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BACKGROUND AND AIMS: Elevated lipoprotein(a) [Lp(a)], high-sensitivity C-Reactive Protein (hs-CRP), and total homocysteine (tHcy) are associated with atherosclerotic cardiovascular disease (ASCVD) risk. This study investigated the individual and joint associations of Lp(a), hs-CRP and tHcy with coronary heart disease (CHD) and stroke. METHODS: This study was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (2000-2017) (CHD analytic N = 6,676; stroke analytic N = 6,674 men and women). Associations between Lp(a) (

BACKGROUND: Lipid-lowering therapy (LLT) plays a central role in managing atherosclerotic cardiovascular disease (ASCVD) risk, but its underuse is reported in over 40% of the qualified population in the United States. Studies on factors, particularly actionable factors associated with guideline-directed LLT are limited. METHODS: This study evaluated participants from the Multi-Ethnic Study of Atherosclerosis (MESA) on their qualification for LLT at exam 5 (2010-2012) according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on cholesterol management. Participants were categorized as on-LLT or off-LLT at the following exam (2016-2018). Multi-variable relative risk (RR) models were used to analyze between LLT usage and factors prior to 2013, including age, gender, race/ethnicity, education level and medical insurance, income, smoking, body mass index (BMI), diabetes, hypertension, and presence of coronary artery calcium (CAC). RESULTS: Among the 2114 participants qualified for LLT at exam 5 with an average age of 70.7, 1,129 (53.4%) were on LLT while 985 (46.6%) were off LLT at exam 6. Black participants were less likely to be on LLT compared to the reference white participants (RR 0.80, 95% confidence interval CI 0.71-0.90). Higher BMI showed borderline significant association with LLT. Comorbidities of diabetes and hypertension were positively associated with LLT use (RR 1.39 and 1.23, 95% CI 1.27-1.52 and 1.10-1.36, respectively). CAC score > 0 as an indicator of subclinical ASCVD was strongly associated with LLT too, independent of other demographic or comorbidity factors (RR 1.38, 95% CI 1.21-1.56). CONCLUSIONS: This study identifies key factors influencing LLT use among MESA participants. Black participants were less likely to be on LLT, highlighting healthcare disparities. CAC presence was strongly associated with LLT use, suggesting that CAC measurement could be an actionable factor to improve adherence to LLT guidelines.

BACKGROUND AND AIMS: Although several biomarkers have been studied in thromboembolic stroke, measuring the balance between thrombus formation and thrombolysis and data on its role in predicting stroke and atrial fibrillation (AF)-related stroke is limited. We sought to assess atherothrombotic biomarkers grouped into composite factors that reflect thrombotic and thrombolytic potential, and the balance between these factors as it relates to incident stroke or transient ischemic attack (TIA) and stroke/TIA in AF. METHODS: A Thrombotic Factor, derived from fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a); and a Thrombolytic Factor, derived from plasminogen and oxidized phospholipids on plasminogen, were evaluated at baseline in 5,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We evaluated the association between these two factors representative of thrombotic and thrombolytic potential and incident stroke/TIA (n = 402), and AF-related stroke/TIA (n = 82) over a median of 13.9 and 3.7 years, respectively. Cox proportional hazard models adjusted for medication use, cardiovascular risk factors and CHA2DS2-VASc score were utilized. Harrells C-index was estimated to evaluate model performance. RESULTS: In models including both factors, Thrombotic Factor was positively while Thrombolytic Factor was inversely associated with incident stroke/TIA and AF-related stroke/TIA. Incorporating these factors along with the CHA2DS2-VASc in adjusted models resulted in a small improvement in risk prediction of incident stroke/TIA and AF-related stroke/TIA compared to models without the factors (C-index from 0.697 to 0.704, and from 0.657 to 0.675, respectively). CONCLUSIONS: Composite biomarker factors, representative of the balance between thrombotic and thrombolytic propensity, provided an improvement in predicting stroke/TIA beyond CHA2DS2-VASc score.

