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Non-invasive surveillance methods for rejection have been increasingly used following heart transplantation (HT). The purpose of this study was to evaluate the degree of concordance between two donor-derived cell-free DNA (dd-cfDNA) assays in a real-world cohort of HT recipients. From March to August 2022, individuals within our HT program were non-invasively monitored for rejection as part of clinical care using two commercially available dd-cfDNA assays: AlloSure® (CareDx, Inc) and Prospera™ Heart (Natera, Inc.). Samples were drawn within 48 hours of each other. Patients who were within 28 days of transplant or who underwent dual-organ transplantation were excluded. Raw data with absolute values were obtained from CareDx, Inc and Natera, Inc. for results reported below <0.12% and <0.08%, respectively. As has been used in prior analyses, a positive result was considered a value of 0.15% or greater for Prospera and 0.12% or greater for AlloSure. The strength of the relationship was assessed using the Pearson correlation coefficient. 170 paired samples were collected from 139 individuals. Of the 139 individuals, median age was 61 years with 32% women, 19% Black, 15% Hispanic. Seven patients (5%) had history of re-transplant. 38% had a history of donor-specific antibodies, 27% had a history of treated acute cellular rejection, and 7% had a history of antibody-mediated rejection. In 107 (63%) pairs, dd-cfDNA was not elevated in either assay, while in 47 (28%) of cases dd-cfDNA was elevated above respective thresholds for both assays. There were 16 (9%) discordant cases; in 3 cases, patients underwent endomyocardial biopsy all of which were negative. If a cutoff of 0.2% or greater was used for both assays, only two paired samples (1%) would be discordant. There was a strong correlation between the two assays, r2 = 0.81 (Figure). In this single-center cohort, the performance of two commercially available dd-cfDNA assays was similar. [ABSTRACT FROM AUTHOR]

In heart transplant (HT) recipients, cardiac allograft vasculopathy (CAV) can manifest as microvascular disease, which can be detected noninvasively with cardiac PET scanning. In this study, we sought to determine if microvascular CAV is associated with elevated levels of dd-cfDNA. A retrospective review of HT recipients at a large-volume center who had at least one dd-cfDNA result collected between April 2020 and August 2022. Patients who underwent cardiac PET scanning were included in this analysis. Patients were grouped by the presence of microvascular disease (MVD), defined as myocardial blood flow reserve (MBFR) <2.0. Values of dd-cfDNA <0.12% were recorded as 0.11%. 132 patients were identified and included. The median age was 56 years and 73.5 % were male. The median time from transplant to dd-cfDNA level was 84.1 months [51.0, 113]. A higher prevalence of donor-specific antibodies was observed in the MVD group (54.1 % vs. 31.6%; p =0.03). The average dd-cfDNA was 0.21% [0.11, 0.75] in the MVD group vs. 0.11% [0.11, 0.18] in the non-MVD group (p=0.03). Of 333 samples, 55% were positive in the MVD group vs. 37% in the no-MVD group. In our cohort, HT recipients with evidence of microvascular CAV have higher levels of dd-cfDNA. Further study is needed to determine the prognostic value of dd-cfDNA in these patients. [ABSTRACT FROM AUTHOR]

Donor-derived cell-free DNA (dd-cfDNA) has emerged as a reliable, noninvasive method for the detection of allograft rejection in heart transplantation (HT) patients. We sought to evaluate dd-cfDNA levels in patients who received a heart from a donor with a different blood type than their own. A retrospective review of all HT recipients at our center with at least one dd-cfDNA collected between 4/2019 and 9/2022. dd-cfDNA percentages were quantified and correlated with allograft rejection. Acute cellular rejection (ACR) was defined as ISHLT grade > 2R and antibody mediated rejection (AMR)> pAMR0 within 2 weeks of when dd-cfDNA level was obtained. ABO mismatch was defined as Blood type O organ to blood type A,B,AB recipient or A,B organ to AB recipient. Of 559 HT patients with dd-cfDNA levels, 63 patients had an ABO mismatched organ transplanted. Median age was 54 years, 27.9% were female; median time from HT to dd-cfDNA level was 1750 days [731, 4030]. DSA were present in 17 patient (27.0%) in the ABO mismatched group vs. 117 (23.6%) in the ABO matched group. Of 2530 samples, the average dd-cfDNA levels per patient were 0.111% [0.110, 0.160] in the ABO mismatch group vs. 0.110% [0.110, 0.176] in the ABO matched group, respectively. ACR occurred in 2 patients (3.2%) in the ABO mismatched group vs. 10 patient (2.0%) in the ABO matched group. AMR occurred in 0 patients in the ABO mismatched group vs. 6 (1.2%) in the ABO matched group. In our cohort, patients who received a donor heart from a donor with a different ABO group had similar levels of dd-cfDNA compared to those who received a heart from a donor with same ABO group.. [ABSTRACT FROM AUTHOR]

