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. 2014 Nov 4;64(18):1908-14.
doi: 10.1016/j.jacc.2014.02.617. Epub 2014 Oct 27.

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

W H Wilson Tang  1 , Zeneng Wang  2 , Yiying Fan  3 , Bruce Levison  2 , Jennie E Hazen  2 , Lillian M Donahue  2 , Yuping Wu  3 , Stanley L Hazen  4
Affiliations

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

W H Wilson Tang et al. J Am Coll Cardiol. .

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.

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Figures

FIGURE 1
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
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
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
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.
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Comment in

  • Gut feelings about heart failure.
    Cannon JA, McMurray JJ. Cannon JA, et al. J Am Coll Cardiol. 2014 Nov 4;64(18):1915-6. doi: 10.1016/j.jacc.2014.04.088. Epub 2014 Oct 27. J Am Coll Cardiol. 2014. PMID: 25444146 No abstract available.

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