Machine-learning facilitates selection of a novel diagnostic panel of metabolites for the detection of heart failure.

The metabolic derangement is common in heart failure with reduced ejection fraction (HFrEF). The aim of the study was to check feasibility of the combined approach of untargeted metabolomics and machine learning to create a simple and potentially clinically useful diagnostic panel for HFrEF. The study included 67 chronic HFrEF patients (left ventricular ejection fraction-LVEF 24.3 ± 5.9%) and 39 controls without the disease. Fasting serum samples were fingerprinted by liquid chromatography-mass spectrometry. Feature selection based on random-forest models fitted to resampled data and followed by linear modelling, resulted in selection of eight metabolites (uric acid, two isomers of LPC 18:2, LPC 20:1, deoxycholic acid, docosahexaenoic acid and one unknown metabolite), demonstrating their predictive value in HFrEF. The accuracy of a model based on metabolites panel was comparable to BNP (0.85 vs 0.82), as verified on the test set. Selected metabolites correlated with clinical, echocardiographic and functional parameters. The combination of two innovative tools (metabolomics and machine-learning methods), both unrestrained by the gaps in the current knowledge, enables identification of a novel diagnostic panel. Its diagnostic value seems to be comparable to BNP. Large scale, multi-center studies using validated targeted methods are crucial to confirm clinical utility of proposed markers.

LC-MS-based serum fingerprinting reveals significant dysregulation of phospholipids in chronic heart failure.

Cardiac and extracardiac lipid metabolism is known to be significantly altered in the course of the heart failure with reduced ejection fraction (HF-REF), however the precise mechanisms are not fully elucidated. The aim of the study was to use of untargeted metabolomics to identify and validate changes in the blood metabolites profile, occurring as a result of HF-REF development. The analyses were performed first in the derivation set (36 chronic HF-REF patients and 19 controls without the disease) and repeated in validation cohort (31 chronic HF-REF patients and 20 controls). Independent analyses of both sets revealed statistically significant decline in intensities of phosphatidylcholine (PC): 34:4 and 36:5, lysophosphatidylcholine (lyso-PC): 14:0, 15:0, 18:0, 18:2, 20:3, lysophosphatidylethanolamine (lyso-PE): 18:1 and 18:2 in chronic HF-REF patients. More symptomatic patients and those with ischaemic etiology of HF-REF presented greater deficit in phospholipids (PLs) intensities. The decrease of identified PLs intensities (as compared to controls) correlated with decreased serum cholesterol level, impaired renal function, reduced exercise capacity, enhanced ventilatory response and metabolic parameters associated with altered fatty acids oxidation. In multiple regression analysis PLs deficit was significantly associated with age, carnitines serum intensity, renal function, uric acid, cholesterol level. In conclusion, HF-REF is associated with significant disturbances in phospholipids metabolism. Greater reduction in serum intensities of particular identified PLs is associated with older age, worse clinical condition, impaired oxidative muscle metabolism and enhanced catabolic status.

Absence of mutagenic activity of benorylate, paracetamol and aspirin in the Salmonella/mammalian microsome test.

Benorylate and its two major hydrolysis products, paracetamol and aspirin were examined for mutagenicity in the Salmonella/mammalian microsome screening test. The compounds were tested in 6 strains of Salmonella typhimurium (TA1535, TA1537, TA1538, TA100, TA97 and TA98) in the presence and absence of a rat-liver microsome activation system. Benorylate did not show evidence of mutagenic activity in the 6 strains tested with or without metabolic activation at concentrations ranging from 0.006 to 3 mg per plate. Paracetamol and aspirin likewise did not show any evidence of mutagenic activity at concentrations ranging from 0.1 to 50 mg per plate for the former and 0.01 to 50 mg per plate for the latter.

An in vitro screening test for the assessment of the irritant potential of parenteral formulations.

A HeLa cell/neutral red cytotoxicity assay has been investigated as an in vitro screen for assessing the irritancy potential of parenteral formulations. Five commercially available intramuscular injectables, three irritants and two non-irritants, were examined for cytotoxic effects in this system. The ranking of the injectables tested, in order of decreasing cytotoxic effects, correlated with both previously reported qualitative in vitro data and their reported irritancy when administered to man. The results show that the HeLa cell/neutral red cytotoxicity assay may provide an alternative to animal studies for the assessment of the irritancy potential of parenteral formulations during the preliminary stages of their development.