Solid organ transplantation (SOT) is a well-established and life-saving treatment for patients with end-stage organ failure. Organ rejection and infections are among the main complications to SOT and ...largely determines the clinical outcome. The correct level of immunosuppression is of major importance to prevent these complications. However, it is a consistent observation that in recipients on the same immunosuppressive regimens the clinical outcome varies, and no reliable marker exists to monitor immune function.
In a prospective, observational study, we plan to enroll 630 adult patients with a planned organ transplantation at Rigshospitalet, University of Copenhagen, Denmark. Prior to and on different time points up to two years after transplantation we will perform a complete immunological profile on the recipients. This profile will consist of classical descriptive immune phenotyping (flow cytometry and circulating biomarkers) and the functional assay TruCulture®. In TruCulture® whole blood is incubated ex vivo with stimulants imitating bacterial, viral and fungal infections, where after a panel of selected cytokines is quantified. Clinical data from electronic health records will be obtained from the PERSIMUNE (Centre of Excellence for Personalized Medicine of Infections Complications in Immune Deficiency at Rigshospitalet, Copenhagen) data repository, a warehouse of data generated as part of routine care including vital signs, biochemistry, microbiology, pathology as well as medication, demographics, diagnoses, hospital contacts, surgical procedures and mortality.
This will be the first large scale study to determine several aspects of immune function and perform a complete immunological profiling in SOT recipients. It is expected that knowledge generated will provide information to generate prediction models identifying patients at increased risk of infection and/or rejection. If the study is successful, we will subsequently use the generated prediction models to propose personalized immunosuppressive regimens to be tested in future randomized controlled trials.
This study has been approved by the Regional ethical committee (H-17024315), the Danish Data Protection Agency (RH-2016-47, RH-2015-04, I-Suite 03605) and the Danish National board of Health (3-3013-1060/1). The trial is retrospectively registered at clinicaltrials.gov ( NCT03847285 ) the 20th February 2019.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectiveTransthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressive and fatal condition caused by deposition of transthyretin amyloid fibrils in the heart. This study aims to identify all ...patients diagnosed with ATTR-CM in Sweden, estimate the prevalence of ATTR-CM, describe patient characteristics and mortality, assess the importance of early symptoms (red flags) for identification of ATTR-CM, and compare with patients with heart failure (HF).MethodsThis retrospective study combined multiple national health registers covering all specialist visits and prescriptions for the entire population of Sweden. Between January 2008 and December 2018, patients with ATTR-CM were identified retrospectively based on a combination of diagnosis codes and compared with matched, all-cause non-ATTR HF patients.ResultsOverall, a total of 994 patients diagnosed with ATTR-CM were identified, with an average age at diagnosis of 73 years, and 30% of whom were female. The prevalence of diagnosed ATTR-CM cases in 2018 was 5.0 per 100 000. The median survival from diagnosis was 37.6 months (CI 33.8 to 43.8), with a lower median survival in women (27.9 months, CI 23.3 to 33.8) compared with men (43.5 months, CI 37.6 to 49.6). Patients with ATTR-CM demonstrated reduced survival compared with patients with HF (p<0.001). Compared with patients with HF, clinical identification of carpal tunnel syndrome, spinal stenosis, and atrioventricular and left bundle branch block can facilitate earlier diagnosis of ATTR-CM.ConclusionsThis study provides the first nationwide estimates of ATTR-CM prevalence and risk factors. The results reinforce the severity of the disease and the importance of earlier diagnosis, especially for female patients, in order to allow effective treatment and prevention of disease progression.
Wild‐type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely ...distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non‐invasive diagnosis by bone scintigraphy, and the development of disease‐modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at‐risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light‐chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at‐risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high‐quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at‐risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment.
