Troponin T as a non-invasive marker of cardiac allograft rejection

Abstract Accumulating evidence has confirmed that the expression of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is downregulated in heart failure and cardiac allograft rejection. Although many SERCA2a-related genes and proteins involved in the regulation of myocardial Ca2+ fluxes have been explored, its related metabolites remain poorly studied. Our main objective was to identify circulating SERCA2a-related metabolites altered in cardiac allograft rejection and to determine whether these could serve as non-invasive biomarkers. Sixty plasma samples from adult heart transplant were included in a metabolomic analysis. Sphingosine-1 phosphate (S1P), metabolite closely related with SERCA, were increased in patients with cardiac rejection (p < 0.0001). S1P discriminated between patients with and without rejection: normal grafts vs. all rejecting grafts (AUC = 0.911, p < 0.0001), normal grafts vs. Grade 1 R (AUC = 0.819, p < 0.01), Grade 2 R (AUC = 0.911, p < 0.0001), Grade 3 R (AUC = 0.996, p < 0.0001). In addition, we found changes in key enzymes and receptors of S1P pathway analysed on explanted hearts from heart failure patients. This preliminary study reveals that circulating S1P determination could be a novel approach to detect cardiac rejection, showing a robust capability for detection that improves gradually with the severity of rejection. These alterations could be relevant to better understand the involvement of calcium regulation on the pathophysiology of rejection.

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Cardiac troponin T and C-reactive protein as markers of acute cardiac allograft rejection

Clinica Chimica Acta ◽

10.1016/s0009-8981(01)00590-3 ◽

2001 ◽

Vol 312 (1-2) ◽

pp. 31-39 ◽

Cited By ~ 23

Author(s):

Jeffrey J Chance ◽

Jodi B Segal ◽

Gail Wallerson ◽

Edward Kasper ◽

Ralph H Hruban ◽

...

Keyword(s):

Allograft Rejection ◽

Cardiac Troponin ◽

Troponin T ◽

Cardiac Allograft ◽

Cardiac Troponin T ◽

C Reactive Protein ◽

Cardiac Allograft Rejection ◽

Reactive Protein

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White Blood Cell Differentials Enrich Whole Blood Expression Data in the Context of Acute Cardiac Allograft Rejection

Bioinformatics and Biology Insights ◽

10.4137/bbi.s9197 ◽

2012 ◽

Vol 6 ◽

pp. BBI.S9197 ◽

Cited By ~ 8

Author(s):

Casey P. Shannon ◽

Zsuzsanna Hollander ◽

Janet Wilson-Mcmanus ◽

Robert Balshaw ◽

Raymond T. Ng ◽

...

Keyword(s):

Whole Blood ◽

Allograft Rejection ◽

Cardiac Allograft ◽

Expression Data ◽

Molecular Processes ◽

Cardiac Allograft Rejection ◽

Non Invasive ◽

False Discovery ◽

Biological Interpretation ◽

Promising Avenue

Acute cardiac allograft rejection is a serious complication of heart transplantation. Investigating molecular processes in whole blood via microarrays is a promising avenue of research in transplantation, particularly due to the non-invasive nature of blood sampling. However, whole blood is a complex tissue and the consequent heterogeneity in composition amongst samples is ignored in traditional microarray analysis. This complicates the biological interpretation of microarray data. Here we have applied a statistical deconvolution approach, cell-specific significance analysis of microarrays (csSAM), to whole blood samples from subjects either undergoing acute heart allograft rejection (AR) or not (NR). We identified eight differentially expressed probe-sets significantly correlated to monocytes (mapping to 6 genes, all down-regulated in ARs versus NRs) at a false discovery rate (FDR) ≤ 15%. None of the genes identified are present in a biomarker panel of acute heart rejection previously published by our group and discovered in the same data.

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P3266 Non-invasive diagnosis of cardiac allograft rejection

European Heart Journal ◽

10.1016/s0195-668x(03)95892-1 ◽

2003 ◽

Vol 24 (5) ◽

pp. 617

Author(s):

C AGUIAR

Keyword(s):

Allograft Rejection ◽

Cardiac Allograft ◽

Cardiac Allograft Rejection ◽

Non Invasive

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Abstract 16438: Serum Exosomal Protein Profiling for the Non-invasive Detection of Cardiac Allograft Rejection

Circulation ◽

10.1161/circ.132.suppl_3.16438 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Peter J Kennel ◽

Dawn Maldonado ◽

Raymond Givens ◽

Danielle Brunjes ◽

Estibaliz Castillero ◽

...

