@article {903, title = {Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {114}, year = {2006}, month = {2006 Jul 18}, pages = {209-15}, abstract = {

BACKGROUND: Intake of trans fatty acids is associated with increased risk of coronary heart disease. Whether different classes of trans fatty acids show similar associations is unclear. We previously reported an association of sudden cardiac death with red cell membrane trans-18:2 but not trans-18:1 fatty acids. To extend these findings, we investigated the associations of plasma phospholipid trans fatty acids with fatal ischemic heart disease (IHD) and sudden cardiac death.

METHODS AND RESULTS: We conducted a case-control study nested in the Cardiovascular Health Study. We identified 214 cases of fatal IHD (fatal myocardial infarction and coronary heart disease death) between 1992 and 1998. We randomly selected 214 controls, matched to cases on demographics, prevalent cardiovascular disease, and timing of blood draw. Plasma phospholipid fatty acids were assessed in blood samples collected earlier. Higher levels of plasma phospholipid trans-18:2 fatty acids were associated with higher risk of fatal IHD (odds ratio [OR] for interquintile range 1.68, 95\% confidence interval [CI] 1.21 to 2.33) after adjustment for risk factors and trans-18:1 levels. Trans-18:1 levels above the 20th percentile were associated with lower risk (OR 0.34, 95\% CI 0.18 to 0.63). In analyses limited to cases of sudden cardiac death (n=95), higher levels of trans-18:2 fatty acids were associated with higher risk (OR 2.34, 95\% CI 1.27 to 4.31) and higher trans-18:1 with lower risk (OR 0.18, 95\% CI 0.06 to 0.54).

CONCLUSIONS: Higher levels of trans-18:2 and lower levels of trans-18:1 fatty acids are associated with higher risks of fatal IHD and sudden cardiac death. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 content.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Coronary Disease, Death, Sudden, Cardiac, Female, Humans, Male, Myocardial Ischemia, Phospholipids, Trans Fatty Acids, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.106.620336}, author = {Lemaitre, Rozenn N and King, Irena B and Mozaffarian, Dariush and Sotoodehnia, Nona and Rea, Thomas D and Kuller, Lewis H and Tracy, Russel P and Siscovick, David S} } @article {1291, title = {Plasma omega-3 fatty acids and incident diabetes in older adults.}, journal = {Am J Clin Nutr}, volume = {94}, year = {2011}, month = {2011 Aug}, pages = {527-33}, abstract = {

BACKGROUND: Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs.

OBJECTIVE: We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes.

DESIGN: We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks.

RESULTS: During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95\% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95\% CIs) for phospholipid α-linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03).

CONCLUSIONS: With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes.

}, keywords = {Aged, Aged, 80 and over, alpha-Linolenic Acid, Diabetes Mellitus, Fatty Acids, Omega-3, Female, Humans, Male, Phospholipids, Proportional Hazards Models, Prospective Studies}, issn = {1938-3207}, doi = {10.3945/ajcn.111.013334}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Ix, Joachim H and Mukamal, Kenneth J and Siscovick, David S and Mozaffarian, Dariush} } @article {6079, title = {Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study.}, journal = {Ann Intern Med}, volume = {158}, year = {2013}, month = {2013 Apr 02}, pages = {515-25}, abstract = {

BACKGROUND: Long-chain ω-3 polyunsaturated fatty acids (ω3-PUFAs), including eicosapentaenoic acid (EPA) (20:5ω-3), docosapentaenoic acid (DPA) (22:5ω-3), and docosahexaenoic acid (DHA) (22:6ω-3), have been shown to reduce cardiovascular risk, but effects on cause-specific and total mortality and potential dose-responses remain controversial. Most observational studies have assessed self-reported dietary intake and most randomized trials have tested effects of adding supplements to dietary intake and evaluated secondary prevention, thus limiting inference for dietary ω3-PUFAs or primary prevention.

OBJECTIVE: To investigate associations of plasma phospholipid EPA, DPA, DHA, and total ω3-PUFA levels with total and cause-specific mortality among healthy older adults not receiving supplements.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PARTICIPANTS: 2692 U.S. adults aged 74 years ({\textpm}5 years) without prevalent coronary heart disease (CHD), stroke, or heart failure at baseline.

MEASUREMENTS: Phospholipid fatty acid levels and cardiovascular risk factors were measured in 1992. Relationships with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke through 2008 were assessed.

RESULTS: During 30 829 person-years, 1625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After adjustment, higher plasma levels of ω3-PUFA biomarkers were associated with lower total mortality, with extreme-quintile hazard ratios of 0.83 for EPA (95\% CI, 0.71 to 0.98; P for trend = 0.005), 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008), 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend < 0.001). Lower risk was largely attributable to fewer cardiovascular than noncardiovascular deaths. Individuals in the highest quintile of phospholipid ω3-PUFA level lived an average of 2.22 more years (CI, 0.75 to 3.13 years) after age 65 years than did those in the lowest quintile.

