Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis

Abstract

Background: Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear.

Objectives: This study investigated the potential pathophysiological contributions of intestinal microbiota in HF.

Methods: We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF.

Results: The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001).

Conclusions: High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.

Keywords: C-reactive protein; TMAO; cardiorenal; intestinal microbiota; mortality.

FIGURE 1. Kaplan-Meier estimates of risk of all-cause mortality according to quartiles of plasma levels of TMAO

Kaplan-Meier curves for 5-year all-cause mortality with trimethylamine-N-oxide (TMAO) stratified as quartiles.

FIGURE 2. Relationship between Plasma TMAO Concentration and Mortality Risk Stratified According to Baseline Characteristics

Forest plot of the hazard ratio (squares) of 5-year all-cause mortality risk comparing first and fourth quartiles of fasting plasma TMAO levels. Bars represent 95% confidence intervals. The wide confidence intervals in some subgroups are in part due to their small sample sizes and event rates. CAD = coronary artery disease; eGFR = estimated glomerular filtration rate; hsCRP = high-sensitivity C-reactive protein.

FIGURE 3. Mortality Rates Stratified by Tertiles of BNP and TMAO

Five-year mortality rates according to BNP tertiles and TMAO tertiles. All cohorts were significantly different compared to the reference cohort of BNP <160 pg/ml and TMAO <3.6 μM (all p < 0.01). BNP = B-type natriuretic peptide; other abbreviations as in Figure 1.

CENTRAL ILLUSTRATION. Comparison of fasting TMAO levels between patients with stable heart failure and apparently healthy normal controls

Trimethylamine-N-oxide (TMAO) concentration was higher in patients with stable heart failure than healthy controls and portended poorer survival at higher levels regardless of B-type natriuretic peptide levels. Kaplan-Meier curves for 5-year all-cause mortality with trimethylamine-N-oxide (TMAO) with TMAO/B-type natriuretic peptide (BNP) stratified at median levels.