HTx Outcomes Research Articles

Heart Transplantation Following Fontan Failure: Long-Term Survival Analysis.

Objectives: Fontan circulation presents significant challenges for patients with congenital heart disease, often necessitating heart transplantation (HTX) due to deteriorating functionality across multiple organ systems. However, the impact of prior Fontan palliation on HTX outcomes remains poorly understood, with early mortality rates suggesting a heightened risk. The aim of our study is to evaluate the long-term results after heart transplantation in patients with univentricular congenital heart disease previously palliated with Fontan circulation. Methods: A retrospective analysis was conducted on patients who underwent HTX for congenital heart disease. Patients were categorized into two groups based on the pre-HTX circulation pathway: the Failing Fontan Group (FFG) and the Biventricular Congenital Group (BCG). Data were collected from patients between 1987 and 2018. Early and late outcomes, including survival rates, were assessed and critically analyzed. Results: Of the 66 patients, 29 (43%) had a failing Fontan palliation (FFG), and 37 had biventricular congenital diseases (BCG) before heart transplantation. Early mortality (30-day) was not statistically different between the two group. The overall survival rate was 82.6 ± 13.9% at 1 year, 79.0 ± 14.9% at 5 years, 67.2 ± 17.6% at 10 years and 63.2 ± 18.2 ± at 15 years for the FFG, and 86.1 ±11.4% at 1 year, 79.5 ± 13.7% at 5 years, 75.7 ± 14.9% at 10 years, 75.7 ± 14.9% at 15 years for the BCG, with no statistically significant difference (Mantel Cox p value: 0.69, 0.89, 0.52 and 0.39, respectively). Regarding Cox-regression analysis, the long-term survival rate was not affected either by previous Fontan surgery or by the era of heart transplantation (before vs. after the year 2000). Conclusions: Although heart transplantation after Fontan palliation showed a higher risk in the early post-operative period, the medium- and long-term survival rates are comparable with biventricular circulation patients. Despite the failing Fontan patients being a challenging set of candidates for transplantation, it is a reasonable option in their treatment.

NOVEL INTEGRATED IMAGING PARAMETERS FOR RISK STRATIFICATION OF ATRIAL FIBRILLATION IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

Abstract Background Atrial fibrillation (AF) impacts prognosis of hypertrophic cardiomyopathy (HCM) by promoting progressive heart failure (HF) and increasing risk of stroke. Over the past years, several indexes and methods to predict AF among HCM patients have been proposed. However, they are limited by a lack of accuracy. Aims of our study was to evaluate the role of new echocardiographic parameters in predicting new onset of AF and to validate them by cardiac magnetic resonance (CMR). Methods and Results We analyzed clinical and imaging data of 141 HCM patients in sinus rhythm who underwent first evaluation at our center (51.2 ± 17.3 years, mean follow up 5.3 ± 3 years). Main parameters analyzed were left atrium (LA) end–diastolic volume (LAV min), end–systolic volume (LAVmax), LA ejection fraction (LAEF), left atrioventricular coupling index (LACI), and LA diameter (LAD). LACI was defined by the LAVmin divided by the LV end–diastolic volume (LVEDV); this parameter was assessed in previous studies as a good detector of early atrial remodeling and impaired LV compliance. 35 patients developed new–onset AF (after a mean period of 4 ± 3.2 years). At the baseline evaluation, LACI, LAD, and LAVmin showed to be significantly greater in patients who developed AF compared to patients who did not. At CMR, LACI >44% accurately predicted new–onset AF (sensitivity 85%, specificity 70%; AUC 0.81). LACI by ETT showed similar accuracy (AUC 0.75) and was superior to that shown by LAD (AUC 0.71) (Figure 1). Patients who did not develop AF had significantly higher LAEF at ETT (49.3 ± 11% vs 37 ± 9.6%; p < 0.0001). CMR analysis confirmed this result. LAEF >43% was a good predictor of AF free survival (log rank<0.001). Conversely, at a multivariate analysis, LAFE <43% by ETT was independently associated with AF occurrence (OR 4.5, 95% CI 1.4–13.7) (Figure 2). 11 patients experienced death or heart transplant (HTx). Higher values of LACI and LAVmin and lower values of LAEF were found to be associated the composite outcome of death or HTx. LACI>60% predicted the composite of death or HTx with good accuracy (AUC 0.74) (Figure 3). Conclusions LACI and LAEF showed to improve accuracy in predicting the new onset of AF in HCM patients without severe LA dilatation (LAD>45mm). Higher LACI and Lower LAEF (namely <43%) identify patients at higher risk of new onset AF, and, therefore, worthy of a more strict follow–up.

