Plasma Metabolomic Profiling Associates Bicuspid Aortic Valve Disease and Ascending Aortic Dilation with a Decrease in Antioxidant Capacity

Abstract

Background: The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV. Methods: Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and/or aortic stenosis (n = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism. Results: We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve. Discussion: Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.

Specific Multiomic Profiling in Aortic Stenosis in Bicuspid Aortic Valve Disease

“…FCGR2a plays a key role in immune processes and is known to mediate changes in the plasma membrane potential of mitochondria and inflammation [51]. The other two most significant RNAs, SCARNA2 and RNU12, were less abundant but also bibliographically related to mitochondria: SCARNA2 is believed to play a role in the miR-342-3p-EGFR/BCL2 pathway [52], which controls mitochondrial apoptosis, and RNU12 also seems to be associated with altered mitochondrial electron transport in other pathologies [53].…”

Urinary Metabolomics Study of Patients with Bicuspid Aortic Valve Disease

“…In cardiovascular medicine, metabolomics studies have been focused principally on the analysis of human plasma or serum [ 23 , 24 , 25 ]. In the particular case of the bicuspid aortic valve (BAV) defect, the metabolic snapshots generated by metabolomics studies on plasma from BAV subjects have highlighted perturbations in purine metabolism and fatty acid biosynthesis, redox imbalance, and deficient energy production [ 16 , 18 ].…”

“…This approach has provided valuable insight also into the metabolic changes associated with cardiovascular diseases [ 12 ] such as myocardial ischemia [ 13 ] and infarction, coronary artery disease [ 14 ], and heart failure [ 15 ]. To the best of our knowledge, only a few metabolomics studies have been performed to identify metabolic alterations in BAV patients [ 16 , 17 , 18 ] with a special focus on the lipid molecular class, it being the dysregulated lipid metabolism recognized as an established risk factor in cardiovascular diseases [ 19 ].…”

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.…”