Heart Recipients Research Articles

The Roles of Bone Marrow-Derived Stem Cells in Coronary Collateral Growth Induced by Repetitive Ischemia.

Many clinical trials have attempted to use stem cells to treat ischemic heart diseases (IHD), but the benefits have been modest. Though coronary collaterals can be a "natural bypass" for IHD patients, the regulation of coronary collateral growth (CCG) and the role of endogenous stem cells in CCG are not fully understood. In this study, we used a bone marrow transplantation scheme to study the role of bone marrow stem cells (BMSCs) in a rat model of CCG. Transgenic GFP rats were used to trace BMSCs after transplantation; GFP bone marrow was harvested or sorted for bone marrow transplantation. After recovering from transplantation, the recipient rats underwent 10 days of repetitive ischemia (RI), with echocardiography before and after RI, to measure cardiac function and myocardial blood flow. At the end of RI, the rats were sacrificed for the collection of bone marrow for flow cytometry or heart tissue for imaging analysis. Our study shows that upon RI stimulation, BMSCs homed to the recipient rat hearts' collateral-dependent zone (CZ), proliferated, differentiated into endothelial cells, and engrafted in the vascular wall for collateral growth. These RI-induced collaterals improved coronary blood flow and cardiac function in the recipients' hearts during ischemia. Depletion of donor CD34+ BMSCs led to impaired CCG in the recipient rats, indicating that this cell population is essential to the process. Overall, these results show that BMSCs contribute to CCG and suggest that regulation of the function of BMSCs to promote CCG might be a potential therapeutic approach for IHD.

Long‐term mortality in pediatric solid organ recipients—A nationwide study

The present study aimed at investigating long-term mortality of patients who underwent solid organ transplantation during childhood and at identifying their causes of death. A cohort of 233 pediatric solid organ transplant recipients who had a kidney, liver, or heart transplantation between 1982 and 2015 in Finland were studied. Year of birth-, sex-, and hometown-matched controls (n=1157) were identified using the Population Register Center registry. The Causes of Death Registry was utilized to identify the causes of death. Among the transplant recipients, there were 60 (25.8%) deaths (median follow-up 18.0 years, interquartile range of 11.0-23.0 years). Transplant recipients' risk of death was nearly 130-fold higher than that of the controls (95% CI 51.9-1784.6). The 20-year survival rates for kidney, liver, and heart recipients were 86.1% (95% CI 79.9%-92.3%), 58.5% (95% CI 46.2%-74.1%), and 61.4% (95% CI 48.1%-78.4%), respectively. The most common causes of death were cardiovascular diseases (23%), infections (22%), and malignancies (17%). There were no significant differences in survival based on sex or transplantation era. The late mortality is still significantly higher among pediatric solid organ recipients in comparison with controls. Cardiovascular complications, infections, and cancers are the main causes of late mortality for all studied transplant groups. These findings emphasize the cruciality of careful monitoring of pediatric transplant recipients in order to reduce long-term mortality.

Severe and Moderate Primary Graft Dysfunction in Adult Heart Recipients.

The aims of this study were to determine the incidence of severe and moderate primary graft dysfunction (PGD) in our center, to identify, retrospectively, donors' and recipients' risk factors for PGD development, and to evaluate the impact of PGD within 30 days after heart transplantation. Donors' and recipients' medical records of 64 consecutive adult cardiac transplantations performed between January 2016 and June 2017 were reviewed. The International Society for Heart and Lung Transplantation (ISHLT) criteria were used to diagnose moderate and severe PGD. Associations of risk factors for combined moderate/severe PGD were assessed with appropriate statistical analyses. Sixty-four patients underwent heart transplantation in this period. Twelve recipients (18.7%) developed severe or moderate PGD. Development of PGD was associated with previous donor cardiopulmonary resuscitation and a history of prior heart surgery in the recipient (P=0.01 and P=0.02, respectively). The 30-day in hospital mortality was similar in both PGD and non-PGD patients. The use of the ISHLT criteria for PGD is important to identify potential risk factor. The development of PGD did not affect short-term survival in our study. More studies should be done to better understand the pathophysiology of PGD.

