The article examines the history of heart transplantation in experiment and in clinical practice. The part focusing on experimental transplantation covers the period from the very first attempts in 1905 up to the introduction of the current technique. The second part provides an outline of the history of transplantation in clinical practice including immunosuppressive therapy and rejection control. The first heart transplantation in the Czech Republic was performed in 1984.

The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

Background Patients with obesity and advanced heart failure face unique challenges on the path to heart transplantation. There are limited data on waitlist and transplantation outcomes in this population. We aimed to evaluate the impact of obesity on heart transplantation outcomes, and to investigate the effects of the new organ procurement and transplantation network allocation system in this population. Methods and Results This cohort study of adult patients listed for heart transplant used the United Network for Organ Sharing database from January 2006 to June 2020. Patients were stratified by body mass index (BMI) (18.5-24.9, 25-29.9, 30-34.9, 35-39.9, and 40-55 kg/m2). Recipient characteristics and donor characteristics were analyzed. Outcomes analyzed included transplantation, waitlist death, and posttransplant death. BMI 18.5 to 24.9 kg/m2 was used as the reference compared with progressive BMI categories. There were 46 645 patients listed for transplantation. Patients in higher BMI categories were less likely to be transplanted. The lowest likelihood of transplantation was in the highest BMI category, 40 to 55 kg/m2 (hazard ratio [HR], 0.19 [0.05-0.76]; P=0.02). Patients within the 2 highest BMI categories had higher risk of posttransplantation death (HR, 1.29; P<0.001 and HR, 1.65; P<0.001, respectively). Left ventricular assist devices among patients in obese BMI categories decreased after the allocation system change (P<0.001, all). After the change, patients with obesity were more likely to undergo transplantation (BMI 30-35 kg/m2: HR, 1.31 [1.18-1.46], P<0.001; BMI 35-55 kg/m2: HR, 1.29 [1.06-1.58]; P=0.01). Conclusions There was an inverse relationship between BMI and likelihood of heart transplantation. Higher BMI was associated with increased risk of posttransplant mortality. Patients with obesity were more likely to undergo transplantation under the revised allocation system.

Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs.

Background Children with Down syndrome (DS) have a high risk of cardiac disease that may prompt consideration for heart transplantation (HTx). However, transplantation in patients with DS is rarely reported. This project aimed to collect and describe waitlist and post- HTx outcomes in children with DS. Methods and Results This is a retrospective case series of children with DS listed for HTx. Pediatric HTx centers were identified by their participation in 2 international registries with centers reporting HTx in a patient with DS providing detailed demographic, medical, surgical, and posttransplant outcome data for analysis. A total of 26 patients with DS were listed for HTx from 1992 to 2020 (median age, 8.5 years; 46% male). High-risk or failed repair of congenital heart disease was the most common indication for transplant (N=18, 69%). A total of 23 (88%) patients survived to transplant. All transplanted patients survived to hospital discharge with a median posttransplant length of stay of 22 days. At a median posttransplant follow-up of 2.8 years, 20 (87%) patients were alive, 2 (9%) developed posttransplant lymphoproliferative disorder, and 8 (35%) were hospitalized for infection within the first year. Waitlist and posttransplant outcomes were similar in patients with and without DS (P=non-significant for all). Conclusions Waitlist and post-HTx outcomes in children with DS selected for transplant listing are comparable to pediatric HTx recipients overall. Given acceptable outcomes, the presence of DS alone should not be considered an absolute contraindication to HTx.

Coronavirus disease 2019 (COVID-19) has significantly impacted the healthcare landscape in the United States in a variety of ways including a nation-wide reduction in operative volume. The impact of COVID-19 on the availability of donor organs and the impact on solid organ transplant remains unclear. We examine the impact of COVID-19 on a single, large-volume heart transplant program.

The value of Forrester's perfusion/congestion profiles assessed by invasive catheter evaluation in non-inotrope advanced heart failure patients listed for heart transplant (HT) is unclear. We aimed to assess the value of haemodynamic evaluation according to Forrester's profiles to predict events on the HT waitlist.

Heart transplantation is the gold standard therapy for end-stage heart failure; however, it is limited by a shortage of available donors. In recent years, heart transplantations have been performed using marginal donor hearts with valvular and/or congenital cardiac abnormalities.

Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR.

To evaluate patient selection for heart transplantation or dynamic cardiomyoplasty.

to analyze the occurrence and predisposing factors for surgical site infection in patients submitted to heart transplantation, evaluating the relationship between cases of infections and the variables related to the patient and the surgical procedure.

Pneumonia is a frequent complication in patients undergoing heart transplantation (HTx) that increases morbidity and mortality in this population. Nevertheless, the risk factors for postoperative pneumonia (POP) are still unknown. The aim of this study was to investigate the predictive risk factors for POP in HTx recipients.

