Search

This thirty-sixth adult lung and heart–lung transplant report summarizes data from 69,200 adult lung and 4,128 adult heart-lung transplants performed through June 30, 2018 and reported to the International Thoracic Organ Transplant Registry. With each year's report, we now provide more detailed analyses on a particular focus theme important to patient outcomes. Since 2013, these have been donor and recipient age; retransplantation; early graft failure; indication for transplant; allograft ischemic time; and multiorgan transplantation. Although widely accepted as critical to decision making at the time of receipt of an organ donor offer, there is surprisingly little literature outlining current practice and the impact of size (mis-)matching on outcomes. Hence this year's report focuses on an overall theme of donor and recipient size matching. In addition to reporting donor and recipient height and weight difference for all adult lung and heart-lung transplant recipients stratified by transplant type (bilateral or single) and indication, we report historical trends and associations between size match and survival. The Registry's online slide sets include results from additional analyses and complementary information not included in this publication (see https://ishltregistries.org/registries/slides.asp ).

Fixed pulmonary hypertension (FPH) is a contraindication for heart transplantation (HTX). However, this condition might be reversed by continuous left-ventricular unloading with a left-ventricular assist device. We present a case of apical hypertrophic cardiomyopathy with extensive left-ventricular endocardial calcification and severe FPH (systolic pulmonary artery pressure, 102 mm Hg). To bridge the patient to candidacy for HTX, two Abbott HeartMate 3 ventricular assist devices were implanted in a total artificial heart (TAH) configuration ("HeartMate 6"). Before TAH implantation, an Abbott CardioMEMS pressure sensor was implanted to assess reversal of FPH before listing for HTX.

Purpose The INTERHEART study previously used microarray assessment of 889 heart transplant biopsies to develop the Molecular Microscope Diagnostic System (MMDx) based on expression of rejection-associated transcripts (RATs). The present study reclassified the rejection-related states in an expanded set of 1320 prospectively collected biopsies from 645 patients from 13 centers. Methods Biopsies were classified by ensembles of classifiers and analyzed for left ventricular ejection fraction (LVEF) and survival. Results New algorithms identified 853 No rejection (NR), 179 ABMR, 76 TCMR, 13 Mixed, 161 possible ABMR (pABMR), and 38 possible TCMR (pTCMR). No rejection was subclassified as NR-Normal 462, NR-Minor 359, and NR-Early-injury 32 (Figure 1A). Compared to NR-Normal, NR-Minor biopsies had mild elevation of many inflammation transcripts (e.g. IFNG-inducible genes) and to a lesser extent parenchymal injury transcripts. NR-minor biopsies were often designated as TCMR1R by histology. In all NR biopsies, NR-Minor scores and histologic TCMR1R increased through the first year, peaking about one year, suggesting that Minor inflammation is a late response to injury, unrelated to rejection. LVEF was similar in NR-Normal and NR-Minor but depressed in TCMR and Early injury. In a 3-year post-biopsy survival analysis, NR-Minor and NR-Normal had similar survival. TCMR and Early-injury were associated with increased graft loss, but many losses were not related to rejection. Surprisingly, 76 hearts with ABMR (149 biopsies) and follow-up data had only 3 losses within 3 years post-biopsy (Figure 1B). Conclusion Many biopsies with molecular no rejection develop minor increases in rejection-related transcripts in the first year, often called TCMR1R by histology, with no apparent effects on function or survival. An unexpected finding was that molecular ABMR was associated with very few graft losses over three years. (ClinicalTrials.gov #NCT02670408).

Summary The Heart Donor Score (HDS) predicts donor organ discard for medical reasons and survival after heart transplantation (HTX) in the Eurotransplant allocation system. Our aim was to adapt the HDS for application in the United Network for Organ Sharing (UNOS) registry. To adjust for differences between the Eurotransplant and UNOS registries, the “adapted HDS” was created (aHDS) by exclusion of the covariates “valve function,” “left‐ventricular hypertrophy,” and exclusion of “drug abuse” from the variable “compromised history.” Two datasets were analyzed to evaluate associations of the aHDS with donor organ discard (n = 70 948) and survival (n = 19 279). The aHDS was significantly associated with donor organ discard [odds ratio 2.72, 95% confidence interval (CI) 2.68–2.76, P

Left ventricular assist device implantation without sternotomy (LIS) may simplify heart transplantation (HTX) by avoiding adhesions and eliminating the need for a re-sternotomy. This study investigates the impact of LIS LVAD implantation on HTX outcomes. A retrospective comparison of 46 patients undergoing HTX between 07/13 and 06/19 after conventional LVAD implantation with a full sternotomy (FS) and LIS LVAD implantation (LIS: n = 27 patients, 59%; FS: n = 19 patients, 41%) was performed. Endpoints were perioperative data including blood product use, de-novo formation of donor specific antibodies (DSAs) and survival. Patient demographics (mean age FS: 60.3 ± 9.3 years vs LIS 58.0 ± 7.7 years, P = 0.313; male gender FS: 84% vs LIS: 82%, P = 1.000; urgent HTX FS: 16% vs LIS 18%, P = 1.000) were comparable between LIS and FS patients. The primary finding was a significantly higher risk to develop de novo donor specific antibodies (DSAs) after HTX in patients of the FS group (FS: 36% vs LIS: 4%; P = 0.006). LIS patients had a significant reduction of intraoperative packed red blood cells (PRBCs) use (LIS: 4 (IQR 2–7) Units vs FS: 7 (IQR 4–8) Units; P = 0.045). Other adverse events rates and in-hospital mortality (LIS: 7% vs FS 5%, P = 1.000) were comparable between both groups. LIS LVAD reduces formation of donor specific antibodies after HTX.

