02863nas a2200265 4500008004100000022001400041245018900055210006900244260001600313300001200329490000600341520197900347100002002326700002902346700001502375700001802390700001902408700001902427700002002446700002402466700002202490700002402512700002502536856003602561 2019 eng d a2047-998000aSerial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study.0 aSerial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesi c2019 Nov 19 ae0128810 v83 a

Background Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6 years, and 13 years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13 years, median follow-up (maximum 22.4 years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95% CI=1.08-1.41; and hazard ratio=0.78, 95% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.

1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLee, Yujin1 aH Y Wu, Jason1 aSong, Xiaoling1 aKing, Irena, B1 aPsaty, Bruce, M1 aLemaitre, Rozenn, N1 aMcKnight, Barbara1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/827502761nas a2200265 4500008004100000022001400041245013400055210006900189260001600258300001200274490000600286520192700292100001502219700002002234700002902254700002402283700002202307700001902329700001902348700002302367700002002390700002402410700002502434856003602459 2020 eng d a2047-998000aSerial Biomarkers of De Novo Lipogenesis Fatty Acids and Incident Heart Failure in Older Adults: The Cardiovascular Health Study.0 aSerial Biomarkers of De Novo Lipogenesis Fatty Acids and Inciden c2020 Feb 18 ae0141190 v93 a

Background De novo lipogenesis (DNL) is an endogenous pathway that converts excess dietary starch, sugar, protein, and alcohol into specific fatty acids (FAs). Although elevated DNL is linked to several metabolic abnormalities, little is known about how long-term habitual levels and changes in levels of FAs in the DNL pathway relate to incident heart failure (HF). Methods and Results We investigated whether habitual levels and changes in serial measures of FAs in the DNL pathway were associated with incident HF among 4249 participants free of HF at baseline. Plasma phospholipid FAs were measured at baseline, 6 years, and 13 years using gas chromatography, and risk factors for HF were measured using standardized methods. Incident HF was centrally adjudicated using medical records. We prospectively evaluated associations with HF risk of (1) habitual FA levels, using cumulative updating to assess long-term exposure, and (2) changes in FA levels over time. During 22.1 years of follow-up, 1304 HF cases occurred. After multivariable adjustment, habitual levels and changes in levels of palmitic acid (16:0) were positively associated with incident HF (interquintile hazard ratio [95% CI]=1.17 [1.00-1.36] and 1.26 [1.03-1.55], respectively). Changes in levels of 7-hexadecenoic acid (16:1n-9) and vaccenic acid (18:1n-7) were each positively associated with risk of HF (1.36 [1.13-1.62], and 1.43 [1.18-1.72], respectively). Habitual levels and changes in levels of myristic acid (14:0), palmitoleic acid (16:1n-7), stearic acid (18:0), and oleic acid (18:1n-9) were not associated with incident HF. Conclusions Both habitual levels and changes in levels of 16:0 were positively associated with incident HF in older adults. Changes in 16:1n-9 and 18:1n-7 were also positively associated with incident HF. These findings support a potential role of DNL or these DNL-related FAs in the development of HF.

1 aLee, Yujin1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aMcKnight, Barbara1 aKing, Irena, B1 aSong, Xiaoling1 aHuggins, Gordon, S1 aVest, Amanda, R1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/824103344nas a2200277 4500008004100000022001400041245010100055210006900156260001600225300001300241490000600254520250600260100001902766700001902785700002002804700002902824700002202853700002202875700002202897700001902919700001902938700002402957700002502981700002403006856003603030 2021 eng d a2574-380500aAssessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging.0 aAssessment of Plasma Phospholipid VeryLongChain Saturated Fatty  c2021 Aug 02 ae21206160 v43 a

Importance: Identifying novel factors that protect against age-related diseases and promote healthy aging is critical to public health. Higher levels of circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism shown to have beneficial associations in cardiovascular disease and total mortality, but whether they are associated with overall healthy aging is unknown.

Objective: To examine the association of circulating levels of 3 VLSFAs with unhealthy aging events, including incident chronic disease (cardiovascular disease, cancer, lung disease or severe kidney disease), physical dysfunction, and cognitive decline.

Design, Setting, and Participants: This cohort study used 1992 to 2014 data from the Cardiovascular Health Study (CHS). The CHS is a multicenter, population-based study of cardiovascular disease among older adults. Among the 4559 CHS participants with available fatty acid data, 1879 participants who had an age-related event before their first measurement were excluded. Data analysis was performed in 2020.

Main Outcomes and Measures: Plasma phospholipid VLSFA levels were measured by thin-layer chromatography followed by gas chromatography. The main outcome was the hazard ratio (HR) of an incident unhealthy aging event associated with serial measures of plasma arachidic acid, behenic acid, and lignoceric acid.

