Assessment of potential donors is an essential part of heart transplantation. Despite the shortage of donor hearts, donor heart procurement from brain-dead organ donors remains low in France, which may be explained by the increasing proportion of high-risk donors, as well as the mismatch between donor assessment and the transplant team's expectations. Improving donor and donor heart assessment is essential to improve the low utilization rate of available donor hearts without increasing post-transplant recipient mortality. This document provides information to practitioners involved in brain-dead donor management, evaluation and selection, concerning the place of medical history, electrocardiography, cardiac imaging, biomarkers and haemodynamic and arrhythmia assessment in the characterization of potential heart donors.

OBJECTIVES: Survival after heart transplantation is steadily improving but primary graft dysfunction (PGD) is still a leading cause of death. Medical management seems useful in mild or moderate PGD, whereas extracorporeal life support (ECLS) could be suggested for severe PGD refractory to conventional treatment. Our aim is to present the results of ECLS for PGD after heart transplantation at a single-centre experience. METHODS: We performed an observational analysis of our local database. According to the International Society for Heart and Lung Transplantation classification, patients were divided into a left and biventricular failure (PGD-LV) or isolated right ventricular failure (PGD-RV) group. The primary end point was survival to hospital discharge. RESULTS: Between January 2010 and December 2016, 38 patients presented with PGD (PGD-LV n = 22, 58%; PGD-RV n=16, 42%) requiring ECLS support. The mean age was 50.8 +/- 12.4 years and 79% were males. Baseline characteristics were comparable between the 2 groups. PGD-LV patients displayed a significantly higher mortality rate on ECLS support as opposed to PGD-RV patients (46% vs 13%, P=0.033). The rate of complications during ECLS support was comparable between the 2 groups. Twenty-three (61%) patients were successfully weaned from ECLS (PGD-LV = 50% vs PGD-RV = 75%, P = 0.111) after a mean support of 9.0 +/- 6.4 days. Seventeen (45%) patients survived to hospital discharge (PGD-LV= 41% vs PGD-RV=50%, P=0.410). CONCLUSIONS: In case of severe PGD with various manifestations of ventricular failure refractory to conventional treatment, ECLS can be considered as a feasible option with satisfactory survival in this critically ill population.

The risk of melanoma in organ transplant recipients (OTR) is increased compared with the general population. This retrospective study registered all cases of post-transplant melanoma in kidney, heart, lung, and liver transplant recipients followed in our specialized post-transplant Dermatology Clinic since 1991. The yearly prevalence of melanoma and skin carcinoma between 2000 and 2015 was computed and compared in this population. Based on another cohort of kidney transplant recipients grafted since 2005, adjusted age- and sex-standardized incidence ratio (SIR) was calculated using a renal transplantation registry. In our overall OTR cohort, between 1991 and 2000, five melanomas occurred in 1800 OTRs (0.28%), whereas between 1991 and 2015, 53 melanomas were diagnosed in 49 of 4510 OTR (1.09%), representing a 3.9-fold increase in prevalence after 2000. Remarkably, the prevalence of nonmelanoma skin cancers remained unchanged over this period. Two deaths related to melanoma were recorded with an overall follow-up of 62 months. In our cohort of 1102 renal transplant recipients, the SIR of melanoma was 4.52. Our data suggest that contrasting with nonmelanoma skin cancer, the risk of post-transplant melanoma has considerably increased over the last decade.

Left ventricular assist devices (LVADs) display better outcome than biventricular assist devices (BiVADs). Right heart failure (RHF) is a common finding in end-stage heart failure and a life-threatening complication after LVAD implantation. The aim of this report is to describe our strategy of very-low threshold for indication of temporary right ventricular assist device (t-RVAD) support in LVAD recipients. We performed a retrospective observational analysis at three university hospitals. t-RVAD was represented by an extracorporeal membrane oxygenation established between the femoral vein and the pulmonary artery via a Dacron prosthesis according to an original technique. Between March 2012 and September 2015, we implanted a t-RVAD in 32 LVAD recipients (mean age 54.2 years, males 87.5%). The indication for LVAD implantation was ischemic (n=14, 43.8%) or idiopathic (n=10, 31.2%) cardiomyopathy and other (n=8, 25%). INTERMACS profile was 1 (n=4, 12.5%), 2 (n=17, 53.1%), 3 (n=8, 25%) and 4 (n=3, 9.4%). Device strategy was bridge-to-transplantation (n=19, 59.4%), destination therapy (n=10, 31.3%), bridge-to-candidacy (n=2, 6.2%) and bridge-to-recovery (n=1, 3.1%). Mean RHF risk score was 3.0 ± 2.3. Six (18.7%) patients died while on t-RVAD support (multiple organ failure n=2, intestinal ischemia n=2, hemorrhagic stroke n=1, gastrointestinal bleeding n=1). Twenty-five (78.1%) patients were successfully weaned off after a mean t-RVAD support of 8.2 ± 4.0 days. Weaning procedures were uneventful in awake patients on local anesthesia directly at bedside. No patient required a further mechanical circulatory support implantation for recurrent RHF. After a median follow-up time of 94.5 days, 11 (34.3%) patients were alive on LVAD support, 10 (31.2%) were successfully bridged to heart transplantation and 5 (15.7%) died on LVAD. A very-low threshold implantation of t-RVAD is a safe and valuable strategy in LVAD recipients with a satisfactory short-term survival rate in such a critically ill population.

