Heart Transplant Rejection 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.

Circulating microRNA Biomarkers in Cellular and Antibody-Mediated Heart Transplant Rejection

<h3>Purpose</h3> Non-invasive monitoring of heart allograft health is an important clinical goal and circulating microRNAs (miRs) have been associated with acute rejection in limited studies. <h3>Methods</h3> The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective study. Patients with no history of rejection after transplant were selected as controls. Cases were patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression analysis and LASSO regression was used to develop ACR and AMR miR panels while adjusting for clinical covariates. The panels were validated in an independent sample from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics are reported. Distinct ACR and AMR clinical scores were developed to translate gene expression data for clinical use. <h3>Results</h3> The GRAfT cohort had a median age of 52 years, with 35% females and 45% Blacks. We included 85 controls and 34 patients with rejection (20 ACR, 14 AMR). In ACR and AMR, using differential gene expression and regression analysis, we identified 11 and 15 miRs that accurately discriminated ACR and AMR (p<0.05). Independent validation of the miR panels within GRAfT led to excellent diagnostic accuracy for ACR AUC 0.92 (95% CI: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.91 (95% CI: 0.82-0.99). Distinct ACR and AMR miR clinical scores were developed ranging from 0-100; using a threshold of 65 identified ACR with a sensitivity of 86%, specificity of 78% and negative predictive value of 98%, for AMR the respective performance was 82%, 84% and 97% (Figure). <h3>Conclusion</h3> The unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers are used not only for rejection surveillance but permit accurate, non-invasive diagnosis of ACR and AMR.

Incorporating Palliative Care as Standard Practice in Heart Transplant Rejection Therapy

<h3>Introduction</h3> Multidisciplinary teams are critical in the management of patients post transplantation. However, inclusion of palliative care modalities can be challenging and nebulous in the transplant community. Herein we describe a cardiac transplant recipient who received a unique outpatient palliative care consultation integrated into the care plan for acute antibody (AMR) rejection. <h3>Case Report</h3> A 70-year-old male patient with systolic heart failure, s/p heart transplantation postoperative course complicated by graft dysfunction requiring ECMO, plasmapheresis, and antithymocyte globulin. He was later diagnosed with AMR and treated with multiple rounds of therapeutic plasma exchange, Immunoglobulin therapy, and months of photopheresis. He unfortunately failed to thrive during AMR treatment and was hospitalized numerous times with complications to include infections, volume retention, dehydration, dysphagia, syncope, and mechanical falls with injury. He became debilitated and struggled with weakness, dyspnea requiring continuous oxygen, lethargy, and dependency on his family for assistance with daily activities. He reported poor quality of life and depression. Due to persistent AMR, there was consideration for re-attempting photopheresis. Palliative care was ultimately consulted to assist patient and family with goals of care discussion. Supported by palliative care and the medical team, the patient was able to define his quality-of-life standards and future goals. This included clarifying his values, fears, strengths, and spirituality. As a result of this approach, he opted to defer any further photopheresis or antirejection therapy. He requested to focus on reducing symptom burden, avoiding hospitalizations, and spending time with family. To date he has avoided hospital readmissions, reports significant reduction in symptom burden, and improved quality of life. <h3>Summary</h3> The World Health Organization (2020) reports that 40 million people are in need of palliative care and only 14% currently are receiving it. This case advocates for seamless integration of palliative care consults for patients undergoing treatment for refractory AMR. Moreover, this aligns the treatment plan with patient values furthering support of their families holistically. Ultimately this intervention will preserve quality and possibly extension of life.

Relationship between donor fraction cell-free DNA and clinical rejection in heart transplantation.

Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. A total of 835samples from 269subjects (57% pediatric) were included for this analysis, including 28samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p<.0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p<.0001). DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.

Nanomaterials as Ultrasound Theragnostic Tools for Heart Disease Treatment/Diagnosis.