BackgroundEffective therapies for reducing cardiovascular disease (CVD) risk in people with elevated lipoprotein(a) are lacking, especially for primary prevention. Because of the potential association of lipoprotein(a) with thrombosis, we evaluated the relationship between aspirin use and CVD events in people with elevated lipoprotein(a).Methods and resultsWe used data from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of baseline cardiovascular disease. Due to potential confounding by indication, we matched aspirin users to nonusers using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, nonfatal myocardial infarction) stratified by baseline lipoprotein(a) level (threshold of 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. After propensity matching, the study cohort included 2183 participants, including 1234 (57%) with baseline aspirin use and 423 (19%) with lipoprotein(a) >50 mg/dL. Participants with lipoprotein(a) >50 mg/dL had a higher burden of CVD risk factors, more frequent aspirin use (61.7% versus 55.3%, P=0.02), and higher rate of incident CHD events (13.7% versus 8.9%, P50 mg/dL and aspirin use had similar CHD risk as those with lipoprotein(a) ≤50 mg/dL regardless of aspirin use.ConclusionsAspirin use was associated with a significantly lower risk for CHD events in participants with lipoprotein(a) >50 mg/dL without baseline CVD. The results of this observational propensity-matched study require confirmation in studies with randomization of aspirin use.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

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.

BACKGROUND: Maternal lipidomic profiling offers promise for characterizing lipid metabolites during pregnancy, but longitudinal data are limited. This study aimed to examine associations of longitudinal lipidomic profiles during pregnancy with multiple neonatal anthropometry using data from a multiracial cohort. METHODS: We measured untargeted plasma lipidome profiles among 321 pregnant women from the NICHD Fetal Growth Study-Singletons using plasma samples collected longitudinally during four study visits at gestational weeks (GW) 10-14, 15-26, 23-31, and 33-39, respectively. We evaluated individual lipidomic metabolites at each study visit in association with neonatal anthropometry. We also evaluated the associations longitudinally by constructing lipid networks using weighted correlation network analysis and common networks using consensus network analysis across four visits using linear mixed-effects models with the adjustment of false discover rate. FINDINGS: Multiple triglycerides (TG) were positively associated with birth weight (BW), BW Z-score, length and head circumference, while some cholesteryl ester (CE), phosphatidylcholine (PC), sphingomyelines (SM), phosphatidylethanolamines (PE), and lysophosphatidylcholines (LPC 20:3) families were inversely associated with BW, length, abdominal and head circumference at different GWs. Longitudinal trajectories of TG, PC, and glucosylcermides (GlcCer) were associated with BW, and CE (18:2) with BW z-score, length, and sum of skinfolds (SS), while some PC and PE were significantly associated with abdominal and head circumference. Modules of TG at GW 10-14 and 15-26 mainly were associated with BW. At GW 33-39, two networks of LPC (20:3) and of PC, TG, and CE, showed inverse associations with abdominal circumference. Distinct trajectories within two consensus modules with changes in TG, CE, PC, and LPC showed significant differences in BW and length. INTERPRETATION: The results demonstrated that longitudinal changes of TGs during early- and mid-pregnancy and changes of PC, LPC, and CE during late-pregnancy were significantly associated with neonatal anthropometry. FUNDING: National Institute of Child Health and Human Development intramural funding.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

Background and aimsLipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) but is not included in the Pooled Cohort Equations (PCE). We aimed to assess how well the PCE predict 10-year event rates in individuals with elevated Lp(a), and whether the addition of Lp(a) improves risk prediction.MethodsWe compared observed versus PCE-predicted 10-year ASCVD event rates, stratified by Lp(a) level and ASCVD risk category using Poisson regression, and evaluated the association between Lp(a) > 50 mg/dL and ASCVD risk using Cox proportional hazards models in the Multi-Ethnic Study of Atherosclerosis (MESA). We evaluated the C-index and net reclassification improvement (NRI) with addition of Lp(a) to the PCE.ResultsThe study population included 6639 individuals (20%, n = 1325 with elevated Lp(a)). The PCE accurately predicted 10-year event rates for individuals with elevated Lp(a) with observed event rates falling within predicted limits. Elevated Lp(a) was associated with increased risk of CVD events overall (HR 1.27, 95% CI 1.00-1.60), particularly in low (HR 2.45, 95% CI 1.40-4.31), and high-risk (HR 1.41, 95% CI 1.02-1.96) individuals. Continuous NRI (95% CI) with the addition of Lp(a) to the PCE for CVD was 0.0963 (0.0158-0.1953) overall, and 0.2999 (0.0876, 0.5525) among low-risk individuals.ConclusionsThe PCE performs well for event rate prediction in individuals with elevated Lp(a). However, Lp(a) is associated with increased CVD risk, and the addition of Lp(a) to the PCE improves risk prediction, particularly among low-risk individuals. These results lend support for increasing use of Lp(a) testing for risk assessment.

