Publications by authors named "James V Pottala"

31 Publications

Longitudinal autoantibody responses against tumor-associated antigens decrease in breast cancer patients according to treatment modality.

BMC Cancer 2018 01 31;18(1):119. Epub 2018 Jan 31.

Cancer Biology Research Center, Sanford Research, Sioux Falls, SD, USA.

Background: Metastatic breast cancer (BCa) is most often diagnosed months after completion of treatment of the primary tumor when a patient reports physical symptoms. Besides a physical examination, no other alternative recurrence screening method is recommended for routine follow-up care. Detection of autoantibodies against tumor-associated antigens (TAAs) has demonstrated promise for distinguishing healthy women from patients diagnosed with primary BCa. However, it is unknown what changes occur to patient autoantibody levels during and after treatment.

Methods: Three serial blood draws were collected from 200 BCa patients: before treatment, 6 and 12 months after surgery. Patients were categorized according to treatment regimen, including surgery, chemotherapy, radiation, trastuzumab and hormonal therapies. The longitudinal samples were assayed for autoantibody responses against 32 conformation-carrying TAAs using a Luminex multiplex bead assay.

Results: The treatment modality groups that had the greatest decrease in autoantibody response levels were radiation + hormonal therapy; radiation + chemotherapy; and radiation + hormonal therapy + chemotherapy. For these three treatment groups, autoantibody responses against 9 TAAs (A1AT, ANGPTL4, CAPC, CST2, DKK1, GFRA1, GRN, LGALS3 and LRP10) were significantly reduced at 12 months after surgery compared to before treatment. One TAA, GRP78, had a significantly increased autoantibody response after 12 months.

Conclusions: Single treatment regimens alone did not significantly alter autoantibodies levels against the studied TAAs. Radiation treatment was the common denominator of the three most affected groups for significant changes in autoantibody response levels.
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http://dx.doi.org/10.1186/s12885-018-4022-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793406PMC
January 2018

Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: Secondary analyses of longitudinal data from the Women's Health Initiative Memory Study (WHIMS).

Prostaglandins Leukot Essent Fatty Acids 2017 Jun 15;121:68-75. Epub 2017 Jun 15.

Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA; OmegaQuant Analytics LLC, Sioux Falls, SD, USA. Electronic address:

Objective: To assess whether red blood cell (RBC) docosahexaenoic acid and eicosapentaenoic acid (DHA+EPA) levels have a protective association with the risk of dementia in older women.

Methods: RBC DHA+EPA levels were assessed at baseline, and cognitive status was evaluated annually in a cohort of 6706 women aged ≥65 years who participated in the Women's Health Initiative Memory Study (WHIMS). Cox regression was used to quantify the association between RBC DHA+EPA and the risk of probable dementia, independent of major dementia risk factors.

Results: During a median follow-up period of 9.8 years, 587 incident cases of probable dementia were identified. After adjusting for demographic, clinical, and behavioral risk factors, a one standard deviation increase in DHA+EPA levels was associated with a significantly lower risk of dementia (HR = 0.92, 95% CI: 0.84, 1.00; p < 0.05). This effect estimate did not meaningfully change after further adjustment for baseline cognitive function and APOE genotype. For women with high DHA+EPA exposure (1SD above mean) compared to low exposure (1SD below mean), the adjusted 15-year absolute risk difference for dementia was 2.1% (95% CI: 0.2%, 4.0%). In secondary analyses, we also observed a protective association with longitudinal change in Modified Mini-Mental State (3MS) Exam scores, but no significant association with incident MCI, PD/MCI, or baseline 3MS scores.

Discussion: Higher levels of DHA+EPA may help protect against the development of dementia. Results from prospective randomized controlled trials of DHA+EPA supplementation are needed to help clarify whether this association is causal.
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http://dx.doi.org/10.1016/j.plefa.2017.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564209PMC
June 2017

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study.

J Clin Lipidol 2017 Jan - Feb;11(1):250-259.e5. Epub 2017 Jan 12.

Department of Epidemiology, College of Public Health and Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, IA, USA.

Background: The prognostic value of circulating polyunsaturated fatty acid (PUFA) levels is unclear.

Objectives: To determine the associations between red blood cell (RBC) PUFA levels and risk for death.

Methods: This prospective cohort study included 6501 women aged 65 to 80 years who participated in the Women's Health Initiative Memory Study (enrolment began 1996). RBC PUFA levels were measured at baseline and expressed as a percent of total RBC PUFAs. PUFAs of primary interest were the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum (the Omega-3 Index). PUFAs of secondary interest included the 2 major n-6 PUFAs, linoleic acid and arachidonic acid, and the PUFA factor score (a calculated variable including 6 PUFAs that accounts for their intercorrelations). The primary outcome was total mortality through August 2014.

