A 1-year randomized controlled study of everolimus versus mycophenolate mofetil with reduced-dose cyclosporine in maintenance heart transplant recipients.

BACKGROUND: The aim of this study was to demonstrate noninferiority of everolimus with reduced cyclosporine (CsA) vs mycophenolate mofetil (MMF) with reduced CsA in improving renal function. METHODS: In this 1-year randomized, open-label, noninferiority study in maintenance heart transplant recipients with impaired renal function 70 patients received everolimus (n = 36) or MMF (n = 34) in combination with reduced CsA. The planned sample size was not reached as the study was prematurely discontinued due to slow recruitment. RESULTS: Noninferiority of the everolimus regimen could not be shown: In the total population MMF seemed to be favorable on renal function assessed by serum creatinine and filtration rates, but not in the subset of patients who reached the intended reduced CsA level. Incidence rates of rejection episodes were significantly higher under MMF at month 6 (P = .0332). CONCLUSIONS: Overall, the results of this trial using reduced CsA in combination with either everolimus or MMF show that there is evidence to reduce the CsA level when everolimus is given concomitantly and that the benefit of MMF with reduced CsA levels is limited due to insufficient immunosuppression.

Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation.

BACKGROUND: Cytomegalovirus (CMV) causes several complications following cardiac transplantation including cardiac allograft vasculopathy. Previous studies suggested that immunosuppressive treatment based on everolimus might reduce CMV infection. Aiming to better characterize the action of everolimus on CMV and its interplay with patient/recipient serology and anti-CMV prophylaxis, we analyzed data from 3 large randomized studies comparing various everolimus regimens with azathioprine (AZA)- and mycophenolate mofetil (MMF)-based regimens. METHODS: CMV data were analyzed from 1009 patients in 3 trials of de novo cardiac transplant recipients who were randomized to everolimus 1.5 mg/day, everolimus 3 mg/day, or AZA 1-3 mg/kg/day, plus standard-dose (SD) cyclosporine (CsA; study B253, n = 634); everolimus 1.5 mg/day plus SD- or reduced-dose (RD)-CsA (study A2403, n = 199); and everolimus 1.5 mg/day plus RD-CsA or MMF plus SD-CsA (study A2411, n = 176). RESULTS: In study B253, patients allocated to everolimus experienced almost a 70% reduction in odds of experiencing CMV infection compared with AZA (P < 0.001). In study A2403, CMV infection was low in both everolimus arms, irrespective of CsA dosing, and in study A2411, patients allocated to everolimus experienced an 80% reduction in odds of experiencing CMV infection, compared with MMF (P < 0.001). CMV syndrome/disease was rare and less frequent in everolimus-treated patients. Subgroup analyses showed that the benefit everolimus provides, in terms of CMV events, is retained in CMV-naïve recipients and is independent of anti-CMV prophylaxis or preemptive approaches. CONCLUSIONS: Everolimus is associated with a lower incidence of CMV infection compared with AZA and MMF, which combined with its immunosuppressive efficacy and antiproliferative effects may positively impact long-term outcomes.

Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients.

