Comparative Analysis of Ischemia-Reperfusion Injury in Heart Transplantation: A Single-Center Study Evaluating Conventional Ice-Cold Storage versus the Paragonix SherpaPak Cardiac Transport System.

BACKGROUND: Since the 2018 allocation system change in heart transplantation (HT), ischemic times have increased, which may be associated with peri-operative and post-operative complications. This study aimed to compare ischemia reperfusion injury (IRI) in hearts preserved using ice-cold storage (ICS) and the Paragonix SherpaPak TM Cardiac Transport System (CTS). METHODS: From January 2021 to June 2022, consecutive endomyocardial biopsies from 90 HT recipients were analyzed by a cardiac pathologist in a single-blinded manner: 33 ICS and 57 CTS. Endomyocardial biopsies were performed at three-time intervals post-HT, and the severity of IRI manifesting histologically as coagulative myocyte necrosis (CMN) was evaluated, along with graft rejection and graft function. RESULTS: The incidence of IRI at weeks 1, 4, and 8 post-HT were similar between the ICS and CTS groups. There was a 59.3% statistically significant reduction in CMN from week 1 to 4 with CTS, but not with ICS. By week 8, there were significant reductions in CMN in both groups. Only 1 out of 33 (3%) patients in the ICS group had an ischemic time >240 mins, compared to 10 out of 52 (19%) patients in the CTS group. During the follow-up period of 8 weeks to 12 months, there were no significant differences in rejection rates, formation of de novo donor-specific antibodies and overall survival between the groups. CONCLUSION: The CTS preservation system had similar rates of IRI and clinical outcomes compared to ICS despite longer overall ischemic times. There is significantly more recovery of IRI in the early post operative period with CTS. This study supports CTS as a viable option for preservation from remote locations, expanding the donor pool.

Impact of age over 70 years in the new allocation system on the outcomes of heart transplantation in the US.

BACKGROUND: United Network for Organ Sharing (UNOS) allocation criteria changed in 2018 to accommodate the increased prevalence of patients on a ventricular assist device as a bridge to heart transplant and prioritize sicker people in anticipation of a heart graft. We aimed to assess the impact of patient age in the new allocation policy on mortality following heart transplantation. Secondary outcomes included the effect of age ≥70 on post-transplant events, including stroke, dialysis, pacemaker, and rejection requiring treatment. METHODS: The UNOS Registry was queried to identify patients who underwent heart transplants alone in the US between 2000 and 2021. Patients were divided into groups according to their age (over 70 and under 70 years old). RESULTS: Patients aged over 70 were more likely to require dialysis during follow-up, but less likely to experience rejection requiring treatment, compared with patients aged <70. Age ≥70 in the new allocation system was a significant predictor of 1-year mortality (adjusted HR: 1.41; 95% CI: 1.05-1.91; p = .024), but its effect on 5-year mortality was not significant after adjusting for potential confounders (adjusted HR: 1.27; 95% CI:.97-1.66; p = .077). Undergoing transplantation under the new allocation policy vs the old allocation policy was not a significant predictor of mortality in patients over 70 years old. CONCLUSIONS: Age ≥70 is a significant predictor of 1-year mortality following heart transplantation, but not at 5 and 10 years; however, the new allocation does not seem to have changed the outcomes for this group of patients.

Procurement Trends, Indications, and Outcomes of Heart-Lung Transplantation in the Contemporary Era.

