title: The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis.
abstract: OBJECTIVE
  γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome.
  
  
  METHODS
  Serum γBB, Carnitine, TML and TMAO were quantified by high performance liquid chromatography in patients with carotid artery atherosclerosis (n = 264) and healthy controls (n = 62).
  
  
  RESULTS
  Serum γBB (p = 0.024) and Carnitine (p = 0.001), but not TMAO or TML, were increased in patients with carotid atherosclerosis. Higher levels of γBB and TML, but not TMAO or Carnitine were independently associated with cardiovascular death also after adjustment for age and eGFR (adjusted HR [95%] 3.3 [1.9-9.1], p = 0.047 and 6.0 [1.8-20.34], p = 0.026, respectively).
  
  
  CONCLUSIONS
  Patients with carotid atherosclerosis had increased serum levels of γBB, and elevated levels of γBB and its precursor TML were associated with cardiovascular mortality. Long-term clinical studies of γBB, as a cardiovascular risk marker, and safety studies regarding dietary supplementation of γBB, are warranted.
authors: Department of Neurology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway. Electronic address: kskagen@ous-hf.no.
authors: Karolina
authors: K
authors: Skagen
authors: Institute of Clinical Medicine, University of Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Norway.
authors: Marius
authors: M
authors: Trøseid
authors: Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; K.G.Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
authors: Thor
authors: T
authors: Ueland
authors: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Hospital for Rheumatic Diseases, Lillehammer, Norway.
authors: Sverre
authors: S
authors: Holm
authors: Institute of Clinical Medicine, University of Oslo, Norway; Department of Neurology, Østfold Hospital, Norway.
authors: Azhar
authors: A
authors: Abbas
authors: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway.
authors: Ida
authors: I
authors: Gregersen
authors: Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; K.G. Jebsen Inflammatory Research Center, Norway; Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Norway.
authors: Martin
authors: M
authors: Kummen
authors: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway.
authors: Vigdis
authors: V
authors: Bjerkeli
authors: Dept of Vascular and Thoracic Surgery, Akershus University Hospital, Norway.
authors: Frode
authors: F
authors: Reier-Nilsen
authors: Department of Neurology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
authors: David
authors: D
authors: Russell
authors: Department of Clinical Science, University of Bergen, Norway.
authors: Asbjørn
authors: A
authors: Svardal
authors: Institute of Clinical Medicine, University of Oslo, Norway; Department of Transplantation Medicine, Section for Gastroenterology, Oslo University Hospital, Oslo, Norway.
authors: Tom Hemming
authors: TH
authors: Karlsen
authors: Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Norway; K.G. Jebsen Inflammatory Research Center, Norway; K.G.Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
authors: Pål
authors: P
authors: Aukrust
authors: Department of Clinical Science, University of Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
authors: Rolf K
authors: RK
authors: Berge
authors: Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Norway; Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Norway; K.G.Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
authors: Johannes E R
authors: JE
authors: Hov
authors: Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; K.G. Jebsen Inflammatory Research Center, Norway.
authors: Bente
authors: B
authors: Halvorsen
authors: Department of Neurology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
authors: Mona
authors: M
authors: Skjelland
mesh_terms: D000368:Aged; D001622:Betaine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002331:Carnitine / Q000097:blood*; D016893:Carotid Stenosis / Q000097:blood* / Q000000981:diagnostic imaging / Q000401:mortality; D016022:Case-Control Studies; D002423:Cause of Death; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D008744:Methylamines / Q000097:blood*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000401:mortality*; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke / Q000175:diagnosis / Q000401:mortality*; D018615:Ultrasonography, Doppler, Color
chemical_list: D015415:Biomarkers; D008744:Methylamines; D001622:Betaine; C003712:trimethyllysine; C002889:gamma-butyrobetaine; C005855:trimethyloxamine; D008239:Lysine; D002331:Carnitine
keywords: Carotid atherosclerosis; Microbiota; Stroke; TMAO; γBB