Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: the significance of baseline glomerular filtration rate.

BACKGROUND: The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure. METHODS: This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance. RESULTS: In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period. CONCLUSIONS: Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Good long-term survival after paediatric heart transplantation.

INTRODUCTION: The brain-death criterion was introduced in Denmark in 1990. The first Danish paediatric heart transplantation (HTx) was performed at Copenhagen University Hospital, Rigshospitalet, in Copenhagen in 1991. We describe our experiences during the first 20 years with paediatric HTx. MATERIAL AND METHODS: This was a retrospective study of 37 paediatric patients (<18 years) who were listed for HTx from 1991 to 2011. RESULTS: A total of 26 of the 37 children listed underwent HTx, nine due to congenital heart disease (CHD) and 17 due to cardiomyopathy (CM). Ten patients died while being on the waiting list. One patient was withdrawn from the list due to spontaneous improvement. A total of 21 patients remain alive. Survival was 92% after five years and 82% after ten years. We had two early (CHD) and three late (CM) deaths. Complications were few, but significant. Early acute rejection occurred in seven patients, whereas one patient with repeated late episodes of acute rejection died from graft failure 5.5 years after HTx. We found a time-related progressive deterioration in renal function. Two patients underwent renal Tx, two others died while being on dialysis. Cardiac allograft vasculopathy occurred in three patients, two of whom died. The third remains alive today, 19 years after HTx. CONCLUSION: Our paediatric HTx results are comparable with those of larger international centres and consistent with true long-term survival. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial.

BACKGROUND: Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. METHODS: In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. RESULTS: No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. CONCLUSIONS: Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

Driveline infections in patients supported with a HeartMate II: incidence, aetiology and outcome.

OBJECTIVES: To investigate the incidence and outcome of driveline infections in patients supported with a continuous flow left ventricular assist device (HeartMate II (HMII)) and to study the microbiological aetiology. DESIGN: Retrospective analysis of 31 patients who received an implantation of a HMII. Follow-up was from implantation to either device explantation, death or closure of the study. Clinical signs of infections were divided into superficial, deep or systemic and compared to culture and gram stain, the clinical course and infectious parameters. RESULTS: The incidence of driveline infections was 1.65 episodes per patient per year. Staphylococcus aureus and Escherichia coli were the most common bacterial aetiology. More than two weeks of treatment was required in 81% of the patients. In terms of detecting superficial driveline infections, leucocyte count demonstrated a sensitivity of 27% and C-reactive protein (CRP) a sensitivity of 28%. In 22 cases of driveline infections plasma pro-calcitonin was found to be normal. CONCLUSION: Driveline infections are common in HMII recipients but primarily remain superficial and are reasonably easy to manage. Infectious agents mostly originate from the skin and gastrointestinal tract. Blood biomarkers did not appear to be helpful in detecting driveline infections.

Primary cardiac tumors: a clinicopathologic evaluation of four cases.

INTRODUCTION: We report the clinical, pathological, and immunohistochemical features of four primary malignant cardiac tumors identified at the Department of Pathology, Rigshospitalet, Denmark. A panel of immunohistochemical markers for classification is proposed. METHODS: Between 2000 and 2008, four patients with malignant cardiac tumors were treated at our hospital. We retrospectively reviewed the medical records and evaluated the patient characteristics and treatment. RESULTS: Three patients presented with severe dyspnea; one patient presented with chest pain. Transthoracic echocardiography demonstrated, in all four cases, abnormal masses in the atria. The cases were, based on morphological features and immunoprofile, classified as myogenic sarcoma (two cases), undifferentiated pleomorphic sarcoma, and leiomyosarcoma. Three of the patients received orthotopic heart transplantation. One patient survived 6.5 years after the diagnosis, and two patients are still alive 2 and 3 years after being diagnosed, respectively. CONCLUSIONS: All four cases were sarcomas. A limited number of immunohistochemical markers can be used in order to define a specific line of differentiation. In this small study, three of the patients were offered orthotopic heart transplantation, and the survival times were generally longer than in most series.

Two-year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open-label, randomized trial.

BACKGROUND: Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. METHODS: In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. RESULTS: Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. CONCLUSIONS: Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.

Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial.

BACKGROUND: The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. METHODS: In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate > or =20 mL/min/1.73m and <90 mL/min/1.73 m) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. RESULTS: Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). CONCLUSION: Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.

[The Mechanical Heart--HeartMate 1--Danish results]. / Det mekaniske hjerte--HeartMate 1--de danske resultater.