Outcomes following heart or bilateral-lung transplantation from donors who died of drug toxicity in British Columbia, Canada.

The illicit drug toxicity (overdose) crisis has worsened across Canada; between 2016 and 2021, more than 28,000 individuals have died of drug toxicity. Organ donation from persons who experience drug toxicity death (DTD) has increased in recent years. This study examines whether survival after heart or bilateral-lung transplantation differed by donor cause of death. We studied transplant recipients in British Columbia who received heart (N=110) or bilateral-lung (N=223) transplantation from deceased donors aged 12-70 years between 2013 and 2019. Transplant recipient survival was compared by donor cause of death from drug toxicity or other. Five-year Kaplan-Meier estimates of survival and 3-year inverse probability treatment weighted Cox proportional hazards models were conducted. DTD donors made up 36% (40/110) of heart and 24% (54/223) of bilateral-lung transplantations. DTD donors were more likely to be young, white, and male. Unadjusted 5-year recipient survival was similar by donor cause of death (heart: 87% for DTD and 86% for non-DTD, p=.75; bilateral- lung: 80% for DTD and 76% for non-DTD, p=.65). Adjusted risk of mortality at 3-years post-transplant was similar between recipients of DTD and non-DTD donor heart (hazard ratio [HR]: .94, 95% confidence interval (CI): .22-4.07, p=.938) and bilateral-lung (HR: 1.06, 95% CI: .41-2.70, p=.908). Recipient survival after heart or bilateral-lung transplantation from DTD donors and non-DTD donors was similar. Donation from DTD donors is safe and should be considered more broadly to increase organ donation.

373 ADONHERS (AGED DONOR HEART RESCUE BY STRESS ECHO) PROTOCOL FOR HEART DONATION FROM MARGINAL DONOR HEARTS: MONOCENTRIC RETROSPECTIVE STUDY ON RECIPIENT'S SURVIVAL AFTER 10-YEAR FOLLOW-UP

Abstract Backgorund Amelioration of therapies and increased survival in heart failure (HF) is leading to a growing number of patients affected by advanced HF, with an overall 1-year prognosis ranging from 25 to 75%. The gold standard treatment for end stage HF is heart transplantation (Htx), but lack of organs donors remains an important limitation. Marginal hearts can potentially improve and be utilized after a re-evaluation by “aggressive” assessment of donor left ventricular function. Purpose In our study we analysed if recipients of marginal donor hearts, selected by dipyridamole stress echocardiography, had different outcome compared to recipients with acceptable donor hearts. Methods Data collected from 2006 and 2014 of patients who received orthotopic Htx from marginal heart donors (group 1) and were retrospectively analysed and compared with recipients of acceptable heart donors (group 2). Bedside standard echocardiography and dipyridamole stress echo was performed for the selection of marginal hearts > 55 years old or < 55 with comorbidities/mildly dysfunctional left ventricle. Clinical, laboratory and instrumental features of the two groups of recipients were evaluated and patients with homogenous baseline characteristics were selected to reduce biases among the two groups. Follow-up through routine heart transplant surveillance included visit, echocardiography, blood tests, serial endomyocardial biopsies and coronary angiography. Results Twenty-two recipients were included in the study. Mean donors age was 41 ± 23, 45 ± 29 years for group 1 vs 36 ± 12 for group 2. The average follow-up was 113 months. Age, cardiovascular risk and morpho-functional characteristics of the left ventricle were comparable between the two population (P> 0.05). Left atrial size was significantly higher in marginal hearts (Optimal: p=0.007; Marginal: p=0.003). Acceptable recipients showed a higher impact of CAV (p= 0.019) together with more elevated values of cholesterol and triglycerides (p = 0.048 and p = 0.012 respectively). No differences concerning cellular or humoral rejection were found between the two groups. Four patients deceased, 3 had received a standard donor heart and 1 was from the marginal donor group, with and overall median time to death of 124 months. Conclusions Our small pilot study shows how the evaluation of marginal donor hearts with echo stress result to no affect recipients survival compared with controls of acceptable hearts. A well-controlled selection of marginal hearts could therefore improve the shortage of organs, reducing the long line of patients waiting for a heart.

