@article {9182, title = {Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {42}, year = {2022}, month = {2022 09}, pages = {e273-e288}, abstract = {

BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways.

METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways.

RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95\% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95\% CI) of 10.6\% (1.0-114.5), 7.8\% (1.0-32.7), and 9.2\% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association.

CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.

}, keywords = {Animals, Atherosclerosis, Cardiovascular Diseases, Carnitine, Humans, Meat, Methylamines, Risk Factors}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.121.316533}, author = {Wang, Meng and Wang, Zeneng and Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Fretts, Amanda and Sotoodehnia, Nona and Budoff, Matthew and DiDonato, Joseph A and McKnight, Barbara and Tang, W H Wilson and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9451, title = {Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Aug 15}, pages = {e8711}, abstract = {

Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60\% (CHS) and 53\% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Atherosclerosis, Female, Humans, Ischemic Stroke, Methylamines, Oxides, Prospective Studies, Risk Factors, Stroke, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029230}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and Sitlani, Colleen M and Nemet, Ina and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Zhu, Weifei and Budoff, Matt and Longstreth, W T and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} }