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Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In spite of renal graft shortage and increasing waiting times for transplant candidates, simultaneous heart and kidney transplantation (HKTx) is an increasingly performed procedure established for patients with combined end-stage cardiac and renal failure. Although data on renal graft outcome in this setting is limited, reports on reduced graft survival in comparison to solitary kidney transplantation (KTx) have led to an ongoing discussion of adequate organ utilization., Methods: This retrospective study was conducted to evaluate prognostic factors and outcomes of 27 patients undergoing HKTx in comparison to a matched cohort of 27 patients undergoing solitary KTx between September 1987 and October 2019 in one of Europe's largest transplant centers., Results: Median follow-up was 100.33 (0.46-362.09) months. Despite lower five-year kidney graft survival (62.6% versus 92.1%; 111.73 versus 183.08 months; p = 0.189), graft function and patient survival (138.90 versus 192.71 months; p = 0.128) were not significantly inferior after HKTx in general. However, in case of prior cardiac surgery requiring sternotomy we observed significantly reduced early graft and patient survival (57.00 and 94.09 months, respectively) when compared to patients undergoing solitary KTx (183.08 and 192.71 months; p < 0.001, respectively) or HKTx without prior cardiac surgery (203.22 and 203.22 months; p = 0.016 and p = 0.019, respectively), most probably explained by the significantly increased rate of primary nonfunction (33.3%) and in-hospital mortality (25.0%)., Conclusions: Our data demonstrates the increased rate of early kidney graft loss and thus significantly inferior graft survival in high-risk patients undergoing HKTx. Thus, we advocate for a "kidney-after-heart" program in such patients to ensure responsible and reasonable utilization of scarce resources in times of ongoing organ shortage crisis., (© 2021. The Author(s).)

Aims: Left ventricular assist device (LVAD) is a common treatment option for patients with heart failure waiting for a donor heart. Living with an LVAD is associated with many burdens and worries. Patients often depend on the support of their relatives, usually their spouses. This can also put a strain on the spouses and be associated with psychological stress for both. In couples, communication proves to be an important form of emotional support. Besides verbal aspects of communication, the extent of emotional arousal (f 0 ) that is vocally encoded plays an essential role as a non-verbal aspect of communication. This study aims to investigate the psychological impact of LVAD on couples in investigating to what extent depression, anxiety, and fear of progression (FoP) differ between patients and partners, the intrapersonal and interpersonal associations of anxiety, depression, and FoP, and differences in emotional arousal., Methods and Results: In this cross-sectional study, male LVAD patients and their female partners (N = 21 couples) responded to self-report questionnaires on depression, anxiety, and FoP. Emotional arousal (f 0 ) was evaluated during social support interactions between both spouses. Female partners experienced more anxiety than male patients (P = 0.016). No differences occurred in depression (P = 0.967) and FoP (P = 0.084). Regarding intrapersonal associations, for patients, correlations appeared between anxiety and depression (r = 0.859, P = 0.000), anxiety and FoP (r = 0.730, P = 0.000), and depression and FoP (r = 0.608, P = 0.004). For caregivers, correlations appeared between anxiety and depression (r = 0.906, P = 0.000), anxiety and FoP (r = 0.665, P = 0.001), and depression and FoP (r = 0.734, P = 0.000). Regarding interpersonal associations, correlations were found between patient's anxiety and caregiver's anxiety (r = 0.461, P = 0.041), caregiver's depression (r = 0.510, P = 0.018), and caregiver's FoP (r = 0.524, P = 0.015). Non-significant correlations were found for caregiver's anxiety and patient's FoP (r = 0.404, P = 0.078) and patient's depression (r = 0.286, P = 0.236). Patient's depression was associated with caregiver's FoP (r = 0.526, P = 0.017), but not with caregiver's depression (r = 0.337, P = 0.146). No significant correlations were found between caregiver's depression and patient's FoP (r = 0.386, P = 0.084) and patient's depression (r = 0.337, P = 0.146). Patient's and caregiver's FoP showed significant associations (r = 0.482, P = 0.027). Patient's and partner's f 0 were interrelated. Patient's f 0 was positively related with his own and his partner's psychological distress. Partner's f 0 showed associations to her own depression and FoP., Conclusions: Findings indicate that women of LVAD patients are burdened similarly or even to a greater extent than men themselves. Women's psychological distress has an impact on patients' psychological distress and vice versa. Early interventions for both patient and partner represent a necessary intervention target., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