T cell repertoire profiling in allografts and native tissues in recipients with COVID-19 after solid organ transplantation: Insight into T cell-mediated allograft protection from viral infection.

The effects of the SARS-CoV-2 virus on the body, and why the effects are more severe in certain patients, remain incompletely understood. One population of special interest is transplant recipients because of their immunosuppressed state. Understanding the pathophysiology of graft dysfunction in transplant patients with the COVID-19 viral syndrome is important for prognosticating the risk to the graft as well as understanding how best to prevent and, if necessary, treat graft injury in these patients. We analyzed multiple types of solid organ transplant recipients (liver, kidney, heart or lung) at our institution who died from SARS-CoV-2 and underwent autopsy (n = 6) or whose grafts were biopsied during active SARS-CoV-2 infection (n = 8). Their serum inflammatory markers were examined together with the histological appearance, viral load, and TCR repertoire of their graft tissue and, for autopsy patients, several native tissues. Histology and clinical lab results revealed a systemic inflammatory pattern that included elevated inflammatory markers and diffuse tissue damage regardless of graft rejection. Virus was detected throughout all tissues, although most abundant in lungs. The TCR repertoire was broadly similar throughout the tissues of each individual, with greater sharing of dominant clones associated with more rapid disease course. There was no difference in viral load or clonal distribution of overall, COVID-associated, or putative SARS-CoV-2-specific TCRs between allograft and native tissue. We further demonstrated that SARSCoV-2-specific TCR sequences in transplant patients lack a donor HLArestricted pattern, regardless of distribution in allograft or native tissues,suggesting that recognition of viral antigens on infiltrating recipient cells can effectively trigger host T cell anti-viral responses in both the host and graft. Our findings suggest a systemic immune response to the SARS-CoV-2 virus in solid organ transplant patients that is not associated with rejection and consistent with a largely destructive effect of recipient HLA-restricted T cell clones that affects donor and native organs similarly.

Utilization of COVID-19 positive donors for heart transplantation and associated short-term outcomes

The safety and efficacy of using COVID-19 positive donors in heart transplantation (HT) are increasingly relevant, but not well established. The present study evaluated the characteristics and utilization of such donors and associated post-HT outcomes. All adult (≥18 years old) potential donors and HT recipients in the United States from April 21, 2020 to March 31, 2022 were included. Donor COVID-19 status was defined by the presence (or absence) of any positive test within 21 days of organ recovery. Donor and recipient characteristics and post-HT outcomes, including a primary composite of death, graft failure, and re-transplantation, were compared by donor COVID-19 status. Of 967 COVID-19(+) potential donors, 19.3% (n=187) were used for HT compared to 26.7% (n=6277) of COVID-19(-) donors (p < 0.001). Transplanted COVID-19(+) vs COVID-19(-) donors were younger, but otherwise were similar. Recipients of hearts from COVID-19+ vs COVID-19(-) donors less frequently received pre-HT inotropes (24.1% vs 31.7%, p=0.023) and ventricular assist device therapy (29.7% vs 36.8%, p=0.040). There were no significant differences in any post-HT outcome by donor COVID-19 status, including the primary composite outcome at 90 days (5.4% vs 5.6%, p=0.91). Among COVID-19(+) donors, the presence of a subsequent negative test prior to transplant was not associated with posttransplant outcomes. Our results suggest that carefully selected COVID-19 positive donors may be used for HT with no difference in short-term post-transplant outcomes. Additional data regarding donor and recipient treatments and impact of vaccination should be collected to better inform our use of organs from COVID(+) donors.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. Across all visits, males (n=150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n=120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.

Impact of predicted heart mass-based size matching on survival after heart transplantation in Korea: Analysis of the Korean Organ Transplant Registry.