A variety of different nanomaterials (NMs) such as microbubbles (MBs), nanobubbles (NBs), nanodroplets (NDs), and silica hollow meso-structures have been tested as ultrasound contrast agents for the detection of heart diseases. The inner part of these NMs is made gaseous to yield an ultrasound contrast, which arises from the difference in acoustic impedance between the interior and exterior of such a structure. Furthermore, to specifically achieve a contrast in the diseased heart region (DHR), NMs can be designed to target this region in essentially three different ways (i.e., passively when NMs are small enough to diffuse through the holes of the vessels supplying the DHR, actively by being associated with a ligand that recognizes a receptor of the DHR, or magnetically by applying a magnetic field orientated in the direction of the DHR on a NM responding to such stimulus). The localization and resolution of ultrasound imaging can be further improved by applying ultrasounds in the DHR, by increasing the ultrasound frequency, or by using harmonic, sub-harmonic, or super-resolution imaging. Local imaging can be achieved with other non-gaseous NMs of metallic composition (i.e., essentially made of Au) by using photoacoustic imaging, thus widening the range of NMs usable for cardiac applications. These contrast agents may also have a therapeutic efficacy by carrying/activating/releasing a heart disease drug, by triggering ultrasound targeted microbubble destruction or enhanced cavitation in the DHR, for example, resulting in thrombolysis or helping to prevent heart transplant rejection.

Heart transplant rejection pathology

Background/Aim. Heart transplantation is the most effective way to treat patients in the terminal stage of heart failure. Endomyocardial biopsy has proven to be a safe and appropriate technique, with little sampling error, and remains, to this day, one of the most commonly used methods for diagnosing acute rejection. In 1990, the International Society of Heart and Lung Transplantation defined a standardized system for grading the severity of acute transplant rejection regarding endomyocardial sampling histopathological analysis. The aim of the study was to assess the morphological, immunohistochemical, and immunofluorescent markers of cell- and antibody-mediated rejection of heart transplants in patients monitored during 2020. Methods. From 31 patients transplanted at the Clinic for Cardiac Surgery of the University Clinical Center of Serbia, endomyocardial biopsy material was obtained, then processed and analyzed at the Institute of Pathology of the Faculty of Medicine, University of Belgrade. Results. The average Transplant Rejection Score (TRS) value was 0.42. The Spearman's correlation test did not show a statistically significant relationship between the TRS value and the difference between the ejection fraction values three and twelve months after transplantation. Conclusion. The mean TRS value obtained in this study suggests dominant cell-mediated graft rejection.

Impaired production of platelet-endothelial cell adhesion molecules as an early diagnostic marker of heart transplant rejection

Reveal the involvement of platelet-endothelial cell adhesion molecules PECAM-1 in the transplanted heart rejection pathogenesis and determine the CD31 marker significance for biopsy diagnostics of the process form and degree. Sections from endomyocardial biopsies of 56 heart transplant recipients were stained with hematoxylin and eosin. The streptavidin-biotin method was used to determine the expression of T-lymphocytes (CD3), B-lymphocytes (CD20), macrophages (CD68) and the C4d component of complement to determine the form and degree of graft rejection. Additionally, the expression of platelet-endothelial cell adhesion molecules PECAM-1 (CD31) was detected. Using computer morphometry in digital images, the area of pathological changes and the area of CD31 expression was measured with the calculation of the staining area coefficient. The highest levels of PECAM-1 expression were found in the absence of a heart transplant rejection. The degree of rejection of 1R is characterized by a decrease in expression by 1.3 times, when there are no significant signs of necrosis in the myocardium, the area of which increases sharply at degree 2R by 163.7 times, and at 3R by 570.7 times compared with 1R. The process proceeds in parallel with a further decrease in the level of CD31 expression and is accompanied by the development of hemorrhagic manifestations. The intensity of hemorrhages in the myocardium increases by 7.3 times with grade 3R compared with 1R. Expression of PECAM-1 reflects the state of the vascular bed of the heart transplant. Its decrease can be considered as an early pathomorphological marker of transplanted heart rejection. The expression of CD31 continues to decrease with increasing severity of rejection and is accompanied by the progressive development of necrosis and hemorrhages in the graft heart muscle.

