Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients

Abstract

Background and Purpose— Trimethylamine N-oxide (TMAO)—a gut derived metabolite—has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods— We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results— After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02–1.46). Consistently, compared with participants in the lowest tertile (<1.79 μmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 μmol/L; odds ratio, 1.34; 95% CI, 1.00–1.81) or in TMAO tertile 3 (≥3.19 μmol/L; odds ratio, 1.43; 95% CI, 1.02–2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions— Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Gut microbiota‐derived metabolite trimethylamine N‐oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose‐response meta‐ analysis

“…The median range of TMAO was 0.43 to 6.29 μmol/L. Two studies were carried out in the United States, two in Germany, two in the United Kingdom, one in Canada, one in Japan, one in Denmark, one in the Netherlands, one in Norway, and one in China . Among the included studies, higher BMI was reported in the highest TMAO categories in five studies while other studies reported no significant association between TMAO and obesity .…”

“…The flowchart of the literature search and study selection is presented in Figure S1. From these studies, six studies were cohort, five were cross‐sectional, and one was a nested‐case‐control study . The studies were independently analysed according to design, disease status, and TMAO sample type (plasma or serum).…”

“…The sample size of included studies varied from 220 to 5469 participants; total participants of 17 628 were included in the final data synthesis. The studies' participants differed according to disease status: seven studies were recruited among community‐based apparently healthy adults, two studies among patients with CVD, one among patients with T 1 DM, two among patients with CKD, and one among patients with incident stroke . According to our study hypothesis, we searched the association between TMAO and obesity measurements independently while we also included other components of metabolic syndrome including HTN, blood lipids, and metabolic syndrome as previously explained.…”

“…Five studies were included for dose‐response association between TMAO and change in BMI with total participants of 56 556, while the study by Svingen was included as two independent studies. One study with nested case control design was excluded. There was an evidence of nonlinear association between increased TMAO and increased BMI in apparently healthy populations ( P ‐ for nonlinearity = .007).…”

“…In a cross‐sectional study among 1286 Canadians, the highest quintile of serum TMAO was associated with increased prevalent CVD after adjustment for potential confounders (OR, 9.33; CI, 1.88‐46.37; P = .006). Increased carotid intima‐media thickness in higher TMAO concentrations was also reported by Randrianarisoa et al Several other studies also reported an association between TMAO and stroke in hypertensive adults, an association with vulnerable plaque characteristics in coronary artery disease (CAD) patients, and a higher mortality risk among patients with type 2 diabetes mellitus (T 2 DM) independent of glycemic status . Most of these studies focused on the association between TMAO and CVD, diabetes, or major advanced cardiac events (MACE) and obesity or body mass index (BMI) were investigated as secondary or even tertiary outcomes in these studies.…”