Abstract Objective Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left atrial pressure during rest and/or exercise. The Reduce LAP-HF (Reduce Elevated Left Atrial ...Pressure in Patients With Heart Failure) trial will evaluate the safety and performance of the Interatrial Shunt Device (IASD) System II, designed to directly reduce elevated left atrial pressure, in patients with HFpEF. Methods The Reduce LAP-HF Trial is a prospective, nonrandomized, open-label trial to evaluate a novel device that creates a small permanent shunt at the level of the atria. A minimum of 60 patients with ejection fraction ≥40% and New York Heart Association functional class III or IV heart failure with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg at rest or ≥25 mm Hg during supine bike exercise will be implanted with an IASD System II, and followed for 6 months to assess the primary and secondary end points. Safety and standard clinical follow-up will continue through 3 years after implantation. Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism). MACCE include death, stroke, myocardial infarction, or requirement of implant removal. Primary outcome measures for device performance include success of device implantation, reduction of PCWP at rest and during exercise, and demonstration of left-to-right flow through the device. Key secondary end points include exercise tolerance, quality of life, and the incidence of heart failure hospitalization. Conclusion Reduce LAP-HF is the first trial intended to lower left atrial pressure in HFpEF by means of creating a permanent shunt through the atrial septum with the use of a device. Although the trial is primarily designed to study safety and device performance, we also test the pathophysiologic hypothesis that reduction of left atrial pressure will improve symptoms and quality of life in patients with HFpEF.
Post-transplant lymphoproliferative disease (PTLD) is a well-recognized complication after transplant. This study aimed to develop and validate a risk score to predict PTLD among solid organ ...transplant (SOT) recipients. Poisson regression identified predictors of PTLD with the best fitting model selected for the risk score. The derivation cohort consisted of 2546 SOT recipients transpanted at Rigshospitalet, Copenhagen between 2004 and 2019; 57 developed PTLD. Predictors of PTLD were high-risk pre-transplant Epstein–Barr Virus (EBV), IgG donor/recipient serostatus, and current positive plasma EBV DNA, abnormal hemoglobin and C-reactive protein levels. Individuals in the high-risk group had almost 7 times higher incidence of PTLD (incidence rate ratio (IRR) 6.75; 95% CI: 4.00–11.41) compared to the low-risk group. In the validation cohort of 1611 SOT recipients from the University Hospital of Zürich, 24 developed PTLD. A similar 7 times higher risk of PTLD was observed in the high-risk group compared to the low-risk group (IRR 7.17, 95% CI: 3.05–16.82). The discriminatory ability was also similar in derivation (Harrell’s C-statistic of 0.82 95% CI (0.76–0.88) and validation (0.82, 95% CI:0.72–0.92) cohorts. The risk score had a good discriminatory ability in both cohorts and helped to identify patients with higher risk of developing PTLD.
There is no consensus on how, when, or at what intensity exercise should be performed after heart transplantation (HTx). We have recently shown that high-intensity interval training (HIT) is safe, ...well tolerated, and efficacious in the maintenance state after HTx, but studies have not investigated HIT effects in the de novo HTx state. We hypothesized that HIT could be introduced early after HTx and that it could lead to clinically meaningful increases in exercise capacity and health-related quality of life.
This multicenter, prospective, randomized, controlled trial included 81 patients a mean of 11 weeks (range, 7-16 weeks) after an HTx. Patients were randomized 1:1 to 9 months of either HIT (4×4-minute intervals at 85%-95% of peak effort) or moderate-intensity continuous training (60%-80% of peak effort). The primary outcome was the effect of HIT versus moderate-intensity continuous training on the change in aerobic exercise capacity, assessed as the peak oxygen consumption (Vo
peak). Secondary outcomes included tolerability, safety, adverse events, isokinetic muscular strength, body composition, health-related quality of life, left ventricular function, hemodynamics, endothelial function, and biomarkers.
From baseline to follow-up, 96% of patients completed the study. There were no serious exercise-related adverse events. The population comprised 73% men, and the mean±SD age was 49±13 years. At the 1-year follow-up, the HIT group demonstrated greater improvements than the moderate-intensity continuous training group; the groups showed significantly different changes in the Vo
peak (mean difference between groups, 1.8 mL·kg
1·min
1), the anaerobic threshold (0.28 L/min), the peak expiratory flow (11%), and the extensor muscle exercise capacity (464 J). The 1.8-mL·kg
1·min
1 difference was equal to ≈0.5 metabolic equivalents, which is regarded as clinically meaningful and relevant. Health-related quality of life was similar between the groups, as indicated by results from the Short Form-36 (version 2), Hospital Anxiety and Depression Scale, and a visual analog scale.