Background An optimal donor work-up to exclude preexisting conditions is recommended, but urgency and technical equipment in donor centers must be considered. We report a case of two coronary stents present in the donor heart and the related long-term outcome. Case presentation A 59-year-old European male patient suffering from dilated cardiomyopathy with severely reduced left ventricular function and presenting with NYHA III underwent cardiac transplantation in 2004. At the one-year follow-up, during routine cardiac catheterization, two stents were found, one in the right coronary artery and one in the circumflex artery, in the patient’s transplanted heart. As no stent implantation was performed since transplantation, these were present prior to transplantation and had been transplanted without causing clinical signs. One of the stents showed in-stent restenosis, and the patient received an additional stent 7 years after transplantation. The other stent still showed a good result, and no further intervention has been required so far. The patient is currently in good clinical condition. Conclusion This is the first case report of favorable long-term stented coronary arteries prior to transplantation. This case highlights the importance of the donor work-up and meticulous palpation of the coronary arteries during donor evaluation.

BACKGROUND A previous donor intervention trial found that induction of mild therapeutic hypothermia in the brain-dead donor reduced the dialysis requirement after kidney transplantation. Consequences on the performance of cardiac allografts after transplantation were not explored to date. METHODS Cohort study investigating 3-year heart allograft survival according to spontaneous core body temperature (CBT) assessed on the day of organ procurement. The study is nested in the database of the randomized trial of donor pretreatment with low-dose dopamine (ClinicalTrials.gov identifier: NCT000115115). RESULTS Ninety-nine heart transplant recipients who had received a cardiac allograft from a multiorgan donor enrolled in the dopamine trial were grouped by tertiles of the donor's CBT assessed by a mere temperature reading 4 to 20 hours before procurement (lowest, 32.0-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C). Baseline characteristics considering demographics of donors and recipients, concomitant donor treatments, donor hemodynamic, and respiratory parameters as well as underlying cardiac diseases in recipients, pretransplant hemodynamic assessments, including pretransplant inotropic/mechanical support, urgency, and waiting time were similar. A lower CBT was associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile; P = 0.02, and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93°C; P = 0.02) when CBT was included as continuous explanatory variable in the Cox regression analysis. CONCLUSIONS A lower CBT in the brain-dead donor before procurement may associate with an unfavorable clinical course after heart transplantation. More research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended.

Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5-7.5 mg/kg is advisable.

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow-up ≤1-year post-transplant and patients with early CAV were excluded. CMV-infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow-up was 7.5 years (IQR: 5.6-10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1-year post-HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89-2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02-1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06-2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long-term follow-up.

Purpose Primary Graft Dysfunction (PGD) is a leading cause of short-term mortality after heart transplantation (HT). Available registries lack data to identify PGD based on post-HT hemodynamics and mechanical circulatory support (MCS). Herein, we describe the development of a multicenter International Consortium on PGD: a registry designed to quantify the incidence, risk factors, and impact of PGD, in order to develop contemporary risk prediction models. Methods We are currently collecting data from 10 participating sites in Europe and North America which will include clinical data from an estimated 3,826 HT recipients (Table 1). We defined PGD using the ISHLT 2014 consensus criteria. Our complete consortium will include data on baseline donors and recipients demographics, pre and post-HT hemodynamics, and the type and duration of MCS after HT. We will use regression models and supervised machine learning (ML) algorithms to develop risk prediction models that reflect the contemporary landscape of HT. Endpoints To date, we have collected preliminary data on 2,178 single-organ HT recipients between 2010 - 2020 (57% of the anticipated final sample size). Our consortium cohort consists of patients with age of 54 ± 12 years, of whom 24.7% (n=537) are female. Pre-transplant MCS included IABP in 3.6% (n=80), ECMO in 1.4% (n=30), and durable LVAD in 8.3% (n=181). Donor age was 37 ± 13 years and ischemic time was 3.4 ± 1.0 hours. A total of 167 (7.7%) recipients met criteria for severe PGD and 76 (6.5%) for moderate PGD. One-year survival was 67% (95% CI 59 - 74%) and 93% (95% CI 92 - 94%) in patients with and without severe PGD, respectively. We aim to develop contemporary tools for risk stratification of HT recipients for incident PGD. Our multicenter, international consortium allows for comprehensive phenotyping of HT recipients based upon a standardized definition of PGD to accurately understand PGD incidence, risk factors, and outcomes in the era of MCS. Interim Results To date, we have collected 106 variables on 2,476 single-organ HT recipients from 2010 to 2020 (Figure 1A). Mean age of cohort is 53.9 ± 12.3 years; 25% female, 330 recipients from Canada, 518 from Europe, and 1628 from the US. Pre-transplant MCS included IABP in 8.4% (n=207), ECMO in 1.3% (n=33), and durable LVAD in 32.1% (n=795) (Figure 1B). Average donor age was 36.4 ± 13.0 years with mean ischemic time 3.4 ± 1.1 hours. A total of 214 (8.6%) of recipients met criteria for severe PGD, requiring VA-ECMO (n=186), RVAD (n=28), or both (n=3). Among 1811 patients with adequate follow up data, 1-year survival was 78% (95% CI 72% – 83%) in patients with severe PGD, and 95% (95% CI 94% – 96%) in those without severe PGD (Figure 1C). The previously-published RADIAL PGD risk score performed poorly in our cohort, with an AUC of 0.50 for severe PGD(Figure 1D).

