Markers Of Cardiac Allograft Rejection Research Articles

CS as a Novel Biomarker for Diagnosis of Cardiac Allograft Rejection

Purpose Cardiac bridging integrator 1 (cBIN1) is a cardiomyocyte protein which regulates excitation-contraction coupling and is downregulated with adverse myocardial remodeling. The natural log of the inverse of cBIN1 plasma concentration known as CS, has been shown to be a diagnostic and prognostic marker for ambulatory heart failure patients. In this pilot study, we examined the performance of CS as a diagnostic marker of cardiac allograft rejection. Methods Out of 708 heart transplant (HT) recipients consented for the study from 2014 to 2018, 12 patients experienced advanced rejection (AMR/ACR grade ≥2) with CS level drawn at the time. Convalescent sera were drawn at least 6 months post therapy. A control group of 11 patients was matched by age, sex and time since HT. CS was measured in plasma samples by Sarcotein, Inc. Pair-wise comparison of CS among the 2 groups was performed using the Wilcoxon signed rank test. Major adverse outcomes (MACE), defined as ventricular tachycardia, cardiac allograft vasculopathy, recurrent rejection, cardiac hospitalization, and death were determined by chart review at most recent clinic visit. Results Rejection occurred at 211 (IQR 127-303) days post-HT. Patients with rejection had significantly lower CS levels compared to controls (1.92[IQR 1.57-2.33] vs 2.36[IQR 1.86-3.71] p=0.03). Following anti-rejection therapy, CS values were determined at 189 (IQR 126.8-303) days after the episode and did not differ significantly from the time of rejection. Notably, post rejection patients experienced a high rate of MACE (7/12) at 4 years of follow-up. Those who experienced MACE had a numerically higher median increase in CS values on follow-up compared to those who did not (1.04 vs 0.50). Conclusion In this pilot study, CS shows promise as a marker of cardiac allograft rejection. CS was significantly decreased by 20% in the setting of rejection compared to matched control samples. Larger studies are needed to validate our findings and determine the prognostic value of CS level changes post-therapy.

Correlation of noninvasive markers of cardiac allograft rejection with endomyocardial biopsy: A case report

Although endomyocardial biopsy remains the gold standard to diagnose cardiac allograft rejection, the search continues for clinical parameters that may aid in the early diagnosis of rejection. We report the case of a 29-year-old man who underwent orthotopic heart transplantation and subsequently had multifocal moderate allograft rejection. During the patient’s hospital course, he exhibited a number of clinical parameters that served as important clues for the worsening rejection. After aggressive immunosuppression, the improvement of these markers hinted toward his eventual recovery.

Serum Matrix Metalloprotease-1 and Vascular Endothelial Growth Factor-A Predict Cardiac Allograft Rejection

Cardiac allograft rejection is currently diagnosed from endomyocardial biopsies (EMB) that are invasive and impractical to repeat. A serological marker could facilitate rejection monitoring and minimize EMB-associated risks. We investigated the relation of serum matrix metalloprotease (MMP)-1 and vascular endothelial growth factor (VEGF)-A concentrations to cardiac allograft rejection, using 1176 EMBs and serum samples obtained from 208 recipients. Acute cellular rejection was diagnosed in 186 EMBs. Mean week 1 and week 2 serum MMP-1 concentrations predicted rejection (p = 0.001, AUC = 0.80). At the optimal cut-off level of >or=7.5 ng/mL, MMP-1 predicted rejection with 82% sensitivity and 72% specificity. Initial serum MMP-1 <5.3 ng/mL (lowest quartile) was associated with rejection-free outcome in 80% of patients. Both MMP-1 (p < 0.001, AUC = 0.67-0.75) and VEGF-A (p < 0.01, AUC = 0.62-0.67) predicted rejection on the next EMB, while rejection at EMB was identified only by VEGF-A (p < 0.02, AUC = 0.70-0.77). Patients receiving combined cyclosporine-A and everolimus had the lowest serum MMP-1 concentrations. While serum MMP-1 predicts rejection-free outcome and VEGF-A identifies rejection on EMB, both markers predict rejection in follow-up of cardiac transplant recipients. Combination of serum MMP-1 and VEGF-A concentration may be a noninvasive prognostic marker of cardiac allograft rejection, and could have important implications for choice of surveillance and immunosuppression protocols.

