Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Bordoni, Laura; Samulak, Joanna J.; Sawicka, Angelika K.; Pelikant‐Małecka, Iwona; Radulska, Adrianna; Lewicki, Łukasz; Kalinowski, Leszek; Gabbianelli, Rosita; Olek, Robert A.

doi:10.1038/s41598-020-75633-1

Cited by 33 publications

(28 citation statements)

References 58 publications

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“…This finding suggests that a reduction of mitochondrial function might occur in individuals that display lower TMA. This is in accordance with our previously published data describing a subtle but significant reduction of TMA in CAD patients with respect to controls, while no significant differences were measured for TMAO between the two groups (Bordoni et al, 2020b).…”

Section: Discussionsupporting

confidence: 93%

“…An increased BMI was also measured in CAD patients with respect to controls (controls: 27.8±4.1; CAD: 28.8±4.5; F=5.18; p=0.023). A detailed comparison of TMA, TMAO, BMI and GFR in the CAD population vs controls in this population has been previously published (Bordoni et al, 2020a).…”

Section: Resultsmentioning

confidence: 99%

“…Plasma TMA and TMAO were determined by the Ultra-Performance Liquid Chromatography (UHPLC) tandem mass spectrometry method, as previously described (Bordoni et al, 2020b).…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial DNA copy number and trimethylamine levels in the blood: new insights on cardiovascular disease biomarkers

Bordoni

Petracci

Pelikant‐Małecka

et al. 2021

Preprint

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Among cardiovascular disease (CVD) biomarkers, the mitochondrial DNA copy number (mtDNAcn) is a promising candidate. A growing attention has been also dedicated to trimethylamine-N-oxide (TMAO), an oxidative derivative of the gut metabolite trimethylamine (TMA). With the aim to identify biomarkers predictive of CVD, we investigated TMA, TMAO and mtDNAcn in a population of 389 coronary artery disease (CAD) patients and 151 healthy controls, in association with established risk factors for CVD (gender, age, hypertension, smoking, diabetes, glomerular filtration rate (GFR)). MtDNAcn was significantly lower in CAD patients and in hypertensive subjects; it correlates with GFR and TMA, but not with TMAO. A biomarker including mtDNAcn, gender, and hypertension (but neither TMA nor TMAO) emerged as a good predictor of CAD. Our findings support the usage of mtDNAcn as a plastic biomarker to monitor the exposure to risk factors and the efficacy of preventive interventions for a personalized CAD risk reduction.Highlights-mtDNAcn measured in whole blood is associated to the cardiovascular health status in humans;-mtDNAcn is reduced in CAD and hypertension, and inversely correlates with GFR;-mtDNA, gender and hypertension together represent a good predictive biomarker for CAD;-TMA metabolism is different in healthy and CAD subjects;-TMA and TMAO are not good predictors of CAD.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Mitochondrial DNA copy number and trimethylamine levels in the blood: new insights on cardiovascular disease biomarkers

Bordoni

Petracci

Pelikant‐Małecka

et al. 2021

Preprint

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“…In our study plasma TMAO was negatively associated with the presence of soft plaque, total plaque burden, and calcified plaque burden in univariate and multivariable models after adjusting for age, sex, and traditional risk factors. Whilst this finding contrasts with some prior studies that have found TMAO is associated with increased incidence of major adverse cardiovascular events in patients with established CAD, peripheral artery disease or chronic kidney disease, it is in keeping with other studies that have not confirmed an association with CAD and have suggested there may be a more nuanced relationship [ 39 , 40 , 41 ]. TMAO is generated through the oxidation of trimethylamine (TMA) by TMA monooxygenase present in some gut microbiota [ 42 ].…”

Section: Discussioncontrasting

confidence: 83%

Metabolic Signatures in Coronary Artery Disease: Results from the BioHEART-CT Study