Results: After a median of 14.9 years of follow-up, 1851 women (28.5%) had died. RBC levels of EPA and DHA were higher in the survivors (P < .002 for each). In the fully adjusted models, the hazard ratios (99% confidence intervals) for mortality associated with a 1 standard deviation PUFA increase for total mortality were 0.92 (0.85, 0.98) for the Omega-3 Index, 0.89 (0.82, 0.96) for EPA, 0.93 (0.87, 1.0) for DHA, and 0.76 (0.64, 0.90) for the PUFA factor score. There were no significant associations of alpha-linolenic acid, arachidonic acid or linoleic acid with total mortality.

Conclusions: Higher RBC levels of marine n-3 PUFAs were associated with reduced risk for all-cause mortality. These findings support the beneficial relationship between the Omega-3 Index and health outcomes.
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http://dx.doi.org/10.1016/j.jacl.2016.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563382PMC
October 2017

Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial.

Circulation 2016 Aug;134(5):378-91

From Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women's Hospital, Boston, MA (B.H., S.A., R.S., S.A., D.M., J.H.F., R.B., M.S., M.J.-H., R.Y.K.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.H., S.A., R.S., S.A., D.M., J.H.F., E.M.A., R.Y.K.); Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Fall (J.V.P., W.H.); Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston (R.S., S.A.F.); Department of Radiology, Massachusetts General Hospital, Boston (H.L., B.B.G., U.F.); Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.A.); Health Diagnostic Laboratory, Inc., Richmond, VA (J.P.M.); and OmegaQuant Analytics, LLC, Sioux Falls, SD (W.H.).

Background: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown.

Methods: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size.

Results: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy.

Conclusions: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.019949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973577PMC
August 2016

Red Blood Cell Fatty Acids and Incident Diabetes Mellitus in the Women's Health Initiative Memory Study.

PLoS One 2016 16;11(2):e0147894. Epub 2016 Feb 16.

Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.

Context: The relations between dietary and/or circulating levels of fatty acids and the development of type 2 diabetes is unclear. Protective associations with the marine omega-3 fatty acids and linoleic acid, and with a marker of fatty acid desaturase activity delta-5 desaturase (D5D ratio) have been reported, as have adverse relations with saturated fatty acids and D6D ratio.

Objective: To determine the associations between red blood cell (RBC) fatty acid distributions and incident type 2 diabetes.

Design: Prospective observational cohort study nested in the Women's Health Initiative Memory Study.

Setting: General population.

Subjects: Postmenopausal women.

Main Outcome Measures: Self-reported incident type 2 diabetes.

Results: There were 703 new cases of type 2 diabetes over 11 years of follow up among 6379 postmenopausal women. In the fully adjusted models, baseline RBC D5D ratio was inversely associated with incident type 2 diabetes [Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.81-0.95) per 1 SD increase. Similarly, baseline RBC D6D ratio and palmitic acid were directly associated with incident type 2 diabetes (HR 1.14, 95% CI 1.04-1.25; and HR 1.24, 95% CI 1.14-1.35, respectively). None of these relations were materially altered by excluding incident cases in the first two years of follow-up. There were no significant relations with eicosapentaenoic, docosahexaenoic or linoleic acids.

Conclusions: Whether altered fatty acid desaturase activities or palmitic acid levels are causally related to the development of type 2 diabetes cannot be determined from this study, but our findings suggest that proportions of certain fatty acids in RBC membranes are associated with risk for type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147894PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755935PMC
July 2016

Comparison of cardiometabolic risk biomarkers from a national clinical laboratory with the US adult population.

J Clin Lipidol 2015 Nov-Dec;9(6):817-823. Epub 2015 Aug 8.

Department of Research and Development, Health Diagnostic Laboratory, Inc., Richmond, VA, USA; Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. Electronic address:

Background: Clinical laboratory patient databases are an untapped source of valuable diagnostic and prognostic information. However, the lack of associated clinical and/or demographic information and questionable generalizability to nonpatient populations often limit utility of these data.

Objectives: This study compared levels of cardiometabolic biomarkers between a national clinical laboratory patient cohort (Health Diagnostic Laboratory [HD Lab]) and the US population as inferred from the National Health and Nutrition Examination Survey (NHANES, 2011-2012).

Methods: Sample sizes for HD Lab ranged from 199,000 to 739,000 and for NHANES from 2200 to 5300. The latter were weighted to represent the adult US population (∼220 million). Descriptive statistics were compared for body mass index, 5 lipid biomarkers, and 3 glycemic biomarkers.

Results: Using age- and sex-matched data, mean biomarker values (mg/dL unless noted) and percent differences (%) for HD Lab vs NHANES were body mass index (kg/m(2)), 29.1 vs 28.6 (1.7%); total cholesterol, 185 vs 193 (-4.1%); apolipoprotein B, 92 vs 90 (2.2%); low-density lipoprotein cholesterol, 107 vs 115 (-7%); high-density lipoprotein cholesterol, 53 vs 53 (0%); triglycerides, 128 vs 127 (0.8%); glucose, 99 vs 108 (-8.3%); insulin (uU/mL), 13.7 vs 13.4 (2.2%); and hemoglobin A1c (%), 5.6 vs 5.8 (-3.4%). Although all differences were statistically significant, only low-density lipoprotein cholesterol and glucose differed by more than 5%. These may reflect a greater use of medications among HD Lab patients and/or preanalytical factors.

