Thymic function is a major determinant of onset of antibody-mediated rejection in heart transplantation.

Thymic function decreases progressively with age but may be boosted in certain circumstances. We questioned whether heart transplantation was such a situation and whether thymic function was related to the onset of rejection. Twenty-eight antithymocyte globulin-treated heart transplant recipients were included. Patients diagnosed for an antibody-mediated rejection on endomyocardial biopsy had a higher proportion of circulating recent thymic emigrant CD4+ T cells and T cell receptor excision circle levels than other transplanted subjects. Thymus volume and density, assessed by computed tomography in a subset of patients, was also higher in patients experiencing antibody-mediated rejection. We demonstrate that thymic function is a major determinant of onset of antibody-mediated rejection and question whether thymectomy could be a prophylactic strategy to prevent alloimmune humoral responses.

[Combined heart and kidney transplantation in Fabry's disease: Long-term outcomes in two patients]. / Transplantation combinée cœur­rein au cours de la maladie de Fabry : suivi à long terme de deux patients.

INTRODUCTION: Fabry disease is a lysosomal storage disorder linked to an alpha-galactosidase A deficiency that can lead to heart and kidney failure. There is little data about the prognosis of patients who undergo a combined heart and kidney transplantation. CASE REPORTS: Two brothers who were diagnosed with Fabry disease after the age of 30 years underwent a combined heart and kidney transplantation at respectively 49 and 42 years of age because of a severe hypertrophic cardiomyopathy with end stage renal failure. They are alive respectively 4 and 9 years after the transplantation. No recurrence of the disease in the transplanted organs has been found. CONCLUSION: Combined heart and kidney transplantation in Fabry disease is an efficient therapy for the cardiomyopathy and kidney failure. Its prognosis can be good when the patients are carefully selected. However, an early diagnosis is critical in order to avoid a procedure associated with a high perioperative mortality.

[The role of the French Agence de la biomédecine in lung transplantation]. / Le rôle de l'Agence de la biomédecine dans la greffe pulmonaire.

The Agence de la biomédecine is a public institution in charge of organs tissues cells transplantation, reproduction, embryology and genetics. It interacts with the hospital coordinators and the transplant teams and ensure the regulation of organ retrieval and allocation. Its strategic missions are the revision of the graft allocation rules and the optimization of transplant organization. These last years, after redefining the graft selection criteria, the activity of lung transplantation increased drastically. The lung procurement efficacy must be still improved, while various machines of perfusion are going to be available. In July 2007, a national priority status for the patients with a life-threatening condition in the very short-term was put in place. The use of a graft allocation score taking into account the urgency and the individual benefit from transplantation is in evaluation. The optimization of the patient access to the waiting list needs a network approach of the end-stage lung diseases.

Fluvastatin synergistically improves the antiproliferative effect of everolimus on rat smooth muscle cells by altering p27Kip1/cyclin E expression.

Multiple intracellular signaling pathways stimulate quiescent smooth muscle cells (SMCs) to exit from G(0) and re-enter the cell cycle. Thus, a combination of two drugs with different mechanisms of action may represent a suitable approach to control SMC proliferation, a prominent feature of in-stent restenosis. In the present study, we investigated the effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on proliferation of rat SMCs. The antiproliferative action of everolimus was amplified by 2.5-fold by the addition of subliminal concentrations of fluvastatin (5 x 10(-7) M), lowering the IC(50) value from 2.5 x 10(-9) to 1.0 x 10(-9) M. The increased antiproliferative effect of everolimus by fluvastatin was prevented in the presence of mevalonate, farnesol, or geranylgeraniol, suggesting the involvement of prenylated proteins. Cell cycle analysis and [3H]thymidine incorporation assay demonstrated that the two drugs synergistically interfered with the progression of G(1) phase. In particular, the drug combination significantly up-regulated p27(Kip1) levels by 47.0%, suppressed cyclin E by 43.0%, and it reduced retinoblastoma (Rb) hyperphosphorylation by 79.0%, compared with everolimus alone. Retroviral overexpression of cyclin E conferred a significant resistance of rat SMCs to the antiproliferative action of the drug combination, measured by cell counting, [3H]thymidine incorporation, and cell cycle analysis, with higher levels of hyperphosphorylated form of Rb. Taken together, these results demonstrated that everolimus acts synergistically with fluvastatin to inhibit SMC proliferation by altering the expression of cyclin E and p27(kip1), which affects Rb phosphorylation and leads to G(1) phase arrest.