Donor-derived cell-free DNA (dd-cfDNA) has emerged as a reliable, noninvasive method for the detection of allograft rejection in heart transplantation (HT) patients. dd-cfDNA is widely used in HT, but its utility in multiorgan transplants (HT + another organ) is unknown. We describe the experience using dd-cfDNA in multiorgan transplant patients. Retrospective review of all HT patients transplanted between 1998-2022 at our center that had at least one dd-cfDNA collected between 5/2020 and 8/2022. Patients that had multiorgan transplant were identified and enrolled to this study. dd-cfDNA percentages were quantified and correlated with allograft rejection. The dd-cfDNA variability score was calculated by the variance/mean test value per person. Acute cellular rejection (ACR) was defined as ISHLT grade ≥ 2R and antibody mediated rejection (AMR) > pAMR0. Of 654 HT patients with dd-cfDNA levels, 35 patients had multiorgan transplant. Median age was 55 years, 37.1% were female; median time from HT was 554 days [264, 1660]. 22 patients had heart-kidney (H-K), 8 patients had heart-liver (H-Li) and 5 patients had heart-lung (H-Lu). Of 153 samples, the average dd-cfDNA levels per patient were 0.243 % [0.149, 0.431], 1.49 % [1.02, 2.33] and 0.727% [0.653, 0.790] in the H-K, H-Li and H-Lu group, respectively. No patients had ACR or AMR. 31 patients had multiple levels drawn with a median of 4 samples [2, 6]. The median variability score for each patient was 0.009, 0.263 and 0.0516 in the H-K, H-Li and H-Lu group, respectively. dd-cfDNA is chronically elevated in most multiorgan transplant recipients. There is a high degree of variability in levels (particularly for H-Li and H-Lu recipients), which may limit the utility of this assay in multiorgan transplant recipients. [ABSTRACT FROM AUTHOR]

Coronary allograft vasculopathy (CAV) is a common complication following heart transplantation (HT) and has previously been described as associated with elevated donor-derived cell free DNA (dd-cfDNA) levels. We aimed to investigate this association in a large cohort, including an analysis of CAV grading by intravascular ultrasound (IVUS). We retrospectively reviewed HT recipients at a large volume center who had at least one dd-cfDNA result collected between April 2020 and August 2022. Patients with a CAV analysis by coronary angiography were included. Patients were stratified by presence of CAV and dd-cfDNA levels were compared between the groups. Biopsies performed within 2 weeks of the first dd-cfDNA level were assessed for acute cellular rejection (ACR) > 2R and antibody mediated rejection (AMR) > pAMR0. Values of dd-cfDNA < 0.12% were recorded as 0.11%. 132 patients were identified and included. Median age was 56 years. 26% were female. Median time from transplant to dd-cfDNA level was 2520 days [1530, 3390] and was longer in the CAV group (p=0.001). 63 patients had a CAV grade > 1, and 69 patients had CAV grade 0. In the CAV group, 92.1% had CAV grade 1, 4.8% had CAV grade 2 and 3.2% had CAV grade 3. Of 333 samples, dd-cfDNA was 0.11% [0.11, 0.177] in the CAV group vs. 0.11% [0.11, 0.55] in the non-CAV group (p=0.13). A similar frequency of persistently elevated dd-cfDNA levels (3 consecutive levels of > 0.11%) were found between the groups (12.7 % vs. 13%). No episodes of ACR or AMR were identified. A similar frequency of positive DSA was present in both groups (36.5% vs.39%). Dd-cfDNA levels were similar for ISHLT grade 1 CAV (0.11% [0.11, 0.17]) as compared to ISHLT grade 2-3 CAV (0.11% [0.11, 0.19]). Among 94 patients with IVUS data, the dd-cfDNA level was 0.11% [0.11, 0.16] for those with intimal medial thickness < 0.5 mm as compared to 0.112% [0.11, 0.48] among those with IMT ≥ 0.5 mm. Levels of dd-cfDNA were no affected by the presence or absence of CAV in our single-center cohort. [ABSTRACT FROM AUTHOR]