Background This study evaluated the impact of hepatitis C-positive (HCV+) donors on outcomes of heart transplantation in the United States. Methods and Results Adults undergoing isolated heart transplantation in the United States between January 1, 2016, and December 31, 2018, were included. The primary outcome was 1-year post-transplant survival. Multivariable Cox regression and 2:1 propensity matching were used to compare outcomes between transplants with HCV+ and hepatitis C-negative (HCV-) donors. A subanalysis was performed to evaluate the impact of nucleic acid amplification test positivity on outcomes. Of 7889 isolated heart transplants performed during the study period, 343 (4.4%) used HCV+ donors. Overall unadjusted 1-year posttransplant survival was not statistically different between HCV- versus HCV+ donors (91.1% versus 90.2%; P=0.86), a finding that persisted after risk adjustment (hazard ratio, 1.05; 95% CI, 0.70-1.58; P=0.80). Propensity matching resulted in 675 well-balanced patients (437 HCV- and 238 HCV+). Overall 1-year posttransplant survival was not statistically different in propensity-matched analysis (89.8% HCV- versus 89.2% HCV+; P=0.88). Rates of 1-year drug-treated rejection (21.1% versus 22.1%; P=0.84), postoperative dialysis (11.4% versus 14.7%; P=0.22), and stroke (4.6% versus 2.1%; P=0.10) were also not statistically different between HCV- and HCV+ groups, respectively. Outcomes were not statistically different between nucleic acid amplification test-negative and nucleic acid amplification test-positive HCV+ donors. Conclusions Adult heart transplants using HCV+ donors, including those that are nucleic acid amplification test positive, can be performed without an adverse impact on 1-year survival. Wider implementation of protocols for using HCV+ donors and an assessment of longer-term outcomes including seroconversion rates will be important in maximizing the effect of HCV+ donors on national donor shortages.

While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging. Pharmacological activation of soluble guanylate cyclase (sGC) and increased cGMP-signalling have been reported to have cardioprotective properties. Gemfibrozil has recently been shown to exert sGC activating effects in vitro. We aimed to investigate whether pharmacological preconditioning of donor hearts with gemfibrozil could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat HTX model. Donor Lewis rats received p.o. gemfibrozil (150 mg/kg body weight) or vehicle for 2 days. The hearts were explanted, stored for 1 h in cold preservation solution, and heterotopically transplanted. 1 h after starting reperfusion, left ventricular (LV) pressure-volume relations and coronary blood flow (CBF) were assessed to evaluate early post-transplant graft function. After 1 h reperfusion, LV contractility, active relaxation and CBF were significantly (p < 0.05) improved in the gemfibrozil pretreated hearts compared to that of controls. Additionally, gemfibrozil treatment reduced nitro-oxidative stress and apoptosis, and improved cGMP-signalling in HTX. Pharmacological preconditioning with gemfibrozil reduces ischemia/reperfusion injury and preserves graft function in a rat HTX model, which could be the consequence of enhanced myocardial cGMP-signalling. Gemfibrozil might represent a useful tool for cardioprotection in the clinical setting of HTX surgery soon.

The most limiting factor in heart transplantation is the lack of donor organs. With enhanced prediction of outcome, it may be possible to increase the life-years from the organs that become available. Applications of machine learning to tabular data, typical of clinical decision support, pose the practical question of interpretation, which has technical and potential ethical implications. In particular, there is an issue of principle about the predictability of complex data and whether this is inherent in the data or strongly dependent on the choice of machine learning model, leading to the so-called accuracy-interpretability trade-off. We model 1-year mortality in heart transplantation data with a self-explaining neural network, which is benchmarked against a deep learning model on the same development data, in an external validation study with two data sets: (1) UNOS transplants in 2017-2018 (n = 4750) for which the self-explaining and deep learning models are comparable in their AUROC 0.628 [0.602,0.654] cf. 0.635 [0.609,0.662] and (2) Scandinavian transplants during 1997-2018 (n = 2293), showing good calibration with AUROCs of 0.626 [0.588,0.665] and 0.634 [0.570, 0.698], respectively, with and without missing data (n = 982). This shows that for tabular data, predictive models can be transparent and capture important nonlinearities, retaining full predictive performance.

The primary objective of this study is to compare the accuracy of two risk models, International Heart Transplantation Survival Algorithm (IHTSA), developed using deep learning technique, and Index for Mortality Prediction After Cardiac Transplantation (IMPACT), to predict survival after heart transplantation. Data from adult heart transplanted patients between January 1997 to December 2011 were collected from the UNOS registry. The study included 27,860 heart transplantations, corresponding to 27,705 patients. The study cohorts were divided into patients transplanted before 2009 (derivation cohort) and from 2009 (test cohort). The receiver operating characteristic (ROC) values, for the validation cohort, computed for one-year mortality, were 0.654 (95% CI: 0.629-0.679) for IHTSA and 0.608 (0.583-0.634) for the IMPACT model. The discrimination reached a C-index for long-term survival of 0.627 (0.608-0.646) for IHTSA, compared with 0.584 (0.564-0.605) for the IMPACT model. These figures correspond to an error reduction of 12% for ROC and 10% for C-index by using deep learning technique. The predicted one-year mortality rates for were 12% and 22% for IHTSA and IMPACT, respectively, versus an actual mortality rate of 10%. The IHTSA model showed superior discriminatory power to predict one-year mortality and survival over time after heart transplantation compared to the IMPACT model.

Heart transplantation is an uncommon treatment for unresectable and non-metastatic primary cardiac sarcomas, and the role of it is unclear. This study aims to offer a survival analysis of it.

The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population.

Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.

Cell damage, tissue and vascular injury are associated with the exposure and release of intracellular components such as RNA, which promote inflammatory reactions and thrombosis. Based on the counteracting anti-inflammatory and cardioprotective functions of ribonuclease A (RNase A) in this context, its role in an experimental model of heart transplantation in rats was studied.