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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.

Pharmacokinetics of mycophenolate mofetil (MMF) show large interindividual variability. Concentration-controlled dosing of MMF based on routine therapeutic drug monitoring, which requires area under the concentration-time curve (mycophenolic acid [MPA]-AUC0-12h) determinations, is uncommon. Dose adjustments are based on predose concentrations (C0h) or side effects. The aim of this study was to compare C0h with postdose concentrations (C0.5h-C12h) and to develop practical methods for estimation of MPA-AUCs on the basis of a limited sampling strategy (LSS) in heart transplant recipients under MMF and tacrolimus maintenance immunosuppression. Full MPA-AUC0-12h profiles were generated by high-performance liquid chromatography in 28 patients. Statistical analysis for MPA-AUC0-12h was performed by a case resampling bootstrap method. Bland and Altmann analysis was performed to test agreement between "predicted AUC" and "measured AUC." C1h provided the highest coefficient of determination (r2 = 0.57) among the concentrations determined during the 12-hour interval, which were correlated with AUC. All other MPA levels were better surrogates of the MPA-AUC0-12h when compared with C0h (r2 = 0.14). The best estimation of MPA-AUC0-12h was achieved with four sampling points with the algorithm AUC = 1.25*C1h + 5.29*C4h + 2.90*C8h + 3.61*C10h (r2 = 0.95). Since LSS with four time points appeared unpractical, the authors prefer models with three or two points. To optimize practicability, LSS with sample points within the first 2 hours were evaluated resulting in the algorithms: AUC = 1.09*C0.5h + 1.19*C1h + 3.60*C2h (r2 = 0.84) and AUC = 1.65*C0.5h + 4.74*C2h (r2 = 0.75) for three and two sample points, respectively. The results provide strong evidence for the use of either LSS or the use of time points other than C0h for therapeutic drug monitoring of MMF. Using the algorithms for the estimation of MPA-AUC0-12h based on LSS within the first 2 hours after MMF dosing may help to optimize treatment with MMF by individualization of dosing.

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.

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.

Background: It has been demonstrated that ventricular sympathetic reinnervation after cardiac transplantation improves exercise performance. The extent of reinnervation increases with time but is variable. Little is known about other influencing factors., Methods and Results: Seventy-seven nonrejecting transplant recipients were cross-sectionally studied by PET with the catecholamine analogue C-11 hydroxyephedrine at 4.8+/-3.5 years after transplantation. Results were compared with history-derived parameters related to recipient's clinical course before, during, and after surgery; donor characteristics; and immunogenetics. Partial reinnervation was observed in 52 patients (extent, 21+/-16% of left ventricle). Complete denervation was found in 25 patients at various times after transplantation. Reinnervation extent correlated with time after surgery (r=0.387; P<0.001) but also inversely with donor age (r=-0.309, P=0.006) and recipient age (r=-0.243, P=0.032). Maximal hydroxyephedrine retention correlated inversely with frequency of rejection episodes (r=-0.267, P=0.019), was reduced when aortic complications occurred perioperatively (9 patients), and correlated inversely with aortic cross-clamp time (r=-0.331, P=0.006). Other parameters were not associated with reinnervation. Patients were surveyed for clinical complications over >12 months after PET (until 7.3+/-4.2 years after transplantation), but significant effects of reinnervation on outcome were not observed., Conclusions: The present data suggest that sympathetic reinnervation after cardiac transplantation is not simply a function of time. Reinnervation is more likely with young age, fast and uncomplicated surgery, and low rejection frequency. Despite few effects on prognosis in otherwise healthy recipients, improved understanding of clinical determinants may contribute to enhance allograft reinnervation and thereby augment exercise capacity in the future.

Background: Little is known about the progressiveness of sympathetic reinnervation late after cardiac transplantation (HTX). The aim of the present study was to describe individual growth of sympathetic terminals after HTX by a longitudinal quantitative assessment., Methods and Results: In 20 patients after HTX, dynamic PET with C-11 hydroxyephedrine (HED) was performed twice within 3.0+/-0.5 years. According to the time interval between HTX and first PET, subgroups of patients early (group A, <1.5 years; n=7), intermediate (group B, 1.5 to 7 years; n=7) and late (group C, >7 years; n=6) after HTX were defined. At the time of first HED PET, 10 patients were completely denervated (7 in group A, 2 in group B, and 1 in group C). Only 3 remained denervated at second PET. A significant increase of reinnervated myocardium between first and second PET was found in all 3 groups (0% to 9+/-9% of left ventricle for group A, P<0.05; 13+/-12% to 23+/-17% for group B, P<0.05; 21+/-21% to 37+/-23% for group C, P<0.05). The magnitude of increase was similar between groups. Reinnervation was first surveyed in the basal anterior region, then toward apex, septal, and lateral wall. Inferior wall remained denervated. The largest reinnervated area surveyed in an individuum was 66% of the left ventricle., Conclusions: The present data confirm the low likelihood of sympathetic reinnervation within 18 months after HTX. Once the reinnervation process is initiated, a continuous growth is observed even late after HTX, suggesting a progressive nature of reinnervation. Reinnervation, however, remained regionally heterogeneous, and a complete restoration was not found until 15 years after HTX.

Cardiac reinnervation late after heart transplantation has been reported in individual patients. As a measure for reinnervation, circadian changes in arterial blood pressure and heart rate have been used but not yet systemically evaluated in cardiac transplant recipients. Ambulatory blood pressure and heart rate monitoring was performed in 62 patients for 24 hr early (<6 months, mean 26 days, range 5-90 days, n=30) and late (> or = 6 months, mean 12 months, range 7-78 months, n=32) after heart transplantation. A loss of physiological nocturnal decline in blood pressure and heart rate was noted early after transplantation, whereas late after operation an improvement in circadian changes of blood pressure and heart rate was observed. The patients late after heart transplantation had a significant higher diastolic blood pressure. A pathological circadian blood pressure and heart rate pattern was observed in patients early after heart transplantation, which was improved late after operation. This could be explained by partial reinnervation of the heart. Diastolic hypertension late after transplantation may be due to cyclosporine treatment and/or neuroendocrine hyperactivity.