BACKGROUND: Evolving trends in organ procurement and technological innovation prompted an investigation into recent trends, indications, and outcomes following combined heart-lung transplantation (HLTx). METHODS: The United Network for Organ Sharing database was queried for all adult (≥18 years) HLTx performed between July 1, 2013 and June 30, 2023. Patients with previous transplants were excluded. The primary endpoint was the effect of donor, recipient, and transplantation characteristics on 1- and 5-year survival. Secondary analyses included a comparison of HLTx at high- and low-volume centers, an assessment of HLTx following donation after circulatory death (DCD), and an evaluation of HLTx volume over time. Cox proportional-hazards models were used to assess factors associated with mortality. Temporal trends were evaluated with linear regression. RESULTS: After exclusions, 319 patients were analyzed, of whom 5 (1.6%) were DCD. HLTx volume increased from 2013 to 2023 (p < 0.001). One- and 5-year survival following HLTx was 84.0% and 59.5%, respectively. One-year survival was higher for patients undergoing HLTx at a high-volume center (88.3% vs. 77.9%; p = 0.012). After risk adjustment, extracorporeal membrane oxygenation support 72 h posttransplant and predischarge dialysis were associated with increased 1-year mortality (HR = 3.19, 95% CI = 1.86-5.49 and HR = 3.47, 95% CI = 2.17-5.54, respectively) and 5-year mortality (HR = 2.901, 95% CI = 1.679-5.011 and HR = 3.327, 95% CI = 2.085-5.311, respectively), but HLTx at a high-volume center was not associated with either. CONCLUSIONS: HLTx volume has resurged, with DCD HLTx emerging as a viable procurement strategy. Factors associated with 1- and 5-year survival may be used to guide postoperative management following HLTx.

Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

The decline in kidney function after heart transplantation and its impact on survival.

BACKGROUND: Evidence of decline in native renal function after heart transplantation (HTx) in the Asian population is limited. This study determined the incidence and risk factors associated with declining kidney function after HTx and its impact on survival. METHODS: A retrospective study of consecutive adult heart transplant patients was conducted in a single center between 2010 and 2020. The decline in kidney function was defined as the presence of one of the following criteria, including a ≥ 40% decline in eGFR, absolute value <15 mL/min/1.73 m2 (calculated by the CKD-EPI method), doubling of serum creatinine, or dialysis. RESULTS: A total of 79 patients (77% male, mean age 44.5 ± 11.53 years, with a mean eGFR at discharge from the heart transplant admission of 87.9 ± 25.48 mL/min/1.73 m2 ) were included. During the median follow-up of 42 months, the rate of decline in eGFR was 3.9 mL/min/1.73 m2 per year, with a cumulative probability of decline in kidney function of 22% at 1 year and 43% at 5 years. The need for dialysis was 2.5% at 1 year and 5% at 5 years. The decline in kidney function within 1 year after discharge (hazard ratio (HR), 22.24; p = .007) and pre-HTx diabetes mellitus (DM) (HR, 8.99; p = .034) were independently associated with the need for dialysis. Post-HTx dialysis predicted all-cause mortality (HR, 4.47; p = .017). CONCLUSIONS: Approximately 20% of HTx patients developed a decline in kidney function within 1 year after discharge. These individuals and pre-HTx DM patients needed preventive measures to prevent progression to chronic dialysis, which impacted survival. (thaiclinicaltrials.org number, TCTR20230620004).

Role of ascorbic acid in cardiac allograft vasculopathy.

PURPOSE OF THE REVIEW: Cardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long-term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post-transplant care. RECENT DATA: Recent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial. SUMMARY: CAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large-scale randomized control studies of ascorbic acid are needed to establish the role in routine post-transplant management.

Predicted heart mass based on ideal body weight for donor-to-recipient size matching.

BACKGROUND: Predicted heart mass (PHM) is a commonly used tool for donor-to-recipient size matching. However, incorporating body weight as part of PHM can be considered problematic given its high variability, and low metabolic nature of fat. We sought to assess whether substituting the actual donor and recipient weight with the ideal body weight (IBW) would affect the association of donor-to-recipient PHM ratio with 1-year and overall survival after heart transplantation. METHODS: The United Network for Organ Sharing (UNOS) database was queried for adult patients who received a primary heart transplant between January 2000 and September 2021. RESULTS: Both PHM and ideal PHM (IPHM) ratios were associated with one-year (PHM: p = .003; IPHM: p = .0007) and overall (PHM: p = .02; IPHM: p = .02) survival. In the continuous analysis with restricted cubic splines, both PHM (p = .0003) and IPHM (p = .00001) were associated with relative hazards of death. CONCLUSION: IPHM is significantly associated with post-transplant survival and may be a useful compliment to PHM.