The role of uPA in tissue remodeling and cell migration is already well established. In addition, uPA was reported to stabilize p53, a key cell cycle control, DNA repair and apoptosis initiation protein. We aimed to determine the role of uPA-uPAR signaling towards cell survival or apoptosis in human adult cardiac myocytes (HACM). HACM were stimulated with uPA and DNA damage was inflicted by incubating cells with 200 µM H2O2. To analyze for apoptotic cells we applied TUNEL staining. Oxidative damage foci were analyzed by staining for 8-oxoguanine base pairs. In vivo qPCR analysis from RNA extracted from failing human hearts demonstrated a close relation of uPA with apoptosis and the p53 pathway. Furthermore, we observed a close correlation of uPA and p53 protein in homogenized tissue lysates. In vitro studies revealed that uPA preincubation protected HACM from oxidative damage induced cell death and reduced oxidative damage foci. uPA protection is independent of its catalytic activity, as the amino terminal fragment of uPA showed similar protection. A key enzyme for repairing oxidative DNA damage is the p53 target hOGG1. We found a significant increase of hOGG1 after pretreatment of HACM with uPA. Knockdown of hOGG1 completely abrogated the protective effect of uPA. We conclude that uPA might have a tissue protective role in human hearts besides its role in tissue remodeling. Tissue protection is mediated by the DNA repair protein hOGG1. This might be beneficial during tissue remodeling and thus could be a target for therapeutic approaches in the diseased heart.

// Matthias Zimmermann 1 , Lucian Beer 1,2 , Robert Ullrich 3 , Dominika Lukovic 4 , Elisabeth Simader 1 , Denise Traxler 1,4 , Tanja Wagner 5 , Lucas Nemec 5 , Lukas Altenburger 5 , Andreas Zuckermann 6 , Mariann Gyongyosi 4 , Hendrik Jan Ankersmit 1,5 and Michael Mildner 7 1 Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria 2 Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria 3 Department of Pathology, Medical University of Vienna, Vienna, Austria 4 Department of Cardiology, Medical University of Vienna, Vienna, Austria 5 Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria 6 Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria 7 Department of Dermatology, Research Division of Biology and Pathobiology of the Skin, Medical University of Vienna, Vienna, Austria Correspondence to: Michael Mildner, email: // Hendrik Jan Ankersmit, email: // Keywords : myocardial infarction, systemic effect, paracrine factors, transcription factor, Klf4, Immunology and Microbiology Section, Immune response, Immunity Received : April 05, 2017 Accepted : May 03, 2017 Published : May 17, 2017 Abstract Aims: Ischemic myocardial injury leads to the activation of inflammatory mechanisms and results in ventricular remodeling. Although great efforts have been made to unravel the molecular and cellular processes taking place in the ischemic myocardium, little is known about the effects on the surrounding tissue and other organs. The aim of this study was to determine region specific differences in the myocardium and in distant organs after experimental myocardial infarction by using a bioinformatics approach. Methods and Results: A porcine closed chest reperfused acute myocardial infarction model and mRNA microarrays have been used to evaluate gene expression changes. Myocardial infarction changed the expression of 8903 genes in myocardial-, 856 in hepatic- and 338 in splenic tissue. Identification of myocardial region specific differences as well as expression profiling of distant organs revealed clear gene-regulation patterns within the first 24 hours after ischemia. Transcription factor binding site analysis suggested a strong role for Kruppel like factor 4 (Klf4) in the regulation of gene expression following myocardial infarction, and was therefore investigated further by immunohistochemistry. Strong nuclear Klf4 expression with clear region specific differences was detectable in porcine and human heart samples after myocardial infarction. Conclusion: Apart from presenting a post myocardial infarction gene expression database and specific response pathways, the key message of this work is that myocardial ischemia does not end at the injured myocardium. The present results have enlarged the spectrum of organs affected, and suggest that a variety of organ systems are involved in the co-ordination of the organism´s response to myocardial infarction.

Heme oxygenase-1 (HO-1) catalyses the degradation of heme to biliverdin, free iron, and carbon monoxide. The promoter region contains a highly polymorphic (GT)n repeat, where shorter (GT)n repeat sequences are linked to higher transcriptional activity, which was shown to correlate with a cytoprotective effect. Higher HO-1 levels may protect from cardiac allograft vasculopathy. Cardiac allograft recipients transplanted between 1988 and 2012 were analyzed for the HO-1 (GT)n repeat polymorphism using PCR and DNA fragment analysis with capillary electrophoresis. A relation to cardiac allograft vasculopathy (CAV) was analyzed using Cox regression including common risk factors for CAV and the occurrence of rejection episodes as explanatory variables. A total of 344 patients were analyzed, of which 127 patients were positive for CAV (36.9%). In our multivariable Cox regression analysis, the short homozygous HO-1 (GT)n genotype with

Aims Levosimendan is an inodilator for the treatment of acute decompensated heart failure (HF). Data from clinical studies suggest that levosimendan is particularly effective in HF due to myocardial infarction. After acute revascularization, no reflow-phenomenon is a common complication that may lead to pump failure and cardiogenic shock. Our aim was to examine whether levosimendan interferes with the pro-thrombotic phenotype of activated endothelial cells in vitro. Methods Human heart microvascular endothelial cells (HHMEC) and human umbilical vein endothelial cells (HUVEC) were treated with interleukin-1β (IL-1β) (200 U/mL) or thrombin (5 U/mL) and co-treated with or without levosimendan (0.1–10 μM) for 2–24 h. In addition, flow experiments were performed. Effects on plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression and activity were measured by rt-PCR, specific ELISA and flow cytometry. Results Treatment with IL-1β or thrombin significantly increased the expression of PAI-1 and TF in endothelial cells. Co-treatment with levosimendan strongly attenuated the effects of IL-1β and thrombin on PAI-1 and TF mRNA by up to 50% and 45%, in a dose- and time-dependent manner. Similar results were obtained under flow conditions. Furthermore, co-treatment with levosimendan dampened the antigen production of PAI-1 and the surface expression of TF by 35% and 45%, respectively. Additionally, levosimendan diminished both TF and PAI-1 activity. Conclusion Levosimendan down-regulates the expression of the pro-thrombotic and anti-fibrinolytic biomolecules TF and PAI-1 in activated human endothelial cells. Our findings may, at least in part, explain some of the beneficial effects of levosimendan after myocardial reperfusion.

