Rejection In Heart Transplant Recipients Research Articles

European Society for Organ Transplantation (ESOT) Consensus Statement on the Use of Non-invasive Biomarkers for Cardiothoracic Transplant Rejection Surveillance.

While allograft rejection (AR) continues to threaten the success of cardiothoracic transplantation, lack of accurate and repeatable surveillance tools to diagnose AR is a major unmet need in the clinical management of cardiothoracic transplant recipients. Endomyocardial biopsy (EMB) and transbronchial biopsy (TBBx) have been the cornerstone of rejection monitoring since the field's incipience, but both suffer from significant limitations, including poor concordance of biopsy interpretation among pathologists. In recent years, novel molecular tools for AR monitoring have emerged and their performance characteristics have been evaluated in multiple studies. An international working group convened by ESOT has reviewed the existing literature and provides a series of recommendations to guide the use of these biomarkers in clinical practice. While acknowledging some caveats, the group recognized that Gene-expression profiling and donor-derived cell-free DNA (dd-cfDNA) may be used to rule out rejection in heart transplant recipients, but they are not recommended for cardiac allograft vasculopathy screening. Other traditional biomarkers (NT-proBNP, BNP or troponin) do not have sufficient evidence to support their use to diagnose AR. Regarding lung transplant, dd-cfDNA could be used to rule out clinical rejection and infection, but its use to monitor treatment response is not recommended.

(1095) - Early Donor Derived Cell-Free DNA Ratios Can Help Predict Future Rejection in Heart Transplant Recipients

(1095) - Early Donor Derived Cell-Free DNA Ratios Can Help Predict Future Rejection in Heart Transplant Recipients

(342) - Antithymocyte Globulin as an Adjunctive Therapy for Antibody-Mediated Rejection in Heart Transplant Recipients More Consistently Decreased Donor-Specific HLA Antibodies and Histopathologic Grading Than PP/IVIG Alone

(342) - Antithymocyte Globulin as an Adjunctive Therapy for Antibody-Mediated Rejection in Heart Transplant Recipients More Consistently Decreased Donor-Specific HLA Antibodies and Histopathologic Grading Than PP/IVIG Alone

(512) - Are the Bleeding and Thrombosis Complications in Left Ventricular Assist Device Patients as Impactful as Infection and Rejection in Heart Transplant Recipients?

(512) - Are the Bleeding and Thrombosis Complications in Left Ventricular Assist Device Patients as Impactful as Infection and Rejection in Heart Transplant Recipients?

(1397) - Eculizumab as Rescue Therapy for Severe Acute Antibody Mediated Rejection in Heart Transplant Recipients

(1397) - Eculizumab as Rescue Therapy for Severe Acute Antibody Mediated Rejection in Heart Transplant Recipients

(1081) - Effects of Belatacept Therapy on Gene Expression Profiling and Rejection in Heart Transplant Recipients: A Molecular Microscope (MMDx) Evaluation

(1081) - Effects of Belatacept Therapy on Gene Expression Profiling and Rejection in Heart Transplant Recipients: A Molecular Microscope (MMDx) Evaluation

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 <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 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

Human cytomegalovirus and Epstein-Barr virus infections occurring early after transplantation are risk factors for antibody-mediated rejection in heart transplant recipients.

Antibody-mediated rejection (AMR) is a serious complication affecting the survival of patients receiving transplantation. Human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are common viral infections that occur after transplantation, frequently emerging as viral reactivation in donor grafts or transplant recipients. The present study aimed to investigate the association between CMV and EBV infections and early-onset AMR. This study was conducted at the Heart Transplantation Center of Padova General Hospital and included a cohort of 47 heart transplant recipients (HTxs), including 24 HTxs diagnosed with AMR and 23 control HTxs with no episodes of AMR. Only early cases of CMV and/or EBV infections (1-90 days after transplantation) were considered. Fisher's exact test and logistic regression analysis were used to statistically analyze the correlation and association between AMR and CMV or EBV infection. We observed a positive statistical association between CMV and EBV infections (two-sided Fisher's exact test, p = 0.0136) and between EBV infection and AMR (two-sided Fisher's exact test, p = 0.0034). Logistic regression analysis revealed a direct statistical association between CMV and EBV infections and AMR risk (p = 0.037 and 0.006 and odds ratio = 1.72 and 2.19, respectively). AMR occurrence was associated with increased viral loads of both CMV and EBV early after transplantation. These findings suggest the role of CMV and EBV infections as relevant risk factors for AMR in HTxs for the first time.

