Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts.

BACKGROUND: Research suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. OBJECTIVES: We evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. METHODS: Omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. RESULTS: In the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. CONCLUSION: This study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

ASSOCIATION OF PLASMA ω-3 FATTY ACIDS WITH EARLY AGE-RELATED MACULAR DEGENERATION IN THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS.

PURPOSE: To examine the association between omega-3 polyunsaturated fatty acids, docosahexaenoic acid, and eicosapentaenoic acid and age-related macular degeneration (AMD) in the Multi-Ethnic Study of Atherosclerosis cohort. METHODS: Multi-Ethnic Study of Atherosclerosis is a multicenter, prospective cohort study designed to identify risk factors for cardiovascular disease in four ethnic groups. Six thousand eight hundred and fourteen participants of White, African American, Hispanic/Latino, and Chinese descent, aged 45-84 years, were recruited, with those found to have cardiovascular disease excluded. Our study population included all Multi-Ethnic Study of Atherosclerosis participants with baseline polyunsaturated fatty acid measurements and retinal photography at Examination 5 (n = 3,772). Fundus photographs were assessed for AMD using a standard grading protocol. Relative risk regression (log link) determined associations between polyunsaturated fatty acid levels and AMD. RESULTS: There was a significant association between increasing docosahexaenoic acid levels and increasing docosahexaenoic acid + eicosapentaenoic acid levels with reduced risk for early AMD (n = 214 participants with early AMD, of which n = 99 (46.3%) are non-White). Eicosapentaenoic acid levels alone were not significantly associated with AMD. CONCLUSION: Our analysis suggests increasing levels of docosahexaenoic acid are associated with reduced risk for early AMD in a multiethnic cohort. This represents the first racially diverse study demonstrating an association between omega-3 polyunsaturated fatty acids and AMD risk.

Small dense low-density lipoprotein cholesterol compared to other lipoprotein biomarkers for predicting coronary heart disease among individuals with normal fasting glucose: The Multi-Ethnic Study of Atherosclerosis.

Objective: This study compared small dense low-density lipoprotein cholesterol (sdLDL-C) with apolipoprotein B (apo B), and low-density lipoprotein particles (LDL-P) in predicting CHD risk in generally healthy adults with normal fasting glucose (NFG). Methods: This study was conducted among participants with NFG in the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort with measurements of sdLDL-C, LDL-P, and apo B available at baseline (2000-2002) and follow-up CHD data (through 2015) (N = 3,258). Biomarkers were evaluated as quartiles, and in categories using clinically and 75th percentile-defined cut-points. Discordance/concordance of sdLDL-C relative to other biomarkers was calculated using 75th percentile cut-points and linear regression residuals. Associations between individual biomarkers, sdLDL-C discordance and CHD incidence were evaluated using Cox proportional hazards regression. Results: There were 241 incident CHD events in this population through 2015. Higher sdLDL-C, apo B, LDL-P were similarly associated with increased CHD in individuals with NFG. Discordance of sdLDL-C with apo B or LDL-P by 75th percentiles was not significantly associated with CHD. Residuals discordantly higher/lower sdLDL-C relative to apo B (discordant high HR=1.26, 95% CI: 0.89, 1.78; discordant low HR=0.94, 95% CI: 0.68, 1.29) and LDL-P (discordant high HR=1.25, 95% CI: 0.88, 1.75; discordant low HR=0.84, 95% CI:0.60, 1.16), compared to those with concordant measures, had non-statistically significant higher/lower risk of CHD. Conclusions: Results suggest sdLDL-C, apo B and LDL-P are generally comparable for predicting CHD events in normoglycemic individuals. Larger studies are needed to confirm findings and to investigate whether measurement of sdLDL-C may be beneficial to evaluate as an additional risk-enhancing factor.

Plasma omega-3 and saturated fatty acids are differentially related to pericardial adipose tissue volume across race/ethnicity: the Multi-ethnic Study of Atherosclerosis.

BACKGROUND: Pericardial adipose tissue (PAT) is a cardiometabolic risk factor influenced by race/ethnicity, inflammation, and metabolic dysfunction. Omega-3 fatty acids (FAs) and saturated FAs (SFAs) are known to affect these latter phenomena and may influence PAT accumulation. We aimed to determine whether plasma levels of these FAs are related to PAT volume and its rate of change over a median 3-year follow-up. METHODS: Cardiac computed tomography assessed PAT in 6785 Multi-Ethnic Study of Atherosclerosis participants. Gas chromatography flame-ionization estimated plasma phospholipid FAs. Regression analyses estimated associations of FAs with PAT volume and its rate of change with adjustments for other risk factors. Race-interactions were tested. RESULTS: In cross-section, top tertiles of omega-3 FAs and odd-chained SFAs were associated with 2.8 and 4.93 cm3 lower PAT volumes, respectively; race/ethnicity was a significant modifying variable (p < 0.002). Even-chained SFAs were associated with 3.5 cm3 greater PAT volume. With stratification by race/ethnicity, Chinese Americans in the top tertile of omega-3 FAs showed 10.5 cm3 greater PAT volume than those in the referent tertile. Black individuals in the top tertile of odd-chained SFAs showed 5.0 cm3 lower PAT compared to referents. Black and Chinese Americans in top tertiles of even-chained SFAs showed respective 3.7 and 5.9 cm3 greater PAT volumes compared to referents. Two associations were observed in prospective analyses among Caucasians; race interactions were non-significant. CONCLUSIONS: Cross-sectional and prospective findings provide inconclusive evidence as to whether plasma FAs are related to PAT in healthy individuals. Cohort studies with longer follow-up periods are warranted.