Conclusions: Cardiometabolic risk markers from a national clinical laboratory were broadly similar to those of the US population; thus, with certain caveats, data from the former may be generalizable to the latter.
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http://dx.doi.org/10.1016/j.jacl.2015.07.014DOI Listing
September 2016

A comparative study of four independent methods to measure LDL particle concentration.

Atherosclerosis 2015 Nov 3;243(1):99-106. Epub 2015 Sep 3.

Cardiovascular Genetics, Cardiovascular Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84108, USA.

Background: Low-density lipoprotein particle concentration (LDL-P) is generally more predictive of clinical cardiovascular endpoints than LDL cholesterol (LDL-C). Few studies have directly compared multiple LDL-P methods, particularly with ultracentrifugation.

Objective: Examine comparability and precision of 4 LDL-P methods.

Methods: We divided serum from 48 subjects into blinded triplicates and measured LDL-P in 3 separate laboratories by 4 methods: ultracentrifugation (reference method), a novel electrophoretic method, and nuclear magnetic resonance spectroscopy (NMR) by 2 independent methods: a 400 MHz Vantera(®) instrument supplied by Liposcience (LS-NMR) and operated at ARUP Laboratories, and a 600 MHz Bruker instrument (ASCEND 600) operated at Health Diagnostic Laboratory (HD-NMR).

Results: Of the 4 methods, ultracentrifugation was the most precise and LS-NMR the least; the latter had a significantly greater CV (p < 0.0001) as compared with all 3 of the other methods, although all CVs were clinically acceptable. The electrophoretic method showed similar precision to ultracentrifugation, while HD-NMR was intermediate. The HD-NMR had the slope closest to 1 (0.90, 95% CI 0.71 to 1.09) and the intercept closest to 0 (-48, -353 to 256) compared to the ultracentrifugation method in Deming regression models. While the two NMR methods correlated well (r = 0.95) with each other and had a slope equivalent to 1 (1.08, 0.98 to 1.19), their intercept in Deming regression excluded 0 (194, 53 to 335) indicating a vertical shift between the two methods.

Conclusions: This LDL-P method comparison may prove useful for future research and clinical applications.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.042DOI Listing
November 2015

Serum α-hydroxybutyrate (α-HB) predicts elevated 1 h glucose levels and early-phase β-cell dysfunction during OGTT.

BMJ Open Diabetes Res Care 2014 24;2(1):e000038. Epub 2014 Sep 24.

Department of Medicine, Biochemistry and Nutrition , University of Utah , Salt Lake City, Utah , USA.

Objective: Serum α-hydroxybutyrate (α-HB) is elevated in insulin resistance and diabetes. We tested the hypothesis that the α-HB level predicts abnormal 1 h glucose levels and β-cell dysfunction inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT).

Research Design And Methods: This cross-sectional study included 217 patients at increased risk for diabetes. 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period. OGTT responses were analyzed by repeated measures analysis of variance (ANOVA). Multivariable logistic regression was used to predict 1 h glucose ≥155 mg/dL with α-HB added to traditional risk factors.

Results: Mean±SD age was 51±15 years (44% male, 25% with impaired glucose tolerance). Fasting glucose and insulin levels, but not age or body mass index (BMI), were significantly higher in the second/third α-HB tertiles (>3.9 µg/mL) than in the first tertile. Patients in the second/third α-HB tertiles exhibited a higher glucose area under the receiver operating characteristics curve (AUC) and reduced initial slope of insulin response during OGTT. The AUC for predicting 1 h glucose ≥155 mg/dL was 0.82 for a base model that included age, gender, BMI, fasting glucose, glycated hemoglobin (HbA1c), and insulin, and increased to 0.86 with α-HB added (p=0.015), with a net reclassification index of 52% (p<0.0001).

Conclusions: Fasting serum α-HB levels predicted elevated 1 h glucose during OGTT, potentially due to impaired insulin secretion kinetics. This association persisted even in patients with an otherwise normal insulin-glucose homeostasis. Measuring serum α-HB could thus provide a rapid, inexpensive screening tool for detecting early subclinical hyperglycemia, β-cell dysfunction, and increased risk for diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2014-000038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212560PMC
December 2014

Comprehensive biomarker testing of glycemia, insulin resistance, and beta cell function has greater sensitivity to detect diabetes risk than fasting glucose and HbA1c and is associated with improved glycemic control in clinical practice.

J Cardiovasc Transl Res 2014 Aug 29;7(6):597-606. Epub 2014 Jul 29.