Examining a 12-year experience within Kazakhstan’s national heart transplantation program

Kazakhstan has one of the lowest heart transplantation (HTx) rates globally, but there are no studies evaluating the outcomes of HTx. This study aimed to provide a comprehensive analysis of the national HTx program over a 12-year period (2012–2023). Survival analysis of the national HTx cohort was conducted using life tables, Kaplan‒Meier curves, and Cox regression methods. Time series analysis was applied to analyze historical trends in HTx per million population (pmp) and to make future projections until 2030. The number of patients awaiting HTx in Kazakhstan was evaluated with a regional breakdown. The pmp rates of HTx ranged from 0.06 to 1.08, with no discernible increasing trend. Survival analysis revealed a rapid decrease in the first year after HTx, reaching 77.0% at 379 days, with an overall survival rate of 58.1% at the end of the follow-up period. Among the various factors analyzed, recipient blood levels of creatinine and total bilirubin before surgery, as well as the presence of infection or sepsis and the use of ECMO after surgery, were found to be significant contributors to the survival of HTx patients. There is a need for public health action to improve the HTx programme.

Recipient Pericardial Apolipoprotein Levels Might Be an Indicator of Worse Outcomes after Orthotopic Heart Transplantation.

End-stage heart failure (ESHF) leads to hypoperfusion and edema formation throughout the body and is accompanied by neurohormonal and immunological alterations. Orthotopic heart transplantation (HTX) has been used as a beneficial option for ESHF. Due to the shortage of donor hearts, the ideal matching and timing of donors and recipients has become more important. In this study, our aim was to explore the relationship between the clinical outcomes of HTX and the cytokine and apolipoprotein profiles of the recipient pericardial fluid obtained at heart transplantation after opening the pericardial sac. The clinical data and the interleukin, adipokine, and lipoprotein levels in the pericardial fluid of twenty HTX recipients were investigated. Outcome variables included primer graft dysfunction (PGD), the need for post-transplantation mechanical cardiac support (MCS), International Society for Heart and Lung Transplantation grade ≥2R rejection, and mortality. Recipient risk scores were also investigated. Leptin levels were significantly lower in patients with PGD than in those without PGD (median: 6.36 (IQR: 5.55-6.62) versus 7.54 (IQR = 6.71-10.44); p = 0.029). Higher ApoCII levels (median: 14.91 (IQR: 11.55-21.30) versus 10.31 (IQR = 10.02-13.07); p = 0.042) and ApoCIII levels (median: 60.32 (IQR: 43.00-81.66) versus 22.84 (IQR = 15.84-33.39); p = 0.005) were found in patients (n = 5) who died in the first 5 years after HTX. In patients who exhibited rejection (n = 4) in the first month after transplantation, the levels of adiponectin (median: 74.48 (IQR: 35.51-131.70) versus 29.96 (IQR: 19.86-42.28); p = 0.039), ApoCII (median: 20.11 (IQR: 13.06-23.54) versus 10.32 (IQR: 10.02-12.84); p = 0.007), and ApoCIII (median: 70.97 (IQR: 34.72-82.22) versus 26.33 (IQR: 17.18-40.17); p = 0.029) were higher than in the nonrejection group. Moreover, the pericardial thyroxine (T4) levels (median: 3.96 (IQR: 3.49-4.46) versus 4.69 (IQR: 4.23-5.77); p = 0.022) were lower in patients with rejection than in patients who did not develop rejection. Our results indicate that apolipoproteins can facilitate the monitoring of rejection and could be a useful tool in the forecasting of early and late complications.

Heart Transplantation.

Heart transplantation (HTx) remains the last therapeutic resort for patients with advanced heart failure. The present work is a clinically focused review discussing current issues in heart transplantation. Several factors have been associated with the outcome of HTx, such as ABO and HLA compatibility, graft size, ischemic time, age, infections, and the cause of death, as well as imaging and laboratory tests. In 2018, UNOS changed the organ allocation policy for HTx. The aim of this change was to prioritize patients with a more severe clinical condition resulting in a reduction in mortality of people on the waiting list. Advanced heart failure and resistant angina are among the main indications of HTx, whereas active infection, peripheral vascular disease, malignancies, and increased body mass index (BMI) are important contraindications. The main complications of HTx include graft rejection, graft angiopathy, primary graft failure, infection, neoplasms, and retransplantation. Recent advances in the field of HTx include the first two porcine-to-human xenotransplantations, the inclusion of hepatitis C donors, donation after circulatory death, novel monitoring for acute cellular rejection and antibody-mediated rejection, and advances in donor heart preservation and transportation. Lastly, novel immunosuppression therapies such as daratumumab, belatacept, IL 6 directed therapy, and IgG endopeptidase have shown promising results.

