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Background  Clinical studies implicate trimethylamine N‐oxide ( TMAO ; a gut microbiota‐dependent nutrient metabolite) in cardiovascular disease risk. There is a lack of population‐based data on the role of  TMAO  in advancing early atherosclerotic disease. We tested the prospective associations between  TMAO  and coronary artery calcium ( CAC ) and carotid intima‐media thickness ( cIMT ).    Methods and Results  Data were from the Coronary Artery Risk Development in Young Adults Study ( CARDIA ), a biracial cohort of  US  adults recruited in 1985–1986 (n=5115). We randomly sampled 817 participants (aged 33–55 years) who attended examinations in 2000–2001, 2005–2006, and 2010–2011, at which  CAC  was measured by computed tomography and  cIMT  (2005–2006) by ultrasound.  TMAO  was quantified using liquid chromotography mass spectrometry on plasma collected in 2000–2001. Outcomes were incident  CAC , defined as Agatston units=0 in 2000–2001 and >0 over 10‐year follow‐up,  CAC  progression (any increase over 10‐year follow‐up), and continuous  cIMT . Over the study period, 25% (n=184) of those free of  CAC  in 2000–2001 (n=746) developed detectable  CAC . In 2000–2001, median (interquartile range)  TMAO  was 2.6 (1.8–4.2) μmol/L. In multivariable‐adjusted models,  TMAO  was not associated with 10‐year  CAC  incidence (rate ratio=1.03; 95%  CI : 0.71–1.52) or  CAC  progression (0.97; 0.68–1.38) in Poisson regression, or  cIMT  (beta coefficient: −0.009; −0.03 to 0.01) in linear regression, comparing the fourth to the first quartiles of TMAO.    Conclusions  In this population‐based study,  TMAO  was not associated with measures of atherosclerosis:  CAC  incidence,  CAC  progression, or  cIMT . These data indicate that  TMAO  may not contribute significantly to advancing early atherosclerotic disease risk among healthy early‐middle‐aged adults.

journal of the american heart association

Microbiota‐Dependent Metabolite Trimethylamine N‐Oxide and Coronary Artery Calcium in the Coronary Artery Risk Development in Young Adults Study ( CARDIA )