Early elevated donor-derived cell-free DNA levels in heart transplant recipients following precision-controlled cardiac transport system or ice-cooled organ transport.

BACKGROUND: Recent innovations in temperature-controlled cardiac transportation allow for static hypothermic preservation of transplant organs during transportation. We assessed differences in donor-derived cell-free DNA (dd-cfDNA) using the SherpaPak cardiac transport system (SCTS) and traditional ice transportation. METHODS: Single-organ heart transplant recipients between January 2020 and January 2022 were included if they had dd-cfDNA measures ≤6 weeks post-transplant along with the baseline biopsy at 6 weeks as part of the surveillance protocol and no biopsy-confirmed rejection ≤90 days. Elevated dd-cfDNA ≥.20% were compared between groups using logistic regression including a subject effect. RESULTS: Of 65 hearts transplanted, 30 were transported with SCTS and 35 on ice. Recipient characteristics were similar between groups. Donors in the SCTS group were older (34 vs. 40 years, p = .04) with a longer total ischemic time (171 vs. 212 min, p = .002). Recipients in the SCTS group had a greater risk of elevated dd-cfDNA unadjusted and adjusted for donor age, and prolonged ischemic times > 3.5 h (Unadjusted odds ratio: 4.9, 95%-CI: 1.08-22.5, p = .039 and Adjusted odds ratio: 5.5, 95%-CI: 1.03-29.6, p = .046). Primary graft dysfunction rates and 1-year mortality were comparable between groups. CONCLUSION: Elevated dd-cfDNA in patients procured with SCTS may indicate that graft injury was not negated relative to ice transport. However, there were no clinical differences noted in short or long-term outcomes including mortality despite a longer ischemic time in the SCTS group.

Positive donor blood cultures are not associated with worse heart transplant survival.

BACKGROUND: Recent evidence has demonstrated that transplantation of hearts with blood culture positive donors (BCPDs) to pediatric recipients is safe and effective. Few studies have analyzed the effect of BCPD on adult heart transplant recipients. METHODS: The United Network for Organ Sharing (UNOS) database was retrospectively reviewed from September, 1987 to March, 2021. Exclusion criteria included pediatric donors/recipients, donor ejection fraction <10% or >85%, inactive listed recipients, donors missing blood cultures, and recipients missing follow-up time. Outcomes were compared with fully adjusted logistic models. To account for discrepancies in BCPD and non-BCPD covariates, an inverse proportionally weighted model with regression adjustment (IPWRA) was used. RESULTS: A total of 60 592 donors were non-BCPD, while 4009 were BCPD. 7% of hearts not transplanted were BCPD, while 6% of hearts transplanted were BCPD (p = .001). These rates have been nearly constant since 2005. There were no differences in short term survival between the two groups in the adjusted or IPWRA models (p = .103 and .277, respectively). Additionally, the BCPD group had longer ischemic time (3.24 vs. 3.06 h, p < .001), older donor age (32.73 vs. 31.65 years, p < .001), and older recipient age (52.76 vs. 52.09 years, p = .001). The IPWRA revealed an average additional 3.4 years of overall survival and 2.25 years of graft function for BCPD versus non-BCPD recipients, although these results failed to reach statistical significance (p = .387 and .527, respectively). CONCLUSIONS: Given the need for more donor hearts, donors with positive blood cultures should be considered. Great care in evaluating such patients is advised to eliminate donors with untreated infections, while carefully selected donors can be considered and used.