Abstract 18197: Relationship Between Donor Ejection Fraction and Left Ventricular Wall Thickness With Mortality Among Heart Transplants Recipients

Introduction: Limited availability of donor hearts contributes to significant mortality in patients waitlisted for heart transplantation (HTx). Donor hearts with reduced ejection fraction (EF) and left ventricular hypertrophy are considered to adversely affect long term HTX outcomes and are rejected. Objective: To determine the relationship of donor’s EF and left ventricular wall thickness (LVWT) with mortality in HTx recipients. Method: Retrospective analysis from The United Network for Organ Sharing (UNOS) registry. Adult HTx recipients with donor's EF and LVWT recorded from 2006 to 2022 were included. Study sample was grouped into four groups (Group 1 EF>50% & LVWT<1.4cm, group 2 EF≤50% & LVWT<1.4cm, group 3 EF>50% & LVWT≥1.4cm, and group 4 EF≤50% & LVWT≥1.4cm) according to donor characteristics. Primary end point: mortality (30 days, 1 year, and 5 years). Results: 21,012 patients were included, in which 19,205(91.4%) were in group 1, 898(4.3%) in group 2, 867(4.1%) in group 3, and 42(0.2%) in group 4. There were significant differences in baseline characteristics between the groups (Table 1). Unadjusted mortality was 6.3%, 6.0%, 6.0%, and 2.4% (p=0.86) at 30 days; 16.2%, 13.5%, 16.8%, and 7.3% (p=0.08) at 1 year; and 32.2%, 29.2%, 35.4%, and 29.0% (p=0.18) at 5 years, respectively (Table 1 and Figure 1). Neither adjusted mortality was different across the groups (Table 2). Conclusion: There were no significant differences in recipient mortality in different groups based on donor EF and LVWT. Expanding the donor selection criteria would allow for increase in the donor pool and assist in decreasing the mortality, while on the wait list for HTx.

Cardiac transplantation in adult congenital heart disease: a narrative review.

As more children with congenital heart disease survive to adulthood, adult congenital heart disease (ACHD) prevalence will increase (currently ~1 million US patients). Heart failure (HF) accounts for 26-42% of ACHD deaths. The rate of ACHD heart transplantations (ACHD HTx) is also increasing. We describe the ACHD HTx recipient/candidate cohort, analyze ACHD HTx outcomes, identify ACHD HTx specific challenges, and discuss opportunities to better serve more patients with ACHD HF. PubMed literature search including articles published from 2010-2023. Reviewed 89 studies, 67 included. Our search focused on the challenges of ACHD HTx and potential solutions. ACHD HTx recipients are young [median age 35 years, interquartile range (IQR): 24-46 years]. 87-95% of ACHD HTx recipients had prior cardiac surgery. The most common underlying diagnoses include transposition of the great arteries (31%) and Fontan/Glenn circulation (28%). 63% of listed ACHD HTx candidates received a transplant within one year of listing. Post-transplant 1-year survival is 80%, 5-year survival 74%, and 10-year survival 59%. There are 4 unique ACHD HTx challenges: (I) difficulty in assessing pulmonary hypertension, resulting in some centers selecting oversized donor hearts. However, selecting oversized hearts does not improve post-operative mortality and could prolong waitlist time. (II) Increased immunologic sensitization, increasing rejection risk. Desensitization therapy has enabled sensitized HTx recipients to enjoy outcomes similar to non-sensitized recipients. (III) Procedural complexity with ~30% of cases requiring additional surgical reconstruction. Detailed multidisciplinary planning, extensive imaging, and transferring the patient into the operating room early can help manage the complexities and reduce organ ischemic time. (IV) Increased intraoperative bleeding due to patients' surgical histories and circulatory collaterals. Preoperative collateral coil embolization and select utilization of hypothermic circulatory arrest can help reduce bleeding. Additional Fontan specific challenges include extensive great artery repair, liver failure, plastic bronchitis, and protein loss enteropathy. Finally, given limited donor heart availability, mechanical circulatory support is a promising technology for patients with ACHD HF. The prevalence of ACHD HTx is slowly but steadily increasing. The operational complexity of ACHD HTx can be managed, and the majority of recipients have excellent outcomes (59% 10-year survival).

Exercise Oscillatory Ventilation Improves Heart Failure Prognostic Scores.

