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J Heart Lung Transplant. 2019 Jun 19. pii: S1053-2498(19)31545-1. doi: 10.1016/j.healun.2019.06.003. [Epub ahead of print]

The carnitine-butyrobetaine-TMAO pathway after cardiac transplant: Impact on cardiac allograft vasculopathy and acute rejection.

Author information

1
Research Institute of Internal Medicine; Section of Clinical Immunology and Infectious Diseases; Norwegian PSC Research Center and Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: marius.troseid@medisin.uio.no.
2
Research Institute of Internal Medicine; K.G. Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
3
Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
4
Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
5
Department of Clinical Sciences, University of Bergen, Bergen, Norway.
6
Research Institute of Internal Medicine; Norwegian PSC Research Center and Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
7
Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
8
Department of Clinical Sciences, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
9
Research Institute of Internal Medicine; Section of Clinical Immunology and Infectious Diseases; K.G. Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway.
10
Research Institute of Internal Medicine; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway.

Abstract

BACKGROUND:

Alterations in the partly microbiota-dependent carnitine-γ-butyrobetaine (γBB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection.

METHODS:

We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound.

RESULTS:

Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant.

CONCLUSIONS:

Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.

KEYWORDS:

TMAO; acute rejection; allograft vasculopathy; gut microbiota; metabolites

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