AlloMap Score Research Articles

The Gut Microbiome as a Marker of Early Cardiac Allograft Injury

<h3>Purpose</h3> Gut microbial dysbiosis has been correlated to solid organ and stem cell transplant rejection and death. The HeartCare lab test (CareDx) is increasingly used as routine surveillance for heart transplant (HT) injury and rejection. We investigated whether the microbiome can serve as a noninvasive marker of immune activation and allograft injury among HT recipients. <h3>Methods</h3> We conducted a single-center, prospective cohort study of single organ HT recipients from 2020-2021. Shotgun metagenomic sequencing was performed on peri-HT stool samples. Gut microbial diversity and composition were correlated with the highest abnormal AlloSure or AlloMap obtained within 6 months post-HT. <h3>Results</h3> Thirty-eight HT recipients were included. Stool samples were collected 5.3 ± 7.4 days from HT. The highest HeartCare lab values were measured 72 days (IQR [41, 103]) post-HT. Seven HT recipients had high AlloSure (median 0.2%, IQR [0.14, 0.26]) and 7 had high AlloMap (median 32, IQR [30, 33]) scores. The high and low AlloSure and AlloMap groups had similar within sample microbial i.e. α-diversity. Low AlloSure scores significantly correlated with an increased abundance of phylum <i>Bacteroidetes</i> (34.5% vs 14.4%, p=0.04), and class <i>Bacteroidia</i> (34.3% vs 14.3%, p=0.04); and tended to have lower abundance of the phylum <i>Proteobacteria</i> (5.0% vs 23.3%, p=0.06) (Fig. 1A). Higher AlloMap scores correlated with higher abundance of class <i>Deltaproteobacteria</i> (1.3% vs 0.10%, p=0.04) and order <i>Desulfovibrionales</i> (1.25% vs 0.07%, p=0.02), and a trend towards lower abundance of <i>Firmicutes</i> (36.8% vs 57.3%, p=0.08) (Fig. 1B). Intergroup β-diversity analysis showed clustering based on AlloSure but not AlloMap scores (Fig. 1C). <h3>Conclusion</h3> In our cohort, increased abundance of certain gut microbial taxa in the peri-HT period correlated with increased HeartCare values. The gut microbiome may play a role in immune activation and allograft injury or serve as a biomarker. Further investigation into the mechanistic ties between the gut microbiome and alloimmunity is needed.

Longitudinal Variation in Absolute and Relative AlloMap Score in Heart Transplant Recipients

<h3>Purpose</h3> The non-invasive AlloMap gene expression profiling test has been demonstrated to possess high negative predictive value for detecting cardiac allograft rejection and dysfunction after heart transplant. We assessed longitudinal trends in AlloMap score post-transplant. <h3>Methods</h3> We retrospectively analyzed AlloMap scores, organized by season and year post-transplant, for patients undergoing heart transplantation at our center. Patients with multiple tests in one season had their scores averaged. Relative AlloMap score was calculated for each patient as (AlloMap score)/(average AlloMap score across all tests). The association between season and AlloMap score was also investigated. Seasons were defined as the following: (1) Winter: January - March, (2) Spring: April - June, (3) Summer: July - September, (4) Fall: October - December. <h3>Results</h3> A total of 658 tests were included in our study. AlloMap scores were significantly greater in tests done more than one-year post-transplant compared to those completed in the first year (median: 32 (29, 34) vs 28 (24.5, 32), p <0.0001). Similarly, the relative AlloMap score increased over time, observed to be significantly higher in tests performed after one-year compared to those done in the first year (median: 1.07 (1.01, 1.14) vs 0.97 (0.875, 1.02), p <0.0001). There was a trend towards increased AlloMap score in winter and fall, but this was not significant (p = 0.089). <h3>Conclusion</h3> We observed longitudinal trends of rising absolute and relative AlloMap scores after one-year post-transplant. Clinically, the variability score may be more meaningful than the raw score in the long-term due to more specific comparison of patient level variation from baseline. Further analyses with multicenter data are warranted.