Several heart failure (HF) prognostic risk scores are available to guide the ideal time for listing candidates for a heart transplant (HTx). The detection of exercise oscillatory ventilation (EOV) during cardiopulmonary exercise testing (CPET) is associated with advanced HF and a worse prognosis, and yet it is not accounted for in these risk scores. Therefore, this study aimed to assess whether EOV further adds prognostic value to HF scores. A single-centre retrospective cohort study was undertaken of consecutive HF patients with reduced ejection fraction (HFrEF) who underwent CPET from 1996 to 2018. The Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta-analysis Global Group In Chronic Heart Failure (MAGGIC), and Metabolic Exercise Cardiac Kidney Index (MECKI) were calculated. The added value of EOV on top of those scores was assessed using a Cox proportional hazard model. The added discriminative power was also assessed by receiver operating characteristic curve comparison. A total of 390 HF patients with a median age of 58 (IQR 50-65) years were investigated, of whom 78% were male and 54% had ischaemic heart disease. The median peak oxygen consumption was 15.7 mL/kg/min (IQR 12.8-20.1). Exercise oscillatory ventilation was detected in 153 (39.2%) patients. Over a median follow-up of 2 years, 61 patients died (49 due to a cardiovascular reason) and 54 had a HTx. Exercise oscillatory ventilation independently predicted the composite outcome of all-cause death and HTx. Furthermore, the presence of this ventilatory pattern significantly improved the prognostic performance of both HFSS and MAGGIC scores. Exercise oscillatory ventilation was often found in a cohort of HF patients with reduced LVEF who underwent CPET. It was found that EOV added further prognostic value to contemporary HF scores, suggesting that this easily obtained parameter should be included in future modified HF scores.

Heart Transplantation in High-Risk Recipients Employing Donor Marginal Grafts Preserved With Ex-Vivo Perfusion.

Extending selection criteria to face donor organ shortage in heart transplantation (HTx) may increase the risk of mortality. Ex-vivo normothermic perfusion (EVP) limits ischemic time allowing assessment of graft function. We investigated the outcome of HTx in 80 high-risk recipients transplanted with marginal donor and EVP-preserved grafts, from 2016 to 2021. The recipients median age was 57years (range, 13-75), with chronic renal failure in 61%, impaired liver function in 11% and previous cardiac surgery in 90%; 80% were mechanically supported. Median RADIAL score was 3. Mean graft ischemic time was 118 ± 25min, "out-of-body" time 420 ± 66min and median cardiopulmonary bypass (CPB) time 228min (126-416). In-hospital mortality was 11% and ≥moderate primary graft dysfunction 16%. At univariable analysis, CPB time and high central venous pressure were risk factors for mortality. Actuarial survival at 1 and 3years was 83% ± 4%, and 72% ± 7%, with a median follow-up of 16months (range 2-43). Recipient and donor ages, pre-HTx extracorporeal life support and intra-aortic balloon pump were risk factors for late mortality. In conclusion, the use of EVP allows extension of the graft pool by recruitment of marginal donors to successfully perform HTx even in high-risk recipients.

Utilization of the percutaneous left ventricular support as bridge to heart transplantation across the United States: In-depth UNOS database analysis

Intra-aortic balloon pump (IABP) and Impella device utilization as a bridge to heart transplantation (HTx) have risen exponentially. We aimed to explore the influence of device selection on HTx outcomes, considering regional practice variation. A retrospective longitudinal study was performed on a United Network for Organ Sharing (UNOS) registry dataset. We included adult patients listed for HTx between Oct 2018 and April 2022 as status 2, as justified by requiring IABP or Impella support. The primary endpoint was successful bridging to HTx as status 2. Of 32,806 HTx during the study period, 4,178 met inclusion criteria (Impella n = 650, IABP n = 3,528). Waitlist mortality increased from a nadir of 16 (in 2019) to a peak of 36 (in 2022) per thousand status 2 listed patients. Impella annual use increased from 8% in 2019 to 19% in 2021. Compared to IABP, Impella patients demonstrated higher medical acuity and lower success rate of transplantation as status 2 (92.1% vs. 88.9 %, P < 0.001). The IABP: Impella utilization ratio varied widely between regions, ranging from 1.77 to 21.31, with high Impella use in Southern and Western states. However, this difference was not justified by medical acuity, regional transplant volume, or waitlist time and did not correlate with waitlist mortality. The shift in utilizing Impella as opposed to IABP did not improve waitlist outcomes. Our results suggest that clinical practice patterns beyond mere device selection determine successful bridging to HTx. There is a critical need for objective evidence to guide tMCS utilization and a paradigm shift in the UNOS allocation system to achieve equitable HTx practice across the United States.