Previous studies regarding donor-recipient size and sex matching in heart transplantation (HTx) mainly included Caucasians with only a small portion of Asians. Even predicted heart mass (PHM) has not yet been elucidated in Asians. We evaluated the association between donor-recipient sex and size matching, including mismatching by PHM, and post-heart transplant survival in Korea. We enrolled 660 adult HTx recipients between January 2014 and December 2020 using the Korean Organ Transplant Registry data. Recipients were categorized based on donor-recipient PHM, body weight, and sex matching. The primary outcome was 1-year mortality and retransplantation after HTx and survival analyses were performed using Kaplan-Meier method and Cox proportional hazard models. Among 660 patients, 74 (11.2%), 404 (61.2%), and 182 (27.6%) received undersized (<-15%), matched (-15% to 20%), and oversized (>20%) hearts by PHM, respectively. Size mismatching by PHM was present in a large number of sex-mismatched patients with 85.1% of male donor-female recipients being classified as oversized by PHM and 62.2% of female donor-male recipients being classified as undersized by PHM. Recipients of undersized or oversized hearts by PHM showed an increased 1-year mortality compared with recipients of matched-size hearts (14.8% versus 9.7%; log-rank p=0.038). The increased mortality persisted after adjusting for other factors affecting mortality (hazard ratio=1.60, 95% confidence interval: 1.01-2.56). These associations were not shown in obese recipients (body mass index ≥25 kg/m2). Heart size mismatching by body weight (log-rank p=0.332) or sex mismatching (all, log-rank p > 0.05) did not predict 1-year mortality after HTx. Heart size matching by PHM, not by body weight or sex, was associated with increased 1-year mortality after HTx in Korea.

Cardiovascular mechanism of donor brain death and heart recipient survival.

Heart donation after donor brain death from cardiac arrest despite successful resuscitation may be associated with worse recipient outcomes due to potential graft ischemia or underlying rhythmic/structural defects. However, selected grafts from such donors often have normal cardiac function and anatomy. We investigated whether a cardiovascular mechanism of donor brain death (CV-DBD) was associated with worse recipient outcomes. We queried the United Network for Organ Sharing (UNOS) database for first-time, single-organ, adult (age 18+) heart transplant recipients and their associated donors between January 2005 and March 2021. Recipients were stratified by donor status (CV-DBD vs. non-CV-DBD). We performed multivariable Cox proportional hazards modeling to ascertain whether receiving a CV-DBD graft was independently associated with mortality. Of 35,833 included recipients, 2,702 (7.5%) received CV-DBD grafts. The associated donors were significantly more likely to be female, older, and have a history of diabetes, hypertension, and substance use (all p < .001). On unadjusted Kaplan-Meier analysis, CV-DBD recipients had a significantly reduced median survival than non-CV-DBD recipients (12.0 vs. 13.1 years, log-rank p = .04). However, after adjusting for donor/recipient age, recipient comorbidities, annualized center volume, and transplantation era, CV-DBD organ status was not associated with recipient mortality (hazard ratio: 1.05, 95% confidence interval: 0.96-1.13, p = .28). In this analysis of over 35,000 heart transplants, CV-DBD status was not associated with adjusted recipient survival. Donor brain death due to cardiac arrest should not be an absolute contraindication to heart donation, although graft function should be carefully assessed before transplantation.

Pancreatitis as a Potential Trigger for Severe Accelerated Cardiac Allograft Vasculopathy Early Post Heart Transplant: A Case Report