PTLD is a severe complication in transplant recipients. Detection of increased EBV load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We analyzed the time course of the disease, its severity, the organs involved, and mortality rates in our institutional experience of pediatric heart transplantation. This paper identifies risk factors for PTLD and describes the different ways of diagnosing and treating the disease. PTLD was screened for in 146 pediatric heart transplant patients using a retrospective analysis in patients who received transplantation before 1998. Prospective determination was performed in 72/146 patients transplanted after 1998 within the post-transplant follow-up. The occurrence of PTLD with all interventions, including tapering of immunosuppression, surgery, viral monitoring, and antiviral interventions, was recorded. PTLD was diagnosed in 12/147 (8.2%) children at a mean age of 7.2 +/- 3.3 yr after a mean post-transplant period of 3.2 +/- 2.2 yr. PTLD manifested in: lymph nodes (n = 4), intestine (n = 3), tonsils and adenoids (n = 2), eye (n = 2), and lung (n = 1). It was diagnosed in 7/12 as a monomorphic B-cell lymphoma and in four patients as a monomorphic Burkitt lymphoma, a polymorphic B-cell lymphoma, a T-cell rich or angiocentric lymphoma (Liebow) and as reactive plasmacytic hyperplasia (early lesion), respectively. Histology was not possible in one patient with ocular manifestation. EBV association was 83%. Risk factors in the comparison with patients without PTLD were age at time of Tx, primary EBV infection after Tx, use of Azathioprine and >or=3 doses of ATG. CMV mismatch and CMV infection, rejection episodes and steroids were not risk factors. Despite reduction of immunosuppression, treatment consisted of surgical procedures to remove tumor masses (n = 6), Rituximab (n = 5), polychemotherapy (n = 3), antiviral (n = 1) and autologous T-cell therapy (n = 1). All patients demonstrated full remission without death related to PTLD or treatment at 3.9 (1.3-6.2) yr median follow-up time. The manifestation of PTLD in pediatric heart transplant recipients is associated with EBV infection and is predominantly in the form of a B-cell lymphoma. A tight and specific follow-up including early assessment of immunity status and specific therapeutic intervention to improve cellular immunity is warranted and may contribute to a significant reduction of PTLD-related morbidity and mortality.

[Heart failure--are there gender aspects?]. / Herzinsuffizienz--geschlechtsspezifische Aspekte?

Gender differences in the syndrome of heart failure (HF) occur in etiology and pathophysiology, in the clinical presentation and course of the syndrome. In addition, gender specific treatment responses and gender associated differences in the behavior of treating physicians are found. Hypertension and diabetes play a major role as causes of HF in women and both interact in their pathophysiology with the renin angiotensin system (RAS). Modulation of the RAS by estrogens explains specific differences between pre- and postmenopausal women and men. Myocardial growth processes and myocardial calcium handling are differentially regulated in female and male myocytes. Myocardial remodeling with age and as a consequence of mechanical load differs in women and men. For yet unknown reasons, HF with preserved systolic function seems to be more frequent in women than in men and the clinical course of systolic failure is different in both genders.

Advantages of C2 monitoring to avoid acute rejection in pediatric heart transplant recipients.

BACKGROUND: Inadequate cyclosporine (CsA) blood levels are a major risk factor for acute rejection in transplant recipients. The CsA trough level (C0 level) measured just before the next dose is commonly used to adjust the oral dosage. However, the 2-hour post-CsA dose concentration (C2 level) is favored as the best single-point correlate of CsA area-under-the-curve concentration and may better reflect the immunosuppressive effect of CsA. Because an adequate C2 level has not yet been defined, this study was performed to assess the value of C2 monitoring for the prevention of acute rejection and to define target levels in pediatric heart transplant recipients. METHODS: C2 levels were assessed in 50 pediatric heart transplant patients with oral CsA therapy and compared with trough C0 levels using full blood sampling, mass spectrometry and a blinded analysis. Acute graft rejection was detected using intramyocardial electrocardiogram (IMEG) and serial conventional and tissue Doppler echocardiography (TDE). Rejection was confirmed or excluded by endomyocardial biopsy. RESULTS: C2 and not C0 levels were significantly reduced in patients with acute graft rejection (ISHLT Grade > or =2). Patients with a C2 level <600 ng/ml had a significantly higher risk of developing acute rejection (100% sensitivity and 82% specificity). Patients with impaired CsA absorption were identified with C2 monitoring and switched to another calcineurin inhibitor. CONCLUSIONS: Monitoring of the C2 rather than the C0 level better reflects immunosuppressive efficiency and identifies patients at increased risk of acute rejection. A C2 level of >600 ng/ml should be the target to prevent acute rejection.

Gender aspects in heart failure. Pathophysiology and medical therapy.