ObjectiveThis 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).MethodsThis 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.ResultsThere 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.ConclusionsResults 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.

BackgroundThis study explored the longitudinal relationship of Lp(a) (lipoprotein[a]) and hypertension to cardiovascular outcomes in a large multiethnic cohort free of baseline cardiovascular disease.MethodsIndividuals from the MESA (Multi-Ethnic Study of Atherosclerosis; N=6674) were grouped as follows: group 1: Lp(a)

BACKGROUND: Circulating individual SFAs in pregnant females are critical for maternal and fetal health. However, research on identifying their modifiable factors is limited. OBJECTIVES: We aimed to examine the associations of total physical activity (PA) and types of PA with circulating individual SFAs during pregnancy in a multiracial/multiethnic cohort of pregnant females in the United States. METHODS: The study included participants in a nested case-control study (n = 321) from the Eunice Kennedy Shriver NICHD Fetal Growth Studies-Singleton Cohort. Sampling weights were applied, so the results represented the entire Fetal Growth Cohort. Plasma phospholipid SFAs were measured at 4 visits [10-14 (visit 1), 15-26 (visit 2), 23-31 (visit 3), and 33-39 (visit 4) weeks of gestation] throughout pregnancy. PA of the previous year at visit 1 and since the previous visit at the subsequent visits was assessed using the validated Pregnancy PA Questionnaire. Time-specific and longitudinal associations were examined using multivariable linear and generalized estimating equation models. RESULTS: Total PA (metabolic equivalent of task-h/wk) was positively associated with circulating heptadecanoic acid (17:0) at visit 1 (β × 103: 0.07; 95% CI: 0.02, 0.11) and pentadecanoic acid (15:0) at visit 3 (β × 103: 0.09; 95% CI: 0.03, 0.14) independent of sociodemographic, reproductive, pregnancy, and dietary factors. Across the 4 visits, the positive associations with total PA were consistent for pentadecanoic acid (β × 103: 0.06; 95% CI: 0.02, 0.10) and heptadecanoic acid (β × 103: 0.10; 95% CI: 0.06, 0.14). Out of the 4 PA types (i.e., sports/exercise, household/caregiving, transportation, and occupational PA) considered, the magnitude of positive associations was the largest for sports/exercise PA. CONCLUSIONS: Our findings suggest that maternal PA is positively associated with circulating pentadecanoic and heptadecanoic acids. The findings warrant confirmation by future studies.This trial was registered at clinicaltrials.gov as NCT00912132.

