Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes

Abstract

Aims Trimethyllysine (TML) serves as a nutrient precursor of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and is associated with incident cardiovascular (CV) events in stable subjects. We examined the relationship between plasma TML levels and incident CV events in patients presenting with acute coronary syndromes (ACS). Methods and results Plasma levels of TML were quantified in two independent cohorts using mass spectrometry, and its relationship with CV events was investigated. In a Cleveland Cohort (N = 530), comprised of patients presenting to the emergency department with chest pain and suspected ACS, TML was associated with major adverse cardiac events (MACE, myocardial infarction, stroke, need for revascularization, or all-cause mortality) over both 30 days [3rd tertile (T3), adjusted odds ratio (OR) 1.77, 95% confidence interval (CI) 1.04–3.01; P < 0.05] and 6 months (T3, adjusted OR 1.95, 95% CI 1.15–3.32; P < 0.05) of follow-up independent of traditional CV risk factors and indices of renal function. Elevated TML levels were also associated with incident long-term (7-year) all-cause mortality [T3, adjusted hazard ratio (HR) 2.52, 95% CI 1.50–4.24; P < 0.001], and MACE even amongst patients persistently negative for cardiac Troponin T at presentation (e.g. 30-day MACE, T3, adjusted OR 4.49, 95% CI 2.06–9.79; P < 0.001). Trimethyllysine in combination with TMAO showed additive significance for near- and long-term CV events, including patients with ‘negative’ high-sensitivity Troponin T levels. In a multicentre Swiss Cohort (N = 1683) comprised of ACS patients, similar associations between TML and incident 1-year adverse cardiac risks were observed (e.g. mortality, adjusted T3 HR 2.74, 95% CI 1.28–5.85; P < 0.05; and MACE, adjusted T3 HR 1.55, 95% CI 1.04–2.31; P < 0.05). Conclusion Plasma TML levels, alone and together with TMAO, are associated with both near- and long-term CV events in patients with chest pain and ACS.

Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

“…10D) also showed a biphasic response, continuing to elevate over 14 days in females. This metabolite, when found in the blood, is a known risk factor for acute cardiac events (Li et al 2019) and has also been associated with possible cardiac illness-induced changes in the gut microbiome (Chioncel & Ambrosy, 2019).…”

Plasma Trimethylamine N-Oxide and Its Precursors: Population Epidemiology, Parent–Child Concordance, and Associations with Reported Dietary Intake in 11- to 12-Year-Old Children and Their Parents

“…Trimethylamine N-oxide (TMAO) has gained increasing attention over the past decade owing to its potential links to metabolic syndrome and cardiovascular disease ( 1– 8 ). TMAO concentrations, and those of its precursors, have prognostic utility in predicting cardiovascular events ( 4 ). Despite this, links between TMAO concentrations and cardiovascular disease have been inconsistent ( 9 , 2 , 3 – 7 , 10–16 ), with stronger relations found in diseased patients ( 4 ) than in “healthy” population settings ( 11 ).…”

“…TMAO concentrations, and those of its precursors, have prognostic utility in predicting cardiovascular events ( 4 ). Despite this, links between TMAO concentrations and cardiovascular disease have been inconsistent ( 9 , 2 , 3 – 7 , 10–16 ), with stronger relations found in diseased patients ( 4 ) than in “healthy” population settings ( 11 ). Varying results may also, in part, be due to baseline concentrations of TMAO, with a U-shaped curve of association with cardiovascular outcomes being reported ( 17 ).…”

“…Cardiovascular disease is one of the leading causes of death worldwide ( 33 ). Measures of TMAO and of its precursors have shown utility in the prediction and prognosis of cardiovascular disease ( 2 , 4 ), and these metabolites’ concentrations can be altered by the diet ( 5 , 21 , 22 ). Although cardiometabolic conditions have their origins in early life ( 34 ), baseline reference values of TMAO concentrations in healthy populations of children, and across generations, are generally lacking ( 11 , 35 , 36 ).…”

The year in cardiology: acute coronary syndromes

“…Four new biomarkers have been investigated in different trials in the setting of ACS: (i) galectin-3, implicated in fibrosis; (24) (ii) impaired endogenous fibrinolysis; (25) (iii) trimethyllysine and TMAO, gut-microbiota derived metabolite; (26) and (iv) serum cholesterol efflux capacity. (27) All these biomarkers were found to be independently associated with MACE at follow-up.…”