Long-term survival rates for pediatric heart transplant (HT) recipients continue to improve, increasing the number that will transition care to adult specialists. There are limited data evaluating a transition plan specific to pediatric HT recipients. The purpose of this study is to describe the transition of pediatric HT patients to the adult HT program at a single large transplant center. We retrospectively reviewed all patients who underwent transition from pediatric to adult HT program at our center between Jan 2011 and June 2021. We collected demographic characteristics at time of HT and adverse events including graft rejection, infection, hemodynamics and renal function before and after the transition. We also collected psychosocial and psychiatric history, work/educational status and reports of poor medical adherence. 72 patients were identified,54.1% were male. Mean age at time of transition was 23 (Table1) after a median of 11.6 years in the pediatric program. Patients were followed for a median of 3.8 years post-transition. Overall patient survival following transition was 90.3%. New graft dysfunction was demonstrated in 17 patients with a mean EF decrease of 19.8 % and 10 patients (13.8%) required re-transplant during the study follow up. Incidence of cellular rejection (2R,3R rejection) was 27.7% before transition, while none of the patients experience cellular rejection after transition. AMR rates were 13.6% and 12.3 % before and after transition. Incidence of depression or other psychological conditions was 20.8%. Excellent patient outcome can be achieved although with higher rates of re-transplantation due to graft dysfunction following transition from pediatric to adult care. Because the transition period occurs during a vulnerable time of emerging adulthood, the development of a formalized transition plan has the potential to favorably influence outcomes through additional clinical and psychosocial support. [ABSTRACT FROM AUTHOR]

Left ventricular assist devices (LVAD) improve two-year survival and quality of life in patients with advanced heart failure. Following the MOMENTUM 3 study, Heartmate 3 (HM3) LVAD is the only device approved in the US and Europe. Data for event-free survival beyond two years on HM 3 is limited. The aim of this study was to assess the adverse event profile in patients who survive more than 2 years on support. We retrospectively reviewed all patients who received a HM3 LVAD at our center between 5/8/2015-10/29/2018. Patients who were alive two years following LVAD implant and were still on LVAD support were included in the study and followed for an additional two years. Patient outcomes including hospitalizations over the subsequent two years of follow-up were recorded (between year 2 and 4). Event percent per year (EPPY) was calculated for each of these outcomes. 127 patients received an LVAD during the study period with a 2 year survival rate of 85.1%. Within the first 2 years, 19 patients died, 39 patients were transplanted, and 13 transferred institutions or were lost to follow up. 56 patients remained on support and were included in this analysis and followed for an additional 2 years. The average age was 61 ± 14, 81% were male. Of those 56 patients, 50 patients were alive on support 4 years after LVAD implant (89%) (3 died and 3 patients underwent transplant). Between years 2 and 4 years from HM 3 implant, 51% were hospitalized. The most common causes of hospitalization were ADHF (0.142 EPPY), drive line infection (DLI) (.0268 EPPY) and GI bleed (0.0089 EPPY). In patients surviving 2 years on HM3 LVAD support the overall survival rate for additional 2 years is excellent. However, half of the patients will be hospitalized during long-term support, highlighting the need for more studies of medical management to prevent complications in this cohort of patients. [ABSTRACT FROM AUTHOR]