Calcific aortic valve disease, a condition of chronic inflammation, is associated with increased cardiovascular events and all-cause mortality. Omega-3 fatty acids (O3FAs) reduce both acute and chronic inflammation, but their associations with aortic valve calcium (AVC) have not been studied. The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6,814 adults without clinical cardiovascular disease. Plasma fatty acid levels and cardiac computed tomography (CT) scans were performed at baseline, and CT scans were performed at subsequent clinical visits over a median 9-year period. We assessed whether plasma levels of O3FAs and their species correlate with the presence, severity, and progression of AVC measured by CT in Multi-Ethnic Study of Atherosclerosis. The mean age of the 6,510 included participants with baseline fatty acid levels, AVC, and covariate data was 62.1 ± 10.2 years, and 47.1% of the participants were male. Race distribution was 38.6% White, 27.2% Black, 22.1% Hispanic/Latino, and 12.1% Chinese. Among the 6,510 participants, 5,884 had a subsequent CT scan, and 3,304 had a third CT scan with AVC measurements. At baseline, 862 participants (13.2%) had prevalent AVC (Agatston score >0), and were more likely to be of older age, male, of the White race, have a lower education level, and have co-morbidities that are associated with a higher risk for AVC. Plasma tertiles of eicosapentaenoic acid, docosahexaenoic acid, and total O3FA were not associated with prevalent AVC at baseline, incident AVC, or change in AVC. In conclusion, plasma levels of O3FAs in subjects not routinely supplemented with O3FAs are not useful for predicting the presence or development of AVC. Whether high plasma O3FA levels, achievable by high-dose O3FA over-the-counter supplementation or pharmacotherapy, is associated with AVC requires further investigation.

BackgroundAortic valve calcification (AVC) shares pathological features with atherosclerosis. Lipoprotein components have been detected in aortic valve tissue, including HDL (high-density lipoprotein). HDL measures have inverse associations with cardiovascular disease, but relationships with long-term AVC progression are unclear. We investigated associations of HDL cholesterol, HDL-particle number and size, apoC3-defined HDL subtypes, and, secondarily, CETP (cholesteryl ester transfer protein) mass and activity, with long-term incidence and progression of AVC.MethodsWe used linear mixed-effects models to evaluate the associations of baseline HDL indices with AVC. AVC was quantified by Agatston scoring of up to 3 serial computed tomography scans over a median of 8.9 (maximum 11.2) years of follow-up in the Multi-Ethnic Study of Atherosclerosis (n=6784).ResultsAfter adjustment, higher concentrations of HDL-C (high-density lipoprotein cholesterol), HDL-P (HDL particles), large HDL-P, and apoC3-lacking HDL-C were significantly associated with lower incidence/progression of AVC. Neither small or medium HDL-P nor apoC3-containing HDL-C was significantly associated with AVC incidence/progression. When included together, a significant association was observed only for HDL-C, but not for HDL-P. Secondary analyses showed an inverse relationship between CETP mass, but not activity, and AVC incidence/progression. In exploratory assessments, inverse associations for HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL with AVC incidence/progression were more pronounced for older, male, and White participants. ApoC3-containing HDL-C only showed a positive association with AVC in these subgroups.ConclusionsIn a multiethnic population, HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL-C were inversely associated with long-term incidence and progression of AVC. Further investigation of HDL composition and mechanisms could be useful in understanding pathways that slow AVC.

Background and aimsHigh-dose eicosapentaenoic acid (EPA) therapy was beneficial in high-risk patients without clinical cardiovascular disease (CVD). Whether higher plasma levels of EPA and docosahexaenoic acid (DHA) have similar benefits in those without subclinical CVD is unclear. We aim to evaluate the interplay between plasma omega-3 fatty acids and coronary artery calcium (CAC) in relation to CVD events.MethodsWe examined 6568 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with plasma EPA and DHA levels and CAC measured at baseline. The primary outcome was incident CVD events (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Hazard ratios for the primary outcome were adjusted for potential confounder using Cox regression.ResultsMean ± SD age was 62.1 ± 10.2 years and 52.9% were females. The median follow-up time was 15.6 years. Higher loge(EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74-0.94) and loge(DHA) (aHR = 0.79; 95% CI, 0.66-0.96) were independently associated with fewer CVD events. The difference in absolute CVD event rates between lowest vs. highest EPA tertile increased at higher CAC levels. The adjusted HR for highest vs. lowest EPA tertile within CAC = 0 was 1.02 (95% CI, 0.72-1.46), CAC = 1-99 was 0.71 (95% CI, 0.51-0.99), and CAC≥100 was 0.67 (95% CI, 0.52-0.84). A similar association was seen in tertiles of DHA by CAC category.ConclusionsIn an ethnically diverse population free of clinical CVD, higher plasma omega-3 fatty acid levels were associated with fewer long-term CVD events. The absolute decrease in CVD events with higher omega-3 fatty acid levels was more apparent at higher CAC scores.