Diagnostic and management roles of FDG PET/CT imaging in post-transplant lympho-proliferation in pediatric heart transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of pediatric heart transplant (PHTx). 18F-FDG PET/CT has been used to differentiate early lympho-proliferation from more advanced PTLD. We report our experience with PET/CT in the management of PTLD following PHTx. METHODS: This was a retrospective study of 100 consecutive PHTx recipients at our institution between 2004 and 2018. Patients who underwent PET/CT or conventional CT scans to evaluate for PTLD or high Epstein-Barr viral load were included. RESULTS: Males, eight females. Median age at transplant was 3.5 months (IQR = 1.5-27.5). Median age at PTLD diagnosis was 13.3 years (IQR = 9.2-16.1). Median time between transplant and PTLD diagnosis was 9.5 (IQR = 4.5-15) years. Induction agents were used in 12 patients (50%): Thymoglobulin (N = 9), anti-IL2 (N = 2), and Rituximab (N = 1). Eighteen patients (75%) had PET/CT, of whom 14 had 18FDG-avid PTLD. Six had conventional CT. Nineteen patients (79.2%) had diagnostic biopsy confirmation of PTLD, and 5 (20.8%) had excisional biopsies. Two patients had Hodgkin's lymphoma; nine had monomorphic PTLD; eight had polymorphic PTLD; five were classified as other. Nine patients had monomorphic PTLD, including seven with diffuse large cell lymphoma (DLBC) and one with T cell lymphoma. The majority (16/24) had multi-site involvement at PTLD diagnosis, and PET/CT showed that 31.3% (5/16) had easily accessible subcutaneous nodes. Seventeen patients (overall survival 71%) underwent successful treatment without recurrence of PTLD. Of seven deaths (7/24, 29%), five had DLBC lymphoma, one had polymorphic PTLD and one had T-cell lymphoma. CONCLUSION: PET-CT allowed simultaneous anatomical and functional assessment of PTLD lesions, while guiding biopsy. In patients with multiple lesions, PET/CT revealed the most prominent and active lesions, improving diagnostic accuracy.

Long-term follow-up of acute and chronic rejection in heart transplant recipients from hepatitis C viremic (NAT+) donors.

The long-term safety of heart transplants from hepatitis C viremic (NAT+) donors remains uncertain. We conducted a prospective study of all patients who underwent heart transplantation at our center from January 2018 through August 2020. Routine testing was performed to assess for donor-derived cell-free DNA, acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV). Allograft dysfunction and mortality were also monitored. Seventy-five NAT- recipients and 32 NAT+ recipients were enrolled in the study. All NAT+ recipients developed viremia detected by PCR, were treated with glecaprevir/pibrentasvir at the time of viremia detection, and cleared the virus by 59 days post-transplant. Patients who underwent NAT testing starting on post-operative day 7 (NAT+ Group 1) had significantly higher viral loads and were viremic for a longer period compared with patients tested on post-operative day 1 (NAT+ Group 2). Through 3.5 years of follow-up, there were no statistically significant differences in timing, severity, or frequency of ACR in NAT+ recipients compared with the NAT- cohort, nor were there differences in noninvasive measures of graft injury, incidence or severity of CAV, graft dysfunction, or mortality. There were five episodes of AMR, all in the NAT- group. There were no statistically significant differences between Group 1 and Group 2 NAT+ cohorts. Overall, these findings underscore the safety of heart transplantation from NAT+ donors.

Targeting IL-6 to prevent cardiac allograft rejection.

Outcomes following heart transplantation remain suboptimal with acute and chronic rejection being major contributors to poor long-term survival. IL-6 is increasingly recognized as a critical pro-inflammatory cytokine involved in allograft injury and has been shown to play a key role in regulating the inflammatory and alloimmune responses following heart transplantation. Therapies that inhibit IL-6 signaling have emerged as promising strategies to prevent allograft rejection. Here, we review experimental and pre-clinical evidence that supports the potential use of IL-6 signaling blockade to improve outcomes in heart transplant recipients.

Outcomes of diabetic patients with end-stage heart failure listed for heart transplantation: A propensity-matched analysis.