Results: Among the 2680 study participants (976 men [36.4%]), the mean (SD) age was 74.7 (4.8) years old at entry. During a median (interquartile range) of 6.4 (2.9-12.9) years of follow-up, 2484 participants experienced an unhealthy event. Compared with the lowest quintile, levels of behenic acid in the highest quintile of the fatty acid distribution were associated with 15% lower risk of an unhealthy event (HR, 0.85; 95% CI, 0.74-0.97; P for trend = .01) after adjustment for demographic characteristics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of lignoceric acid were similarly associated with 16% lower risk of an unhealthy event (HR, 0.84; 95% CI, 0.73-0.95; P for trend = .001).

Conclusions and Relevance: These findings suggest that higher levels of circulating behenic acid and lignoceric acid are associated with lower risk of unhealthy aging events. These results highlight the need to explore determinants of circulating VLSFAs for potential novel efforts to promote healthy aging.

1 aBockus, Lee, B1 aBiggs, Mary, L1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aFretts, Amanda, M1 aMcKnight, Barbara1 aSotoodehnia, Nona1 aKing, Irena, B1 aSong, Xiaoling1 aSiscovick, David, S1 aMozaffarian, Dariush1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/882603651nas a2200313 4500008004100000022001400041245015000055210006900205260001600274300001200290520265600302100001502958700001502973700001702988700002003005700002903025700002403054700002203078700002203100700002003122700002403142700002203166700002203188700002003210700002403230700002203254700002503276856003603301 2021 eng d a2047-998000aLongitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults.0 aLongitudinal Plasma Measures of Trimethylamine NOxide and Risk o c2021 Aug 16 ae0206463 a

Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <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, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02-1.42; -trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1.07; 95% CI, 0.90-1.27), as well as modified by eGFR (-interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m: HR, 1.56 [95% CI, 1.13-2.14]; -trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m: HR, 1.03 [95% CI, 0.85-1.25]; -trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01-1.56]; -trend=0.009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

1 aLee, Yujin1 aNemet, Ina1 aWang, Zeneng1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aFretts, Amanda, M1 aSotoodehnia, Nona1 aBudoff, Matthew1 aDiDonato, Joseph, A1 aMcKnight, Barbara1 aTang, W, H Wilson1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/883103344nas a2200421 4500008004100000022001400041245015100055210006900206260001200275300001400287490000700301520211000308653001202418653002002430653002802450653001402478653001102492653000902503653001702512653001702529100001502546700001702561700001502578700002002593700002902613700002402642700001902666700002202685700002002707700002402727700002202751700002202773700002002795700002402815700002202839700002502861856003602886 2022 eng d a1524-463600aDietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.0 aDietary Meat Trimethylamine NOxideRelated Metabolites and Incide c2022 09 ae273-e2880 v423 a

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.

10aAnimals10aAtherosclerosis10aCardiovascular Diseases10aCarnitine10aHumans10aMeat10aMethylamines10aRisk Factors1 aWang, Meng1 aWang, Zeneng1 aLee, Yujin1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aFretts, Amanda1 aSotoodehnia, Nona1 aBudoff, Matthew1 aDiDonato, Joseph, A1 aMcKnight, Barbara1 aTang, W, H Wilson1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/918203708nas a2200553 4500008004100000022001400041245014100055210006900196260001300265300001200278490000700290520217500297653000902472653002202481653001202503653001502515653001402530653001202544653001102556653003202567653001802599653001102617653001402628653000902642653001702651653001602668653001702684653001802701100002202719700002402741700002002765700001502785700001702800700001802817700001502835700001502850700002002865700002902885700002202914700002202936700002402958700002202982700002003004700002403024700002303048700002503071700002203096856003603118 2024 eng d a1941-329700aTrimethylamine -Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations.0 aTrimethylamine Oxide and Related Gut MicrobeDerived Metabolites  c2024 Aug ae0115690 v173 a

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.

10aAged10aAged, 80 and over10aBetaine10aBiomarkers10aCarnitine10aCholine10aFemale10aGastrointestinal Microbiome10aHeart Failure10aHumans10aIncidence10aMale10aMethylamines10aMiddle Aged10aRisk Factors10aUnited States1 aTang, W, H Wilson1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aWang, Meng1 aWang, Zeneng1 aLi, Xinmin, S1 aNemet, Ina1 aLee, Yujin1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aFretts, Amanda, M1 aSotoodehnia, Nona1 aDiDonato, Joseph, A1 aBäckhed, Fredrik1 aPsaty, Bruce, M1 aSiscovick, David, S1 aBudoff, Matthew, J1 aMozaffarian, Dariush1 aHazen, Stanley, L uhttps://chs-nhlbi.org/node/9747