LIMITATION: Temporal changes in fatty acid levels and misclassification of causes of death may have resulted in underestimated associations, and unmeasured or imperfectly measured covariates may have caused residual confounding.

CONCLUSION: Higher circulating individual and total ω3-PUFA levels are associated with lower total mortality, especially CHD death, in older adults.

PRIMARY FUNDING SOURCE: National Institutes of Health.

}, keywords = {Aged, Biomarkers, Cause of Death, Coronary Disease, Diet Records, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Feeding Behavior, Female, Humans, Male, Prospective Studies, Risk Assessment, Stroke}, issn = {1539-3704}, doi = {10.7326/0003-4819-158-7-201304020-00003}, author = {Mozaffarian, Dariush and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Huang, Hongyan and Sacks, Frank M and Rimm, Eric B and Wang, Molin and Siscovick, David S} } @article {6562, title = {Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study.}, journal = {Br J Nutr}, volume = {112}, year = {2014}, month = {2014 Oct 14}, pages = {1206-13}, abstract = {

Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18~:~3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged >=~65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0{\textperiodcentered}73 (95~\% CI 0{\textperiodcentered}61, 0{\textperiodcentered}88) and 0{\textperiodcentered}64 (95~\% CI 0{\textperiodcentered}52, 0{\textperiodcentered}80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.

}, keywords = {Aged, alpha-Linolenic Acid, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Diet, Female, Humans, Male, Mortality, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke, United States}, issn = {1475-2662}, doi = {10.1017/S0007114514001925}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Sitlani, Colleen and Psaty, Bruce M and Rimm, Eric B and Song, Xiaoling and McKnight, Barbara and Spiegelman, Donna and King, Irena B and Lemaitre, Rozenn N} } @article {6397, title = {Plasma phospholipid saturated fatty acids and incident atrial fibrillation: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {3}, year = {2014}, month = {2014 Jun 26}, pages = {e000889}, abstract = {

BACKGROUND: Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF.

METHODS AND RESULTS: The study population included 2899 participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long-chain saturated fatty acids-palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)-with incident AF. During a median of 11.2 years of follow-up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95\% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95\% CI) for AF in the top and bottom quartiles were 0.76 (95\% CI: 0.61, 0.95) for 18:0; 0.78 (95\% CI: 0.63, 0.97) for 20:0; 0.62 (95\% CI: 0.50, 0.78) for 22:0; and 0.68 (95\% CI: 0.55, 0.85) for 24:0.

CONCLUSIONS: Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer-chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Eicosanoic Acids, Fatty Acids, Female, Humans, Longitudinal Studies, Male, Palmitic Acid, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors, Stearic Acids, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.114.000889}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Djouss{\'e}, Luc and Heckbert, Susan R and King, Irena B and McKnight, Barbara and Sitlani, Colleen and Sacks, Frank M and Song, Xiaoling and Sotoodehnia, Nona and Spiegelman, Donna and Wallace, Erin R and Lemaitre, Rozenn N} } @article {6609, title = {Plasma phospholipid trans-fatty acids levels, cardiovascular diseases, and total mortality: the cardiovascular health study.}, journal = {J Am Heart Assoc}, volume = {3}, year = {2014}, month = {2014 Aug}, abstract = {

BACKGROUND: While self-reported trans-fatty acid (TFA) consumption is linked to coronary heart disease (CHD), relationships between objective biomarkers of TFA subtypes (t-16:1n9, total t-18:1, and cis/trans-(c/t-), t/c- and t/t-18:2) and cardiovascular disease (CVD) or total mortality are not well established.

METHODS AND RESULTS: We evaluated 2742 adults in the Cardiovascular Health Study, aged 74{\textpm}5 years and free of prevalent CVD, with plasma phospholipid TFA measures in 1992. Incident fatal and nonfatal CHD events, CVD and non-CVD mortality, and total mortality were centrally adjudicated through 2010. Risks were assessed using Cox proportional hazards. During 31 494 person-years, 1735 total deaths and 639 total CHD events occurred. In the multivariate model including mutual adjustment for the 5 TFA subtypes, circulating t/t-18:2 was associated with higher total mortality (extreme quintile hazard ratio (HR)=1.23, 95\% CI=1.04 to 1.44, P-trend=0.01), CVD mortality (HR=1.40, 95\% CI=1.05 to 1.86, P-trend=0.02), and total CHD (HR=1.39, 95\% CI=1.06 to 1.83, P-trend=0.01). t/c-18:2 was positively related to total mortality (HR=1.19, P-trend=0.05), total CHD (HR=1.67, P-trend=0.002), and nonfatal CHD (HR=2.06, P-trend=0.002) after mutual adjustment; these associations were insignificant without mutual adjustment. Neither t-16:1n9 nor t-18:1 was significantly associated with total mortality or CVD, nor was c/t-18:2 if we excluded early cases.