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Shotgun Immunoproteomics for Identification of Nonhuman Leukocyte Antigens Associated With Cellular Dysfunction in Heart Transplant Rejection.

The International Society for Heart and Lung Transplant consensus panel notes that too little data exist regarding the role of non-HLA in allograft rejection. We developed a novel shotgun immunoproteomic approach to determine the identities and potential roles non-HLA play in antibody-mediated rejection (AMR) in heart transplant recipients. Serum was collected longitudinally from heart transplant recipients experiencing AMR in the absence of donor-specific anti-HLA antibodies (n = 6) and matched no rejection controls (n = 7). Antidonor heart affinity chromatography columns were formed by recipient immunoglobulin G immobilization at transplantation, acute rejection, and chronic postrejection time points. Affinity chromatography columns were used to capture antigens from individual patient's donor heart biopsies collected at transplantation. Captured proteins were subjected to quantitative proteomic analysis and the longitudinal response was calculated. Overlap in antigen-specific response between AMR and non-AMR patients was only 8.3%. In AMR patients, a total of 155 non-HLAs were identified, with responses toward 43 high prevalence antigens found in ≥50% of patients. Immunofluorescence staining for representative high prevalence antigens demonstrated that their abundance increased at acute rejection, correlating with their respective non-HLA antibody response. Physiological changes in cardiomyocyte and endothelial cell function, following in vitro culture with patient immunoglobulin G, correlated with response toward several high prevalence antigens. This work demonstrates a novel high-throughput strategy to identify clinically relevant non-HLA from donor endomyocardial biopsy. Such a technique has the potential to improve understanding of longitudinal timing of antigen-specific responses and their cause and effect relationship in graft rejection.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address (1) preterm birth association with ventricular fibrosis and diastolic dysfunction in adulthood, (2) shared decision-making as a viable strategy to counsel patients with long QT syndrome to return to play, (3) using pulmonary-to-aortic surgical shunt in patients with severe pulmonary hypertension which is associated with similar 5-year survival compared to lung transplant, (4) the use of donor-derived cell-free DNA to screen for heart transplant rejection, and (5) the role of microvasculature in hypoplastic left heart syndrome using cardiac magnetic resonance.

Targeting peripheral immune organs with self-assembling prodrug nanoparticles ameliorates allogeneic heart transplant rejection

Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.

Distinct Microbial Communities in Dilated Cardiomyopathy Explanted Hearts Are Associated With Different Myocardial Rejection Outcomes.

BackgroundIdiopathic dilated cardiomyopathy (IDCM) myocardial inflammation may be associated with external triggering factors such as infectious agents. Here, we searched if moderate/severe heart transplantation rejection is related to the presence of myocardial inflammation in IDCM explanted hearts, associated with microbial communities.MethodReceptor myocardial samples from 18 explanted hearts were separated into groups according to post-transplant outcome: persistent moderate rejection (PMR; n = 6), moderate rejection (MR; n = 7) that regressed after pulse therapy, and no rejection (NR; n = 5)/light intensity rejection. Inflammation was quantified through immunohistochemistry (IHC), and infectious agents were evaluated by IHC, molecular biology, in situ hybridization technique, and transmission electron microscopy (TEM).ResultsNR presented lower numbers of macrophages, as well as B cells (p = 0.0001), and higher HLA class II expression (p ≤ 0.0001). PMR and MR showed higher levels of Mycoplasma pneumoniae (p = 0.003) and hepatitis B core (p = 0.0009) antigens. NR presented higher levels of parvovirus B19 (PVB19) and human herpes virus 6 (HHV6) and a positive correlation between Borrelia burgdorferi (Bb) and enterovirus genes. Molecular biology demonstrated the presence of M. pneumoniae, Bb, HHV6, and PVB19 genes in all studied groups. TEM revealed structures compatible with the cited microorganisms.ConclusionsThis initial study investigating on infectious agents and inflammation in the IDCM explanted hearts showed that the association between M. pneumoniae and hepatitis B core was associated with a worse outcome after HT, represented by MR and PMR, suggesting that different IDCM microbial communities may be contributing to post-transplant myocardial rejection.

