Anti-EMB monoclonal antibody Made to order

Background. Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs. Methods. We collected 64 routines or clinically indicated EMB from 47 patients after heart transplant. The EMBs were subjected to mRNA sequencing. We conducted weighted gene coexpression network analysis to construct module-derived eigengenes. The modules were assessed by gene ontology enrichment and hub gene analysis. Modules were correlated with the EMBs following the International Society of Heart and Lung Transplantation histology-based criteria and a classification based on GE alone; we also correlated with clinical parameters. Results. The modules enriched with mitochondria-related and immune-response genes showed the strongest correlation to the clinical traits. Compared with the no-rejection samples, rejection samples had a decreased activity of mitochondrial-related genes and an increased activity of immune-response genes. Biologic processes and hub genes in the mitochondria-related modules were primarily involved with energy generation, substrate metabolism, and regulation of oxidative stress. Compared with International Society of Heart and Lung Transplantation criteria, GE-based classification had stronger correlation to the weighted gene coexpression network analysis-derived functional modules. The brain natriuretic peptide level, ImmuKnow, and Allomap scores had negative relationships with the expression of mitochondria-related modules and positive relationships with immune-response modules. Conclusions. During acute cardiac allograft rejection, there was a decreased activity of mitochondrial-related genes, related to an increased activity of immune-response genes, and depressed allograft function manifested by brain natriuretic peptide elevation. This suggests a rejection-associated mitochondrial impairment.

Background: Myocarditis may be self-limited but has been identified as an important contributor to downstream cardiomyopathy. Aldosterone mediates myocardial damage in various conditions, but has not been considered specifically as a therapeutic target for inflammatory damage in acute myocarditis. We sought to demonstrate local aldosterone synthesis in human myocardium affected by acute myocarditis. Methods: We evaluated myocardial samples obtained via endomyocardial biopsy (EMB) for expression of CYP11B2, the final and key enzyme for aldosterone synthesis, from patients with acute myocarditis and from stable heart transplant recipients with no evidence of rejection as negative controls. Excised adrenal glands from patients with aldosterone-secreting adenomas were used as positive controls. An experienced cardiovascular pathologist blinded to clinical information rated CYP11B2 stains as negative, positive, or borderline, also recording location of any CYP11B2-positivity. Results: Sixteen patients' EMB samples showing definite acute myocarditis were identified (50% female). CYP11B2 was positive in 13/16 cases (81%), typically showing diffuse intracardiomyocyte cytoplasmic staining, vs. 2/16 borderline stains in transplant controls (p < 0.001 myocarditis vs. negative controls). All 3 adrenalectomy samples stained positive for CYP11B2 (diffuse intracellular staining). Importantly, no myocarditis or transplant patients were on aldosterone antagonist therapy at the time of biopsy. Conclusions: In this proof-of-concept study, myocardium from patients with acute myocarditis demonstrates evidence and high prevalence of local aldosterone synthesis by immunohistochemistry that showed high accuracy, specificity, and sensitivity. Aldosterone warrants consideration as a specific target for therapy in patients with myocardial damage due to inflammation towards strategies that reduce downstream complications. (c) 2018 Elsevier B.V. All rights reserved.