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

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journal contribution
posted on 2022-06-01, 16:36 authored by MZ Israr, H Zhan, A Salzano, AA Voors, JG Cleland, SD Anker, M Metra, DJ van Veldhuisen, CC Lang, F Zannad, NJ Samani, LL Ng, T Suzuki
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.


BIOSTAT-CHF was supported by the European Commission ([FP7-242209-BIOSTAT-CHF; EudraCT 2010- 020808-29)

the Japan Heart Foundation

National Institute for Health Research (Leicester Biomedical Research Centre)

the British Heart Foundation (BHF)

Medical Research Council (MRC) UK Consortium on MetAbolic Phenotyping (MAP/UK)



American Heart Journal Volume 248, June 2022, Pages 108-119

Author affiliation

Department of Cardiovascular Sciences, University of Leicester


  • AM (Accepted Manuscript)

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American Heart Journal




108 - 119


Elsevier BV





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United States