94: The Inhibitor of Apoptosis Birc6 Is a Sensitive and Specific Marker of Cardiac Allograft Rejection

The Inhibitor of Apoptosis Birc6 Is a Sensitive and Specific Marker of Cardiac Allograft Rejection S. Aharinejad, O. Andrukhova, R. Schaefer, K. Krenn, C. May, A. Zuckermann, D. Zimpfer, M. Grimm, Dept. of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria; Lab. for Cardiovasc. Research, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria; Dept. of Internal Medicine II, Medical University of Vienna, Vienna, Austria

Early growth responsive gene (Egr)-1 expression correlates with cardiac allograft rejection.

Early growth response factor (Egr)-1 is a transcription factor induced by inflammatory cytokines that regulates the expression of cytokines, adhesion molecules, other genes pertinent to inflammatory, and proliferative pathologies. Its expression in allografted tissue and role in the pathogenesis of graft rejection has not been explored. The goal of this work is to determine whether Egr-1 expression could be used as a surrogate marker of cardiac allograft rejection. Egr-1 protein expression was analyzed in endomyocardial biopsies of different rejection grades by immunohistochemistry. Egr-1 mRNA expression was analyzed in 106 biopsies from 11 transplant patients by semiquantitative reverse-transcriptase polymerase chain reaction. Egr-1 was also analyzed in coronary arteries from patients with coronary artery vasculopathy (CAV) by Western blot and immunohistochemistry. No expression of Egr-1 protein was observed in grade 0 biopsies by immunohistochemistry. Strong nuclear Egr-1 was noted in leukocytes and cardiac myocytes in grade 3 biopsies. A clear pattern emerged where 20% (6/30), 34% (20/58), 22% (2/9), and 89%(8/9) of International Society For Heart and Lung Transplantation grade 0, 1, 2, and 3 biopsies were positive for Egr-1 mRNA. There was a significant (P<0.005) relationship between Egr-1 mRNA expression and rejection grade in endomyocardial biopsies. The calculated odds ratio indicates that a biopsy has a 2.18% greater probability of Egr-1 expression per increasing grade of rejection. Egr-1 was also up-regulated in vascular cells in coronary arteries from patients with CAV. In consideration of its role as a transcription factor for genes involved in pathologic processes, Egr-1 expression in endomyocardial biopsies may act as a surrogate marker of cardiac allograft rejection.

Use of Proteomics to Discover Novel Markers of Cardiac Allograft Rejection

Endomyocardial biopsy remains the most reliable method of detecting rejection following cardiac transplantation. Despite numerous attempts to detect rejection using a blood assay, none have proved reliable enough to replace the biopsy. Here, we have investigated the hypothesis that proteomics has the potential to reveal many molecules which are upregulated in the heart during rejection, some of which may serve as novel blood markers of rejection. Initially, sequential cardiac biopsies (33 in total) from 4 patients were analysed by two-dimensional gel electrophoresis according to whether they showed rejection (n = 16) or no rejection (n = 17); over 100 proteins were found to be upregulated by between 2- and 50-fold during rejection. Of these, 13 were identified and were found to be cardiac specific or heat shock proteins. Two of these (alphaB-crystallin, tropomyosin) were measured by ELISA in the sera of 17 patients followed for 3 months after their transplants. Mean levels of alphaB-crystallin and tropomyosin were significantly higher in sera associated with biopsies showing 1A (p = 0.007) or all grades of rejection (p = 0.022) compared to no rejection. These studies demonstrate that proteomics is a powerful method that can be used to identify novel serum markers of human cardiac allograft rejection.

The utility of pacemaker evoked T wave amplitude for the noninvasive diagnosis of cardiac allograft rejection.

