Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-Oxide in Patients With Heart Failure

Abstract

BACKGROUND Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. OBJECTIVE This study investigated the potential pathophysiologic contributions of intestinal microbiota in HF. METHODS We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over 5-year follow-up in 720 stable subjects with HF. RESULTS Median TMAO level was 5.0 μM, which was higher than in non-HF subjects (3.5 -μM; p < 0.001). There was modest but significant correlation between TMAO and B-type natriuretic peptide (BNP) (r = 0.23; p < 0.001). Higher plasma TMAO level was associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% confidence interval [CI]: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001). CONCLUSION High TMAO levels are observed in patients with HF and elevated TMAO levels portend higher long-term mortality risk independent of traditional risk factors.

High mass accuracy assay for trimethylamine N-oxide using stable-isotope dilution with liquid chromatography coupled to orthogonal acceleration time of flight mass spectrometry with multiple reaction monitoring

“…When comparing with reported TMAO concentrations, healthy control participants showed similar median values to previous healthy cohorts [2,6]. Patients suffering from SHF reported elevated levels to other HF cohorts [2,3], but similar to those suffering from chronic kidney disease [6]. This result, although interesting, is derived from a limited patient population but demonstrates the clinical applicability of the described method.…”

“…To our knowledge, we describe the first example of a clinical assay utilising a Synapt generation ToF-MRM assay for a compound that can provide clinical prognostic value to a variety of diseases [1][2][3]25]. The assay is linear over nearly 3 orders of magnitude, has a limit of detection of 0.05 µmol\L and has a total injection-to-injection run time of 3 min.…”

“…Trimethylamine N-oxide (TMAO) is a downstream metabolite of carnitine and choline, driven by intestinal microbiota, which has engendered considerable research effort as a new biomarker for a variety of cardiovascular diseases [1][2][3]. It is also being investigated in other diseases where the aetiology is thought to be related to a perturbance of the gut microbiome, including colorectal cancer [4], diabetes [5] and renal disease [6] as well as being a putative central mediator in cholesterol balance [7].…”

Heart failure is associated with depletion of core intestinal microbiota

“…However, a functional relevance of an impaired and/or altered bacterial profile as a primary risk factor or early disease marker for the initial onset of heart failure seems to be conceivable as well. Of note, recent studies have shown that intestinal bacterial‐dependent generated trimethylamine‐N‐oxide (TMAO) levels in blood are a prognostic factor for long‐term mortality risk in HF patients independent of traditional risk factors and indices 43, 44. In our study we focused on HF patients mostly in an acute state of decompensation.…”

Clinical Mass Spectrometry in Heart Disease

“…9 When analysed in a subset of chronic heart failure patients, elevated levels of TMAO were independently predictive of all-cause mortality within 5 years. 10 TMAO is commonly analysed using stable isotope dilution-LC-MS/MS with multiple reaction monitoring (MRM). In MRM, the instrument is tailored to filter a selective list of ions, perform fragmentation on them and monitor all reactions in parallel.…”