Surveillance Endomyocardial Biopsy Research Articles

Patient Adapted Paternalism for Endomyocardial Biopsy Policy Changes in Heart Transplant Patients: A Mixed-Methods Study.

Endomyocardial biopsies (EMB) are invasive procedures performed in heart transplant (HTx) patients for surveillance of acute rejection. However, patient preferences for replacing EMBs with noninvasive assays in the context of potential institutional policy changes are unknown. A mixed-methods design was used with 28 semi-structured patient interviews and 123 self-administered online survey questionnaires in English and Spanish between January to June 2023. Additionally, we performed semi-structured interviews with 18 HTx team members. Three dominant themes were identified: alleviating patient anxiety and distress, consistent patient-provider communication, and strong interpersonal trust with the HTx team. We found that strong interpersonal trust with the HTx team by the patients was more highly prioritized than their own opinions on whether to replace EMBs with noninvasive assays. Thus, HTx patients often considered surveillance EMBs important to their care (93%), based on the recommendations provided by their HTx team. HTx faculty physicians stated that more multicenter trials are needed prior to replacing EMBs with noninvasive assays. In conclusion, patients identified strong interpersonal trust with HTx team members to justify patient adapted paternalism, where the provider decides in accordance with the patient's situation, as their preferred shared decision-making paradigm when considering institutional policy on surveillance EMBs.

Decreasing Endomyocardial Biopsy Frequency in Pediatric Heart Transplantation Using A Rejection Risk Prediction Score-A Single Center Study.

Rejection remains an important cause of morbidity and mortality after pediatric heart transplantation (HT). Endomyocardial biopsy (EMB) is the gold standard for rejection diagnosis, but it comes with procedural risk. The frequency of EMB varies significantly across centers. Since April 2018, our center's surveillance EMB schedule is based on a rejection risk prediction score employing age, pre-HT diagnosis, and panel reactive antibodies (PRA). We aimed to evaluate outcomes in the 1st year post-HT before and after risk score implementation. Patients who underwent HT at our center at ≤ 18 years of age from January 2015 to December 2020 were reviewed. The primary endpoint was rejection-free survival at 1 year-post- HT. Clinical characteristics were compared for patients transplanted in Era 1 (January 2015-April 2018) and Era 2 (April 2018-December 2020). Cumulative 1-year survival free from rejection and from rejection with hemodynamic compromise (RHC) was compared between eras using Kaplan-Meier survival analysis. 115 patients underwent HT during our study period (52 in Era 1 and 63 in Era 2). There was an increase in VAD utilization between eras (19% in Era 1 vs. 40% in Era 2, p = 0.025), but otherwise no significant difference in demographic or clinical variables between the two eras. No statistically significant difference in freedom from rejection or freedom from RHC was identified between the two eras. There was a 60% reduction in the median number of EMB per patient in the first year post-HT after employing the score (5 in Era 1 vs. 2 in Era 2, p < 0.001). After employing a rejection risk prediction score, our center decreased the frequency of EMB without worsening early post-HT outcomes, thus establishing the clinical applicability of this tool.

Donor-derived Cell-free DNA as a New Biomarker for Cardiac Allograft Rejection: a Prospective Study (FreeDNA-CAR)

