Intestinal Microbiota-Dependent Phosphatidylcholine Metabolites, Diastolic Dysfunction, and Adverse Clinical Outcomes in Chronic Systolic Heart Failure

Abstract

Background Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aim to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). Methods and Results In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median TMAO levels, choline, and betaine levels were 5.8 [3.6, 12.1] μM, 10.9 [8.4, 14.0] μM, 43.8 [37.1, 53.0] μM, respectively, and were correlated with each other (all p<0.0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9, 13.2] vs 4.8 [3.4, 9.8] μM, p=0.005) and in subjects with New York Heart Association (NYHA) class III or greater (7.0 [4.7, 14.8] vs 4.7 [3.4, 11.3] μM, p=0.02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma NT-proBNP levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (Hazard ratio (HR) 1.64 [95% CI: 1.22 2.20], p=0.001), betaine (HR 1.51 [1.10–2.08], p=0.01), and TMAO (HR 1.48 [1.10–1.96], p=0.01) predicted increased risk for 5-year adverse clinical events (death/transplant). Only higher TMAO levels predicted incident adverse clinical events independent of age, eGFR, mitral E/septal Ea, and NT-proBNP levels (HR 1.46 [1.03 2.14], p=0.03). Conclusion Elevated plasma TMAO, choline and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO levels was associated with poor prognosis after adjustment for cardio-renal indices.

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].…”

Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

“…Specifically, gut microbes were shown to play an obligatory role in trimethylamine N-oxide (TMAO) formation upon processing of common dietary components (e.g., choline in egg yolk or Lcarnitine in meat) both in mice 4,5 and in humans. [6][7][8][9] These studies also demonstrated that TMAO was not merely a biomarker, but it was also a mediator of alterations in cholesterol and sterol metabolism and can directly enhance atherogenesis. 4,5 Pathophysiologically, TMAO may also interact with other host neurohormonal systems, as observed in a rat model whereby angiotensin II infusion in the setting of elevated TMAO levels led to sustained augmentation of BP.…”

Trimethylamine Oxide (TMAO): A New Toxic Kid on the Block

“…Several studies have reported an association between plasma TMAO and choline levels in patients with heart failure [9][10][11][12]. TMAO negatively regulates glucose metabolism which leads to diabetes mellitus [13].…”