title: Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study.
abstract: Betaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk?
  
  
  
  Plasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days).
  
  
  
  High and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1-7.1) for death, 4.0 (1.6-9.8) for myocardial infarction, 4.6 (2.0-10.7) for heart failure, 9.1 (2.8-29.7) for unstable angina and 2.0 (1.1-3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6-4.8) and heart failure, HR 1.9 (1.1-3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.
  
  
  
  Elevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand; Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Michael
authors.initials: M
authors.lastname: Lever
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand; Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Peter M
authors.initials: PM
authors.lastname: George
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand; Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Sandy
authors.initials: S
authors.lastname: Slow
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: Bellamy
authors.affiliation: The Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Young
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Markus
authors.initials: M
authors.lastname: Ho
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McEntyre
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Elmslie
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Wendy
authors.initials: W
authors.lastname: Atkinson
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Molyneux
authors.affiliation: The Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Troughton
authors.affiliation: The Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Frampton
authors.affiliation: The Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Chambers
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000150:complications; D000368:Aged; D000369:Aged, 80 and over; D001622:Betaine / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008744:Methylamines / Q000097:blood*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D008744:Methylamines; D001622:Betaine; C005855:trimethyloxamine