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The proposed donor heart selection guidelines provide evidence-based and expert-consensus recommendations for the selection of donor hearts following brain death. These recommendations were compiled by an international panel of experts based on an extensive literature review. © 2022 International Society for Heart and Lung Transplantation

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

OBJECTIVE Tricuspid regurgitation (TR) in heart transplant patients is associated with poor outcome. The increased risk for surgical and post-operative complications might be reduced in these vulnerable patients by transcatheter therapies. METHODS All patients with prior heart transplantation (HTX) undergoing transcatheter edge-to-edge repair in tricuspid position (T-TEER) were prospectively enrolled in an institutional registry. RESULTS Seven transplanted patients (5/7 female) at a mean age of 53 [48; 64] and median TRI-SCORE of 14 [7; 22] underwent T-TEER to treat symptomatic TR ≥ IV in an elective (n = 6) and urgent (n = 1) setting, respectively. Median time from HTX to T-TEER was 13 years. A total of 2 (n = 4) and 3 (n = 3) clips were implanted with a technical success in 6/7 (one single device detachment). TR reduction was effective and durable within a median echocardiographic follow-up time of 10 months (TR baseline vs last follow-up: p = 0.03). Further, a significant right ventricular remodelling (right ventricular end-diastolic diameter: 50 mm to 36 mm, p = 0.02), decrease in the inferior vena cava diameter (24 mm to 18 mm, p = 0.04) and in the gamma-glutamyl-transferase (255 U/l to 159 U/l, p = 0.04) was found. Four of 7 patients were free of cardiovascular death (n = 1, 267 days after T-TEER), cardiac redo surgery (n = 1), heart failure hospitalization (n = 2) and had no further clinical signs of right heart failure. CONCLUSIONS T-TEER after HTX demonstrates to be feasible and effective regarding TR reduction in a short-term follow-up. The initial results may pave the way of a novel approach in TR management in HTX patients.

Controlled organ donation after circulatory determination of death is increasingly being used for the donation of organs also in thoracic transplantation. This document outlines the position of the International Society for Heart and Lung Transplantation on thoracic organ transplantation in circulatory determination of death. The document also includes a position regarding some of the methods applied to ensure the viability of Donation after Circulatory Death organs retrieved after certification of death.

BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

For over 30 years, the International Society for Heart and Lung Transplantation (ISHLT) International Thoracic Organ Transplant (TTX) Registry has gathered data regarding transplant procedures, donor and recipient characteristics, and outcomes from a global community of transplant centers. Almost 70,000 adult lung transplant procedures have been reported to the Registry since its inception, each one providing an opportunity for a recipient with end-stage lung disease to regain quality of life and longevity. With each year’s report, we provide more detailed analyses on a particular focus theme important to recipient outcomes. Since 2013, these have been donor and recipient age; retransplantation; early graft failure; indication for transplant; allograft ischemic time; multiorgan transplantation; and donor and recipient size matching.(1–7) In response to a changing regulatory environment, the ISHLT TTX Registry is undergoing an update in data acquisition, and the patient cohort examined in this report is therefore derived from the same data source or datasets as that examined in the 2019 annual reports.(2,8–10) We refer the reader to the 2019 and prior reports for a detailed description of the baseline characteristics of the cohort, and additional core analyses not directly related to the focus explored in this year’s report. To complement the 2020 report which focussed on donor characteristics, the goal of this year’s report was to focus entirely on changes in recipient factors over the past 3 decades and to identify important recipient characteristics and transplant processes that may influence post-transplant outcomes. Due to small numbers, heart-lung transplant recipient characteristics and transplant outcomes have not been included. This 38th annual adult lung transplant report is hence basedon data submitted to the ISHLT TTX Registry on 67,493 adult recipients of deceased recipient transplants between January 1, 1992 and June 30, 2018.

Polycytemia vera (PV) is a rare myeloproliferative neoplasm associated with microcirculatory disturbances, thrombosis and bleeding. Patients suffering from PV have a high risk of perioperative adverse events, but the literature regarding on‐pump procedures in PV patients is scarce. We report two cases of acute and severe oxygenator failure during cardiopulmonary bypass and present valid exit scenarios.

