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Cited by 464Gut microbiota and healthHeart Failure Treatment and ManagementSepsis Diagnosis and Treatment

Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure

Open access
Trøseid, M., Ueland, T., Hov, J. R., Svardal, A., Gregersen, I., Dahl, C. P., Aakhus, S., Gude, E. +7 more·2015·Journal of Internal Medicine
DOI 10.1111/joim.12328
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Abstract

Objectives: Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine‐N‐oxide (TMAO), a microbiota‐dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF. Design: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant‐free survival in the patients with HF were explored. Results: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant‐free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow‐up (unadjusted Cox‐regression: hazard ratio 2.24, 95% confidence interval 1.28–3.92, P = 0.005). Conclusions: TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.

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Registry

Crossref · 10.1111/joim.12328

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 6 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Plasma TMAO levels are elevated in patients with chronic heart failure compared with healthy control subjects (P = 0.01).

    “Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects”
    Quote in the paperSubstantial claim
  • Findingown data

    The association between TMAO and transplant-free survival was attenuated and no longer significant after forced multivariable adjustment (HR 1.79, 95% CI 0.90-1.79, P = 0.097).

    “However, this association was attenuated and no longer significant after forced multivariable adjustment for covariates as described in the Methods (HR 1.79, 95% CI 0.90-1.79,P = 0.097).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The set of covariates included in the multivariable Cox regression is sufficient to control for confounding of the association between TMAO and survival.
  • Findingown data

    TMAO levels are highest in patients with ischaemic heart failure, followed by those with stable coronary artery disease and then nonischaemic heart failure.

    “Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Plasma betaine levels are elevated in patients with chronic heart failure compared with healthy control subjects (P < 0.001).

    “Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects”
    Quote in the paperNot a substantial claim
  • Findingown data

    Betaine, but not TMAO or choline, is positively associated with CRP level.

    “Finally, betaine, but not TMAO and choline, was positively associated with CRP level.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 20

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    TMAO and choline, but not betaine, are positively associated with age.

    “Thirdly, TMAO and choline, but not betaine, were positively associated with age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TMAO, but not choline or betaine, is associated with reduced transplant-free survival in patients with chronic heart failure.

    “TMAO, but not choline or betaine, was associated with reduced transplant-free survival”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TMAO, but not choline or betaine, is associated with previous myocardial infarction.

    “Secondly, TMAO, but not choline or betaine, was associated with previous MI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TMAO, choline, and betaine are positively correlated with NT-proBNP and negatively correlated with eGFR in patients with heart failure.

    “TMAO, choline and betaine were all positively correlated with levels of NT-proBNP (a marker of cardiac haemodynamic stress) and negatively with renal function, as assessed by eGFR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Choline and betaine, but not TMAO, are positively associated with right atrial pressure and E/A ratio, and negatively correlated with cardiac output.

    “choline and betaine, but not TMAO, were positively associated with right atrial pressure and E/A ratio, and negatively correlated with cardiac output”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All three metabolites (TMAO, choline, betaine) are correlated with increased pulmonary capillary wedge pressure and mean pulmonary artery pressure, with stronger correlations for choline and betaine than TMAO.

    “All markers were correlated with increased pulmonary capillary wedge pressure and mean pulmonary artery pressure, but the correlation coefficients were stronger for choline and betaine compared to TMAO (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Choline and betaine, but not TMAO, are negatively correlated with estimated cardiac output and positively correlated with mean right atrial pressure and E/A ratio.

    “Furthermore, choline and betaine, but not TMAO, were negatively correlated with estimated cardiac output and positively correlated with mean right atrial pressure and E/A ratio (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Betaine levels are negatively correlated with plasma LPS and BMI.

    “Betaine levels were in fact negatively correlated with plasma LPS as well as BMI”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is a positive association between TMAO levels and plasma carnitine levels in the heart failure patient group (r = 0.24, P = 0.003), which is not significant in the coronary artery disease group without heart failure (r = 0.16, P = 0.106).