We thank Cacciatore and colleagues for their valuable comments. Our study was the first in cardiac transplantation to investigate, in an exploratory manner, whether the Epitope MisMatch Algorithm (HLA-EMMA) could serve for post-transplant risk stratification. Numerous studies have previously shown that a higher HLA allele mismatch is associated with inferior clinical outcomes, as has been correctly pointed out.

Background Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. It has confirmed recognition in well‐known documented conditions such as graft‐versus‐host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. Materials and methods In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. Results and conclusion These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T‐cell lymphoma, chronic graft‐versus‐host disease and acute graft‐versus‐host disease while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

Background Endomyocardial fibrosis (EMF) represents the most common cause of restrictive cardiomyopathy worldwide. Despite a high prevalence in tropical regions, it occasionally occurs in patients who have never visited these areas. While researches have proposed various possible triggers for EMF, etiology and pathogenesis remain largely unknown. Diagnosis is based on patient history, heart failure symptoms, and echocardiographic signs of restrictive ventricular filling, atrioventricular valve regurgitation and frequently apical thrombus. Following is a case report of an Austrian patient with EMF who eventually had to undergo a heart transplant. This case report strives to promote awareness for this in non-tropical areas uncommon but nevertheless detrimental disease. Case presentation A 40-year-old woman was presented at our emergency department with chest pain and fever up to 38.1° Celsius. Plasma troponin-T levels and inflammatory markers were slightly elevated, but the echocardiogram was without pathological findings. The patient was hospitalized on the suspicion of acute myocarditis and discharged soon after improvement. Eight months later, she was presented again with chest pain and symptoms of heart failure. The echocardiogram showed normal systolic left ventricular (LV) function with LV wall thickening and severe restrictive mitral regurgitation as well as aortic and tricuspid regurgitation. Coronary angiogram was normal but right heart catheterization showed pulmonary hypertension due to left heart disease. Further diagnostic workup with cardiac magnetic resonance imaging revealed subendocardial late enhancement and apical thrombus formation in the left ventricle compatible with the diagnosis of EMF. A comprehensive diagnostic workup showed no evidence of infection, systemic immunologic or hematological disease, in particular hypereosinophilic syndrome. After a multidisciplinary consideration of several therapeutic options, the patient was listed for heart transplantation. On the waiting list, she deteriorated rapidly due to progressive heart failure and finally underwent a heart transplantation. Histological examination confirmed the diagnosis of EMF. Six years after her heart transplantation, the patient was presented in an excellent clinical condition. Conclusions Even in non-tropical regions, the diagnosis of EMF should always be considered in restrictive cardiomyopathy. Knowledge of the distinct phenotype of EMF facilitates diagnosis, but comprehensive workup and therapeutic management remain challenging and require a multidisciplinary approach.

Background Prognosis of patients with HFrEF remains poor despite recent advances in pharmacologic therapy as the introduction of the angiotensin-receptor neprilysin-inhibitor (ARNI). The Renin-Angiotensin-System (RAS) is dysregulated in HF with elevated AngII levels as a central driver of disease progression. The myocardium is capable of synthesizing all RAS components resulting in tissue specific angiotensin levels. Neprilysin (NEP) catalyzes the generation of Ang1–7 which counteracts the deleterious effects of AngII. Myocardial tissue angiotensins of the failing heart and the role of long-lasting RAS-inhibitor therapy and particularly NEP inhibition on tissue RAS have not been investigated yet. Methods Concentrations of AngI, AngII, Ang1–7, AngIII, Ang1–5 and AngIV (RAS-fingerprints) were investigated in myocardial samples of end-stage HFrEF patients undergoing heart transplantation with a mass-spectrometry based method. Patients were stratified according to background therapy with RAS-inhibitors and variables were compared by a non-parametrical test. Results A total of 30 patients were included (n=6 without RAS-blockade, n=16 with ACE-I, n=6 with ARB and n=2 with ARNI). Median age was 55 (IQR 45–63) years and 87% of patients were male. 40% of patients had an ischemic etiology of HF, median NT-proBNP levels were 3498pg/ml (IQR 1761–8400). Tissue RAS patterns were visually similar between all groups (Figure 1). Myocardial AngI, Ang1–7, Ang1–5 and AngIV levels were below the detection limit for all samples. Median tissue AngII and AngIII concentrations across all samples were 83.1pg/ml (IQR 29.3–196.6) and 26.4pg/ml (IQR 5.0–64.5). Despite different background RAS-inhibitor therapy, AngII and AngIII levels were comparable between all groups [median (IQR) in pg/ml – AngII: 51.5 (41.5–123.8) vs. 72.4 (28.5–177.6) vs. 176.1 (22.4–286.8) vs. 266.0 (108.2–423.8); p=ns and 26.4 (5.0–89.2) vs. 23.2 (5.0–59.3) vs. 39.4 (5.0–94.3) vs. 105.9 (46.5–165.3); p=ns for no therapy, ACE-I, ARB and ARNI respectively]. Figure 1. RAS-fingerprints of the failing heart according to RAS-inhibiton. Numbers in brackets indicate the specific angiotensin peptides. Side of spheres and numbers beside represent absolute concentrations of angiotensins (pg/ml, median value). Conclusions Although in the plasma of HFrEF patients only AngI and AngII are detectable at substantial concentrations, the predominant angiotensins of the failing heart are AngII and AngIII. AngII levels are high in the failing heart supporting the hypothesis that excess AngII is involved in disease progression. AngIII similarly increases cardiac sympathetic activity assumedly potentiating further deteoriation. The modality of long established RAS-inhibitor therapy in end-stage HF, particularly the inhibition of NEP, seems to have no (more) influence on myocardial tissue RAS regulation. The impact of NEP inhibition by ARNI on tissue RAS enzymes and mechanism of action need to be further investigated.

