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Microvascular dysfunction (MVD) is considered a form of cardiac allograft vasculopathy (CAV), independently associated with poor prognosis after heart transplantation (HTX). It is unknown whether traditional risk factors for CAV are also applicable to MVD. We retrospectively analyzed factors associated with MVD in 94 HTX recipients who completed a PET scan after a normal baseline left heart catheterization excluding epicardial CAV. MVD was defined by abnormal PET blood flow. The mean age was 52 ± 14 and MVD was found in 49 patients (53%). No donor risk factors were significantly associated with recipient MVD. Recipients risk factors for MVD included—diabetes mellitus (51% vs. 27%, p = 0.016) and hypertension (78% vs. 49%, p = 0.004) in patients with and without MVD, respectively. In a multivariate model, recipient hypertension and diabetes were the only significant determinants of MVD development (OR = 2.63, 95% CI [1.69–36.98], p = 0.009 and OR 2.1, 95% CI [1.10–15.38], p = 0.035, respectively). In conclusion, MVD was more associated with metabolic risk determinants rather than traditional CAV risk factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Complement inhibition offers a novel treatment approach for antibody‐mediated rejection (AMR). We examined patients with hemodynamic compromise AMR 2010–2020, comparing eight patients supplemented with eculizumab to 10 patients without; administration was at the treating physician's discretion. There were no significant differences between groups though eculizumab patients had a non‐significantly higher inotrope score (208.8 mcg/kg/min vs. 2.6 mcg/kg/min; P =.22), more extracorporeal membrane oxygenation (ECMO) (62.5% vs. 20%; P =.066), and worse 1‐year survival (37.5% vs. 60%; P =.63). The role of eculizumab is uncertain in AMR; multicenter collaborative studies are essential to better define its role. [ABSTRACT FROM AUTHOR]

Extended‐release tacrolimus for prophylaxis of allograft rejection in orthotopic heart transplant (OHT) recipients is currently not FDA‐approved. One such extended‐release formulation of tacrolimus known as LCPT allows once‐daily dosing and improves bioavailability compared to immediate‐release tacrolimus (IR‐tacrolimus). We compared the efficacy and safety of LCPT to IR‐tacrolimus applied de novo in adult OHT recipients. Twenty‐five prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR‐tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 1 year was compared using non‐inferiority analysis. LCPT demonstrated non‐inferiority to IR‐tacrolimus, with a primary outcome risk reduction of 20% (90% CI: ‐40%, ‐.5%; non‐inferiority P =.001). Tacrolimus trough levels peaked at 2–3 months and were higher in LCPT (median 14.5 vs. 12.7 ng/ml; P =.03) with similar dose levels (LCPT vs. IR‐tacrolimus:.08 vs..09 mg/kg/day; P =.33). Cardiovascular‐related readmissions were reduced by 62% (P =.046) in LCPT patients. The complication rate per transplant admission and all‐cause readmission rate did not differ significantly. These results suggest that LCPT is non‐inferior in efficacy to IR‐tacrolimus with a similar safety profile and improved bioavailability in OHT. [ABSTRACT FROM AUTHOR]

Background: Cardiac allograft vasculopathy (CAV) causes late graft dysfunction and post‐transplant mortality. Currently, the effects of different donor‐specific antibodies (DSA) on the severity of CAV remain unclear. Method: We evaluated 526 adult heart transplant recipients at a single center between January 2010 and August 2015. Subjects were divided into those with DSA (n = 142) and those without DSA (n = 384, control). The DSA group was stratified into persistent DSA (n = 34), transient DSA (n = 105), 1:8 dilution DSA (n = 45), complement‐binding (C1q) DSA (n = 36), Class I DSA (n = 37), and Class II DSA (n = 105). The primary outcome was the incidence of moderate‐to‐severe CAV (CAV 2/3) at 5‐year follow‐up. Results: Subjects with persistent DSA, 1:8 dilution DSA, and C1q DSA had higher incidence of CAV 2/3 compared the control group (17.6%, 13.3%, and 16.7% vs. 3.1%, respectively; P≤.001). The incidence of CAV 2/3 between subjects with transient DSA and the control group was similar (2.8% vs. 3.1%; P =.888). Subjects with Class II DSA also had higher incidence of CAV 2/3 (7.6% vs. 3.1%; P =.039). Conclusion: DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. These DSA characteristics may prognosticate disease and warrant consideration for treatment. [ABSTRACT FROM AUTHOR]