We present a case of severe accelerated cardiac allograft vasculopathy (CAV), an infrequent finding usually related to dismal prognosis, in a heart recipient with recurrent episodes of acute pancreatitis. A 38-year-old male was transplanted owing to advanced heart failure related to nonischemic dilated cardiomyopathy. On the fifth day after transplantation, a nonbiliary acute ischemic pancreatitis occurred. Recurrent relapses ensued within the following year requiring hospital readmissions for both supportive and pain management. The patient developed graft dysfunction by the 18th month post-transplant with severe multivessel CAV. A trial of bortezomib and percutaneous coronary interventions with drug-eluting stents at coronary arteries were attempted but the patient died suddenly, before the scheduled staged percutaneous coronary intervention for the coronary total occlusion was performed. The causal mechanisms of aggressive accelerated CAV are unclear, but it is suggested that important inflammatory and/or humoral responses may play a pivotal role in this life-threatening disease pathogenesis. Increased levels of biomarkers have been linked to advanced CAV, as well as pancreatitis pathogenesis, related to cytokine activation with remarkable systemic inflammatory response. Some of those inflammatory mediators have been reported as central in both pancreatitis and CAV, more specifically interleukin-6. A pro-inflammatory state due to recurrent acute pancreatitis early after transplantation may have contributed to severely accelerated CAV development in the presented case. Comprehensive evaluation of risk factors may assist in close surveillance and targeted therapies in the management of this challenging post-heart transplant scenario.

Outcomes of Over 1000 Heart Transplants Using Hepatitis C–Positive Donors in the Modern Era

BackgroundAdvances in hepatitis C virus (HCV) treatment and the ongoing opioid epidemic have made HCV-positive donors increasingly available for heart transplantation (HT). This analysis reports outcomes of over 1000 HCV-positive HTs in the United States in the modern era. MethodsThe United Network of Organ Sharing registry was used to identify HTs between 2015 and 2021. Recipients were grouped by donor HCV status and by nucleic acid amplification test (NAT) positivity. The primary outcome was 1-year mortality, and secondary outcomes included 3-year mortality. A subanalysis compared HCV-positive HT outcomes between NAT-positive and NAT-negative donors. Risk adjustment was performed using Cox regression. Kaplan-Meier analysis was used to estimate survival. ResultsThe frequency of HCV-positive HT increased from 0.12% of HTs in 2015 to 12.9% in 2021 (P < .001). Of 16,648 HTs, 1170 (7.0%) used an organ from an HCV-positive donor. Recipients of HCV-positive organs were more likely to be HCV seropositive, older, and White. Unadjusted 1- and 3-year survival rates were not significantly different between recipients of HCV-negative and HCV-positive organs. After risk adjustment HCV-positive donor status was not associated with an elevated risk for 1-year (hazard ratio, 0.92; 95% CI, 0.71-1.19; P = .518) or 3-year mortality. Among HCV-positive HTs 772 (61.7%) were NAT positive. After risk adjustment NAT positivity did not impact 1-year mortality. ConclusionsThe proportion of HCV-positive HTs has increased over 100-fold in recent years. This analysis of the US experience demonstrates that recipients of HCV-positive hearts, including those that are NAT positive, have acceptable outcomes with similar early to midterm survival as recipients of HCV-negative organs.

Abstract 15042: Cardiac-Enhanced Adeno-Associated Viral Vector Achieves Long-Term Transgene Expression in Transplanted Porcine Hearts When Administered During Ex Vivo Perfusion

Introduction: Use of gene therapy for cardiac transplantation is limited by the lack of an effective recombinant Adeno-associated viral vector (rAAV) gene delivery strategy. Ex vivo normothermic perfusion has been increasingly used in clinical practice and is an effective platform for achieving robust global gene delivery to a donor heart. Here we utilized a rationally designed cardiac-enhanced AAV3b variant, SASTG, to deliver the gene firefly luciferase to porcine hearts and evaluated transgene expression 30-days post-transplantation. Methods: Heterotopic heart transplantation was performed using blood-type and MHC matched Yucatan pigs (n=4). Donor hearts underwent ex vivo perfusion for 2-hours with perfusate containing the rAAV SASTG-Luciferase. Three different doses of rAAV were used: 2x10 13 , 8x10 13 , 1x10 14 viral genome copies (VGC). Recipients were survived for 30 days at which time they were euthanized and donor and recipient hearts were examined for overall levels of luciferase activity, luciferase DNA copy number, and histology for luciferase expression on immunostaining and evidence of inflammation. Results: There was a dose-dependent response in luciferase activity observed in the donor heart ventricles with the lowest activity detected at the 2x10 13 VGC dose (1.5-9.9x10 3 RLU/mg) mid-level activity at the 8x10 13 VGC dose (32.7-71.2x10 3 RLU/mg) and highest activity at the 1x10 14 VGC dose (27.6-278.1x10 3 RLU/mg). Luciferase DNA was detectable in a dose-dependent manner in the donor heart ventricles (0.02-131.1x10 3 VGC/pg of DNA), but undetectable in all native hearts. Finally, immunostaining demonstrated diffuse luciferase expression in the donor heart but none in the recipient hearts. There was also no evidence of inflammation in any of the donor hearts. Conclusions: The cardiac-enhanced AAV3b variant, SASTG, is associated with robust, global transgene expression in porcine cardiac allografts when administered during ex vivo perfusion.

