@article {9091, title = {Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 05 02}, pages = {e2213242}, abstract = {

Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.

Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.

Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.

Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.

Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.

Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3\%) were male, 3184 (59.7\%) were female, 848 (15.9\%) were African American, 4450 (83.4\%) were White, and 35 (0.01\%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95\% CI, 1.17-1.44) for TMAO, 1.19 (95\% CI, 1.08-1.32) for choline, 1.26 (95\% CI, 1.15-1.40) for carnitine, and 1.26 (95\% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.

Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.

}, keywords = {Aged, Betaine, Cardiovascular Diseases, Carnitine, Choline, Cohort Studies, Female, Humans, Male, Methylamines, Prospective Studies}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.13242}, author = {Fretts, Amanda M and Hazen, Stanley L and Jensen, Paul and Budoff, Matthew and Sitlani, Colleen M and Wang, Meng and de Oliveira Otto, Marcia C and DiDonato, Joseph A and Lee, Yujin and Psaty, Bruce M and Siscovick, David S and Sotoodehnia, Nona and Tang, W H Wilson and Lai, Heidi and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {9747, title = {Trimethylamine -Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations.}, journal = {Circ Heart Fail}, volume = {17}, year = {2024}, month = {2024 Aug}, pages = {e011569}, abstract = {

BACKGROUND: Growing evidence indicates that trimethylamine -oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine -oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF).

METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors.

RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine -oxide (hazard ratio, 1.15 [95\% CI, 1.09-1.20]; <0.001), choline (hazard ratio, 1.44 [95\% CI, 1.26-1.64]; <0.001), and crotonobetaine (hazard ratio, 1.24 [95\% CI, 1.16-1.32]; <0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race.

CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine -oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF.

REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.

}, keywords = {Aged, Aged, 80 and over, Betaine, Biomarkers, Carnitine, Choline, Female, Gastrointestinal Microbiome, Heart Failure, Humans, Incidence, Male, Methylamines, Middle Aged, Risk Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.124.011569}, author = {Tang, W H Wilson and Lemaitre, Rozenn N and Jensen, Paul N and Wang, Meng and Wang, Zeneng and Li, Xinmin S and Nemet, Ina and Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Fretts, Amanda M and Sotoodehnia, Nona and DiDonato, Joseph A and B{\"a}ckhed, Fredrik and Psaty, Bruce M and Siscovick, David S and Budoff, Matthew J and Mozaffarian, Dariush and Hazen, Stanley L} }