Background: Heart transplantation, as a therapeutic option for patients with advanced heart failure, possesses a high rate of morbidity and mortality. One of the complications associated with this procedure is the development of postoperative acute kidney injury (AKI) Material and methods: We aimed to evaluate the incidence of early postoperative AKI and the need for continuous renal replacement therapy (RRT) after heart transplantation. Data of 126 patients who underwent heart transplantation from January 2015 to November 2019 were collected. Statistical analysis was performed to identify the predictors of postoperative AKI. Results: Out of 126 patients, 74 (58.7 %) developed AKI and 13 (10%) required RRT after transplant. Independent predictors of AKI are shown to be factors associated with surgical procedures such as graft ischemic time as were previous cardiac operation, administered Voluven (starch) dose > 400 ml, and transfusion of more than four blood units. Conclusion: Our findings suggest that modifiable factors exist that can affect the risk of developing AKI following heart transplantation. [ABSTRACT FROM AUTHOR]

Background: Atrial flutter is the most common arrhythmia post cardiac transplantation. Observational studies in the non‐transplant population have shown prognostic benefit with catheter ablation; however, there are no data in the heart transplant population. Objectives: This study evaluated the experience of catheter ablation in atrial flutter post cardiac transplantation. Methods: A retrospective review of experience of late onset atrial flutter at the Freeman Hospital, Newcastle‐upon‐Tyne, UK, between 1985 and January 2020. Results: Sixty eight of the 722 patients who survived 6 months post cardiac transplantation developed late atrial flutter giving an incidence of 9.4%. Thirty‐two patients were managed with ablation with treatment largely determined by time of flutter onset. Kaplan Meier estimates for arrhythmia free survival post first ablation for organized atrial arrhythmias was 83.3% at 1 year. Kaplan‐Meier estimates for median survival post onset of atrial arrhythmias treated with ablation was 11.34 years (95% CI 8.00–14.57), compared to 5.79 years in patients managed medically (95%CI 2.26–9.32) (P =.026). Conclusions: Atrial flutter is an important late complication of cardiac transplantation. Patients treated with ablation in the modern era had increased survival compared to a historical cohort. [ABSTRACT FROM AUTHOR]

Problem: Mathematical modeling suggests aggressive ganciclovir dosing in the first week of cytomegalovirus disease (CMV) treatment may improve response. This has not been evaluated clinically. Methods: Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19–7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step‐down to standard‐of‐care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16–3/2/19) served as a comparator. Primary objective: rate of viral clearance (delta log CMV) at therapy day 7. Secondary objective: safety/short term efficacy. Results: Fifty‐four patients met inclusion criteria; 22 high‐dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P =.03) and higher presenting viral‐load in the high‐dose group (log 6.0±.7 vs. log 5.2±1.2, P =.02). High‐dose resulted in significantly greater response to therapy at day 7 (log ‐.92±.51 vs. log ‐.56±.79, P =.04). Change in WBC at day 7 was not different (‐.49±1.92 vs. ‐.45±5.1, P =.97). Short‐term clinical outcomes were similar between groups including mean hospital length‐of‐stay (P =.52), readmission rates (30 d: P =.38; 90 d: P =.5) and achievement of CMV viral‐load less‐than‐lower‐limit‐of‐quantification by day 90 (73% vs. 84%, P =.06). Rejection after CMV as well as graft/patient survival were similar between groups (P =.56, P >.99, P >.99). Conclusion: A high‐dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Early aspirin (ASA) use after orthotopic heart transplantation (OHT) has been associated with lower rates of cardiac allograft vasculopathy (CAV). We hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection. Methods: Patients receiving OHT at a single center 2004–2010 (n = 120) were categorized by early ASA use post‐transplant (ASA use for > 6 months in the first year) and the presence of biopsy‐defined acute cellular rejection (ACR) and/or antibody‐mediated rejection (AMR) during 5‐year follow‐up. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to moderate/severe CAV (ISHLT ≥ 2) was investigated. Results: Among patients with ACR or AMR, ASA therapy was associated with significantly lower rates of CAV≥ 2 (3.3 vs. 30.1%; P =.001; HRadj.07; 95% CI.01–.52), whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs. 5.3%; P =.90; HRadj 1.26; 95% CI.08–20.30; pinteraction =.09). Conclusions: Early ASA use after OHT was associated with lower rates of moderate to severe CAV only in those patients with episodes of allograft rejection. [ABSTRACT FROM AUTHOR]

