Acute Cardiac Transplant Rejection Research Articles

Cardiac magnetic resonance imaging characterization of acute rejection in a porcine heterotopic heart transplantation model.

Preclinical disease models are important for the advancement of therapeutics towards human clinical trials. One of the difficult tasks of developing a well-characterized model is having a reliable modality with which to trend the progression of disease. Acute rejection is one of the most devastating complications that can occur following organ transplantation. Specifically in cardiac transplantation, approximately 12% of patients will experience at least one episode of moderate or severe acute rejection in the first year. Currently, the gold standard for monitoring rejection in the clinical setting is to perform serial endomyocardial biopsies for direct histological assessment. However, this is difficult to reproduce in a porcine model of acute rejection in cardiac transplantation where the heart is heterotopically transplanted in an abdominal position. Cardiac magnetic resonance imaging is arising as an alternative for serial screening for acute rejection in cardiac transplantation. This is an exploratory study to create and define a standardized cardiac magnetic resonance screening protocol for characterizing changes associated with the presence of acute rejection in this preclinical model of disease. Results demonstrate that increases in T1 mapping, T2 mapping, left ventricular mass, and in late gadolinium enhancement are significantly correlated with presence of acute rejection.

ВОПРОСЫ ДОГОСПИТАЛЬНОЙ ДИАГНОСТИКИ ОСТРОЙ РЕАКЦИИ ОТТОРЖЕНИЯ У ПАЦИЕНТА, ПЕРЕНЕСШЕГО ОРТОТОПИЧЕСКУЮ ТРАНСПЛАНТАЦИЮ СЕРДЦА

An acute cardiac transplant rejection is a reaction of the recipient’s immune system, which includes the cellular and/or humoral pathway of the immune response. This reaction is directed against the tissues of the “alien” donor organ. The alertness of clinicians regarding the possible development of an acute rejection reaction during the first year after heart transplantation is due to the extremely high risk of developing life-threatening conditions mediated by graft dysfunction. These include various cardiac arrhythmias and a progressive decrease in myocardial contractility. In case of untimely diagnosis of this serious complication, the risk of mortality of the patient who underwent orthotopic heart transplantation is extremely high. What changes in clinical, laboratory and instrumental examination parameters at the outpatient stage can help a practicing cardiologist to suspect the presence of an acute rejection reaction of a heart transplant in a patient who has undergone orthotopic heart transplantation? At present, there is no unambiguous answer to this question, and the topic of early detection and prediction of the development of an acute heart transplant rejection reaction is extremely relevant for modern scientific research and is of great practical interest in the field of transplantology and cardiology, in particular.

Small-molecule BCL6 inhibitor protects chronic cardiac transplant rejection and inhibits T follicular helper cell expansion and humoral response.

Background: B cell lymphoma 6 (BCL6) is an important transcription factor of T follicular helper (Tfh) cells, which regulate the humoral response by supporting the maturation of germinal center B cells and plasma cells. The aim of this study is to investigate the expansion of T follicular helper cells and the effect of the BCL6 inhibitor FX1 in acute and chronic cardiac transplant rejection models. Methods: A mouse model of acute and chronic cardiac transplant rejection was established. Splenocytes were collected at different time points after transplantation for CXCR5+PD-1+ and CXCR5+BCL6+ Tfh cells detection by flow cytometry (FCM). Next, we treated the cardiac transplant with BCL6 inhibitor FX1 and the survival of grafts was recorded. The hematoxylin and eosin, Elastica van Gieson, and Masson staining of cardiac grafts was performed for the pathological analysis. Furthermore, the proportion and number of CD4+ T cells, effector CD4+ T cells (CD44+CD62L-), proliferating CD4+ T cells (Ki67+), and Tfh cells in the spleen were detected by FCM. The cells related to humoral response (plasma cells, germinal center B cells, IgG1+ B cells) and donor-specific antibody were also detected. Results: We found that the Tfh cells were significantly increased in the recipient mice on day 14 post transplantation. During the acute cardiac transplant rejection, even the BCL6 inhibitor FX1 did not prolong the survival or attenuate the immune response of cardiac graft, the expansion of Tfh cell expansion inhibit. During the chronic cardiac transplant rejection, FX1 prolonged survival of cardiac graft, and prevented occlusion and fibrosis of vascular in cardiac grafts. FX1 also decreased the proportion and number of splenic CD4+ T cells, effector CD4+ T cells, proliferating CD4+ T cells, and Tfh cells in mice with chronic rejection. Moreover, FX1 also inhibited the proportion and number of splenic plasma cells, germinal center B cells, IgG1+ B cells, and the donor-specific antibody in recipient mice. Conclusion: We found BCL6 inhibitor FX1 protects chronic cardiac transplant rejection and inhibits the expansion of Tfh cells and the humoral response, which suggest that BCL6 is a potential therapeutic target of the treatment for chronic cardiac transplant rejection.