ObjectiveTrans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.Research design and methodsWe included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged ≥18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.ResultsDuring a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P ≥ 0.1).ConclusionsCirculating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.

AimsTraditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events.Methods and resultsThe association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2.ConclusionTwo atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.

Backgroundn-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.ObjectivesWe sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.MethodsHarmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.ResultsIn pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.ConclusionsParticipants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

BACKGROUND: Physical activity (PA) during pregnancy influences women and offsprings health via fatty acids metabolism. However, studies on associations of PA with plasma monounsaturated fatty acids (MUFAs) across pregnancy are sparse. Thus, our study aimed to examine associations of PA with individual plasma phospholipid MUFAs throughout pregnancy in a prospective and longitudinal study in the United States (US). MATERIALS AND METHODS: The study included 318 pregnant women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons cohort. PA was measured four times: PA reported at 10-14 gestational weeks (GWs) representing PA in the past year, and at 15-26 GWs, 23-31 GWs, and 33-39 GWs representing PA since the last visit. Plasma phospholipid MUFAs were measured at the same four visits as the measurement of PA. Associations between moderate-to-vigorous PA (MVPA) and the total MUFAs and seven individual plasma phospholipid MUFAs (i.e., palmitoleic acid, 18:1n6-9 trans, 18:1n6c, cis-vaccenic acid, oleic acid, eicosenoic acid, and nervonic acid) were assessed at each visit using multivariable linear regression models adjusting for confounders. RESULTS: MVPA (hours/week) reported at 15-26 GWs representing MVPA since the last visit was positively associated with total MUFAs (% of total fatty acids) [adjusted β*102 (standard error (SE)*102) = 10.41 (3.19), P = 0.001] at 15-26 GWs. For individual MUFAs, MVPA reported at 15-26 GWs representing MVPA since the last visit was positively associated with oleic acid [adjusted β*102 (SE*102) = 8.56 (2.65), P = 0.001] and eicosenoic acid [adjusted β*102 (SE*102) = 0.55 (0.20), P = 0.01] at 15-26 GWs. MVPA reported at 23-31 GWs representing MVPA since the last visit was positively associated with palmitoleic acid [adjusted β*102 (SE*102) = 2.24 (0.64), P = 0.001] at 23-31 GWs. MVPA reported at 10-14 GWs and 33-39 GWs was not associated with total or individual MUFAs. CONCLUSION: We found novel positive associations of MVPA with individual MUFAs, such as oleic acid, eicosenoic acid, and palmitoleic acid, during middle-to-late pregnancy. These findings suggest that MVPA represents a potentially modifiable factor for plasma individual MUFA levels during pregnancy.

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Background Randomized trials of pharmacologic strength omega-3 fatty acid (n3-FA)-based therapies suggest a dose-dependent cardiovascular benefit. Whether blood n3-FA levels also mediate safety signals observed in these trials, such as increased bleeding and atrial fibrillation (AF), remains uncertain. We hypothesized that higher baseline n3-FA levels would be associated with incident bleeding and AF events in MESA (Multi-Ethnic Study of Atherosclerosis), which included a population free of clinical cardiovascular disease at baseline. Methods and Results We examined the association between baseline plasma n3-FA levels (expressed as percent mass of total fatty acid) with incident bleeding and AF in MESA, an ongoing prospective cohort study. Bleeding events were identified from review of hospitalization International Classification of Diseases, Ninth Revision (ICD-9), and International Classification of Diseases, Tenth Revision (ICD-10), codes, and AF from participant report, discharge diagnoses, Medicare claims data, and study ECGs performed at MESA visit 5. Separate multivariable Cox proportional hazard modeling was used to estimate hazard ratios of the association of continuous n3-FA (log eicosapentaenoic acid [EPA], log docosahexaenoic acid [DHA], log [EPA+DHA]) and incident hospitalized bleeding events and AF. Among 6546 participants, the mean age was 62.1 years and 53% were women. For incident bleeding, consistent statistically significant associations with lower rates were seen with increasing levels of EPA and EPA+DHA in unadjusted and adjusted models including medications that modulate bleeding risk (aspirin, NSAIDS, corticosteroids, and proton pump inhibitors). For incident AF, a significant association with lower rates was seen with increasing levels of DHA, but not for EPA or EPA+DHA. Conclusions In MESA, higher plasma levels of n3-FA (EPA and EPA+DHA, but not DHA) were associated with significantly fewer hospitalized bleeding events, and higher DHA levels (but not EPA or EPA+DHA) with fewer incident AF events.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

