@article {1362, title = {Association of plasma phospholipid long-chain ω-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {125}, year = {2012}, month = {2012 Mar 06}, pages = {1084-93}, abstract = {

BACKGROUND: Experimental studies suggest that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) may reduce the risk of atrial fibrillation (AF). Prior studies evaluating fish or n-3 PUFA consumption from dietary questionnaires and incident AF have been conflicting. Circulating levels of n-3 PUFAs provide an objective measurement of exposure.

METHODS AND RESULTS: Among 3326 US men and women >=65 years of age and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were measured at baseline by use of standardized methods. Incident AF (789 cases) was identified prospectively from hospital discharge records and study visit ECGs during 31 169 person-years of follow-up (1992-2006). In multivariable Cox models adjusted for other risk factors, the relative risk in the top versus lowest quartile of total n-3 PUFAs (eicosapentaenoic acid+docosapentaenoic acid+docosahexaenoic acid) levels was 0.71 (95\% confidence interval, 0.57-0.89; P for trend=0.004) and of DHA levels was 0.77 (95\% confidence interval, 0.62-0.96; P for trend=0.01). Eicosapentaenoic acid and docosapentaenoic acid levels were not significantly associated with incident AF. Evaluated nonparametrically, both total n-3 PUFAs and docosahexaenoic acid showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results.

CONCLUSIONS: In older adults, higher circulating total long-chain n-3 PUFA and docosahexaenoic acid levels were associated with lower risk of incident AF. These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for the primary prevention of AF.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Dietary Fats, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Female, Follow-Up Studies, Humans, Incidence, Male, Proportional Hazards Models, Risk Factors, Seafood}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.111.062653}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Sacks, Frank M and Rimm, Eric B and Heckbert, Susan R and Siscovick, David S and Mozaffarian, Dariush} } @article {5846, title = {Associations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {2}, year = {2013}, month = {2013 Jan 31}, pages = {e003814}, abstract = {

BACKGROUND: Few studies have examined the relationship of α-linolenic acid (ALA 18:3n-3), an intermediate-chain essential n-3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).

METHODS AND RESULTS: The study population included participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95\% CI, 0.90 to 1.37), 1.09 (95\% CI, 0.88 to 1.35), and 0.92 (95\% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.

CONCLUSIONS: Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.

}, keywords = {Age Factors, Aged, Aged, 80 and over, alpha-Linolenic Acid, Atrial Fibrillation, Biomarkers, Diet, Female, Humans, Incidence, Linear Models, Longitudinal Studies, Male, Nutritional Status, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.112.003814}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Heckbert, Susan R and McKnight, Barbara and King, Irena B and Rimm, Eric B and Psaty, Bruce M and Sacks, Frank M and Song, Xiaoling and Spiegelman, Donna and Lemaitre, Rozenn N} } @article {6929, title = {Associations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length.}, journal = {J Nutr}, volume = {146}, year = {2016}, month = {2016 Feb}, pages = {298-305}, abstract = {

BACKGROUND: Not much is known about the relations of circulating saturated fatty acids (SFAs), which are influenced by both metabolic and dietary determinants, with total and cause-specific mortality.

OBJECTIVE: We examined the associations of plasma phospholipid SFAs with total and cause-specific mortality among 3941 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged >=65 y who were followed from 1992 through 2011.

METHODS: The relations of total and cause-specific mortality with plasma phospholipid palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) were assessed using Cox proportional hazards models.

RESULTS: During 45,450 person-years of follow-up, 3134 deaths occurred. Higher concentrations of the plasma phospholipid SFAs 18:0, 22:0, and 24:0 were associated with a lower risk of total mortality [multivariable-adjusted HRs (95\% CIs)] for the top compared with the bottom quintile: 0.85 (0.75, 0.95) for 18:0; 0.85 (0.75, 0.95) for 22:0; and 0.80 (0.71, 0.90) for 24:0. In contrast, plasma 16:0 concentrations in the highest quintile were associated with a higher risk of total mortality compared with concentrations in the lowest quintile [1.25 (1.11, 1.41)]. We also found no association of plasma phospholipid 20:0 with total mortality.