(280) Comparison of Two Commercially Available Donor-Derived Cell-Free DNA Assays for Surveillance of Rejection in Heart Transplant Recipients

(280) Comparison of Two Commercially Available Donor-Derived Cell-Free DNA Assays for Surveillance of Rejection in Heart Transplant Recipients

(277) Association of Early Testing of Donor Derived Cell-Free DNA with the Risk of Antibody Mediated Rejection in Heart Transplant Recipients

(277) Association of Early Testing of Donor Derived Cell-Free DNA with the Risk of Antibody Mediated Rejection in Heart Transplant Recipients

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

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

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.

Prognostic Value of Left and right ventricular deformation strain analysis on Acute Cellular rejection in Heart Transplant recipients: A 6-year outcome study

PurposeTwo-dimensional (2D) strain analysis is a sensitive method for detecting myocardial dysfunction in acute cellular rejection (ACR) from post-transplant complications. This study aims to evaluate the utility of novel left (LV) and right ventricular (RV) strain parameters for prognostic risk stratification associated with ACR burden at 1-year post transplantation.Methods128 Heart transplant patients, assessed between 2012 and 2018, underwent transthoracic echocardiography and endomyocardial biopsy. 2D strain analysis was performed and history of rejection burden was assessed and grouped according to ACR burden at 1-year post transplantation. The primary endpoint was all-cause mortality at 6-years follow up.Results21 patients met primary the endpoint. Multivariate analysis of 6-year all-cause mortality showed LV global longitudinal strain (LV GLS) (Hazard Ratio [HR] = 1.21, CI = 1.06–1.49), LV early diastolic strain rate (LV ESr) (HR = 1.31, CI = 1.12–1.54), RV GLS (HR = 1.12, CI = 1.02–1.25) and RV ESr (HR = 1.26, CI = 1.12–1.47) were significant predictors of outcome. Univariate analysis also showed LV GLS, LV ESr, RV GLS and RV ESr were significant predictors of outcome. Optimal cut-off for predicting 6-year mortality for LV GLS by receive operator characteristic was 15.5% (sensitivity: 92%, specificity: 79%). Significant reductions (p < 0.05) in LV GLS, RV GLS and LV and RV ESr between rejection groups were seen.ConclusionsNon-invasive LV and RV strain parameters are predictors of mortality in post-transplant patient with ACR. LV GLS and LV ESr are superior to other strain and conventional echo parameters.

Prevalence of Clinical Events Following High Donor Derived Cell Free DNA in the Absence of Rejection in Heart Transplant Recipients

