Human Cardiac Transplantation Research Articles

Magnesium lithospermate B enhances the potential of human-induced pluripotent stem cell-derived cardiomyocytes for myocardial repair.

We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model. In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups (n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro. MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.

Nanowired human cardiac organoid transplantation enables highly efficient and effective recovery of infarcted hearts.

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium. Nanowired human cardiac organoids were then engineered with hPSC-CMs, nonmyocyte supporting cells, and e-SiNWs. Nonmyocyte supporting cells promoted greater ischemia tolerance of cardiac organoids, and e-SiNWs significantly improved electrical pacing capacity. After transplantation into ischemia/reperfusion-injured rat hearts, nanowired cardiac organoids significantly improved contractile development of engrafted hPSC-CMs, induced potent cardiac functional recovery, and reduced maladaptive left ventricular remodeling. Compared to contemporary studies with an identical injury model, greater functional recovery was achieved with a 20-fold lower dose of hPSC-CMs, revealing therapeutic synergy between conductive nanomaterials and human cardiac organoids for efficient heart repair.

Organ Preservation in the 2020s: XVIVO Heart Box (Part 2)

The XVIVO Heart Box (XHB) is an emerging technology in cardiac transplantation that protects the donor heart via non-ischaemic heart preservation (NIHP). A first-in-human trial utilising XHB demonstrated its safe use in human cardiac transplantation [ [1] Nilsson J, Jernryd V, Qin G, Paskevicius A, Metzsch C, Sjöberg T, et al. A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation. Nat Commun. 2020;11:2976. Google Scholar ]. In response, an Australian and New Zealand multicentre trial of extended (6–8 hours) NIHP of donor hearts for transplantation utilising XHB is underway. The current study is an open-labelled, single-arm, multicentre clinical trial. It aims to investigate the effect of NIHP on donor hearts with extended ischaemic time (6–8 hours) with respect to immediate and long-term post-transplant heart allograft function.

Current Status of Cardiac Transplantation in the 21st Century

Advanced heart failure is an entity where irreversible structural heart disease is associated with persistent, refractory symptoms and quantitative decrease in cardiopulmonary capacity. Despite advanced and comprehensive medical therapy, patients are at high risk of death due to cardiogenic shock or cardiac arrest. Heart transplantation was developed as a surgical intervention to replace the failing recipient heart with a healthy heart from a recently deceased donor. In this article, we discuss the current state of cardiac transplantation, more than 5 decades after the first human cardiac transplantation was performed. Apart from an historical overview of the development of surgical techniques, we focus on appropriate patient selection, pretransplant evaluation, and recognition and treatment of post-transplant complications.

Mast Cell Expression in Heart Transplant Acute Cellular Rejection (ACR): A Retrospective Single Institution Analysis

Purpose Heart transplant patients require close follow-up with endomyocardial biopsies, which is the gold standard. Acute cellular rejection (ACR) in endomyocardial biopsies is graded using ISHLT criteria (1990, 2005). The role of mast cells is not very well studied in ACR; results of experimental murine models are ambiguous. To our knowledge, there are no studies specifically analyzing mast cells in ACR for human cardiac transplantation. In our study, we aimed to show whether or not mast cell infiltrates can be used to differentiate low from high grade ACR. Methods This single-institution retrospective study included 42 cases of grade 2/1R (ISHLT 1990/2005) and higher grades of ACR between 2/2016 and 9/2018. 8 cases of ISHLT grade 0 were also examined to serve as a control set. All cases were divided into 3 groups (Table). Mast cells were identified and counted using CD117 immunohistochemistry at 400x magnification. Total mast cell count per biopsy as well as average number of mast cell per fragment (defined by 2mm square) were evaluated. ANOVA and post hoc analysis were performed. Results Biopsies with any ACR showed statistically higher mast cells when compared to negative biopsies. A one way between subjects ANOVA of the three groups was performed and showed a statistically significant difference (p=0.0007). Post hoc analysis utilizing the Tukey-Kramer test revealed a statistically significant difference between grades 3a/3b and grade 0 (q=5.81) and grade 2 and grade 0 (q=3.73). Although grades 3a/3b showed higher average and total number of mast cells when compared to grade 2 ACR, this was not statistically significant. Conclusion Our results show that the total and average number of mast cells per fragment in higher grades of ACR (3a,3b, 2) are significantly higher than grade 0 ACR. The average number of mast cells between grades 3a/3b and grade 2 was not statistically significant. Overall, these results show that mast cells may play an active role in higher stages of acute cellular rejection.