Keyword(s):

Allograft Rejection ◽

Cardiac Allograft ◽

Protein Profiling ◽

Target Cells ◽

Complement Factor ◽

Cardiac Allograft Rejection ◽

Non Invasive ◽

Elisa Testing ◽

Significant Difference ◽

Protein Signature

Introduction: Exosomes are cell-derived vesicles in the extracellular environment present in biological fluids. Exosomal content is actively assembled containing mRNA, miRNA and proteins. Exosomal-derived molecules have messenger function on target cells. Hypothesis: The serum-derived exosomal proteome is altered in acute cardiac allograft rejection allowing a distinction between non-rejection and acute rejection episodes with specifics for the type of rejection. Methods: Serum samples were collected from heart transplant (HTx) recipients with no rejection (n=10), acute cellular rejection (n=10) and antibody-mediated rejection (n=8) confirmed by myocardial biopsy and histopathology report. Exosome isolation was performed using an isolation kit (Invitrogen). Proteomic analyses were performed by LC-MS/MS analysis using the Fusion Tribrid Orbitrap Mass Spectrometer. To confirm these findings, one of the proteins found by proteomic analysis, C1Q, was compared across samples with ELISA (Abcam). Results: A distinct pattern was detectable separating each group by clustering analysis. A exosomal protein signature totaling 24 proteins (FDR<2%) was found in the rejection group compared to the no rejection group. Further, patients with ACR had a distinctly different exosomal protein signature compared to patients with AMR. Of note, complement factor components such as C1QA (-53%), C1QB (-36%) and immunoglobulin subfractions such as IGHM (+42%) were the most significantly regulated proteins. Confirmatory ELISA testing of exosomal C1Q levels revealed a trend (p=0.077) towards decreased levels of C1Q in the AMR group but no significant difference in the ACR group. Conclusions: These data suggest a distinct exosomal proteome signature in cardiac allograft rejection patients as compared to patients without rejection, mainly involving complement cascade proteins, immunoglobulin fractions and structural proteins. Exosomal proteome analysis shows potential for non-invasive characterization of cardiac allograft rejection with distinct profiles in patients with ACR and AMR.

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A Changing Paradigm in Heart Transplantation: An Integrative Approach for Invasive and Non-Invasive Allograft Rejection Monitoring

Biomolecules ◽

10.3390/biom11020201 ◽

2021 ◽

Vol 11 (2) ◽

pp. 201

Author(s):

Alessia Giarraputo ◽

Ilaria Barison ◽

Marny Fedrigo ◽

Jacopo Burrello ◽

Chiara Castellani ◽

...

Keyword(s):

Heart Transplantation ◽

Heart Transplant ◽

Allograft Rejection ◽

Exclusion Process ◽

Cardiac Allograft ◽

Molecular Techniques ◽

Integrative Approach ◽

Comprehensive Overview ◽

Cardiac Allograft Rejection ◽

Non Invasive

Cardiac allograft rejection following heart transplantation is challenging to diagnose. Tissue biopsies are the gold standard in monitoring the different types of rejection. The last decade has seen an increased emphasis on identifying non-invasive methods to improve rejection diagnosis and overcome tissue biopsy invasiveness. Liquid biopsy, as an efficient non-invasive diagnostic and prognostic oncological monitoring tool, seems to be applicable in heart transplant follow-ups. Moreover, molecular techniques applied on blood can be translated to tissue samples to provide novel perspectives on tissue and reveal new diagnostic and prognostic biomarkers. This review aims to provide a comprehensive overview of the state-of-the-art of the new methodologies in cardiac allograft rejection monitoring and investigate the future perspectives on invasive and non-invasive rejection biomarkers identification. We reviewed literature from the most used scientific databases, such as PubMed, Google Scholar, and Scopus. We extracted 192 papers and, after a selection and exclusion process, we included in the review 81 papers. The described limitations notwithstanding, this review show how molecular biology techniques and omics science could be deployed complementarily to the histopathological rejection diagnosis on tissue biopsies, thus representing an integrated approach for heart transplant patients monitoring.

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