A Comparison of AlloMap versus Echocardiographic Doppler Tissue Imaging in Assessing the Presence of Rejection in Orthotopic Heart Transplant Recipients

Purpose Cardiac allograft rejection is a significant concern amongst individuals who have undergone orthotopic heart transplantation. Currently, surveillance is performed through routine endomyocardial biopsy (EMB). While relatively safe in experienced hands, the invasive nature of the procedure lends itself to occasional complications. Several non-invasive techniques for evaluation of cardiac allograft rejection have been evaluated. In this study, we aim to compare the efficacy of two non-invasive methods of detecting rejection against the gold standard of EMB; gene expression profiling with AlloMap and echocardiographic doppler tissue imaging (DTI). Methods This was a single-center, retrospective analysis. Electronic medical records of all patients who underwent orthotopic heart transplant at our institution and had at least two concomitant measurements of AlloMap, echocardiogram DTI and endomyocardial biopsy from January 1st, 2015 to December 31st, 2017 were reviewed. Statistical analyses were performed to calculate sensitivity, specificity, negative predictive value (NPV) and positive predictive value. Rejection for EMB was defined using ISHLT guidelines and was considered present with either acute cellular rejection of 1R or greater or antibody mediated rejection pAMR1 or greater. For non-invasive studies, we considered an AlloMap score of > 34 and a DTI Results A total of 107 patients with available data were reviewed. 77% were male. Mean age was 57 years old ± 13 years with a range of 22-77 years. AlloMap and DTI performed similarly in our cohort and had NPV of 92% and 88%, respectively when compared to similarly timed EMB. Positive predictive value was 9% for AlloMap and 8% for DTI. Sensitivity was 37% for AlloMap and 18% for DTI and specificity was 65% for AlloMap and 74% for DTI. Conclusion In our cohort, AlloMap and DTI performed similarly and demonstrated excellent NPV in ruling out rejection. AlloMap has known excellent NPV and has been well-validated for this purpose. The NPV of DTI has been less studied, but performed similarly and is highly cost effective. This could have implications on future screening protocols. This study is limited by the inherent errors of a single-center, retrospective analysis. Further prospective studies to validate this data are ongoing.

Impact of cytomegalovirus infection on gene expression profile in heart transplant recipients

Cytomegalovirus (CMV) infection has been implicated in the pathogenesis of allograft rejection in heart transplant (HT) recipients. The effect of a CMV infection on the gene expression profiling (GEP, AlloMap) scores in the absence of acute rejection is not known. Data from 14,985 samples collected from 2,288 adult HT recipients enrolled in Outcomes AlloMap Registry were analyzed. Patients with known CMV serology at the time of HT who had at least 1 AlloMap score reported during follow-up were included. AlloMap scores for those patients with CMV (but no ongoing rejection) were compared with those who were never infected. An exploratory analysis on the impact of CMV on available donor-derived cell-free DNA (AlloSure) was also performed. A total of 218 patients (10%) were reported to have CMV infection after transplantation. AlloMap score in those samples with CMV infection (n = 311) had a GEP score (34; range: 29-36) significantly higher than the GEP score from samples (n = 14,674) obtained in the absence of CMV infection (30; range: 26-34; p < 0.0001). Both asymptomatic viremia and CMV disease demonstrated significantly higher AlloMap scores than no CMV infection samples (median scores: 33, 35, and 30, respectively; p < 0.0001). AlloSure levels, available for 776 samples, were not significantly different (median: 0.23% in 18 samples with CMV infection vs 0.15% in 776 samples without CMV infection; p = 0.66). CMV infection in HT recipients is associated with an increase in AlloMap score, whereas AlloSure results do not appear to be impacted. This information should be considered when clinically interpreting abnormal/high AlloMap scores in HT recipients.

Rejection-associated Mitochondrial Impairment After Heart Transplantation.

Background.Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs.Methods.We collected 64 routines or clinically indicated EMB from 47 patients after heart transplant. The EMBs were subjected to mRNA sequencing. We conducted weighted gene coexpression network analysis to construct module-derived eigengenes. The modules were assessed by gene ontology enrichment and hub gene analysis. Modules were correlated with the EMBs following the International Society of Heart and Lung Transplantation histology-based criteria and a classification based on GE alone; we also correlated with clinical parameters.Results.The modules enriched with mitochondria-related and immune-response genes showed the strongest correlation to the clinical traits. Compared with the no-rejection samples, rejection samples had a decreased activity of mitochondrial-related genes and an increased activity of immune-response genes. Biologic processes and hub genes in the mitochondria-related modules were primarily involved with energy generation, substrate metabolism, and regulation of oxidative stress. Compared with International Society of Heart and Lung Transplantation criteria, GE-based classification had stronger correlation to the weighted gene coexpression network analysis–derived functional modules. The brain natriuretic peptide level, ImmuKnow, and Allomap scores had negative relationships with the expression of mitochondria-related modules and positive relationships with immune-response modules.Conclusions.During acute cardiac allograft rejection, there was a decreased activity of mitochondrial-related genes, related to an increased activity of immune-response genes, and depressed allograft function manifested by brain natriuretic peptide elevation. This suggests a rejection-associated mitochondrial impairment.