To date, there are no established noninvasive biomarkers available for prediction of cardiac allograft vasculopathy (CAV) after orthotopic heart transplantation (OHT). Inflammatory processes are supposed to play a central role in the pathogenesis of CAV. Recent studies have suggested that immune mediators could serve as biomarkers for cardiovascular diseases. We hypothesized particular cytokines or a combination thereof may serve as noninvasive biomarkers for CAV. Plasma cytokines were screened from 27 patients with CAV and 27 patients without CAV after OHT. The concentrations of interleukins-4, -6, -10, -21, -23, -31, -33, interferon gamma, tumor necrosis factor alpha, and the soluble activation marker CD40 ligand were determined using Luminex-based multiplex analyses. Although concentrations of all cytokines except interferon gamma were on average higher in the CAV group, there were no significant differences between the groups for any 1 cytokine. Using a binary logistic regression model, we were able to develop a probability score for detecting patients at elevated risk for advanced CAV with a sensitivity of 92.31% and a specificity of 60.71% (receiver-operating characteristic area under the curve 0.799 ± 0.06; p<0.0001). In conclusion, analyzing the concentration of specific inflammatory cytokines could be meaningfully included in evaluation of CAV after OHT., (Copyright © 2019. Published by Elsevier Inc.)

Background: Decision-making when offered a donor heart for transplantation is complex, and supportive data describing outcomes according to acceptance or non-acceptance choices are sparse. Our aim was to analyze donor heart acceptance decisions and associated outcomes at a single center, and after subsequent acceptance elsewhere., Methods: This investigation was a retrospective analysis of data obtained from the University of Vienna Medical Center and Eurotransplant centers for the period 2001 to 2015., Results: Our center accepted 31.8% (699 of 2,199) of donor hearts offered. Unlike other centers, the acceptance rate, with or without transplantation, did not increase over time. Of the donor hearts rejected by our center, 38.1% (572 of 1,500) were later accepted elsewhere. Acceptance rates were twice as high for donor hearts initially rejected for non-quality reasons (339 of 601, 56.4%) compared with initial rejection for quality reasons (233 of 899, 25.9%). Three-year patient survival rate was 79% at Vienna; for donor hearts initially rejected by Vienna for non-quality reasons or quality reasons, it was 73% and 63%, respectively (p < 0.001). Outcomes at other centers after transplantation of grafts rejected by Vienna varied according to the reason for rejection, with good 3-year survival rates for rejection due to positive virology (77%), high catecholamines (68%), long ischemic time (71%), or low ejection fraction (68%), but poor survival was observed for hearts rejected for hypernatremia (46%), cardiac arrest (21%), or valve pathology (50%)., Conclusions: A less restrictive policy for accepting donor hearts at our center, particularly regarding rejection for non-quality reasons or for positive virology, high catecholamine levels, longer ischemic time, or low ejection fraction, could expand our donor pool while maintaining good outcomes., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac allograft vasculopathy (CAV) remains the leading cause of morbidity and mortality after orthotopic heart transplantation (OHT). Because of its clinically silent progression and lack of symptoms, detection is often difficult and invasive coronary angiography is performed routinely. To date, there are no established noninvasive biomarkers available for prediction of CAV in transplanted patients.MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules that negatively regulate gene expression. As they are detectable in peripheral blood, recent studies have suggested miRNAs as biomarkers for various cardiovascular diseases. Thus, we hypothesized that circulating miRNAs may serve as noninvasive biomarkers for CAV., Methods: To determine the regulation of circulating miRNAs, we performed miRNA profiling studies in plasma samples of OHT patients with confirmed high-degree CAV and a matched control group consisting of patients without any signs of CAV at least 5 years after OHT. Candidate miRNAs were verified by quantitative reverse transcriptase polymerase chain reaction., Results: Microarray analysis revealed 5 candidate miRNAs (miR-34a, miR-98, miR-155, miR-204, miR-628-5p) that were differentially regulated in plasma samples of patients with CAV and therefore were selected for verification by quantitative reverse transcriptase polymerase chain reaction. In CAV patients, plasma levels of miR-628-5p and miR-155 were significantly increased (P = 0.001 and P = 0.028, respectively). A miR628-5p value above 1.336 was able to predict CAV with a sensitivity of 72% and a specificity of 83%., Conclusions: For the first time, the present study identifies the circulating miRNA miR-628-5p as a novel potential biomarker of CAV in patients after OHT.