Free fatty acids and heart failure in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Free fatty acids (FFAs) may be associated with heart failure (HF) risk, but prospective research is lacking. OBJECTIVE: This study investigated associations between fasting FFAs and HF incidence overall and by ejection fraction (EF) subtypes [HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF)] to evaluate FFAs as a potential biomarker for HF risk prediction. METHODS: This study was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort among 6,667 participants with complete baseline (2000-2002) FFAs and HF follow-up (through 2015). Associations between FFAs and HF incidence were evaluated with Cox proportional hazards regression. Cross-sectional associations between FFAs and HF risk markers were also evaluated using linear regression [N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular (LV) mass index] and logistic regression [LV hypertrophy (LVH)]. Stratification and cross-product terms were utilized to evaluate differences by age, sex, race/ethnicity and diabetes. RESULTS: FFAs were not associated with HF overall or with HFrEF. FFAs were not associated with HFpEF in the overall population or among males, but were borderline positively associated with risk among females (fully-adjusted tertile 3 vs. 1 HR=2.17, 95% CI: 1.06, 4.42) (sex P-interaction=0.05). FFAs were not associated with NT-proBNP, but were inversely associated with LV mass index and LVH with stronger associations among females (P-interaction≥0.10). Associations did not differ by age, race/ethnicity or diabetes status. CONCLUSIONS: FFAs generally do not appear to be an independent predictor for HF risk. Additional research is needed to confirm findings particularly studies evaluating associations by sex and EF subtypes.

Free fatty acids, cardiovascular disease, and mortality in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Fasting free fatty acid (FFA) levels may be associated with cardiovascular disease (CVD) and mortality, but research among generally healthy adults, females, and racially/ethnically diverse populations is lacking. OBJECTIVE: The primary aim of this project was to investigate prospective associations between fasting FFAs and coronary heart disease (CHD) and CVD incidence and CVD-specific and all-cause mortality in a generally healthy age, sex, and racially/ethnically heterogeneous population. METHODS: This study was conducted in the Multi-Ethnic Study of Atherosclerosis cohort using baseline (2000-2002) fasting FFAs and outcome data through 2015 (N = 6678). Cox proportional hazards regression was used to calculate hazard ratios for associations between FFAs and CHD, CVD, CVD-specific mortality, and all-cause mortality. Interactions by age, sex, race/ethnicity, and metabolic syndrome were evaluated by stratification and cross-product terms. A secondary analysis was conducted to evaluate associations between FFAs, and inflammatory and endothelial activation biomarkers were evaluated using linear regression (analytic N range: 964-6662). RESULTS: FFA levels were not associated with CHD or CVD incidence. Higher FFAs were associated with CVD-specific and all-cause mortality, but associations were attenuated in fully adjusted models with a borderline significant association remaining only for all-cause mortality (fully adjusted, per standard deviation increase hazard ratio = 1.07, 95% confidence interval: 1.00-1.14). Associations did not differ by age, sex, race/ethnicity, or metabolic syndrome. CONCLUSIONS: Fasting FFAs were not associated with CHD, CVD, or CVD-specific mortality and were modestly associated with all-cause mortality, regardless of age, sex, race/ethnicity, or metabolic syndrome status.

Association Between Homocysteine and Vascular Calcification Incidence, Prevalence, and Progression in the MESA Cohort.

Background While elevated homocysteine has been associated with calcification in several studies, its importance as a cardiovascular risk factor remains unclear. This study examines the relationship between homocysteine and vascular and valve calcification in the MESA (Multi-ethnic Study of Atherosclerosis) cohort. Methods and Results MESA participants with baseline homocysteine measurements and cardiac computed tomography scans were included (N=6789). Baseline and follow-up assessment of vascular (coronary artery [CAC], descending thoracic aorta [DTAC]) and valve (aortic valve [AVC], mitral annular [MAC]) calcification was performed. Prevalence ratio/relative risk regression was used to assess the relationship of homocysteine with prevalent and incident calcification, and multivariable logistic regression was used to assess associations between homocysteine and calcification progression. Elevated homocysteine was associated with greater relative risk of prevalent and incident CAC and incident DTAC. We also identified a strong association between elevated homocysteine and CAC and DTAC progression. Elevated homocysteine was found to confer a >2-fold increased risk of severe CAC progression (defined as ΔCAC ≥100/year) and an ≈1.5-fold increased risk for severe DTAC progression (defined as ΔDTAC ≥100/year). Conclusions To our knowledge, this is the first study demonstrating an association between elevated homocysteine and both incidence and progression of coronary and extra-coronary vascular calcification. Our findings suggest a potential role for elevated homocysteine as a risk factor for severe vascular calcification progression. Future studies are warranted to further assess the utility of homocysteine as a biomarker for vascular calcification incidence and progression. Clinical Trial Registration https://www.clinicaltrials.gov/. Unique identifier: NCT00005487.