Purpose Donor-derived cell free DNA (dd-cfDNA) is a noninvasive biomarker used to assess graft injury following heart transplant (HTx). While the relationship between increased levels of dd-cfDNA and acute cellular rejection (ACR) and antibody mediated rejection (AMR) has been well studied, less is known about the frequency of other processes that damage the allograft following an elevated dd-cfDNA measurement. The goal of this analysis was to assess the prevalence of clinical events following a high dd-cfDNA measurement in the absence of rejection. Methods This retrospective study included 223 HTx recipients from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR) with elevated dd-cfDNA (AlloSure®), defined as a level ≥0.20% that did not occur within 14 days of biopsy proven ACR (grade ≥2R) or AMR (pAMR≥1). Clinical events included the presence of donor specific antibodies (DSA), cardiac allograft vasculopathy (CAV; ISHLT grade ≥1), graft dysfunction [left ventricular ejection fraction (LVEF) ≤45% or a proportional decrease in LVEF ≥25% from the first D-OAR study visit], ACR, AMR and death. Clinical data were collected for 180 days following the first elevated dd-cfDNA. Allosensitization was defined as a pre-transplant panel reactive antibody ≥10%. Results The study consisted of 68% men and 71% Caucasians (mean ± SD age at HTx 52 ± 14 years), with non-ischemic cardiomyopathy (46%) representing the primary reason for HTx. The median time post-HTx to the first non-rejection elevated dd-cfDNA was 241 days (IQR 154-362). Fifty-seven of the 223 patients (26%), of whom 6 were allosensitized, experienced 70 clinical events in the 180 days post-elevated dd-cfDNA. The presence of at least one DSA (n=36) was the most common clinical event, of which 28/36 (78%) were de novo DSA. Graft dysfunction (n=14), CAV (n=9), AMR (n=5), death (n=4), and ACR (n=2) were the next most common. Median time (IQR) from elevated dd-cfDNA to these events was as follows: DSA, 37 days (15-104); graft dysfunction, 22 days (0-77); AMR, 70 days (42-91); and death, 100 days (75-124). Conclusion Elevated dd-cfDNA levels in the absence of allograft rejection appeared to precede the development of clinically relevant events within the next 6 months. Further studies are needed to determine whether elevated dd-cfDNA should trigger a change in clinical management. Donor-derived cell free DNA (dd-cfDNA) is a noninvasive biomarker used to assess graft injury following heart transplant (HTx). While the relationship between increased levels of dd-cfDNA and acute cellular rejection (ACR) and antibody mediated rejection (AMR) has been well studied, less is known about the frequency of other processes that damage the allograft following an elevated dd-cfDNA measurement. The goal of this analysis was to assess the prevalence of clinical events following a high dd-cfDNA measurement in the absence of rejection. This retrospective study included 223 HTx recipients from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR) with elevated dd-cfDNA (AlloSure®), defined as a level ≥0.20% that did not occur within 14 days of biopsy proven ACR (grade ≥2R) or AMR (pAMR≥1). Clinical events included the presence of donor specific antibodies (DSA), cardiac allograft vasculopathy (CAV; ISHLT grade ≥1), graft dysfunction [left ventricular ejection fraction (LVEF) ≤45% or a proportional decrease in LVEF ≥25% from the first D-OAR study visit], ACR, AMR and death. Clinical data were collected for 180 days following the first elevated dd-cfDNA. Allosensitization was defined as a pre-transplant panel reactive antibody ≥10%. The study consisted of 68% men and 71% Caucasians (mean ± SD age at HTx 52 ± 14 years), with non-ischemic cardiomyopathy (46%) representing the primary reason for HTx. The median time post-HTx to the first non-rejection elevated dd-cfDNA was 241 days (IQR 154-362). Fifty-seven of the 223 patients (26%), of whom 6 were allosensitized, experienced 70 clinical events in the 180 days post-elevated dd-cfDNA. The presence of at least one DSA (n=36) was the most common clinical event, of which 28/36 (78%) were de novo DSA. Graft dysfunction (n=14), CAV (n=9), AMR (n=5), death (n=4), and ACR (n=2) were the next most common. Median time (IQR) from elevated dd-cfDNA to these events was as follows: DSA, 37 days (15-104); graft dysfunction, 22 days (0-77); AMR, 70 days (42-91); and death, 100 days (75-124). Elevated dd-cfDNA levels in the absence of allograft rejection appeared to precede the development of clinically relevant events within the next 6 months. Further studies are needed to determine whether elevated dd-cfDNA should trigger a change in clinical management.

Impact of Donor Hepatitis C Viremia on Acute Rejection in Heart Transplant Recipients

