title: Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure.
abstract: BACKGROUND
  Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF).
  
  
  RESULTS
  In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) μmol/L, 10.9 (8.4-14.0) μmol/L, and 43.8 (37.1-53.0) μmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03).
  
  
  CONCLUSIONS
  Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.
authors.affiliation: Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: tangw@ccf.org.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shrestha
authors.affiliation: Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Allen G
authors.initials: AG
authors.lastname: Borowski
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, Ohio.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Troughton
authors.affiliation: Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Allan L
authors.initials: AL
authors.lastname: Klein
authors.affiliation: Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000328:Adult; D000368:Aged; D001622:Betaine / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D002794:Choline / Q000378:metabolism; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D054143:Heart Failure, Systolic / Q000175:diagnosis* / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008744:Methylamines / Q000378:metabolism; D064307:Microbiota / Q000502:physiology*; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000378:metabolism*; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D008744:Methylamines; D010713:Phosphatidylcholines; D001622:Betaine; C005855:trimethyloxamine; D002794:Choline
keywords: Intestinal microbiota; diastolic dysfunction; heart failure; trimethylamine-N-oxide