The clinical spectrum of COVID‐19 in heart transplant recipients has not been fully defined, because asymptomatic and sub‐clinical cases are difficult to capture. Seroprevalence surveys are an important tool to identify not just cases that have come to clinical attention, but all previously infected recipients. We performed a seroprevalence survey of the adult heart transplant program at a large New York City Hospital System. A total of 232 (87% of recipients being followed) subjects were tested, of whom 37 (15.9%) were found to be previously infected. This is comparable to the overall rate of prior infection in the NYC metro area. Disease course tended to be more severe than in the general population; however, this was at least partially driven by traditional risk factors of age and comorbidities. Lastly, 9 of 10 recipients who were initially found to be PCR positive subsequently tested positive for antibodies, confirming the ability of this population to mount a humoral response. In conclusion, prevalence of COVID‐19 in heart transplant recipients on immunosuppression was comparable to that in the general population of NYC, and 90% of those with an initially positive viral swab developed antibodies. In those who are infected, disease course tends to be more severe. [ABSTRACT FROM AUTHOR]

The absence of afferent nerves for heart rate (HR) regulation leaves the transplanted heart under the influence of its internal and hormonal control. The HR of heart transplantation (HTx) recipients varies from to 90–110 bpm, indicating a lack of vagal parasympathetic tone. We hypothesized that the reduction in mean HR using an If‐channel antagonist (ivabradine) could be effective and safe in HTx recipients. The primary objective of this open‐label randomized clinical trial was to compare the mean HR at 3, 6, 12, 18, 24, 30, and 36 months after randomization between an ivabradine plus conventional treatment group (IG) and conventional treatment alone group (CG). The secondary objectives were reduction in mortality, graft dysfunction, and ventricular mass. All patients were randomized between 1 and 12 months after HTx. Ivabradine started at randomization. Of the 35 patients, 54.28% were in the CG and 45.72% in the IG. There were no significant between‐group differences in demographics. Over time, the HR differences between the groups became significant (P <.01). There were no significant between‐group differences in mortality, graft dysfunction, and ventricular mass. We conclude that ivabradine could effectively and consistently reduce the HR in HTx recipients. [ABSTRACT FROM AUTHOR]

Background: The use of direct‐acting antivirals (DAA) has expanded transplantation from hepatitis C viremic donors (HCV‐VIR). Our team has conducted an open‐label, prospective trial to assess outcomes transplanting HCV viremic hearts. Glecaprevir/pibrentasvir (GLE/PIB) was our sole DAA. Methods: Serial quantitative hepatitis C virus (HCV) RNA PCR was obtained to assess HCV viral titers. Between January 2018 and June 2019, a total of 50 recipients were transplanted. Of these, 22/50 (44%) were from HCV‐VIR, the remaining 28 from non‐viremic (HCV NON‐VIR) donors. An 8‐week course of GLE/PIB was initiated at 1 week post‐transplant. Results: There was no difference in demographic or clinical parameters between groups. All 22 recipients of HCV‐VIR transplants became viremic. GLE/PIB was effective in decreasing viremia to undetectable levels by 6 weeks post‐transplant in all patients. The median time to first undetectable HCV quantitative PCR was (4.3 weeks, IQR: 4‐5.7 weeks). All patients demonstrated sustained undetectable viral load through 1‐year follow‐up. There was no difference in survival at one year between HCV NON‐VIR 28/28: (100%) vs HCV‐VIR 21/22 (95%) recipients. Conclusions: Our center reports excellent outcomes in transplanting utilizing hearts from HCV‐VIR donors. No effect on survival or co‐morbidity was found. An 8‐week GLE/PIB course was safe and effective when initiated approximately 1 week post‐transplant. [ABSTRACT FROM AUTHOR]

