Assessment of endothelial function and myocardial flow reserve using (15)O-water PET without attenuation correction.

PURPOSE: Myocardial blood flow (MBF) measurement using positron emission tomography (PET) from the washout rate of (15)O-water is theoretically independent of tissue attenuation. The aim of this study was to evaluate the impact of not using attenuation correction in the assessment of coronary endothelial function and myocardial flow reserve (MFR) using (15)O-water PET. METHODS: We retrospectively processed 70 consecutive (15)O-water PET examinations obtained at rest and during cold pressor testing (CPT) in patients with dilated cardiomyopathy (n = 58), or at rest and during adenosine infusion in heart transplant recipients (n = 12). Data were reconstructed with attenuation correction (AC) and without attenuation correction (NAC) using filtered backprojection, and MBF was quantified using a single compartmental model. The agreement between AC and NAC data was assessed using Lin's concordance correlation coefficient followed by Bland-Altman plot analysis. RESULTS: Regarding endothelial function, NAC PET showed poor reproducibility and poor agreement with AC PET data. Conversely, NAC PET demonstrated high reproducibility and a strong agreement with AC PET for the assessment of MFR. CONCLUSION: Non-attenuation-corrected (15)O-water PET provided an accurate measurement of MFR compared to attenuation-corrected PET. However, non-attenuation-corrected PET data were less effective for the assessment of endothelial function using CPT in this population.

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.

Ciclosporin population pharmacokinetics and Bayesian estimation in thoracic transplant recipients.

BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring of ciclosporin has been recognized as an essential tool in the management of allograft transplant recipients, as it could help improve their outcome. However, there is still no consensus about the optimal method for monitoring ciclosporin after thoracic transplantation. Better knowledge of the pharmacokinetics of ciclosporin in thoracic transplant patients and design of tools dedicated to ciclosporin monitoring could help its practice and its outcome in this population of patients. The aims of this study were to (i) investigate the population pharmacokinetics of ciclosporin in thoracic (heart or lung) transplant patients and study the influence of a range of potential covariates, including demographic, clinical and genetic factors, on pharmacokinetic parameters; and (ii) develop a Bayesian estimator able to predict the individual pharmacokinetic parameters and exposures indices in this population of patients. METHODS: The analysis was performed with 187 full pharmacokinetic profiles obtained in 57 lung and 19 heart transplant patients within the first year post-transplantation. A population pharmacokinetic model was developed by non-linear mixed-effects modelling using NONMEM(®) (version 7.1) from an index dataset (118 profiles). On the basis of this population model and a limited number of blood samples, a Bayesian estimator able to determine ciclosporin area under the blood concentration-time curve (AUC) during a dosage interval was built and evaluated in the validation dataset (69 profiles). RESULTS: Ciclosporin pharmacokinetics were described using a two-compartment model with time-lagged first order absorption and first-order elimination. The final population model included sex as a covariate: ciclosporin apparent oral clearance was on average 37 % faster in male than in female patients (34.8 vs. 25.4 L/h, p < 0.001). Good predictive performance of the Bayesian estimator was obtained using three blood concentrations measured at 40 min, 2 h and 4 h post-dose, with a non-significant bias of -5 % between the estimated and the reference trapezoidal AUC and a good precision (relative mean square error = 13 %). CONCLUSION: Ciclosporin population pharmacokinetic analysis in thoracic transplant patients (including patients with cystic fibrosis) showed a significant influence of sex on apparent clearance. The Bayesian estimator developed in this study yielded accurate prediction of ciclosporin exposure in this population throughout the first year post-transplantation. This tool may allow routine ciclosporin dose individualization.

Impact of the early reduction of cyclosporine on renal function in heart transplant patients: a French randomised controlled trial.

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.

Diagnostic and prognostic value of myocardial perfusion gated SPECT in orthotopic heart transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation. Diagnostic and prognostic value of gated single photon emission computed tomography (gated SPECT) has not been documented in this setting. METHODS AND RESULTS: We identified 110 consecutive heart transplant recipients (with transplantation >18 months) who underwent stress-rest gated SPECT and coronary angiography within 1 month, and were clinically monitored in a single heart transplantation center. Visual scoring of perfusion and wall motion images used a 16-segment model. Left ventricular function was automatically calculated. Coronary angiography was normal in 64 patients (58%) and abnormal in 46 (any CAV, 42%), of whom 19 had severe stenoses. Sensitivity and negative predictive (NPV) value were .63 and .75 for identification of any CAV, and .84 and .96 for severe CAV. Cox regression analysis showed that independent predictors of cardiac death and retransplantation were the presence of any angiographic CAV lesions (RR = 8.816, P = .043) and a stress perfusion defect >3 segments (RR = 5.607, P = .0053). A stress perfusion defect >3 segments predicted the need for late coronary revascularization >2 months (RR = 6.11, P = .0002). CONCLUSIONS: We conclude that perfusion gated SPECT is a useful noninvasive screening test and may be proposed to help identify heart transplant recipients with a high risk of poor clinical outcome. A normal gated SPECT was associated with a low risk of cardiac hard event and might alleviate the need for coronary angiography.