CONCLUSIONS: Among circulating TFAs, t/t-18:2 was most adversely associated with total mortality, mainly due to the increased risk of CVD. t/c-18:2 was also positively associated with total mortality and CHD, but only after adjustment for other TFAs. These results highlight the need for further investigation of dietary sources, nondietary determinants, and health effects of specific TFA subtypes, especially t-18:2 isomers.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cohort Studies, Dietary Fats, Female, Follow-Up Studies, Humans, Incidence, Male, Mortality, Phospholipids, Prognosis, Proportional Hazards Models, Prospective Studies, Trans Fatty Acids}, issn = {2047-9980}, doi = {10.1161/JAHA.114.000914}, author = {Wang, Qianyi and Imamura, Fumiaki and Lemaitre, Rozenn N and Rimm, Eric B and Wang, Molin and King, Irena B and Song, Xiaoling and Siscovick, David and Mozaffarian, Dariush} } @article {6663, title = {Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 May}, pages = {1047-54}, abstract = {

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47\% lower risk of diabetes (95\% CI: 23\%, 63\%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33\% (95\% CI: 6\%, 53\%; P-trend: 0.02) and 37\% (95\% CI: 11\%, 55\%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32\% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cross-Sectional Studies, Diabetes Mellitus, Diet, Eicosanoic Acids, Fatty Acids, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Observational Studies as Topic, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101857}, author = {Lemaitre, Rozenn N and Fretts, Amanda M and Sitlani, Colleen M and Biggs, Mary L and Mukamal, Kenneth and King, Irena B and Song, Xiaoling and Djouss{\'e}, Luc and Siscovick, David S and McKnight, Barbara and Sotoodehnia, Nona and Kizer, Jorge R and Mozaffarian, Dariush} } @article {6616, title = {Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {153-63}, abstract = {

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95\% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95\% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95\% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

}, keywords = {Aged, Biomarkers, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Incidence, Lipogenesis, Liver, Male, Palmitic Acid, Phospholipids, Prevalence, Proportional Hazards Models, Risk Factors, Stearic Acids, United States, Up-Regulation}, issn = {1938-3207}, doi = {10.3945/ajcn.114.092601}, author = {Ma, Wenjie and Wu, Jason H Y and Wang, Qianyi and Lemaitre, Rozenn N and Mukamal, Kenneth J and Djouss{\'e}, Luc and King, Irena B and Song, Xiaoling and Biggs, Mary L and Delaney, Joseph A and Kizer, Jorge R and Siscovick, David S and Mozaffarian, Dariush} } @article {8105, title = {Plasma Ceramides and Sphingomyelins in Relation to Heart Failure Risk.}, journal = {Circ Heart Fail}, volume = {12}, year = {2019}, month = {2019 Jul}, pages = {e005708}, abstract = {

BACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention.

METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95\% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction.

CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.118.005708}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Hoofnagle, Andrew and McKnight, Barbara and Fretts, Amanda M and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona} } @article {8284, title = {Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Feb 18}, pages = {e012853}, abstract = {

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76~years; 40\% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7~years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95\% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95\% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95\% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95\% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.012853}, author = {Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and Sitlani, Colleen M and McKnight, Barbara and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8909, title = {Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.}, journal = {J Lipid Res}, year = {2021}, month = {2021 Sep 20}, pages = {100119}, abstract = {

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here we investigated associations of 15 ceramide and sphingomyelin species (i.e., all sphingolipids, measured with coefficient of variation less than 20\%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose >=126 mg/dL or non-fasting glucose >=200 mg/dL; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each ceramide species were: 1.21 (95\% CI 1.09-1.34) for Cer-16, 1.23 (95\% CI 1.10-1.37) for Cer-18, 1.14 (95\% CI 1.02-1.26) for Cer-20, and 1.18 (95\% CI 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

}, issn = {1539-7262}, doi = {10.1016/j.jlr.2021.100119}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Howard, Barbara V and Umans, Jason and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Djouss{\'e}, Luc and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9171, title = {Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.}, journal = {EBioMedicine}, volume = {83}, year = {2022}, month = {2022 Sep}, pages = {104189}, abstract = {

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free~+~esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95\% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95\% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

}, keywords = {Animals, Arachidonic Acids, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Eicosanoids, Humans, Ischemic Stroke, Prospective Studies}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2022.104189}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Zeigler, Maxwell and Fretts, Amanda M and Umans, Jason G and Howard, Barbara V and Sitlani, Colleen M and McKnight, Barbara and Gharib, Sina A and King, Irena B and Siscovick, David S and Psaty, Bruce M and Sotoodehnia, Nona and Totah, Rheem A} } @article {9533, title = {Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Nov 01}, pages = {e2343854}, abstract = {

IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1\%] women; 6 [0.1\%] American Indian; 4 [0.1\%] Asian; 718 [15.6\%] Black; 3869 [83.9\%] White, and 15 [0.3\%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95\% CI, 1.12-1.59]; HR for SM-16, 1.37 [95\% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95\% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95\% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95\% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95\% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95\% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95\% CI, 0.72-1.03]).

CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

}, keywords = {Aged, Ceramides, Cohort Studies, Death, Sudden, Cardiac, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Sphingolipids, Sphingomyelins}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.43854}, author = {Bockus, Lee B and Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} }