04157nas a2200289 4500008004100000022001400041245013900055210006900194260001600263300001300279490000600292520325200298100002403550700002003574700001703594700002203611700002203633700001503655700001903670700002203689700002903711700002003740700002403760700002203784700002503806856003603831 2021 eng d a2574-380500aAssociation of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study.0 aAssociation of Trimethylamine NOxide and Related Metabolites in  c2021 Aug 02 ae21228440 v43 a

Importance: Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.

Objective: To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).

Design, Setting, and Participants: This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.

Exposures: Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.

Main Outcomes and Measures: Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.

Results: The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95% CI, 1.04-1.10] for TMAO; 1.07 [95% CI, 1.03-1.10] for carnitine; 1.05 [95% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95% CI, 4.32-8.60] and 2.27 [95% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95% CI, 0.94-1.55] for TMAO; 0.96 [95% CI, 0.74-1.24] for choline; 0.88 [95% CI, 0.67-1.15] for betaine; 1.07 [95% CI, 0.83-1.37] for carnitine; 0.79 [95% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95% CI, 0.83-1.35] for crotonobetaine).

Conclusions and Relevance: Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.

1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aWang, Zeneng1 aFretts, Amanda, M1 aMcKnight, Barbara1 aNemet, Ina1 aBiggs, Mary, L1 aSotoodehnia, Nona1 aOtto, Marcia, C de Olive1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/892203651nas 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/883102819nas a2200289 4500008004100000022001400041245015800055210006900213260001600282520189100298100002902189700001802218700001702236700002102253700002002274700002502294700001502319700001502334700001502349700001902364700002402383700002202407700001702429700002202446700002502468856003602493 2022 eng d a1875-890800aLongitudinal Associations of Plasma TMAO and Related Metabolites with Cognitive Impairment and Dementia in Older Adults: The Cardiovascular Health Study.0 aLongitudinal Associations of Plasma TMAO and Related Metabolites c2022 Sep 023 a

BACKGROUND: Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear.

OBJECTIVE: We examined prospective associations of TMAO, γ-butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS).

METHODS: TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models.

RESULTS: Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20-32% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ-butyrobetaine was associated with ∼25% lower risk of the same cognitive outcomes per IQR.∥Conclusion:These findings suggest that γ-butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life.

1 aOtto, Marcia, C de Olive1 aLi, Xinmin, S1 aWang, Zeneng1 aSiscovick, David1 aNewman, Anne, B1 aLai, Heidi, Tsz Mung1 aNemet, Ina1 aLee, Yujin1 aWang, Meng1 aFretts, Amanda1 aLemaitre, Rozenn, N1 aTang, W, H Wilson1 aLopez, Oscar1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/915703034nas a2200409 4500008004100000022001400041245011900055210006900174260001200243300001100255490000800266520189800274653002702172653000902199653001702208653001102225653001802236653001102254653000902265653001702274653001702291100002002308700002102328700002402349700001702373700001502390700002302405700002002428700002002448700001502468700002102483700001502504700002202519700002502541700002202566856003602588 2022 eng d a1873-276300aTrimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.0 aTrimethylamine Noxide and hip fracture and bone mineral density  c2022 08 a1164310 v1613 a

CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain.

OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults.

DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study.

PARTICIPANTS: 5019 U.S. adults aged ≥65 years.

EXPOSURE: Plasma TMAO.

MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400).

RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight.

CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.

10aAbsorptiometry, Photon10aAged10aBone Density10aFemale10aHip Fractures10aHumans10aMale10aMethylamines10aRisk Factors1 aElam, Rachel, E1 aBůzková, Petra1 aBarzilay, Joshua, I1 aWang, Zeneng1 aNemet, Ina1 aBudoff, Matthew, J1 aCauley, Jane, A1 aFink, Howard, A1 aLee, Yujin1 aRobbins, John, A1 aWang, Meng1 aHazen, Stanley, L1 aMozaffarian, Dariush1 aCarbone, Laura, D uhttps://chs-nhlbi.org/node/908902887nas a2200445 4500008004100000022001400041245014200055210006900197260001600266300001000282490000700292520162000299653000901919653002001928653001101948653001101959653002001970653001701990653001102007653002402018653001702042653001102059653001802070100002402088700002002112700001702132700002202149700002402171700001502195700002202210700002902232700001602261700001702277700002002294700002002314700002402334700002202358700002502380856003602405 2023 eng d a2047-998000aPlasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.0 aPlasma TrimethylamineOxide and Incident Ischemic Stroke The Card c2023 Aug 15 ae87110 v123 a

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.

10aAged10aAtherosclerosis10aFemale10aHumans10aIschemic Stroke10aMethylamines10aOxides10aProspective Studies10aRisk Factors10aStroke10aUnited States1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aWang, Zeneng1 aFretts, Amanda, M1 aSitlani, Colleen, M1 aNemet, Ina1 aSotoodehnia, Nona1 aOtto, Marcia, C de Olive1 aZhu, Weifei1 aBudoff, Matt1 aLongstreth, W T1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/945103419nas 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