Natalie L. Weir

Plasma Phospholipid Concentration of Cis Palmitoleic Acid and Risk of Heart Failure

Background—Although plasma palmitoleic acid has been positively associated with blood pressure, inflammation, and insulin resistance, its association with heart failure has not been investigated. We assessed whether plasma phospholipid cis-palmitoleic acid was associated with heart failure risk. Methods and Results—This ancillary study of the Physicians’ Health Study used a risk set sampling method to select 788 matched pairs. For each case of incident heart failure, we randomly selected a control among subjects that were free of heart failure and alive at the time of index case diagnosis and matched on age, year of birth, race, and time of blood collection. Plasma phospholipid fatty acids were measured using gas chromatography. Heart failure was ascertained using annual follow-up questionnaire and validated in a subsample. In a multivariable conditional logistic regression, odds ratios (95% CI) for heart failure were 1.0 (ref), 1.06 (0.75–1.48), 1.20 (0.85–1.68), and 1.58 (1.11–2.25) across consecutive quartiles of cis-palmitoleic acid (P for trend 0.009). Each SD increase in plasma cis-palmitoleic acid was associated with 17% higher odds of heart failure (95% CI: 2% to 33%) in a multivariable model. In a secondary analysis, each SD increase of log-stearoyl-coA desaturase activity (16:1n-7/16:0 ratio) was positively associated with the risk of heart failure (odds ratio: 1.14 [95% CI: 1.00 to 1.29]), whereas oleic acid and cis-vaccenic acid concentrations were not related to heart failure risk. Conclusions—Our data showed a positive association between plasma phospholipid cis- palmitoleic acid and heart failure risk in male physicians.

APOE genotype modifies the association between plasma omega-3 fatty acids and plasma lipids in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE The benefits of fish oil fatty acids eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) on plasma lipid profiles have been inconsistent but may partially depend on individual Apolipoprotein E (APOE) genotypes. We aimed to determine whether APOE genotype modifies the association of lipid profile characteristics with plasma EPA and DHA levels. METHODS APOE genotype was determined in this cross-sectional analysis of 2340 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Relative plasma phospholipid EPA and DHA levels, plasma lipids, and lipoprotein subclass particle sizes and concentrations were measured. RESULTS Significant gene-EPA interactions were found with HDL-C, and particle concentrations of large and total HDL (p(interaction) = 0.0002, 0.006, and 0.007, respectively). The above lipid targets were positively associated with EPA in the E2 groups, whereas negative trends were observed among the E4 participants. Gene-DHA interactions were noted for small LDL particle concentrations alone (p(interaction) = 0.01), where a positive trend was found among E4 but not E2 or E3 participants. CONCLUSIONS These results indicate a significant contribution of the APOE genotype to the EPA-lipid profile relationship; however, the results do not explain the differences in previous findings regarding LDL-C, triglycerides or total cholesterol. Future investigators examining the effects of EPA on HDL-C or lipoprotein characteristics may consider including APOE genotype in their analyses.

Plasma galectin 3 and heart failure risk in the Physicians' Health Study.

We sought to test the hypothesis that plasma galectin 3 (Gal‐3) is positively associated with the risk of heart failure (HF) in male subjects.

Plasma cis-vaccenic acid and risk of heart failure with antecedent coronary heart disease in male physicians

BACKGROUND & AIMS Although an inverse association of red blood cell cis-vaccenic acid and risk of myocardial infarction has been reported, it is unclear whether cis-vaccenic acid might lower the risk of heart failure (HF) with antecedent coronary heart disease (CHD). We sought to examine the relation of plasma cis-vaccenic acid with HF with antecedent CHD. METHODS This nested case-control study was based on 788 incident HF cases (of whom 258 cases had antecedent CHD) and 788 controls. Each control was selected using a risk set sampling technique at the time of the occurrence of the index case and matched on year of birth, age at blood collection, and race. Fatty acids were measured using gas chromatography and incident HF was self-reported on annual questionnaires and validation in a subsample using medical records. RESULTS In a multivariable conditional logistic regression, the odds ratio (95% confidence interval) for HF with prior CHD were 1.0 (ref), 0.72 (0.33-1.57), 0.28 (0.12-0.67), and 0.23 (0.09-0.58) across consecutive quartiles of cis-vaccenic acid (p_trend 0.0004). Each standard deviation of cis-vaccenic acid was associated with a 41% lower risk of HF with antecedent CHD (95% CI: 17%-59%) in a multivariable adjusted model. CONCLUSIONS Our data suggest that higher plasma levels of plasma cis-vaccenic acid may be associated with a lower risk of HF with antecedent CHD. Confirmation of these results in the general population including women and other ethnic groups is warranted.

n-3 Fatty Acids Attenuate the Risk of Diabetes Associated With Elevated Serum Nonesterified Fatty Acids: The Multi-Ethnic Study of Atherosclerosis