Beyond the AJR: Cardiac MRI Accurately Detects Acute Cardiac Transplant Rejection.

Beyond the AJR: Cardiac MRI Accurately Detects Acute Cardiac Transplant RejectionChristopher J. François, MD1Audio Available | Share

The Combination of Rhodosin and MMF Prolongs Cardiac Allograft Survival by Inhibiting DC Maturation by Promoting Mitochondrial Fusion.

Despite being the gold-standard treatment for end-stage heart disease, heart transplantation is associated with acute cardiac rejection within 1 year of transplantation. The continuous application of immunosuppressants may cause side effects such as hepatic and renal toxicity, infection, and malignancy. Developing new pharmaceutical strategies to alleviate acute rejection after heart transplantation effectively and safely is of critical importance. In this study, we performed a murine model of MHC-full mismatch cardiac transplantation and showed that the combination of Rhodosin (Rho) and mycophenolate mofetil (MMF) could prevent acute rejection and oxidative stress injury and prolong the survival time of murine heart transplants. The use of Rho plus MMF in allografts improved the balance of Tregs/Teff cells, which had a protective effect on allotransplantation. We also isolated bone marrow-derived dendritic cells (BMDCs) and determined that Rho inhibited DC maturation by promoting mitochondrial fusion mainly through the mitochondrial fusion-related protein MFN1. Herein, we demonstrated that Rho, an active ingredient isolated from the plant Rhodiola rosea with antioxidant and anti-inflammatory activities, could efficiently alleviate acute rejection and significantly prolong murine heart allograft survival when used with a low dose of MMF. More importantly, we found that Rho restrained DC maturation by promoting mitochondrial fusion and decreasing reactive oxygen species (ROS) levels, which then alleviated acute rejection in murine cardiac transplantation. Interestingly, as a novel immunosuppressant, Rho has almost no side effects compared with other traditional immunosuppressants. Taken together, these results suggest that Rho has good clinical auxiliary applications as an effective immunosuppressant and antioxidant, and this study provides an efficient strategy to overcome the side effects of immunosuppressive agents that are currently used in organ transplantation.

Diagnostic Accuracy of Cardiovascular Magnetic Resonance for Cardiac Transplant Rejection: A Meta-Analysis

ObjectivesThe aim of this meta-analysis was to assess the diagnostic performance of various CMR imaging parameters for evaluating acute cardiac transplant rejection. BackgroundEndomyocardial biopsy is the current gold standard for detection of acute cardiac transplant rejection. Cardiac magnetic resonance (CMR) is uniquely capable of myocardial tissue characterization and may be useful as a noninvasive alternative for the diagnosis of graft rejection. MethodsPubMed and Web of Science were searched for relevant publications reporting on the use of CMR myocardial tissue characterization for detection of acute cardiac transplant rejection with endomyocardial biopsy as the reference standard. Pooled sensitivity, specificity, and hierarchical modeling–based summary receiver-operating characteristic curves were calculated. ResultsOf 478 papers, 10 studies comprising 564 patients were included. The sensitivity and specificity for the detection of acute cardiac transplant rejection were 84.6 (95% CI: 65.6-94.0) and 70.1 (95% CI: 54.2-82.2) for T1, 86.5 (95% CI: 72.1-94.1) and 85.9 (95% CI: 65.2-94.6) for T2, 91.3 (95% CI: 63.9-98.4) and 67.6 (95% CI: 56.1-77.4) for extracellular volume fraction (ECV), and 50.1 (95% CI: 31.2-68.9) and 60.2 (95% CI: 36.7-79.7) for late gadolinium enhancement (LGE). The areas under the hierarchical modeling–based summary receiver-operating characteristic curve were 0.84 (95% CI: 0.81-0.87) for T1, 0.92 (95% CI: 0.89-94) for T2, 0.78 (95% CI: 0.74-0.81) for ECV, and 0.56 (95% CI: 0.51-0.60) for LGE. T2 values demonstrated the highest diagnostic accuracy, followed by native T1, ECV, and LGE (all P values <0.001 for T1, ECV, and LGE vs T2). ConclusionsT2 mapping demonstrated higher diagnostic accuracy than other CMR techniques. Native T1 and ECV provide high diagnostic use but lower diagnostic accuracy compared with T2, which was related primarily to lower specificity. LGE showed poor diagnostic performance for detection of rejection.