Long-term survival of heart transplant recipients with lung cancer: the role of chest computed tomography screening.

OBJECTIVE: We sought to evaluate the screening modality and outcome of lung cancer occurring in heart transplant recipients (HTR) during a 21-year period. METHODS: We conducted a retrospective review to investigate the incidence, risk factors, screening modality, treatment, and outcomes in HTR with lung cancer. We compared them with a case-matched HTR control group. RESULTS: Out of 829 recipients of heart transplants, 19 cases of bronchogenic carcinoma were found either by routine chest X-ray (n = 10), chest computed tomographic (CT) scanning (n = 4), or by assessment of clinical symptoms (n = 5). The mean time from transplantation to bronchogenic carcinoma diagnosis was 68.8 +/- 42.4 months. A history of smoking was the only risk factor in HTR with bronchogenic carcinoma compared to their case-matched HTR control group ( P < 0.05). Of 18 patients with non-small cell lung cancer (NSCLC), 13 underwent surgery and 5 with advanced cancer underwent chemotherapy and/or radiotherapy. NSCLC was diagnosed by chest X-ray (n = 10), and 6 of these patients died after an average of 43.7 +/- 62.2 months following cancer detection. NSCLC was also diagnosed on the basis of clinical symptoms (n = 4), and 2 of these patients died after a mean follow-up of 9 +/- 4.2 months after cancer diagnosis. All 4 patients in whom cancer was detected by CT scan were alive at an average of 53.5 +/- 36.7 months following cancer detection. The survival rates did not differ between the study and control groups ( P = 0.5). CONCLUSIONS: Optimal outcomes of treatment for primary lung cancer after heart transplantation seem to be related to early detection. A high proportion of deaths from NSCLC may be prevented by chest CT scan screening.

[Value of the protein profile in the diagnosis of infectious endocarditis when hemolysis is present]. / Apport du profil protéique pour le diagnostic d'endocardite infectieuse quand il révèle une hémolyse.

PURPOSE: Haptoglobin (H) and orosomucoid (O) are acute phase proteins that increase in a parallel manner. When hemolysis and inflammation are both present, study of the O-H couple on the protein profile may reveal an unknown hemolysis. METHODS: To determine if hemolysis is more frequent during infectious endocarditis than during septicemia without valvulopathy or during valvulopathy without septicemia. Study of three groups of patients: 26 patients with infectious endocarditis, 13 patients with septicemia and 36 patients with valvulopathy without septicemia. Studied parameters were the O-H couple, hemoglobin and rate of O. RESULTS: Hemolysis is clear in patients with endocarditis. The difference O-H is significantly more important during endocarditis than during septicemia without valvulopathy (P < 0.001) and during valvulopathy without sepsis (P < 0.001). CONCLUSION: Study of the O-H couple may be useful for the diagnosis of endocarditis showing a difficult-to-diagnose hemolysis.

Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders.

PURPOSE: Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkin's lymphoma International Prognostic Index (IPI) in 61 patients with PTLD. PATIENTS AND METHODS: We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates. RESULTS: In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) > or = (P =.0001) and nondetection of Epstein-Barr virus (EBV) in the tumor (P =.01). Only a negative link with PS > or = 2 was observed in multivariate analysis. In univariate analysis, factors predictive of lower survival were PS > or = 2, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy. The IPI failed to identify a patient subgroup with better survival and was less predictive of the response rate than was a specific index using two risk factors (PS and number of involved sites), which defined three groups of patients: low-risk patients whose median survival time has not yet been reached, intermediate-risk patients with a median survival time of 34 months, and high-risk patients with a median survival time of 1 month. CONCLUSION: PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Clinical features and contribution of virological findings to the management of Kaposi sarcoma in organ-allograft recipients.

