Trimethylamine N-Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations

Abstract

Background: Growing evidence indicates that trimethylamine N-oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N-oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF).

Methods: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors.

Results: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N-oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; P<0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; P<0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; P<0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (P=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (P<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race.

Conclusions: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine N-oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF.

Registration: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.

Keywords: cardiovascular diseases; carnitine; choline; gastrointestinal microbiome; gut microbiota; heart failure.

Figure 1.. STROBE Diagram for Patient Characteristics.

Abbreviations: CHS = Cardiovascular Health Study; MESA = Multiethnic Study of Atherosclerosis; TMAO = trimethylamine N-oxide; HF = heart failure.

Figure 2.. Restricted cubic spline plots of gut microbial metabolites with incident HF Risk.

Cubic spline plots showing associations between incident HF risk and A) TMAO, B) choline, C) betaine, D) carnitine, E) γ-butyrobetaine, and F) crotonobetaine. The x-axis represents the metabolite concentrations expressed in log scale. The y-axis represents the HR relative to the median metabolite value (reference level). The curves were truncated symmetrically at 2.5th and 97.5th percentiles to represent the middle 95% of the data. The shading represents the 95% confidence interval, and data ranged from 1–97.5th percentiles The dotted lines on each plot represent the thresholds for the 5^th, 25^th, 50^th, 75^th, and 95^th percentile values. All associations were adjusted for age (years), sex (male/female), race (Black vs. other), enrollment site (4–6 sites per study), education (<high school, high school graduate, some college, college graduate) , self-reported annual income (<12k, $12k-24.9k, $25k-49.9k, >$50k), body mass index (kg/m2), smoking status (never/former/current), physical activity (total kcals per week), systolic blood pressure (mmHg), treated hypertension (yes/no), low-density lipoprotein cholesterol (mg/dL), fasting glucose (mg/dL), and prevalent diabetes (yes/no), atrial fibrillation (yes/no), or coronary heart disease (yes/no). P values for nonlinearity were >0.05 for all metabolites. Abbreviations: TMAO = trimethylamine N-oxide; HR = hazard ratio.