Background In heart failure with reduced ejection fraction (HFrEF) the renin-angiotensin-system (RAS) is dysregulated and serves as therapeutic target. Research has been focusing on plasma RAS. Information on tissue RAS is scarce although assumedly more crucial for myocardial function. Among known angiotensins, only AngII and AngIII are detectable in the failing heart. Plasma samples in HFrEF show high AngI and AngII levels with clearly distinguishable AngI/AngII ratios for different RAS-inhibitors. AngII and AngIII levels in the myocardium were comparable for different RAS-inhibitors, i.e. no RAS-blocker, ACE-inhibitor, ARB or angiotensin-receptor neprilysin-inhibitor (ARNI). Here we aimed to elucidate the metabolic regulation of tissue RAS enzymes for these four different modalities of RAS-inhibition. Methods Enzyme regulation and metabolic activities were investigated in myocardial samples of end-stage HFrEF patients undergoing heart transplantation with a mass-spectrometry based method. Concentrations of respective angiotensin metabolites AngI, AngII, Ang1–7, AngIII, Ang1–5 and AngIV (RAS-fingerprints) were investigated after adding AngI or AngII and incubation to display metabolic patterns of the main plasma angiotensins. Metabolic activities of distinct enzymes have been assessed for the no therapy and ACE-I subgroups. Patients were stratified according to background therapy with RAS-inhibitors. Results A total of 30 patients were included (n=6 without RAS-blockade, n=16 with ACE-I, n=6 with ARB, n=2 with ARNI). Median age was 55 (IQR 45–63) years, 87%were male. Etiology of HF was ischemic in 40%, median NT-proBNP levels were 3498pg/ml (IQR 1761–8400). Patterns for tissue RAS metabolism of AngI and AngII was visually similar for all groups, indicating comparable regulation of tissue RAS enzymes independent from therapy (Figure 1). The formation of AngII from AngI was mainly chymase dependent with conversion rates of 99.4 (IQR 77.0–254.1) (pg/μg protein)/h for ACE-I and 141.8 (IQR 67.9–369.2) (pg/μg protein)/h for no RAS-blockade, whereas ACE-related generation of AngII was under the detection limit. The formation of Ang1–7 from AngI was mediated by NEP and PEP. The contribution of NEP was significantly higher [5022 (IQR 5002–5286) (pg/μg)/h vs 3555 (IQR 3351–3849) (pg/μg)/h, p=0.005 for the ACE-I group and 4729 (IQR 4438–6135) (pg/μg)/h vs 3601 (IQR 3052–4182) (pg/μg)/h, p=0.012 for no RAS-blockade]. No differences in tissue enzymatic activities between ACE-I and no therapy, as already indicated by the metabolization patterns occurred. Figure 1 Conclusions Enzymatic tissue RAS regulation in end-stage HF seems to be independent from the mode of established RAS-inhibitor therapy.In contrast to plasma, AngII formation of the tissue is mainly chymase dependent, whereas ACE seems to play an unsignificant role. NEP has a substantial role in generating beneficial Ang1–7 from AngI. The impact of NEP inhibition by ARNI on tissue RAS and mechanism of action have to be further investigated.

Antibody-mediated rejection (AMR) is a major contributor of impaired long-term survival after heart transplantation (HTx). The presence of circulating donor-specific antihuman leukocyte antigen (HLA) antibodies (DSAs) is considered as a mandatory criterion for AMR after HTx. DSA are known prognostic biomarkers of outcome, for example, recipients with de-novo DSA have a three-fold increased risk of mortality.Although the awareness of the impact and prognosis of DSA on the survival has been increased in the HTx community over the last decade, the management of DSA pre and posttransplant varies among centers and is mainly based on the experience of transplant physicians. Thus, firm consensus strategies for each HTx recipient should be established by a center advisory board of experts in the field of HLA genetics, transplantation immunology, and HTx to evaluate the immunological risk preoperatively and also continuously during the posttransplant course. Consequently, the recent advances of invasive and noninvasive diagnostic tools should be applied, according to the risk, laboratory findings, and clinical events of the recipient. Such individual strategy will result in tailored therapeutic options.Novel standards for the management of DSA in HTx recipients on the basis of an interdisciplinary approach of experts will improve diagnostics for personalized medicine.