Gender differences in the syndrome of heart failure (HF) occur in etiology and pathophysiology and lead to differences in the clinical presentation and course of the syndrome. In addition, gender specific treatment responses and gender associated differences in the behavior of treating physicians are found. Hypertension and diabetes play a major role as causes of HF in women and both interact in their pathophysiology with the renin angiotensin system (RAS). Modulation of the RAS by estrogens explains specific differences between pre- and post-menopausal women and men. Myocardial growth processes and myocardial calcium handling are differentially regulated in female and male myocytes. Myocardial remodeling with age and as a consequence of mechanical load differs in women and men. For yet unknown reasons, HF with preserved systolic function seems to be more frequent in women than in men and the clinical course of systolic HF is different in both genders. Medical therapy in heart failure has usually not been specified according to gender and gender specific analysis has been neglected in most large survival trials. Only a post-hoc analysis of gender differences led to the recognition of increased mortality with digitalis therapy in women. Single studies on angiotensin converting enzyme inhibitors (ACEI) or beta-receptor blockers did not reach significant end points in women whereas meta-analyses showed overall positive effects. Side effects of ACEI are more common and pharmacokinetics of beta-blockers are different in women. Angiotensin receptor blockers (ARB) are equally well tolerated in women and men. RAS inhibition may be particularly advantageous in postmenopausal women in whom the natural modulation of the RAS by estrogens is lost.

Magnetic resonance real-time imaging for the evaluation of left ventricular function.

New ultrafast gradient systems and hybrid imaging sequences make it possible to acquire a complete image in real time, without the need for breathholding or electrocardiogram (ECG) triggering. In 21 patients, left ventricular function was assessed by the use of a turbo-gradient echo technique, an echo-planar imaging (EPI) technique, and a new real-time imaging technique. End-diastolic and end-systolic volumes, left ventricular muscle mass, and ejection fraction of the ultrafast techniques were compared with the turbo-gradient echo technique. Inter- and intraobserver variability was determined for each technique. Image quality was sufficient for automated contour detection in all but two patients in whom foldover occurred in the real-time images. Results of the ultrafast imaging techniques were comparable with conventional turbo-gradient echo techniques. There was a tendency to overestimate the end-diastolic volume by 3.9 and 1.3 ml with EPI real-time imaging, the end-systolic volume by 0.9 and 5.0 ml, and the left ventricular mass by 2.6 and 23.8 g. Ejection fraction showed a tendency to be overestimated by 1.1% with EPI and underestimated by 4.5% with real-time imaging. Correlation between EPI real-time imaging and turbo-gradient echo were 0.94 and O.95, respectively, for end-diastolic volumes, 0.98 and 0.96, respectively, for end-systolic volumes, and 0.96 and 0.89, respectively, for left ventricular mass. Inter- and intraobserver variability was low with all three techniques. Real-time imaging allows an accurate determination of left ventricular function without ECG triggering. Scan times can be reduced significantly with this new technique. Further studies will have to assess the value of real-time imaging for the detection of wall motion abnornmalities and the imaging of patients with atrial fibrillation.

[Influence of image quality on the diagnostic accuracy of dobutamine stress magnetic resonance imaging in comparison with dobutamine stress echocardiography for the noninvasive detection of myocardial ischemia]. / Einfluss der Bildqualität auf die Genauigkeit der nichtinvasiven Ischämiediagnostik mit der Dobutamin-Stressmagnetresonanztomographie im Vergleich zur Dobutamin-Stressechokardiographie.