The Use of AlloMap and AlloSure in Combined Heart-Kidney Transplantation

Kidney disease is a common comorbidity seen in heart disease, and so the number of patients undergoing combined heart-kidney transplantation (HKT) continues to increase, as well as the number of waitlisted patients for HKT. Recent evidence suggests a favorable immunomodulatory effect for combined HKT, making these patients ideal candidates for non-invasive monitoring for rejection and injury. The use of gene-expression profile testing (AlloMap®) in HKT recipients vs heat transplant (HT) alone has remained uncertain with earlier reports suggesting higher values in HKT, while more recent reports suggesting equivocal results between the two. Additionally, the profile of donor-derived cell-free DNA (dd-cfDNA) (AlloSure®) in HKT has not yet been evaluated. The Utility of dd-cfDNA in Association with Gene Expression Profiling (D-OAR) registry is a prospective, observation study of HT recipients monitored with AlloMap and AlloSure. The D-OAR registry and prospectively collected data from UCLA Medical Center were assessed for patients who underwent HKT with associated AlloSure and AlloMap scores and compared to patients who underwent HT alone. The cumulative distribution functions of AlloMap and AlloSure scores were stratified by HT vs. HKT. Patients with CMV and acute cellular rejection (≥2R) were excluded from the analysis. There were 300 HT recipients and 14 HKT recipients. Baseline characteristics were similar between groups. The median AlloMap and AlloSure scores for HT recipients (N=300) were 29 and 0.09% respectively, while for HKT recipients (N=14) AlloMap and AlloSure scores were 33.5 and 0.41% respectively. See table 1 CONCLUSION: There were slightly higher AlloMap scores in HKT vs HT patients, while AlloSure results in HKT were significantly higher. Further work to establish baseline parameters and understand changes to these parameters during rejection episodes would benefit HKT patients by allowing non-invasive monitoring for rejection and graft injury.

Is There Any Role of Gene Expression Profiling Test in Asymptomatic Pediatric Heart Transplant Recipients?

Our objective was to correlate AlloMap score with acute cellular rejection (ACR) by endomyocardial biopsy (EMB), donor specific antibody (DSA), cardiac hemodynamic data, cardiac allograft vasculopathy (CAV), and allograft function by echocardiography in pediatric heart transplant (HT) recipients. Retrospective data were collected on all consecutive pediatric HT patients, who had AlloMap tests, cardiac catheterization, EMB, left ventricular shortening fraction (LV SF), ejection fraction (LV EF), and fractional area change in right ventricle (RV FAC) by echocardiography that were obtained concomitantly on same day for routine surveillance for cardiac rejections in asymptomatic patients. Fifty five patients included in the study. Median age at HT was 5.1 years (range, 0.9 -14.1). Median number of RHC was 4 and both RHC and LHC was 2 per patient. The median AlloMap score for entire cohort was 32 (range, 18-37), in both grade 0R (n=67) and grade 1R (n=140) were 32 (range, 29-35), whereas in grade 2R (n=3) score was 35 (range, 33-37). There was no significant difference in AlloMap scores between ACR grades (Fig A), DSA (Fig B), or CAV status (Fig C). There was modest correlation between AlloMap scores and mean RAP (R2 = 0.05, p = 0.002), and PCWP (R2 = 0.03, p = 0.02). Patients on Tacrolimus only had higher scores (Fig D). No correlation between AlloMap score was found with LV SF (p=0.3), LV EF (p=0.5), or RV FAC (p=0.8). AlloMap scores were higher in <2 versus ≥2 years of age at HT (Fig E), and scores were trending higher with time after HT (Fig F). AlloMap scores are not predictive of ACR in asymptomatic pediatric HT recipients. Moreover, AlloMap scores are higher in children <2 years of age at the time of HT. Monitoring of serial AlloMap scores could potentially reflect changes in allograft performance which could help determine indications for EMB. Patients have predictably higher AlloMap scores with time after HT due to changes in hemodynamics associated with cardiac remodeling.