Heart transplantation in systemic (AL) amyloidosis: a retrospective study of eight French patients.

BACKGROUND: Immunoglobulinic (AL) amyloidosis is a complication of plasma cell dyscrasia, characterized by widespread deposition of amyloid fibrils derived from monoclonal light chains. Cardiac amyloid is the main prognostic factor, with a median survival of six months. Cardiac transplantation in AL amyloidosis is associated with high mortality, due to disease recurrence in the allograft and systemic progression. Suppression of light chain (LC) production with chemotherapy by melphalan plus dexamethasone (MD) or high dose melphalan followed by autologous stem cell transplantation (HDM/ASCT) improves survival. However, both the indications and results of chemotherapy in patients transplanted for cardiac AL amyloidosis remain unclear. AIMS: To assess the outcome of cardiac transplantation and haematological therapy in patients with cardiac AL amyloidosis. METHODS: Eight French patients, who underwent heart transplantation for cardiac AL amyloidosis between 2001 and 2006 were studied retrospectively. RESULTS: Before transplantation, six patients received MD (n=5) or HDM/ASCT (n=1). Haematological remission was obtained in three patients treated with MD. In the three remaining patients, postoperative HDM/ASCT (n=2) or allogeneic bone marrow transplantation (n=1) resulted in haematological remission in one patient. In 2 patients not treated before transplantation, post-operative treatment with MD resulted in complete hematological remission in one. After a median follow-up of 26 months from cardiac transplantation, six patients were alive and four had sustained haematological remission, as indicated by normal serum free LC levels. CONCLUSION: Appropriate haematological therapy, including MD, may result in a survival benefit in AL amyloidosis patients with advanced heart failure requiring transplantation.

Occurrence of an ascending aorta aneurysm 25 years after cure of a tetralogy of Fallot.

The patient, who had undergone a complete cure of a tetralogy of Fallot 25 years previously, was discovered to have an ascending aorta aneurysm on echography. Bentall's procedure was carried-out, using a modified indirect coronary artery transplantation based on the Cabrol technique. As reported in the literature complications are mainly right sided and less frequently occur on the left side in this disease. Including the hypothesis of the overload volume which may provoke aortic root dilation, there is also an intrinsic pathology of the media which could often be related to embryogenesis abnormalities, i.e., abnormal migration of cardiac neural crest cells which may explain this condition.

Lower risk of infectious deaths in cardiac transplant patients receiving basiliximab versus anti-thymocyte globulin as induction therapy.

BACKGROUND: Conventional antibody induction therapy is currently used in heart transplantation despite safety concerns. This 6-month, prospective, randomized, multicenter, open-label study examined whether basiliximab offers a tolerability benefit compared with anti-thymocyte globulin (ATG) while maintaining similar efficacy in de novo heart transplant recipients. METHODS: Adult heart transplant recipients were randomized to receive basiliximab (20 mg on Day 0 and Day 4) or ATG (2.5 mg/kg/day for 3 to 5 days) with cyclosporine, mycophenolate mofetil and steroids. The primary safety end-point was a composite of serum sickness, fever, cutaneous rash, anaphylaxis, infection, thrombocytopenia, leukopenia and post-transplant proliferative disease. Efficacy was assessed by a composite end-point of death, graft loss, acute rejection Grade > 1B, acute rejection associated with hemodynamic compromise or treated with antibody therapy, or loss to follow-up, whichever occurred first. RESULTS: Eighty patients were randomized and analyzed. By Month 6, the incidence of the composite safety end-point was significantly lower with basiliximab than with ATG (50.0% vs 78.6%, p = 0.01), and infectious death was less frequent in the basiliximab group (0 of 38 vs 6 of 42, p = 0.027). The composite efficacy end-point occurred in 24 patients (63.2%) in the basiliximab arm vs 28 patients (66.7%, p = not significant [NS]) receiving ATG. Acute rejection episodes of Grade > or = 1B were reported with similar frequency (50% with basiliximab vs 45.2% with ATG, p = NS); 7 patients (18.4%) in the basiliximab group and 3 (7.1%) in the ATG group had rejection Grade > or = 3A. CONCLUSIONS: These results suggest that basiliximab offers improved tolerability with similar efficacy compared with current polyclonal antibody induction therapy in de novo heart transplant patients.