Abstract 12658: Does Cell-Free DNA Rise With a Higher MFI Titer of DSA?

Introduction: The use of donor-derived cell-free DNA (dd-cfDNA) has been demonstrated to detect heart transplant rejection as the donor has different DNA from the recipient. dd-cfDNA has also been correlated to the detection of donor-specific antibodies (DSA). It is believed that these DSA do cause injury to the donor heart, thus exposing the donor DNA to the recipient’s bloodstream. It is not known whether the degree or binding capacity of the dd-cfDNA correlates to the binding intensity of the DSA, characterized by mean fluorescence intensity (MFI). Methods: Between 2017 and 2020, we assessed 32 heart transplant patients who were sensitized and had a dd-cfDNA level drawn. Positive dd-cfDNA was defined as ≥0.25% and was then correlated to MFI binding of the DSA categorized as weak binding (MFI 2500-5000), moderate binding (MFI 5000-10000), and strong binding (MFI &gt;10000). 62 dd-cfDNA and associated HLA blood draws were used for this study. The Luminex Single Antigen Neat test was used to determine MFI binding of DSAs. Results: Positive dd-cfDNA did not correlate to the presence of DSA. However, there was a trend for positive dd-cfDNA correlating to DSA with higher MFI levels (see table). Conclusion: dd-cfDNA might signal the presence of DSA with higher MFI levels. This might suggest that these higher levels of DSA might be involved in injury to the donor heart. Larger number of patients will be needed to confirm this finding.

Antibody-mediated rejection in heart transplantation

The role of antibody-mediated rejection in predicting survival among heart recipients has been studied in clinical transplantology for over 20 years. This condition is a significant risk factor for heart failure and graft vasculopathy. Antibody-mediated rejection results from activation of the humoral immune system and production of donorspecific antibodies that cause myocardial injury through the complement system. The presence of donor-specific antibodies is associated with lower allograft survival. Treatment of antibody-mediated rejection should take into account the rejection category and the presence or absence of graft dysfunction. The main principle of treatment is to suppress humoral immunity at different levels. World clinical practice has made significant inroads into the study of this issue. However, further research is required to identify and develop optimal treatment regimens for patients with humoral rejection in cardiac transplantation.

The natural killer cell activating receptor, NKG2D, is critical to antibody-dependent chronic rejection in heart transplantation

Chronic rejection is among the most pressing clinical challenges in solid organ transplantation. Interestingly, in a mouse model of heterotopic heart transplantation, antibody-dependent, natural killer (NK) cell-mediated chronic cardiac allograft vasculopathy occurs in some donor-recipient strain combinations, but not others. In this study, we sought to identify the mechanism underlying this unexplained phenomenon. Cardiac allografts from major histocompatibility complex (MHC) mismatched donors were transplanted into immune-deficient C57Bl/6.rag-/- recipients, followed by administration of a monoclonal antibody against the donor MHC class I antigen. We found marked allograft vasculopathy in hearts from C3H donors, but near-complete protection of BALB/c allografts from injury. We found no difference in recipient NK cell phenotype or intrinsic responsiveness to activating signals between recipients of C3H versus BALB/c allografts. However, cardiac endothelial cells from C3H allografts showed an approximately twofold higher expression of Rae-1, an activating ligand of the NK cell receptor natural killer group 2D (NKG2D). Importantly, the administration of a neutralizing antibody against NKG2D abrogated the development of allograft vasculopathy in recipients of C3H allografts, even in the presence of donor-specific antibodies. Therefore, the activating NK cell receptor NKG2D is necessary in this model of chronic cardiac allograft vasculopathy, and strain-dependent expression of NK activating ligands correlates with the development of this disease.