Vernon

Tang

Kim

et al. 2021

Cells

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Despite effective prevention programs targeting cardiovascular risk factors, coronary artery disease (CAD) remains the leading cause of death. Novel biomarkers are needed for improved risk stratification and primary prevention. To assess for independent associations between plasma metabolites and specific CAD plaque phenotypes we performed liquid chromatography mass-spectrometry on plasma from 1002 patients in the BioHEART-CT study. Four metabolites were examined as candidate biomarkers. Dimethylguanidino valerate (DMGV) was associated with presence and amount of CAD (OR) 1.41 (95% Confidence Interval [CI] 1.12–1.79, p = 0.004), calcified plaque, and obstructive CAD (p < 0.05 for both). The association with amount of plaque remained after adjustment for traditional risk factors, ß-coefficient 0.17 (95% CI 0.02–0.32, p = 0.026). Glutamate was associated with the presence of non-calcified plaque, OR 1.48 (95% CI 1.09–2.01, p = 0.011). Phenylalanine was associated with amount of CAD, ß-coefficient 0.33 (95% CI 0.04–0.62, p = 0.025), amount of calcified plaque, (ß-coefficient 0.88, 95% CI 0.23–1.53, p = 0.008), and obstructive CAD, OR 1.84 (95% CI 1.01–3.31, p = 0.046). Trimethylamine N-oxide was negatively associated non-calcified plaque OR 0.72 (95% CI 0.53–0.97, p = 0.029) and the association remained when adjusted for traditional risk factors. In targeted metabolomic analyses including 53 known metabolites and controlling for a 5% false discovery rate, DMGV was strongly associated with the presence of calcified plaque, OR 1.59 (95% CI 1.26–2.01, p = 0.006), obstructive CAD, OR 2.33 (95% CI 1.59–3.43, p = 0.0009), and amount of CAD, ß-coefficient 0.3 (95% CI 0.14–0.45, p = 0.014). In multivariate analyses the lipid and nucleotide metabolic pathways were both associated with the presence of CAD, after adjustment for traditional risk factors. We report novel associations between CAD plaque phenotypes and four metabolites previously associated with CAD. We also identified two metabolic pathways strongly associated with CAD, independent of traditional risk factors. These pathways warrant further investigation at both a biomarker and mechanistic level.

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“…TMAO has been shown in animal models to up-regulate macrophage receptors associated with atherosclerosis [ 29 ]. Elevated serum concentrations of TMAO have been linked to adverse cardiovascular outcomes in humans [ 29 , 30 ] and TMAO has been identified as a cardiovascular disease risk factor and biomarker in humans [ 31 ]. TMAO is also a product of phospholipid and carnitine metabolism by the intestinal microbiome.…”

Section: Discussionmentioning

confidence: 99%

Dietary Annatto-Extracted Tocotrienol Reduces Inflammation and Oxidative Stress, and Improves Macronutrient Metabolism in Obese Mice: A Metabolic Profiling Study

et al. 2021

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Obesity and its related complications are a world-wide health problem. Dietary tocotrienols (TT) have been shown to improve obesity-associated metabolic disorders, such as hypercholesterolemia, hyperglycemia, and gut dysbiosis. This study examined the hypothesis that the antioxidant capacity of TT alters metabolites of oxidative stress and improves systemic metabolism. C57BL/6J mice were fed either a high-fat diet (HFD control) or HFD supplemented with 800 mg annatto-extracted TT/kg (HFD+TT800) for 14 weeks. Sera from obese mice were examined by non-targeted metabolite analysis using UHPLC/MS. Compared to the HFD group, the HFD+TT800 group had higher levels of serum metabolites, essential amino acids (lysine and methionine), sphingomyelins, phosphatidylcholine, lysophospholipids, and vitamins (pantothenate, pyridoxamine, pyridoxal, and retinol). TT-treated mice had lowered levels of serum metabolites, dicarboxylic fatty acids, and inflammatory/oxidative stress markers (trimethylamine N-oxide, kynurenate, 12,13-DiHOME, and 13-HODE + 9-HODE) compared to the control. The results suggest that TT supplementation lowered inflammation and oxidative stress (oxidized glutathione and GSH/GSSH) and improved macronutrient metabolism (carbohydrates) in obese mice. Thus, TT actions on metabolites were beneficial in reducing obesity-associated hypercholesterolemia/hyperglycemia. The effects of a non-toxic dose of TT in mice support the potential for clinical applications in obesity and metabolic disease.

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Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Cited by 33 publications

References 58 publications

Mitochondrial DNA copy number and trimethylamine levels in the blood: new insights on cardiovascular disease biomarkers

Mitochondrial DNA copy number and trimethylamine levels in the blood: new insights on cardiovascular disease biomarkers

Metabolic Signatures in Coronary Artery Disease: Results from the BioHEART-CT Study

Dietary Annatto-Extracted Tocotrienol Reduces Inflammation and Oxidative Stress, and Improves Macronutrient Metabolism in Obese Mice: A Metabolic Profiling Study

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