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 (e.g., 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 hospitalisation or all-cause mortality at 3 years [HR 2.04-2.93 (95% CI 1.30-4.71) p≤0.002]. 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<0.001), higher plasma concentrations of B-type natriuretic peptide (p<0.001), 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≤0.011, NRI 13.5-21.1 (95% CI 2.7-31.9) p≤0.014]. 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