Affiliation:
1. Department of Food and Nutrition Myongji University Yongin Korea
2. Friedman School of Nutrition Science and Policy Tufts University Boston MA
3. Department of Cardiovascular & Metabolic Sciences Lerner Research Institute Cleveland OH
4. Center for Microbiome and Human Health Cleveland OH
5. Department of Primary Care and Public Health Imperial College London London UK
6. Division of Epidemiology, Human Genetics and Environmental Sciences School of Public Health The University of Texas Health Science Center at Houston (UTHealth) Houston TX
7. Department of Medicine Cardiovascular Health Research UnitUniversity of Washington Seattle WA
8. Department of Epidemiology University of Washington Seattle WA
9. Department of Medicine Lundquist InstituteHarbor UCLA Medical Center Torrance CA
10. Department of Biostatistics University of Washington Seattle WA
11. Department of Cardiovascular Medicine Heart Vascular & Thoracic InstituteCleveland Clinic Cleveland OH
12. Kaiser Permanente Washington Health Research Institute Seattle WA
13. The New York Academy of Medicine New York City NY
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, 0.90–1.27), 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 m
2
: 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 m
2
: 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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
35 articles.
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