Soluble fibrinogen-like protein 2 ameliorates acute rejection of liver transplantation in rat via inducing Kupffer cells M2 polarization.

Soluble fibrinogen‐like protein 2 (sFGL2) could ameliorate acute rejection (AR) in rat cardiac transplantation. However, the role of sFGL2 in AR of liver transplantation has not been addressed. In this study, we found that FGL2 was upregulated in rat orthotropic liver transplantation (OLT) models of tolerance and positive correlation with the frequency of M2 Kupffer cells (KCs). Gain‐of‐function experiments in vitro showed that sFGL2 promoted the secretion of anti‐inflammatory cytokines (IL‐10, TGF‐β) and the expression of CD206, and inhibited the activities of STAT1 and NF‐κB signaling pathway. Consistently, in vivo assays showed that adeno‐associated virus‐mediated FGL2 (AAV‐FGL2) transfer to recipients could ameliorate AR of rat OLT and induce KCs M2 polarization in allografts. Notably, we found that the recipients receiving transferred KCs from AAV‐FGL2‐treated allograft showed alleviated AR. Taken together, we revealed that sFGL2 ameliorated AR by inducing KCs M2 polarization.

Advanced Parameters of Cardiac Function Out Perform Traditional Echocardiographic Indices in the Identification of Pediatric Patients with Acute Antibody-Mediated Cardiac Transplant Rejection

Antibody-mediated allograft rejection is a less understood and often undiagnosed entity despite resulting in high rates of cardiovascular death. Adult studies have shown that traditional echocardiographic markers have poor sensitivity in mild rejection and thus cannot supplant endomyocardial biopsy. Aim of our study was to describe acute changes in echocardiographic markers of rejection in a population of children with acute antibody-mediated rejection.

Molecular Imaging of Acute Cardiac Transplant Rejection: Animal Experiments and Prospects.

Acute rejection (AR) remains the biggest challenge during the first year after heart transplantation despite advances in immunosuppressive therapy. The early detection and curbing of AR are crucial to the survival of transplant recipients. However, as the criterion standard for AR, endomyocardial biopsy has several limitations because of its inherent invasiveness and morbidity. Traditional imaging techniques, such as echocardiography and cardiac magnetic resonance imaging, are of certain value for AR, but their diagnostic criteria and accuracy remain in question. Molecular imaging sheds new light on AR diagnosis because it can provide information about gene expression and the location of molecules and cells. This article reviews the latest research and applications of several typical modalities of molecular imaging used in AR and discusses their advantages and disadvantages.

The Matrikine Acetylated Proline-Glycine-Proline Couples Vascular Inflammation and Acute Cardiac Rejection

The extracellular matrix (ECM) is a dynamic, bioactive structure critical to organ development, structure and function. Excessive remodeling of the ECM is a hallmark of a variety of inflammatory conditions including vascular disease. Endothelin-1 (ET1) synthesis is understood to promote cardiovascular diseases including acute cardiac transplant rejection; however, the contribution of ECM-derived chemokines (matrikines) to vascular inflammation remains poorly understood. Herein we report that the matrikine acetylated Pro-Gly-Pro (PGP) stimulates vascular inflammation through activation of endothelial CXC Chemokine Receptor 2 (CXCR2) and production of endothelin-1 both in vitro and in vivo. As a proof of hypothesis, we demonstrate that coronary PGP levels associate with both circulating endothelin-1 and acute rejection in cardiac transplant patients (sensitivity of 100% and specificity of 86%). These findings establish PGP as a novel mediator in cardiovascular disease, and implicate bioactive matrix fragments as underappreciated agents potentially active in numerous conditions propagated by progressive vascular inflammation.