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 ).

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).

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.

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).

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 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.

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

Purpose In heart and kidney transplants, rejection is a major cause of graft loss. In kidneys, antibody-mediated rejection (ABMR) is more important than T cell-mediated rejection (TCMR), and molecules predict graft loss better than histology (JASN 26 (7):1711-1720, 2015). We examined the relative importance of ABMR vs TCMR in heart transplant endomyocardial biopsies (EMBs), and the molecules predicting graft survival. Methods The INTERHEART population includes 1219 transplant biopsies from 8 centers in Canada, USA, Australia and Europe. Gene expression was studied using microarrays, selecting the most recent biopsy per patient. Random forest classifiers were used to assess predictive accuracy and determine the importance of molecular predictors, including gene sets and scores from analyses in a reference set of 889 EMBs. Results We studied 3-year survival in 484 patients with follow-up times. Graft failure occurred in 60 patients. Median follow-up was 435 days; biopsies were mainly for indications. Surprisingly, TCMR was a greater short-term hazard than ABMR. The molecular archetype clusters for TCMR and injury (Fig. 1) had the highest risk of graft failure. Fig. 2 combines these clusters since they have similar characteristics. Conclusion Unlike kidneys, graft loss (particularly within one year) after EMB is highly associated with TCMR but not ABMR. TCMR may reflect failure of immunosuppression or non-adherence. This difference between the heart and renal transplant populations raises the possibility that TCMR is relatively more destructive, and ABMR less destructive, in heart than in kidney transplants. ClinicalTrials.gov # NCT02670408

Purpose Hyperlipidemia is a major factor in the development of graft vasculopathy (GVP) after heart transplant. The incidence of hyperlipidaemia in heart transplant (HTX) patients under immunosuppressive therapy is 74% in the first year, and 91% in the first five years. Lipid-lowering therapy with statins presents a great challenge due to interactions and adverse effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have already proven very effective in high-risk cardiovascular patients. In our centre, PCSK9-inhibitors have been administered to selected HTX-patients, in which the target LDL-Cholesterol of 100mg/dl could not be reached with reasonable doses of statins and/or Etizimib. Methods In the period 02/2017 to 06/2018, 15 adult HTX-patients (median age 55.3, (25-75%: 48.2-64.6), 25% female) were selected. The patients were at a median of 35.1 (25-75%: 28.4-78.6) months post-HTX. The selected patients were evaluated together in the lipid clinic (licenced for PCSK9-inhibitors). Therapy was initiated with Alirocumab 75mg. Statin-therapy was changed and appropriately documented when changes in lipid-parameters and/or adverse effects occurred. In order to evaluate incidence and prevalence of myopathy and hepatotoxicity, CK and liver enzymes and were measured 1, 3, 6, 9, 12, and 15 months post conversion. Analysis of effectiveness were conducted by measuring blood lipids (LDL-C, HDL, total cholesterol, triglycerides, and LP(a)). Results Total cholesterol (231 (198-245) vs. 151 (139-175) mg/dl; p Conclusion Therapy with PCSK9-inhibitors (Alirocumab) constitutes an effective and safe option in therapy of hyperlipidaemia after heart transplant. Under treatment liver and kidney parameters stayed stable, while a significant reduction of lipid levels could be achieved. To evaluate the long-term effects of PCSK9-Inhibitors longer observation period is necessary.