Abstract 12595: De Novo Lymphoproliferative Disorders in Heart Transplant Recipients: Predictors and Clinical Outcomes

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is an important cause of morbidity and mortality in heart transplant (HTx) recipients. However, clinical characteristics and predictors of PTLD in the real world have not been well studied. Methods We retrospectively analyzed clinical characteristics, predictors, and outcomes of PTLD, in 28,136 recipients of heart alone transplants between January 2000 and June 2015 from the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry. Results Ten-year incidence of PTLD after successful discharge from HTx during 2000-2007 was 3.8%. The adjusted overall risk of mortality was significantly higher in patients diagnosed with PTLD within 3 years after HTx compared to those without PTLD (HR 2.22, 95% CI 1.86-2.65, p&lt;0.001). Bimodal age peak of the PTLD incidence within the 3 years of HTx and mortality after the diagnosis of PTLD was noted. Both adjusted risk of PTLD incidence and mortality were lower in recent HTx; lower incidence and mortality in era of 2008-2015, compared to 2000-2007 (Incidence: HR 0.75, 95% CI 0.57-0.98, p=0.038) (Mortality: HR 0.86, 95% CI 0.81-0.91, p&lt;0.001). Age at transplant, male recipient, high risk Epstein-Barr virus (EBV) mismatch (donor positive and recipient negative for EBV) were independent risk factors, while primary maintenance therapy with cyclosporine (vs. tacrolimus) at initial discharge was a protective factor for PTLD within 3 years. Conclusions The incidence as well as mortality of PTLD has decreased in recent years of HTx, possibly with advances in changed pattern of immunosuppression according to patient profile. Clinical characteristics such as age, male gender, EBV status and rejection history are key factors for assessing the risk of PTLD, which can be detrimental in the course of post HTx care.

Abstract 15145: Aldehyde Dehydrogenase 2 Agonist Reverses Fibroblast Activation in the End Stage Human Right Ventricle Failure via 3’Utr Regulation of Profibrotic Genes