BackgroundThere is a long-standing need for a non-invasive biomarker that allows monitoring of cardiac allograft rejection, avoiding the need for periodic endomyocardial biopsies (EMB). MethodsMulticenter, observational, prospective study, performed between 2019 and 2023 (NCT 04973943). All patients underwent 7 per-protocol surveillance EMB during the first post-HT year. Donor-derived cell-free DNA (dd-cfDNA) levels were determined before each EMB, using Next Generation Sequencing Technology (Allonext™ assay, Eurofins Genome). The primary endpoint was the association between dd-cfDNA levels and the presence of acute cellular rejection (ACR) in EMB. ResultsThe study included 206 patients from 12 centers, with 1090 pairs of EMB/dd-cfDNA determinations available for analysis. EMB with ACR (n=49) were associated to dd-cfDNA levels significantly higher than those without, median 0.189% (IQR 0.05-0.70) vs 0.095% (0.04-0.23), p=0.013. A dd-cfDNA threshold of 0.10% showed a negative predictive value for ACR of 97%.A statistically significant association between NTproBNP and dd-cfDNA was also found, with an increase of 0.007% dd-cfDNA (95%CI 0.003-0.011) for every 500 units of NTproBNP, p <0.001. The combination of both biomarkers for diagnosis of ACR showed an area under the ROC curve of 0.681, and this combined approach was significantly better than dd-cfDNA alone (area under the ROC curve 0.603), p = 0.016. Using a cut-off point of 0.10% for dd-cfDNA and 1000 UI/ml for NTproBNP, negative predictive value increased to 98.1%. ConclusionsDd-cfDNA may be a useful biomarker to rule out significant ACR in a low-risk population. However, a dd-cfDNA value above normal threshold does not correlate robustly with the presence of disease. The combination with NTproBNP, a readily available biomarker, increased the discrimination power of dd-cfDNA alone.

Donor-derived cell-free DNA versus left ventricular global longitudinal strain in noninvasive detection of heart allograft injury

Abstract Introduction Invasive endomyocardial biopsy (EMB) is still considered the gold standard method for monitoring heart transplant (HTx) rejection. However, it is associated with potentially serious complications, and its histopathologic interpretation has high interobserver variability. Thus, noninvasive methods for surveillance of the transplanted organ remains of great interest. The noninvasive donor-derived cell-free DNA is a marker of graft injury which can indicate acute rejection, even before the histopathological diagnosis of rejection detected by EMB. The assay has a high negative predictive value for acute rejection. Left ventricular global longitudinal strain (LV GLS) is an emerging marker of subclinical myocardial injury which plays a crucial role in the evaluation of several cardiac diseases; however, its role in HTx injury has so far been poorly investigated. Purpose We aimed to investigate the efficacy of a local laboratory-run dd-cfDNA assay-based heart transplant rejection surveillance programme, and the prognostic and discriminatory performance of LV GLS for subsequent heart allograft injury. Methods HTx recipients without a history of allograft rejection requiring intensification of immunosuppressive therapy were transitioned from our EMB-based surveillance protocol to dd-cfDNA-based rejection surveillance. We assessed the percentage of dd-cfDNA to total cell-free DNA. Injury cut-off was defined by a dd-cfDNA level ≥0.20%, while the severe injury threshold was at ≥0.35%. LV ejection fraction was calculated using 2D Simpson’s method. To derive LV GLS, we analyzed apical 4-chamber, 2-chamber, and long-axis images by 2D speckle tracking echocardiography. Results A total of 244 dd-cfDNA samples were analyzed from 46 patients in fifteen runs performed monthly between October 2022 and December 2023. The dd-cfDNA fraction remained below the injury cut-off in most patients (81%). There were no missed rejection episodes. 88% of routine EMBs that would have otherwise been performed were safely avoided. Eighteen for-cause EMBs were performed based on dd-cfDNA levels suggesting injury. One EMB verified moderate cellular rejection (ISHLT grade 2R) that required steroid pulse therapy. Two EMBs proved mild cellular rejection, one EMB confirmed mild antibody-mediated rejection, while one EMB proved mixed rejection. Thirteen EMBs found no rejection. Mean LVEF was preserved (57.6%±7.6%). Mean LV GLS was -15.1%±2.5% in the whole cohort, while -15.6%±4.7% in recipients with HTx rejection on indication EMB. There was no significant correlation between dd-cfDNA and LV GLS (n=159). Conclusion The noninvasive dd-cfDNA assay is effective in ruling out acute rejection and safely decreases the necessity of invasive surveillance EMBs after HTx. LV GLS is less sensitive in comparison with the dd-cfDNA assay for detection of myocardial injury in the early stages of graft rejection in HTx recipients at low risk for rejection.

Endomyocardial biopsy through the left internal jugular vein in heart transplant recipients: a single center experience.