Purpose To assess the therapeutic effect of advanced organ preservation technology compared to conventional methods on heart transplant recipient perioperative and short-term clinical outcomes. Methods The Global Utilization And Registry Database for Improved heArt preservatioN (GUARDIAN) study is an international multi-center retrospective-prospective registry assessing clinical outcomes after heart transplantation. This is the first publication of a multi-center study comparing two methodologies of hypothermic storage: patients with donor hearts preserved by the only FDA cleared and CE marked heart preservation and transportation system [Paragonix SherpaPak Cardiac Transport System], and patients with donor hearts transported by conventional preservation methods (ice protocol). Data on baseline donor, recipient, and procedure characteristics are captured to compare baseline characteristics of the two cohorts. Endpoints Comparisons will be made on peri-operative and short-term patient outcomes including hemodynamic characteristics, required surgical and medical interventions, and length-of-stay data.

Background Kidney function is an important aspect for patient outcome after heart transplantation (HTX). Acute kidney injury (AKI) is defined by changes in serum creatinine (SCr) and diuresis with risk/injury/failure/loss/end stage (RIFLE), acute kidney injury network (AKIN), or kidney disease: improving global outcomes (KDIGO) scores. Methods We investigated the effect of perioperative AKI on 1-year mortality after HTX over a period of 10 years at a single-center university hospital. Multivariable Cox proportional-hazards regression analyzed the association between 1-year mortality and potential risk factors. Receiver operating curves for 1-year mortality were calculated to determine sensitivity and specificity of scores. Results Sixty of 346 patients (17%) died within the first year. Acute kidney injury was a predictor of mortality only in the high-risk AKI groups of all scores: Hazard ratios (95% confidence interval) for RIFLE F: 7.164 (3.307-15.523); KDIGO/AKIN stage 3: 3.492 (2.006-6.081). Within each score, we identified patient groups, which had no elevated risk for an adverse outcome despite their allocation to the milder forms of AKI. In multivariable regression analysis, primary graft dysfunction was the predominant perioperative risk factor for 1-year mortality. Conclusions In contrast to other patient cohorts, mild forms of perioperative AKI are of subordinate influence on patient outcome in HTX.

BACKGROUND Optimal dosing strategies have not been established for rabbit antithymocyte globulin (rATG) after heart transplantation, and there is currently wide variability in rATG regimens with respect to both dose and duration. METHODS In a retrospective, single-center analysis, 523 patients undergoing heart transplantation during 1996 to 2009 were stratified by cumulative rATG dose: less than 4.5 mg/kg (group A), 4.5 to 7.5 mg/kg (group B) or greater than 7.5 mg/kg (group C). RESULTS Survival at 1 year after transplantation was 80% in group A, 90% in group B, and 88% in group C (P = 0.062). Incidence of acute rejection per 1000 patient-years was significantly higher in group A (hazards ratio [HR], 54.8; 95% confidence interval [95% CI], 33.9-83.8) compared to groups B (19.6; 95% CI, 11.4-31.4) and C (23.6; 95% CI, 17.5-31.3). Incidence of severe infection 10 years after transplantation was higher in group C (45%) than groups A (37%) or B (23%) (P < 0.001); cytomegalovirus infection rates were 35%, 20% and 23%, respectively (P = 0.009). Multivariable Cox regression showed an HR of 0.51 (95% CI, 0.25-1.02) for acute rejection with group B versus group A, and 0.54 (95% CI, 0.33-0.88; P = 0.013) for severe infection. The rate of malignancy per 1000 patient-years was higher in groups B (13.85) and C (14.95) than group A (7.83). CONCLUSIONS These retrospective data suggest that a cumulative rATG dose of 4.5 to 7.5 mg/kg may offer a better risk-benefit ratio than lower or higher doses, with acceptable rates of infection and posttransplant malignancy. Prospective trials are needed.

Purpose The use of induction therapy for orthotopic heart transplant (OHT) recipients is inconsistent between centers and there are limited data that explore the association with post-transplant outcomes. We used the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry to investigate induction therapy use after OHT and its relationship to 1-year survival. Methods This is a retrospective cohort study from the global ISHLT Registry of adult patients who received a first OHT between 1/2005 and 6/2017. We excluded multi-organ transplant recipients, and those with missing induction data or no post-transplant follow up. We describe recipient and donor characteristics, stratified by induction therapy use. We used Kaplan-Meier methods to estimate 1-year mortality for induction therapy use and non-use, with comparison by the log-rank test. Results Of 27,400 OHT recipients included in this analysis, 13,711 (50%) received induction therapy at the time of transplant. The use of induction therapy remained stable over the study period. Both groups had median age of 55 years and had nonischemic cardiomyopathy as the most frequent diagnosis. There was a higher rate of females in the induction group (25.5% vs 24.2%). Recipients who received induction therapy had higher rates of pre-transplant dialysis (2.5% vs 2.1%) and ventilator use (2.6% vs 1.1%) but not ventricular assist device use (35.5% vs 39.9%). Atgam/thymoglobulin and basiliximab were the most frequently used therapies (N=5139 [37.5%] and N=7691 [56.1%], respectively). There was no significant difference in 1-year unadjusted survival between those who received induction therapy and those who did not. (Figure) Conclusion In a large international cohort, approximately half of OHT recipients received induction therapy after heart transplantation, with similar one-year survival compared to those who did not receive induction therapy. Further study is warranted to determine which recipients warrant consideration for induction therapy and the optimal agent.

