Longitudinal Measures of Trimethylamine N-oxide and Incident Atherosclerotic Cardiovascular Disease Events in Older Adults: The Cardiovascular Health Study

Objectives Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine and phosphatidylcholine-rich animal foods. Based on experimental studies and cohorts with prevalent disease, elevated TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction and elevated cystatin-C. Yet, the associations of serial TMAO levels with incident ASCVD in a community-based prospective cohort, and the potential mediating and modifying role of renal function, are not established. Methods We investigated the associations of serial measures of plasma TMAO, assessed at baseline and 7 years post baseline, with incident ASCVD among 4144 older adults in the Cardiovascular Health Study (CHS). TMAO was measured using stable isotope dilution LC/MS/MS (lab CV <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression including time-varying demographics, lifestyle factors, medical history, and laboratory and dietary variables. We assessed potential mediating effects and interaction by renal function estimated by cystatin-C. Results During a median 15 years follow-up, 1757 ASCVD events occurred. After multivariable adjustment, TMAO was associated with a higher risk of ASCVD, with an extreme quintile HR (95% CI) of 1.22 (1.04, 1.44), P-trend = 0.01. This relationship appeared further mediated or confounded by estimated glomerular filtration rate (eGFR): adjusting for cystatin-C-based eGFR, the HR (95% CI) was 1.06 (0.98–1.25). Significant interaction was also observed by renal function (P-interaction < 0.001), with TMAO associated with higher risk of ASCVD among individuals with impaired renal function (eGFR ≤ 60) [1.63 (1.03–2.59)], but not normal baseline renal function (eGFR > 60) [1.15 (0.96–1.37)], even with further adjustment for continuous eGFR. Conclusions In this large community-based cohort of older US adults, higher serial measures of TMAO were associated with an elevated risk of ASCVD, in particular among those with impaired renal function. Funding Sources NIH, NHLBI.