Sanchez-Gimenez Raul, Peiró Óscar M, Bonet Gil, Carrasquer Anna, Fragkiadakis Georgios A, Bulló Mònica, Papandreou Christopher, Bardaji Alfredo
Department of Cardiology, Joan XXIII University Hospital, Tarragona, Spain.
Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain.
Front Cardiovasc Med. 2022 Sep 21;9:1000815. doi: 10.3389/fcvm.2022.1000815. eCollection 2022.
To examine associations of the gut microbial metabolite trimethylamine-N-oxide (TMAO) and its precursors with risk of cardiovascular events in acute coronary syndrome (ACS), and determine whether these associations were mediated by renal function.
In this prospective cohort study, we included 309 patients with ACS. During a mean follow-up of 6.7 years, 131 patients developed major adverse cardiovascular events (MACE) (myocardial infarction, hospitalization for heart failure, and all-cause mortality). Plasma concentrations of TMAO, trimethylamine (TMA), choline, betaine, dimethylglycine and L-carnitine were profiled by liquid chromatography tandem mass spectrometry. Hazard ratios were estimated with multivariable Cox regression models. The mediating role of estimated glomerular filtration rate (eGFR) was tested under a counterfactual framework.
After adjustment for traditional cardiovascular risk factors and medications, participants in the highest tertile vs. the lowest tertile of baseline TMAO and dimethylglycine concentrations had a higher risk of MACE [(HR: 1.83; 95% CI: 1.08, 3.09) and (HR: 2.26; 95% CI: 1.17, 3.99), respectively]. However, with regards to TMAO these associations were no longer significant, whereas for dimethylglycine, the associations were attenuated after additional adjustment for eGFR. eGFR mediated the associations of TMAO (58%) and dimethylglycine (32%) with MACE incidence. The associations between dimethylglycine and incident MACE were confirmed in an internal validation. No significant associations were found for TMA, choline, betaine and L-carnitine.
These findings suggest that renal function may be a key mediator in the association of plasma TMAO with the development of cardiovascular events after ACS. The present findings also support a role of dimethylglycine in the pathogenesis of MACE, which may be mediated, at least partially, by renal function.
研究肠道微生物代谢产物氧化三甲胺（TMAO）及其前体与急性冠状动脉综合征（ACS）患者心血管事件风险的关联，并确定这些关联是否由肾功能介导。
在这项前瞻性队列研究中，我们纳入了309例ACS患者。在平均6.7年的随访期间，131例患者发生了主要不良心血管事件（MACE）（心肌梗死、因心力衰竭住院和全因死亡）。通过液相色谱串联质谱法分析血浆中TMAO、三甲胺（TMA）、胆碱、甜菜碱、二甲基甘氨酸和左旋肉碱的浓度。采用多变量Cox回归模型估计风险比。在反事实框架下测试估计肾小球滤过率（eGFR）的中介作用。
在调整传统心血管危险因素和药物后，基线TMAO和二甲基甘氨酸浓度处于最高三分位数组的参与者与最低三分位数组相比，发生MACE的风险更高[分别为（HR：1.83；95%CI：1.08，3.09）和（HR：2.26；95%CI：1.17，3.99）]。然而，就TMAO而言，这些关联不再显著，而对于二甲基甘氨酸，在进一步调整eGFR后，关联减弱。eGFR介导了TMAO（58%）和二甲基甘氨酸（32%）与MACE发生率的关联。二甲基甘氨酸与新发MACE之间的关联在内部验证中得到证实。未发现TMA、胆碱、甜菜碱和左旋肉碱有显著关联。
这些发现表明，肾功能可能是血浆TMAO与ACS后心血管事件发生之间关联的关键中介因素。本研究结果还支持二甲基甘氨酸在MACE发病机制中的作用，这可能至少部分由肾功能介导。
