Abstract- TMAO and Incident Subclinical CVD, Clinical CVD, and Mortality
Trimethylamine-N-oxide (TMAO) is an intestinal microbiome-dependent metabolite of
L-carnitine, a nutrient in red meat, chicken, and fish, and lecithin, a nutrient in eggs, milk, meats
and fish. In in vitro and animal models, TMAO promotes atherosclerosis, independently of
traditional cardiovascular disease (CVD) risk factors. Thus, TMAO represents a novel molecule
that may account for links between diet and CVD and provide a clinically relevant molecular
target for novel interventions to reduce risk.
Yet, the effects of TMAO on CVD risk in humans are not well established, with
mixed evidence from a limited number of prior studies. This research will provide critical
evidence on how TMAO relates to initiation, extent, and onset of atherosclerosis and clinical
CVD in two independent, large, well-established, prospective community-based US cohort
studies: the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study
(CHS). MESA allows prospective investigation of onset of subclinical atherosclerosis (coronary
artery calcium, CAC); and CHS, of clinical CVD events. This will provide robust, complementary
evidence on how TMAO may influence atherosclerotic risk. The large number of health
behaviors, risk factors, and subclinical and clinical disease outcomes in these cohorts will also
facilitate multivariable adjustment as well as analyses related to other subclinical CVD
outcomes.
The inclusion of two separate, large, prospective community-based cohorts of well-
phenotyped US adults, including both middle-aged and older adults of diverse races/ethnicities
with existing standardized measures of sociodemographics, diet, lifestyle, CVD risk factors,
coronary calcium, subclinical CVD, and incident CVD events, will provide the most complete
picture of how TMAO relates to initiation, extent, and clinical onset of CVD, of the independence
of these relationships from other sociodemographic and lifestyle factors, and of possible
heterogeneity in these relationships. The results will have tremendous impact for understanding
whether and how TMAO influences CVD, directly informing the need for and design of large
intervention studies to reduce TMAO levels including novel lifestyle strategies and novel
pharmacologic and molecular interventions targeting both TMAO and the microbiome in
humans.