<h3>Purpose</h3> With the advent of direct acting antivirals, hepatitis C viremic donors are being increasingly used for heart transplantation. Single institutions have reported increased incidence of acute rejection when utilizing these hearts. The goal of this study was to evaluate one-year acute rejection following heart transplant from HCV viremic donors. <h3>Methods</h3> We conducted retrospective review of UNOS of all primary adult heart transplants conducted between March 31, 2015 and June 30, 2020, excluding recipients with prior transplants, multiorgan transplants, or those waitlisted for other organs. Donors were dichotomized as being HCV NAT+ or HCV NAT-. One-year acute rejection requiring treatment was compared and evaluated by univariable and multivariable logistic regression. <h3>Results</h3> Of 11,058 heart transplant recipients in our cohort during the study period, 432 (3.9%) came from HCV NAT+ donors. HCV NAT+ donors were significantly older (34±8 vs 32±11 years, p<0.01), more likely to be white (82% vs 64%, p<0.01), blood group O (61% vs 49%, p<0.01), CDC high risk (88% vs 30%, p<0.01), and have drug use as cause of death (61% vs 17%, p<0.01). Recipients in the HCV NAT+ group were older [58(49-64) vs 56 (46-63) years, p<0.01), had higher ischemic times (3.5±1.0 vs 3.1±1.1 hours, p<0.01) and were more likely to be blood group O (49% vs 39%, p<0.01) and HCV antibody positive (5% vs 2%, p<0.01). They were less likely to be on inotropes (31% vs 37%, p<0.01) or any life support (81% vs 86%, p<0.01) at the time of transplant. Incidence of acute rejection requiring treatment within one year was not significantly different between the two groups (21% HCV NAT+ vs 19% HCV NAT-, p = 0.31). Donor HCV NAT+ was not associated with one-year acute rejection on either univariable (OR 1.13, 95% CI 0.89-1.43) or multivariable (aOR 1.08, 95% CI 0.84-1.41) logistic regression. <h3>Conclusion</h3> Despite single center studies reporting potential increases in acute rejection when utilizing HCV-viremic donor hearts for transplantation, our UNOS registry analysis did not demonstrate increased treatment for acute rejection after one year. We should continue to utilize these donor hearts with careful surveillance and monitoring of long-term outcomes.

Utility of AlloMap® Scores in Younger Pediatric Heart Transplant Recipients

<h3>Purpose</h3> AlloMap® is used to predict acute cellular rejection (ACR) post heart transplant (HT) in pediatric patients > 15 years old. Data on its utility in a younger pediatric cohort are limited. We examine the correlation of AlloMap® score with hemodynamic, echocardiographic (echo), and endomyocardial biopsy (EMB) markers of rejection in HT recipients ≤ 15 years old. <h3>Methods</h3> Retrospective study of all pediatric patients ≤ 15 years old at our institution who had AlloMap® testing with routine cardiac catheterization and EMB, or when rejection was suspected based on clinical/echo evidence. <h3>Results</h3> 438 AlloMap® scores obtained from 57 children from 2010-2017. Median age at HT was 2.4 years (IQR 0.6-11.9 years) and 56% (n=32) were male. Indication for HT was cardiomyopathy (CM) in 56.1% (n=32) and congenital heart disease (CHD) in 43.9% (n=25) of patients. AlloMap® scores did not differ between CHD and CM groups (32.8 ± 3.5 vs 32.4 ± 3.7, p=.2). Scores were highest in those <2 years old. Scores differed between patients aged < 2 versus 2-10 years (p<.001) and between patients aged 2-10 and > 10 years old (p<.001). 32 rejection episodes were identified in 18 patients; 5 patients (27.8%) were < 1 year old. ACR grade 0/1R and 2R/3R were seen in 84.4% (n=27) and 15.6% (n=5), respectively. Those with ACR 0R had lower AlloMap® scores than those with ACR 1R (p=.024), but there was no difference between 1R and higher grade rejection. AlloMap® score weakly correlated with left ventricular end diastolic pressure (LVEDP) (r=.149, p=.026), but not with echo variables. <h3>Conclusion</h3> AlloMap® scores are similar in CM and CHD patients. Scores decrease with age, which may represent differing gene expression profiles over time. Scores are lower for those with ACR 0R versus 1R, but do not differ significantly between 1R and higher grade ACR. AlloMap® score correlates weakly with LVEDP, but not echo variables. Sample size is small with few rejection episodes. A larger study is needed to determine the utility of routine AlloMap® surveillance in HT recipients ≤ 15 years of age.

Insight into Noninvasive Radiological Modalities to Detect Heart Transplant Rejection.

