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Shearer G.C.,Cardiovascular Health Research Center | Harris W.S.,Cardiovascular Health Research Center | Pedersen T.L.,University of California at Davis | Newman J.W.,University of California at Davis
Journal of Lipid Research | Year: 2010

The long-chain omega-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) have beneficial health effects, but the molecular mediators of these effects are not well characterized. Oxygenated n-3 FAs (oxylipins) may be an important class of mediators. Members of this chemical class include epoxides, alcohols, diols, and ketones, many of which have bioactivity in vitro. Neither the presence of n-3 oxylipins in human plasma nor the effect of n-3 FA ingestion on their levels has been documented. We measured plasma oxylipins derived from both the n-3 and n-6 FA classes in healthy volunteers (n = 10) before and after 4 weeks of treatment with prescription n-3 FA ethyl esters (4 g/day). At baseline, EPA and DHA oxylipins were detected in low (1-50 nM) range, with alcohols > epoxides ≥ diols. Treatment increased n-3 oxylipin levels 2- to 5-fold and reduced selected n-6 oxylipins by ∼20%. This is the first documentation that endogenous n-3 oxylipin levels can be modulated by n-3 FA treatment in humans. The extent to which the beneficial cardiovascular effects of n-3 FAs are mediated by increased n-3 and/or reduced n-6 oxylipin levels remains to be explored.


Pottala J.V.,OmegaQuant LLC | Polreis J.,OmegaQuant LLC | Robinson J.,University of Iowa | Harris W.S.,OmegaQuant LLC | And 3 more authors.
Lipids | Year: 2012

Red blood cell (RBC) fatty acid (FA) patterns have been shown to predict risk for cardiovascular and other chronic diseases. As part of a project analyzing RBC samples from the Women's Health Initiative Memory Study (WHIMS) we observed implausibly low levels of highly unsaturated fatty acids (HUFA) suggestive of degradation. This was hypothesized to be due to short term storage (<1 month) at -20 °C during sample aliquoting. The purpose of this study was to measure the extent of degradation that occurs under these conditions, and then to use regression calibration equations with multiple imputations to correct the biases. Samples from the Women's Health Initiative that had always been stored at -80 °C were obtained and subjected to similar conditions as the WHIMS samples. General linear mixed models were used to develop bias-corrected calibration equations for each fatty acid. Sample degradation occurred at -20 °C with the average HUFA loss of 3.5 to 5.9 % per week depending on aliquot size (250 and 80 μL, respectively). Using the ratio of HUFA to saturated fatty acids (HUFA/SAT) as a marker of degradation, this bias-correction method raised the HUFA/SAT from 0.70 to 0.81, which was similar to that (0.78) seen in another large study with optimal processing. In summary, RBC samples should always be stored at -80 °C. The FA compositions of the degraded RBC samples from WHIMS were rehabilitated by application of regression calibration equations and multiple imputations, and these imputed datasets should be used in all future WHIMS studies. © AOCS 2012.


Pottala J.V.,Cardiovascular Health Research Center | Garg S.,Emory University | Cohen B.E.,University of California | Whooley M.A.,University of California | Harris W.S.,Cardiovascular Health Research Center
Circulation: Cardiovascular Quality and Outcomes | Year: 2010

Background-Omega-3 fatty acid (n-3 FA) blood levels and intake have been inversely associated with risk for sudden cardiac death, but their relationship with all-cause mortality is unclear. The purpose of this study was to determine the extent to which baseline blood n-3 FA levels are associated with reduced risk for all-cause mortality in patients with stable coronary heart disease. Methods and Results-The Heart and Soul study used a prospective cohort design with a median follow-up of 5.9 years. Patients were recruited between 2000 and 2002 from 12 outpatient facilities in the San Francisco Bay Area. Standard cardiovascular risk factors, demographics, socioeconomic status, health behaviors, and inflammatory markers were collected at baseline. Fasting blood levels of eicosapentaenoic and docosahexaenoic acids were measured and expressed as a percent of total blood FAs. Vital status was assessed with annual telephone interviews and confirmed by review of death certificates. There were 237 deaths among 956 patients. Cox proportional hazards models were used to evaluate the extent to which blood eicosapentaenoic and docosahexaenoic acids were independently associated with all cause mortality. Compared with patients having baseline eicosapentaenoic and docosahexaenoic acids levels below the median (<3.6%), those at or above the median had a 27% decreased risk of death (hazard ratio, 0.73; 95% confidence interval, 0.56-0.94). This association was unaffected by adjustment for age, sex, ethnicity, center, socioeconomic status, traditional cardiovascular risk factors, and inflammatory markers (hazard ratio, 0.74; 95% confidence interval, 0.55-1.00, P<0.05). Conclusions-In these outpatients with stable coronary heart disease, blood n-3 FA levels were inversely associated with total mortality independent of standard and emerging risk factors, suggesting that reduced tissue n-3 FA levels may adversely impact metabolism. © 2010 American Heart Association, Inc.


