02586nas a2200289 4500008004100000022001400041245011400055210006900169260001600238520170000254100002601954700002101980700002402001700002302025700002002048700002002068700002002088700001802108700002202126700001902148700002002167700001302187700001902200700001702219700002402236856003602260 2017 eng d a1523-468100aSoluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study.0 aSoluble Inflammatory Markers and Risk of Incident Fractures in O c2017 Oct 043 a

Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95% CI, 1.02 to 1.30) overall and HR 1.17 (95% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95% CI, 1.01 to 1.06) overall and HR 1.06 (95% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. © 2017 American Society for Bone and Mineral Research.

1 aStojanović, Danijela1 aBůzková, Petra1 aMukamal, Kenneth, J1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aFink, Howard, A1 aCauley, Jane, A1 aWallace, Erin1 aCurtis, Lesley, H1 aHirsch, Calvin1 aBudoff, Matthew1 aLi, Dong1 aYoung, Rebekah1 aJalal, Diana1 aDelaney, Joseph, Ac uhttps://chs-nhlbi.org/node/759203651nas 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/883104438nas a2200457 4500008004100000022001400041245009000055210006900145260001500214300001300229490000600242520319000248653000903438653001203447653002803459653001403487653001203501653001903513653001103532653001103543653000903554653001703563653002403580100002203604700002203626700001703648700002003665700002403685700001503709700002903724700002403753700001503777700002003792700002403812700002203836700002203858700001503880700002403895700002503919856003603944 2022 eng d a2574-380500aAssociation of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults.0 aAssociation of Trimethylamine NOxide and Metabolites With Mortal c2022 05 02 ae22132420 v53 a

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.

10aAged10aBetaine10aCardiovascular Diseases10aCarnitine10aCholine10aCohort Studies10aFemale10aHumans10aMale10aMethylamines10aProspective Studies1 aFretts, Amanda, M1 aHazen, Stanley, L1 aJensen, Paul1 aBudoff, Matthew1 aSitlani, Colleen, M1 aWang, Meng1 aOtto, Marcia, C de Olive1 aDiDonato, Joseph, A1 aLee, Yujin1 aPsaty, Bruce, M1 aSiscovick, David, S1 aSotoodehnia, Nona1 aTang, W, H Wilson1 aLai, Heidi1 aLemaitre, Rozenn, N1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/909103344nas 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/918203419nas a2200349 4500008004100000022001400041245010000055210006900155260001600224520237600240100001502616700002202631700001802653700002902671700001502700700002402715700001902739700001502758700002202773700002402795700002002819700002402839700001702863700001802880700002402898700002002922700002402942700002002966700002502986700002203011856003603033 2024 eng d a1533-345000aThe Gut Microbial Metabolite Trimethylamine N-oxide, Incident CKD, and Kidney Function Decline.0 aGut Microbial Metabolite Trimethylamine Noxide Incident CKD and  c2024 Apr 093 a

BACKGROUND: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline.

METHODS: We included 10,564 participants from two community-based, prospective cohorts with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and Cystatin C were measured up to 4 times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline ≥ 30% from baseline and a resulting eGFR<60 ml/min/1.73 m2. Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels.

RESULTS: During a median follow-up of 9.4 years (interquartile range: 9.1-11.6 years), 979 incident CKD events occurred. Higher TMAO levels associated with higher risk of incident CKD (2nd to 5th vs. 1st quintile HR[95%CI]= 1.65 [1.22-2.23], 1.68 [1.26-2.25], 2.28 [1.72-3.02], and 2.24[1.68-2.98], respectively) and greater annualized eGFR decline ( 2nd to 5th vs. 1st quintile annualized eGFR change= -0.21 [-0.32, -0.09], -0.17 [-0.29, -0.05], -0.35 [-0.47, -0.22], and -0.43[-0.56, -0.30], respectively) with monotonic dose-response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors including diabetes, per 10 mmHg of higher systolic blood pressure, per 10 years of older age, and Black race.

CONCLUSIONS: In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.

1 aWang, Meng1 aTang, W, H Wilson1 aLi, Xinmin, S1 aOtto, Marcia, C de Olive1 aLee, Yujin1 aLemaitre, Rozenn, N1 aFretts, Amanda1 aNemet, Ina1 aSotoodehnia, Nona1 aSitlani, Colleen, M1 aBudoff, Matthew1 aDiDonato, Joseph, A1 aWang, Zeneng1 aBansal, Nisha1 aShlipak, Michael, G1 aPsaty, Bruce, M1 aSiscovick, David, S1 aSarnak, Mark, J1 aMozaffarian, Dariush1 aHazen, Stanley, L uhttps://chs-nhlbi.org/node/9648