M Trøseid1,2,3,4,5, T Ueland2,3,4, J R Hov2,3,4,6,7, A Svardal8, I Gregersen2,4, C P Dahl2,9,10, S Aakhus9, E Gude9, B Bjørndal11, B Halvorsen2,3,4, T H Karlsen2,3,4,6,7,12, P Aukrust2,3,4,5, L Gullestad4,8,10,11,13, R K Berge8,11, A Yndestad2,3,4,10. 1. Department of Infectious Diseases, Oslo University Hospital, Ullevål, Norway. 2. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway. 3. K.G. Jebsen Centre for Inflammation Research, Norway. 4. Institute of Clinical Medicine, University of Oslo, Norway. 5. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway. 6. Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital, Norway. 7. Norwegian PSC Research Center, Norway. 8. Department of Clinical Science, University of Bergen, Norway. 9. Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway. 10. Centre for Heart Failure Research, Oslo University Hospital, Norway. 11. Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. 12. Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway. 13. K.G. Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway.
Abstract
OBJECTIVES: Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF. DESIGN: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored. RESULTS: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005). CONCLUSIONS: TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.
OBJECTIVES: Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF. DESIGN: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored. RESULTS: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005). CONCLUSIONS:TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.
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