OBJECTIVE Chronically high nonesterified fatty acids (NEFAs) are a marker of metabolic dysfunction and likely increase risk of type 2 diabetes. By comparison, n-3 fatty acids (FAs) have been shown to have various health benefits and may protect against disease development. In 5,697 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we examined whether serum levels of NEFAs relate to risk of incident type 2 diabetes and further tested whether plasma n-3 FA levels may interact with this relation. RESEARCH DESIGN AND METHODS NEFAs were measured in fasting serum using an enzymatic colorimetric assay and phospholipid n-3 FAs eicosapentaenoic and docosahexaenoic acids were determined in plasma through gas chromatography-flame ionization detection in 5,697 MESA participants. Cox proportional hazards regression evaluated the association between NEFA levels and incident type 2 diabetes and whether plasma n-3 FAs modified this association adjusting for age, sex, race, education, field center, smoking, and alcohol use. RESULTS Over a mean 11.4 years of the study period, higher diabetes incidence was found across successive NEFA quartiles (Q) (hazard ratio [95% CI]): Q1, 1.0; Q2, 1.35 (1.07, 1.71); Q3, 1.58 (1.24, 2.00); and Q4, 1.86 (1.45, 2.38) (Ptrend < 0.001). A significant interaction of n-3 FAs on the relation between NEFAs and type 2 diabetes was also observed (Pinteraction = 0.03). For individuals with lower n-3 levels (<75th percentile), a higher risk of type 2 diabetes was observed across quartiles of NEFAs: Q1, 1.0; Q2, 1.41 (1.07, 1.84); Q3, 1.77 (1.35, 2.31); and Q4, 2.18 (1.65, 2.88) (Ptrend < 0.001). No significant associations were observed in those with n-3 FAs ≥75th percentile (Ptrend = 0.54). CONCLUSIONS NEFAs are a marker of type 2 diabetes and may have clinical utility for detecting risk of its development. The modifying influence of n-3 FAs suggests a protective effect against disease and/or metabolic dysfunction related to NEFAs and requires further study.

Plasma concentrations of lipids during pregnancy and the risk of gestational diabetes mellitus: A longitudinal study

Abnormal lipid profiles have been associated with gestational diabetes mellitus (GDM), but studies with longitudinal measures of lipids throughout pregnancy are sparse. The aim of the present study was to characterize longitudinal changes in lipid profiles throughout pregnancy and prospectively examine the associations of plasma lipid concentrations with risk of GDM.

5‐Lipoxygenase Gene Variants Are Not Associated With Atherosclerosis or Incident Coronary Heart Disease in the Multi‐Ethnic Study of Atherosclerosis Cohort

Background The arachidonate 5‐lipoxygenase enzyme plays a crucial role in mediating inflammation to maintain homeostasis, yet certain allelic variants of the 5‐lipoxygenase gene, ALOX5, may increase risk of atherosclerosis and coronary heart disease (CHD). Further, relations between ALOX5 and disease outcomes may be enhanced or attenuated depending on the bioavailability of 5‐lipoxygenase enzyme substrates. By using a candidate gene approach in 6153 Multi‐Ethnic Study of Atherosclerosis (MESA) participants, associations were determined among 1348 ALOX5 single nucleotide polymorphisms (SNPs) and carotid intima‐media thickness (cIMT) as well as incident CHD, and interactions with plasma concentrations of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid were tested. Methods and Results Multivariable linear regression was used to test for associations between cIMT and ALOX5 SNPs, and Cox regression was used for incident CHD. Bonferroni correction was used for multiple hypothesis testing. No significant associations between ALOX5 SNPs and cIMT or CHD events were observed. Levels of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid concentrations did not modify the relations of ALOX5 with either outcome. Conclusions ALOX5 gene variants do not appear to be related to clinical CHD events or subclinical atherosclerosis regardless of bioavailable enzyme substrate levels in this multiethnic cohort. Further studies that directly examine protein expression or enzyme activity may better define the arachidonate 5‐lipoxygenase pathway in disease development and progression.

Pilot study of placental tissue collection, processing, and measurement procedures for large scale assessment of placental inflammation

Background Placental dysfunction is related to many pregnancy complications, but collecting placental specimens for investigation in large scale epidemiologic studies is often infeasible. Standard procedures involving immediate collection after birth and snap freezing are often cost prohibitive. We aimed to collect pilot data regarding the feasibility and precision of a simpler approach, the collection of tissue samples following 24 hours of refrigeration of whole placentae at 4°C, as compared to the “gold standard” of snap freezing excised tissue within 40 minutes of delivery for the assessment of inflammatory cytokines. Methods Placentae were collected from 12 women after delivering live-born singleton babies via uncomplicated vaginal delivery. Two placentae were utilized to establish laboratory tissue processing and assay protocols. The other 10 placentae were utilized in a comparison of three tissue collection conditions. Specifically, key inflammatory cytokines were measured in 3 sections, representing three collection conditions. Sections 1 (full thickness) and 2 (excised prior to freezing) were obtained within 40 minutes of delivery and snap frozen in liquid nitrogen, and section 3 (full thickness) was obtained after refrigerating the placenta at 4°C for 24 hours. Results IL-6, IL-10, and IL-8 all had comparable concentrations and variability overall in all three section types. Levels of tumor necrosis factor alpha (TNF-α) were too low among samples to reliably measure using immunoassay. Conclusions Refrigeration of placentae prior to processing does not appear to compromise detection of these cytokines for purposes of large scale studies. These findings provide a framework and preliminary data for the study of inflammatory cytokines within the placenta in large scale and/or resource-limited settings.