Background: Cardiac fibrosis, a prominent feature of pressure overloaded right ventricle (RV) in pulmonary hypertension (PH), is fundamental to the development of right ventricle failure (RVF). We found that a defect in alternative polyadenylation (APA) of profibrotic genes is a driving factor that induces fibrosis. Oxidative stress-mediated reactive aldehydes, such as 4-hydroxy-2-nonenal (4HNE) contribute to fibrosis and extracellular matrix (ECM) remodeling. However, the role of 4HNE in APA is unknown. Methods: We compared isolated cardiac fibroblasts from the RVs of explanted transplanted hearts of recipients with pulmonary hypertension patients to control hearts. Results: Compared to controls, tissue and fibroblasts derived from failing RV human hearts have greater deposition of extracellular matrix (ECM) proteins, such as collagen type I alpha (COL1A) and fibronectin (FN1), the expression of alpha smooth muscle actin (α-SMA), indicative of myofibroblast differentiation, and nuclear factor kappa B subunit (NFκB), a transcription factor critical for profibrotic genes transcriptional activation. Moreover, alternative polyadenylation (APA) isoforms of mRNA for COL1A, FN1, NFκB, TGF-β1 and its receptor - transforming growth factor beta receptor 1 (TGFβR1) are associated with shortened 3’UTR in RVF tissues or fibroblasts. Likewise, reduced expression and activity of aldehyde dehydrogenase 2 (ALDH2) expression, a 4HNE detoxifying enzyme, correlated with increased 4HNE adduction in tissues and cardiac fibroblasts derived from RVF hearts. Moreover, ALDH2 activation by its agonist, Alda-1, decreased 4HNE adduction and oxidative stress and most importantly downregulated the gene and protein expression of profibrotic genes, simultaneously lengthening the 3’UTR of the previously shortened profibrotic genes. Conclusion: In RVF, fibroblasts express mRNA of profibrotic genes with shortened 3'UTRs, suggesting the feasibility of developing antifibrotic therapies targeting 3'UTRs in myofibroblasts. Furthermore, our findings suggest that Alda-1 has a therapeutic role in mitigating cardiac fibrosis in RVF hearts by attenuating 4HNE-mediated dysregulation of APA.

Abstract 10563: Differences in Donor-Derived Cell-Free DNA Levels During Allograft Rejections in Hepatitis C Positive Donor Recipient Heart Transplant Patients

Introduction: Non-invasive quantification of donor-derived cell-free DNA (dd-cfDNA) has recently been shown to correlate with endomyocardial biopsy (EMB) for diagnosis of allograft rejection in heart transplant (HTx) patients. Hepatitis C virus-positive (HCV+) donor hearts are being more utilized with comparable survival outcomes. Hypothesis: The aim of this study is to evaluate the utility of dd-cfDNA monitoring in different types of rejections in recipients of HCV+ donor hearts. Methods: We performed a retrospective review of recipients of HCV+ donor hearts between 2018-2022 with paired dd-cfDNA/GEP and EMB results. The levels of dd-cfDNA/GEP were compared in different rejection types and no rejection for patients using non-parametric comparison. CMR ISHLT ≥ Grade 2R and AMR ≥ Grade 1 from histology were considered as allograft rejection. Results: There were 17 patients who underwent heart transplant from HCV+ donor heart. There was a total of 89 paired samples with dd-cfDNA and EMB. The reason for the biopsy was mostly for routine surveillance (N=68, 76.4%). There was a total of 1 case (1.1%) of grade 2 CMR and 16 cases of pAMR (18%; 10 cases of grade 1, 6 cases of grade 2). Levels of dd-cfDNA were elevated in cases of AMR when compared to no rejection (Median: 0.24% vs. 0.12%, respectively, P&lt;0.001; Figure 1A). There were 57 samples (78%) with dd-cfDNA reference values of &lt;0.12%. In patients with no rejection, dd-cfDNA levels were all below 0.25%. The AUC for elevation of dd-cfDNA and allograft rejection was 0.85 [95% C.I.: 0.72-0.97; P&lt;0.001; Figure 1B]. Conclusions: Non-invasive quantitation of dd-cfDNA levels is elevated in allograft rejection as assessed by traditional microscopy from EMB. There was no false-positive rate of dd-cfDNA in allograft rejection at a threshold of 0.25%. Further studies are indicated to study whether dd-cfDNA levels transiently increase only in the setting of allograft rejection or active hepatitis C viremia at the time of biopsy.

Impact of occurrence of cardiac arrest in the donor on long-term outcomes of pediatric heart transplantation.