Gene Expression Profile Scores by Allomap® are Higher in Heart Transplant Patients with Non-Skin Cancer Malignancy

Gene expression profile (GEP) monitoring by AlloMap® is ISHLT-guideline recommended for graft surveillance after heart transplant (HT). The Outcomes in AlloMap Registry (OAR) is an observational, prospective study of HT patients monitored by AlloMap. The effect of malignancy on AlloMap scores is not well characterized. The large cohort of OAR patients with clinical data associated with AlloMap scores permits this characterization. Patients enrolled in the OAR study and >6 months post-HT were assessed for malignancy status and stratified by HT recipients with malignancy and those without. The malignancy groups were further stratified by non-skin cancers and skin cancers, where mean AlloMap scores were compared between groups. 135 patients in the OAR registry (1.4%) with de-novo malignancy (including skin cancer) and 9395 patients with no de-novo malignancy >6 months post-HT and associated AlloMap scores were identified. Mean AlloMap score in patients with malignancy was significantly higher than in patients without malignancy (30.9 vs 30.1; p=0.0354) (Table 1). For HT patients with skin cancer vs no malignancy, there was not a statistically significant difference between GEP scores (30.7 vs 30.1; p=0.1390). AlloMap scores were higher in HT recipients with any malignancy compared to HT patients without malignancy; however, scores were not statistically significant when looking only at skin-cancer versus no malignancy. Although statistically significant, the absolute difference was only small and therefore unlikely to have clinical impact. The GEP score comprises changes in gene expression in peripheral blood mononuclear cells (PBMCs). Recently, malignancy has been shown to cause changes in gene expression in PBMCs, which may explain this observed difference. Further studies are warranted to replicate these findings and to determine whether cancer development causes an elevated AlloMap score.

Gene Expression Profiling Scores (Allomap) Can Successfully Predict the Absence of Serious Rejection in a Pediatric Heart Transplant Population; Single Center Experience

Allomap has been used successfully in adult cardiac transplantation as a screening tool to predict the absence of serious rejection. In adult studies, an Allomap score less than 34 has been highly correlated (Negative Predictive Value [NPV] of 98%) with biopsy grade 0-1R rejection. However, there are minimal studies using Allomap in pediatric patients. We sought to determine if using an Allomap score in pediatric patients ages 10-21 years old could also predict absence of serious rejection in our population. Heart transplant recipients >more than 3 months after transplant, who were between 10-21 years of age at the time of testing, who were taking a prednisone dose less than 15 mg/day and who had cardiac catheterization with biopsy performed had blood drawn for Allomap testing the same day. The blood was handled by a certified lab according to CareDx protocol and then sent to CareDx for testing. Allomap scores were then compared to cellular biopsy grading (serious rejection = 2R or greater). The data points were assessed for sensitivity and specificity using the Youden index and distance to (0,1), as was done in the CARGO studies. Eighty-one patients (mean age 14 +/- 2.9 years, 44% female) had 265 total Allomap tests and biopsy pairs evaluated between 2013 and 2019. Sixty-three (63) patients had more than one Allomap sample and biopsy pair. Race mix was Caucasian 44%, Hispanic 38%, African American 12%, Asian 2.5%, others 3.5%. Biopsy grade 0-1R represented 94% of the sample population. The NPVs for Allomap scores were 100% at 32 and 98.8% at 34, similar to what was found for adults in the CARGO studies. ROC curve demonstrates a c-statistic of 0.7566. Allomap scores in children and adolescents can be used to successfully predict absence of rejection with NPVs between 98%-100%; scores less than or equal to 32 correlated 100% with biopsy grades of 0-1R in this population. Given these results, we speculate that Allomap use will lead to a reduced need for cardiac catheterization and biopsy in this population but further studies in a larger pediatric transplant population is warranted.

The Effect of Pre-Transplant Mechanical Circulatory Support Devices on the Post-Transplant dd-cfDNA and GEP in Heart Transplantation

