Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults.
Level 3 - non-randomized controlled study
Prospective cohort study with serial biomarker measurements and longitudinal event follow-up.
PubMed 34398665 · doi:10.1161/JAHA.120.020646
What was done
Serial plasma trimethylamine N-oxide (TMAO) concentrations were measured at baseline and after 7 years using stable isotope dilution liquid chromatography-tandem mass spectrometry in community-dwelling older US adults. The study analyzed associations with centrally adjudicated incident ASCVD (n = 4131) and recurrent ASCVD (n = 1449). Multivariable Cox proportional hazards models adjusted for time-varying demographics, lifestyle factors, medical history, laboratory parameters, and diet, and tested for mediation and effect modification by estimated glomerular filtration rate (eGFR).
What was found
During follow-up, 1766 incident and 897 recurrent ASCVD events occurred. Comparing the highest to lowest TMAO quintile, elevated TMAO was associated with incident ASCVD (HR 1.21; 95% CI, 1.02–1.42; P-trend = 0.029), but adjusting for eGFR attenuated the association (HR 1.07; 95% CI, 0.90–1.27). eGFR significantly modified this relationship (P-interaction < 0.001): TMAO was associated with incident ASCVD in individuals with eGFR < 60 mL/min/1.73 m² (HR 1.56; 95% CI, 1.13–2.14; P-trend = 0.007), but not in those with eGFR ≥ 60 mL/min/1.73 m² (HR 1.03; 95% CI, 0.85–1.25; P-trend = 0.668). For recurrent ASCVD, higher TMAO was associated with increased risk (HR 1.25; 95% CI, 1.01–1.56; P-trend = 0.009) without significant eGFR modification.
Why it matters
The relationship between circulating TMAO and primary cardiovascular events in older adults is heavily modified or confounded by kidney function, whereas TMAO remains an independent marker for recurrent vascular events.
Limits
Observational cohort design cannot determine whether TMAO is a causal mediator or a non-causal marker of impaired renal clearance and subclinical disease. The study population was restricted to older US adults, limiting generalizability to younger age groups.
Cited by
- supports TMAO is a gut-derived compound associated with atherosclerosis and heart disease that is synthesized from dietary precursors including L-carnitine in red meat and choline in eggs.