The analysis of wall motion abnormalities with dobutamine stress echocardiography is an established method for the detection of myocardial ischemia. With ultrafast magnetic resonance tomography, the application of identical stress protocols as used for echocardiography is possible. In 208 consecutive patients (147 M, 61 F) with suspected coronary artery disease, dobutamine stress echocardiography partially using harmonic imaging and dobutamine stress magnetic resonance tomography (DSMR) were performed prior to cardiac catheterization. DSMR images were acquired during short breath holds in 3 short axis-, a 4-, and a 2-chamber view using a turbo gradient echo technique. Patients were examined at rest and during a standard dobutamine-atropine scheme until submaximal heart rate was reached. Regional wall motion was assessed in a 16 segment model. Significant coronary heart disease was defined as angiographic >/=50% diameter stenosis. With DSMR, significantly more patients yielded very good (69%) or good (13%) image quality in comparison with dobutamine stress echocardiography (20% and 31%, p<0. 05). Moderate image quality occurred in 16% with MR and 41% with dobutamine stress echocardiography (p<0.05), 2% and 8% were non-diagnostic. With each technique 18 patients could not be examined (DSE: emphysema: 10, adipositas: 8, DSMR: claustrophobia: 11, adipositas: 6, contraindication: 1). Four patients did not reach target heart rate. In 107 patients, significant coronary artery disease was found. With DSMR sensitivity was 88.7% (dobutamine stress echocardiography: 74.3%; p<0.05) and specificity 85.7% (dobutamine stress echocardiography: 69.8%; p <0.05). This difference was most pronounced in the group with moderate echocardiographic image quality. High dose DSMR is superior to dobutamine stress echocardiography and can replace this technique especially in patients with moderate echocardiographic image quality.

Characterization of two distinct mechanisms for induction of apoptosis in human vascular endothelial cells.

Tissue homeostasis is fundamentally influenced by the functional integrity and state of endothelial cells. Survival and death of endothelial cells are encountered in cardiovascular disease and may, moreover, affect and determine the development of atherosclerosis and restenosis following intracoronary therapeutical interventions. Apoptosis was studied in cultured human umbilical vein endothelial cells (HUVEC) to investigate the regulation of endothelial cell death following serum/growth factor depletion as well as incubation with actinomycin-D. Apoptosis was verified by DNA fragmentation and quantified by fluorescence activated cell sorting (FACS) analysis after TdT-mediated deoxyuridine-triphosphate nick end-labeling (TUNEL). An ELISA was used for detecting intracytoplasmatic nucleosomes. Untreated HUVEC showed 16+/-6% TUNEL positive cells after 24 hours as analyzed by FACS. Serum/growth factor depletion increased apoptosis by 79+/-7%, while 50 ng/ml of the pro-apoptotic drug actinomycin-D induced comparable effects (72+/-11%). Apoptosis by serum/ growth factor depletion could be blocked completely by the anti-apoptotic agent cycloheximide (2 microg/ml), but was ineffective in blocking actinomycin-D-induced apoptosis. Pyrrolidine dithiocarbamate (PDTC) also acted as an anti-apoptotic agent by blocking apoptosis induced by actinomycin-D, but had no effect on apoptosis induced by factor depletion. Thus, two independent mechanisms for regulation of apoptosis are suggested to be present in human vascular endothelial cells.

Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography.

BACKGROUND: The analysis of wall motion abnormalities with dobutamine stress echocardiography (DSE) is an established method for the detection of myocardial ischemia. With ultrafast magnetic resonance tomography, identical stress protocols as used for echocardiography can be applied. METHODS AND RESULTS: In 208 consecutive patients (147 men, 61 women) with suspected coronary artery disease, DSE with harmonic imaging and dobutamine stress magnetic resonance (DSMR) (1.5 T) were performed before cardiac catheterization. DSMR images were acquired during short breath-holds in 3 short-axis views and a 4- and a 2-chamber view (gradient echo technique). Patients were examined at rest and during a standard dobutamine-atropine scheme until submaximal heart rate was reached. Regional wall motion was assessed in a 16-segment model. Significant coronary heart disease was defined as >/=50% diameter stenosis. Eighteen patients could not be examined by DSMR (claustrophobia 11 and adipositas 6) and 18 patients by DSE (poor image quality). Four patients did not reach target heart rate. In 107 patients, coronary artery disease was found. With DSMR, sensitivity was increased from 74.3% to 86.2% and specificity from 69.8% to 85.7% (both P<0.05) compared with DSE. Analysis for women yielded similar results. CONCLUSIONS: High-dose dobutamine magnetic resonance tomography can be performed with a standard dobutamine/atropine stress protocol. Detection of wall motion abnormalities by DSMR yields a significantly higher diagnostic accuracy in comparison to DSE.