Optimizing Surgical Skills in Cardiac Surgery Residents with Cardiac Transplant in the High-Fidelity Porcine Model.

Simulation is a pivotal tool within cardiac surgery to facilitate learner growth and skill acquisition. There are many methods of simulation and it is possible to develop and implement new curricula incorporating these modalities. The objective of this paper is to describe the feasibility of a high-fidelity cardiac transplant simulation curriculum for surgical residents. Our simulation setting was the Animal Resource Center at the University of Calgary. It was set up with 4 separate operating rooms, 2 for donor heart retrievals and 2 for heart implantations. This was done to allow 2 learners to participate with each animal, replicating the true intraoperative environment. Our teaching sessions were facilitated by 2 surgeons experienced in cardiac transplantation. In addition, we had support staff including multiple perfusionists, nurses, and anesthesia technologists. The curriculum was evaluated from many perspectives in real time throughout the simulation as well as afterward in posttest qualitative interviews with all participants. The residents readily identified the acquisition of and increased proficiency in specifically targeted surgical skills. In addition, the residents were able to practice communication, collaboration, and management. Furthermore, the simulation session and our debriefings contributed significantly to fostering a team approach. The pig is an excellent preclinical model for acquiring and developing the skills necessary for human cardiac transplantation. The residents partaking in the curriculum were satisfied with the learning they received and saw value in the swine transplant curriculum. The overall curriculum was cost-effective, due to the low overall operating costs associated with it.

The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town

Original publication: Barnard C.N. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S. Afr. Med. J. 1967;41(48):1271-4. The article translated into Russian with the official permission of South African Medical Association. The list of references has been reproduced exactly as it originally appeared. Translated by Vasily I. Kaleda, vasily.kaleda@gmail.com; http://orcid.org/0000-0003-4002-873X

Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

Innate immune mechanisms in transplant allograft vasculopathy.

Allograft vasculopathy is the leading cause of late allograft loss following solid organ transplantation. Ischemia reperfusion injury and donor-specific antibody-induced complement activation confer heightened risk for allograft vasculopathy via numerous innate immune mechanisms, including MyD88, high-mobility group box 1 (HMGB1), and complement-induced noncanonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The role of MyD88, a signal adaptor downstream of the Toll-like receptors (TLR), has been defined in an experimental heart transplant model, which demonstrated that recipient MyD88 enhanced allograft vasculopathy. Importantly, triggering receptor on myeloid receptor 1, a MyD88 amplifying signal, was present in rejecting human cardiac transplant biopsies and enhanced the development of allograft vasculopathy in mice. HMGB1, a nuclear protein that activates Toll-like receptors, also enhanced the development of allograft vasculopathy. Complement activation elicits assembly of membrane attack complexes on endothelial cells which activate noncanonical NF-κB signaling, a novel complement effector pathway that induces proinflammatory genes and potentiates endothelial cell-mediated alloimmune T-cell activation, processes which enhance allograft vasculopathy. Innate immune mediators, including HMGB1, MyD88, and noncanonical NF-κB signaling via complement activation contribute to allograft vasculopathy. These pathways represent potential therapeutic targets to reduce allograft vasculopathy after solid organ transplantation.

The International Society of Biological and Environmental Repositories presents Abstracts from their Annual MeetingBridging the Canyon – Connecting Biobank Communities through Innovations in Global Health, Research and Environmental PreservationMay 5–9, 2015Phoenix, Arizona

The International Society of Biological and Environmental Repositories presents Abstracts from their Annual MeetingBridging the Canyon – Connecting Biobank Communities through Innovations in Global Health, Research and Environmental PreservationMay 5–9, 2015Phoenix, Arizona

Computational chemical imaging for cardiovascular pathology: chemical microscopic imaging accurately determines cardiac transplant rejection.

Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR) spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients’ biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures.

Mechanisms of AMR Mediated By DSA: Activation of Endothelial Notch Pathway Triggers M1/M2 Polarization in Human Cardiac Transplants.

Notch signaling is a major pathway in cell fate decisions and it is considered as an important player in vascular homeostasis through the control of cell differentiation, proliferation and apoptosis. However, the contribution of the Notch pathway to vascular injury and endothelial dysfunction in transplantation remains unclear. This study investigated the contribution of Notch receptors and ligands to vascular injury associated with donor specific antibody (DSA)-mediated rejection (AMR) in human cardiac allografts.Regulation of Notch receptors (Notch1, 2, 3, 4) and ligands (Jagged1, Dll4) was analyzed by quantitative PCR and by immunohistochemistry in cardiac biopsies from patients with stable graft or non failing heart (n=13) or with AMR (n=8). The impact of Notch signaling activity was further investigated by modulating Dll4 in cellular co-culture models using endothelial cells (EC) isolated from donor transplants and monocytes. Our results show that AMR is characterized by an up-regulation in Notch1, -2, Dll4 and Jagged1 transcripts (respectively, 3.7-, 4.7-, 4.5- and 2.1-fold increase versus controls, p<0.01) and a drastic down-regulation of Notch3 and of the endothelial Notch4 (5.1-fold decrease versus controls, p<0.01). A Notch4/Dll4 imbalance, at endothelial level, upon AMR was confirmed by immunohistochemistry on biopsies and also observed in cellular models. We also found that overexpression of Dll4 in human EC strongly induces Notch activity in monocytes, reflected by increased Hes1 expression. Moreover, Dll4 enhances IL-1β, IL-6, IL-8 and TNF mRNA expression in monocytes and induces a phenotypic switch of monocyte markers.Overall, our findings provide the first evidence that impaired Notch activity in graft EC is a key event associated with AMR triggering EC dysfunction and monocytes/macrophages polarization.

De novo expression of fetal ED-A(+) fibronectin and B (+) tenascin-C splicing variants in human cardiac allografts: potential impact for targeted therapy of rejection.

Management of acute and especially chronic rejection after human cardiac transplantation is still challenging. Chronic rejection, represented by allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) is known to cause severe long-term complications. Rejection associated tissue-remodelling entails the reoccurrence of fetal variants of Fibronectin (Fn) and Tenascin-C (Tn-C), which are virtually absent in adult human organs. In a rat model, an extensive re-expression could be demonstrated for ED-A(+) Fn with spatial association to CAV and CIF. Thus, it is of great interest to investigate the cardiac tissue expression and distribution in human samples. From 48 heart transplanted patients, 64 tissue specimens derived from right ventricular biopsies were available. Histopathological analysis was performed according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines for the detection of acute rejection. By immunohistochemistry, protein expression of ED-A(+) Fn, B(+) Tn-C, alpha-smooth muscle actin, CD31 and CD45 was assessed and analysed semiquantitatively. Co-localisation studies were performed by means of immunofluorescence double labelling. Histopathological analysis of the 64 samples revealed different ISHLT grades (0R in 36 cases, 1R in 20 cases and 2R in 8 cases). There was a distinct and quantitatively relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C in most samples. Semi-quantitative evaluation did not show any correlation to the acute rejection grade for all markers. Interestingly, significant correlations to the extent of inflammation could be shown for ED-A(+) Fn (r=0.442, p=0.000) and B(+) Tn-C (r=0.408, p=0.001) as well as between both proteins (r=0.663, p=0.000). A spatial association of ED-A(+) Fn and B(+) Tn-C to CAV and CIF could be demonstrated. A relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C following human heart transplantation could be demonstrated with spatial association to signs of rejection and a significant correlation to tissue inflammation. These data might contribute to the identification of novel biomarkers reflecting the rejection process and to the development of promising strategies to image, prevent or treat cardiac rejection.