Health Diagnostic Laboratory, Inc., 737, Richmond, VA, 23219, USA,

Blood-based biomarker testing of insulin resistance (IR) and beta cell dysfunction may identify diabetes risk earlier than current glycemia-based approaches. This retrospective cohort study assessed 1,687 US patients at risk for cardiovascular disease (CVD) under routine clinical care with a comprehensive panel of 19 biomarkers and derived factors related to IR, beta cell function, and glycemic control. The mean age was 53 ± 15, 42 % were male, and 25 % had glycemic indicators consistent with prediabetes. An additional 45 % of the patients who had normal glycemic indicators were identified with IR or beta cell abnormalities. After 5.3 months of median follow-up, significantly more patients had improved than worsened their glycemic status in the prediabetic category (35 vs. 9 %; P < 0.0001) and in the "high normal" category (HbA1c values of 5.5-5.6; 56 vs. 18 %, p < 0.0001). Biomarker testing can identify IR early, enable and inform treatment, and improve glycemic control in a high proportion of patients.
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http://dx.doi.org/10.1007/s12265-014-9577-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137169PMC
August 2014

Structural equation modeling for analyzing erythrocyte fatty acids in Framingham.

Comput Math Methods Med 2014 15;2014:160520. Epub 2014 Apr 15.

Health Diagnostic Laboratory Inc., Richmond, VA 23219, USA ; Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA ; OmegaQuant Analytics, Sioux Falls, SD 57107, USA.

Research has shown that several types of erythrocyte fatty acids (i.e., omega-3, omega-6, and trans) are associated with risk for cardiovascular diseases. However, there are complex metabolic and dietary relations among fatty acids, which induce correlations that are typically ignored when using them as risk predictors. A latent variable approach could summarize these complex relations into a few latent variable scores for use in statistical models. Twenty-two red blood cell (RBC) fatty acids were measured in Framingham (N = 3196). The correlation matrix of the fatty acids was modeled using structural equation modeling; the model was tested for goodness-of-fit and gender invariance. Thirteen fatty acids were summarized by three latent variables, and gender invariance was rejected so separate models were developed for men and women. A score was developed for the polyunsaturated fatty acid (PUFA) latent variable, which explained about 30% of the variance in the data. The PUFA score included loadings in opposing directions among three omega-3 and three omega-6 fatty acids, and incorporated the biosynthetic and dietary relations among them. Whether the PUFA factor score can improve the performance of risk prediction in cardiovascular diseases remains to be tested.
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http://dx.doi.org/10.1155/2014/160520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052884PMC
January 2015

Classifying patients for breast cancer by detection of autoantibodies against a panel of conformation-carrying antigens.

Cancer Prev Res (Phila) 2014 May 18;7(5):545-55. Epub 2014 Mar 18.

2301 East 60th Street North, Sioux Falls, SD 57104.

Patients with breast cancer elicit an autoantibody response against cancer proteins, which reflects and amplifies the cellular changes associated with tumorigenesis. Detection of autoantibodies in plasma may provide a minimally invasive mechanism for early detection of breast cancer. To identify cancer proteins that elicit a humoral response, we generated a cDNA library enriched for breast cancer genes that encode membrane and secreted proteins, which are more likely to induce an antibody response compared with intracellular proteins. To generate conformation-carrying antigens that are efficiently recognized by patients' antibodies, a eukaryotic expression strategy was established. Plasma from 200 patients with breast cancer and 200 age-matched healthy controls were measured for autoantibody activity against 20 different antigens designed to have conformational epitopes using ELISA. A conditional logistic regression model was used to select a combination of autoantibody responses against the 20 different antigens to classify patients with breast cancer from healthy controls. The best combination included ANGPTL4, DKK1, GAL1, MUC1, GFRA1, GRN, and LRRC15; however, autoantibody responses against GFRA1, GRN, and LRRC15 were inversely correlated with breast cancer. When the autoantibody responses against the 7 antigens were added to the base model, including age, BMI, race and current smoking status, the assay had the following diagnostic capabilities: c-stat (95% CI), 0.82 (0.78-0.86); sensitivity, 73%; specificity, 76%; and positive likelihood ratio (95% CI), 3.04 (2.34-3.94). The model was calibrated across risk deciles (Hosmer-Lemeshow, P = 0.13) and performed well in specific subtypes of breast cancer including estrogen receptor positive, HER-2 positive, invasive, in situ and tumor sizes >1 cm.
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http://dx.doi.org/10.1158/1940-6207.CAPR-13-0416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437507PMC
May 2014

Does APOE genotype modify the relations between serum lipid and erythrocyte omega-3 fatty acid levels?

J Cardiovasc Transl Res 2014 Jul 5;7(5):526-32. Epub 2014 Mar 5.