Combination of matrine and tacrolimus alleviates acute rejection in murine heart transplantation by inhibiting DCs maturation through ROS/ERK/NF-κB pathway

Matrine, an alkaloid derived from traditional Chinese herbs, has been confirmed to regulate immunity and exert anti-inflammatory effects. Matrine injection has been widely used in clinic therapy for anti-tumor and anti-inflammatory diseases. Heart transplantation(HT) is the only solution for the end-stage heart failure, but it is restricted by the cardiac allograft rejection. One of the important pathophysiological processes of post-transplantation rejection is inflammatory cell infiltration. Matrine has been shown to exert a positive protective effect against oxidative stress injury and inflammation, which likely benefits allograft survival. However, it remains unclear whether matrine inhibits alloimmunity or allograft rejection. In this study, we established the heart transplantation model in mouse and extracted bone marrow-derived dendritic cells (BMDCs) to explore the function and mechanism of matrine in heart transplantation. Moreover, combination treatment with matrine and tacrolimus(FK506) had a synergistic effect in preventing acute rejection of heart transplants. Here we found that matrine can prolong the survival of post-transplant and inhibit inflammatory cell infiltration in transplanted hearts of mice. At the same time, matrine increased Treg ratio and decreased CD4+/CD8 + ratio in mice. More importantly, matrine inhibited DCs maturation in mice and reduced oxidative damage and apoptosis in allograft hearts. Furthermore, matrine also downregulated NF-κB pathway and upregulated ERK1/2 signaling pathway. Overall, our study reveals a novel immunosuppressive agent that has the potential to reduce the side effects of existing immunosuppressive agents when used in combination with them.

Alterations in the Nucleocytoplasmic Transport in Heart Transplant Rejection

Nucleocytoplasmic transport is a crucial process for cell function. Previous studies have observed alterations in different molecules involved in it, relating them to ventricular function. However, there are no published data evaluating possible differences in the expression of these molecules in heart transplantation (HT) recipients. Our objective is to evaluate whether its levels are related to the appearance of cellular rejection (CR) during the first year after HT. A prospective clinical cohort that included patients undergoing HT between January 2017 and January 2019 (n=46). Blood samples for the analysis of importin 5 (IMP5), nucleoporin 153 (Nup153); RAN-GTPaseAP1 (RanGAP1), and sarcoplasmic reticulum calcium ATPase (ATP-aseCaTransp) were collected approximately 2 months post-HT. The levels obtained were correlated with the incidence of at least moderate CR during the first year of follow-up. Results showed that 17.39% of the patients had at least moderate CR during the first year of follow-up. Higher levels of IMP5, Nup153, and RanGAP1 were observed in this group. This difference was statistically significant in the case of Nup153 and RanGAP1 (15.94 ± 14.00 vs 28.62 ± 23.61, P=.048; 21.95 ± 15.97 vs 40.90 ± 27.16, P=.026, respectively); there was an opposite trend in the ATP-aseCaTransp case. Patients with at least a moderate degree of CR during follow-up showed higher serum levels of IMP5, Nup153, and RanGAP1. The prognostic usefulness of the determination of these biomarkers and whether their elevation during follow-up would facilitate early, noninvasive identification of patients with CR remains to be clarified.

13N-ammonia positron emission tomography-derived left-ventricular strain in patients after heart transplantation validated using cardiovascular magnetic resonance feature tracking as reference.

Heart transplant rejection leads to cardiac allograft vasculopathy (CAV). 13N-ammonia positron emission tomography (PET) can be useful in detecting CAV, as it can evaluate both epicardial vessels and microvasculature. In this study, we evaluated the regional wall motion in heart transplant patients using our PET-specific feature-tracking (FT) algorithm for myocardial strain calculation and validated it using a cardiovascular magnetic resonance (CMR) FT strain as a reference. A total of 15 heart transplant patients who underwent both 13N-ammonia PET and CMR within 3months were retrospectively enrolled. The same slice position of short-axis cine images of the middle slice of left ventricle (LV) and the same slice position of horizontal long-axis cine images were selected for the two modalities to measure the circumferential strain (CS) and longitudinal strain (LS), respectively. Based on the FT technique, time-strain curves were calculated by semi-automatic tracking of the endocardial contour on cine images throughout a cardiac cycle. The peak value in the time-strain curve was defined as the representative value. Correlations of CS and LS between PET and CMR were analyzed using Pearson correlation coefficients. The inter-modality error of strain measurements was evaluated using intraclass correlation coefficients (ICCs) with two-way random single measures. Excellent correlations of CS and LS between PET and CMR were observed (CS: r = 0.80; p < 0.01; LS: r = 0.87; p < 0.01). Excellent ICCs were observed (0.89 and 0.85) in CS and LS derived from PET. We propose the first PET strain showing an excellent agreement with the CMR strain and high reproducibility in measurement.