Left Ventricular Assist Devices (LVAD) improve the survival and quality of patients with advanced heart failure. LVAD implant centers are frequently located remotely from patients' homes, which can be challenging when frequent follow-up is required. Shared care is a system where care these patients are managed by a collaboration between the implanting center and local, shared-care sites. This study aimed to assess the outcome of patients treated in a shared care model Retrospective analysis of all patients implanted with a LVAD at a large academic center between 1/2015-9/2021 and were treated in a shared care model. 30 LVAD patients were identified for the analysis. The mean age was 61±10 years, 24 (80%) were men, and the median time of follow-up was 741 (IQR 398, 1381) days. Most patients were implanted as destination therapy (21, 70%), and 16 (53%) received a HeartMate III LVAD. During follow-up, 6 (20%) patients died at a median follow-up of 743 (IQR 403,1371) days, 7 (23%) were transplanted at a median follow-up of 739 (IQR 398,1338) days, and 17 (56%) are alive (Figure). 9 (30%) patients had major bleeding events, 6 (20%) had driveline infections, and 3 (10%) had device malfunction and 3 (10%) had device thrombosis. A shared care model is a feasible and effective way to care for LVAD patients who live far from their implanting center. In this study, adverse outcomes occurred in this population at an expected rate. [ABSTRACT FROM AUTHOR]

Belatacept (BTC) is a high-affinity CTLA4-Ig variant indicated for prophylaxis of graft rejection in adults receiving a kidney transplant. Data on the utilization of BTC therapy in heart transplant (HT) recipients are scarce. The aim of this study was to describe the use of BTC as a treatment option in selected HT pts We conducted a retrospective analysis of all pts who underwent HT between 1/2017 and 4/2020 and received BTC. Baseline characteristics, rejection and infection history were collected. Key laboratory finding and graft function were compared at 6 and 12 months. Out of 776 patients who received a HT during the study period, 21 pts were treated with BTC and were included in this analysis. Mean age at time of HT was 53 ±12 years, 38% were female. BTC was initiated a median of 22.6 months IQR [22.6-66.8] after HT. The most common indication for BTC was elevated DSA (61.9% of patients) followed by renal protection (23.8%). Only 1 patient experienced grade 2R rejection in the 12 months following initiation of BTC and 1 additional pts had pAMR 1H. Graft function was unchanged at 6 and 12 months. Serum creatinine improved in 76.2% of the patients from a median of 1.58 IQR [1.0-2.1] at baseline to 1.45 IQR [1.1-1.9] at 12 months (p=0.054). At 6 and 12 months following BTC therapy, no significant differences were found in hemoglobin (11.3 vs 11.1 g/dl) or white blood cell count (5.9 vs 6.1 × 103uL). 33.3% experienced infection (71.4% viral infection, 28.5% bacterial 14.2% fungal). 33.3% of the patients required temporary discontinuation of treatment due to the side effects and 4 patients were switched back to CNI (19%). BTC therapy was used predominantly for management of elevated DSA or for renal protection. BTC therapy resulted in improved kidney function and was associated with a low rejection rate and preserved graft function. Infections were common during BTC therapy and BCT was discontinued in 19% of patients due to side effects. Further randomized studies are needed to assess the efficacy and safety of BTC in HT recipients. [ABSTRACT FROM AUTHOR]