Endomyocardial biopsies for rejection monitoring after heart transplantation are generally performed through the right internal jugular vein. We aimed to assess the feasibility and safety of using the left internal jugular vein approach as a valid alternative to a femoral vein for endomyocardial biopsies whenever thrombosis of the right internal jugular vein precludes insertion of a bioptome. We have reviewed our experience with heart transplantation in the last 2 decades to identify patients in whom surveillance endomyocardial biopsy was performed through the left internal jugular vein. We herein describe the step-by-step procedure and report the preliminary results. From May 1, 2000 to January 31, 2024, 561 orthotopic heart transplants have been performed in our unit. In 49 patients (8.7%), the right internal jugular vein access was found to be unsuitable or occluded at eco-Doppler evaluation; in 15 of them (30%) a total of 206 endomyocardial biopsies have been performed, using the left internal jugular vein, without complications. Our experience demonstrates that the left internal jugular vein is a valid alternative approach for endomyocardial biopsies when the right internal jugular vein is not available. This technique is feasible, safe and reproducible and allows adequate rejection monitoring after heart transplantation.

(790) - Clinical Monitoring with Donor-Derived Cell-Free DNA, Time to End the Surveillance Endomyocardial Biopsy?

(790) - Clinical Monitoring with Donor-Derived Cell-Free DNA, Time to End the Surveillance Endomyocardial Biopsy?

A gentler approach to monitor for heart transplant rejection.

Despite developments in circulating biomarker and imaging technology in the assessment of cardiovascular disease, the surveillance and diagnosis of heart transplant rejection has continued to rely on histopathologic interpretation of the endomyocardial biopsy. Increasing evidence shows the utility of molecular evaluations, such as donor-specific antibodies and donor-derived cell-free DNA, as well as advanced imaging techniques, such as cardiac magnetic resonance imaging, in the assessment of rejection, resulting in the elimination of many surveillance endomyocardial biopsies. As non-invasive technologies in heart transplant rejection continue to evolve and are incorporated into practice, they may supplant endomyocardial biopsy even when rejection is suspected, allowing for more precise and expeditious rejection therapy. This review describes the current and near-future states for the evaluation of heart transplant rejection, both in the settings of rejection surveillance and rejection diagnosis. As biomarkers of rejection continue to evolve, rejection risk prediction may allow for a more personalized approach to immunosuppression.

Cardiac magnetic resonance assessment of acute rejection and cardiac allograft vasculopathy in pediatric heart transplant

In pediatric heart transplant (PHT), cardiac catheterization with endomyocardial biopsy (EMB) is standard for diagnosing acute rejection (AR) and cardiac allograft vasculopathy (CAV) but is costly and invasive. To evaluate the ability of cardiac magnetic resonance (CMR) to noninvasively identify differences in PHT patients with AR and CAV. Patients were enrolled at three children's hospitals. Data were collected from surveillance EMB or EMB for-cause AR. Patients were excluded if they had concurrent diagnoses of AR and CAV, CMR obtained >7days from AR diagnosis, they had EMB negative AR, or could not undergo contrasted, unsedated CMR. Kruskal-Wallis test was used to compare groups: (1) No AR or CAV (Healthy), (2) AR, (3) CAV. Wilcoxon rank-sum test was used for pairwise comparisons. Fifty-nine patients met inclusion criteria (median age 17years [IQR 15-19]) 10 (17%) with AR, and 11 (19%) with CAV. AR subjects had worse left ventricular ejection fraction compared to Healthy patients (p=0.001). Global circumferential strain (GCS) was worse in AR (p=0.054) and CAV (p=0.019), compared to Healthy patients. ECV, native T1, and T2 z-scores were elevated in patients with AR. CMR was able to identify differences between CAV and AR. CAV subjects had normal global function but abnormal GCS which may suggest subclinical dysfunction. AR patients have abnormal function and tissue characteristics consistent with edema (elevated ECV, native T1 and T2 z-scores). Characterization of CMR patterns is critical for the development of noninvasive biomarkers for PHT and may decrease dependence on EMB.

Incidence of Acute Rejection Compared With Endomyocardial Biopsy Complications for Heart Transplant Patients in the Contemporary Era.