Trends, risk factors and mortality of unplanned 30-day readmission after heart transplantation

Abstract Introduction Outcomes after heart transplantation have improved, but the burden of readmissions is understudied. We sought to examine the incidence, risk factors, and associated mortality of unplanned 30-day readmissions following heart transplantation. Methods This cohort study examined patient data from the United States population-based Nationwide Readmissions Database. All adults (age ≥18 years) who underwent isolated heart transplantation in US hospitals between January to November of 2012 to 2018 were included. The primary outcomes were 30-day readmission rates and readmission mortality. Results A total of 14,784 patients who underwent heart transplantation from 2012 to 2018 were included in our analysis. A total of 3299 (22.3%) patients were readmitted within 30 days after discharge. The median time from discharge to readmission was 9 days, and approximately 70% of the readmissions occurred within 15 days. After multivariable analysis, only CKD (Hazard ratio (HR): 1.11 95% CI 1.00–1.23) and length of stay (HR: 1.002; 95% CI 1.001–1.003; p&amp;lt;0.001) were associated with increased 30-day post-heart transplantation readmission. Readmissions diagnoses were heart transplantation complications, heart transplant rejection, postoperative infection, acute kidney injury, heart failure, pulmonary embolism, pneumonia, and pericardial effusion. The overall incidence of infection as a cause of readmission was 24.9%, with an associated mortality of 2.6% and a Median LOS of 7 days (4–14). The overall incidence of rejection was 38.0%, with a mortality of 1.2% and a median LOS of 5 days (3–8). Conclusion Approximately 1 in 5 patients will be readmitted within 30 days after heart transplantation, and most of those readmissions will occur during the first two weeks after discharge. Readmissions were associated with a low mortality rate. Funding Acknowledgement Type of funding sources: None.

Heart transplantation and antibody-mediated rejection: role of myocardial strain as an early marker of cardiac dysfunction in patients with anti-HLA antibody

Abstract Background Antibody-mediated rejection of the transplanted heart is still currently diagnosed by endomyocardial biopsy whereas clinical elements, anti-Human Leukocite Antigens (HLA) antibody and graft dysfunction represents supplementary components. Purpose The aim of the study was to identify though a non-invasive imaging technique, such as advanced transthoracic echocardiography, early signs of altered cardiac function in patients with anti-HLA antibodies and no histological signs of antibody-mediated rejection. Methods The study population included 117 heart transplanted patients, in whom both acute and chronic rejection was excluded. They were divided into two groups “HLA+`' (45 patients) and “HLA−” (72 patients), based on the presence and the absence of circulating anti-HLA antibodies, respectively. The echocardiographic exam was performed within one week from the biopsy, including Speckle Tracking analysis. Results Deceleration Time of E wave was the strongest traditional echocardiographic parameter which correlated with circulating anti-HLA antibodies (165±39,5 vs 196,5±25; p&amp;lt;0.001). Regarding strain analysis, both left ventricular global longitudinal strain (−16,1±3,4 vs −19,8±2,0; p&amp;lt;0.001) and right ventricular strain (−17,2±0,7 vs −20,6±0,5; p=0.0002) differed significantly between the two subgroups (Figure 1). On the other hand, neither peak atrial longitudinal strain nor peak atrial contraction strain showed a significant correlation with anti-HLA antibodies. Conclusion The presence of circulating anti-HLA antibodies seems to be correlated with a mild cardiac dysfunction, even in the absence of antibody-mediated rejection. This subtle dysfunction is not completely detectable by standard echocardiographic parameters, whereas strain analysis has showed promising results since it revealed more clearly an impaired function of both ventricles in heart transplanted HLA+ patients, with potentially important clinical repercussion. Funding Acknowledgement Type of funding sources: None. Figure 1