ABSTRACT
Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. These have been linked to the development of heart failure (HF). Circulating biomarkers generated by OS offer potential utility in patient management and therapeutic targeting. Novel OS-related biomarkers such as NADPH oxidases (sNox2-dp, Nrf2), advanced glycation end-products (AGE), and myeloperoxidase (MPO), are signaling molecules reflecting pathobiological changes in HF. This review aims to evaluate current OS-related biomarkers and their associations with clinical outcomes and to highlight those with greatest promise in diagnosis, risk stratification and therapeutic targeting in HF.
ABSTRACT
Background: We aimed to determine primary markers of oxidative stress (OS) in ED patients which predict hospital length of stay (LoS), intensive care unit (ICU) LoS, and sepsis severity. Materials and methods: This prospective, single center observational study was conducted in adult patients recruited from the ED who were diagnosed with either sepsis, infection without sepsis, or non-infectious, age-matched controls. 290 patients were admitted to the hospital and 24 patients had direct admission to the ICU. A panel of 269 OS and related metabolic markers were profiled for each cohort. Clinical outcomes were direct ICU admission, hospital LoS, ICU LoS, and post-hoc, adjudicated sepsis severity scoring. Bonferroni correction was used for pairwise comparisons. Principal component regression was used for dimensionality reduction and selection of plasma metabolites associated with sepsis. Multivariable negative binomial regression was applied to predict admission, hospital, and ICU LoS. Results: Homoarginine (hArg) was the top discriminator of sepsis severity [sepsis vs. control: ROC-AUC = 0.86 (95% CI 0.81-0.91)], [sepsis vs. infection: ROC-AUC = 0.73 (95% CI 0.68-0.78)]. The 25th percentile of hArg [odds ratio (OR) = 8.57 (95% CI 1.05-70.06)] was associated with hospital LoS [IRR = 2.54 (95% CI 1.83-3.52)] and ICU LOS [IRR = 18.73 (95% CI 4.32-81.27)]. In prediction of outcomes, hArg had superior performance compared to arginine (Arg) [hArg ROC-AUC = 0.77 (95% CI 0.67-0.88) vs. Arg ROC-AUC = 0.66 (95% CI 0.55-0.78)], and dimethylarginines [SDMA ROC-AUC 0.68 (95% CI 0.55-0.79) and ADMA ROC-AUC = 0.68 (95% CI 0.56-0.79)]. Ratio of hArg and Arg/NO metabolic markers and creatinine clearance provided modest improvements in clinical prediction. Conclusion: Homoarginine is associated with sepsis severity and predicts hospital and ICU LoS, making it a useful biomarker in guiding treatment decisions for ED patients.
ABSTRACT
BACKGROUND: There is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA). OBJECTIVES: We sought to characterize the transcriptomic and metabolomic profiles of patients with NIUA undergoing aspirin desensitization. METHODS: PBMCs and plasma were separated from the blood of patients with NIUA undergoing aspirin desensitization for coronary artery disease and NSAID-tolerant controls. RNA was isolated from PBMCs and subjected to messenger RNA (mRNA)- and long noncoding RNA (lncRNA)-sequencing. Plasma samples were analyzed using LC-MS/MS for metabolite shifts using a semitargeted metabolomics panel. RESULTS: Eleven patients with NIUA and 10 healthy controls were recruited. The mRNA gene profiles of predesensitization versus postdesensitization and healthy control versus postdesensitization did not differ significantly. However, we identified 739 mRNAs and 888 lncRNAs as differentially expressed from preaspirin desensitization patients and controls. A 12-mRNA gene signature was trained using a machine learning algorithm to distinguish between controls, postdose, and predose samples. Ingenuity Pathway Analysis identified 5 canonical pathways that were significantly enriched in preaspirin desensitization samples. IL-22 was the most upregulated pathway. To investigate the potential regulatory roles of the differentially expressed lncRNA on the mRNAs, 9 lncRNAs and 12 mRNAs showed significantly correlated expression patterns in the IL-22 pathway. To validate the transcriptomics data, IL-22 was measured in the plasma samples of the subjects using ELISA. IL-22 was significantly higher in preaspirin desensitization patients compared with controls. In parallel, metabolomic analysis revealed stark differences in plasma profiles of preaspirin desensitization patients and healthy controls. In particular, 2-hydroxybenzoic acid (salicylic acid) was significantly lower in preaspirin desensitization patients compared with healthy controls. CONCLUSIONS: This is the first study to combine both transcriptomic and metabolomic approaches in patients with NIUA, which contributes to a deeper understanding about the pathogenesis of NIUA and may potentially pave the way toward a molecular diagnosis of NSAID hypersensitivity.