The impact of cardiac arrest in the donor on long-term outcomes of pediatric heart transplantation has not been studied. The UNOS database was queried for primary pediatric heart transplantation (1999-2020). The cohort was divided into recipients who received a cardiac allograft from a donor who had a cardiac arrest (CA) versus a donor who did not (NCA). Univariable and multivariable analysis was done to compare recipient outcomes, followed by survival analysis using the Kaplan-Meier method. A total of 7300 patients underwent heart transplantation, of which 579 (7.9%) patients belonged to the CA group. The CA group was younger (median 3 vs. 5 years, p < .001), male (51% vs. 47%, p = .03), and smaller in weight (13 vs. 17 kg, p < .001) and height (101 vs. 109 cm, p < .001) than the NCA group. The groups were similar in recipient heart failure diagnosis and blood type. The CA donors were younger (3 vs. 6 years, p < .001) versus nonwhite (48% vs. 45%, p = .003) and died from drowning and asphyxiation compared to blunt injury and intracranial hemorrhage in the NCA group. The left-ventricular ejection fraction was similar between the groups. There was no difference in VAD and ECMO use before the transplant. The listing status, waitlist days, and allograft ischemic times were similar. Posttransplant morbidity such as stroke, dialysis, pacemaker implantation, and treated rejection were similar. Donor cardiac arrest (hazard ratio = 0.93, p = .5) was not an independent predictor of mortality on multivariable analysis. There was no survival difference even beyond 20 years of follow-up between the groups (p = .88). The occurrence of donor cardiac arrest has no impact on long-term survival in pediatric heart transplant recipients.

Female donor hearts can improve survival for male pediatric heart transplant recipients.

Both gender- and weight-matching between donor and recipient are thought to impact survival in pediatric heart transplantation, with clinical dogma holding that male donor hearts and "ideal" weight-matching yield superior survival. The composite impacts of gender and weight on post-transplant survival (PTS) are understudied. All pediatric (age <18) heart recipients between 1989 and 2021 with the complete recipient and donor gender and weight data were identified in the United Network for Organ Sharing database. Patients were grouped by recipient-donor gender (M & F) and donor-to-recipient weight ratio (DRWR; undersized [<0.8], ideal-sized [0.8-1.5], oversized [>1.5]). A total of 10697 patients were identified. Among male recipients, PTS was greatest with oversized DRWR from either male or female donors (median 22.4 and 20.6 years; p < .001 vs. others) and lowest for undersized DRWR from either male or female donors (median 13.4 and 13.2 years; p < .001 vs. others). The majority (64%) of male recipients received ideal-sized DRWR, among which female donor hearts yielded superior survival to males (median 18.9 vs. 17.4 years, p=.014). No differences in PTS existed for female recipients on the basis of gender-match, DRWR, and gender/DRWR together (all p > .1). When considered together, gender and DRWR pairings impact PTS in male-but not female-pediatric heart transplant recipients. For males receiving ideal-sized DRWR organs (most common pairing, >60%), male recipients achieve superior survival when female donor hearts are transplanted. These findings suggest that if weight is being used for size-matching, donor gender should also be considered, particularly for male recipients.

Female sex and advanced age are associated with invasive cytomegalovirus disease in solid organ transplant recipients.

Limited data exist to describe sex-based differences in the severity of cytomegalovirus (CMV) infection after solid organ transplant (SOT). We sought to identify if a difference exists in likelihood of tissue-invasive disease between male and female SOT recipients and to understand how age affects this relationship. A retrospective cohort of 180 heart, liver, and kidney recipients treated for CMV was examined. A logistic regression model was developed to assess the relationship between female sex and CMV type (noninvasive vs. invasive). A secondary regression analysis looked at the relationship of invasive CMV with a variable combining sex with age above or below 50. There were 37 cases of proven or probable invasive CMV, occurring in 30% of females versus 16% of males. After adjustment for potential confounders, females with CMV infection were significantly more likely to have invasive disease (odds ratio (OR) 2.69, 95% confidence interval (CI) 1.25-5.90, p = .01). Females 50 years or older were at particular risk compared with males under 50 years (adjusted OR 4.54, 95% CI 1.33-18.83, p = .02). Female SOT recipients with CMV in our cohort were more likely than males to have tissue-invasive disease, with the highest risk among older females. Further prospective studies are warranted to explore underlying immunologic mechanisms.

Posttransplant Complications and Genetic Loci Involved in Telomere Maintenance in Heart Transplant Patients.

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients.