Role of HLA matching and donor specific antibody development in long-term survival, acute rejection and cardiac allograft vasculopathy.

Although there are different data supporting benefits of HLA matching in kidney transplantation, its role in heart transplantation is still unclear. HLA mismatch (MM) between donor and recipient can lead to the development of donor-specific antibodies (DSA) which produces negative events on the outcome of heart transplantation. Moreover, DSAs are involved in the development of antibody-mediated rejection (AMR) and are associated with an increase in cardiac allograft vasculopathy (CAV). In this study it is analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, AMR and CAV in heart transplantation. For this retrospective study are recruited heart transplanted patients at the Cardiac Transplantation Centre of Naples between 2000 and 2019. Among the 155 heart transplant patients, the mean number of HLA-A, B, -DR MM (0 to 6) between donor and recipient was 4.5 ± 1.1. The results show a negative association between MM HLA-DR and survival (p = 0.01). Comparison of patients with 0-1 MM at each locus to all others with 2 MM, for both HLA class I and class II, has not showed significant differences in the development of CAV. Our analysis detected DSA in 38.1% of patients. The production of de novo DSA reveals that there is not an influence on survival (p = 0.72) and/or AMR (p = 0.39). Instead, there is an association between the production of DSA class II and the probability of CAV development (p = 0.03). Mean fluorescence intensity (MFI) values were significantly higher in CAV-positive patients that CAV-negative patients (p = 0.02). Prospective studies are needed to evaluate HLA class II matching as an additional parameter for heart allocation, especially considering the increment of waiting list time.

European multicenter study on the real-world use and clinical impact of extracorporeal photopheresis after heart transplantation.

BACKGROUND: Aim of this study was to describe the real-world use of extracorporeal photopheresis (ECP) and assess its impact on clinical outcomes in the modern era of heart transplantation. METHODS: Seven transplant centers from 5 European countries participated in this retrospective, observational, single-arm chart review study. All patients received ECP after heart transplantation in 2015 or later. Data were extracted from medical records between November 2020 and December 2021. RESULTS: Overall, 105 patients were enrolled and followed for an average of 2 years after initiation of ECP. Reasons to start ECP were acute cellular rejection (35.2%), rejection prevention (32.4%), mixed rejection (18.1%), and antibody-mediated rejection (14.3%). Rejection ISHLT grades improved from start to end of ECP treatment in 92% of patients treated with ECP for rejection. Of patients who started ECP to prevent rejection, 88% remained free from any rejection despite a reduction of calcineurin inhibitors. Overall survival was 95%, and no deaths were related to ECP. Safety events occurred in 18 patients, of which 13 experienced complications with venous access. CONCLUSIONS: This study, the largest European ECP study in heart transplantation, demonstrates that ECP can effectively be used to treat different rejection types and to prevent rejection in the modern era of immunosuppression. Patients with rejections who have received ECP have shown high response as measured by histological improvements in ISHLT classification. A high percentage of patients in the prevention group remained free from rejection despite reduction in immunosuppression, in particular calcineurin inhibitors.

ESOT Consensus Platform for Organ Transplantation: Setting the Stage for a Rigorous, Regularly Updated Development Process.

The European Society for Organ Transplantation (ESOT) has created a platform for the development of rigorous and regularly updated evidence based guidelines for clinical practice in the transplantation field. A dedicated Guideline Taskforce, including ESOT-council members, a representative from the Centre for Evidence in Transplantation, editors of the journal Transplant International has developed transparent procedures to guide the development of guidelines, recommendations, and consensus statements. During ESOT's first Consensus Conference in November 2022, leading experts will present in-depth evidence based reviews of nine themes and will propose recommendations aimed at reaching a consensus after public discussion and assessment by an independent jury. All recommendations and consensus statements produced for the nine selected topics will be published including the entire evidence-based consensus-finding process. An extensive literature review of each topic was conducted to provide final evidence and/or expert opinion.

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts.

BACKGROUND: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. OBJECTIVES: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. METHODS: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis. RESULTS: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. CONCLUSION: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT03546062.

