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. 2021 Sep 7;10(17):e020646.
doi: 10.1161/JAHA.120.020646. Epub 2021 Aug 16.

Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults

Yujin Lee  1   2 , Ina Nemet  3   4 , Zeneng Wang  3   4 , Heidi T M Lai  5 , Marcia C de Oliveira Otto  6 , Rozenn N Lemaitre  7 , Amanda M Fretts  7   8 , Nona Sotoodehnia  7   8 , Matthew Budoff  9 , Joseph A DiDonato  3   4 , Barbara McKnight  7   10 , W H Wilson Tang  3   4   11 , Bruce M Psaty  7   8   12 , David S Siscovick  13 , Stanley L Hazen  4   11 , Dariush Mozaffarian  2
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Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults (VSports注册入口)

Yujin Lee et al. J Am Heart Assoc. .

Abstract

Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time-varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1. 21 (95% CI, 1. 02-1. 42; P-trend=0. 029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1. 07; 95% CI, 0 VSports手机版. 90-1. 27), as well as modified by eGFR (P-interaction <0. 001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1. 73 m2: HR, 1. 56 [95% CI, 1. 13-2. 14]; P-trend=0. 007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1. 73 m2: HR, 1. 03 [95% CI, 0. 85-1. 25]; P-trend=0. 668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1. 25 [95% CI, 1. 01-1. 56]; P-trend=0. 009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD. .

Keywords: animal food; atherosclerotic cardiovascular disease; renal function; trimethylamine N‐oxide. V体育安卓版.

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Conflict of interest statement

Dr Mozaffarian reports research funding from the National Institutes of Health, the Gates Foundation, and the Rockefeller Foundation; personal fees from GOED, Bunge, Indigo Agriculture, Motif FoodWorks, Amarin, Acasti Pharma, Cleveland Clinic Foundation, America's Test Kitchen, and Danone; participating on scientific advisory boards of start‐up companies focused on innovations for health, including Brightseed, DayTwo, Elysium Health, Filtricine, Foodome, HumanCo, and Tiny Organics; and chapter royalties from UpToDate. Drs Hazen and Wang report being named as coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Dr Hazen also reports being a paid consultant for P&G and having received research funds from P&G and Roche Diagnostics; both Drs Hazen and Wang report being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab (a subsidiary of Quest Diagnostics) and P&G V体育ios版. Dr Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

Figures

Figure 1
Figure 1. Multivariable‐adjusted relationship of long‐term levels of log‐transformed trimethylamine N‐oxide with risk of atherosclerotic cardiovascular disease by renal function, with estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 (A) or eGFR ≥60 mL/min per 1.73 m2 (B).
The solid lines and shaded area represent the central risk estimate and 95% CI, respectively. The dotted vertical lines correspond to the 10th, 25th, 50th, 75th, and 90th percentiles. The top and bottom 1% of participants were omitted as outliers to provide better visualization. P values for linear associations are presented. Evidence for nonlinearity was calculated by performing a likelihood ratio test between a multivariable model with all spline terms vs a multivariable model with only the linear term. Significant linearity was found in individuals with eGFR <60 mL/min per 1.73 m2 (P‐linearity=0.01). Estimates were adjusted for potential confounders (see the footnote in Table 2).
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