We demonstrated that HIT was a safe, efficient exercise method in de novo HTx recipients. HIT, compared with moderate-intensity continuous training, resulted in a clinically significantly greater change in exercise capacity based on the Vo
peak values (25% versus 15%), anaerobic threshold, peak expiratory flow, and muscular exercise capacity.
URL: https://www.clinicaltrials.gov . Unique identifier NCT01796379.
Aim
Heart transplantation (HTx) has become a standard treatment for patients with end‐stage heart disease. The aim of this study was to report the long‐term outcome after HTx in Scandinavia.
Methods ...and results
During the period, 1983–2009, 2333 HTxs were performed in 2293 patients (mean age 45 ± 16 years, range 0–70, 78% male). The main indications for HTx were non‐ischaemic cardiomyopathy (50%), ischaemic cardiomyopathy (34%), valvular cardiomyopathy (3%), congenital heart disease (7%), retransplantation (2%), and miscellaneous (4%). The registry consists of pre‐operative data from recipients and donors, data from pre‐operative procedures, and long‐term follow‐up data. Mean follow‐up was 7.8 ± 6.6 years (median 6.9, interquartile range 2.5–12.3, interval 0–27) and no patients were lost to follow‐up. Long‐term survival for HTx patients was 85, 76, 61, 43, and 30% at 1, 5, 10, 15, and 20 years of follow‐up, respectively. Ten‐year survival in patients bridged with mechanical circulatory support, in children, after retransplantation, and after concomitant other organ transplantation was 56, 74, 38, and 43%, respectively. Older patients (age >55 years) had a significantly worse survival (P < 0.001). Patients transplanted more recently had a significantly better survival (P < 0.001). In a multivariate Cox regression analysis, independent predictors of long‐term survival were recipient age (P < 0.001), donor age (P < 0.001), diagnosis (P = 0.001), and era of transplantation (P < 0.001).
Conclusions
HTx in Scandinavia proves to have a significantly better survival among patients transplanted in the last decade. HTxs from mechanical circulatory support, in children, after retransplantation, and with concomitant other organ transplantation were performed with acceptable results.
Abstract Background Copeptin, a stable fragment of the vasopressin prohormone, has been shown to be a significant biomarker for morbidity and mortality in heart failure. The aims of this study were ...to evaluate the influence of plasma sodium on the prognostic significance of copeptin concentrations in heart failure outpatients and to determine whether increased copeptin concentrations predict future development of hyponatremia. Methods and Results A total of 340 heart failure patients with left ventricular systolic dysfunction were followed for 55 months (median) in a Danish heart failure clinic. A baseline measurement of plasma copeptin, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and sodium was performed, and the sodium concentrations were recorded during 3 months after the baseline visit in the heart failure clinic. Patients were divided into 3 groups according to copeptin tertiles. In multivariate Cox proportional hazard models adjusted for confounders, including plasma sodium, loop diuretic dose, and NT-proBNP, copeptin was a significant predictor of hospitalization or death (hazard ratio 1.4, 95% confidence interval 1.1–1.9; P < .019) but did not predict mortality independently from NT-proBNP. Additionally, copeptin concentrations did not predict future development of hyponatremia. Conclusions Plasma copeptin levels predict mortality in outpatients with chronic heart failure independently from clinical variables, plasma sodium, and loop diuretic doses. Furthermore, copeptin predicts the combined end point of hospitalization or death independently from NT-proBNP.
Aims
Transthyretin amyloid cardiomyopathy (ATTR CM) is a progressive and severe heart disease with physical and psychological implications. The Nordic PROACT study was conducted to investigate the ...health‐related quality of life (HRQoL) in ATTR CM patients.