Malignancy after solid organ transplantation remains a major cause of posttransplant mortality. The mammalian target of rapamycin (mTOR) inhibitor class of immunosuppressants exerts various antioncogenic effects, and the mTOR inhibitor everolimus is licensed for the treatment of several solid cancers. In kidney transplantation, evidence from registry studies indicates a lower rate ofde novomalignancy under mTOR inhibition, with some potentially supportive data from randomized trials of everolimus. Case reports and small single-center series have suggested that switch to everolimus may be beneficial following diagnosis of posttransplant malignancy, particularly for Kaposi’s sarcoma and nonmelanoma skin cancer, but prospective studies are lacking. A systematic review has shown mTOR inhibition to be associated with a significantly lower rate of hepatocellular carcinoma (HCC) recurrence versus standard calcineurin inhibitor therapy. One meta-analysis has concluded that patients with nontransplant HCC experience a low but significant survival benefit under everolimus monotherapy, so far unconfirmed in a transplant population. Data are limited in heart transplantation, although observational data and case reports have indicated that introduction of everolimus is helpful in reducing the recurrence of skin cancers. Overall, it can be concluded that, in certain settings, everolimus appears a promising option to lessen the toll of posttransplant malignancy.

Despite the successes from refined peri-operative management techniques and immunosuppressive therapies, antibodies remain a serious cause of morbidity and mortality for patients both before and after heart transplantation. Patients awaiting transplant who possess antibodies against human leukocyte antigen are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. The number of pre-sensitized patients has been increasing, a trend that is likely due to the increased use of mechanical circulatory support devices. Even patients who are not pre-sensitized can go on to produce donor-specific antibodies after transplant, which are associated with worse outcomes. The difficulty in managing antibodies is uncertainty over which antibodies are of clinical relevance, which patients to treat, and which treatments are most effective and safe. There is a distinct lack of data from prospective trials. An international consensus conference was organized and attended by 103 participants from 75 centers to debate contentious issues, determine the best practices, and formulate ideas for future research on antibodies. Prominent experts presented state-of-the-art talks on antibodies, which were followed by group discussions, and then, finally, a reconvened session to establish consensus where possible. Herein we address the discussion, consensus points, and research ideas.

Objectives Fixed pulmonary hypertension (fPH) is a contraindication for heart transplantation (HTX). Left ventricular assist device (LVAD) implantation as a bridge to candidacy can reverse fPH in patients with terminal heart failure by chronic left ventricular unloading. We report our institutional experience with terminal heart failure patients and fPH that were successfully bridged to candidacy and underwent subsequent HTX. Methods We retrospectively reviewed the data of 79 patients with terminal heart failure and fPH who were successfully bridged to candidacy for HTX with 6 different LVAD devices at our centre from October 1998 to September 2016 (Novacor n = 4, MicroMed DeBakey n = 29, DuraHeart n = 2, HeartMate II n = 14, HVAD n = 29 and MVAD n = 1). Median duration of LVAD support was 288 days (range 45-2279 days). Within the same timeframe, a control group of 48 patients underwent HTX after bridge-to-transplant LVAD therapy for reasons other than PH. Study end points were (i) development of fPH after LVAD implantation, (ii) post-transplant outcomes and (iii) incidence of severe adverse events. Results Pulmonary vascular resistance, assessed by vasodynamic catheterization, was 4.3 ± 1.8 WU before LVAD implantation. After a median support period of 89 days (interquartile range 4-156 days), pulmonary vascular resistance decreased to 2.0 ± 0.9 WU (P ≤ 0.001), and patients were listed for HTX. Median duration of LVAD support in the study group was 288 days (45-2279 days). We observed 2 patients (2.5%) with acute right heart failure who required extracorporeal mechanical support after HTX in the study group. Long-term post-transplant survival between the study group (3 years: 83.5%, 5 years: 81.0%) and the control group (3 years: 87.5%, 5 years: 85.4%) was comparable (log-rank: P = 0.585). Conclusions LVAD implantation as a bridge to candidacy reverses fPH in patients with terminal heart failure. Post-HTX survival is excellent and comparable to results obtained in patients without fPH at the time of HTX listing.

