Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate

Abstract

There is intense interest in the identification of novel biomarkers which improve the diagnosis of heart failure. Serum samples from 52 patients with systolic heart failure (EF < 40% plus signs and symptoms of failure) and 57 controls were analyzed by gas chromatography -time of flight -mass spectrometry and the raw data reduced to 272 statistically robust metabolite peaks. 38 peaks showed a significant difference between case and control (p < 5·10 )5 ). Two such metabolites were pseudouridine, a modified nucleotide present in t-and rRNA and a marker of cell turnover, as well as the tricarboxylic acid cycle intermediate 2-oxoglutarate. Furthermore, 3 further new compounds were also excellent discriminators between patients and controls: 2-hydroxy, 2-methylpropanoic acid, erythritol and 2,4,6-trihydroxypyrimidine. Although renal disease may be associated with heart failure, and metabolites associated with renal disease and other markers were also elevated (e.g. urea, creatinine and uric acid), there was no correlation within the patient group between these metabolites and our heart failure biomarkers, indicating that these were indeed biomarkers of heart failure and not renal disease per se. These findings demonstrate the power of data-driven metabolomics approaches to identify such markers of disease.

Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure: A Scientific Statement From the American Heart Association

“…A study of 52 patients with HF and 57 controls demonstrated differences in pseudouridine (modified nucleotide), 2-oxoglutarate (tricarboxylic acid cycle), 2-hydroxy 2-methylpropanoic acid, erythritol (a sugar alcohol), and 2,4,6-trihydroxypyrimidine between cases and controls. 274 Another study examined differences in urinary metabolites between HF cases and controls (n=15 and 20, respectively). 275 Urinary acetate and acetone were nominally higher in cases.…”

Metabolomic does not predict response to cardiac resynchronization therapy in patients with heart failure

“…In the study by Lin et al, 26 who used the same techniques as our study, the metabolomic fingerprint was characterized by higher levels of acetoacetate and urea and by lower levels of threonine, glycine, ethanol, histidine, alanine and tyrosine, results which were significantly different from our heart failure patient population. In the study by Dunn et al, 27 who employed gas chromatography and mass spectrometry, pseudopurine and 2-oxoglutarate were identified as two good indicators of heart failure. These metabolites were different from those reported by Lin et al and in our studies.…”

“…These metabolites were different from those reported by Lin et al and in our studies. These results could be due to the different characteristics of patients investigated (Lin et al 26 analyzed end-stage heart failure patients just before transplantation) or to the different samples analysis technique performed (Dunn et al 27 used gas chromatography). It is possible to affirm that metabolomic approach is able to identify a fingerprint characterizing heart failure patients, but a univocal and reproducible pattern is still not emerged in the literature.…”

Metabolome-Wide Association Study of Primary Open Angle Glaucoma

“…Importantly, greater than 90% of the KEGG metabolites have distinct elemental composition 13 so that they can be measured based upon the accurate mass and mass resolution without requiring ion dissociation. [14][15][16] Metabolomic analysis of serum and plasma has revealed panels of metabolites that distinguish patients with cardiovascular disease, 17 breast cancer, 18,19 Parkinson disease, 20 and diabetes 21 from control patients. This technique is able to differentiate between individuals despite intraindividual variation due to factors such as dietary intake.…”