The reference standard of detecting acute rejection (AR) in adult heart transplant (HTx) patients is an endomyocardial biopsy (EMB). The majority of EMBs are performed in asymptomatic patients. However, the incidence of treated AR compared with EMB complications has not been compared in the contemporary era (2010-current). The authors retrospectively analyzed 2769 EMBs obtained in 326 consecutive HTx patients between August 2019 and August 2022. Variables included surveillance versus for-cause indication, recipient and donor characteristics, EMB procedural data and pathological grades, treatment for AR, and clinical outcomes. The overall EMB complications rate was 1.6%. EMBs performed within 1 mo after HTx compared with after 1 mo from HTx showed significantly increased complications (OR, 12.74, P < 0.001). The treated AR rate was 14.2% in the for-cause EMBs and 1.2% in the surveillance EMBs. We found the incidence of AR versus EMB complications was significantly lower in the surveillance compared with the for-cause EMB group (OR, 0.05, P < 0.001). We also found the incidence of EMB complications was higher than treated AR in surveillance EMBs. The yield of surveillance EMBs has declined in the contemporary era, with a higher incidence of EMB complications compared with detected AR. The risk of EMB complications was highest within 1 mo after HTx. Surveillance EMB protocols in the contemporary era may need to be reevaluated.

Donor-derived cell-free DNA as a new biomarker for acute rejection in heart transplant recipients: results from the freedna car study

Abstract Background There is an increasing body of evidence supporting the potential utility of donor-derived cell-free DNA as a non-invasive biomarker that could allow surveillance of rejection without the need of repeated endomyocardial biopsies (EMB) in heart transplant (HT) recipients. Methods Free-DNA CAR was a multicenter, observational, prospective study, performed between 2019 and 2022 (NCT 04973943). All patients underwent per-protocol surveillance EMB at 0.5, 1, 2, 3, 4, 6 and 12 months post-HT. Dd-cfDNA levels were determined prior to each EMB, using Next Generation Sequencing technology. Primary end-point was the association between dd-cfDNA levels and the presence of clinically relevant rejection defined as ACR grade ≥2R and/or pAMR≥1. Results The cohort included 206 patients from 12 HT centers (mean age 54 ± 12 years, 74% male), with a total of 1006 pairs of EMB-dd-cfDNA determinations. ACR ≥2 was present in 44 EMB (4.4%) and AMR ≥1 in 17 EMB (1.7%). Two samples had simultaneous ACR≥2 and pAMR≥1. Patients with clinically relevant rejection had dd-cfDNA levels significantly higher than those without, 0.189% (0.058-0.6) vs 0.097% (0.04-0.24), p=0.0049 (Figure 1A, with %dd-cfDNA logtransformed as log2(x+0.01) in order to reduce the skewness). Median (IQR) dd-cfDNA values for each group are shown in figure 1B. Using GEE (generalized estimating equation) models in order to account for repeated individual measures, a trend to significant association between %dd-cfDNA and rejection was found (OR 1.25, IC95% 0.95-1.64) (Figure 2), even though it did not reach statistical significance (p = 0.109). In the subgroup of samples evaluated for ACR (n =991, after excluding 15 samples that did not have ACR but had AMR ≥1), there was also a significant difference between those with and without rejection: 0.205% (0.06-0.65) in ACR≥2 vs 0.097 (0.04-0.24) in ACR 0-1, p = 0.0097. Area under the ROC curve for the composite endpoint was 0,61. A 0.15% dd-cfDNA threshold showed a negative predictive value of 96%, which could allow to safely eliminate 61% of EMB. Conclusions Dd-cfDNA appears to be an excellent biomarker to rule out ACR and AMR. Its high negative predictive value could allow to eliminate a significant percentage of surveillance EMB currently performed in HT recipients.Median (IQR) dd-cfDNA values

Role of NTproBNP and donor-derived cell-free DNA in the diagnosis of acute rejection in heart transplant recipients: a prospective study