Background. Because of improved long-term survival after heart transplantation (HTx), late graft pathologies such as valvular disease or cardiac allograft vasculopathy (CAV) might need surgical intervention to enhance longer survival and ensure quality of life. To this date, there exist no guidelines for indication of cardiac surgery other than retransplantation after HTx. Methods. In this retrospective, single-center study, we evaluated patients who underwent cardiac surgery after HTx at our institution. Results. Between March 1984 and October 2016, 17 (1.16%) of 1466 HTx patients underwent cardiac surgery other than retransplantation after HTx. Indication were valvular disease (n = 7), CAV (n = 6), and other (n = 4). Of these, 29.4% (n = 5) were emergency procedures and 70.6% were elective cases. Median age at time of surgery was 61 years (interquartile range, 52-66 years); 82.4% (n = 14) were male. Median time to surgery after HTx was 9.3 years (2.7-11.1 years). In-hospital, mortality was 11.8% (n = 2); later need of retransplantation was 11.8% (n = 2) due to progressing CAV 3 to 9 months after surgery. One-year survival was 82.35%; overall survival was 47.1% (n = 8) with a median follow-up of 1477 days (416-2135 days). Overall survival after emergency procedures was 209 days (36-1119.5 days) whereas, for elective procedures, it was 1583.5 days (901.5-4319 days). Conclusions. Incidence of cardiac surgery after HTx in our cohort was low (1.16%) compared with that of other studies. In elective cases, long-term survival was good.

BACKGROUND: Decision-making when offered a donor heart for transplantation is complex, and supportive data describing outcomes according to acceptance or non-acceptance choices are sparse. Our aim was to analyze donor heart acceptance decisions and associated outcomes at a single center, and after subsequent acceptance elsewhere.METHODS: This investigation was a retrospective analysis of data obtained from the University of Vienna Medical Center and Eurotransplant centers for the period 2001 to 2015RESULTS: Our center accepted 31.8% (699 of 2,199) of donor hearts offered. Unlike other centers, the acceptance rate, with or without transplantation, did not increase over time. Of the donor hearts rejected by our center, 38.1% (572 of 1,500) were later accepted elsewhere. Acceptance rates were twice as high for donor hearts initially rejected for non-quality reasons (339 of 601, 56.4%) compared with initial rejection for quality reasons (233 of 899, 25.9%). Three-year patient survival rate was 79% at Vienna; for donor hearts initially rejected by Vienna for non-quality reasons or quality reasons, it was 73% and 63%, respectively (p CONCLUSIONS: A less restrictive policy for accepting donor hearts at our center, particularly regarding rejection for non-quality reasons or for positive virology, high catecholamine levels, longer ischemic time, or low ejection fraction, could expand our donor pool while maintaining good outcomes. (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved.

Background Higher dose norepinephrine donor support is a frequent reason for donor heart decline, but its associations with outcomes after heart transplantation are unclear. Methods We retrospectively analyzed 965 patients transplanted between 1992 and 2015 in the Heart Transplant Program Vienna. Stratification was performed according to donor norepinephrine dose administered before organ procurement (Group 0: 0 µg/kg/min; Group 1: 0.01 to 0.1 µg/kg/min; Group 2: >0.1 µg/kg/min). Sub-stratification of Group 2 was performed for comparison of high-dose subgroups (Group HD 1: 0.11 to 0.4 µg/kg/min; Group HD 2: >0.4 µg/kg/min). Associations between groups and outcome variables were investigated using a multivariable Cox proportional hazards model and logistic regression analyses. Results Donor norepinephrine dose groups were not associated with overall mortality (Group 1 vs 0: hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.87 to 1.43; Group 2 vs 0: HR 1.07, 95% CI 0.82 to 1.39; p = 0.669). No significant group differences were found for rates of 30-day mortality ( p = 0.35), 1-year mortality ( p = 0.897), primary graft dysfunction ( p = 0.898), prolonged ventilation ( p = 0.133) and renal replacement therapy ( p = 0.324). Groups 1 and 2 showed higher rates of prolonged intensive care unit stay (18.9% vs 28.5% vs 27.5%, p = 0.005). High-dose subgroups did not differ significantly in 1-year mortality (Group HD 1: 14.3%; Group HD 2: 17.8%; p = 0.549). Conclusions Acceptance of selected donor hearts supported by higher doses of norepinephrine may be a safe option to increase the donor organ pool.