Clinical applications of multi-parametric CMR in myocarditis and systemic inflammatory diseases

Cardiac magnetic resonance (CMR) has changed the management of suspected viral myocarditis by providing a ‘positive’ diagnostic test and has lead to new insights into myocardial involvement in systemic inflammatory conditions. In this review we analyse the use of CMR tissue characterisation techniques across the available studies including T2 weighted imaging, early gadolinium enhancement, late gadolinium enhancement, Lake Louise Criteria, T2 mapping, T1 mapping and extracellular volume assessment. We also discuss the use of multiparametric CMR in acute cardiac transplant rejection and a variety of inflammatory conditions such as sarcoidosis, systemic lupus erythrematous, rheumatoid arthritis and systemic sclerosis.

Hp: an inflammatory indicator in cardiovascular disease.

Over the past decade significant advancement has occurred in the biological and pathological role that Hp has in cardiovascular disease. Hp is an acute-phase protein with a role in the neutralization and clearance of free heme. Iron has tremendous potential for initiating vascular oxidation, inflammation and exacerbating coronary atherosclerosis. Hp genotype has been linked as a prognostic biomarker of acute myocardial infarction, heart failure, restenosis and cardiac transplant rejection. The increased understanding of Hp as a biomarker has provided new insights into the mechanisms of inflammation after cardiac injury and support the concept that Hp is not only an important antioxidant in vascular inflammation and atherosclerosis, but also an enhancer of inflammation in cardiac transplant.

Combination of C-X-C motif chemokine 9 and C-X-C motif chemokine 10 antibodies with FTY720 prolongs the survival of cardiac retransplantation allografts in a mouse model.

The upregulation of chemokine genes and the subsequent T-lymphocyte recruitment to the graft are early events in the development of acute cardiac transplant rejection or cardiac allograft vasculopathy. In the present study, a combined immunosuppressive regimen of C-X-C motif chemokine 9 (CXCL9) antibody (Ab), CXCL10 Ab and FTY720 was used in order to reduce the infiltration of memory T lymphocytes and prolong graft survival in a retransplantation murine model. BALB/c donor hearts were transplanted heterotopically into C57BL/6 mice at day 28 after skin transplantation. The mice were divided into four groups: i) Control (normal saline), ii) CXCL9 Ab and CXCL10 Ab [150 μg; once daily (qd); intraperitoneal (ip)], iii) FTY720 (0.2 mg/day; qd; ip) and iv) combined (2 mg/kg/day; qd; ip). Measurements of the median survival time of the cardiac grafts, histological examination, reverse transcription-quantitative polymerase chain reaction analysis, enzyme-linked immunosorbent assay and a mixed lymphocyte reaction were performed. The median graft survival time of the combined group was prolonged (9.3 days) compared with that of the control group (3.5 days) (P<0.001). Histological examination revealed that the combined treatment group graft rejection pathological score was 0.50, while the control group score was 3.62 (P<0.001). In addition, the gene expression level of interleukin (IL)-2 was significantly lower and the levels of IL-10 and transforming growth factor-β (TGF-β) were significantly higher in the combined group compared with those in the control group (P<0.001). Furthermore, the serum concentration levels of IL-2 and interferon-γ (IFN-γ) were significantly lower (P<0.001) and the concentration of IL-10 was significantly higher (P<0.05) in the combined group compared with those in the control group. In the mixed lymphocyte reaction, T-cell proliferation was found to be significantly lower in the combined treatment group than that in the control group (P<0.001). In conclusion, treatment with CXCL9 Ab and CXCL10 Ab or FTY720 reduced the graft infiltration of inflammatory cells, inhibited T-cell proliferation and prolonged graft survival. The combined treatment regimen of CXCL9 Ab, CXCL10 Ab and FTY720 was found to significantly reduce the infiltration of inflammatory cells in the graft and prolong graft survival.

