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      TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology

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          Abstract

          Trimethylamine-N-oxide (TMAO) has been suggested as a marker and mediator of cardiovascular diseases. However, data are contradictory, and the mechanisms are obscure. Strikingly, the role of the TMAO precursor trimethylamine (TMA) has not drawn attention in cardiovascular studies even though toxic effects of TMA were proposed several decades ago. We assessed plasma TMA and TMAO levels in healthy humans (HH) and cardiovascular patients qualified for aortic valve replacement (CP). The cytotoxicity of TMA and TMAO in rat cardiomyocytes was evaluated using an MTT test. The effects of TMA and TMAO on albumin and lactate dehydrogenase (LDH) were assessed using fluorescence correlation spectroscopy. In comparison to HH, CP had a two-fold higher plasma TMA ( p < 0.001) and a trend towards higher plasma TMAO ( p = 0.07). In CP plasma, TMA was inversely correlated with an estimated glomerular filtration rate (eGFR, p = 0.002). TMA but not TMAO reduced cardiomyocytes viability. Incubation with TMA but not TMAO resulted in the degradation of the protein structure of LDH and albumin. In conclusion, CP show increased plasma TMA, which is inversely correlated with eGFR. TMA but not TMAO exerts negative effects on cardiomyocytes, likely due to its disturbing effect on proteins. Therefore, TMA but not TMAO may be a toxin and a marker of cardiovascular risk.

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          Most cited references33

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          Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure.

          Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF.
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            Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.

            Echocardiography is the key tool for the diagnosis and evaluation of aortic stenosis. Because clinical decision-making is based on the echocardiographic assessment of its severity, it is essential that standards are adopted to maintain accuracy and consistency across echocardiographic laboratories. Detailed recommendations for the echocardiographic assessment of valve stenosis were published by the European Association of Echocardiography and the American Society of Echocardiography in 2009. In the meantime, numerous new studies on aortic stenosis have been published with particular new insights into the difficult subgroup of low gradient aortic stenosis making an update of recommendations necessary. The document focuses in particular on the optimization of left ventricular outflow tract assessment, low flow, low gradient aortic stenosis with preserved ejection fraction, a new classification of aortic stenosis by gradient, flow and ejection fraction, and a grading algorithm for an integrated and stepwise approach of artic stenosis assessment in clinical practice.
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              Trimethylamine N-Oxide: The Good, the Bad and the Unknown

              Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.
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                Author and article information

                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                26 August 2019
                September 2019
                : 11
                : 9
                : 490
                Affiliations
                [1 ]Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-106 Warsaw, Poland
                [2 ]Department of Hypertension and Diabetology, Medical University of Gdansk, 80-211 Gdansk, Poland
                [3 ]Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
                [4 ]Department of Soft Condensed Matter, Institute of Physical Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
                [5 ]1st Chair and Department of Cardiology, Medical University of Warsaw, 02-106 Warsaw, Poland
                Author notes
                [* ]Correspondence: mufnal@ 123456wum.edu.pl ; Tel.: +48-221-166-195
                Author information
                https://orcid.org/0000-0002-0281-015X
                https://orcid.org/0000-0003-4649-9524
                https://orcid.org/0000-0002-7519-2532
                https://orcid.org/0000-0002-1111-1748
                https://orcid.org/0000-0003-0088-8284
                Article
                toxins-11-00490
                10.3390/toxins11090490
                6784008
                31454905
                b4c5e6e9-55d4-4398-88d9-b0634c6550f5
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 August 2019
                : 23 August 2019
                Categories
                Article

                Molecular medicine
                trimethylamine,tmao,bacterial metabolites,biomarkers
                Molecular medicine
                trimethylamine, tmao, bacterial metabolites, biomarkers

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