Early reoccurrence of fetal ED-A+ Fibronectin and B+ Tenascin-C splicing variants after human cardiac transplantation: potential impact for targeted therapy of chronic rejection

Early reoccurrence of fetal ED-A+ Fibronectin and B+ Tenascin-C splicing variants after human cardiac transplantation: potential impact for targeted therapy of chronic rejection

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Kunstherz und Herztransplantation

The advances in the treatment of many different heart diseases have on the one side led to a significant prolongation of life expectancy but have also contributed to an increase of patients with heart failure. This tendency is supported even more so by the demographic development of our population. The replacement of insufficient organs has always been in the focus of medical research. In the 1960's Shumway and Lower developed the technique of cardiac transplantation and also worked intensively on the treatment and diagnosis of rejection. However, it was Barnard who, in 1967 performed the first human cardiac transplantation. Other centers followed worldwide but the mortality was high and the new therapy was controversially discussed in many journals. By the introduction of cyclosporin as a new immunosuppressive agent in 1978, results improved rapidly and cardiac transplantation became an accepted therapeutic option for patients with end stage heart failure and also for children and newborns with congenital heart defects. Today, with newer immunosuppressive regimens and improved techniques, cardiac transplantation offers excellent results with a long-term survival of nearly 50% of patients after 15 years and among the pediatric population even after 20 years. However, the donor organ shortage as well as the increasing number of elderly patients with end stage heart failure has necessitated work on other alternatives. Neither stem cell transplantation nor xenotransplantation of animal organs are yet an option and there are still some obstacles to be overcome. In contrast, the development of so-called artificial hearts has made significant progress. While the first implants of totally artificial hearts were associated with many comorbidities and patients were seriously debilitated, new devices today offer a reasonable quality of life and long-term survival. Most of these systems are no longer replacing but mainly assisting the heart, which remains in place. These ventricular assist devices have been used as a bridge to transplantation for a long time and are now also offered as a destination therapy for patients who for a variety of reasons are no longer amenable to heart transplantation. Further miniaturization and a decrease of the costs will make these devices a realistic alternative to a sole medical therapy and studies have already proven the superiority in terms of survival as well as rehospitalization rates. However, at present they are still not an alternative to heart transplantation.

Mechanism of Accommodation in a Sensitized Human Leukocyte Antigen Transgenic Murine Cardiac Transplant Model

Presence of donor-specific antibodies (Abs) is detrimental to posttransplant allograft function. Some sensitized recipients have successfully undergone transplantation after pretransplant conditioning regimen using plasmapheresis and/or intravenous immunoglobulin therapy, but underlying mechanisms that confer such allograft protection are undefined. We developed a single human leukocyte antigen (HLA)-mismatched heterotopic murine heart transplant model (HLA-A2 into HLA-A2-sensitized-C57BL/6) to determine whether pretreatment of donors with low concentration of HLA class I (W6/32) or control Ab (C1.18.4) will confer protection. Expression levels of survival genes, Bcl-2 and heme oxygenase-1, were analyzed by gene array analysis and quantitative real-time polymerase chain reaction. Expression levels of cytokine panel were analyzed by Luminex. Role of Bcl-2 in the induction of allograft protection was analyzed by silencing the Bcl-2 expression in the donor hearts using a small hairpin (shRNA) specific for Bcl-2. Control Ab-pretreated hearts were rejected in less than 5 days demonstrating hemorrhage, Ab, and C4 deposition. In contrast, W6/32-pretreated hearts were rejected at 15 days (P<0.05) that was prolonged to 25 days with antilymphocyte serum treatment. W6/32-pretreated hearts on day 5 exhibited increased expression of Bcl-2 (5.5-folds), Bcl-xl (5.5-folds), and heme oxygenase-1 (4.4-folds); decreased expression of ICAM-1, VCAM-1 (3.2-fold), along with reduced levels of cytokines interleukin (IL)-1β (4.4-folds), tumor necrosis factor α (3.7-folds), IL-6 (7.5-folds), IL-12 (2.3-folds) and chemokines monocyte chemotactic protein 1 (4.5-folds), MIG (4.4-folds), MIP-1α (3.4-folds), and IL-8 (3.1-folds). Silencing of Bcl-2 in accommodated hearts before transplant resulted in loss of protection with rejection (9±3 vs. 15±2days, P<0.05). Pretreatment of hearts with low levels of anti-HLA Abs increases expression of antiapoptotic genes that inhibits caspases, leading to decreased inflammatory cytokines and chemokines, which promote allograft survival.