Predicting major events in ambulatory patients with advanced heart failure awaiting heart transplantation: a pilot study.

AIMS: In heart failure (HF), prognostic risk scores focus on all-cause mortality prediction. However, in advanced HF (AdHF) ambulatory patients awaiting heart transplantation (HTx), hospitalizations for acutely decompensated/worsening HF are relevant to clinical decision-making, but unpredicted by common risk functions. METHODS: Among consecutive ambulatory patients added to the waitlist for HTx, event discriminators within 2 years from recruitment were assessed prospectively by area under the curve from receiver-operating characteristic curves, and by Cox proportional hazards models. Primary composite end points included the first between all-cause mortality and acutely decompensated/worsening HF requiring hospitalization and specific treatments. RESULTS: In 89 patients, 36 primary composite events were recorded in a 2-year follow-up (40% of the study sample), and associated with nonischemic etiology and nonsinus rhythm, with lower systolic blood pressure (BP), lower plasma sodium and hemoglobin concentrations, and with higher N-terminal pro-brain natriuretic peptide (NT-proBNP), larger left ventricular (LV) dimensions and lower LV ejection fraction, greater proportion of significant mitral regurgitation, lower tricuspid annulus peak systolic excursion (TAPSE), lower percentage of predicted distance at 6-minute walking test (%p6MWT) and lower global symptoms burden by the Kansas City Cardiomyopathy Questionnaire, lower peak oxygen uptake by cardiopulmonary exercise, and higher wedge pressure by right heart catheterization, as compared with those with no events (P < 0.05). Only Metabolic Exercise Cardiac Kidney Index (MECKI) at recruitment was higher with patients reporting events, which predicted composite end points in addition to and independently of NT-proBNP, and lower systolic BP (all P < 0.05). In an alternative risk model, severe mitral regurgitation and lower TAPSE replaced MECKI and BP but not NT-proBNP (all P < 0.01). CONCLUSION: Higher NT-pro-BNP, lower systolic BP and higher MECKI may contribute to predicting all-cause death and acutely decompensated/worsening HF among ambulatory patients awaiting HTx, with lower TAPSE and severe mitral regurgitation representing further alternative independent prognosticators.

Human Cardiac Progenitor Cell-Derived Extracellular Vesicles Exhibit Promising Potential for Supporting Cardiac Repair in Vitro.

Although human Cardiac Progenitor Cells (hCPCs) are not retained by host myocardium they still improve cardiac function when injected into ischemic heart. Emerging evidence supports the hypothesis that hCPC beneficial effects are induced by paracrine action on resident cells. Extracellular vesicles (EVs) are an intriguing mechanism of cell communication based on the transport and transfer of peptides, lipids, and nucleic acids that have the potential to modulate signaling pathways, cell growth, migration, and proliferation of recipient cells. We hypothesize that EVs are involved in the paracrine effects elicited by hCPCs and held accountable for the response of the infarcted myocardium to hCPC-based cell therapy. To test this theory, we collected EVs released by hCPCs isolated from healthy myocardium and evaluated the effects they elicited when administered to resident hCPC and cardiac fibroblasts (CFs) isolated from patients with post-ischemic end-stage heart failure. Evidence emerging from our study indicated that hCPC-derived EVs impacted upon proliferation and survival of hCPCs residing in the ischemic heart and regulated the synthesis and deposition of extracellular-matrix by CFs. These findings suggest that beneficial effects exerted by hCPC injection are, at least to some extent, ascribable to the delivery of signals conveyed by EVs.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.

BACKGROUND: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment. METHODS: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX. RESULTS: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment. CONCLUSION: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.

Mini-organs forum: how to advance organoid technology to organ transplant community.

The generation of human mini-organs, the so-called organoids, is one of the biggest scientific advances in regenerative medicine. This technology exploits traditional three-dimensional culture techniques that support cell-autonomous self-organization responses of stem cells to derive micrometer to millimeter size versions of human organs. The convergence of the organoid technology with organ transplantation is still in its infancy but this alliance is expected to open new venues to change the way we conduct both transplant and organoid research. In this Forum we provide a summary on early achievements facilitating organoid derivation and culture. We further discuss on early advances of organoid transplantation also offering a comprehensive overview of current limitations and challenges to instruct organoid maturation. We expect that this Forum sets the ground for initial discussions between stem cell biologists, bioengineers, and the transplant community to better direct organoid basic research to advance the organ transplantation field.

