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


METHODS
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.
Department of Infectious Diseases, Oslo University Hospital, Ullevål, Norway.|Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway.
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M
Trøseid
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.
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Ueland
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.|Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital, Norway.|Norwegian PSC Research Center, Norway.
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JR
Hov
Department of Clinical Science, University of Bergen, Norway.
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A
Svardal
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.
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Gregersen
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway.|Centre for Heart Failure Research, Oslo University Hospital, Norway.
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CP
Dahl
Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway.
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S
Aakhus
Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway.
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E
Gude
Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
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B
Bjørndal
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.
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Halvorsen
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.|Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital, Norway.|Norwegian PSC Research Center, Norway.|Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway.
T H
TH
Karlsen
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway.
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P
Aukrust
Institute of Clinical Medicine, University of Oslo, Norway.|Department of Clinical Science, University of Bergen, Norway.|Centre for Heart Failure Research, Oslo University Hospital, Norway.|Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.|K.G. Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway.
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L
Gullestad
Department of Clinical Science, University of Bergen, Norway.|Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
R K
RK
Berge
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.|K.G. Jebsen Centre for Inflammation Research, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.|Centre for Heart Failure Research, Oslo University Hospital, Norway.
A
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Yndestad
D000368:Aged; D001622:Betaine / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002794:Choline / Q000097:blood*; D002908:Chronic Disease; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D008082:Lipotropic Agents / Q000097:blood*; D008297:Male; D008744:Methylamines / Q000097:blood*; D064307:Microbiota; D008875:Middle Aged; D016877:Oxidants / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D016019:Survival Analysis
D015415:Biomarkers; D008082:Lipotropic Agents; D008744:Methylamines; D016877:Oxidants; D001622:Betaine; C005855:trimethyloxamine; D002794:Choline
gut microbiota; heart failure; nutrition; survival; trimethylamine-N-oxide