Evidence around sensitization and increased risk of rejection from use of pre-transplant mechanical circulatory support (MCS) devices remains conflicting. Some evidence suggests devices cause inflammation and association with increased antibody production, which has been shown to be associated with AMR, CMR, and early onset of microvasculopathy at one year post-heart transplant. However other evidence suggests no difference or increased risk of adverse outcome using pre-transplant MCS devices. dd-cfDNA (AlloSure) has been shown to rise in advance to the new formation of de-novo anti-HLA antibodies, with changes in AlloMap also seen in patients who become newly sensitized. The aim of this study was to review MCS patients post-transplant with AlloSure and AlloMap to assess if they had different patterns from those who had no MCS, to support suggestion of early post-transplant complications. Patients who were enrolled in Outcomes AlloMap® Registry (OAR) and the dd-cfDNA extension (D-OAR) were included in this analysis if pre-transplant MCS history was recorded and signs or symptoms of rejection during a visit with an accompanying blood draw were absent (i.e. no biopsy accompanied the visit or if a biopsy occurred it yielded Grade 0R). A total of 282 patients met these criteria, 130 had pre-transplant MCS and 152 did not. A total of 652 samples were collected where both AlloSure and AlloMap scores were obtained. The cumulative distribution of AlloSure and AlloMap scores were assessed via a two-sample Kolmogorov-Smirnov test to determine if differences were observed that may be attributed to mechanical assist support prior to transplant. No difference in the distribution of AlloMap scores from patients that received pre-transplant mechanical support versus those that did not was observed, similarly for AlloSure measurements, there was no statistically significant difference in the distribution of AlloSure scores between those that receive pre-transplant mechanical assist support versus those that do not receive support. Pre-transplant MCS does not correlate with increased dd-cfDNA or GEP score, suggesting the adverse outcomes seen early post-transplant are unlikely to be due to MCS devices.

Combined AlloSure and AlloMap Testing in Multi-Organ Heart Transplantation Rejection Surveillance

AlloSure test is a non-invasive blood test designed to detect the presence of donor cell-free DNA in the recipients blood as a measure of the probability of rejection in heart transplant recipients. The result is displayed as a percent of donor-derived cell-free DNA (dd-cfDNA) in the totalcell-free DNA (cfDNA). Recommended threshold of 0.2% dd-cfDNA has been predictive of low likelihood of rejection. There is no data looking at its value and validation in multi-organ transplant. We aimed to study this area by reviewing our transplant database. All patients who received more than one solid organ transplant at our center and had AlloSure testing were included. Study outcomes included one year survival, rejection grade 2R or more, and hemodynamically significant graft dysfunction. There were (7) patients included in the study, average AlloSure score was 0.93% ±0.61% with an average AlloMap score of 33.8±2.14. Four patients (57.1%) had heart and kidney transplant, 3 patients (42.9%) had heart and liver transplantation. Average AlloSure score for heart/kidney transplant recipients was 0.52±0.17% with an average AlloMap score of 33.6±2.28. The while average AlloSure score for heart/liver transplant recipients was 1.21±0.55% mean AlloMap score of 33.93±2.32. None of our patients had graft dysfunction or biopsy-proven rejection >=2R. Survival rate was 100% for the first year in our patients CONCLUSION: AlloSure levels were higher in heart-liver vs. heart-kidney recipients, and in both cohorts higher than the 0.2% threshold recommended for heart transplant prediction of rejection, however did not predict rejection. In our cohort, while AlloMap scores were consistent in both groups, (33.93±2.32 vs. 33.6±2.28 respectively). Elevated AlloSure was not predictive of rejection in multiorgan heart transplant recipients.

Correlation of gene expression profiling score, cardiac hemodynamics and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant recipients.

To correlate gene expression profiling scores obtained by AlloMap® with cardiac hemodynamics, cardiac allograft vasculopathy (CAV), and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant (HT) recipients. Single-institution retrospective study of 210 AlloMap scores obtained concomitantly with cardiac catheterization and echocardiogram from 55 children during follow-up after cardiac transplantation. The median age at HT was 5.1years (range, 0.9-14.1), with 29 males and 26 females. AlloMap scores were high in <2years vs ≥2years of age at the time of HT (P=.001), and trending higher with time after HT (R2 =.04, P=.004). There was no significant difference in scores between ACR grades 0 and 1R or CAV. There was mild to modest correlation of AlloMap scores with the mean right atrial pressure (P=.002), and pulmonary capillary wedge pressure (P=.02), but no correlation was found with LV SF% (P=.3), LV EF% (P=.5), or RV FAC % (P=.8). Our study provides preliminary data that the AlloMap score must be studied carefully before it can be used in children, particularly in those under 2years of age. Monitoring of serial scores for each patient could potentially reflect changes in allograft performance that may determine indications for catheterization and biopsy which needs to be validated in future studies.