INTRODUCTION: In 1998 the Heart Centre at the Danish National University Hospital implemented a new programme with long-term mechanical circulatory assist to patients with terminal heart failure who could not wait for a donor heart. A so-called Mechanical Heart, HeartMate 1, was to replace a failing left ventricle so that the patient could be resuscitated and await heart transplantation. The aim of the present study is to describe the results of this new treatment in Denmark. MATERIALS AND METHODS: A total of 28 patients with a mean age of 41 years were treated with the HeartMate 1 system in the period 1998 to 2006. Two patients had the system changed to a new HeartMate 1 due to mechanical problems. Both patients were later successfully heart transplanted. A third patient had the system successfully changed to a HeartMate 2 and he is waiting for a donor heart. RESULTS: Hemodynamic observations reveal fast improvement after implantation of the HeartMate system. Patients who were later heart transplanted had the HeartMate system implanted for a mean of 220 days. About 90% of those that were transplanted later improved due to the system from New York Heart Associations class IV to class I-II and they could often be discharged to a normal social life with a well-functioning HeartMate. Calculated 1-year survival with the HeartMate system was 82%. CONCLUSION: Patients with terminal heart failure can be treated and improved by implantation of the HeartMate system and await successful heart transplantation. Permanent advanced assist systems do exist today and these can be applied as a final treatment in selected patients--so-called destination therapy with mechanical circulatory support. The present study shows that it is very likely that the Heart Centre at the Danish National University Hospital will be able to establish a well-functioning programme for destination therapy.

[Destination therapy in end-stage heart failure. A possible alternative to heart transplantation?]. / Destinationsterapi ved terminalt hjertesvigt. Et muligt alternativ til hjertetransplantation?

The incidence of heart failure continues to increase but the number of available heart donors is limited. Implantation of circulatory assist devices as a permanent alternative to heart transplantation has become a promising new alternative in patients not eligible for heart transplantation (destination therapy). New technical advances have increased the durability of the devices and reduced complications.New generations of rotator pumps are smaller and more durable and will expand the use of these devices for destination therapy. This review discusses the current state of knowledge and indications for destination therapy in end-stage heart failure.

Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance.

Increasing success in renal transplantation and longer patient survival has meant that post-transplant malignancies are having an increasing impact on long-term graft and patient survival. Choice of the immunosuppressive agents provides one of the controllable risk factors for the development of malignancies in this population. Calcineurin inhibitors (CNIs) are associated with an increased incidence of cancers, whereas the proliferation signal inhibitors (PSIs), everolimus and sirolimus have demonstrated anti-oncogenic effects in pre-clinical models and are currently being investigated as anti-cancer agents in clinical trials. There is increasing evidence demonstrating a lower incidence of post-transplant malignancies in renal transplant recipients receiving PSI-based immunosuppression compared with those receiving CNIs. Conversion from CNIs to PSIs has been shown to lead to the regression of Kaposi's sarcoma in renal transplant recipients and is now part of accepted standard care for this tumour in this setting. The anti-cancer properties of PSI-based regimens have the potential to combine the dual benefits of immunosuppression without the use of CNIs and the direct anti-oncogenic effects through their inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. In the absence of formal clinical trial evidence on the best way to use PSIs in this setting, a workshop was held to provide practical guidance on immunosuppressive strategies in the context of malignancy, given the current state of knowledge.

[Cardiac sarcoidosis]. / Kardial sarkoidose.

The paper gives a review of the epidemiology, clinical manifestations, diagnosis, treatment and prognosis of cardiac sarcoidosis. Approximately 30% of patients with systemic sarcoidosis have granulomas in the myocardium, and 5% have clinical signs of cardiac affection. Cardiac manifestations comprise pericarditis, heart block, ventricular arrhythmias, valvular disease, ventricular aneurism, congestive heart failure and sudden cardiac death. Most frequent causes of death are sudden death and heart failure. Adequate treatment improves the prognosis of the disease.

[Cardiac sarcoidosis--a difficult diagnosis. A report of 8 consecutive patients with arrhythmias and cardiomyopathy]. / Kardial sarkoidose--en svaer diagnose. Beskrivelse af otte patienter med arytmi/kardiomyopati udlost af sarkoidose.

During the period 1984-2005, eight patients aged 25-57 years were treated for cardiac sarcoidosis. Diagnosis was obtained in three patients by endomyocardial biopsy, in three at heart transplantation (HTx) and in two at autopsy. Two patients had heart block, five ventricular arrhythmias and six dilated cardiomyopathy with congestive heart failure. Five patients died, one by sudden death, two of heart failure and two after HTx. Diagnosing cardiac sarcoidosis remains difficult, although MRI and PET scan have renewed the awareness of the disease.

Induction therapy after cardiac transplantation: a comparison of anti-thymocyte globulin and daclizumab in the prevention of acute rejection.

