Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure

Abstract

Objectives. Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiotadependent 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.

Structure and Function of CutC Choline Lyase from Human Microbiota Bacterium Klebsiella pneumoniae

“…The association of the microbiota with diseases such as cancer (31), diabetes (32), and cardiovascular diseases (33) has been demonstrated. TMAO is a metabolite created in the host liver from microbiota-produced TMA, and it has been associated with several diseases (3)(4)(5)(6)(7)(8)(9)(10). TMA production in the intestine can be suppressed by antibiotics (34,35), but this effect is not complete, and long-term antibiotic treatment may lead to an imbalance in the microbiota (36).…”

“…High levels of TMAO, which are produced from choline (6) and carnitine (3) with the assistance of the intestinal microflora, have been shown to be a cause of atherosclerosis in mice. Studies with human volunteers (3,7) have confirmed TMA production from carnitine and choline by the intestinal microflora, and clinical data cross-examinations have associated high levels of TMAO with an elevated risk of atherosclerosis (7), severe heart failure (8), and renal failure (9). Lowering TMA and TMAO levels in humans could therefore have potentially preventive and therapeutic effects on trimethylaminuria and cardiovascular diseases.…”

The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease

“…18 Two other observational studies linked plasma TMAO levels to severity of heart failure. Both a Norwegian study of 155 heart failure patients 25 and a North American study of 112 patients 26 reported associations between higher plasma TMAO, symptom severity and risk of all-cause mortality or heart transplantation over a 5-year follow-up period. 25,26 Importantly, increased age, previous myocardial infarction 25 and reduced kidney function assessed by estimated glomerular filtration rate (eGFR) strongly predicted blood TMAO levels.…”

Effect of <smlcap>L</smlcap>-Carnitine Supplementation on Reverse Remodeling in Patients with Ischemic Heart Disease Undergoing Coronary Artery Bypass Grafting: A Randomized, Placebo-Controlled Trial

“…L -carnitine plays an important role in energy production from FA. It also acts in the removal of mitochondrial metabolism products and participates in cellular defense against apoptosis and ROS [13]. Its homeostasis is maintained through dietary ingestion, endogenous synthesis, transport to tissues and renal excretion [14,15].…”