Aims: A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance., Methods and Results: Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively., Conclusion: For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events., Methods: We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated., Results: The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8)., Conclusion: In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score., Trial Registration: Clinicaltrials.gov identifier NCT00761787.

Context: Studies of all types of organ transplant recipients have suggested that weight gain, expressed as an increase in body mass index (BMI), after transplant is common., Objectives: To describe weight gain during the first year after transplant and to determine risk factors associated with weight gain with particular attention to type of transplant., Design, Setting, and Participants: A prospective study of 502 consecutive organ transplant recipients (261 kidney, 73 liver, 29 heart, 139 lung) to identify patterns of BMI change. Measurements were made during regular outpatient clinical visits at 2, 6, and 12 months after transplant. Data were retrieved from patients' charts and correlated with maintenance corticosteroid doses., Results: Overall, mean BMI (SD; range) was 23.9 (4.5; 13.6-44.1) at 2 months and increased to 25.4 (4.0; 13.0-42.2) by the end of the first postoperative year. BMI levels organized by World Health Organization categories showed a trend toward overweight/obesity in kidney (53.4%), liver (51.5%), heart (51.7%), and lung (33.1%) patients by 12 months after transplant. BMI changed significantly (P= .05) for all organ types and between all assessment points, except in kidney recipients. Maintenance corticosteroid doses were not a predictor of BMI at 12 months after transplant for most patients., Conclusions: Weight gain was common among patients undergoing kidney, liver, heart, and lung transplant; however, many showed BMI values close to normality at the end of the first year after transplant. In most cases, increased BMI levels were related to obesity before transplant and not to maintenance corticosteroid therapy.

Objective: Depression represents a relevant co-morbidity in patients with chronic heart disease and may diminish the overall success for long-term survival after heart transplantation (HTx). This study aimed to assess the prevalence of depression symptoms in long-term HTx survivors, and to compare depressive patients to those without depression with respect to chronic artery vasculopathy (CAV)., Methods: A sample of 203 HTx patients, median 11.5 (IQR 7-17) years after transplant, provided detailed data of depression symptoms, and other psychosocial symptoms including anxiety, family support, professional re-integration, and health-related quality of life (HRQoL). Data were analyzed for an association with CAV., Results: Overall, 14.8% patients (95% CI: 10.2-20.4) showed relevant depression symptoms. No significant differences were seen between non-depressed vs. depressed patients with respect to demographics, clinical variables, and cardiovascular risk factors. Anxiety was prevalent in 9.0% (95% CI: 5.4-13.9) of the sample. Depression symptoms showed impaired HRQoL in the SF-36 physical (P=.012) and psychosocial (P=.0001) components. CAV was prevalent in 34.0% (95% CI: 27.5-41.0), and depression symptoms and CAV were not significantly associated. CAV-patients did not report their physical HRQoL being lower relative to those without CAV (P=.40). Multivariate analysis revealed overweight BMI (OR=2.20; P=.04), longer time since transplant (OR=1.10; P=.001), and older age (OR=1.04; P=.01) being associated with CAV., Conclusion: Depression symptoms are prevalent in long-term survivors after HTx, and psychological impairments decrease patients' perceptions of HRQoL. More research seems necessary to identify the inter-relationship between depression symptoms and CAV, in order to develop targeted interventions to overcome this problem., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Patients' perceptions of immunosuppression-related symptom experience impact on quality of life and medication adherence. Using The Modified Transplant Symptom Occurrence and Symptom Distress Scale capturing items on symptom occurrence and symptom distress, 261 heart transplant recipients reported on their symptom experiences. Symptoms occurring with the highest prevalence were tiredness, lack of energy, and nervousness. Men showed erectile dysfunction causing the most distress. Women and younger patients reported significantly higher levels of symptom distress. Distress levels increased with time after transplant. Investigating responses to immunosuppression-related symptom experiences should help develop interventional methods to support long-term outcome.

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., (© 2012 John Wiley & Sons A/S.)

Background: There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs)., Methods: We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers)., Results: Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both., Conclusion: The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.

The safety and efficacy of ivabradine applied in heart transplant (HTx) recipients with permanent sinus tachycardia (PST) has been depicted in previous short-term follow-up studies. We sought to investigate the long-term impact of ivabradine in this patient population. From May to November 2006, 29 HTx recipients with PST, who exhibited either contraindications or intolerance of beta-blocker medication or insufficient heart rate (HR) reduction on beta-blocker treatment, first received oral ivabradine treatment (5 mg bid). Ivabradine treatment was discontinued in three patients due to adverse events within the first week. In the remaining 26 patients, resting HR was significantly lowered from 106.8 ± 9.2 at baseline to 83.2 ± 5.1 bpm after 3 months (p < 0.001). This effect remained stable in the long-term follow-up (82.1 ± 11.8 bpm after 4 years), whilst blood pressure was not affected. Apart from the corrected QT interval (QTc), there were no significant changes in ECG. The elongated QTc at baseline (469.4 ± 29.5 ms) decreased to 444.3 ± 33.1 ms after 3 months ivabradine treatment (p < 0.001). A decrease in QTc until month 9 was observed, followed by a partial increase to the upper limit of the normal value. Neither allograft rejection nor changes in left ventricular ejection fraction were observed over the follow-up period. In conclusion, ivabradine appears to be a safe and feasible long-term therapeutic option for HTx recipients with PST. It reduced the resting HR without impairment of blood pressure, myocardial contractility and cardiac conduction. The prognostic value of normalised QTc following ivabradine administration requires further observation.

Objectives: We determined the outcome of cardiac allografts from multiorgan donors enrolled in a randomized trial of donor pre-treatment with dopamine., Background: Treatment of the brain-dead donor with low-dose dopamine improves immediate graft function after kidney transplantation., Methods: A cohort study of 93 heart transplants from 21 European centers was undertaken between March 2004 and August 2007. We assessed post-transplant left ventricular function (LVF), requirement of a left ventricular assist device (LVAD) or biventricular assist device (BVAD), need for hemofiltration, acute rejection, and survival of recipients of a dopamine-treated versus untreated graft., Results: Donor dopamine was associated with improved survival 3 years after transplantation (87.0% vs. 67.8%, p = 0.03). Fewer recipients of a pre-treated graft required hemofiltration after transplant (21.7% vs. 40.4%, p = 0.05). Impaired LVF (15.2% vs. 21.3%, p = 0.59), requirement of a LVAD (4.4% vs. 10.6%, p = 0.44), and biopsy-proven acute rejection (19.6% vs. 14.9%, p = 0.59) were not statistically different between groups. Post-transplant impaired LVF (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.08 to 11.79; p < 0.001), requirement of LVAD (HR: 6.65; 95% CI: 2.40 to 18.45; p < 0.001), and hemofiltration (HR: 2.83; 95% CI: 1.20 to 6.69; p = 0.02) were predictive of death. The survival benefit remained (HR: 0.33; 95% CI: 0.12 to 0.89; p = 0.03) after adjustment for various risks affecting mortality, including pre-transplant LVAD/BVAD, inotropic support, and impaired kidney function., Conclusions: Treatment of brain-dead donors with dopamine of 4 μg/kg/min will not harm cardiac allografts but appears to improve the clinical course of the heart allograft recipient. (Prospective Randomized Trial to Evaluate the Efficacy of Donor Preconditioning With Dopamine on Initial Graft Function After Kidney Transplantation; NCT00115115)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs., (© 2011 John Wiley & Sons A/S.)

Background: The risk factors for moderate or severe chronic renal dysfunction (MSCRD) among heart transplant recipients may be distinct from those previously recognized owing to recently improved clinical care., Methods: We examined the clinical records of 88 adult patients who underwent first heart transplantations from 2000 to 2005 and survived 2 years. MSCRD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) at 2 years after transplantation. Fifty patients were included in the MSCRD group and 38 in the non-MSCRD group., Results: Loss of renal function was observed largely during the first 9 months after transplantation in the MSCRD group. The pretransplantation GFR was lower in the MSCRD group. Besides older age in the MSCRD group, there were no differences in baseline characteristics, immunosuppressive regimens, incidences of acute rejection episodes, cardiac allograft vasculopathy, or severe infections. The MSCRD group showed permanent lower posttransplantation hemoglobin levels. In multivariate logistic regression analysis, recipient age, pretransplantation GFR, postoperative intensive care unit stay and hemoglobin level at 9 month were unfavorable factors for posttransplantation MSCRD., Conclusions: In addition to recipient age and pretransplantation GFR as well established risk factors, our results suggest a prognostic value of a low early hemoglobin level for the development of chronic renal dysfunction after heart transplantation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to evaluate and compare health-related quality of life (HRQoL) and physical exercise tolerance in patients after heart transplantation (HTx) or implantation of a left ventricular assist device (LVAD)., Methods: A prospective, comparative design was used to characterize changes over time in HRQoL (SF-36) and exercise tolerance in patients after HTx (n = 54) and during LVAD support (n = 36). Nine LVAD patients were lost for follow-up. The majority of patients in both groups were male (97%); the LVAD cohort tended to be younger (p = 0.06)., Results: HRQoL improved significantly in HTx patients in the SF-36 physical (p = 0.02), but not in the psychosocial (p = 0.27) component score during follow-up. In the LVAD group, HRQoL showed improvements for both the SF-36 physical and psychosocial component scores (both p = 0.04). Between-group comparisons revealed better HRQoL for the HTx cohort than the LVAD cohort for 2 of 8 SF-36 subscales. Age-, gender- and body mass index (BMI)-adjusted exercise tolerance (workload; VO(2max)) showed significant improvements for both HTx (p = 0.01) and LVAD (p = 0.01) patients. Adjusted maximum oxygen consumption was higher for HTx patients (p = 0.05) relative to LVAD patients at 8 ± 1 months after implant., Conclusion: HRQoL and exercise capacity increased in both groups over the time-course of the study. After adjusting for relevant variables, HTx patients showed a higher exercise tolerance compared with the LVAD group during follow-up. Thus, future large-scale intervention studies should emphasize the specific needs of these patient cohorts., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aim of this retrospective analysis was to evaluate the effects of ivabradine given primarily as a heart rate-lowering agent on allograft function and cardiopulmonary performance in heart transplant recipients with permanent sinus tachycardia. Starting May 2006, 26 heart transplant recipients with permanent sinus tachycardia received ivabradine (5 mg bid). It was discontinued early in 3 patients (11.5%) due to adverse events. In the remaining 23 patients, resting heart rate (HR) was significantly lowered from 106.3 +/- 9.1 to 82.2 +/- 6.3 bpm after 3 weeks of treatment. The effect remained constant during the remaining treatment period, whereas resting blood pressure was not affected. After 12 weeks of ivabradine treatment, the corrected QT interval was significantly reduced into the range seen in normal individuals. Left ventricular (LV) end-diastolic posterior wall thickness, LV mass and LV mass index were also found to have decreased significantly. There was a trend to improvement of cardiopulmonary performance and LV ejection fraction, both of which did not reach statistical significance, however. It may be concluded that ivabradine successfully reduced the resting HR of heart transplant recipients with sinus tachycardia without negatively influencing the blood pressure. The definitive impact of ivabradine on LV mass regression and cardiopulmonary performance require further prospective, randomized and controlled trials.