This study assessed the long-term outcome of heart (HTx) and heart-lung transplantation (HLTx) in patients with congenital heart disease (CHD) and children with non-congenital cardiac or pulmonary disease.

HT patients survival is altered by chronic rejection including rapidly progressive cardiac allograft vasculopathy (CAV), myocardial contractile dysfunction, recurrent cellular rejection. Together with graft failure, death related to CAV increases with time and is a leading cause of death or retransplantation in long survivors. Determinant of humorally mediated rejection leading to CAV are still under investigation. Donor Specific Antibodies (DSA) have been associated with CAV. However not all DSA patients develop CAV. Identification of predictors of risk of CAV or graft failure is of major interest. We tested whether de novo C3d fixing HLA DSA (C3dDSA) were associated with poor outcome or development of CAV. 271 files were screened and 242 patients files were included. Inclusion was based on presence of de novo single antigen HLA antibody within 365 days prior to coronary angiogram and echocardiography (positive patients). Patients without HLA Ab at the time of or after coronarography were considered as negative patients. Coronarographies were classified according to CAV ISHLT grading. Echocardiographies were analyzed for left ventricle dysfunction or diastolic alteration. All patients with DSA-HLA antibodies were tested for C3d fixation. 27 patients (11%) had developed de novo HLA antibodies. Average age was 48±1 yo. Antibodies (Ab) were detected 2389 +-1696 days post-transplant. Mean time between Ab detection and angiography was 47 days (ET92). Among the deceased patients all (100%) were carrying DSA Ab and 6 (55%) were fixing C3d. 16 patients survived with HLAAb ; 10 with DSA but in only 2 cases were fixing C3d (20%). Presence of DSA did not significantly affect LVEF (61,1%±18,5 vs 59,9%±10,6). Survival as assessed by Kaplan-Meier method was reduced when HLA Ab were detected (log rang<0,02 vs absence HLA Ab). While averaged CAV score was significantly increased in deceased patients vs alive (1,29 vs 0,67; p<0,01), it was also significantly higher in patients with C3d fixing HLA DSA vs absence of HLA Ab (1,62±0,46 vs 0,84±0,01; p<0,05 LSD fisher). In conclusion this observational study points out that presence of HLA Ab specifically when fixing C3d is associated with worse prognosis and more severe CAV. Such information could help prevent fatal cardiovascular events in HT patients.

AimsCalcineurin 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.MethodsWe 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.ResultsEight 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 I2 = 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 I2 = 75%.ConclusionsThis 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.

