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

BACKGROUND: Alterations in the partly microbiota-dependent carnitine-gamma-butyrobetaine (gamma BB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating gamma BB, 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 gamma BB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in gamma BB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in gamma BB 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-gamma BB-TMAO pathway after heart transplant, with increasing levels of gamma BB 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. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.