BACKGROUND: We investigated the current trends and outcomes of diabetic patients listed for heart transplants in the U.S. and provided a method for risk-stratification. METHODS: Using data from the United Network for Organ Sharing (UNOS), we identified heart failure patients listed for heart transplants between 2010 and 2019. Diabetic patients were propensity-matched with non-diabetics, and waitlist mortality as well as post-transplant graft survival were compared between the two groups. Further risk-stratification of diabetic patients was done based on the risk factors that independently predict graft failure. RESULTS: 28,928 adult patients (30% diabetic) with end-stage heart failure were added to the waitlist over the study period. In the propensity-matched cohort, waitlist mortality was higher in diabetic patients compared to non-diabetics (HR = 1.13 (95% CI = 1.04-1.22, P = .002). Over the study period, 5739 patients with diabetes were transplanted. In the propensity-matched cohorts of transplant recipients, the rate of graft failure was significantly higher for diabetic patients (23.3%) compared to non-diabetics (20.4%); HR = 1.17, 95% CI = 1.08-1.26, P < .001. We identified 12 risk factors of graft failure among diabetic patients and developed a risk score that further risk-stratify these patients. Diabetic patients at low risk (score≤4) had similar graft survival as patients without diabetes (HR = .91, 95% CI = .82-1.01, P = .06). On the other hand, high-risk diabetic patients had worse graft survival compared to non-diabetics (HR = 1.52, 95% CI = 1.38-1.67, P < .001). CONCLUSION: Among patients with end-stage heart failure, pre-existing diabetes was associated with higher waitlist mortality and worse graft survival. However, with careful patient selection, graft survival is similar to those without diabetes.

Functional status of heart transplant recipients predicts survival.

INTRODUCTION: Recipient functional status prior to transplantation can significantly impact post-transplant survival. METHODS: The United Network for Organ Sharing database was queried for adult heart transplants including data on functional capacity and from February 1, 2005 to March 1, 2021; there were 32 875 cases included. The four functional categories studied were based on adult daily activities of living and were separated into total assistance required, some assistance required, no assistance required, and near death. Survival outcomes were compared for recipient's pretransplant level of functional status versus those with near death status. These were compared using adjusted logistic regression (odds of death at 30 days and 1 year) and conditional Cox models (overall survival and time until post-transplant rejection). All models were adjusted for donor age, sex, ethnicity, ischemic time, as well as recipient age, sex, ethnicity, length of stay, UNOS region, ventricular assist device, creatinine, days on the waiting list, and status at transplant. RESULTS: There were 12 953 recipients classified as "near death" or "severely disabled"; 7711 "required total assistance in daily living", 7,328 "needed some", and 4883 "needed none". In adjusted models, the probabilities of death for the lowest functioning groups within 30 days and 1 year were 5% and 10%, respectively. Those "requiring total assistance" had analogous probabilities of 3% (OR = 0.58; p < 0.001) and 9% (OR = 0.81; p < 0.001). Those "requiring some assistance" had probabilities of 3% (OR = 0.56; p < 0.001) and 9% (OR = 0.74; p < 0.001). Lastly, those "requiring no assistance" had probabilities of death of 2% (OR = 0.35; p < 0.001) and 7% (OR = 0.63; p < 0.001). CONCLUSION: Recipient functional status assessed pre-transplant and recorded in the UNOS database is a strong predictor of post-transplant survival.

Long-term outcomes after heart transplantation using ex vivo allograft perfusion in standard risk donors: A single-center experience.