BACKGROUND: Induction therapy with antibodies decreases and delays early allograft rejection. We compared the safety and efficacy of daclizumab and anti-thymocyte globulin (ATG) with respect to the frequency and severity of acute cardiac allograft rejection in heart transplant recipients. METHODS: Forty sequential adult patients were retrospectively studied. In the first 20 patients ATG (2.5 mg/kg daily for 3 to 5 days peri-/and post-operatively) was used as induction therapy and, in the remaining 20 patients, daclizumab (1 mg/kg peri-operatively and every 2 weeks thereafter for a total of 5 doses) was used. A standard triple-drug immunosuppression regimen was administered to all patients. RESULTS: Baseline characteristics and trough levels of cyclosporine in the 2 groups were similar. During the induction period, defined as the first 3 months, 12 acute rejection episodes requiring treatment (ISHLT Grade > or =2) occurred in the ATG group and 9 in the daclizumab group (p > 0.05). However, the number of biopsies with Grade 1 rejection was increased >2-fold in the daclizumab group (n = 35) compared with the ATG group (n = 17; p = 0.04). The total number of biopsies performed within the first 3 months increased by 26% in the daclizumab group. The number and severity of rejection episodes after 3 months was similar in the 2 groups. The overall occurrence of bacterial infections was significantly higher in the ATG group than in the daclizumab group (p = 0.05). CONCLUSIONS: ATG and daclizumab are equally effective in preventing acute rejections requiring treatment (ISHLT Grade > or =2). Due to the significantly greater frequency of Grade 1 rejections, daclizumab was found to be associated with an increased number of additional biopsies for monitoring rejection status. This implies additional costs to the transplant program, and the long-term implications of the increased number of low-grade rejection episodes remains to be determined.

Overview on coenzyme Q10 as adjunctive therapy in chronic heart failure. Rationale, design and end-points of "Q-symbio"--a multinational trial.

Energy starvation of the myocardium is probably a dominant feature of heart failure and attention has been directed towards agents which may stabilize myocardial metabolism and maintain adequate energy stores. A reduced myocardial tissue content of the essential redox-component and natural antioxidant Coenzyme Q10 (CoQ10) has been detected in patients with heart failure and the observed level of CoQ10 deficiency was correlated to the severity of heart failure. CoQ10 fulfills various criteria of an obvious adjunct in patients with symptomatic heart failure: it is devoid of significant side effects and it improves symptoms and quality of life. Till this date, several double-blind placebo-controlled trials with CoQ10 supplementation in more than 1000 patients have been positive and statistically significant with respect to various clinical parameters, e.g. improvement in NYHA Class, exercise capacity and reduced hospitalisation frequency. Also treatment with CoQ10 led to a significant improvement of relevant hemodynamic parameters. In only 3 out of 13 double-blind studies comprising 10% of the total number of patients treated the results were neutral. Thus, based on the available controlled data CoQ10 is a promising, effective and safe approach in chronic heart failure. This is why a double-blind multicenter trial with focus on morbidity and mortality has been planned to start in 2003: Q-SYMBIO. Patients in NYHA classes III to IV (N=550) receiving standard therapy are being randomized to treatment with CoQ10 100 mg t.i.d. or placebo in parallel groups. End-points in a short-term evaluation phase of 3 months include symptoms, functional capacity and biomarker status (BNP). The aim of a subsequent 2-year follow-up study is to test the hypothesis that CoQ10 may reduce cardiovascular morbidity (unplanned cardiovascular hospitalisation due to worsening heart failure) and mortality as a composite endpoint. This trial should help to establish the future role of CoQ10 as part of a maintenance therapy in patients with chronic heart failure.

Serum coenzyme Q10 concentrations in healthy men supplemented with 30 mg or 100 mg coenzyme Q10 for two months in a randomised controlled study.

Serum coenzyme Q10 (Q10) concentrations were evaluated in healthy male volunteers supplemented with 30 mg or 100 mg Q10 or placebo as a single daily dose for two months in a randomised, double-blind, placebo-controlled study. Median baseline serum Q10 concentration in 99 men was 1.26 mg/l (10%, 90% fractiles: 0.82, 1.83). Baseline serum Q10 concentration did not depend on age, while borderline significant positive associations were found for body weight and smoking 1-10 cigarettes/d. Supplementation with 30 mg or 100 mg Q10 resulted in median increases in serum Q10 concentration of 0.55 mg/l and 1.36 mg/l, respectively, compared with a median decrease of 0.23 mg/l with placebo. The changes in the Q10 groups were significantly different from that in the placebo group, and the increase in the 100 mg Q10 group was significantly greater than that in the 30 mg Q10 group. The change in serum Q10 concentration in the Q10 groups did not depend on baseline serum Q10 concentration, age, or body weight.