PurposeBasiliximab ( Simulect ) is a monoclonal antibody specifically directed against the alpha chain ( CD25 ) of the interleukin 2 receptor. It inhibits the activation of T lymphocytes that play a major role in the mechanism of acute rejection. It is indicated for the prevention of acute rejection in de novo allogeneic renal transplantation in adults and children and is commonly used as induction therapy in solid organ transplantation. We report a retrospective analysis of the efficacy and safety of basiliximab administered as curative treatment of acute rejection in heart transplantation.MethodsThe study involved the treatment of 22 cellular rejection in 17 patients failing to control rejection by conventional strategies (corticosteroid resistant: n = 12; intolerance or contraindications to switched or increased immunosuppression n = 8). Basiliximab was administered in two doses of 20 mg IV over 20 min with 4 days intervals. A semi -quantitative score of rejection was used to compare the results of biopsies before and after treatment with basiliximab. We respectively assigned a score of 0, 1, 2, 3 or 4 to stages ISHLT 0R -1A- 1B -3A- 3B. The analysis is made from the patient records.ResultsAfter basiliximab, the semi- quantitative score of rejection dropped from 50 to 18 (64 % reduction), reflecting improved histology. Rejection is considered resolved in 47.6 % of cases. There were four treatment failures (unmodified rejection) and the use of two courses of basiliximab for five patients and three times in one case. The cure of basiliximab was the only intervention for 6 patients (28%) and accompanied by an adjustment or change of immunosuppressants in other cases. The global efficiency is 81%, taking into account both resolved rejections ( n = 10) and improved ( n = 7) after treatment with basiliximab. No adverse effects related to basiliximab have been observed.ConclusionThis study reports the first use of basiliximab in heart transplantation for treatment of acute cellular rejection in the absence of alternative or in addition to an adjustment of the immunosuppressive treatment. No incidents have been observed and these encouraging results suggest the need for prospective studies. PurposeBasiliximab ( Simulect ) is a monoclonal antibody specifically directed against the alpha chain ( CD25 ) of the interleukin 2 receptor. It inhibits the activation of T lymphocytes that play a major role in the mechanism of acute rejection. It is indicated for the prevention of acute rejection in de novo allogeneic renal transplantation in adults and children and is commonly used as induction therapy in solid organ transplantation. We report a retrospective analysis of the efficacy and safety of basiliximab administered as curative treatment of acute rejection in heart transplantation. Basiliximab ( Simulect ) is a monoclonal antibody specifically directed against the alpha chain ( CD25 ) of the interleukin 2 receptor. It inhibits the activation of T lymphocytes that play a major role in the mechanism of acute rejection. It is indicated for the prevention of acute rejection in de novo allogeneic renal transplantation in adults and children and is commonly used as induction therapy in solid organ transplantation. We report a retrospective analysis of the efficacy and safety of basiliximab administered as curative treatment of acute rejection in heart transplantation. MethodsThe study involved the treatment of 22 cellular rejection in 17 patients failing to control rejection by conventional strategies (corticosteroid resistant: n = 12; intolerance or contraindications to switched or increased immunosuppression n = 8). Basiliximab was administered in two doses of 20 mg IV over 20 min with 4 days intervals. A semi -quantitative score of rejection was used to compare the results of biopsies before and after treatment with basiliximab. We respectively assigned a score of 0, 1, 2, 3 or 4 to stages ISHLT 0R -1A- 1B -3A- 3B. The analysis is made from the patient records. The study involved the treatment of 22 cellular rejection in 17 patients failing to control rejection by conventional strategies (corticosteroid resistant: n = 12; intolerance or contraindications to switched or increased immunosuppression n = 8). Basiliximab was administered in two doses of 20 mg IV over 20 min with 4 days intervals. A semi -quantitative score of rejection was used to compare the results of biopsies before and after treatment with basiliximab. We respectively assigned a score of 0, 1, 2, 3 or 4 to stages ISHLT 0R -1A- 1B -3A- 3B. The analysis is made from the patient records. ResultsAfter basiliximab, the semi- quantitative score of rejection dropped from 50 to 18 (64 % reduction), reflecting improved histology. Rejection is considered resolved in 47.6 % of cases. There were four treatment failures (unmodified rejection) and the use of two courses of basiliximab for five patients and three times in one case. The cure of basiliximab was the only intervention for 6 patients (28%) and accompanied by an adjustment or change of immunosuppressants in other cases. The global efficiency is 81%, taking into account both resolved rejections ( n = 10) and improved ( n = 7) after treatment with basiliximab. No adverse effects related to basiliximab have been observed. After basiliximab, the semi- quantitative score of rejection dropped from 50 to 18 (64 % reduction), reflecting improved histology. Rejection is considered resolved in 47.6 % of cases. There were four treatment failures (unmodified rejection) and the use of two courses of basiliximab for five patients and three times in one case. The cure of basiliximab was the only intervention for 6 patients (28%) and accompanied by an adjustment or change of immunosuppressants in other cases. The global efficiency is 81%, taking into account both resolved rejections ( n = 10) and improved ( n = 7) after treatment with basiliximab. No adverse effects related to basiliximab have been observed. ConclusionThis study reports the first use of basiliximab in heart transplantation for treatment of acute cellular rejection in the absence of alternative or in addition to an adjustment of the immunosuppressive treatment. No incidents have been observed and these encouraging results suggest the need for prospective studies. This study reports the first use of basiliximab in heart transplantation for treatment of acute cellular rejection in the absence of alternative or in addition to an adjustment of the immunosuppressive treatment. No incidents have been observed and these encouraging results suggest the need for prospective studies.