Distinct Patterns of Gene Expression Identified Longitudinally and within AlloMap Score Ranges are Associated with Clinical Outcomes

Summary of Objectives Gene expression profiling (GEP, AlloMap) has become the standard of care in heart transplant patient management with over 120,000 performed. The large size of the dataset enables identification of distinct patterns of longitudinal and component gene expression. OAR is a prospective observational heart transplant registry with integrated GEP testing to elucidate factors that contribute to long term outcomes. Samples with GEP scores and individual gene data but not included in OAR have been examined by unsupervised methods to identify patterns of gene expression. These patterns can then be correlated with outcomes collected in OAR to identify specific signals that are indicative of different outcomes. Methods Latent class mixed models were used to estimate profiles of GEP score over time with 62,833 samples from 8,066 patients with at least two GEP score measures. Distinct patterns were identified in a 3-class model; with 69% of the 8,066 patients in a class with a gradual increase in GEP score over time; 23% with a stable GEP score, and 8% with a rapid increase in GEP score. The full dataset of 19,761 patients and 104,827 samples was used to identify patterns of gene expression among the 7 gene terms and the principle components contributing to the GEP Scores. PDCD1, ITGA4, RHOU, and SEMA7A were correlated more closely than the remaining terms. Additionally, the 7 terms were used in an archetypal analysis that identified eight unique archetype patterns of gene expression. For example, two archetypes, #4 and #8 have median GEP scores of 29.4 and 29.9, but different gene patterns. Archetype #4 has high RHOU and PF4/G6B1, but low SEMA7A. Archetype #8 has high IL1R2/FLT3/ITGAM and low PF4/G6B1. Endpoints The principal components analysis identified correlations that match the known and hypothesized biological mechanisms of the genes; the highest correlation was among four genes known or hypothesized to be indicators of T cell activation. The identified archetypal patterns will be assigned to patients in the OAR registry to identify clinical correlates with each archetype group. Among the clinical factors that will be investigated are malignancies, infections, cellular rejection, and cardiac allograft vasculopathy.

Low Allomap Ordinal and Variability Scores Are Associated with Increased Malignancy Post Heart Transplant

This study assessed the relationship between AlloMap scores, score variability (AMV) and the development of malignancy post heart transplant (HT).

(67) - Utility of Gene Expression (Allomap Score) in Antibody Mediated Rejection Detection

s S33 Results: Four of the six HTG EdgeSeq and NanoString nCounter recalibrated panels had negative predictive value (NPV) of at least 99% when tested in the replication cohort. The positive predictive value (PPV) was between 4 and 5% for all panels. Combining 2 or 3 of the panels into an ensemble improved the PPV slightly to 7% while keeping the NPV at > 99%. Sensitivity for detection of true rejection positives was 100% for most panels. These performance characteristics apply to all timepoints post-transplant. Conclusion: Blood-based biomarkers to monitor for absence of acute cardiac rejection have been identified and replicated, then transferred to and tested on two clinically relevant platforms. The HTG assay is being deployed at the local clinical laboratory. The team is currently designing a North American clinical trial to assess the validity of the selected biomarkers in a clinical setting. Once clinically validated, the assay and instrument will be deployed to other transplant centres.

(809) - Clinical Profiles and Outcomes of Cardiac Transplant Recipients Using Allomap and Cylex Immuknow Assays