IntroductionDisruption of lipid metabolism is implicated in gestational diabetes (GDM). However, prospective studies on lipidomics and GDM risk in race/ethnically diverse populations are sparse. Here, we aimed to (1) identify lipid networks in early pregnancy to mid-pregnancy that are associated with subsequent GDM risk and (2) examine the associations of lipid networks with glycemic biomarkers to understand the underlying mechanisms.Research design and methodsThis study included 107 GDM cases confirmed using the Carpenter and Coustan criteria and 214 non-GDM matched controls from the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, untargeted lipidomics data of 420 metabolites (328 annotated and 92 unannotated), and information on glycemic biomarkers in maternal plasma at visit 0 (10-14 weeks) and visit 1 (15-26 weeks). We constructed lipid networks using weighted correlation network analysis technique. We examined prospective associations of lipid networks and individual lipids with GDM risk using linear mixed effect models. Furthermore, we calculated Pearson's partial correlation for GDM-related lipid networks and individual lipids with plasma glucose, insulin, C-peptide and glycated hemoglobin at both study visits.ResultsLipid networks primarily characterized by elevated plasma diglycerides and short, saturated/low unsaturated triglycerides and lower plasma cholesteryl esters, sphingomyelins and phosphatidylcholines were associated with higher risk of developing GDM (false discovery rate (FDR)

BackgroundElevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular risk factors could affect their relationship.MethodsWe tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline.ResultsElevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm3/year higher for Lp(a) ≥30 versus

BackgroundLipoprotein (a) [Lp(a)] is a risk factor for coronary heart disease and calcific aortic valve disease. We determined the relationships of Lp(a) with prevalence and progression of coronary artery calcification (CAC), mitral annular calcification (MAC), and thoracic aortic calcification (TAC) in a multi-ethnic cohort of middle to older-aged adults.MethodsThis analysis included 6705 Multi-Ethnic Study of Atherosclerosis participants. Lp(a) was measured with a turbidimetric immunoassay. CAC, MAC, and TAC were assessed by cardiac computed tomography both at baseline and once during follow-up.ResultsIn adjusted relative risk regression cross-sectional analysis, a Lp(a) level ≥50 ​mg/dL was associated with a 22% higher prevalence of MAC (relative risk (RR) ​= ​1.22, 95% confidence interval (CI) 1.00, 1.49). No significant associations were observed for prevalent CAC or TAC. In adjusted prospective analyses, participants with Lp(a) ≥50 ​mg/dL were at significantly higher risk for rapid CAC progression (median follow-up ​= ​8.9 years), defined as ≥100 units/year, compared to those with lower Lp(a) levels (RR ​= ​1.67, 95% CI ​= ​1.23, 2.27). The association between higher Lp(a) levels and incident CHD was no longer significant after adjusting for CAC progression. No significant associations were observed for MAC or TAC progression (median follow-up ​= ​2.6 years).ConclusionsHigher Lp(a) levels are associated with more rapid CAC progression. Additional study is needed to better understand how this relationship can further improve the ability of Lp(a) to enhance cardiovascular disease risk prediction.