Myocardial tissue characterisation by Cardiovascular Magnetic Resonance diagnoses and tracks recovery after cardiac transplant rejection

Introduction: Routine surveillance endomyocardial biopsies (EMBx) are associated with serious complications. Cardiovascular magnetic resonance (CMR) accurately and non-invasively diagnoses myocarditis. This study aimed to determine whether CMR is able to diagnose acute rejection in cardiac transplant recipients using a novel T2-mapping sequence. Methods: Patients underwent CMR within 24 hours of their surveillance or clinically-indicated EMBx starting from six weeks after transplantation. The T2 value was measured using a navigated black-blood turbo spin echo sequence in a single mid-short-axis slice at 1.5T (Philips Medical Systems, Best, Netherlands). Results: Thirty-six studies were performed. Using the ISHLT grading system, 12 biopsies were grade 0 (group 0), 13 grade 1R (group 1), 5 grade 3R or antibody mediated rejection (group 3). Four biopsies demonstrated no histological evidence of rejection; however, these patients were treated for acute rejection based on a decline in ejection fraction or strong clinical suspicion (group 4). Two grade 2R rejections were not included in the analysis because n=2 was too small for meaningful statistical analysis. T2 values were significantly different across groups (P<0.001; ANOVA [table]) driven by a difference between recipients with grade 3R rejection (74.8 +/-1.6; mean+/- SEM) and both grades 0 (57.2+/-1.2; P <0.05) and 1R (56.9+/-2.1; P <0.05). There was no significant difference between groups 0 and 1R (57.2+/-1.2 vs 56.9+/-2.1 (P &gt0.05)). Recipients in group 4 had elevated T2 values despite no histological evidence of cardiac rejection. Conclusion: Myocardial tissue characterisation by CMR holds promise for the detection of acute cardiac transplant rejection and may reduce the dependency on routine surveillance EMBx after cardiac transplantation.

(762) - Efficacy and Safety of Basiliximab as Curative Treatment of Persistent or Complicated Acute Rejection in Cardiac Transplantation

Basiliximab ( Simulect ) is a monoclonal antibody specifically directed against the alpha chain ( CD25 ) of the interleukin 2 receptor. It inhibits the activation of T lymphocytes that play a major role in the mechanism of acute rejection. It is indicated for the prevention of acute rejection in de novo allogeneic renal transplantation in adults and children and is commonly used as induction therapy in solid organ transplantation. We report a retrospective analysis of the efficacy and safety of basiliximab administered as curative treatment of acute rejection in heart transplantation.

Prevention of acute rejection by RelB siRNA-silenced dendritic cells

Objective To prevente acute rejection in cardiac transplantation by using tolerogenic dendritic cells (DC).Methods The mixed lymphocyte reaction (MLR) was performed by RelB siRNA-DC with allogenic antigen-specific T cells.The apoptosis rate of T cells and the ratio of CD4 + CD25 + Foxp3 + regulatory T cells were detected by using flow cytometry after MLR.In the murine model of cardiac transplantation,the survival time was observed after infusion of RelB siRNA-DC before transplantation.HE staining was used to examine the rejection degree in the specimens of allografts.Results Mature DC and LucR siRNA DC could stimulate the proliferation of T cells more strongly than immature DC and RelB siRNA-DC (P ＜ 0.05).The RelB siRNA-DC could induce allogeneic T cell hyporesponsiveness,but had no specific reactivity on the third kind T cells (P ＞ 0.05).RelB siRNA-DC induced T cell apoptosis [(29.21 ± 7.55)％,P ＜ 0.05] and promoted T cells differentation into CD4 + CD25 + Foxp3 + regulatory T cells [(65.3 ± 12.6)％,P ＜ 0.05].In the mouse cardiac transplantation model,infusion of donor-derived Lenti-RelB siRNA-DC could prolong the graft survival time (P ＜ 0.05) and reduce rejection occurrence.Conclusion Donor-derived RelB-siRNA-induced tolerogenic DC can significantly induce immune tolerance in vitro and in vivo. Key words: Dendritic cell; Heart transplantation; Rejection; Regulatory T cell

Cardiac Magnetic Resonance T2 Mapping in the Monitoring and Follow-up of Acute Cardiac Transplant Rejection