Succesfull twelve hours of cardiac preservation with Custodiol-N, a novel organ protection solution in an orthotopic heart transplantation model

/2.3% vs. DCD 64.1 /3.1%, p 0.61). Extension of the circulatory arrest time to 30 minutes still allowed for resuscitation and transplantation of the heart. Conclusions: Our findings suggest that the DCD heart can support the circulation after transplantation. Function was comparable to the transplanted BSD heart. Contrary to previous concerns over impairment of RV function in the DCD heart, load-independent assessment of RV function revealed good contractility before and after transplantation. Utilization of DCD hearts for human cardiac transplantation may allow for expansion of the donor pool.

Donor-specific antibodies to human leukocyte antigens are associated with and precede antibodies to major histocompatibility complex class I–related chain A in antibody-mediated rejection and cardiac allograft vasculopathy after human cardiac transplantation

Humoral immune responses to mismatched donor human leukocyte antigen (HLA) and major histocompatibility complex (MHC) class I–related chain A (MICA) have been reported to contribute to immunopathogenesis of antibody-mediated rejection (AMR) in the early period and cardiac allograft vasculopathy (CAV) in the late period after cardiac transplantation (HTx). The goal of this study is to define the roles of donor-specific antibodies (DSA) and anti-MICA in AMR and CAV. A total of 95 post-HTx recipients were enrolled; 43 patients in the early period (≤12 months post-HTx) and 52 patients in the late period (>12 months post-HTx). Development of DSA and anti-MICA were serially monitored using Luminex. Development of DSA (AMR+: n = 6/8.75%, AMR−: n = 4/35.11%, p = 0.009) and anti-MICA (AMR+: n = 5/8.63%, AMR−: n = 4/35.11%, p = 0.002) was significantly associated with AMR. AMR+DSA+ patients demonstrated increased anti-MICA levels compared with AMR+DSA− patients ( p=0.01). Serial monitoring revealed DSA (2.7 ± 1.4 months) preceded development of anti-MICA (6.5 ± 2.1 months) in recipients diagnosed with AMR at 8.3 ± 2.5 months post-HTx. Development of DSA (CAV+: n = 8/12.67%, CAV−: n = 5/40.13%, p = 0.004) and anti-MICA (CAV+: n = 9/12.75%, CAV−: n = 5/40.13%, p = 0.001) was significantly associated with CAV. CAV+DSA+ patients demonstrated increased anti-MICA levels compared with CAV+DSA− patients ( p = 0.01). Antibodies to HLA are associated with and precede development of anti-MICA in AMR and CAV. Therefore, DSA and anti-MICA can be used as noninvasive markers for monitoring AMR and CAV.

Neutrophil Immunosurveillance for Heart Transplant Rejection: A Prospective Study

Immunologic surveillance for rejection detection in human heart transplantation offers many potential advantages. To date, investigative efforts have focused primarily on the acquired immune system, particularly the lymphocyte. Little attention has been given to aspects of innate immune function. We have previously reported that perioperative neutrophil adhesion molecule expression is associated with early rejection episodes after human cardiac transplantation. Herein we have investigated the utility of neutrophil immunosurveillance in human heart transplant recipients at later time points. We recruited patients more than 3 months after transplantation. Neutrophil assessment was performed simultaneously with an endomyocardial biopsy that showed rejection. No significant relationship was seen between neutrophil maturity ( P = .622; n = 34), adhesion marker expression ( P = .567; n = 34), respiratory burst ( P = .604; n = 34), or apoptosis rates ( P = .662; n = 34) and contemporary rejection status at >3 months after transplantation. However, interesting relationships were noted between neutrophil adhesion markers at this late stage and historical rejection status. Higher levels of the adhesion protein CD11b observed at this late stage were significantly associated with a history of higher rejection grades in the first postoperative biopsy (Spearman rank coefficient 0.359; R = 0.304; P = .005; n = 62). Other aspects of neutrophil function and persistence were not significantly associated with rejection history. This finding, combined with the previously reported findings, supports a role for an individual phenotype in neutrophil function in early rejection episodes after transplantation.