The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis

• Published in: Atherosclerosis Vol. 247; pp. 64 - 69
• Main Authors: Skagen, Karolina, Trøseid, Marius, Ueland, Thor, Holm, Sverre, Abbas, Azhar, Gregersen, Ida, Kummen, Martin, Bjerkeli, Vigdis, Reier-Nilsen, Frode, Russell, David, Svardal, Asbjørn, Karlsen, Tom Hemming, Aukrust, Pål, Berge, Rolf K, Hov, Johannes E.R, Halvorsen, Bente, Skjelland, Mona
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.04.2016
• Subjects: Aged; Betaine - analogs & derivatives; Betaine - blood; Biomarkers - blood; Cardiovascular; Carnitine - blood; Carotid atherosclerosis; Carotid Stenosis - blood; Carotid Stenosis - diagnostic imaging; Carotid Stenosis - mortality; Case-Control Studies; Cause of Death; Chromatography, High Pressure Liquid; Female; Humans; Kaplan-Meier Estimate; Lysine - analogs & derivatives; Lysine - blood; Male; Methylamines - blood; Microbiota; Middle Aged; Myocardial Infarction - diagnosis; Myocardial Infarction - mortality; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke; Stroke - diagnosis; Stroke - mortality; TMAO; Ultrasonography, Doppler, Color; γBB; TMAO; Stroke; Microbiota; Carotid atherosclerosis; γBB
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2016.01.033

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.