Abstract Background Donor-derived cell-free DNA (dd-cfDNA) has shown a good ability to rule out rejection in heart transplant (HT) recipients, but there is scarce information on the utility of NTproBNP (and the combination of both biomarkers) in this setting. Methods We prospectively obtained levels of both biomarkers in all patients included in the FreeDNA-CAR study (NCT 04973943), just before performing surveillance endomyocardial biopsies (EMB) at 0.5, 1, 2, 3, 4, 6 and 12 months post-HT. Primary end-point was the correlation between dd-cfDNA and NTproBNP levels. Results A total of 206 HT patients from 12 different centers were included (mean age 54±12 years, 74% male), with a median of 5.6 EBM per patient. After excluding visits with missing data, 883 pairs of EBM-both biomarkers were available for analysis. ACR, defined as grade ≥2R, was present in 37 EMB (4.2%), and AMR ≥1 in 16 EMB (1.8%). Median (IQR) NTproBNP values for each ACR group were: 0R 1067 pg/ml (454-2563), 1R 1300 pg/ml (562-3298) and 2R-3R 1780 pg/ml (943-4880) and median dd-cfDNA values: 0R 0.08% (0.038-0.178), 1R 0.105% (0.04-0.34), 2R-3R 0.22% (0.058-0.7). Regarding AMR, median NTproBNP in pAMR0 was 1200 pg/ml (504-2840) and in pAMR≥1 2230 pg/ml (806-4256) (Figures 1A and 1B). Using a GEE (generalized estimating equation) approach to account for repeated measures in each individual, a statistically significant correlation between both biomarkers was found, with a coefficient of 0.001 (CI95% 0.0006-0.002), meaning that for every increase of 100 units of NTproBNP, %dd-cfDNA increased in 0.001, p &amp;lt;0.001 (Figure 2). Moreover, in a multivariable analysis, both biomarkers were associated with the risk of acute rejection, with an OR 1.48 (CI95% 1.04-2.11), p=0.03 for dd-cfDNA, and OR 1.007 (IC95% 1.001-1-013) p=0.017 for each additional 100 pg/ml of NTproBNP. Conclusion In a cohort of HT patients in their first post-transplant year, dd-cfDNA and NT-proBNP levels were associated with acute rejection and showed a good correlation between them. Further studies are needed in order to determine if the combination of both biomarkers could improve individual performance and increase the number of EMB that could be safely eliminated.Median (IQR) NTproBNP levels (pg/ml)Linear prediction of dd-cfDNA

Donor-derived cell-free DNA kinetics in the first year post-transplant in patients without acute cellular rejection

Abstract Background Donor-derived cell-free DNA (dd-cfDNA) appears to be an excellent biomarker for acute cellular rejection (ACR) in heart transplant (HT) recipients. However, a significant rise in the immediate post-transplant phase probably related to direct myocardial damage during harvesting-implantation process has been described, and could potentially affect the biomarker’s performance in the first post-HT month. We sought to describe the biomarker’s kinetics in the first year post-HT in patients without ACR. Methods Prospective, multicentre study performed between 2019 and 2022. All patients underwent surveillance endomyocardial biopsy (EMB) at 7 pre-specified time points in the first post-HT year (0.5, 1, 2, 3, 4, 6 and 12 months). Dd-cfDNA levels were determined prior to each EMB, using Next Generation Sequencing technology. Results A total of 1006 pairs of EMB-dd-cfDNA from 206 patients were available for analysis (mean age 54 ±12 years, 74% male). Of these, 44 (4.3%) had clinically relevant rejection, defined as ACR grade ≥2, and 962 (95.7%) did not (562 0R and 400 1R). 15 samples that had pAMR≥1 were excluded from this analysis. We divided the 947 samples with ACR 0-1 into three subgroups, according to the time of blood sampling: at 15 days (time point 1), at 30 days (time point 2) and 2 to 12 months post-HT (time point 3). Samples with 0R that were drawn at 15 and 30 days showed significantly higher levels of dd-cfDNA than those drawn between the second month and first year post-transplant (p &amp;lt;0.001) (Figure 1A). When we included patients with 1R, a similar trend was observed (p &amp;lt;0.001) (Figure 1B). Median dd-cfDNA levels for 0R and for 0-1R at the three time points are shown in Figure 2. Conclusions Dd-cfDNA levels in patients without clinically relevant rejection are significantly higher in the first month post-transplant. Further studies are needed in order to determine if a different cut-off point for ACR during the first post-HT month is useful for ACR diagnosis.Donor-derived cell-free DNA kineticsDd-cfDNA values at three time points