INTRODUCTION: The Organ Care System (OCS) is an ex vivo perfusion platform for donor heart preservation. Short/mid-term post-transplant outcomes after its use are comparable to standard cold storage (CS). We evaluated long-term outcomes following its use. METHODS: Between 2011 and 2013, 38 patients from a single center were randomized as a part of the PROCEED II trial to receive allografts preserved with CS (n = 19) or OCS (n = 19). Endpoints included 8-year survival, survival free from graft-related deaths, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejections. RESULTS: Eight-year survival was 57.9% in the OCS group and 73.7% in the CS group (p = .24). Freedom from CAV was 89.5% in the OCS group and 67.8% in the CS group (p = .13). Freedom from NF-MACE was 89.5% in the OCS group and 67.5% in the CS group (p = .14). Eight-year survival free from graft-related death was equivalent between the two groups (84.2% vs. 84.2%, p = .93). No differences in rejection episodes were observed (all p > .5). CONCLUSIONS: In select patients receiving OCS preserved allografts, late post-transplant survival trended lower than those transplanted with an allograft preserved with CS. This is based on a small single-center series, and larger numbers are needed to confirm these findings.

Predictors of 1-year outcome after cardiac re-transplantation: Machine learning analysis.

BACKGROUND: As cardiac re-transplantation is associated with inferior outcomes compared with primary transplantation, allocating scarce resources to appropriate re-transplant candidates is important. The aim of this study is to elucidate the factors associated with 1-year mortality in cardiac re-transplantation using the random forests algorithm for survival analysis. METHODS: We retrospectively reviewed the United Network for Organ Sharing registry and identified all adult (> 17 years old) recipients who underwent cardiac re-transplantation between January 2000 and March 2020. The random forest algorithm on Cox modeling was used to calculate the variable importance (VIMP) of independent variables for contributing to 1-year mortality. RESULTS: A total of 1294 patients underwent cardiac re-transplantation. Of these, 137 patients were re-transplanted within 1 year of their first transplant, while 1157 patients were re-transplanted more than 1 year after their first transplant. One-year mortality was significantly higher for patients receiving early transplantation compared with those receiving late transplantation (Early 40.6% vs. Late 13.6%, log-rank P < .001). Machine learning analysis showed that total bilirubin (> 2 mg/dl) (VIMP, 2.99%) was an independent predictor of 1-year mortality after early re-transplant. High BMI (> 30.0 kg/m2 ) (VIMP, 1.43%) and ventilator dependence (VIMP, 1.47%) were independent predictors of 1-year mortality for the late re-transplantation group. CONCLUSION: Machine learning showed that optimal 1-year survival following cardiac re-transplantation was significantly related to liver function in early re-transplantation, and to obesity and preoperative ventilator dependence in late re-transplantation.

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor ß chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFß) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.

Hypothermic, oxygenated perfusion (HOPE) provides cardioprotection via succinate oxidation prior to normothermic perfusion in a rat model of donation after circulatory death (DCD).

In donation after circulatory death (DCD), cardiac grafts are subjected to warm ischemia in situ, prior to a brief period of cold, static storage (CSS) at procurement, and ex situ, normothermic, machine perfusion (NMP) for transport and graft evaluation. Cold ischemia and normothermic reoxygenation during NMP could aggravate graft injury through continued accumulation and oxidation, respectively, of mitochondrial succinate, and the resultant oxidative stress. We hypothesized that replacing CSS with hypothermic, oxygenated perfusion (HOPE) could provide cardioprotection by reducing cardiac succinate levels before NMP. DCD was simulated in male Wistar rats. Following 21 minutes in situ ischemia, explanted hearts underwent 30 minutes hypothermic storage with 1 of the following: (1) CSS, (2) HOPE, (3) hypothermic deoxygenated perfusion (HNPE), or (4) HOPE + AA5 (succinate dehydrogenase inhibitor) followed by normothermic reperfusion to measure cardiac and metabolic recovery. After hypothermic storage, tissue ATP/ADP levels were higher and succinate concentration was lower in HOPE vs CSS, HNPE, and HOPE + AA5 hearts. After 60 minutes reperfusion, cardiac function was increased and cellular injury was decreased in HOPE compared with CSS, HNPE, and HOPE + AA5 hearts. HOPE provides improved cardioprotection via succinate oxidation prior to normothermic reperfusion compared with CSS, and therefore is a promising strategy for preservation of cardiac grafts obtained with DCD.

Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection.

Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction . Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1ß maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.