Health Diagnostic Laboratory, Inc., 737 N. 5th St, Suite 103, Richmond, VA, 23219, USA,

Earlier reports indicated that patients with the apolipoprotein APOE ε4 allele responded to fish oil supplementation with a rise in serum low-density lipoprotein cholesterol (LDL-C) compared to ε3 homozygotes. In this study, we used clinical laboratory data to test the hypothesis that the cross-sectional relation between RBC omega-3 fatty acid status (the Omega-3 Index) and LDL-C was modified by APOE genotype. Data from 136,701 patients were available to compare lipid biomarker levels across Omega-3 Index categories associated with heart disease risk in all APOE genotypes. We found no adverse interactions between APOE genotype and the Omega-3 Index for LDL-C, LDL particle number, apoB, HDL-C, or triglycerides. However, we did find evidence that ε2 homozygotes lack an association between omega-3 status and LDL-C, apoB, and LDL particle number. In summary, we found no evidence for a deleterious relationship between lipid biomarkers and the Omega-3 Index by APOE genotype.
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http://dx.doi.org/10.1007/s12265-014-9554-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098055PMC
July 2014

Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study.

Neurology 2014 Feb 22;82(5):435-42. Epub 2014 Jan 22.

From the Department of Internal Medicine (J.V.P., W.S.H.), Sanford School of Medicine, University of South Dakota, Sioux Falls; Health Diagnostic Laboratory Inc. (J.V.P., W.S.H.), Richmond, VA; Department of Psychiatry (K.Y.), University of California Medical Center, San Francisco; Departments of Epidemiology and Internal Medicine (J.R., R.W.), University of Iowa College of Public Health, Iowa City; Department of Biostatistical Services (M.A.E.), Wake Forest School of Medicine, Winston-Salem, NC; and OmegaQuant Analytics (W.S.H.), Sioux Falls, SD.

Objective: To test whether red blood cell (RBC) levels of marine omega-3 fatty acids measured in the Women's Health Initiative Memory Study were related to MRI brain volumes measured 8 years later.

Methods: RBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes were assessed in 1,111 postmenopausal women from the Women's Health Initiative Memory Study. The endpoints were total brain volume and anatomical regions. Linear mixed models included multiple imputations of fatty acids and were adjusted for hormone therapy, time since randomization, demographics, intracranial volume, and cardiovascular disease risk factors.

Results: In fully adjusted models, a 1 SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm(3) larger brain volume (p = 0.048). DHA was marginally correlated (p = 0.063) with total brain volume while EPA was less so (p = 0.11). There were no correlations between ischemic lesion volumes and EPA, DHA, or EPA + DHA. A 1 SD greater omega-3 index was correlated with greater hippocampal volume (50 mm(3), p = 0.036) in fully adjusted models. Comparing the fourth quartile vs the first quartile of the omega-3 index confirmed greater hippocampal volume (159 mm(3), p = 0.034).

Conclusion: A higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured 8 years later. While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy. Future studies should examine whether maintaining higher RBC EPA + DHA levels slows the rate of hippocampal or overall brain atrophy.
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http://dx.doi.org/10.1212/WNL.0000000000000080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917688PMC
February 2014

Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: implications for clinical utility.

J Clin Lipidol 2013 Sep-Oct;7(5):433-40. Epub 2013 May 7.

Health Diagnostic Laboratory, Inc, 737 N 5th Street, Suite 103, Richmond, VA 23219, USA; OmegaQuant Analytics, LLC, Sioux Falls, SD, USA; Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. Electronic address:

Background: Omega-3 fatty acid (n-3 FA) biostatus can be estimated with red blood cell (RBC) membranes or plasma. The matrix that exhibits the lower within-person variability and is less affected by an acute dose of n-3 FA is preferred in clinical practice.

Objective: We compared the acute effects of a large dose of n-3 FA on RBC and plasma levels of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA).

Methods: Healthy volunteers (n = 20) were given 4 capsules containing 3.6 g of n-3 FA with a standardized breakfast. Blood samples were drawn at 0, 2, 4, 6, 8, and 24 hours. The EPA + DHA content of RBC membranes and plasma (the latter expressed as a percentage of total FA and as a concentration) were determined. General linear mixed models were used to analyze the mean response profiles in FA changes over time for plasma and RBCs.

Results: At 6 hours after load, the plasma concentration of EPA + DHA had increased by 47% (95% confidence interval [CI], 24% to 73%) and the plasma EPA + DHA percentage of total FA by 19% (95% CI, 4.7% to 36%). The RBC EPA + DHA percentage of composition was unchanged [-0.6% (95% CI, -2.6% to 1.5%)]. At 24 hours, the change in both of the plasma EPA + DHA markers was 10-fold greater than that in RBCs.

Conclusions: An acute dose of n-3 FA (eg, a meal of oily fish or fish oil supplements) taken within a day before a doctor's visit can elevate levels of EPA + DHA in plasma, whether expressed as a percentage or a concentration, but not in RBC membranes. Similar to hemoglobin A1c, which is not affected by an acute glycemic deviation, RBCs provide a more reliable estimate of a patient's chronic EPA + DHA status than does plasma.
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http://dx.doi.org/10.1016/j.jacl.2013.05.001DOI Listing
October 2014

ω-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA.