    “we found a positive association between TMAO levels and plasma levels of carnitine in the HF patient group (r = 0.24, P = 0.003), which was not significant in the CAD group without HF (r = 0.16, P = 0.106).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is no correlation between LPS levels and choline or TMAO, and there is an inverse relationship between LPS and betaine (r = -0.20, P = 0.01).

    “There was, however, no correlation between levels of LPS and choline or TMAO (r = 0.02 and r = 0.01, respectively), and there was an inverse relationship with betaine levels (r = À0.20,P = 0.01).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TMAO levels in patients with heart failure of ischaemic origin are significantly raised compared with patients with dilated cardiomyopathy and compared with those with stable coronary artery disease.

    “However, TMAO levels in patients with HF of ischaemic origin were significantly raised not only compared to patients with DCM but also compared to those with stable CAD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    None of TMAO, choline, or betaine is associated with hypertension, type 2 diabetes, or current smoking.

    “None of the metabolites was associated with hypertension, type 2 diabetes or current smoking.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elevated TMAO levels strongly predict coronary artery disease, at least partly because increased TMAO enhances atherogenesis.

    “Recent studies have shown that elevated TMAO levels strongly predict coronary artery disease (CAD), at least partly reflecting the ability of increased levels to enhance atherogenesis [6][7][8]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6][7][8]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO is produced in the liver from TMA, and TMA is generated exclusively by gut microbiota from dietary phosphatidylcholine, choline, and carnitine.

    “Trimethylamine-N-oxide (TMAO) is formed in the liver from trimethylamine (TMA), which is exclusively generated by the gut microbiota from dietary phosphatidylcholine, choline and carnitine [6][7][8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6][7][8]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TMAO can also be produced from betaine, which is an oxidation product of choline.

    “TMAO may also be generated from betaine, which is an oxidation product of choline [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The prognostic value of choline and betaine depends on a simultaneous elevation of TMAO levels.

    “whereas the prognostic values of choline and betaine depend on concomitant elevation of TMAO levels, suggesting links between alterations of the microbiota, dietary composition and atherosclerosis [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was approved by the regional committee for ethics in medicine and conducted according to the Declaration of Helsinki.

    “The study was approved by the regional committee for ethics in medicine and conducted according to the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No information was available from patient records about the possibility of excessive intake of vitamins, fish oils, antioxidants, or micronutrients.

    “No information was available from the patient records of the possibility of excessive intake of vitamins, fish oils, antioxidants or micronutrients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Myocardial failure is probably also involved in elevated TMAO levels, and the combination of heart failure and an ischaemic aetiology seems particularly important.

    “Hence, although an ischaemic aetiology seems to contribute to the elevated TMAO levels, myocardial failure is probably also involved, and the combination of HF and an ischaemic aetiology seems to be particularly important.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Informed consent was obtained from all individuals.

    “Informed consent was obtained from all individuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A strict and standardized blood sampling protocol with similar conditions for all patients and control subjects was used.

    “although we used a strict and standardized blood sampling protocol with similar conditions for all patients and control subjects, the use of nonfasting samples is a limitation of this study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    All three markers (TMAO, choline, betaine) are correlated with clinical, haemodynamic, and neurohormonal disease severity, but only TMAO levels are associated with adverse outcomes during follow-up.

    “All three markers were correlated with clinical, haemodynamic and neurohormonal disease severity, but only TMAO levels were associated with adverse outcomes during follow-up.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Multicolinearity in the regression models was evaluated by examining tolerance and variance inflation factor; tolerance was >0.4 and VIF <2.5 for all independent variables.

    “Multicolinearity in the regression models was evaluated by examining the tolerance and variance inflation factor (VIF) in linear regression.The tolerance was >0.4 and the VIF <2.5 for all independent variables.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The study data show that circulating TMAO levels are elevated in patients with chronic heart failure and are associated with disease severity, ischaemic aetiology, and reduced survival.