Purpose The standard technology for heart preservation for transplantation is cold static storange on ice. No temperature control is performed routinley and therefore lower or higher temperatures can occur leading to injury of the graft. The Paragonix SherpaPak™Cardiac Transportation System (CTS) (Paragonix Technologies, MA, USA) has been approved in Europe and the USA for clinical use. This single-use disposable device is designed for cold preservation of donor hearts. We report our first clinical experience with the SherpaPak™ Methods Since November 2018 SherpaPak™ has been used in 6 non consecutive cases in our insitutition. Decision to use the device was done in procurements with either high risk donors, long ischemic times or both. Donor risk was calculated with both the Eurotransplant donor heart risk score and the donor heart risk index (both JHLT 2012). Recipient risk was calculated via the IMPACT score (Ann Thor Surg 2011). Results Median recipient age was 64,5 years. All patients were male and 50% had previous sternotomies (2 VAD patients). Median impact score was 9,5 (17% expected 1 year mortality). All donors were male with a median age of 45,5 years. Median LVEF was 55%. Median norepinephrine support was 0,11mcg/kg/min. Median ET donor risk score was 18 (40% risk of non-acceptance) and median Donor risk score was 7 (18% expected 1-year mortality). Median ischemic time was 290 minutes. Donor hearts were preserved at a median of 5,5C temperature. 4 Patients were successfully weaned from bypass at the first attempt with low inotropic support. 2 Patients developed primary graft dysfunction ISHLT Grade 2 and were weaned from bypass via ECMO. Both heart recovered within 72 hours and ECMO could be explanted. All patients could be extubated within 7 days post transplant and are alive at a median of 6 months post transplant with normal graft function. Conclusion The Paragonix SherpaPak™ provides consistent temperature during transportation of grafts and could be successfully used with long ischemic times and high risk donor hearts.

Purpose Extracorporeal photopheresis (ECP) is an established therapy for treatment of heart transplant rejection. We started a protocol with avoidance of antibody induction therapy and calcineurin inhibitor (CNI) delay in high risk patients after HTX incorporating ECP as rejection prophylaxis. Methods We report our first experience on 16 patients that were treated according to this protocol. Inclusion criteria were: history of cancer (n=4), bridge to transplant via extracorporeal membrane oxygenation (ECMO) (n=4) and eight patients had infections within one month before HTX. None of the patients received antithymocyte globuline (ATG) as induction therapy. Immunosuppression consisted of low dose tacrolimus with a delayed start (2 to 7 days post HTX) mycophenolate mofetil, and steroids. ECP was applied according to the protocol published by M. Barr (NEJM 1998) on days 2+3, 5+6, 10+11, 17+18, 27+28, 2 times every other week for month 2 and 3, and 2 times every 4 weeks month 4 - 6 after HTX. Routine biopsy protocol was performed in weeks 2,3,4, Months 2,3,6 and 12. Results Fifteen of 16 (82%) patients are alive with excellent graft function after a median follow-up of 8.3 (range, 0.25 - 33) months after HTX. Two patients showed biopsy proven signs of cellular rejection. One patient (2R rejection according to histology) was treated with steroids and in another patient with (1R) immunosuppression was switched from MMF to Ev. No signs of antibody-mediated rejection (ABMR) with C4d or C3d positivity were found in regular biopsies. Two patients developed severe pneumonia and one fever of unknown origin. One patient experienced candida septicemia but had candida positive skin swabs at the ECMO cannula insertion region pre-transplant. The latter patient died one week after HTX due to multi organ failure. One patient with history of cancer showed recurrence of disease and died 12 months after transplantation due to disease progression. Conclusion This is the first report on prophylactic ECP with avoidance of induction therapy and CNI delay in HTX patients. Infectious complications remain a problem in this high risk group and occur in approximately 24%. However, ECP is a safe and effective strategy for patients at risk for cancer recurrence or sepsis to avoid organ rejection.

Purpose Long-term survival after heart transplant is still limited due to immunological and drug related adverse events. Immunosuppressive therapy is solely managed via pharmacokinetic analysis and clinical events. TTV (Torque Teno Virus) is a small single-stranded DNA virus associated with increasing viral load under immune compromising conditions. Studies in both kidney and lung transplantation have already shown that the level of plasma TTV - DNA load is associated with the magnitude of immunosuppression. The aim of this prospective observational study was to analyze TTV viral load in patients after heart transplantation (HTX). Methods We prospectively determined the TTV load in 50 heart transplant patients. Samples were collected at pre-transplant and each HTX visit in the out-patient clinic. Viral load analysis was performed by PCR from plasma or serum on the Department of Virology. TTV viral load was compared between pre-transplant and peak levels post transplant. Pre-TX TTV load was compared between different patient groups and between different immunosuppressive protocols after transplantation. Results Patients were transplanted between 1/2016-6/2018. Median age at transplant was 60 (42-67) years and 38% were female. 50%(n=25) of patients were transplanted due to ischemic disease, 44% (n=22) due to dilative Cardiomyopathy and 6% (n=3) due to other disease. 16% of patients were bridged with a mechanical assist device (n=8). Pretransplant TTV levels were 4.4E+00±2.03E+00 cps/ml and significantly increased to 9.39E+00 ±0.75E+00 (p Conclusion TTV viral load increases significantly after heart transplantation and reaches its peak after 90-120 days. VAD pretransplant has an influence of TTV viral load and the choice of calcineurin inhibitor drug seems to be associated with differences in TTV viral load. TTV viral load might be useful as a biomarker for the state of immunosuppression.