T- and B-cell therapy in solid organ transplantation: current evidence and future expectations.

Cell therapy has emerged as an attractive therapeutic option in organ transplantation. During the last decade, the therapeutic potency of Treg immunotherapy has been shown in various preclinical animal models and safety was demonstrated in first clinical trials. However, there are still critical open questions regarding specificity, survival, and migration to the target tissue so the best Treg population for infusion into patients is still under debate. Recent advances in CAR technology hold the promise for Treg-functional superiority. Another exciting strategy is the generation of B-cell antibody receptor (BAR) Treg/cytotoxic T cells to specifically regulate or deplete alloreactive memory B cells. Finally, B cells are also capable of immune regulation, making them promising candidates for immunomodulatory therapeutic strategies. This article summarizes available literature on cell-based innovative therapeutic approaches aiming at modulating alloimmune response for transplantation. Crucial areas of investigation that need a joined effort of the transplant community for moving the field toward successful achievement of tolerance are highlighted.

Risk Factors and Outcome of Multidrug-Resistant Infections after Heart Transplant: A Contemporary Single Center Experience.

(1) Background: The aim of this study was to assess risk factors for multidrug-resistant/extensively drug-resistant (MDR/XDR) bacterial infections in heart transplant (HT) patients within three months after surgery and its impact on patient outcome. (2) Methods: Retrospective analysis of clinical, hemato-chemical, imaging, treatment and outcome data from 47 heart transplant recipients from January 2016 to December 2018. MDR/XDR infections were compared to non-MDR/XDR and noninfected patients. (3) Results: Most participants were males, median age 51 years: 35 (74.5%) developed an infection after HT; 14 (29.8%) were MDR/XDR infections. Prolonged hospital stay before HT correlated to MDR/XDR infection (p < 0.001). Sequential organ failure assessment (SOFA) score at sampling day was higher in MDR/XDR (p = 0.027). MDR/XDR were mostly blood-stream (BSI) (p = 0.043) and skin-soft tissue (SSTI) (p = 0.047) infections. Gram-negative infections were the most frequent, specifically carbapenem-resistant Klebsiella pneumoniae. Antibiotic therapy duration for MDR/XDR infections was longer (p = 0.057), eradication rate lower (p = 0.083) and hospital stay longer (p = 0.005) but not associated with a worse outcome. (4) Conclusions: MDR/XDR infections affect compromised HT recipients with a history of prolonged hospitalization, causing a lower rate of eradication and increased hospital stay. These frequently present as BSI and SSTI. We emphasize the need to prevent contamination of central venous catheters and the surgical site.

A new hemodynamic index to predict late right failure in patients implanted with last generation centrifugal pump.

BACKGROUND: Right ventricular failure (RVF) is a severe event that increases perioperative mortality after left ventricle assist device (LVAD) implantation. Right ventricular (RV) function is particularly affected by the LVAD speed by altering RV preload and afterload as well as the position of the interventricular septum. However, there are no studies focusing on the relationship between pump speed optimization and risk factors for the development of late RVF. METHODS: Between 2015 and 2019, 50 patients received LVAD implantation at San Camillo Hospital in Rome. Of these, 38 who underwent pump speed optimization were included. Post-optimization hemodynamic data were collected. We assessed a new Hemodynamic Index (HI), calculated as follows:  HI = MAP × PCWP CVP × RPM set RPM max , to determine the risk of late RVF, which was defined as the requirement for rehospitalization and inotropic support. RESULTS: Ten patients had late RVF after LVAD implantation. Five patients required diuretic therapy and speed optimization. Three patients required inotropic support with adrenaline 0.05 µg/kg/min. Two patients needed prolonged continuous venovenous hemofiltration and high dose inotropic support. Multivariate analysis revealed that a low HI (odds ratio 11.5, 95% confidence interval, 1.85-65.5, p [.003]) was an independent risk factor for late RVF after LVAD implantation. CONCLUSION: We demonstrated a low HI being a significant risk factor for the development of RVF after LVAD implantation. We suggest implementing HI as a decision support tool for goal-direct optimization of the device aiming to reduce the burden of late-onset RVF during the follow-up.