PurposeThis study aimed to examine how clinical profiles based on Allomap scores and Cylex can predict 1-year clinical outcomes (allograft rejection and infection) in patients with heart transplantation.MethodsAllomap scores and Cylex measured at 6 months post cardiac transplantation from 80 consecutive patients from a single heart transplant center. Clinical profiles were defined based on Allomap scores and Cylex; Profile 1 (Allomap<34/Cylex:226-524); Profile 2 (Allomap<34/Cylex<225); Profile 3 (Allomap<34/Cylex>525); Profile 4 (Allomap >34/Cylex:226-524); Profile 5(Allomap>34/Cylex<225); Profile 6 (Allomap>34/Cylex>525). Clinical outcomes included composite of acute cellular or antibody mediated rejection and infection at 1 year post-transplant.ResultsIn the total cohort, mean age was 52±12 years, 61% were males. The following clinical profiles were identified: Profile 1 (46%); Profile 2 (25 %); Profile 3 (9%); Profile 4 (10%); Profile 5 (9%) and Profile 6 (1 %). Patients with profile 5 (Allomap>34/Cylex<225) were more likely to reach the clinical end point of composite of acute cellular or antibody mediated rejection and infection at 1 year post-transplant when compared to patients with profile 4 (Allomap >34/Cylex:226-524) (57.1% vs. 12.5% respectively). Allograft rejection and infection were more common in cardiac transplant recipients with Profiles 2 and 5. Interestingly, cardiac transplant recipients with Profile 4 (Allomap >34/Cylex: 226-524) had the lowest rates of rejection and infection (0% and 12.5% respectively).ConclusionThe utilization of clinical profiles defined by Allomap and Cylex scores may be useful in predicting the presence clinical outcomes of allograft rejection, infection at 1 year post-transplant. PurposeThis study aimed to examine how clinical profiles based on Allomap scores and Cylex can predict 1-year clinical outcomes (allograft rejection and infection) in patients with heart transplantation. This study aimed to examine how clinical profiles based on Allomap scores and Cylex can predict 1-year clinical outcomes (allograft rejection and infection) in patients with heart transplantation. MethodsAllomap scores and Cylex measured at 6 months post cardiac transplantation from 80 consecutive patients from a single heart transplant center. Clinical profiles were defined based on Allomap scores and Cylex; Profile 1 (Allomap<34/Cylex:226-524); Profile 2 (Allomap<34/Cylex<225); Profile 3 (Allomap<34/Cylex>525); Profile 4 (Allomap >34/Cylex:226-524); Profile 5(Allomap>34/Cylex<225); Profile 6 (Allomap>34/Cylex>525). Clinical outcomes included composite of acute cellular or antibody mediated rejection and infection at 1 year post-transplant. Allomap scores and Cylex measured at 6 months post cardiac transplantation from 80 consecutive patients from a single heart transplant center. Clinical profiles were defined based on Allomap scores and Cylex; Profile 1 (Allomap<34/Cylex:226-524); Profile 2 (Allomap<34/Cylex<225); Profile 3 (Allomap<34/Cylex>525); Profile 4 (Allomap >34/Cylex:226-524); Profile 5(Allomap>34/Cylex<225); Profile 6 (Allomap>34/Cylex>525). Clinical outcomes included composite of acute cellular or antibody mediated rejection and infection at 1 year post-transplant. ResultsIn the total cohort, mean age was 52±12 years, 61% were males. The following clinical profiles were identified: Profile 1 (46%); Profile 2 (25 %); Profile 3 (9%); Profile 4 (10%); Profile 5 (9%) and Profile 6 (1 %). Patients with profile 5 (Allomap>34/Cylex<225) were more likely to reach the clinical end point of composite of acute cellular or antibody mediated rejection and infection at 1 year post-transplant when compared to patients with profile 4 (Allomap >34/Cylex:226-524) (57.1% vs. 12.5% respectively). Allograft rejection and infection were more common in cardiac transplant recipients with Profiles 2 and 5. Interestingly, cardiac transplant recipients with Profile 4 (Allomap >34/Cylex: 226-524) had the lowest rates of rejection and infection (0% and 12.5% respectively). In the total cohort, mean age was 52±12 years, 61% were males. The following clinical profiles were identified: Profile 1 (46%); Profile 2 (25 %); Profile 3 (9%); Profile 4 (10%); Profile 5 (9%) and Profile 6 (1 %). Patients with profile 5 (Allomap>34/Cylex<225) were more likely to reach the clinical end point of composite of acute cellular or antibody mediated rejection and infection at 1 year post-transplant when compared to patients with profile 4 (Allomap >34/Cylex:226-524) (57.1% vs. 12.5% respectively). Allograft rejection and infection were more common in cardiac transplant recipients with Profiles 2 and 5. Interestingly, cardiac transplant recipients with Profile 4 (Allomap >34/Cylex: 226-524) had the lowest rates of rejection and infection (0% and 12.5% respectively). ConclusionThe utilization of clinical profiles defined by Allomap and Cylex scores may be useful in predicting the presence clinical outcomes of allograft rejection, infection at 1 year post-transplant. The utilization of clinical profiles defined by Allomap and Cylex scores may be useful in predicting the presence clinical outcomes of allograft rejection, infection at 1 year post-transplant.

