysfunction, diabetes mellitus, CMV infection, or malignancy was detected. CONCLUSION: Cross-over effects because of treatment switch may result in impairment of significance between the groups. The long-term analysis resulted in a significant difference in manifestation of CAV between the groups after 10 years. Less rejection in the TAC-group might have contributed to the lower incidence of CAV. Superior freedom from AR and CAV in the TAC-MMF group did not result in better long-term survival.

Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure.

BACKGROUND: Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated. METHODS: Since 2004, 63 HTx-patients (0.5-18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39+/-15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8-14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5-4 microg/mL). RESULTS: Patients demographics and survival (mean follow-up time: 16.7+/-9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53+/-24 mg/dL [group 1] vs. 38+/-20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively. CONCLUSIONS: Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.