Clinical relevance and outcome of routine endomyocardial biopsy to detect rejection after heart transplantation

Abstract Background After heart transplantation (HTx), endomyocardial biopsies (EMBs) are the gold standard to monitor cardiac allograft rejection. However, a clear consensus on the optimal frequency and duration of EMB monitoring is lacking. Purpose Since the first HTx in 1985 in our center, EMB protocols have gradually changed to a low-frequency schedule. We assessed the diagnostic yield and complication rate of the three different EMB protocols used during the past 37 years. Methods In this retrospective, single centre, observational study, all biopsy data of routine EMBs after HTx between 1985 and 2022 were collected for analysis. Patients with symptom-driven biopsies or follow up in another hospital were excluded. The total number of biopsies, type of rejection and complications were evaluated. Results In a total of 431 patients (69.6% male, mean age at transplant 48±13 years), 6692 routine surveillance EMB procedures were performed. The average number of biopsy procedures per patient was 25.1±8.1 for protocol 1 (n=44, 1985-1994), 17.0 ±3.6 for protocol 2 (n= 213, 1994-2009) and 11.3±2.6 for protocol 3 (n=174, 2009-2022). Cellular rejection was detected in 8.93%, of which grade I, II and III cellular rejections were seen in 7.32%, 1.58% and 0.03%, respectively. The frequency of ≥ ISHLT grade 2R requiring additional treatment was 1.61% and decreased over time with each EMB protocol (2.80%, 1.72%, and 0.76%). Complication rate was 1.63%, mainly consisting of puncture of the carotid artery (57.9%). Independent of the EMB protocol used, the majority of rejections occurred within the first six months after HTx (68.7%). Conclusion Complications of EMB after HTx are rare. Cellular rejection mostly occurs within the first 6 months after HTx. The incidence of clinically relevant cellular rejection (≥ISHLT grade 2) has declined over time, partly due to improved immunosuppressive therapy. A conservative approach using a low-frequency EMB schedule seems feasible and safe.Cellular rejection per protocol

Abstract 15922: Integrative Analysis of Extracellular Vesicles in Heart Transplant Rejection: From Biomarker Discovery to Novel Immune Mechanisms

Introduction: At the forefront of post-heart transplant care is early detection of transplant rejection. However, the current gold standard for detecting acute cellular transplant rejection is recurrent invasive endomyocardial biopsies (EMB). We aimed at developing a non-invasive biomarker for acute cellular heart transplant rejection (ACR) using a plasma extracellular vesicle (EV) platform. Methods: Peripheral and coronary sinus plasma samples were prospectively collected from 183 (31.7% female) patients from 2020 to 2023 during routine surveillance EMB. A discovery cohort comprised five patients who displayed ISHLT 0-1R biopsy followed by an ISHLT 2R grade rejection event. Plasma EVs were isolated from the baseline (0-1R) and rejection (2R) time points. Subsequently, integrative analysis of plasma EV proteomic, miRNomic, and metabolomics was performed pairwise with the samples. Results: The study collected 943 sample time points from 183 patients. Of these sample collections, 43 (4.5%) cases were 2R rejections. Our proteomic analysis of the plasma EVs identified 28 proteins found explicitly during a grade 2R rejection and 87 differentially expressed proteins during a 2R rejection event. An Ingenuity Pathway Analysis (IPA) analysis of the upregulated proteins highlighted EVs mediated mTOR signaling and antigen presentation as central to rejection events. Although all patients in the discovery cohort were negative for antibody-mediated rejection (AMR), the proteomic findings also revealed increased B-cell receptor signaling, implying a mechanistic intersection of ACR and AMR. Conclusions: A distinct set of proteins were found in plasma EVs during ACR events, providing potentially specific and sensitive biomarkers to reduce the need for EMB that could be exploited for ACR diagnosis. The proteins identified formed an immune signaling network that suggests a novel role for EVs in ACR pathogenesis.