CONCLUSIONS: These findings suggest that the associations of plasma phospholipid SFAs with the risk of death differ according to SFA chain length and support future studies to better characterize the determinants of circulating SFAs and to explore the mechanisms underlying these relations.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Diet, Dietary Fats, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Mortality, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Stearic Acids}, issn = {1541-6100}, doi = {10.3945/jn.115.222117}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Rimm, Eric B and Sitlani, Colleen and Sacks, Frank M and Song, Xiaoling and Sotoodehnia, Nona and Spiegelman, Donna and Lemaitre, Rozenn N} } @article {8826, title = {Assessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging.}, journal = {JAMA Netw Open}, volume = {4}, year = {2021}, month = {2021 Aug 02}, pages = {e2120616}, abstract = {

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.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2021.20616}, author = {Bockus, Lee B and Biggs, Mary L and Lai, Heidi T M and de Olivera Otto, Marcia C and Fretts, Amanda M and McKnight, Barbara and Sotoodehnia, Nona and King, Irena B and Song, Xiaoling and Siscovick, David S and Mozaffarian, Dariush and Lemaitre, Rozenn N} } @article {8922, title = {Association of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {4}, year = {2021}, month = {2021 Aug 02}, pages = {e2122844}, abstract = {

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.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2021.22844}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and McKnight, Barbara and Nemet, Ina and Biggs, Mary L and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9091, title = {Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 05 02}, pages = {e2213242}, abstract = {

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.

}, keywords = {Aged, Betaine, Cardiovascular Diseases, Carnitine, Choline, Cohort Studies, Female, Humans, Male, Methylamines, Prospective Studies}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.13242}, author = {Fretts, Amanda M and Hazen, Stanley L and Jensen, Paul and Budoff, Matthew and Sitlani, Colleen M and Wang, Meng and de Oliveira Otto, Marcia C and DiDonato, Joseph A and Lee, Yujin and Psaty, Bruce M and Siscovick, David S and Sotoodehnia, Nona and Tang, W H Wilson and Lai, Heidi and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {9456, title = {Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.}, journal = {BMJ}, volume = {380}, year = {2023}, month = {2023 Jan 18}, pages = {e072909}, abstract = {

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75\% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3\%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95\% confidence interval 0.86 to 0.98; P=0.009, I=9.9\%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13\% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0\%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8\%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (>=60 <60 years), estimated glomerular filtration rate (60-89 >=90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

}, keywords = {alpha-Linolenic Acid, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Humans, Middle Aged, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors}, issn = {1756-1833}, doi = {10.1136/bmj-2022-072909}, author = {Ong, Kwok Leung and Marklund, Matti and Huang, Liping and Rye, Kerry-Anne and Hui, Nicholas and Pan, Xiong-Fei and Rebholz, Casey M and Kim, Hyunju and Steffen, Lyn M and van Westing, Anniek C and Geleijnse, Johanna M and Hoogeveen, Ellen K and Chen, Yun-Yu and Chien, Kuo-Liong and Fretts, Amanda M and Lemaitre, Rozenn N and Imamura, Fumiaki and Forouhi, Nita G and Wareham, Nicholas J and Birukov, Anna and J{\"a}ger, Susanne and Kuxhaus, Olga and Schulze, Matthias B and de Mello, Vanessa Derenji and Tuomilehto, Jaakko and Uusitupa, Matti and Lindstr{\"o}m, Jaana and Tintle, Nathan and Harris, William S and Yamasaki, Keisuke and Hirakawa, Yoichiro and Ninomiya, Toshiharu and Tanaka, Toshiko and Ferrucci, Luigi and Bandinelli, Stefania and Virtanen, Jyrki K and Voutilainen, Ari and Jayasena, Tharusha and Thalamuthu, Anbupalam and Poljak, Anne and Bustamante, Sonia and Sachdev, Perminder S and Senn, Mackenzie K and Rich, Stephen S and Tsai, Michael Y and Wood, Alexis C and Laakso, Markku and Lankinen, Maria and Yang, Xiaowei and Sun, Liang and Li, Huaixing and Lin, Xu and Nowak, Christoph and Arnl{\"o}v, Johan and Riserus, Ulf and Lind, Lars and Le Goff, M{\'e}lanie and Samieri, Cecilia and Helmer, Catherine and Qian, Frank and Micha, Renata and Tin, Adrienne and K{\"o}ttgen, Anna and de Boer, Ian H and Siscovick, David S and Mozaffarian, Dariush and Wu, Jason HY} }