[Cardiology units and organizational models of heart transplantation centers in Italy: a survey by the Italian Association of Hospital Cardiologists-Italian Society of Organ Transplantation (ANMCO-SITO)]. / Cardiologie e modelli organizzativi dei centri trapianto di cuore: indagine ANMCO-SITO.

BACKGROUND: The extent and quality of the involvement of cardiology units in health programs delivered by Italian centers for heart transplantation (HTx) have not been investigated previously. METHODS: The Italian Association of Hospital Cardiologists (ANMCO) and the Italian Society for Organ Transplantation (SITO) developed and delivered a nationwide survey to the Directors of the Italian centers for HTx to investigate the extent to which cardiology units contribute to HTx programs. The survey investigated: (i) the organization of the centers and institutional frame under which cardiology units contributed to HTx programs; (ii) the volumes of procedures and clinical services delivered by cardiology units to HTx centers for listing patients, following those waiting for HTx, managing acute heart failure, selecting and allocating organs to recipients, following and managing organ rejection after HTx. RESULTS: Of the 14 Italian centers involved, 13 provided full responses to the survey. Between 2017-2019, on average, 46% of the respondents performed up to 15 HTx/year, and additional 46% performed between 16 and 30 HTx/year. Of the respondents, 62% were included in a department of cardiac Surgery which did not include a cardiology unit; furthermore, 54% declared not to be included in a formal network for heart failure management. Cardiology units were the source for referrals of candidates to HTx in 85% cases. Of the respondents, 15% declared to be able to provide cardiological services thorough intra-center multidisciplinary team including cardiologists, whereas cardiological services were outsourced in 61% of the respondents. The clinical follow-up of patients waiting for HTx was performed directly by surgeons in 38% of the respondents. Worsening heart failure was managed directly by the HTx center in 33% of the cases using dedicated beds. Post-HTx follow-up, including endomyocardial biopsy, involved external cardiology units in less than 25% of the centers. CONCLUSIONS: The ANMCO-SITO survey shows that in Italy a very wide variability exists in terms of organization of HTx centers and their relationships with cardiology units for delivering specific cardiological services and procedures. In large majority, patient referral to HTx centers is mediated by cardiology units, whereas HTx was rarely included in a structured cardiological network for heart failure management.

Post-heart transplantation lymphoproliferative diseases (PTLDs) and the diagnostic role of [18f] FDG-PET/CT.

BACKGROUND: The incidence of cancer is higher in transplant patients than in the normal population, mostly due to the assumption of immunosuppressants able to reduce the possibility of rejection. In addition, immunocompromised patients have a greater susceptibility to EBV, HPV and HIV, infectious agents that by themselves may favor the onset of malignancies. Post-transplant lymphoproliferative diseases (PLDs) are among the most frequent neoplasms in transplant patients which like other aggressive neoplasms may be identified by the [18f] fluoro-D-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). METHODS: We evaluated the clinical use of FDG-PET/CT in detecting PTLDs and other neoplasms performed at the lowest clinical or laboratory suspicion of malignancy in 127 consecutive subjects who underwent heart transplantation. RESULTS: A SUV>4 more confirmed the suspect of malignancy and induced us to further investigations. Of the 127 transplant subjects who underwent FDG-PET/CT, 64 showed a SUV value >4. Of these 64, 8 had PTLDs, 49 other neoplasms (urinary tract tumors, thyroid cancer, HPV cancer related, Kaposi' sarcoma and EBV related head and neck neoplasms) and 7 patients with chronic non-neoplastic inflammatory diseases. CONCLUSIONS: In the present study, FDG-PET/CT examination was of great use for an early identification and for an early treatment of PTLDs and other neoplasms.