Previous studies suggested a potential relationship between plasma lipoprotein (a) [Lp(a)] and elevated depressive symptoms. We aimed to investigate any such relationship in the Multi-Ethnic Study of Atherosclerosis participants who were free of cardiovascular events. Analysis included 4938 participants without elevated depressive symptoms and with Lp(a) levels measured at baseline. Participants were examined at four clinic visits over a 10-year period. Elevated depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D) and were defined as a CES-D score ≥16 or use of anti-depressants. Lp(a) level was measured with a latex-enhanced turbidimetric immunoassay. After adjusting for demographics, socioeconomic factors and other confounding factors in Cox regression analyses, a higher ln-transformed Lp(a) level was associated with new elevated depressive symptoms since baseline (hazard ratio [95% CI] = 1.09 [1.02-1.16] per SD increment in ln-transformed level, P = 0.01). However, no association was found when elevated Lp(a) levels were assessed using clinical cut-off point (≥30 or 50 mg/dL), nor in sensitivity analyses using alternative definitions of elevated depressive symptoms. No significant interaction with race/ethnicity was found for all the above analyses. Also, no significant association was found between baseline Lp(a) levels and absolute or relative changes in CES-D score between baseline and last follow-up visits. Our study suggests a potential association between Lp(a) level and new elevated depressive symptoms, but such association was not robust in the sensitivity analyses. Future studies are warranted to investigate the role of Lp(a) in depressive symptoms in other cohorts.

ObjectiveLp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P≤5×10-8). In addition to validating previous associations at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; P=2.8×10-13) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; P=3.8×10-42). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; P=0.0071).ConclusionsIn a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

Maternal plasma phospholipid polyunsaturated fatty acids (PUFAs) play critical roles in maternal health and fetal development. Beyond dietary factors, maternal moderate-to-vigorous physical activity (MVPA) has been linked to multiple health benefits for both the mother and offspring, but studies investigating the influence of maternal MVPA on maternal PUFA profile are scarce. The objective of present study was to examine the time-specific and prospective associations of MVPA with plasma PUFA profile among pregnant women. This study included 321 participants from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort. Maternal plasma phospholipid PUFAs and MPVA were measured at four visits during pregnancy (10-14, 15-26, 23-31, and 33-39 gestational weeks (GW)). Associations of maternal MVPA with individual plasma PUFAs and desaturase activity were examined using generalized linear models. Maternal MVPA was associated inversely with plasma phospholipid linoleic acid, gamma-linolenic acid, and Δ6-desaturase in late pregnancy (23-31 or 33-39 GW), independent of maternal age, race, education, parity, pre-pregnancy body mass index, and dietary factors. Findings from this longitudinal study indicate that maternal habitual MVPA may play a role on PUFAs metabolism, particular by alerting plasma n-6 subclass and desaturase activity in late pregnancy. These associations are novel and merit confirmation in future studies.

Background and aimsSouth Asians are at increased risk for cardiovascular disease (CVD). Aortic valve calcium (AVC) is associated with CVD risk and aortic stenosis. Elevated Lp(a) is a heritable risk factor for CVD and AVC. AVC prevalence and its association with Lp(a) have not been studied in South Asians.MethodsAmong participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study (n = 695), AVC prevalence and extent were compared to four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA) (n = 4671). Multivariable regression was performed to evaluate associations between Lp(a) and AVC stratified by race/ethnic groups, adjusting for cardiovascular risk factors.ResultsAfter age and sex adjustment, South Asians had higher median Lp(a) (17.0 mg/dL) compared to Whites (12.9 mg/dL), Hispanics (13.1 mg/dL) and Chinese Americans (12.9 mg/dL), and Blacks had highest Lp(a) levels (35.1 mg/dL). There were no differences in the odds of AVC in South Asians compared with Whites or Hispanics, after age and sex adjustment (p = 0.64 and 0.63, respectively). Odds of AVC was lower in Chinese (OR 0.35; 95%CI 0.23-0.54) and somewhat lower in Blacks compared with South Asians (OR 0.76; 0.56-1.04). There were no associations between Lp(a) and AVC presence or extent in South Asians. Lp(a) was associated with AVC only among Blacks and Whites.ConclusionsAlthough present in Whites and Blacks, there were no associations between Lp(a) and AVC in South Asians. These differences may be due to statistic power or race specific modifying factors that influences the effect of Lp(a) particles on AVC pathogenesis.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

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