Plasma and urine metabolomic analyses in aortic valve stenosis reveal shared and biofluid-specific changes in metabolite levels

Abstract

Aortic valve stenosis (AVS) is a prevalent condition among the elderly population that eventually requires aortic valve replacement. The lack of reliable biomarkers for AVS poses a challenge for its early diagnosis and the application of preventive measures. Untargeted gas chromatography mass spectrometry (GC-MS) metabolomics was applied in 46 AVS cases and 46 controls to identify plasma and urine metabolites underlying AVS risk. Multivariate data analyses were performed on pre-processed data (e.g. spectral peak alignment), in order to detect changes in metabolite levels in AVS patients and to evaluate their performance in group separation and sensitivity of AVS prediction, followed by regression analyses to test for their association with AVS. Through untargeted analysis of 190 urine and 130 plasma features that could be detected and quantified in the GC-MS spectra, we identified contrasting levels of 22 urine and 21 plasma features between AVS patients and control subjects. Following metabolite assignment, we observed significant changes in the concentration of known metabolites in urine (n = 14) and plasma (n = 15) that distinguish the metabolomic profiles of AVS patients from healthy controls. Associations with AVS were replicated in both plasma and urine for about half of these metabolites. Among these, 2-Oxovaleric acid, elaidic acid, myristic acid, palmitic acid, estrone, myo-inositol showed contrasting trends of regulation in the two biofluids. Only trans-Aconitic acid and 2,4-Di-tert-butylphenol showed consistent patterns of regulation in both plasma and urine. These results illustrate the power of metabolomics in identifying potential disease-associated biomarkers and provide a foundation for further studies towards early diagnostic applications in severe heart conditions that may prevent surgery in the elderly.

The Potency of Water Clover (<I>Marsilea crenata</I> C. Presl.) Leaves as Anticholesterolemic Functional Foods Through <I>In Silico</I> Study

“…Eucalyptol is a monoterpene oxide that shows antioxidant and anti-inflammatory activity on high cholesterol zebrafish and in rainbow trout that were subjected to crowding stress (Borges et al, 2018;Mirghaed et al, 2018). 2,4-di-tert-butylphenol is a lipophilic phenol that shows antioxidant activity against LDL oxidation; therefore, it has the potential to prevent atherosclerosis and anti-inflammation properties by decreasing TNF-α, interleukin IL-6, and IL-1b expression in rat macrophage cell lines (Al Hageh et al, 2020). Phytol is a diterpene that has antimicrobial, antioxidant, and anticancer properties.…”

High-Throughput Metabolomics Applications in Pathogenesis and Diagnosis of Valvular Heart Disease

“…Considering the proximity to the biologic phenotype, metabolomics holds great potential in objectively measuring and understanding tissue pathophysiological processes, including the impact of multiple genetic, nutritional, and environmental factors. Due to the early pathological changes in metabolic profiles and the technical capabilities to analyse multiple features at once, metabolomics can facilitate in-depth investigations of VHD [ 24 , 25 , 26 , 27 , 28 , 29 ]. Researchers need to decide a priori whether to use targeted or untargeted metabolomics approaches for their studies (Fig.…”

“…The remaining 14 studies were included and reviewed and are summarised in Table 1 (Ref. [ 24 , 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]) and are discussed below.…”

“…Further, a study that compared plasma and urine metabolic profiles reported biomarkers with capabilities of differentiating aortic valve stenosis patients from healthy controls [ 25 ]. It was also one of the few studies that investigated the comparability of different biofluids in their utility as biomaterials for biomarker research [ 25 ].…”

Diabetes Mellitus and Its Implications in Aortic Stenosis Patients

“…Several metabolomics studies have been carried out in recent years and some of these even combined metabolomics and proteomics, highlighting the involvement of inflammation, lipid metabolism, coagulation and haemostasis, extracellular matrix remodelling, and oxidative stress [90,91]. Several studies analysed plasma and urine to define molecular profiles of the disease [92,93], or to obtain information about the effects of valve replacement [94], yet without obtaining prognostic information. A comprehensive metabolomics study was recently published, in which 106 stenotic valves were analysed, demonstrating that the levels of lysophosphatidic acid were correlated with faster hemodynamic progression, permitting patients at risk of a faster progression rate to be selected [95].…”