P58: Heart Transplantation Outcomes In Patients Bridged With Mechanical Circulatory Support Devices: Kazakhstan Experience

Background: The management of end-stage heart failure (HF) with heart transplantation (HTx) as the gold standard therapy relies on a long-term mechanical circulatory support (MCS) devices for bridging patients. This study aimed to analyze clinical outcomes of HTx in bridge-to-transplant population in Kazakhstan. Methods: In this retrospective, single-center study we included 40 patients with MCS devices who were transplanted in Kazakhstan between 2014 and 2022. Results: Of the 85 transplantations performed, 40 (47%) were bridged with MCS including 31 (77,5%) with durable left ventricular assist devices (LVAD), 3 (7,5%) with total artificial heart (TAH), 2 (5 %) with fully implantable LVAD (FIVAD), 3 patients (7.5%) right ventricular plus LVAD, 1 (2.5%) with biventricular support device (Levitronix CentriMag). 25 (62.5%) HTx performed by using Organ Care System Transmedics due to large territory of Kazakhstan. Average age was 41,3 years (interquartile range, 17–64) and 4 patients (10%) were female. 26 patients (65%) with dilated cardiomyopathy. The most common complications on LVAD support before HTx were driveline infection (57.5%), arrhythmias (20%) and allosensitization (17.5%). Minimum waiting time was 15 days, maximum waiting time – 1999 days, average waiting time - 809±635 days. According to the Kaplan-Meier survival analysis unadjusted survival at 1 and 5 years posttransplant was 80 % and 67.5 %. For comparison, posttransplant survival of HF patients without LVAD was 80% and 57.7% respectively. Maximum life span after HTx was 7.8 years, median – 3.6 years. The most common causes of death in group of transplants bridged with MCS were multiorgan failure (n=6, 46.2%), infection/sepsis (n= 4, 30.7%) and acute graft rejection (n=1, 7.7%). In group of transplants without LVAD the most common causes of death were acute graft rejection (n=5, 22.7%), COVID-19 (n=4, 18.2%), kidney disease (n=4, 18.2%). Conclusion: Long waiting time in consequence of donor organ shortage in Kazakhstan and life-threatening complications on MCS device support are serious issue with particular significance in the bridge-to-transplant population. Despite these limiting factors, HTx in patients bridged with MCS demonstrated favorable survival outcomes similar in other published studies.

Impact of donor ventricular function on heart transplantation outcomes.

Some heart transplant (HTx) centers have expanded their donor eligibility criteria in response to the organ shortage; one area of active interest involves utilizing hearts with ventricular dysfunction. Our study seeks to identify if a relationship exists between donor left ventricular ejection fraction (LVEF) and ischemic time or donor age on HTx outcomes. We performed a retrospective analysis on adult patients who had a HTx between 1996 and 2021 (n=46,936). Donor LVEF (dLVEF) values were categorized into three groups:<50%, 50%-70%, and >70%. Ischemic time and donor age were stratified into four groups: ≤2.0, 2.1-3.0, 3.1-4.0,>4.0h, and ≤30, 31-40, 41-50, >50 years, respectively. The outcome of interest was long-term survival. Multivariable survival analysis found a slight increase in overall mortality risk for patients with donor ejection fractions <50% (HR=1.16, p=.013). However, subsequent subgroup investigation discovered that this elevated hazard was only applicable when ischemic time was prolonged to>3.0h (3.1-4.0h: HR=1.23, p=.024;>4.0h: HR=1.52, p<.001). There was no significant difference in survival between dLVEF groups when ischemic time was limited to ≤3.0h or when stratified by donor age. HTx patients with a low donor ejection fraction have comparable survival to recipients with a normal dLVEF when ischemic time is limited to ≤3.0h. Reduced dLVEF does not appear to be sensitive to advanced donor age. The clinical implications of our study may encourage the recruitment of more donor hearts for transplantation.

Comparing Cardiac Mechanics and Myocardial Fibrosis in DBD and DCD Heart Transplant Recipients

BackgroundHeart transplantation (HTx) after donation after circulatory death (DCD) is an expanding practice but is associated with increased warm ischemic time. The impact of DCD HTx on cardiac mechanics and myocardial fibrosis has not been reported. We aimed to compare cardiac mechanics and myocardial fibrosis using cardiovascular magnetic resonance (CMR) imaging in donation after brain death (DBD) and DCD HTx recipients and healthy controls. Methods and ResultsConsecutive HTx recipients between March 2015 and March 2021 who underwent routine surveillance CMR imaging were included. Cardiac mechanics were assessed using CMR feature tracking to compute global longitudinal strain, global circumferential strain, and right ventricular free-wall longitudinal myocardial strain. Fibrosis was assessed using late gadolinium enhancement imaging and estimation of extracellular volume. There were 82 (DBD n = 42, DCD n = 40) HTx recipients (aged 53 years, interquartile range 41–59 years, 24% female) who underwent CMR imaging at median of 9 months (interquartile range 6–14 months) after transplantation. HTx recipients had increased extracellular volume (29.7 ± 3.6%) compared with normal ranges (25.9%, interquartile range 25.4–26.5). Myocardial strain was impaired after transplantation compared with controls (global longitudinal strain –12.6 ± 3.1% vs –17.2 ± 1.8%, P < .0001; global circumferential strain –16.9 ± 3.1% vs –19.2 ± 2.0%, P = .002; right ventricular free-wall longitudinal strain –15.7 ± 4.5% vs –21.6 ± 4.7%, P < .0001). There were no differences in fibrosis burden (extracellular volume 30.6 ± 4.4% vs 29.2 ± 3.2%; P = .39) or cardiac mechanics (global longitudinal strain –13.1 ± 3.0% vs –12.1 ± 3.1%, P = .14; global circumferential strain –17.3 ± 2.9% vs –16.6 ± 3.1%, P = .27; right ventricular free-wall longitudinal strain –15.9 ± 4.9% vs –15.5 ± 4.1%, P = .71) between DCD and DBD HTx. ConclusionsHTx recipients have impaired cardiac mechanics compared with controls, with increased myocardial fibrosis. There were no differences in early CMR imaging characteristics between DBD and DCD heart transplants, providing further evidence that DCD and DBD HTx outcomes are comparable.