OBJECTIVES: To describe the clinical features of Kaposi sarcoma (KS) in organ-allograft recipients and to determine the contribution of human herpesvirus 8 (HHV-8) investigations to the management of KS. DESIGN, SETTING, AND PATIENTS: We examined 20 organ-allograft recipients with KS at Pitié-Salpêtrière Hospital, Paris, France, between November 1, 1991, and May 31, 1999. METHODS: We detected HHV-8 antibodies using an indirect immunofluorescence assay and the HHV-8 DNA genome using nonnested polymerase chain reaction with KS-associated herpesvirus 330(233) primers in peripheral blood mononuclear cells collected at transplantation and KS diagnosis. We detected the HHV-8 genome in involved and uninvolved tissue specimens and in 10 patients' serum samples collected 1 month before the first manifestation of KS. We determined the HHV-8 double-strand DNA sequence and subtypes of open reading frame 26. INTERVENTION: Management of KS consisted of progressively tapering immunosuppressive therapy regardless of KS dissemination. Associated infections were treated when possible. Chemotherapy was prescribed only when a functional disability persisted, and polychemotherapy was prescribed for life-threatening disease. MAIN OUTCOME MEASURES: Percentage of recipients with KS remission and stabilization, organ-graft survival, and death rates. RESULTS: Remission of KS was obtained in 9 (45%) of the 20 patients independently of disease dissemination, with a mean follow-up of 35 months. The kidney graft survived in 12 (67%) of the 18 patients. Only 1 patient (5%) died of KS progression. All allograft recipients had anti-HHV-8 antibodies before transplantation. We detected HHV-8 DNA in all involved tissue samples but not in serum samples 1 month before KS onset. The most prevalent subtype was HHV-8 C (9 [53%] of 17 patients) and was not associated with extradermatological extension of KS compared with subtypes A and B'. CONCLUSIONS: Virological investigations of HHV-8 contribute poorly to KS management. Prospective studies are needed to determine the role of HHV-8 virological investigations and to identify associated cofactors so as to prevent KS in organ-allograft recipients.

Hepatitis virus infections in heart transplant recipients: epidemiology, natural history, characteristics, and impact on survival.

BACKGROUND & AIMS: We have observed a high prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in heart transplant recipients (HTRs). The aim of this study was to assess the epidemiology, natural history, and clinical and biological characteristics of viral hepatitis in HTRs. METHODS: From 1983 to 1992, 874 patients underwent heart transplantation at the Pitié-Salpêtrière Hospital, Paris, France, 459 of whom qualified for analysis. A total of 140 patients had posttransplantation hepatitis B, C, or non-A-E. Sixty-nine patients developed HBV infection, 49 HCV infection, 11 HBV-HCV coinfection, and 11 non-A-E hepatitis. RESULTS: HBV was transmitted nosocomially from patient to patient, most likely during endomyocardial biopsies. HCV was mainly transmitted through blood transfusions or the transplanted organ. Clinical and biological findings after 2 years of follow-up showed that 3 patients with an HBV genotype A precore mutant had severe or subfulminant hepatitis and that patients with HBV and HCV infection always progressed to chronicity. In general, patients had mild alanine aminotransferase level increases, a high level of viral replication, and few severe histologic lesions, except for patients infected by precore HBV mutants. Patients coinfected by HBV and HCV tended to have more severe liver lesions. The survival rate 5 years after transplantation in patients with viral hepatitis (HBV, 81%; HCV, 89%; HBV and HCV coinfection, 100%; non-A-E hepatitis, 73%) was similar to that in patients without liver test abnormalities (76%). The actuarial survival curve was also similar in patients with or without liver test abnormalities. CONCLUSIONS: In our experience, histologic liver lesions do not progress rapidly in patients with post-heart transplant infection caused by HBV or HCV. HBV or HCV infection seems to have little impact on the 5-year survival rate of HTRs.

The role of percutaneous transluminal coronary angioplasty in heart transplant recipients.