The angiotensin blocker (ARB) eprosartan (600 mg once daily) and the calcium antagonist diltiazem (90 mg twice daily) were studied in a 24-month prospective, randomized, double-blind trial involving 53 heart transplant patients. The study compared their effects on the development of post-transplant cardiac allograft vasculopathy, a condition that frequently impairs long-term post-transplantation survival and where angiotensin blockers might be expected to play a preventive role. From baseline to month 12, the mean plaque volume increased by 7.7 mm(3) for eprosartan-treated patients and by 34.4 mm(3) for diltiazem-treated patients, but the eprosartan-related trend for reduced myointimal hyperplasia was not statistically significant. The trend in favour of eprosartan for secondary parameters (mean intimal index, vessel volume, lumen volume and coronary flow reserve) also failed to reach significance. The lack of effect might be due to a lower than planned sample size and observation periods due to recruitment difficulties. A larger study is required to confirm these preliminary findings.

Background: In this study we sought to compare the long-term effects of anti-thymocyte globulin (ATG) and muromonab-CD3 (OKT3) as induction therapy after heart transplantation, with special regard to cardiac allograft vasculopathy (CAV), post-transplant infections, post-transplant non-skin cancers and patient survival., Methods: From 1988 to 1991, 25 heart transplant patients received OKT3 as induction treatment. Accordingly, 25 consecutive patients who received ATG and 25 consecutive patients without induction therapy were enrolled., Results: At a follow-up period of 13.4 +/- 4.6 years, time to onset of non-significant and significant CAV was 8.77 +/- 3.38 and 11.60 +/- 4.28 years, respectively, in the ATG group, which was significantly delayed compared with 5.71 +/- 3.08 and 7.44 +/- 2.74 years, respectively, in the non-induction group. In the OKT3 group, time to onset of non-significant and significant CAV (6.10 +/- 2.73 and 7.86 +/- 3.19 years, respectively) did not differ significantly from the non-induction group. Ten- and 15-year actuarial survival rates of ATG- and OKT3-treated patients were not significantly different from those of patients without induction treatment., Conclusions: Our study suggests the long-term advantage of ATG in prevention of cardiac allograft vasculopathy. In contrast, OKT3 failed to show such benefit. However, induction therapy with either ATG or OKT3 did not exhibit a significant beneficial effect on long-term patient survival.

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

Background: Cytomegalovirus (CMV) infection in recipients of cardiac transplants is associated with higher rates of morbidity. A recent phase III trial showed highly significantly (P<0.001) lower CMV rates with the proliferation signal inhibitor everolimus compared to azathioprine (AZA). To better define this association, data on CMV risk factors were collected retrospectively and analyzed., Methods: Data on CMV risk factors from a multicenter phase III trial on de novo heart transplant recipients (n=634) receiving a triple immunosuppressive regimen randomized to everolimus 1.5 mg/day (group 1), everolimus 3 mg/day (group 2), or AZA (group 3) were merged with prospectively collected CMV-related outcome data and analyzed., Results: CMV-positive donors (D+) and CMV-negative recipients (R-) were evenly distributed across groups 1-3 at 36/209 (17.2%), 48/211 (22.7%), and 38/214 (17.8%), respectively. CMV prophylaxis had been given for a mean (SD) of 175 (127.8), 183 (137.1), and 177 (132.9) days, respectively. In the high-risk D+/R- subgroup with prophylaxis, the proportions of patients with CMV infection compared with group 3 (12/29 [41.4%]) were 3/25 (12.0%) in group 1 (P=0.031) and 6/36 (16.7%) in group 2 (P=0.049). In D+/R+ subgroups either with or without prophylaxis, the everolimus groups had less CMV disease (P<0.001). The incidence of CMV syndrome, organ involvement, and laboratory evidence was lower with everolimus use compared to AZA., Conclusions: Everolimus is associated with lower rates of CMV infection, syndrome, or organ involvement, suggesting an additional advantage from the use of everolimus in cardiac transplant recipients.