The transition from pediatric to adult care occurs during a vulnerable time of emerging adulthood (between 18 and 25 years of age) for pediatric heart transplant (HT) recipients, and multiple factors can lead to poor health outcomes. Disorders of depression, anxiety and adjustment disorder are common in this population and are associated with medication non-adherence and adverse patient outcomes. The purpose of this study is to explore the psychosocial history of pediatric HT recipients transferring to adult care in order to identify necessary areas for support when developing a formalized transition plan. We retrospectively reviewed all patients who underwent transition from the pediatric to the adult HT program at our center between January 2011 and June 2021. We collected demographic characteristics at time of HT and adverse events including graft rejection, infection, hemodynamics and renal function before and after the transition. We also collected psychosocial history, work/educational status and reports of poor medication adherence at the time of transition. 72 patients were identified, 54.1% were male and 54.2% were white. Heart failure etiology was predominantly dilated cardiomyopathy (59.7%) and congenital heart disease (20.7%). The mean age at time of transplant was 13 years and the mean age at time of transition visit was 23 years. 76.3% were living with parents/fxandparents, 81.9% completed high school and 50% were employed at time of transition. 30% had reports of poor medication adherence during adolescence and 20.8% had a psychiatric diagnosis. 27.7% reported active substance use. Patients were followed for a median of 3.8 years following transition to adult care and overall survival was 90.3%. All seven patients that died following their transition had a history of psychiatric illness or substance use. We observed relatively high rates of psychiatric illness, substance use and poor medication adherence in our population of adolescent and young adult HT recipients transferring to adult care, all of which can contribute to adverse patient outcomes. A formalized transition plan should focus on robust mental health services and substance use counseling in order to favorably influence outcomes following their transition. [ABSTRACT FROM AUTHOR]

Left Ventricular Assist Device (LVAD) as a bridge to heart transplantation (BTT) has been described as a risk factor for post-heart transplantation (HT) sensitization and rejection. Donor-derived cell-free-DNA (dd-cfDNA) test is a noninvasive method for surveillance of allograft injury. We sought to characterize dd-cfDNA in LVAD-BTT recipients as compared to non-LVAD patients and its impact on post-HT outcomes. Patients who underwent HT in our institution between January 2019 and July 2022 and had at least one dd-cfDNA result were included in the analysis. Patients were grouped based on the presence of pre-HT durable LVAD. Dd-cfDNA was considered positive if ≥0.12%. Samples reported as <0.12% were analyzed as 0.11% for the purpose of this analysis. A total of 225 patients were identified. 66 LVAD-BTT and 159 non-LVAD patients were included. The median age was 56 years and was similar between the groups. The majority (73%) were males. 45 patients (68%) were supported on HeartMate 3 LVAD. The median number of dd-cfDNA samples per patient was similar in both groups (8 [6,10] vs. 8 [4.5,9]) and positive samples were found in 67% and 64% of the LVAD-BTT and non-LVAD, respectively. Dd-cfDNA levels were similar between the groups (0.119 [0.110, 0.156] vs. 0.117 [0.110, 0.186]; p=0.65). Similarly, there was no significant difference in the incidence of cellular and antibody-mediated rejection. Patients supported with LVAD prior to undergoing heart transplantation had similar dd-cfDNA levels compared to recipients who were not supported with LVAD. [ABSTRACT FROM AUTHOR]