Neurology 2013 Oct 25;81(17):1484-91. Epub 2013 Sep 25.

From the Department of Epidemiology (E.M.A., R.W., R.M.C., J.G.R.), College of Public Health, and Departments of Internal Medicine (R.W., J.G.R.) and Neurology (N.L.D.), College of Medicine, University of Iowa, Iowa City; OmegaQuant Analytics (J.V.P., W.S.H.), Sioux Falls; Department of Medicine (W.S.H.), Sanford School of Medicine, University of South Dakota, Vermillion; and Department of Biostatistical Sciences (M.A.E.), Wake Forest School of Medicine, Winston-Salem, NC.

Objective: To test the hypothesis that higher levels of red blood cell (RBC) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have a protective association with domain-specific cognitive function in women aged 65 years and older.

Methods: A total of 2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy were followed with annual cognitive testing for a median of 5.9 years. In this retrospective cohort study, we assessed the relationship between prerandomization RBC DHA + EPA levels and a) cognitive measures at baseline, and b) cognitive change over time. Endpoints were composite cognitive function and performance in 7 cognitive domains: fine motor speed, verbal memory, visual memory, spatial ability, verbal knowledge, verbal fluency, and working memory.

Results: After adjustment for demographic, clinical, and behavioral characteristics, no significant (p < 0.01) cross-sectional cognitive differences were found between women in the high and low DHA + EPA tertiles at the time of the first annual cognitive battery. In addition, no significant (p < 0.01) differences were found between the high and low DHA + EPA tertiles in the rate of cognitive change over time.

Conclusions: We did not find an association between RBC DHA + EPA levels and age-associated cognitive decline in a cohort of older, dementia-free women.
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http://dx.doi.org/10.1212/WNL.0b013e3182a9584cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888166PMC
October 2013

Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.

Prostaglandins Leukot Essent Fatty Acids 2013 Apr 31;88(4):257-63. Epub 2013 Jan 31.

Health Diagnostic Laboratory, Inc., Richmond, VA, United States.

Background: The fatty acid (FA) composition of the red blood cell (RBC) has been reported to provide prognostic information regarding risk for coronary heart disease (CHD). In particular, the Omega-3 Index (RBC eicosapentaenoic acid+docosahexaenoic acid, EPA+DHA) has been shown to be independently and inversely related to risk for sudden cardiac death and for acute coronary syndromes. Higher linoleic acid (n-6) and lower trans FA levels have also been associated with improved CHD outcomes. Accordingly, the RBC FA panel has recently been introduced in routine clinical laboratory testing.

Objective: The purpose of this study was to define age- and gender-based norms for RBC FA levels.

Methods: RBC FA profiles from about 160,000 patients (48% from males, 52% from females) were measured at Health Diagnostic Laboratory. These data were used to create age decade and gender-specific norms (percentiles). FA values were expressed as a percent of total identified FA.

Results: Compared to men, women generally had higher C18 trans levels, and between the ages of 10-29 years, they had DHA and lower EPA levels. Among the major FA classes, saturated (41% of total) and trans (∼0.85%) fats did not vary appreciably by age, whereas monounsaturated fats tended to rise slightly. Of the two major n-6 polyunsaturates, arachidonic and linoleic acids, the former was unchanged across decades (16.4% abundance) whereas the latter decreased by about 2 percentage points (13.0-11.1%). The overall median Omega-3 Index was 4.5%, and across the decades it increased by about 1.5 percentage points. The Omega-3 Index and linoleic acid stabilized after age 70.

Conclusion: Whereas RBC saturated, mono- and polyunsaturated FA levels are generally stable across the lifespan, there is a shift in the composition of the latter, with an increase in the Omega-3 Index and a decrease in linoleic acid. Higher DHA and lower EPA levels in younger women is consistent with enhanced conversion of EPA to DHA during the early reproductive years. The availability of RBC FA norms will facilitate research into the relationships between altered FA status and human disease, and will help physicians evaluate the n-3 FA status of their patients.
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http://dx.doi.org/10.1016/j.plefa.2012.12.004DOI Listing
April 2013

A Comprehensive Comparison of Open-Bay and Single-Family-Room Neonatal Intensive Care Units at Sanford Children's Hospital.

HERD 2012 ;5(4):23-39

Corresponding Author: Dennis C. Stevens, MD, Medical Director and Attending Neonatologist, Boekelheide Neonatal Intensive Care Unit, Sanford Children's Hospital and Specialty Clinic, 1600 West 22nd St., Sioux Falls, SD, 57117-5039

Objective: This paper summarizes the results of a comprehensive comparison of open-bay (OPBY) and single-family-room (SFR) neonatal intensive care unit (NICU) designs.