Abstract 14430: Sex Differences in Heart Transplantation - Analysis of the National Inpatient Sample 2012-2019

Introduction: Advanced heart failure therapies and heart transplantation (HTx) have been underutilized in women. Therefore, we aimed to explore the clinical characteristics and outcomes of HTx by sex. Methods: We conducted a retrospective analysis of adult discharges from the National Inpatient Sample (NIS) between 2012 and 2019. International Classification of Disease (ICD) procedure codes were used to identify those who underwent HTx. Results: A total of 20,180 HTx hospitalizations were identified from 2012-2019. Among them, 28% were female. Women undergoing HTx were younger (mean age 51 vs. 54.5 years, p&lt;0.001). HTx hospitalizations among men were more likely to have atrial fibrillation, diabetes, hypertension, renal failure, dyslipidemia, smoking, and ischemic heart disease. HTx hospitalizations among women were more likely to have hypothyroidism and valvular heart disease. HTx hospitalizations in women were associated with no significant difference in risk of in-hospital mortality (adjusted odds ratio [OR] 0.82; 95% confidence interval [CI] 0.58-1.16, p=0.271), no significant difference in length of stay or inflation-adjusted cost as shown in the Table. Men were more likely to develop acute kidney injury during HTx hospitalization (69.2% vs. 59.7%, adjusted OR 0.71, 95% CI 0.61-0.83, p&lt;0.001). Conclusions: HTx utilization is lower in women. However, most major in-hospital outcomes for HTx are similar between the sexes. Further studies are need to explore the causes of lower rates of HTx in women.

Abstract 13448: Time Course and Predictors of Renal Function Decline After Pediatric Heart Transplantation: A PHTS Multi-Institutional Analysis

Introduction: Decline in renal function can impact both the management and outcomes of pediatric heart transplantation (HTx). Initial renal function decline may be subclinical and underappreciated. We sought to identify the time course and predictors of decline in renal function and the impact of these changes on HTx outcomes. Methods: The Pediatric Heart Transplant Society (PHTS) database was queried to identify HTx recipients at participating centers from 1996 to 2019 with at least 1 year of follow-up. Patients with simultaneous or previous kidney transplant were excluded. Renal function was measured by modified Schwartz formula eGFR on annual follow-up forms and stratified into eGFR groups by National Kidney Foundation chronic kidney disease staging guidelines. “Initial renal function decline” was defined as the initial drop by at least one eGFR group relative to stage at 1 year post transplant (“baseline”). Results: Of the 5,250 patients who met inclusion criteria, initial renal function decline occurred, relative to baseline, in 7.4%, 18.7%, and 55.7%, by 1, 5, and 10 years of follow up, respectively (Figure A). eGFR group distribution for the cohort progressively worsened over the follow up period (Figure B). On multivariate Cox modeling, risk factors for renal function decline were increased BSA at 1 year post-transplant (HR 1.24 [1.02, 1.52]), acute rejection with hemodynamic compromise (HR 1.24 [1.10, 1.39]), and Black race (HR 1.21 [1.08, 1.36]) with the use of tacrolimus (vs cyclosporine) being protective (HR 0.77 [0.69, 0.85]). Patients whose eGFR was &lt; 30 mL/min at 1 year follow up had an increased risk of graft loss (P &lt; 0.0001 compared to all other groups). Conclusions: Decline in renal function occurs progressively, affecting over 50% of HTx recipients in long term follow up, independent of renal condition at the time of HTx. Avoidance of potentially nephrotoxic events and medications must be considered at all times in the long term management of pediatric HTx.