Background: CC chemokine receptor 5 (CCR5) contributes to the alloimmune response following solid organ transplantation. In individuals homozygous for the CCR5Delta32 mutation, the receptor is inactive and lymphocyte recruitment and leukocyte trafficking during rejection are inhibited. A significant improvement in graft survival following renal transplantation has been observed in homozygous CCR5Delta32 patients, although conflicting data exist. To determine whether CCR5Delta32 homozygous heart transplant recipients may also benefit compared to those with a normally functioning CCR receptor, the proportion of patients with CCR5Delta32 mutation was examined in a large cohort of patients surviving for a long period after heart transplantation., Methods: The prevalence of CCR5 genotype was identified in patients who had survived >or=7 years after heart transplantation. Genotyping was performed centrally by polymerase chain reaction (PCR)., Results: A total of 555 patients were recruited at three heart transplant centers in Germany. Of these, 442 patients (79.6%) were homozygous for the wild-type allele, 106 (19.1%) were heterozygous for CCR5Delta32 and 7 (1.3%) were homozygous for CCR5Delta32. No statistically significantly differences were observed between the incidence of CCR5Delta32 homozygosity in the study population and the estimated incidence in the normal population., Conclusions: In the absence of a control arm, it cannot be established if homozygous carriers of the CCR5Delta32 allele experience a long-term survival benefit following heart transplantation that may be masked by underrepresentation of the CCR5Delta32 allele in recipients of a heart transplant. To answer this question, the prevalence of CCR5Delta32 homozygosity needs to be established in patients awaiting heart transplantation.

Everolimus (Certican; Novartis Pharma AG, Basel, Switzerland) represents the latest generation of proliferation signal inhibitors (PSIs). Everolimus is indicated for use as an immunosuppressive drug in renal and heart transplantation. This report reflects the recommendations of the second German-Austrian Certican Consensus Conference, held in January 2006, for the clinical use of everolimus.

Background: Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)-free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus., Methods: During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months., Results: After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 +/- 0.6 vs 1.5 +/- 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 +/- 21.6 vs 61.8 +/- 23.4 ml/[min x 1.73 m2], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia (n = 2), skin disorders (n = 2), reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)., Conclusion: Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients.

Chronic hepatitis B progresses to cirrhosis in the majority of immunosuppressed patients. The outcome of long-term antiviral therapy in HBV-infected organ transplant recipients is unknown. In 1996, we included 20 heart transplant (HT) recipients in a pilot trial to treat chronic hepatitis B with famciclovir. At that time, bridging fibrosis or cirrhosis was evident in 15 individuals (75%). From 1998 onwards, patients were switched to lamivudine in case of primary or secondary virological nonresponse to famciclovir. Adefovir or tenofovir became available at our centre for HT recipients in 2002. After 103 months, one patient was still on famciclovir showing a complete virological response. Sixteen patients were switched to lamivudine after 0.5-4 years of famciclovir therapy. Six of those showed a long-term response to lamivudine therapy lasting for up to 7 years. Lamivudine resistance developed in the remaining 10 patients (63%), in 4 of them successful rescue therapy (adefovir n = 3, tenofovir n = 1) could be initiated. Only one hepatocellular carcinoma developed, which was successfully treated by locoregional ablative therapy. Nine patients died (45%), with lamivudine-resistance-related liver failure as the cause of death in five cases. Significant improvement of Ishak fibrosis scores could be demonstrated in six of the seven patients with more than two sequential liver biopsies available. Long-term antiviral therapy of chronic hepatitis B can lead to regression of liver cirrhosis in patients after organ transplantation, unless viral resistance occurs. This study demonstrates the urgent need for further antivirals to overcome antiviral resistance.