OBJECTIVES: Review the acute and late results of percutaneous transluminal coronary angioplasty (PTCA) in heart transplant recipients and examine the factors predictive of restenosis. BACKGROUND: Coronary graft disease (CGD) is the main factor responsible for late graft loss. Medical treatment, surgical revascularization, or retransplantation gives only suboptimal results in this regard. Therefore, PTCA has been attempted in this situation. METHODS: More than 332 heart transplantations in our institution have been performed since 1992, the date of the first PTCA in our patients. We are currently in charge of 450 patients. All the characteristics, procedure-related information, and clinical outcome of patients needing PTCA were assessed by review of each patient's clinical records. All coronary angiograms were reviewed by an independent cardiologist. RESULTS: Since 1992, 53 coronary sites have been dilated in the course of 39 procedures in 29 patients. Indication for PTCA was asymptomatic angiographic coronary graft disease in 35 sites (64.8%), angina in 9 (16.6%), silent ischemia in 2 (3.7%), acute myocardial infarction in 1 (1.8%), and CHF in 7 (12.9%). Primary success (< 50% residual stenosis) was obtained in 50 (94.3%) of 53 lesions. No periprocedural death occurred. Procedural complications were 1 transient acute renal failure and 1 persistent bleeding at the puncture site. Six months restenosis rate (defined as percent stenosis > 50%) was 32.5% (14/43). Mean follow-up was 1.27 year +/- 1.2 (SD). Five deaths (17. 2%) occurred in follow-up and were all in relation to coronary graft disease. Mean time separating PTCA from death was 0.9 year +/- 1.3 (SD). We also sought to look at factors predictive of restenosis. By multivariate analysis, a positive recipient's serology for cytomegalovirus (CMV) before the graft was the only factor found protective against restenosis (odds ratio 22.4; confidence interval 1.1 to 443.4). CONCLUSION: PTCA in heart transplant recipients allows a high level of primary success with a low periprocedural-complication rate. Restenosis rate seems equivalent to restenosis rate in native coronary arteries. Mortality during follow-up is increased in this population and is the consequence of a high level of coronary events. Recipient positivity for CMV before the graft is associated with a protective effect from restenosis.

Effect of cryopreservation on endothelin-1 productions of human mammary artery.

The aim of this study was to determine the ability of human mammary artery cells to maintain a metabolic activity by measuring the artery concentration of two vasoactive substances, endothelin-1 (ET-1) and cyclic guanosyl monophosphate (cGMP), and a neurohumoral substance-neuropeptide Y (NPY)-prior to and following cryostorage. Ten distal segments of internal mammary arteries were obtained at the time of surgery in patients who had undergone coronary artery bypass grafting. One ring of each vessel served as a fresh control for the other ring that was used in cryopreservation experiments. The arteries were frozen with liquid nitrogen at a controlled rate down to -130 degrees C with an automatic freezing machine and were then stored in a liquid nitrogen vapor at -150 degrees C. After mammary artery extraction, ET-1, cGMP, and NPY concentrations were studied before and after cryopreservation. Cryopreserved, compared to fresh arteries, exhibited an increase in ET-1 (11.11+/-1.61 vs. 3. 09+/-0.06 pg/mg; p=0.004) and a decrease in cGMP (9.88+/-2.04 vs. 8. 55+/-2.07 p moles/mg; p<0.02), whereas there was no significant NPY variation. An increase in ET-1 and decrease in cGMP was found in 10 out of 10 and 6 out of 10 of cryopreserved artery specimen, respectively. There was no significant correlation between ET-1 and cGMP production in fresh or in cryopreserved arteries. The present method of cryostorage is effective in preserving "hormonal" mammary artery activity. However, the particularly high ET-1 concentration without associated cGMP concentration may be deleterious by increasing smooth-muscle cell proliferation and vascular tone of cryopreserved arteries.

Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study.

OBJECTIVES: The study investigated the potential role of eight candidate genes in the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several genetic loci have been identified in rare monogenic forms of the disease. These findings led to the hypothesis that genetic factors might also be involved in sporadic forms of the disease. In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate gene approach is a strategy widely used to identify susceptibility genes. All genes coding for proteins involved in biochemical or physiological abnormalities of cardiac function are potential candidates for IDC. METHODS: We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were significantly associated with the risk or the severity of the disease. CONCLUSIONS: We did not find evidence for an involvement of any of the 10 investigated polymorphisms in the susceptibility to IDC.