Background: The NICU expanded from 7000 ft(2) in two large rooms to 27,000 ft(2) with 45 individual family spaces.

Results: Sound measurements indicated a significant reduction in the unoccupied SFR to less than half of the levels in the OPBY NICU. However, respiratory support equipment generated levels well above those of the ambient environment. Illumination was significantly reduced in the SFR. Ambient illumination in nursing work areas was less than recommended. In other comparisons with the OPBY NICU the SFR NICU was shown to have: a shorter interval until full enteric feedings were established; improved parent satisfaction; improved staff perceptions of the environment and care; a decrease in nurses State-Trait Anxiety scores; an increased need for total numbers of staff and nursing staff per shift; increased walking per shift by nurses and nurse practitioners; and improved sleep time in a very small sample of patients. Analysis of the cost of construction showed comparable cost per ft(2); however, the cost per bed in the SFR NICU was much greater because of the increased area of this facility. Highly notable findings of this investigation included the same incidence of adverse outcomes of care and a reduction in the adjusted direct cost of care in the SFR NICU.

Conclusion: These data overwhelmingly support the SFR NICU in preference to the traditional OPBY facility. They substantiate that the SFR NICU should be the new standard for NICU care.
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http://dx.doi.org/10.1177/193758671200500403DOI Listing
April 2016

Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial.

J Lipid Res 2012 Nov 14;53(11):2429-35. Epub 2012 Aug 14.

Sanford Research/USD, University of South Dakota, Sioux Falls, SD, USA.

The metabolic syndrome includes both dyslipidemia and impaired vascular function. Because extended-release niacin (ERN) and prescription omega-3 acid ethyl-esters (P-OM3) independently improve these characteristics, we tested their effects in combination. Sixty metabolic syndrome subjects were randomized to 16 weeks of treatment on dual placebo, P-OM3 (4 g/day), ERN (2 g/day), or combination in a double-blind trial. Lipoprotein subfractions and vascular endpoints were measured and tested using ANCOVA. ERN increased HDL cholesterol by 5.4 mg/dl from baseline (P = 0.04), decreased triglycerides (TG) by 39 mg/dl (-21%, P = 0.003), and decreased the augmentation index, which is a measure of vascular stiffness, by 3.5 units (P = 0.04). P-OM3 reduced TG by 26 mg/dl (-13%, P = 0.04). Combination treatment increased HDL cholesterol by 7.8 mg/dl (P = 002) and decreased TG by 72 mg/dl (-34%) but there was no improvement in vascular stiffness. Detailed analysis of lipoprotein subfractions revealed increased large, bouyant HDL(2) (3.3 mg/dl; P = 0.002) and decreased VLDL(1+2) (-32%; P < 0.0001), among subjects treated with combination therapy, that were not present with either therapy alone. ERN and P-OM3 alone improved characteristics of metabolic syndrome; however, whereas subjects on combination therapy did not have improved vascular stiffness, TG and HDL levels improved as did certain lipoprotein subfractions.
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http://dx.doi.org/10.1194/jlr.P022392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466011PMC
November 2012

Regulation of gene expression with thyroid hormone in rats with myocardial infarction.

PLoS One 2012 1;7(8):e40161. Epub 2012 Aug 1.

Department of Biomedical Sciences, New York College of Osteopathic Medicine of New York Institute of Technology, Old Westbury, New York, United States of America.

Introduction: The expression of hundreds of genes is altered in response to left ventricular (LV) remodeling following large transmural myocardial infarction (MI). Thyroid hormone (TH) improves LV remodeling and cardiac performance after MI. However, the molecular basis is unknown.

Methods: MI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3 mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from LV non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform.

Results: Signals were detected in 13,188 genes (out of 22,523), of which the expression of 154 genes were decreased and the expression of 200 genes were increased in MI rats compared with Sham MI rats (false discovery rate (FDR) <0.05). Compared to MI rats, T4 treatment decreased expression of 27 genes and increased expression of 28 genes. In particular, 6 genes down-regulated by MI and 12 genes up-regulated by MI were reversed by T4. Most of the 55 genes altered by T4 treatment are in the category of molecular function under binding (24) and biological processes which includes immune system process (9), multi-organism process (5) and biological regulation (19) nonexclusively.

Conclusions: These results suggest that altered expression of genes for molecular function and biological process may be involved in the beneficial effects of thyroid hormone treatment following MI in rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411604PMC
February 2013

Correcting the effects of -20 °C storage and aliquot size on erythrocyte fatty acid content in the Women's Health Initiative.

Lipids 2012 Sep 11;47(9):835-46. Epub 2012 Jul 11.

OmegaQuant LLC, Sioux Falls, SD, USA.

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.
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http://dx.doi.org/10.1007/s11745-012-3693-yDOI Listing
September 2012

Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study.

Atherosclerosis 2012 Dec 7;225(2):425-31. Epub 2012 Jun 7.

