Meng Wang1, Zeneng Wang2,3, Stanley L Hazen2,3,4, Dariush Mozaffarian1, Yujin Lee5, Heidi T M Lai6, Marcia C de Oliveira Otto7, Rozenn N Lemaitre8, Amanda Fretts8,9, Nona Sotoodehnia8, Matthew Budoff10, Joseph A DiDonato2,3, Barbara McKnight8,11, W H Wilson Tang2,3,4, Bruce M Psaty8,9,12, David S Siscovick13. 1. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (M.W., D.M.). 2. Department of Cardiovascular and Metabolic Sciences (Z.W., J.A.D., W.H.W.T., S.L.H.), Cleveland Clinic, OH. 3. Center for Microbiome and Human Health (Z.W., J.A.D., W.H.W.T., S.L.H.), Cleveland Clinic, OH. 4. Lerner Research Institute and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T., S.L.H.), Cleveland Clinic, OH. 5. Department of Food and Nutrition, Myongji University, Yongin, South Korea (Y.L.). 6. Department of Primary Care and Public Health, Imperial College London, United Kingdom (H.T.M.L.). 7. Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Houston, TX (M.C.d.O.O.). 8. Cardiovascular Health Research Unit, Department of Medicine (R.N.L., A.F., N.S., B.M., B.M.P.), University of Washington, Seattle. 9. Department of Epidemiology (A.F., B.M.P.), University of Washington, Seattle. 10. Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA (M.B.). 11. Department of Biostatistics (B.M.), University of Washington, Seattle. 12. Department of Health Systems and Population Health (B.M.P.), University of Washington, Seattle. 13. The New York Academy of Medicine, New York (D.S.S.).
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.
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.
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