Background— Acute rejection is a major factor impacting survival in the first 12 months after cardiac transplantation. Transplant monitoring requires invasive techniques. Cardiac magnetic resonance (CMR), noninvasive testing, has been used in monitoring heart transplants. Prolonged T2 relaxation has been related to transplant edema and possibly rejection. We hypothesize that prolonged T2 reflects transplant rejection and that quantitative T2 mapping will concur with the pathological and clinical findings of acute rejection. Methods and Results— Patients were recruited within the first year after transplantation. Biopsies were graded according to the International Society for Heart Lung Transplant system for cellular rejection with immunohistochemistry for humoral rejection. Rejection was also considered if patients presented with signs and symptoms of hemodynamic compromise without biopsy evidence of rejection who subsequently improved with treatment. Patients underwent a novel single-shot T2-prepared steady-state free precession 4-chamber and 3 short axis sequences and regions of interest were drawn overlying T2 maps by 2 independent blinded reviewers. A total of 74 (68 analyzable) CMRs T2 maps in 53 patients were performed. There were 4 cellular, 2 humoral, and 2 hemodynamic rejection cases. The average T2 relaxation time for grade 0R (n=46) and grade 1R (n=17) was 52.5±2.2 and 53.1±3.3 ms (mean±SD), respectively. The average T2 relaxation for grade 2R (n=3) was 59.6±3.1 ms and 3R (n=1) was 60.3 ms (all P value &lt;0.05 compared with controls). The T2 average in humoral rejection cases (n=2) was 59.2±3.3 ms and the hemodynamic rejection (n=2) was 61.1±1.8 ms ( P &lt;0.05 versus controls). The average T2 relaxation time for all-cause rejection versus no rejection is 60.1±2.1 versus 52.8±2.7 ms ( P &lt;0.05). All rejection cases were rescanned 2.5 months after treatment and demonstrated T2 normalization with average of 51.4±1.6 ms. No difference was found in ventricular function between nonrejection and rejection patients, except in ventricular mass 107.8±10.3 versus 127.5±10.4 g ( P &lt; 0.05). Conclusions— Quantitative T2 mapping offers a novel noninvasive tool for transplant monitoring, and these initial findings suggest potential use in characterizing rejections. Given the limited numbers, a larger multi-institution study may help elucidate the benefits of T2 mapping as an adjunctive tool in routine monitoring of cardiac transplants.

Two‐dimensional speckle tracking echocardiography of acute cardiac transplant rejection following pregnancy

A 44-year-old woman, who had undergone orthotopic cardiac transplantation in 1999, presented acute allograft rejection 4 months after childbirth. Analysis of myocardial deformation by speckle tracking echocardiography showed, in contrast with traditional markers of systolic function, a strong reduction of left ventricular strain, which recovered, together with rejection, under pharmacological treatment. This case documents the potential advantages of speckle tracking echocardiography in the noninvasive management of transplant recipients.

Successful Use of the TandemHeart Percutaneous Ventricular Assist Device as a Bridge to Recovery for Acute Cellular Rejection in a Cardiac Transplant Patient

In this report, we presented a patient who benefited from hemodynamic support with the TandemHeart Percutaneous Ventricular Assist Device (pVAD; Cardiac Assist, Inc) implantation in the setting of early acute graft rejection 2 months after orthotopic heart transplant. The TandemHeart initially had been used for temporary hemodynamic assistance during postcardiotomy heart failure and high-risk coronary interventions. More recently, its use in patients with cardiogenic shock from acute myocardial infarction, fulminant myocarditis, and critical aortic stenosis has been reported. To our knowledge, this is one of the first reported cases in which the TandemHeart pVAD served as a successful device for support during acute cardiac transplant rejection.

Cardiac magnetic resonance T2 mapping for monitoring acute cardiac transplant rejection

Cardiac transplantation is the treatment for some patients with end-stage heart failure. After transplantation asymptomatic acute allograft rejection is a major factor impacting survival in the first 12 months. Current transplant monitoring requires frequent right heart catheterizations, endomyocardial biopsies (EMB), and echocardiography. CMR imaging, comparatively less invasive, has been studied previously in the transplanted heart and prolonged T2 relaxation has shown correlation to transplant edema and rejection [1]. We hypothesize that prolonged T2 relaxation in transplant edema reflects rejection, and that quantitative T2 mapping will correlate with pathological and clinical findings.