Summary: There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels. [ABSTRACT FROM AUTHOR]

Abstract: Background: Model of End‐Stage Liver Disease eXcluding INR (MELD‐XI) at cardiac transplant has demonstrated prognostic survival utility, but has not been specifically validated in adult congenital heart disease (ACHD) in a registry study. Methods: Adults undergoing first‐time orthotopic heart transplant from 2005 to 2015 in the United Network for Organ Sharing (UNOS) registry were examined in parallel: ACHD (n = 543), ischemic‐dilated cardiomyopathy (IDCM, n = 6954) and valvular heart disease (VHD, n = 355). Our primary endpoint was a composite of death, graft failure, and retransplantation assessed at 3 months (early), and those with freedom from early endpoint were reassessed at 5 years (late). Interactions between hepatorenal indices and waitlist time were examined. Secondary outcomes relating to long‐term morbidity were assessed at late endpoint. Freedom from endpoint analysis in ACHD at clinically relevant endpoints was also conducted. Results: Model of End‐Stage Liver Disease eXcluding INR score at transplant associated with an increased risk of early endpoint in all cohorts. At late endpoint, bilirubin level associated with increased risk uniquely in ACHD. Conclusions: Model of End‐Stage Liver Disease eXcluding INR holds prognostic application to ACHD in early time points and demonstrates unique waitlist interactions. Transplant bilirubin level may hold significance in long‐term risk stratification of the ACHD population. Time on waitlist is an important consideration to contextualize these values. [ABSTRACT FROM AUTHOR]

We prospectively studied efficacy and safety outcomes of two 10-mg doses of intravenous basiliximab on day 0 and day 4 for induction therapy in 17 consecutive de novo heart transplant recipients. By the 2-week assessment post-transplant, there were no deaths, graft failures, or acute cellular rejections ( ACRs) ISHLT grade ≥ 2R. By the 1-year assessment post-transplant, there were 1 (6%) infectious death, no graft failures, 2 (12%) grade 2R ACRs, 6 (35%) asymptomatic cytomegalovirus ( CMV) infections, and 4 (25%) treated infections. Our study was the first to show that low-dose basiliximab induction in heart transplant resulted in favorable efficacy and safety outcomes. Additionally, calcineurin inhibitor ( CNI) initiation in a low-risk population could be safely delayed using the strategy of modified low-dose postoperative basiliximab. This strategy also appears to allow subsequent early corticosteroid wean, although with the concomitant maintenance of higher CNI levels and higher dosing of mycophenolate. [ABSTRACT FROM AUTHOR]

Aims We examined the relationship between donor-specific HLA antibody (DSA) presence and graft function, hemodynamics, cardiac allograft vasculopathy (CAV), and major adverse cardiac events (MACE) in stable long-term heart-transplanted (HTx) patients. Methods Sera from 79 patients (median 7.5 years after HTx) were analyzed for DSA presence. Graft function was evaluated by echocardiography and right heart catheterization. CAV burden was determined by coronary angiography, optical coherence tomography (OCT), and coronary flow velocity reserve (CFVR). Patients were prospectively followed after DSA assessment. MACE included significant CAV progression, heart failure, treated rejection, and cardiovascular death. Results Sixty patients had no DSA, and 19 patients were sensitized. The vasculopathy burden by angiography, OCT, and CFVR was more pronounced in DSA-positive patients than in DSA-negative patients. DSA-positive patients had higher pulmonary capillary wedge pressure (16 [8; 21] vs 9 mm Hg [7; 11], P<.05) and right atrial pressure (8 [6; 9] vs 4 mm Hg [2; 6], P<.01) and lower global longitudinal strain (−13% [−10; −15] vs −16% [−14; −17], P<.01) than DSA-negative patients. DSA presence was a strong MACE predictor (HR 4.7 (95% CI 2.0-11.4), P<.001). Conclusions DSA-positive patients had higher vasculopathy burden, higher filling pressures, and lower longitudinal myocardial deformation than DSA-negative patients. The DSA presence was a strong MACE predictor. [ABSTRACT FROM AUTHOR]