Block R.,University of Rochester | Kakinami L.,University of Rochester | Liebman S.,University of Rochester | Shearer G.C.,Cardiovascular Health Research Center | And 2 more authors.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2012

Introduction: Data on the associations of fatty acids with chronic kidney disease (CKD) are sparse. Materials and methods: We performed a cross-sectional study of 2792 men and women from the MESA cohort of African-American, Caucasian, Chinese and Hispanic adults without known cardiovascular disease. Plasma phospholipid fatty acid proportions were associated with estimated glomerular filtration rate (eGFR) and the albumin/creatinine ratio. Results: Cis-vaccenic acid (18:1. n-7), adjusted for other fatty acids using multivariate logistic regression (CI: 1.0-1.4), and step-wise logistic regression (CI: 1.02-1.42), was positively associated with reduced eGFR. The Framingham Risk Score, when adjusting for fatty acid proportions and demographic factors, was positively associated with CKD as measured by the eGFR and the albumin/creatinine ratio. Discussion and conclusions: Plasma phospholipid proportions of the 18 carbon monounsaturated cis-vaccenic acid {18:1. n-7}) and the Framingham Risk Score are associated with kidney function. The potential role of 18:1. n-7 in the development of CKD warrants further investigation. © 2012 Elsevier Ltd.


Shearer G.C.,Cardiovascular Health Research Center | Carrero J.J.,Karolinska Institutet | Heimburger O.,Karolinska Institutet | Barany P.,Karolinska Institutet | Stenvinkel P.,Karolinska Institutet
Journal of Renal Nutrition | Year: 2012

Although the value of red blood cell fatty acids (FAs) in estimating risk for acute coronary syndrome in the general population is evident, the value of FAs in chronic kidney disease (CKD) is unknown. Here, we provide a pilot analysis in a spectrum of CKD patients. Plasma samples were obtained from 20 incident dialysis patients (CKD stage 5), matched with samples from 10 CKD stage 3-4 patients, and 10 control subjects. Whole plasma FAs were measured using gas chromatography. Whereas neither linoleic acid nor arachidonate acid were altered in CKD, metabolic intermediates of arachidonate synthesis (γ-linolenate and dihomo γ-linolenate) were reduced in CKD. Demming (orthogonal) correlation of FA abundance with estimated GFR identified several saturated and unsaturated FAs in addition to the intermediates; again, neither linoleate nor arachidonate were related. Follow-up data within the CKD stage 5 patients revealed that nervonic acid, a component of membrane sphingolipids and phosphatidylethanolamines, was a significant predictor of all-cause mortality; the age-adjusted relative risk for a 0.15% change is 2.1 (1.4, 3.7; 95% CI; P = .0008). These findings support the exploration of FAs in larger studies for validation of the role FAs in cardiovascular risk and mortality in CKD. © 2012 National Kidney Foundation, Inc.


Wright C.D.,Cardiovascular Health Research Center | Wu S.C.,Cardiovascular Health Research Center | Dahl E.F.,Cardiovascular Health Research Center | Sazama A.J.,Cardiovascular Health Research Center | O'Connell T.D.,Cardiovascular Health Research Center
Cellular Signalling | Year: 2012

Conventional models of G-protein coupled receptor (GPCR) signaling describe cell surface receptors binding to external ligands, such as hormones or circulating peptides, to induce intracellular signaling and a physiologic response. However, recent studies identify new paradigms indicating that GPCRs localize to and signal at the nucleus and that GPCR oligomers can influence receptor function. Previously, we reported that endogenous α1-adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. In this study, we examined the mechanisms behind α1-AR nuclear localization and how nuclear localization impacted receptor function. We verified that endogenous α1-ARs localized to the nuclear membrane of intact nuclei isolated from wild-type adult cardiac myocytes. Next, we identified and disrupted putative nuclear localization sequences in both the α1A- and α1B-adrenergic receptors, which led to mis-localization of α1-ARs in cultured adult cardiac myocytes. Using these mutants, we demonstrated that nuclear localization was required for α1-signaling in adult cardiac myocytes. We also found that the nuclear export inhibitor leptomycin B inhibited α1-AR signaling, indicating α1-AR signaling must arise in the nucleus in adult cardiac myocytes. Finally, we found that co-localization of the α1-subtypes at the nuclei in adult cardiac myocytes facilitated the formation of receptor oligomers that could affect receptor signaling. In summary, our data indicate that α1-AR nuclear localization can drive the formation of receptor oligomers and regulate signaling in adult cardiac myocytes. © 2011 Elsevier Inc..


