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. 2014 Apr;35(14):904-10.
doi: 10.1093/eurheartj/ehu002. Epub 2014 Feb 3.

Prognostic Value of Choline and Betaine Depends on Intestinal Microbiota-Generated Metabolite trimethylamine-N-oxide

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Prognostic Value of Choline and Betaine Depends on Intestinal Microbiota-Generated Metabolite trimethylamine-N-oxide

Zeneng Wang et al. Eur Heart J. .
Free PMC article

Abstract

Aims: Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients.

Methods and results: We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4-6.2)μM, 9.8 (7.9-12.2)μM, and 41.1 (32.5-52.1)μM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74), P < 0.05], and betaine levels [1.33 (1.03-1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated.

Conclusion: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.

Keywords: Cardiovascular disease; Choline; Gut microbiota; Myocardial infarction; Nutrition.

Figures

Figure 1
Figure 1
Kaplan–Meier estimates of freedom from major adverse cardiac events (death, myocardial infarction, or stroke) and plasma levels of choline. Data are shown for 3903 participants in the clinical-outcome study according to quartiles of plasma levels of choline. The P-value is for all comparisons.
Figure 2
Figure 2
Kaplan–Meier estimates of freedom from major adverse cardiac events (death, myocardial infarction, or stroke) and plasma levels of betaine. Data are shown for 3903 participants in the clinical-outcome study according to quartiles of plasma levels of betaine. The P-value is for all comparisons.
Figure 3
Figure 3
Deuterium-labelled trimethylamine-N-oxide production from orally ingested deuterium-labelled choline or betaine in mice and an obligatory role for gut flora in generation of plasma trimethylamine-N-oxide. (A) d9-choline or (B) d9-betaine was administered by gastric gavage in C57BL/6J mice, and plasma levels of d9-trimethylamine-N-oxide were monitored at the indicated times as described under ‘Methods’ section. (D) Plasma concentrations of d9-choline or (E) d9-betaine were determined by LC/MS/MS following oral ingestion of d9-choline or d9-betaine, respectively, as described under ‘Methods’ section. (C and F) d9-trimethylamine-N-oxide production and plasma d9-betaine concentration after oral d9-betaine administration in mice following suppression of gut flora with antibiotics (3 weeks). Data are presented as means ± standard error from two (A and D) and three (B and C, E and F) female mice.
Figure 4
Figure 4
Relationship between plasma choline and betaine concentration and risk for major adverse cardiac events (A). Forest plot of the hazard ratio of major adverse cardiac events (3 year) and quartiles of choline levels both unadjusted (closed circles) and after adjusting for traditional cardiovascular risk factors and high-sensitivity (hs) C-reactive protein (open circles), or traditional cardiovascular risk factors plus hs C-reactive protein and trimethylamine-N-oxide (open squares). (B). Forest plot of the hazard ratio of major adverse cardiac events and quartiles of betaine unadjusted (closed circles) and after adjusting for traditional cardiovascular risk factors and hs C-reactive protein (open circles), or traditional cardiovascular risk factors plus hs C-reactive protein and trimethylamine-N-oxide (open squares). Bars represent 95% confidence intervals.
Figure 5
Figure 5
Relationship between plasma choline concentration and risk for major adverse cardiac events in the context of plasma trimethylamine-N-oxide levels. Kaplan–Meier plot and hazard ratio with 95% confidence intervals for unadjusted model, or following adjustments for traditional risk factors and hs C-reactive protein as in Figure 4A. Median plasma concentration of choline (9.8 μM) and trimethylamine-N-oxide (3.7 μM) within the cohorts were used to stratify subjects as ‘high’ (≥median) or ‘low’ (<median) values.
Figure 6
Figure 6
Relationship between plasma betaine concentration and risk for major adverse cardiac events in the context of plasma trimethylamine-N-oxide levels. Kaplan–Meier plot and hazard ratio with 95% confidence intervals for unadjusted model, or following adjustments for traditional risk factors and C-reactive protein as in Figure 4B. Median plasma concentration of betaine (41.1 μM) and trimethylamine-N-oxide (3.7 μM) within the cohorts were used to stratify subjects as ‘high’ (≥median) or ‘low’ (<median) values.

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