BACKGROUND Sympathetic reinnervation after heart transplantation (HTX) is a known phenomenon, which has an impact on patient heart rate variability and exercise capacity. The impact of reinnervation on myocardial structure has not been evaluated yet. PROPOSE To evaluate the feasibility of simultaneous imaging of cardiac reinnervation and cardiac structure using a hybrid PET/MRI system. STUDY TYPE Prospective / pilot study. SUBJECTS Ten patients, 4-21 years after cardiac transplantation. FIELD STRENGTH/SEQUENCE 3 T hybrid PET/MRI system. Cine SSFP, T1 mapping (modified Look-Locker inversion recovery sequence) pre/postcontrast as well as dynamic [11 C]meta-hydroxyephedrine ([11 C]mHED) PET. ASSESSMENT All MRI and PET parameters were evaluated by experienced readers using dedicated postprocessing software packages for cardiac MRI and PET. For all parameters a 16-segment model for the left ventricle was applied. STATISTICAL TESTS Mann-Whitney U-test; Spearman correlations. RESULTS Thirty-six of 160 myocardial segments showed evidence of reinnervation by PET. On a segment-based analysis, mean native T1 relaxation times were nonsignificantly altered in segments with evidence of reinnervation (1305 ± 151 msec vs. 1270 ± 112 msec; P = 0.1), whereas mean extracellular volume (ECV) was significantly higher in segments with evidence of reinnervation (35.8 ± 11% vs. 30.9 ± 7%; P = 0.019). There were no significant differences in wall motion (WM) and wall thickening (WT) between segments with or without reinnervation (mean WM: 7.6 ± 4 mm vs. group B: 9.3 ± 7 mm [P = 0.13]; WT: 79 ± 63% vs. 94 ± 74% [P = 0.27]) under resting conditions. DATA CONCLUSION The assessment of cardiac reinnervation using a hybrid PET/MRI system is feasible. Segments with evidence of reinnervation by PET showed nonsignificantly higher T1 relaxation times and a significantly higher ECV, suggesting a higher percentage of diffuse fibrosis in these segments, without impairment of rest WM and WT. LEVEL OF EVIDENCE 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1326-1335.

Internationally 3% of the donor hearts are distributed to re-transplant patients. In Eurotransplant, only patients with a primary graft dysfunction (PGD) within 1 week after heart transplantation (HTX) are indicated for high urgency listing. The aim of this study is to provide evidence for the discussion on whether these patients should still be allocated with priority. All consecutive HTX performed in the period 1981-2015 were included. Multivariate Cox' model was built including: donor and recipient age and gender, ischaemia time, recipient diagnose, urgency status and era. The study population included 18 490 HTX, of these 463 (2.6%) were repeat transplants. The major indications for re-HTX were cardiac allograft vasculopathy (CAV) (50%), PGD (26%) and acute rejection (21%). In a multivariate model, compared with first HTX hazards ratio and 95% confidence interval for repeat HTX were 2.27 (1.83-2.82) for PGD, 2.24 (1.76-2.85) for acute rejection and 1.22 (1.00-1.48) for CAV (P < 0.0001). Outcome after cardiac re-HTX strongly depends on the indication for re-HTX with acceptable outcomes for CAV. In contrast, just 47.5% of all hearts transplanted in patients who were re-transplanted for PGD still functioned at 1-month post-transplant. Alternative options like VA-ECMO should be first offered before opting for acute re-transplantation. ispartof: TRANSPLANT INTERNATIONAL vol:31 issue:11 pages:1223-1232 ispartof: location:Switzerland status: published

BACKGROUND. Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability to assess injury, potentially confusing it with rejection, whereas molecular changes have potential to distinguish injury from rejection. Building on previous studies of transcripts associated with T cell–mediated rejection (TCMR) and antibody-mediated rejection (ABMR), we explored transcripts reflecting injury. METHODS. Microarray data from 889 prospectively collected endomyocardial biopsies from 454 transplant recipients at 14 centers were subjected to unsupervised principal component analysis and archetypal analysis to detect variation not explained by rejection. The resulting principal component and archetype scores were then examined for their transcript, transcript set, and pathway associations and compared to the histology diagnoses and left ventricular function. RESULTS. Rejection was reflected by principal components PC1 and PC2, and by archetype scores S2TCMR, and S3ABMR, with S1normal indicating normalness. PC3 and a new archetype score, S4injury, identified unexplained variation correlating with expression of transcripts inducible in injury models, many expressed in macrophages and associated with inflammation in pathway analysis. S4injury scores were high in recent transplants, reflecting donation-implantation injury, and both S4injury and S2TCMR were associated with reduced left ventricular ejection fraction. CONCLUSION. Assessment of injury is necessary for accurate estimates of rejection and for understanding heart transplant phenotypes. Biopsies with molecular injury but no molecular rejection were often misdiagnosed rejection by histology. TRAIL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02670408","term_id":"NCT02670408"}}NCT02670408 FUNDING. Roche Organ Transplant Research Foundation, the University of Alberta Hospital Foundation, and Alberta Health Services.

Despite the improvement in medical therapy for heart failure and the advancements in mechanical circulatory support, heart transplantation (HT) still remains the best therapeutic option to improve survival and quality of life in patients with advanced heart failure. Nevertheless, HT recipients are exposed to the risk of several potential complications that may impair their outcomes. In this article, we aim to provide a practical and scholarly framework for clinicians approaching heart transplant medicine, as well as a concise update for the experienced readers on the most relevant post-HT complications. While recognizing that most of the treatments herein discussed are based more on experience than on solid scientific evidence, significant step forward has been made in particular in the recognition and management of primary graft dysfunction, antibody-mediated rejection, and renal dysfunction. Complications after HT may vary according to the time from surgery and can be related to graft function and pathology or to diseases and dysfunctions occurring in other organs or systems, mainly as side effects of immunosuppressive drugs and progression of pre-existing conditions. Future research needs to focus on improving precision diagnostics of causes of graft dysfunction and on reaching an optimal and customized balance between efficacy and toxicities of immunosuppressive strategies.