Geographical location affects the levels and association of trimethylamine N-oxide with heart failure mortality in BIOSTAT-CHF: a post-hoc analysis.

[First paragraph] Elevated circulating levels of the gut microbiota‐derived metabolite, trimethylamine N‐oxide (TMAO), are associated with adverse outcomes in heart failure (HF).1-4 Geographical differences in TMAO levels or in their association with HF outcomes have not been reported. However, we have noticed differences in the reported relationship between TMAO levels and outcomes according to reported geographical region. Independent reports from a British acute HF cohort1 and from a Norwegian chronic HF cohort2 showed attenuation of association of TMAO levels with outcomes after adjustment for main confounders, namely renal function. In contrast, in a German chronic HF population, TMAO levels were reported to be associated with mortality and had a better predictive value than N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) even after adjustment for estimated glomerular filtration rate (eGFR).3 We therefore wondered whether geographical location might account for this apparent difference5 and investigated this hypothesis using the BIOSTAT‐CHF cohort,4, 6, 7 a multinational study done across 11 countries in Europe in which we recently reported the measurements of plasma TMAO levels and their association with outcomes.4