Relation between global longitudinal strain and acute rejection in pediatric patients within the first-year post heart transplant

BackgroundAcute rejection leading to graft dysfunction remains a major cause of morbidity and mortality. In adults, assessment of global longitudinal strain (GLS) using speckle tracking echocardiography (STE) has been used as an early marker for graft dysfunction. Studies evaluating GLS in a sizable pediatric transplant population are scarce. ObjectivesWe sought to determine association between GLS and acute rejection within first-year post-transplantation in pediatric patients. MethodsPatients 0 to 18 years old who received heart transplants (HT) at Cleveland Clinic Children's Hospital after April 2013 were identified. Clinical data was collected from pre-transplant evaluation and post-transplant surveillance endomyocardial biopsy (EMB) visit from time of transplantation to one-year post-transplantation. Left ventricular (LV) GLS was measured retrospectively using vendor independent software. Significant rejection was defined by escalation in immunosuppression therapy due to pathology or clinical diagnosis. Trends of GLS were compared between patients with (Group 1) and without (Group 2) rejection, controlled for age. At the visit of rejection diagnosis, GLS rejection measurements were compared to the range of “normal”, non-rejection measurements. ResultsTwenty-seven patients met inclusion criteria. Eight patients (29.6 %) had at least one clinically significant rejection episode. There was no significant difference in GLS at the first endomyocardial biopsy visit between groups. At last biopsy visit, subjects with rejection had significantly worse GLS (p ≤ 0.001). In a mixed effect model, average global, 3-chamber, and 4-chamber systolic strain had significant interaction of group and time (p = 0.016, 0.033, 0.003, respectively). Systolic strain in those views significantly worsened over time in rejection group while remaining stable in non-rejection group. GLS of subjects with rejection were worse and out of the range of “normal” by the time of the third EMB visit. ConclusionsThere was a trend toward worse GLS in those who developed acute rejection within first year post-transplant compared to those without rejection.

(542) Path to Eliminating Surveillance Endomyocardial Biopsies in Heart Transplant: Early Use of Donor Derived Cell-Free DNA - One Year Follow Up

(542) Path to Eliminating Surveillance Endomyocardial Biopsies in Heart Transplant: Early Use of Donor Derived Cell-Free DNA - One Year Follow Up

Short-term clinical outcomes and predicted cost savings of dd-cfDNA-led surveillance after pediatric heart transplantation.

Endomyocardial biopsy (EMB)-led surveillance is common after pediatric heart transplantation (HT), with some centers performing periodic surveillance EMBs indefinitely after HT. Donor derived cell-free DNA (dd-cfDNA)-led surveillance offers an alternative, but knowledge about its clinical and economic outcomes, both key drivers of potential utilization, are lacking. Using single-center recipient and center-level data, we describe clinical outcomes prior to and since transition from EMB-led surveillance to dd-cfDNA-led surveillance of pediatric and young adult HT recipients. These data were then used to inform Markov models to compare costs between EMB-led and dd-cfDNA-led surveillance strategies. Over 34.5 months, dd-cfDNA-led surveillance decreased the number of EMBs by 81.8% (95% CI 76.3%-86.5%) among 120 HT recipients (median age 13.3 years). There were no differences in the incidences of graft loss or death among all recipients followed at our center prior to and following implementation of dd-cfDNA-led surveillance (graft loss: 2.9 vs. 1.5 per 100 patient-years; p = .17; mortality: 3.7 vs. 2.2 per 100 patient-years; p = .23). Over 20 years from HT, dd-cfDNA-led surveillance is projected to cost $8545 less than EMB-led surveillance. Model findings were robust in sensitivity and scenario analyses, with cost of EMB, cost of dd-cfDNA testing, and probability of elevated dd-cfDNA most influential on model findings. dd-cfDNA-led surveillance shows promise as a less invasive and cost saving alternative to EMB-led surveillance among pediatric and young adult HT recipients.