De-novo donor-specific antibody (dnDSA) formation among heart transplant (HT) recipients represents a high-risk feature for adverse outcomes. Whether the presence of persistently elevated donor-derived cell-free DNA (dd-cfDNA) increases the risk of graft dysfunction, rejection, development of coronary artery vasculopathy (CAV) and mortality following HT remains unknown. Patients with dd-cfDNA and HLA antibody results available from January 2019 to August 2022 were reviewed. Persistently elevated dd-cfDNA (PE-dd-cfDNA) was defined as ≥ 3 sequentially elevated dd-cfDNA results (>0.12%). The PE-dd-cfDNA with dnDSA group was compared to patients with dnDSA with consistently negative or only sporadically (< 3) elevated dd-cfDNA (control group). Our primary outcome was overall survival from the first dd-cfDNA test. Secondary outcomes were graft dysfunction (LVEF < 40%), allograft rejection (acute cellular rejection (ACR) ≥2R and antibody mediated rejection (AMR) > 0) within ± two weeks of a positive dd-cfDNA result, and development of CAV. A total of 141 patients with dnDSA and available dd-cfDNA results were identified and included in this analysis. 49 patients (34.7%) with persistently elevated dd-cfDNA (PE-dd-cfDNA group) and 92 patients (65.3%) in the control group. Baseline demographics were similar and reported in table 1. The PE-cfDNA group had a shorter time duration from HT to the first dd-cfDNA test (460 [82,2570] vs 2410 [708,4080] days, p = 0.021). ACR occurred more frequently in the PE-dd-cfDNA vs. control group (6 [12.2%] vs 2 [2.2%], p= 0.021), while AMR was similar (4 [4.3%] vs 4 [8.2%], p= 0.449). Graft dysfunction and CAV did not differ between the groups. 2-year overall survival did not differ between the groups (p=0.58). High-risk HT recipients with dnDSA and persistently elevated dd-cfDNA levels had a higher rate of ACR, but not AMR. Further studies should target these high-risk populations. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion (I/R) injury is common after heart transplantation (HT) and associated with delayed recovery of graft function. Organ preservation with novel transport systems have been developed to improve graft outcomes. The distinction between I/R injury and graft rejection early after HT can be difficult to discern. We sought to compare conventional cold storage technique (ICE) to Paragonix SherpaPak Cardiac Transport System (CTS) and to assess the different pathological features and short-term outcomes Patients who underwent HT between January 2021 and July 2022 were categorized depending on the method of graft preservation system. Propensity matching was performed based on race and gender. A single pathologist assessed pathological features of 1st and 4th-week endomyocardial biopsy (EMB) in a single-blinded manner. EMB were assessed for allograft rejection and the presence and grade of coagulative myocyte necrosis (CMN) as a definitive manifestation of ischemic injury, which were highlighted by staining for C4d±C3d. Patients with primary graft dysfunction were excluded Sixty two patients were identified (30 and 32 patients in the ICE and CTS group, respectively). CTS patients were older (64 vs. 55 years old, p < 0.001), and 31% were males in both groups. Total ischemic time was longer in the CTS group (3.176 ± 1.08 vs 3.93 ± 1.25 hours, p = 0.006). Analysis of EMBs revealed a similar rejection rate in both groups in the first week (p=0.26). CMN was present in 70% and 78% (p=0.56) of patients in the first week and 53.3% and 65.6% (p=0.79) of patients in the fourth week in the ICE and CTS group, respectively. Higher CMN grade (>2) was more prevalent in both groups and was significantly higher in the CTS group at the first week (Figure 1), p < 0.005). Six month survival was similar in both groups (p=0.95) In our study, ischemic-reperfusion injury manifested by coagulative myocyte necrosis was equally prevalent in both ice and CTS preservation modalities, with no difference in short-term mortality [ABSTRACT FROM AUTHOR]

Heartmate 3 (HM3) left ventricular assist device (LVAD) requires pump speed adjustments for hemodynamic optimization of each patient. We investigated the hemodynamic effect of speed adjustment on stable HM3 recipients undergoing hemodynamic ramp test. Retrospective analysis was conducted on all adult HM3 recipients at a single center between May 2015 to July 2022 who underwent a hemodynamic ramp test. The patients with assessments on at least 4 different speed settings were included in this analysis. Hemodynamic parameters at baseline, minimal, maximal and final-set speeds were collected and analyzed. A total of 53 HM3 recipients with an average age of 61 ± 12 years were identified for analysis. 77% were male, and the median time post LVAD implantation was 11 (5-23) months. The median baseline and final HM3 pump speeds were 5400 (5200-5600) revolutions per minute (rpm) and 5400 (5200-5800) rpm, respectively. CVP and PCWP at baseline speed were 7.6 ± 4.6 and 12.4 ± 6.5, respectively. 47% of the patients had normal filling pressures at baseline defined as central venous pressure (CVP) < 12 mmHg and pulmonary capillary wedge pressure (PCWP) < 18 mmHg. At the end of the ramp test, pump speed was either increased or decreased in 64% of the patients (n=34), with a median speed change of 200 (200-200) rpm. Final speed CVP and PCWP were 7.5 ± 4.6 and 12.2 ± 5.6, respectively. At the final set speed, normal filling pressures were achieved in 74% of the patients. HM3 pump speed was adjusted in most of the patients who underwent a hemodynamic ramp test and resulted in optimized bi-ventricular filling pressures in an additional 27% of the patients. [ABSTRACT FROM AUTHOR]