Purpose Patients with end-stage heart failure who remain symptomatic even with exemplary medical and device therapy are treated with heart transplantation. Multitudes of endeavor have been contrived during the last decennium in the field of noninvasive tests to rule out heart transplant rejection (HTR). In spite of having supportive literature, noninvasive imaging techniques lack acceptable documentation of clinical robustness, and endomyocardial biopsy (EMB) still remains the gold standard. The aim of this review is to shed light on the existing noninvasive radiological modalities to detect rejection among heart transplant recipients. Methods A comprehensive search was conducted for this review article on the basis of literature available including scientific databases of PubMed, Embase, and Google Scholar, using keywords of “Heart transplantation,” “Acute allograft rejection,” “Arrhythmias,” “Echocardiography,” “Speckle tracking echocardiography,” and “Cardiac magnetic resonance imaging” from inception until September 2020. Results After preliminary screening of the databases, details regarding existent noninvasive radiological modalities to detect HTR were gathered and compiled in this review article. Currently, deformation imaging using speckle tracking and T2 time using cardiac magnetic resonance imaging can serve as screening tools based on which further invasive investigations can be planned. Standardization of blood-based and imaging modalities as screening and possible diagnostic tools for rejection would have obvious clinical and financial benefits in the care of growing number of post heart transplant recipients in our country. Conclusion Diagnosis of allograft rejection in heart transplant recipients through noninvasive techniques is demanding. To unravel the potential of noninvasive radiological modalities that can serve as a standard-of-care test, a prospective multicentric study randomizing noninvasive modality as first strategy versus current EMB-based gold standard of care is the need of the hour.

HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study

Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients. In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.9±14.8 years). The assay was carried out on a total of 232 liquid biopsies collected at the same time as endomyocardial biopsy (EMB) during routine post-transplant follow-up. Results show a significant increase of dd-cfDNA related to ischemia-reperfusion injury (2.22±2.09%) and to acute cellular rejection (1.71±3.10%) compared to stable conditions (0.43±1.04%, p < 0.0001). On the contrary, no increase was observed during infections or vascular complications, underlining the potential role of this biomarker for rejection monitoring. With a cut-off of 0.11%, the test showed 70.8% specificity (95% CI, 58.17% - 81.40%) and 64.2% sensitivity (95% CI, 49.80% - 76.86%) in discriminating acute rejection from no rejection. These data demonstrate that this HLA mismatch-based droplet digital PCR method is effective for monitoring rejection in heart transplant recipients. Compared to next generation sequencing approaches, it is far more flexible, less expensive and provides faster results.

Release the Pressure! Does Jugular Venous Pressure Predict Rejection in Cardiac Biopsy?

<h3>Purpose</h3> Rejection in heart transplant recipients is often diagnosed by surveillance biopsies as most patients are asymptomatic. Nevertheless, rejection, if left untreated, can produce progressive diastolic dysfunction followed by systolic heart failure. This in turn will cause an increase in central venous pressure due to decreased ventricular compliance. With this in mind we sought out to determine if elevated central venous pressures measured invasively at the time of the biopsy correlated with the presence of rejection. <h3>Methods</h3> Patients undergoing an endomyocardial biopsy between June and October 2020 were included. The invasive JVP was measured before and after the procedure by measuring the height of the blood column in the side port of the sheath open to the atmospheric pressure. The biopsy results were reported according to the 2004 ISHLT revision. Differences in median JVP for each biopsy result group (0, 1R, 2R, 3R) were compared using a Mann-Whitney test. The histogram density for each biopsy group was graphed using a Kernel density plot. <h3>Results</h3> Eighty-four patients underwent one or more endomyocardial biopsies, with a total of 374 biopsies performed. Of all procedures, 187 were grade 0 for rejection, 168 were grade 1R and 18 were grade 2R. One patient had Grade 3R rejection (not shown in illustration) The median JVP was not statistically different between the three groups and the numerical difference was not clinically meaningful (figure 1 A). The Kernel density plot (figure 1 B) demonstrates the similarities between the groups. The lack of correlation between invasive JVP and rejection persists if data from the first 2 weeks post heart transplant are excluded. <h3>Conclusion</h3> In our dataset, there was no clinical or statistical difference in median invasive JVP and rejection grade between the biopsy result groups. One limitation is that we only had one patient with severe rejection (3R). Overall, our findings reinforce the need for surveillance biopsies.