Savinova O.V.,Cardiovascular Health Research Center | Fillaus K.,Cardiovascular Health Research Center | Harris W.S.,University of South Dakota | Shearer G.C.,Cardiovascular Health Research Center | And 2 more authors.
Atherosclerosis | Year: 2015

Objective: Prescription omega-3 acid ethyl esters (P-OM3) and extended release niacin (ERN) both have beneficial effects on plasma lipids and lipoproteins. The purpose of this study was to describe the effects of mono- and combination (Combo) therapy of these agents in patients with the metabolic syndrome. Methods: Very low density (VLDL), intermediate/low density (IDL/LDL, hereafter LDL), and high density lipoproteins (HDL) were isolated from 56 overweight patients with elevated triglyceride/HDL-C ratios at baseline and after 16 weeks of treatment with placebo, ERN (2g/day), P-OM3 (4g/day), or Combo and then analyzed by quantitative electrophoresis for apolipoproteins (apo) A1, A2, B, C2, C3 and E. Total plasma concentrations and the ratios of each apo with apoB (in VLDL and LDL) and with apoA1 (in HDL) were calculated. An apoC3 glycosylation index (a ratio between di- and mono-sialylated isoforms) was also determined in plasma and in each lipoprotein fraction. Results: ERN reduced plasma apoB (-11%, p<0.05). Combo increased LDL apoE/apoB ratio (64%, p<0.01) and LDL apoA1/apoB (91%, p<0.05). ERN increased the apoC3 glycosylation index only in HDL (37%, p<0.05), whereas P-OM3 and Combo increased the index in whole plasma (48% and 49%, respectively, p<0.05 for both) and in every lipoprotein class (VLDL: 26%, p<0.01 and 26%, p<0.05; LDL: 55%, p<0.01 and 61%, p<0.01; HDL: 43%, p<0.001 and 44%, p<0.001, respectively). All findings were significant after adjustment for age, sex, body mass index (BMI), smoking, medications, and baseline apo value. Conclusions: ERN produced a beneficial reduction in plasma apoB. The enrichment of LDL with apoE and apoA1 was unique to the Combo group and might be beneficial owing to the atheroprotective properties of apoE and HDL2 (a likely source of apoA1 in LDL fraction). The effect of therapies on the apoC3 glycosylation index is a novel finding, the implications of which will require further study. © 2015 Elsevier Ireland Ltd.


Harris W.S.,Cardiovascular Health Research Center | Thomas R.M.,Wheaton College at Illinois
Clinical Biochemistry | Year: 2010

Objectives: We conducted a pilot study to estimate the biological variability and effects of a prior meal on the omega-3 fatty acid (FA) content of 3 blood FA pools. Design and methods: We measured FA levels in red blood cells (RBCs), plasma and plasma phospholipids (PL) obtained from 20 healthy volunteers tested weekly over 6 weeks. Results: The within-subject coefficients of variation were 4.1% ± 1.9%, 15.9% ± 6.4%, and 14.5% ± 8.4%, respectively (RBC vs. others, p < 0.001). RBC omega-3 FA content had the lowest biological variability and was not altered in the fed state. Conclusions: From the perspective of variability and of the sample types tested, RBCs may be the preferred sample type for assessing omega-3 FA status. © 2009 The Canadian Society of Clinical Chemists.


Ladesich J.B.,University of Missouri - Kansas City | Pottala J.V.,Cardiovascular Health Research Center | Romaker A.,Romaker and Associates | Harris W.S.,Cardiovascular Health Research Center | Harris W.S.,University of South Dakota
Journal of Clinical Sleep Medicine | Year: 2011

Background: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular disease (CVD). The omega-3 fatty acid docosahexaenoic acid (DHA) is a major component of neural tissues, and supplementation with fish oils improves autonomic tone and reduces risk for CVD. A link between low DHA status and less mature sleep patterns was observed in newborns. Methods: We investigated the relations between red blood cell (RBC) levels of DHA and OSA severity in 350 sequential patients undergoing sleep studies. Severity categories were defined as none/mild, moderate, and severe, based on apnea hypopnea index (AHI) scores of 0 to 14, 15 to 34, and < 34, respectively. Results: After controlling for age, sex, race, smoking, BMI, alcohol intake, fish intake, and omega-3 supplementation, RBC DHA was inversely related with OSA severity. For each 1-SDincrease in DHA levels, a patient was about 50% less likely to be classified with severe OSA. The odds ratios (95% CI) were 0.47 (0.28 to 0.80) and 0.55 (0.31 to 0.99) for being in the severe group versus the none/mild or moderate groups, respectively. Conclusion: These findings suggest that disordered membrane fatty acid patterns may play a causal role in OSA and that the assessment of RBC DHA levels might help in the diagnosis of OSA. The effects of DHA supplementation on OSA should be explored.


Shearer G.C.,Cardiovascular Health Research Center | Shearer G.C.,University of South Dakota | Savinova O.V.,Cardiovascular Health Research Center | Harris W.S.,University of South Dakota
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2012

Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels. At the pharmaceutical dose, 3.4 g/day, they reduce plasma TG by about 25-50% after one month of treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. © 2011 Elsevier B.V. All rights reserved.

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