Utility of Gene Expression Profiling Test (GEP) Score Instability To Predict Future Clinical Outcomes in Heart Transplant: Results from the CARGO 2 European-Based Multicenter Trial

Purpose GEP (AlloMap) score instability has been shown to predict of events of graft dysfunction or death in an analysis of the IMAGE data set by Deng et al. Our goal is to test this hypothesis in the independent CARGO 2 patient data set. Methods and Materials In a case-cohort design, patients with >2 serial GEP tests were studied in multivariate Cox regression models to predict future clinical events. Intra-patient GEP score instability was defined as the standard deviation of an individual’s cumulative test scores. GEP score (range 0-39), GEP score ≥34, and GEP score stability were studied. Results GEP scores tend to rise and become more stable in the whole population during the first year post-transplantation than after 1 year. After 12 months, GEP score instability (p=0.001) and GEP ≥34 (p=0.06) predict future events. [ figure 1 ]

A Single Center Transition of Care Model from Pediatric Heart to Adult Services

Purpose This first transition year has shown to have increased instances of rejection, graft dysfunction, and death. There is little data or guidelines to transition young adults to adult centered transplant programs. There are no current ISHLT guidelines to establish a transition program. We have two years of data gathered from 2010 to the present from our program. Methods and Materials Benchmarks that have been identified to measure the success of the transition are the following indicators:1.Number of Rejection events. 2. Stable allomap scores and IS levels. 3.Consistent clinical compliance, continued stable mental health -with minimal life style changes/impairment 4. Work/School. Family goals with engagement in departmental return to work program, participation in pregnancy counseling.5. ED visits/hospitalization/ discharges. Results Year to date 12 patients have transitioned. The mean time post transplant has been 12 years. Median age has been 24 years. We have 2 patient deaths; 1 from humoral rejection due to medical non-compliance and 1 patient died from suicide. 5 patients have successfully entered the work force or are attending college.10 others have had good compliance and stable IS/ Allomap levels. There have been no pregnancies reported in our transition program. All 12 patients have been hospitalized for causes including: infection, rejection, rhythm issues, and other end organ failure. Conclusions Initial outcomes shows complexity of establishing a transition program. It is imperative to build an effective transitional care model/program with evidenced based practice without loss of life or graft function. Lessons learned include establishing better education and pre- planning from a peds oriented program to an adult oriented program, establishing a care coordinator to help this special transition population, administrative and financial support, timing of transition criteria (coincide age related mile stones), confidence in the adult team, and establishing peds to adult oriented quality of life benchmarks.

Allomap Gene Expression Profiling In Lieu of Routine Endomyocardial Biopsy (EMB) at 6 Months Post Transplant

Purpose Based on data from the IMAGE trial, gene expression profiling (GEP) has been approved by the 2010 ISHLT guidelines as a Class Iia Level of Evidence B non-invasive method to rule out the presence of grade 2R rejection or greater in low risk patients between 6-months and 5-years post cardiac transplant. We present data from our single center suggesting that this strategy can be utilized to obviate endomyocardial biopsy (EMB) in all patients, regardless of race, sex, age or presence of positive panel reactive antibodies. Methods and Materials We analyzed our experience from 2009-2012 evaluating 711 Allomap scores in 126 patients. Beginning at month 5, patients underwent alternating GEP/EMB procedures until one year post transplant. At one year, surveillance monitoring was based on GEP alone except in patients with concern for acute cellular rejection, antibody mediated rejection or history of an infiltrative/inflammatory process. Decisions regarding scores >34 (reference threshold) were made based on patient test results during the first 5 months, standard clinical assessment and echocardiographic testing. Prediction values were based on IMAGE end points (graft dysfunction, hemodynamic deterioration or death). Technical and professional charges were obtained for the EMB/pathological interpretation arm and GEP/echocardiography for the Allomap strategy. Results No patients with a GEP score equal to or less than 34 developed any IMAGE end points or evidence of grade 2R acute cellular rejection on subsequent EMB resulting in a negative predictive value of 100%. Our economic analysis revealed a savings of over $5,000 utilizing GEP in lieu of EMB. Conclusions GEP is a novel, non-invasive approach that is economically attractive, positively associated with a high level of patient satisfaction and very high negative predictive values. GEP should replace EMB as the routine surveillance tool to monitor for acute cellular rejection in all clinically stable patients 6 months post cardiac transplantation.

77: Does Gene Expression Profiling Scores Correlate with Cardiac Allograft Vasculopathy Assessed by Intravascular Ultrasonography?

Intravascular Ultrasonography (IVUS) is the most reliable tool for the diagnosis of cardiac allograft vasculopathy (CAV) in cardiac transplantation (TX) patients (pts). Presence of intimal thickening on IVUS predicts cardiac events in pts with CAV. Gene expression profiling (Allomap score) has been established as a reliable non-invasive test to detect rejection in TX pts. The AlloMap score is increased in the presence of CAV using conventional angiography. Whether the Allomap score can predict intimal thickness on IVUS in TX pts is not known.