Targeting the gut microbiome in coronary artery disease

Host-microbiota interactions via numerous inflammatory and metabolic pathways contribute to the pathogenesis of a multitude of diseases such as cardiovascular and metabolic diseases.1 Alterations in the microbial flora generate increased circulating levels of microbiota-dependent metabolites associated with disease risk.2 One such metabolite, trimethylamine N-oxide (TMAO), is formed from the metabolism of phosphatidylcholine or L-carnitine into trimethylamine by bacteria, which is converted to TMAO in the liver by flavin-containing monooxygenases (FMO).3 While TMAO is the most commonly studied gut microbiota-derived metabolite demonstrating associations with heart failure,3 myocardial infarction4 and heart disease,5 precursor metabolites to TMAO have also shown similar associations with cardiovascular disease (CVD) risk such as betaine,6 choline,6 γ-butyrobetaine7 and more recently, acetyl-L-carnitine and L-carnitine.8 Given that TMAO can be generated from two pathways; 1) betaine -> choline -> TMAO and 2) carnitine -> TMAO, this demonstrates that TMAO levels are determined from a multitude of sources including dietary (e.g., carnitine from red meat and choline from eggs), microbial flora, medications (e.g., antibiotics), liver flavin monooxygenase activity, as well as age, gender and ethnicity.9., 10., 11. [Opening paragraph

Heart failure and trimethylamine N-oxide: time to transform a ‘gut feeling’ in a fact?

In the last few years, in the context of a growing interest in investigating novel pathways involved in heart failure (HF) pathophysiology, the association between the gastrointestinal (GI) system and HF represents an important model of attention, the so called ‘gut hypothesis’.Despite being classically identified as a ‘simple’ intestinal dysfunction, the main hypothesis is currently focused on the role of inflammation and oxidative stress as a consequence of the intestinal wall ischaemia and/or congestion induced by HF, determining a gut barrier dysfunction and resulting in an increased gut bacterial translocation.With this in mind, two main mechanisms have been proposed to link gut dysfunction and HF; (i) metabolism dependent, via gut-derived metabolites entering the systemic circulation and exerting pro-atherogenic effects and pro-inflammatory effects and (ii) metabolism independent, via bacterial components (e.g. lipopolysaccharides and endotoxins) translocating in the systemic circulation and contributing to the systemic inflammatory state with its well-known negative effects on HF. </p

Impact of acute choline loading on circulating trimethylamine N-oxide levels.

Despite recent efforts to reduce cardiovascular disease risk by dietary intervention,1few markers are useful to assess the efficiency and progress of this. Circulating levels of trimethylamine N-oxide (TMAO) are associated with poor outcomes of cardiovascular disease.2–6TMAO is generated via hepatic flavin monooxygenase 3 (FMO3) mediated oxidation of trimethylamine (TMA),7derived largely from carnitine and choline through gut microbial metabolism. These substrates are found in red meat and eggs, which are representative of a Western diet. Therefore, TMAO levels could be used to monitor the effect of dietary intervention, particularly for the consumption of a Western diet. In this study, we examined the effect of acute choline loading on TMAO levels in healthy adult volunteers

Surrogate markers of gut dysfunction are related to heart failure severity and outcome–from the BIOSTAT-CHF consortium

Background: The contribution of gut dysfunction to heart failure (HF) pathophysiology is not routinely assessed. We sought to investigate whether biomarkers of gut dysfunction would be useful in assessment of HF (eg, severity, adverse outcomes) and risk stratification. Methods: A panel of gut-related biomarkers including metabolites of the choline/carnitine- pathway (acetyl-L-carnitine, betaine, choline, γ-butyrobetaine, L-carnitine and trimethylamine-N-oxide [TMAO]) and the gut peptide, Trefoil factor-3 (TFF-3), were investigated in 1,783 patients with worsening HF enrolled in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and associations with HF severity and outcomes, and use in risk stratification were assessed. Results: Metabolites of the carnitine-TMAO pathway (acetyl-L-carnitine, γ-butyrobetaine, L-carnitine, and TMAO) and TFF-3 were associated with the composite outcome of HF hospitalization or all-cause mortality at 3 years (hazards ratio [HR] 2.04-2.93 [95% confidence interval {CI} 1.30-4.71] P≤.002). Combining the carnitine-TMAO metabolites with TFF-3, as a gut dysfunction panel, showed a graded association; a greater number of elevated markers was associated with higher New York Heart Association class (P<.001), higher plasma concentrations of B-type natriuretic peptide (P<.001), and worse outcome (HR 1.90-4.58 [95% CI 1.19-6.74] P≤ 0.008). Addition of gut dysfunction biomarkers to the contemporary BIOSTAT HF risk model also improved prediction for the aforementioned composite outcome (C-statistics P≤.011, NRI 13.5-21.1 [95% CI 2.7-31.9] P≤.014). Conclusions: A panel of biomarkers of gut dysfunction showed graded association with severity of HF and adverse outcomes. Biomarkers as surrogate markers are potentially useful for assessment of gut dysfunction to HF pathophysiology and in risk stratification

Biomarkers in Heart Failure: Clinical Insights

Heart failure (HF) is a clinical syndrome caused by structural and/or functional cardiac abnormalities and resulting from impaired cardiac output or an in-crease of intracardiac pressures at rest and/or during stress. Typical signs and symptoms of HF include ankle swelling, fatigue, dyspnea and peripheral edema, pulmonary crackles, or increased jugular venous pressure. Usually, patients with ejection fraction (EF) greater than or equal to 50% are defined as HF with preserved EF, where as those with EF less than 40% have HF with reduced EF. Patients with EF between 40% and 49% are now classified as HF with midrange EF