Background We sought to investigate a correlation between serum testosterone levels and graft function early after heart transplantation. Methods In a cross-sectional study, we measured serum testosterone levels 4 weeks after heart transplantation in 49 consecutive male recipients. Echocardiography was carried out to evaluate graft function. Low serum testosterone was defined as <11 nmol/L. Results Low serum testosterone was present in 21 (43%) recipients (Group A), and 28 (57%) had normal testosterone levels (Group B). The two groups did not differ in age and presence of renal dysfunction, arterial hypertension, diabetes, or hyperlipidemia. Donor age and allograft ischemic time were not different between the two groups. Both groups had comparable tacrolimus through levels, dose of mycophenolate mophetil, and methylprednisolone. Patients in Group A had significantly lower LVEF (58±5% vs 65±6% vs Group B, P=.001) and TAPSE (1.3±0.3 cm vs 1.6±0.3 cm in Group B, P=.01). In comparison with Group B, more patients in Group A were found to have low grade (1R) rejection (25% vs 3%; P=.02). Conclusion Low serum testosterone levels appear to be associated with impaired graft function and an increased incidence of low-grade rejection episodes early after heart transplantation. [ABSTRACT FROM AUTHOR]

Background Sinus tachycardia often presents in heart transplantation ( HTx) recipients, but data on its effect on exercise performance are limited. Methods Based on mean heart rate ( HR) value 3 months after HTx, 181 patients transplanted from 2006 to 2015 at University of Nebraska Medical Center were divided into two groups: (i) HR<95 beats/min (bpm, n=93); and (ii) HR≥95 bpm (n=88). Cardiopulmonary exercise testing ( CPET) was performed 1 year after HTx. Results Mean HR at 3 months post- HTx was 94±11 bpm and did not change significantly at 1 year post- HTx (96±11 bpm, P=.13). HR≥95 bpm at 3 months was associated with younger donor age ( OR 1.1; CI 1.0-1.1, P=.02), female donors ( OR −2.4; CI 1.16-5.24 P=.02), and lack of donors' heavy alcohol use ( OR −0.43; CI 0.17-0.61; P=.04). HR≥95 bpm at 3 months post- HTx was independently associated with decreased exercise capacity in metabolic equivalent ( P=.008), reduced peak VO2 ( P=.006), and percent of predicted peak VO2 ( P=.002) during CPET. Conclusions HR≥95 at 3 months following HTx is associated with reduced exercise tolerance in stable HTx recipients. Medical HR reduction after HTx could improve exercise performance after HTx and merits further investigation. [ABSTRACT FROM AUTHOR]

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., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The absence of afferent nerves for heart rate (HR) regulation leaves the transplanted heart under the influence of its internal and hormonal control. The HR of heart transplantation (HTx) recipients varies from to 90-110 bpm, indicating a lack of vagal parasympathetic tone. We hypothesized that the reduction in mean HR using an If-channel antagonist (ivabradine) could be effective and safe in HTx recipients. The primary objective of this open-label randomized clinical trial was to compare the mean HR at 3, 6, 12, 18, 24, 30, and 36 months after randomization between an ivabradine plus conventional treatment group (IG) and conventional treatment alone group (CG). The secondary objectives were reduction in mortality, graft dysfunction, and ventricular mass. All patients were randomized between 1 and 12 months after HTx. Ivabradine started at randomization. Of the 35 patients, 54.28% were in the CG and 45.72% in the IG. There were no significant between-group differences in demographics. Over time, the HR differences between the groups became significant (P < .01). There were no significant between-group differences in mortality, graft dysfunction, and ventricular mass. We conclude that ivabradine could effectively and consistently reduce the HR in HTx recipients., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 β 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 (TGFβ) 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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)