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

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.

Association of Trimethylamine, Trimethylamine N-oxide, and Dimethylamine with Cardiovascular Risk in Children with Chronic Kidney Disease

“…Gut microbiota-derived metabolites TMAO, TMA, and DMA from dietary methylamines have recently gained much attention due to their high association with CV risk [8][9][10]29,30]. In the present study, our results are consistent with previous reported data in CKD adults [31,32], showing that TMAO is increased in CKD with a weak inverse correlation (r = −0.283) between plasma TMAO level and eGFR.…”

Hypertension Programmed by Perinatal High-Fat Diet: Effect of Maternal Gut Microbiota-Targeted Therapy

“…Recent evidence reveals microbiota-derived metabolites TMAO and TMA related to cardiovascular disease [16,17], with not always consistent results [43]. Given that dietary factors are associated with plasma concentrations of TMA [16] and that TMAO level is controlled by its synthesis and metabolism, simultaneously measures of the TMAO-to-TMA ratio and the DMA-to-TMAO ratio were expected to reflect a cumulative state of TMAO. In the current study, perinatal HF diet caused the increases of TMA levels in adult offspring.…”

“…The investigation conformed to the Institutional Animal Care and Use Committee of Kaohsiung Chang Gung Memorial Hospital (permit #201721408) that complies with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Twelve virgin Sprague Dawley (SD) rats (12)(13)(14)(15)(16) weeks old) were purchased from BioLASCO Taiwan Co., Ltd. (Taipei, Taiwan). Rats were housed under 12-h light/12-h dark conditions with a relative humidity of 55% in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)-approved animal facility in our hospital.…”

“…TMAO is formed from TMA, which is generated by the metabolism of gut microbiota from dietary precursors (e.g., choline and L-carnitine) [16]. TMAO and TMA can be metabolized to dimethylamine (DMA).…”

“…Several microbial markers have been linked to hypertension, such as an increased Firmicutes to Bacteroidetes (F/B) ratio and a decreased abundance of beneficial microbes [8,9]. Additionally, gut microbiota-derived metabolites short-chain fatty acids (SCFAs), especially acetate, butyrate, and propionate, and trimethylamine N-oxide (TMAO) are involved in the development of hypertension [16][17][18]. The gut microbiota link between the mother and offspring is continued at and after birth by microbes present during delivery as well as postnatal breast milk [19].…”