Clinical Prediction Model for Antibody-Mediated Rejection: A Strategy to Minimize Surveillance Endomyocardial Biopsies After Heart Transplantation.

In heart transplantation, antibody-mediated rejection (AMR) is a major contributor to patient morbidity and mortality. Multiple routine endomyocardial biopsies (EMB) remain the gold standard to detect AMR, but this invasive procedure suffers from many limitations. We aimed to develop and validate an AMR risk model to improve individual risk stratification of AMR. Heart recipients from 2 referral transplant centers, Cedars-Sinai (US) and Pitié-Salpêtrière (France), were included from 2012 to 2019. Database included detailed clinical, immunologic, imaging, and histological parameters. The US cohort was randomly distributed in a derivation (2/3) and in a test set (1/3). The primary end point was biopsy-proven AMR. A mixed effect logistic regression model with a random intercept was applied to identify variables independently associated with AMR. Simulation analyzes were performed. The US and French cohorts comprised a total of 1341 patients, representing 12 864 EMB. Overall, 490 AMR episodes were diagnosed (3.8% of EMB). Among the 26 potential determinants of AMR, 5 variables showed independent association: time post-transplant (P<0.001), pretransplant sensitizing event (P=0.001), circulating donor-specific anti-human leukocyte antigen antibody (P=0.001), graft dysfunction (P=0.004), and prior history of definite AMR (P<0.001). In the US test set, the calibration and the discrimination of the model were accurate (area under the curve, 0.79 [95% CI, 0.78-0.81]). Those results were confirmed in the external validation cohort (area under the curve, 0.78 [95% CI, 0.77-0.79]) and reinforced by various sensitivity analyses. The model also showed good performance to predict overall cause of rejection. Simulation models revealed that the AMR risk model could safely reduce the number of EMB. Our results support the use of the AMR risk model as a clinical decision tool to minimize the number of routine EMB after heart transplantation.

The Role of Left Atrial Longitudinal Strain in the Diagnosis of Acute Cellular Rejection in Heart Transplant Recipients.

Our aim was to investigate the role of left atrial longitudinal strain (LALS) in the non-invasive diagnosis of acute cellular rejection (ACR) episodes in heart transplant (HTx) recipients. Methods: We performed successive echocardiographic exams in 18 consecutive adult HTx recipients in their first year after HTx within 3 h of the routine surveillance endomyocardial biopsies (EMB) in a single center. LALS parameters were analyzed with two different software. We investigated LALS association with ACR presence, as well as inter-vendor variability in comparable LALS values. Results: A total of 147 pairs of EMB and echo exams were carried out. Lower values of LALS were significantly associated with any grade of ACR presence. Peak atrial longitudinal strain (PALS) offered the best diagnostic value for any grade of ACR, with a C statistic of 0.77 using one software (95% CI 0.68–0.84, p < 0.0005) and 0.64 with the other (95% CI 0.54–0.73, p = 0.013) (p = 0.02 for comparison between both curves). Reproducibility between comparable LALS parameters was poor (intraclass correlation coefficients were 0.60 for PALS, 95% CI 0.42–0.73, p < 0.0005; and 0.42 for PALS rate, 95% CI −0.13–0.68, p < 0.0005). Conclusions: LALS variables might be a sensitive marker of ACR in HTx recipients, principally discriminating between those studies without rejection and those with any grade of ACR. Inter-vendor variability was significant.

Digitising heart transplant rejection

For more than four decades, the monitoring of cardiac allograft rejection (CAR) has been achieved by surveillance endomyocardial biopsies (EMBs) and manual assessment by cardiac pathology experts. The first criteria for histological assessment of EMBs were devised during the 1970s, and the International Society for Heart and Lung Transplantation (ISHLT) developed standardised guidelines in the 1990s that have been frequently updated. Besides rejection, these guidelines also pertain to the subtype of rejection (cellular or antibody) and CAR severity.