Background Using reduced doses of Cyclosporine A immediately after heart transplantation in clinical trials may suggest benefits for renal function by reducing serum creatinine levels without a significant change in clinical endpoints. However, these trials were not sufficiently powered to prove clinical outcomes. Methods In a prospective, multicentre, open-label, parallel-group controlled trial, 95 patients aged 18 to 65 years old, undergoing de novo heart transplantation were centrally randomised to receive either a low (130 < trough CsA concentrations <200 μg/L, n = 47) or a standard dose of Cyclosporine A (200 < trough CsA concentrations<300 μg/L, n = 48) for the three first post-transplant months along with mycophenolate mofetil and corticosteroids. Participants had a stable haemodynamic status, a serum creatinine level <250 μmol/L and the donors’ cold ischemia time was under six hours; multiorgan transplants were excluded. The change in serum creatinine level over 12 months was used as the main criterion for renal function. Intention-to-treat analysis was performed on the 95 randomised patients and a mixed generalised linear model of covariance was applied. Results At 12 months, the mean (± SD) creatinine value was 120.7 μmol/L (± 35.8) in the low-dose group and 132.3 μmol/L (± 49.1) in the standard-dose group ( P = 0.162). Post hoc analyses suggested that patients with higher creatinine levels at baseline benefited significantly from the lower Cyclosporine A target. The number of patients with at least one rejection episode was not significantly different but one patient in the low-dose group and six in the standard-dose group required dialysis. Conclusions In patients with de novo cardiac transplantation, early Cyclosporine A dose reduction was not associated with renal benefit at 12 months. However, the strategy may benefit patients with high creatinine levels before transplantation. Trial registration ClinicalTrials.gov NCT00159159

BACKGROUND: Coronary allograft vasculopathy (CAV) is the major limiting factor for long term survival after heart transplantation. The aim of this study was to identify gene candidates implicated in human CAV using a rat aortic allograft model in tandem with microarrays and quantitative real time PCR (Q-PCR).METHODS: Rat abdominal aortas were isografted (5) or allografted (5) from Brown-Norway to Lewis rats and grafts were harvested after day 8, 25 and 60. Agilent microarrays were then used to highlight differentially expressed genes between isografted and allografted rat aortas. Further investigation of a selected candidate gene was performed on human coronary arteries.RESULTS: 1829, 2582 and 1925 genes (fold changes >2 or <2 and p values <0.05) were differentially expressed at day 8, 25 and 60 respectively between isografs and allografts. Seventeen candidate genes were selected according to significant differential expression at day 60. These rat candidate genes were then validated by quantitative real time polymerase chain reaction (Q-PCR). One of these candidate genes, T-Cadherin (T-Cad) was further investigated, using immunohistochemistry (IHC), in human coronary arteries showing CAV compared to classical atherosclerosis present in ischemic cardiomyopathy (ICM) and normal coronary arteries present in dilated cardiomyopathy (DCM). Results showed an over expression of T-Cad in CAV and classical atherosclerosis compared to normal coronary arteries.CONCLUSIONS: T-Cad was found to be over expressed in CAV. T-Cad could potentially act as a trigger for smooth muscle cells (SMCs) proliferation and vascular remodelling observed in CAV leading to a diffuse narrowing of the arterial lumen. J Heart Lung Transplant 2010;29:792-9 (C) 2010 International Society for Heart and Lung Transplantation. All rights reserved.

Cyclosporine (CsA) related encephalopathy has not been well documented after heart transplantation. We report 2 cases of posterior reversible encephalopathy syndrome (PRES). The first case was a 68-year-old woman who underwent heart transplantation and received immunosuppression with mycophenolate mofetil, prednisone, and CsA. On day 14, she developed arterial hypertension, headache, visual disturbances, and generalized seizures. Fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the brain showed diffuse and bilateral high signals in the frontal posterior and the occipital areas. The second case was a 19-year-old man with a heart transplant receiving immunosuppression with prednisone and CsA. On day 44, he developed acute headache and generalized seizures. T2-weighted MRI of the brain showed diffuse high signals in the cerebellum, right lenticular and occipital areas. In both cases blood CsA concentration was therapeutic. Both cases recovered but in the first case neurologic findings were reversed only after CsA withdrawal.

Coronary allograft vasculopathy (CAV) or chronic rejection (CR) is the major limiting factor for long term survival after heart transplantation (HT). Even though the major components of CAV are already described, their molecular mechanisms are not completely understood.