Background and Aim of the Study: Homograft valves undergo degenerative changes over time, which finally lead to functional deterioration. Immunological events are believed to play a pivotal role in this process. To further evaluate this hypothesis, the valvular morphology and function, as well as comorbidities predisposing to deteriorative processes, were evaluated in patients who had undergone heart transplant more than 10 years previously., Methods: In a consecutive cohort of 146 patients (125 males, 21 females; mean age at transplant 43.8 +/- 11.2 years), heart and valve function were assessed by color Doppler echocardiography at a mean of 5306 +/- 987 days after heart transplant. Evaluated parameters included chamber dimensions, cardiac function, valvular morphology/function, and concomitant diseases., Results: Atrial and ventricular dimensions were within normal ranges for the left atrium (LA; n=7), right atrium (RA; n=7), left ventricle (LV; n=143) and right ventricle (RV; n=119). Slight enlargements occurred in the LA (n=138), RA (n=137), LV (n=1) and RV (n=11), while significant enlargements were seen in the LA (n=1), RA (n=2), LV (n=2), and RV (n=16). With regard to cardiac function, the ejection fraction (EF) was 63.9 +/- 4.9%, left ventricular isovolumic relaxation time (IVRT) 85.04 +/- 14.64 ms, fractional shortening (FS) 34 +/- 12%, and pulmonary artery systolic pressure (PASP) 29.81 +/- 6.4 mmHg. Valvular regurgitation (grade > or =2) was present in 34 patients (31 tricuspid valves, three mitral valves). No patients presented with aortic valve regurgitation. Concomitant conditions with a potential impact on calcium balance/valvular deterioration included immunologic/chronic inflammatory diseases (n=6), malignancies (n=12), kidney (n=41), cardiovascular system (n=39) and thyroid/parathyroid (n=12)., Conclusion: During the long term after heart transplant, heart valves were characterized by normal morphology and function in the majority of cases. Although most patients presented with concomitant conditions strongly predisposing for valvular deterioration/calcification, sole immunosuppressive/anti-inflammatory therapy appears to prevent these processes in heart transplant patients.

Myocardial transplantation of myocytes and bone marrow derived cells is currently under clinical evaluation as an alternative therapy of heart failure. One of the main problems of all clinical studies performed so far is the inability to track the fate of the transplanted cells. The aim of our study was the development of a potentially clinically applicable approach, which allows for detection of the transplanted cells without need for collection of tissue samples. Fetal canine cardiomyocytes were labelled with the non-toxic fluorescent membrane dye Vybrant CM-DiI and delivered into the free wall of the left ventricle of adult mongrel dogs. For subsequent tracking of the cellular graft, the dogs underwent a second operation in which an intra-vital microscope was mounted above the exposed heart within the thorax. A special computer software eliminated artefacts caused by myocardial contraction. Two months after transplantation, the fluorescent graft was macroscopically visible by intra-vital microscopy using a 10x magnification. Histological studies served as microscopic control and confirmed the existence of DiI-labelled cells at the site of injection. Connexin 43 immunoreactivity was visible at junctional complexes between donor and recipient cells, suggesting morphologic and functional coupling as a result of gap junction formation. Our results demonstrate that in vivo detection of transplanted cells in the heart is feasible. Further technical adjustments should allow for thoracoscopic/endoscopic application of this method, making it appropriate for use in other organs and in clinical studies.