Outcomes of heart transplantation in adults and pediatrics congenital heart disease: a systematic review and meta-analysis

Abstract Background Heart transplantation (HTx) has progressed from an experimental therapy option to a well-established therapeutic option for congenital heart disease (CHD) patients in end-stage heart failure, thus we can expect a large number of people with CHD to be evaluated for HTx in the next decades. Objective To create a systematic review and meta-analysis regarding short-term and long-term outcomes of HTx in end-stage adults and pediatrics CHD patients. Methods Four online databases were screened from the date of inception to January 2022, where the acquired studies were assessed using the PRISMA statement. The inclusion criteria were cohort studies that evaluated outcomes of heart transplantation in end-stage congenital heart disease patients. The mortality of adults and pediatrics population were analyzed using random-effect model, showed as summary statistics of overall risk ratio (RR) with 95% confidence interval (CI). Quality appraisal was conducted using the STROBE statement. Result Ten studies met the inclusion criteria and were eligible to be analyzed. The pediatric population had stronger 1-year mortality risk [Std. Mean difference 0.62, 95% CI, 0.12 to 3.07; P&amp;lt;0.00001] and 5-year mortality risk [Std. Mean difference 0.82, 95% CI, 0.37 to 1.84; P&amp;lt;0.00001], while adult population were found to have higher overall post-transplantation mortality risk [Std. mean difference 1.17, 95% CI 0.66 to 2.08; P&amp;lt;0.00001]. Conclusion Adults CHD patients experienced higher mortality rate following heart transplantation, with improved long-term survival in comparison to pediatrics CHD recipients. However, further study should be conducted with standardized subjects as there is moderate quality of evidence and higher heterogeneity during our meta-analysis. Funding Acknowledgement Type of funding sources: None.

333.9: The Effect of Short-term Inhalation of Isoflurane on the Outcomes of Intraportal Hepatocyte Transplantation

Introduction: Liver transplantation is currently established as a treatment for endo-stage liver disease. However, this treatment is considered too invasive for those patients. Hepatocyte transplantation (HTx), which is less invasive in comparison to liver transplantation, has been expected to serve as an alternative therapy to liver transplantation. However, the outcomes of HTx are still far from satisfactory, and it is well known that there is a large discrepancy between the experimental results of animal models and clinical outcomes of HTx. Of particular note, clinical HTx is only performed without general anesthesia, while inhalation anesthetics are usually used in animal experiments. Isoflurane, which is one of the most widely used inhalation anesthetics in animal experiments, is known to have a strong vasodilatory effect, portal pressure inhibitory effect, and cytoprotective effect against cytokine-induced injury. Therefore, we hypothesized that isoflurane may be a possible reason for the discrepancy between the results of animal experiments and the clinical outcomes of HTx. Methods: F344/NSLc rat hepatocytes were isolated. Isolated hepatocytes (1.0×107 cells) were transplanted to analbuminemic rats with (ISO group) and without (AW group) isoflurane. These analbuminemic rats had a syngeneic background to the donor rats. The serum albumin, AST, ALT, LDH levels and several inflammatory mediators in the recipient rats were analyzed. Immunohistochemical staining and ex vivo imaging of transplanted hepatocytes were also performed. Results: The serum albumin levels of the ISO group were significantly higher in comparison to the AW group (p<0.05) (Figure 1). The serum AST, ALT, LDH levels of the ISO group were significantly suppressed in comparison to the AW group (p<0.0001, respectively). The serum levels of IL-1β (p<0.01), IL-10 (p<0.01), IL-18 (p<0.01), MCP-1 (p<0.05), RANTES (p<0.01), Fractalkine (p<0.01), and LIX (p<0.05) in the ISO group were significantly downregulated in comparison to the AW group. The ischemic regions of the recipient livers, which were easily detected in the livers of both groups, tended to be more evident in the AW group (3.69±1.05%) in comparison to the ISO group (2.42±1.76%) (Figure 2). Conclusions: This study showed that the anti-inflammatory effects of isoflurane could efficiently contribute to hepatocyte engraftment. According to the detailed analyses in this study, the anti-inflammatory effects, rather than vasodilatory effects, of isoflurane appeared to be the main mechanism of the abovementioned benefits. Isoflurane may at least in part be a reason for the discrepancy between the results of animal experiments and the clinical outcomes of HTx.