Apolipoprotein B discordance with low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Discordant levels of apolipoprotein B (apo B) relative to low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) may be associated with subclinical atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: The present study investigated whether discordance between apo B and LDL-C or non-HDL-C levels was associated with subclinical ASCVD measured by coronary artery calcium (CAC). METHODS: This study was conducted in a subpopulation of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, aged 45 to 84 years, free of ASCVD, and not taking lipid-lowering medications at the baseline (2000-2002) (prevalence analytic N = 4623; incidence analytic N = 2216; progression analytic N = 3947). Apo B discordance relative to LDL-C and non-HDL-C was defined using residuals and percentile rankings (>5/10/15 percentile). Associations with prevalent and incident CAC (CAC > 0 vs CAC = 0) were assessed using prevalence ratio/relative risk regression and CAC progression (absolute increase/year) using multinomial logistic regression. RESULTS: Higher apo B levels were associated with CAC prevalence, incidence, and progression. Apo B discordance relative to LDL-C or non-HDL-C was inconsistently associated with CAC prevalence and progression. Discordantly high apo B relative to LDL-C and non-HDL-C was associated with CAC progression. Associations for apo B discordance with non-HDL-C remained after further adjustment for metabolic syndrome components. CONCLUSION: Apo B was associated with CAC among adults aged ≥45 years not taking statins, but provided only modest additional predictive value of apo B for CAC prevalence, incidence, or progression beyond LDL-C or non-HDL-C. Apo B discordance may still be important for ASCVD risk assessment and further research is needed to confirm findings.

Associations between omega-6 polyunsaturated fatty acids, hyperinsulinemia and incident diabetes by race/ethnicity: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND & AIMS: Omega-6 polyunsaturated fatty acids (PUFAs) have been shown to relate to insulin resistance and type 2 diabetes (T2D), but influence of race/ethnicity has not been investigated. The aim of this study was to determine whether omega-6 PUFAs, and estimated desaturase enzyme activity, are associated with fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and incident T2D, and whether associations differ by race/ethnicity. METHODS: This study was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) (N = 6282). Associations between baseline plasma phospholipid fatty acids (LA, Linoleic Acid; GLA, γ-linoleic acid; DGLA, Dihomo-γ-linolenic acid; AA, arachidonic acid; D5D, delta-5 desaturase; D6D, delta-6 desaturase), fasting glucose, insulin, and HOMA-IR [(fasting insulin - fasting glucose)/22.5] were evaluated using linear regression. Associations between omega-6 PUFAs (N = 5508 after excluding diabetics at baseline) and T2D incidence were assessed using Cox proportional hazards regression. Analyses were replicated/stratified by race/ethnicity (White, Black, Chinese, Hispanic) and tests for interaction were assessed by inclusion of a cross-product term in models. RESULTS: In fully adjusted models, insulin and HOMA-IR were positively associated with LA (insulin: 0.213 per SD, p = 0.01; HOMA-IR: 0.252 per SD, p < 0.001), GLA (insulin: 0.010 per SD, p < 0.001; HOMA-IR: 0.006 per SD, p < 0.001), DGLA (insulin: 0.279 per SD, p < 0.001; HOMA-IR: 0.175 per SD, p < 0.001) and D6D activity (insulin: 0.001 per SD, p < 0.001; HOMA-IR: 0.006 per SD, p < 0.001), and inversely associated with AA (insulin -0.272 per SD, p < 0.001; HOMA-IR: -0.125 per SD, p = 0.03) and D5D activity (insulin: -0.530 per SD, p < 0.001; HOMA-IR: -0.322 per SD, p < 0.001), while weak or no associations were observed with fasting glucose, and associations appeared to differ by race/ethnicity. After accounting for HOMA-IR at baseline, LA was inversely (HR: 0.87, p = 0.003) and DGLA (HR: 1.17, p < 0.001) and AA (HR: 1.15, p = 0.001) were positively associated with T2D in the overall population, but associations were attenuated or no longer present when stratified by race/ethnicity (P-interaction >0.05). CONCLUSIONS: Results confirm previous reports that omega-6 PUFAs are associated with hyperinsulinemia. Findings suggest omega-6 PUFAs are more likely markers of hyperinsulinemia rather than a protective/risk factor for T2D and indicate racial/ethnic differences in associations, but further research is needed to confirm findings.