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

Abstract

BackgroundClinical 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 ResultsData 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.ConclusionsIn 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.

Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study

“…Findings from a recent study, including 817 participants of the CARDIA (Coronary Artery Risk Development in Young Adults), followed up for 10 years, showed that TMAO was not associated with coronary artery calcium incidence or other measures of CVD risk, including insulin resistance, inflammatory markers, and lipid profile. The authors suggest that it is possible that the adverse effect of TMAO may be more relevant when concentrations of TMAO are higher than in their sample or in later stages of the disease process . In another study comparing the concentrations of TMAO, carnitine, and choline in 34 obese individuals undergoing bariatric surgery, TMAO was not elevated in obese patients before the surgery but increased ≈2‐fold after bariatric surgery .…”

“…This evidence suggests that diet could modulate intestinal microbiota composition and, subsequently, the ability to synthesize trimethylamine and TMAO, thus providing a mechanistic link between diet, gut microbiome, and atherosclerosis . However, not all human studies have confirmed the association between TMAO and cardiovascular events . Indeed, the relation between plasma concentration of choline pathway metabolites and the incidence of hard CVD end points in a population‐based level and the role that diet may play in these associations remain to be elucidated.…”

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

“…Experimental work with atherosclerotic prone ApoE −/− mice on an L-carnitine-rich diet, elevating plasma TMAO levels, correlated with a reduced atherosclerotic lesion size in the aortic root and the thoragic aorta [111]. In addition, TMAO was not found to contribute significantly to advancing early atherosclerotic disease risk among healthy early-middle-aged adults [112]. Therefore, further studies are clearly needed to explore the microbiome of patients with CVD and to determine whether microbiota-derived TMAO promotes atherosclerosis development.…”

Trimethylamine N‐oxide: breathe new life

“…In this population‐based study, TMAO did not show an association with measures of atherosclerosis such as CAC incidence, CAC progression or cIMT. These data indicate that TMAO may not contribute significantly to the progression of early atherosclerotic disease risk among healthy early–middle‐aged adults (Meyer et al, ). TMAO promotes the early pathological process of atherosclerosis by accelerating endothelial activation and dysfunction, including decreasing endothelial self‐repair and increasing monocyte adhesion by activation of a PKC/NF‐κB/vascular cell adhesion molecule 1 (VCAM‐1) pathway; (Ma et al, ).…”