425.6: Recognition of Donor MHCI Disrupts Recipient Reparative Macrophage Differentiation

Introduction: After tissue injury, infiltrating monocytes differentiate into CD86hiLy6chi pro-inflammatory and CD206+CD301+ reparative macrophages (MΦs) that complete repair. MΦs differentiation is coordinated by tissue injury signals, often referred to as damage-associated molecular patterns (DAMPs), and local cytokines. For example, after heart transplant (HTx) IL-33 is released from graft fibroblasts and acts as a reparative/regulatory DAMP that metabolically reprograms MΦs to differentiate into reparative subsets that protect against chronic HTx rejection. Transplanting allogeneic materials is a novel situation where innate allorecognition of mismatched MHCI may disrupt normal MΦ responses to damaged tissues. For instance, paired immunoglobulin-like receptor (PIR)-A3 on C57BL/6 (B6) monocytes recognition of BALB/c H2-Dd triggers their differentiation into pro-inflammatory dendritic cells that promotes HTx rejection. Monocyte PIR-B binding to self MHCI negatively regulates PIR-A signals. How PIRs shapes DAMP-mediated MΦ differentiation after Tx is not understood, so we hypothesize that in addition to DAMPs, recognition of self versus allogeneic MHCI by PIRs modulates reparative or inflammatory MΦ differentiation. Methods: Monocyte-derived MΦ differentiation in response to donor materials was tested by administration of 20x106 irradiated BALB/c allogeneic (H-2d; Allo) or (B6) syngeneic (H-2b; Syn) splenocytes intraperitoneally alone or with recombinant IL-33. Recipients of donor cellular materials were B6 wildtype (WT), Rag2-/-γc-/-, Pira-/- and Pirb-/- mice. The precise impact of H-2Dd (Allo) or H-2Db (Syn) recombinant MHCI on MΦ differentiation was determined using B6 WT and Pira-/- bone marrow-derived MΦs (BMDMs). Flow cytometry was utilized to assess MΦ differentiation. Results: Administration of Syn cells predominantly stimulated monocyte differentiation into CD206+CD301+ reparative MΦs. Allo cells instead drove monocyte differentiation to pro-inflammatory Ly6chiCD86hi MΦs. A similar outcome was observed in Rag2-/-γc-/- recipients, suggesting these changes are not driven by adaptive immunity. Incubation of BMDMs with recombinant allo MHCI, but not syn MHCI, triggered inflammatory Ly6chiCD86hi MΦs in both WT and Pira-/- BMDMs. Co-administration of allo cells with recombinant IL-33 supported differentiation into CD206+CD301+ reparative MΦs. Interestingly, Pirb-/- mice display reduced C206+CD301+ MΦs, which correlated with decreased IL-33 receptor expression. Conclusions: These data indicate allorecognition by monocytes or MΦs disrupts the typical generation of reparative MΦs in response to injury. We show that monocyte-derived MΦs PIR-B recognition of self MHCI may trigger expression of the receptor needed for IL-33-mediated reparative MΦ differentiation. These new data provide important insights into how innate allorecognition and repair pathways intersect to direct the differentiation of reparative or inflammatory MΦs that shape HTx outcomes. #R01AR073527 (HRT) #5T32AI074490-14 (JPW).

Heart Transplantation in Children With Down Syndrome.

BackgroundChildren 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 ResultsThis 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).ConclusionsWaitlist 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.

Improvement in Heart Transplant Outcomes: From Medicare Flagging to Best in the World

<h3>Purpose</h3> SRTR data has recently published that the University of Chicago Medical Center (UCMC) heart transplant (HTx) program possesses the highest one-year survival in the world despite being flagged in the past by Medicare. We assessed UCMC's HTx patient outcomes compared to those from other centers in the United States before and after 2015. <h3>Methods</h3> Using the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research Database, we retrospectively reviewed heart transplants performed from January 1988 to September 2020. Re-transplants and multi-organ transplants were excluded. Survival was assessed with Kaplan-Meier method and compared by log-rank test. Univariate and multivariate cox regression analyses were performed to assess hazard ratios. <h3>Results</h3> A total of 69,174 patients were included in this study. Pre-2015, 1-year survival was 84.9% (95% CI 81.3-88.7) at UCMC versus 86.7% (95% CI 86.5-87) at other centers. Cox regression analyses found a trend towards greater risk for mortality in UCMC patients, HR 1.16 (95% CI 0.88-1.52, p = 0.286). These results were consistent in multivariate analysis adjusting for donor age and recipient age. Post-2015, 1-year survival was 95.7% (95% CI 92.4-99.1) versus 91.8% (95% CI 91.4-92.3) at other centers. Cox regression analyses showed a trend towards reduced hazard for mortality in UCMC patients, HR 0.49 (95% CI 0.22-1.10, p = 0.086). Relative to itself, there was a significant improvement in 1-year survival between the two time periods at UCMC, HR 0.25 (95% CI 0.11-0.59, p = 0.001). <h3>Conclusion</h3> There has been a large improvement in HTx outcomes at UCMC, accompanied by a restructuring and refinement of program practices in the year 2015. One-year survival at UCMC has gone from underperforming relative to other centers in the country to enjoying the highest survival in the nation.