Previous work suggested that pacemaker evoked T wave amplitude (ETWA) may be a sensitive noninvasive marker of cardiac allograft rejection. A Topaz QT sensing rate responsive pacemaker (Vitatron Medical) was implanted at transplantation using epicardial ventricular leads in 45 recipients (35 males; median age 51 years, range 20-63). The median duration of follow-up was 129 days (range 4-327). The ETWA at a paced rate of 100 beats/min was measured daily during hospitalization and at each outpatient attendance (900 readings). Endomyocardial biopsies were at routine intervals or when otherwise clinically indicated (257 biopsies with concurrent ETWA data). There were 58 episodes of rejection > or = grade 3a in 28 patients. The biopsies were classed as either no rejection (grade < 3a) or rejection requiring treatment (grade > or = 3a). The median normalized ETWA was 100.8% (range 24.6-239.7) without rejection and 89.9% (17.0-189.7) with rejection (Mann-Whitney U Test: P = 0.028). The performance of ETWA monitoring as a diagnostic test for the individual recipient was evaluated with exponentially weighted moving average quality control charts. For the diagnosis of all rejection episodes, ETWA monitoring had a sensitivity of 55%, a specificity of 62%, a positive predictive value of 30%, and negative predictive value of 83%. It is concluded that although analysis of pooled data showed a significant reduction in normalized ETWA with biopsy proven rejection, ETWA monitoring requires further refinement to improve sensitivity before it can be considered a clinically useful technique for the non-invasive diagnosis of cardiac allograft rejection in individual recipients.

Urinary polyamines as markers of cardiac allograft rejection: A clinical evaluation

Histologic evaluation of endomyocardial biopsy specimens is the current method of monitoring rejection after cardiac transplantation. Unfortunately, this technique gives a discontinuous evaluation of the recipient immunologic status. A noninvasive marker of immunologic activation and of allograft rejection that would permit a more continuous monitoring than the biopsy technique would be clinically useful. Urinary polyamine excretion reflects cellular proliferation or degeneration and, as a marker of cellular metabolic activity, may also reflect lymphocyte proliferation and organ rejection. From July 1985 to December 1986, urinary polyamines were studied in 18 patients during hospitalization for heart and heart-lung transplantation. Endomyocardial biopsy was performed twice a week and histologic rejection was characterized by standard criteria. Urinary specimens were collected daily and analyzed for polyamines by high-pressure liquid chromatography. Concentrations of acetylputrescine and total urinary polyamines were significantly higher before the 20 rejection episodes than before the 80 biopsies yielding negative results. So that their clinical usefulness could be evaluated, an elevation of polyamines and a daily level variability of 28% or more was chosen to indicate increased metabolic cellular activity and to predict rejection in the next 8 days. On the basis of these definitions, the sensitivity of polyamine assays to predict rejection was 85%, the specificity 88%, and the positive predictive value 79%. Therefore, serial measurements of urinary polyamines may provide daily information on the recipient's immunologic status after cardiac transplantation.

Value of Urinary Polyamines as Noninvasive Markers of Cardiac Allograft Rejection in the Dog

A noninvasive marker of cardiac allograft rejection would be useful clinically. Lymphocyte proliferation and organ rejection may cause changes in urinary polyamine excretion. To test this hypothesis, cervical heterotopic heart transplantations were performed in a group of 6 nonimmunosuppressed dogs and in a group of 9 dogs treated with cyclosporine (N = 3) or cyclosporine and steroids (N = 6). A group (N = 3) having a sham operation was also studied. Serial biopsies of the transplanted hearts were performed. Urinary polyamine levels were measured daily by high-pressure liquid chromatography of urine specimens. Between 2 and 4 days after transplantation, the transplanted hearts of all animals without immunosuppression demonstrated histological rejection. An early increase in putrescine levels and in total urinary polyamine levels was observed in this group. In the treated groups, histological rejection appeared from the second to the eighth day after transplantation. Each episode of rejection occurred from 1 day to 4 days after a significant increase in urinary polyamine levels compared with the preoperative baseline level ( p < 0.01). In contrast, polyamine excretion in 3 dogs after sham operations remained unchanged. Thus, urinary excretion of polyamines increases before the appearance of histological rejection; this suggests that changes in urinary polyamine levels may be a useful marker of cardiac allograft rejection.