Perfil hemodinámico después del trasplante cardiaco ortotópico

La falla del corazón derecho desarrollada después de un trasplante cardiaco, está asociada a una resistencia vascular pulmonar (RVP) elevada en el preoperatorio. Treinta y tres pacientes son estudiados en este protocolo, de un grupo de 66 trasplantados. Son excluidos del estudio los pacientes trasplantados que fueron tratados con drogas inotrópicas, el rechazo miocárdico agudo y los trasplantados con abundante líquido pericárdico. Las medidas fueron realizadas a la semana, al mes y a los tres meses después de realizado el trasplante. Desde la primera semana postoperatoria se observa una mejoría significativa del gasto cardiaco (GC), de la presión arterial pulmonar, de la presión capilar pulmonar y de la resistencia vascular pulmonar. Esta mejoría continúa presentándose hasta el tercer mes. Además de la disminución de la resistencia vascular pulmonar se observa que la presión arterial pulmonar sistólica no presenta modificaciones y esto es debido, probablemente al aumento significativo del gasto cardiaco. Entre la primera semana y el primer mes el incremento del GC es debido a un aumento del volumen de inyección sistólico (VES): 68ñ3 ml vs 82ñ3,5 ml (p<0.001) entre el primer y el tercer mes el VES no se altera de manera significativa; sin embargo, se encuentra una elevación importante de la FC (83ñ1,4 vs 92ñ1,8; p<0.02). La presión de la aurícula derecha recobra valores normales hacia el tercer mes, lo que hace suponer sobre la persistencia de una falla ventricular derecha prolongada

Remplazo valvular aórtico después de valvuloplastia aórtica por estenosis aórtica calcificada: a proposito de 104 pacientes

De febrero de 1987 a diciembre de 1990, 104 pacientes (48 hombres, 56 mujeres) con una edad media de 69 años se beneficiaron de un remplazo valvula aórtico después de una o varias dilataciones percutáneas por sonda de balón. Treinta y un pacientes estaban en clase funcional II, 73 pacientes estaban en una clase III y IV. Un cuadro de angina estaba presente en 22 pacientes (16 en clase I-II, 6 en clase II-IV), 12 pacientes presentaban síncopes o lipotimias de esfuerzo. Las indicaciones de valvuloplastia fueron las siguientes: Un riesgo quirúrgico que se juzga elevado en 46 pacientes, una decisión personal en 41 enfermos; 5 pacientes fueron dilatados de manera pre-operatoria en razón de su alto riesgo quirúrgico, 7 pacientes rechazaron la intervención, 5 fueron operados de urgencia (2 insuficiencias aórticas masivas, una perforación de ventrículo izquierdo, un choque cardiogénico, una endocarditis en choque cardiogénico). El tiempo entre la dilatación y la intervención fue en promedio 472 días. Los pacientes presentaron mejoría sobre un período medio de 261 días. Fuera de las urgencias, los enfermos fueron operados en razón de una re-estenosis. La técnica operatoria consistió en realizar 53 remplazos valvulares por válvula mecánica, 51 remplazos valvulares por válvulas biológicas. Otra intervención quirúrgica asoció en 17 casos (6 monopuentes, 2 puentes dobles, 1 puente triple, 1 sutura del ventrículo izquierdo, 1 intervención de Bigelow, 2 remplazos valvulares mitrales, 1 anuloplastia tricuspidea, 1 endarterectomía de carotida, 1 remplazo de la aorta ascendente, un cierre de una comunicación interauricular). La mortalidad operatoria fue de 7 pacientes (6.7 por ciento). Los hallazgos operatorios permitieron constatar la presencia de 8 lesiones debidas a la dilatación dadas principalmente por desgarros valvulares o desinserciones valvulares que conllevan a realizar una intervención rápida (6 casos) o en urgencia (2 casos) por insuficiencia aórtica masiva. No se halló huella de la dilatación del orificio aórtico, ni aumento de la morbilidad de las valvas en los otros pacientes. Dos grupos fueron realizadosÑ pacientes a riesgo quirúrgico elevado y pacientes con baja fracción de eyección. Nuestra experiencia y la de la mayor parte de la literatura muestran que la dilatación aórtica con balón no debe ser consideranda como una alternativa al remplazo valvular aórtico; ella puede ser propuesta cuando existen ...