Karolina Skagen1, Marius Trøseid2, Thor Ueland3, Sverre Holm4, Azhar Abbas5, Ida Gregersen6, Martin Kummen7, Vigdis Bjerkeli6, Frode Reier-Nilsen8, David Russell9, Asbjørn Svardal10, Tom Hemming Karlsen11, Pål Aukrust12, Rolf K Berge13, Johannes E R Hov14, Bente Halvorsen15, Mona Skjelland9. 1. Department of Neurology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway. Electronic address: kskagen@ous-hf.no. 2. Institute of Clinical Medicine, University of Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Norway. 3. 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. 4. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Hospital for Rheumatic Diseases, Lillehammer, Norway. 5. Institute of Clinical Medicine, University of Oslo, Norway; Department of Neurology, Østfold Hospital, Norway. 6. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway. 7. 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. 8. Dept of Vascular and Thoracic Surgery, Akershus University Hospital, Norway. 9. Department of Neurology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway. 10. Department of Clinical Science, University of Bergen, Norway. 11. Institute of Clinical Medicine, University of Oslo, Norway; Department of Transplantation Medicine, Section for Gastroenterology, Oslo University Hospital, Oslo, Norway. 12. 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. 13. Department of Clinical Science, University of Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. 14. 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. 15. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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.
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