    “In conclusion, the study data show that circulating levels of the microbiota-dependent metabolite TMAO were elevated in patients with chronic HF, and associated with disease severity, ischaemic aetiology and reduced survival.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 155 patients with chronic heart failure included in the study are representative of the broader population of patients with chronic heart failure.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genetic variation seems to play a minor role in determining circulating levels of TMAO.

    “genetic variation seems to play a minor role in determining the circulating levels of TMAO [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study sample size was relatively small, which limits the ability to draw conclusions from multivariate analyses.

    “Finally, the study sample size was relatively small, which limits our ability to draw conclusions from multivariate analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The possibility that dietary differences in intake or the use of antibiotics could have influenced the data cannot be excluded.

    “we cannot exclude the possibility that dietary differences in intake or the use of antibiotics could have influenced our data.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A predefined composite end-point consisting of all-cause and anticipated mortality (heart transplantation) was used in the analyses.

    “A predefined composite end-point consisting of allcause and anticipated mortality [i.e.heart transplantation (HTx)] was used in the analyses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    A large number of correlation analyses were performed, and they should therefore be interpreted with caution.

    “Thirdly, a large number of correlation analyses were performed, and should therefore be interpreted with caution.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The use of nonfasting samples is a limitation of the study.

    “the use of nonfasting samples is a limitation of this study.”
    Quote in the paperNot a substantial claim
30 of 30

  • The authors state this as an assumption.

    The association between TMAO levels and disease severity in patients with heart failure had not been investigated before this study.

    “At present, to our knowledge, the association between TMAO levels and disease severity in patients with HF has not been investigated.”

  • The paper relies on this without support.

    The 155 patients with chronic heart failure included in the study are representative of the broader population of patients with chronic heart failure.

    “A total of 155 consecutive patients with stable HF for >6 months, in New York Heart Association (NYHA) functional class II-IV, were included in the study at the Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway (Table 1).”

  • The paper relies on this without support.

    The set of covariates included in the multivariable Cox regression is sufficient to control for confounding of the association between TMAO and survival.

    “Cox proportional hazard analysis was used to estimate hazard ratios with a forced and stepwise method including NYHA class, age, hypertension, type 2 diabetes, HF aetiology, eGFR, CRP and NT-proBNP.”
3 of 3

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Cites

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Research works printed but not linked: 21

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Cited by

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Authors
Trøseid, M., Ueland, T., Hov, J. R., Svardal, A., Gregersen, I., Dahl, C. P., Aakhus, S., Gude, E., Bjørndal, B., Halvorsen, B., Karlsen, T. H., Aukrust, P., Gullestad, L., Berge, R. K., & Yndestad, A.
Affiliations
  • Oslo University Hospital (NO)
  • University of Bergen (NO)
  • Haukeland University Hospital (NO)
Corresponding author
Trøseid, M.
ORCID
Venue
Journal of Internal Medicine
Publisher
Wiley
Published
2014-12
Volume
277
Issue
6
Pages
717-726
ISSN
  • 0954-6820 (ISSN-L)
  • 1365-2796
DOI
10.1111/joim.12328
OpenAlex
W1991855600
Cited by
464
References
5
Citations by year
2026: 19 · 2025: 32 · 2024: 33 · 2023: 47 · 2022: 69 · 2021: 48 · 2020: 45 · 2019: 51 · 2018: 37 · 2017: 41 · 2016: 26 · 2015: 15
FWCI
11.14
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Internal Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • K.G. Jebsen Centre for Inflammation Research
  • Western Norway Regional Health Authority (911802)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
trimethylamine N-oxide, gut microbiota, chronic heart failure, choline, betaine, transplant-free survival, disease severity, ischemic heart failure, coronary artery disease, prognostic factors, atherosclerosis, L-carnitine
MeSH terms
Aged, Betaine, Choline, Chronic Disease, Female, Heart Failure, Humans, Intestinal Mucosa, Intestines, Lipotropic Agents, Male, Methylamines, Middle Aged, Predictive Value of Tests, Prognosis, Prospective Studies, Risk Factors, Sensitivity and Specificity, Severity of Illness Index, Biomarkers, Survival Analysis, Oxidants, Risk Assessment, Microbiota

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