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

Karolina Skagen; Marius Trøseid; Thor Ueland; Sverre Holm; Azhar Abbas; Ida Gregersen; Martin Kummen; Vigdis Bjerkeli; Frode Reier-Nilsen; David Russell; Asbjørn Svardal; Tom Hemming Karlsen; Pål Aukrust; Rolf K Berge; Johannes E R Hov; Bente Halvorsen; Mona Skjelland

doi:10.1016/j.atherosclerosis.2016.01.033

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

Atherosclerosis. 2016 Apr:247:64-9. doi: 10.1016/j.atherosclerosis.2016.01.033. Epub 2016 Feb 5.

Authors

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

Affiliations

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.

PMID: 26868510
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.

Keywords: Carotid atherosclerosis; Microbiota; Stroke; TMAO; γBB.

MeSH terms

Aged
Betaine / analogs & derivatives*
Betaine / blood
Biomarkers / blood
Carnitine / blood*
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*
Middle Aged
Myocardial Infarction / diagnosis
Myocardial Infarction / mortality*
Prognosis
Proportional Hazards Models
Risk Assessment
Risk Factors
Severity of Illness Index
Stroke / diagnosis
Stroke / mortality*
Ultrasonography, Doppler, Color

Substances

Biomarkers
Methylamines
Betaine
trimethyllysine
gamma-butyrobetaine
trimethyloxamine
Lysine
Carnitine