Methods and results
The Nordic PROACT study was a cross‐sectional non‐interventional study conducted in 12 cardiology hospital clinics across Norway, Sweden, Finland and Denmark. Men and women aged ≥18 years diagnosed with symptomatic ATTR CM were included. The investigator provided information on medical history, biomarkers, current treatment, co‐morbidities and disease severity according to the New York Heart Association (NYHA) class and the National Amyloidosis Centre (NAC) staging. Patients completed the HRQoL questionnaires in the form of the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ‐5D‐5L index with Visual Analog Scale (VAS), and the Major Depression Inventory (MDI). A total of 169 patients (mean ± SD age 77.7 ± 6.2 years) were included. Ninety‐two per cent were men. Seventy‐six per cent had wildtype ATTR CM (ATTRwt CM) and 15% had a hereditary form of ATTR CM (ATTRv CM) while 9% were genetically unclassified. Most patients were in NYHA class II (54%) and NAC stage 1 (53%). Participation in randomized clinical trials (RCT) was noted in 58% of the patients. The 169 ATTR CM patients had a mean ± SD KCCQ score of 64.3 ± 23.1 for total symptom score, 64.8 ± 20.9 for overall summary score (OSS) and 65.1 ± 21.5 for clinical summary score. The EQ‐5D‐5L total utility score was 0.8 ± 0.2 and the EQ‐5D‐5L VAS score was 62.9 ± 20.6. The vast majority (89%) did not report any signs of depression. Patients with ATTRv CM had a higher KCCQ OSS as compared with ATTRwt CM, while EQ‐5D‐5L utility score, EQ‐5D‐5L VAS and MDI were similar. Non‐RCT participants had a poorer HRQoL as compared with RCT participants as reflected in lower KCCQ OSS and EQ‐5D‐5L VAS scores and a higher MDI score. Patients with higher NYHA classes and NAC disease stages had a poorer HRQoL as demonstrated by lower KCCQ and EQ‐5D‐5L scores and higher MDI scores. Correlation between KCCQ, EQ‐5D‐5L and MDI and the covariate NYHA class remained significant (P < 0.05) after adjusting for multiple testing.
Conclusions
KCCQ scores were lower than previously reported for patients with other heart diseases of non‐ATTR CM origin. The HRQoL measures correlated well to NYHA class and NAC disease stage. The prevalence of depression appeared to be low.
•Cardiac expression of procholecystokinin (proCCK) reflects hemodynamic changes in mammalian hearts.•Ventricular cardiomyocytes store proCCK, contrasting natriuretic peptides.•Patients with severe ...systolic heart failure display markedly increased proCCK in plasma.•ProCCK in plasma seems independent of cardiac index and pulmonary capillary pressure.
Cardiac myocytes express the cholecystokinin gene (CCK) at propeptide level. We recently reported that cardiac CCK expression is acutely regulated by isoprenaline in a porcine model.
The regulation of CCK expression after myocardial infarction, in exercise, and in severe heart failure is, however, unknown. Cardiac tissue was obtained from healthy new-born and adolescent farm pigs. Myocardial infarction was induced by coronary artery occlusion in adult minipigs. Healthy male subjects performed a 3-hour exercise test, and patients with severe heart failure referred for right heart catheterization were included. Extracts of porcine cardiac tissue and human plasma were analysed with specific proCCK radioimmunoassays. Cardiac proCCK expression shifted from the right atrium in new-born piglets to include the left atrium in adolescent pigs. Regional proCCK expression in the adolescent pig heart was mainly confined to the atria without different expression in sinus node tissue. In adult minipigs with myocardial infarction, no changes in overall left ventricular function or proCCK expression were observed after 8 weeks. In healthy adults, proCCK in circulation increased markedly during exercise in parallel with pro-B-type natriuretic peptide. Finally, patients with severe heart failure displayed markedly increased proCCK – but not CCK – concentrations in plasma. Taken together, our data shows that regional proCCK expression reflects haemodynamic changes in the mammalian heart. The data supports the notion that cardiac CCK expression resembles that of cardiac natriuretic peptides in atria. The ventricular content of proCCK, however, differs from natriuretic peptides and suggests a distinct secretory pathway in ventricular cardiomyocytes.
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