Non-melanoma skin cancers (NMSC) are the commonest cancers in heart transplant recipients (HTR) [1,2] and include mainly squamous-cell carcinomas (SCC) and basal-cell carcinomas (BCC). After a first SCC, all HTR develop new NMSC within 5 years and at least 25% of them develop also extracutaneous cancers [3]. Kidney transplant patients under mTOR inhibitors develop fewer NMSC compared with those receiving calcineurin inhibitors either in de novo treatment or after conversion [4–10]. So far, limited clinical data exist on the antitumoral properties of everolimus (EVE) [9–11]. We report for the first time the effect of EVE on NMSC in HTR. This observational study included HTR with multiple recurrent skin tumors and/or fast growing SCC switched to EVE since 2006 among the 635 HTR followed over the same period in our center (1428 heart transplantations since 1979). All the reported patients received the initial immunosuppressive regimen following our standard institutional protocol, including polyclonal induction therapy (3–5 days, 1.5 mg/kg/day), corticosteroids, azathioprine until 2000, mycophenolate mofetil afterwards and cyclosporine (whose trough levels were adjusted to time after transplantation according to international guidelines). EVE was started at 1.5 mg/day and adjusted to obtain trough levels 3–10 ng/ml. Each visit included physical examination and standard echocardiography; endomyocardial biopsies were performed according to institutional guidelines. Dermatological assessment recorded the count of histologically proven NMSC and the presence of verrucous lesions. The number of tumors before and after EVE was compared with the Wilcoxon signed rank-test. Because of the delay necessary to assess the impact of immunosuppression alteration on NMSC, only patients with at least 1-year follow-up under EVE were studied. Fourteen men with 115 NMSC were considered. Their mean age was 69 ± 7 years and the mean delay after transplantation 13.5 ± 5 years. Six patients had also developed other malignancies. EVE introduction was always followed by discontinuation of azathioprine and by reduction of calcineurin inhibitors. Cyclosporine was decreased (trough levels targeted at 50–80 ng/ml) in six patients, and withdrawn in seven others (depending on the initial immunosuppression regimen, history of rejection and comorbidities). Dosages of corticosteroids and mycophenolate mofetil were not significantly altered. The total number of immunosuppressants was increased after EVE introduction; no patient had a lower number of drugs and six patients had an additional immunosuppressant. Concerning the effect on skin cancers, 10 patients were evaluable (Table 1) over a mean period of 28 months (four patients were excluded: three EVE discontinuations and one death from hepatocarcinoma). Overall, the mean number of tumors per patient that developed under EVE was significantly lower as compared with the same period before EVE (3.7 vs. 1.5, P = 0.03). Remarkably, the SCC/ BCC ratio was halved. Seven patients did not develop further SCC. Furthermore, three of five patients with multiple verrucous (non-NMSC) lesions experienced a decrease in these lesions. However, two patients kept developing multiple NMSC despite a temporary beneficial effect; one of them experienced lymph-node metastasis of a facial SCC. Among evaluable patients with noncutaneous malignancies before EVE introduction, two (2 and 5) did not relapse. Patient 4 developed recurrence of bladder cancer and patient 7 developed prostatic cancer 1 year after EVE introduction, but no relapse of bladder cancer. Adverse effects occurred in all patients and led to EVE discontinuation in five of them. Discontinuation was decided shortly in three patients because of proteinuria, pneumonitis, and ileitis respectively. Two additional patients (4 and 7) discontinued EVE during months 16 and 17 because of proteinuria. These side effects regressed after EVE withdrawal. Other side effects included edema, aphthae, folliculitis, hidradenitis suppurativa, seborrheic dermatitis exacerbation, diarrhea, fever of unknown origin, and hyperlipidemia. Most side effects were controlled by EVE tapering. Patient 6 experienced a grade 1R (1B) biopsy-proven acute rejection according to the International Society of Heart and Lung Transplantation classification [12] at month 15, which was successfully treated by corticosteroid pulses. Patients 4 and 5 experienced clinically insignificant grade 1R (1A) rejection, which did not require treatment.

Everolimus has been shown to significantly reduce risk of acute rejection and severity/incidence of cardiac allograft vasculopathy versus azathioprine in HTx. However, renal dysfunction may occur when everolimus is used with concomitant full cyclosporine A (CsA) exposure. Renal function and efficacy (biopsy-proven acute rejection; BPAR) were compared in de novo HTx patients receiving concentration-controlled (CC) everolimus with reduced-exposure CsA versus MMF with standard-exposure CsA.