Sanford Research/USD, 2301 E. 60th St. N, Sioux Falls, SD 57104, USA.

Objectives: Red blood cell (RBC) levels of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA, the omega-3 index, expressed as a percent of total fatty acids) are inversely related to risk for cardiovascular disease (CVD). Although several mechanisms underlying this relationship have been proposed, understanding the associations between the omega-3 index and markers of CVD in the community can shed additional light on this question. The objectives of this study were to define the relations between the omega-3 index and clinical factors and to determine the heritability of the omega-3 index.

Methods: RBC samples (n = 3196) drawn between 2005 and 2008 from participants in the Framingham Study [Examination 8 of the Offspring cohort plus Examination 3 of the Omni (minorities) cohort] were analyzed for fatty acid composition by gas chromatography.

Results: The mean (SD) omega-3 index was 5.6% (1.7%). In multivariable regression models, the factors significantly and directly associated with the omega-3 index were age, female sex, higher education, fish oil supplementation, dietary intake of EPA + DHA, aspirin use, lipid pharmacotherapy, and LDL-cholesterol. Factors inversely associated were Offspring cohort, heart rate, waist girth, triglycerides and smoking. The total explained variability in the omega-3 index for the fully adjusted model was 73%, which included major components due to heritability (24%), EPA + DHA intake (25%), and fish oil supplementation (15%).

Conclusion: The variability in the omega-3 index is determined primarily by dietary and genetic factors. An increased omega-3 index is associated with a generally cardioprotective risk factor milieu.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593234PMC
December 2012

Changes in erythrocyte membrane trans and marine fatty acids between 1999 and 2006 in older Americans.

J Nutr 2012 Jul 23;142(7):1297-303. Epub 2012 May 23.

Sanford Research, University of South Dakota, Sioux Falls, SD, USA.

Over the last several years, national programs to lower the content of industrially produced (IP) C18:1 and C18:2 trans fatty acids in foods have been implemented, but whether this has resulted in lower blood trans fatty acid levels is unknown. Likewise, an increased perception of the health benefits of fish oils rich in EPA and DHA may have resulted in an increase in consumption and blood levels of these fatty acids. To explore these issues, we analyzed the changes in RBC fatty acid composition between the 7th (1998-2001) and 8th (2005-2007) examination cycles in a random sample of the Framingham Offspring cohort. This was a retrospective cohort study of 291 participants from whom blood was drawn at both examinations and for whom complete covariate data were available. Overall, the proportion of trans fatty acids in RBC changed by -23% (95% CI: -26 to -21%). RBC EPA+DHA proportions increased by 41% (95% CI: 31 to 52%) in 38 individuals who were taking fish oil supplements at examination 8, but in 253 participants not taking fish oil, the proportion of RBC EPA+DHA did not change. In conclusion, in a random subsample of Framingham Offspring participants with serial observations over 6.7 y, the proportion of trans fatty acids in RBC decreased. Those of EPA+DHA increased in people taking fish oil supplements. These changes could potentially translate into a lower risk for cardiovascular disease.
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http://dx.doi.org/10.3945/jn.112.158295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374668PMC
July 2012

Membrane level of omega-3 docosahexaenoic acid is associated with severity of obstructive sleep apnea.

J Clin Sleep Med 2011 Aug;7(4):391-6

University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

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-SD increase 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.
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http://dx.doi.org/10.5664/JCSM.1198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161771PMC
August 2011

Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: the Heart and Soul study.

Circ Cardiovasc Qual Outcomes 2010 Jul 15;3(4):406-12. Epub 2010 Jun 15.

Cardiovascular Health Research Center, Sanford Research/USD and Sanford School of Medicine, Sioux Falls, SD 57105, USA.

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.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.109.896159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058601PMC
July 2010

Value of hemoglobin A1c in diagnosing diabetes mellitus within a chronic disease management system illustrated by the receiver operating characteristic curve.

Endocr Pract 2010 Jan-Feb;16(1):14-20

Sanford School of Medicine, Sioux Falls, South Dakota, USA.

Objective: To develop a receiver operating characteristic (ROC) curve of glycosylated hemoglobin (HbA1c) for diagnosing diabetes mellitus within a chronic disease management system.

Methods: A case-control study including medical records from January 1, 1997, to December 31, 2005, was conducted at the Sioux Falls Veterans Affairs Medical Center. Medical records for the case group (patients with diabetes) were selected based on 1 of 3 criteria: International Classification of Diseases, Ninth Revision, Clinical Modification or Current Procedural Terminology codes specific for type 1 and type 2 diabetes; patients' use of medications (oral hypoglycemic agents, antidiabetes agents, or insulin); or results from random blood or plasma glucose tests (at least 2 measurements of blood glucose > or = 200 mg/dL). Records for the control group were selected based on patients having HbA1c measured, but not meeting the above diagnostic criteria for diabetes during the study period. Records for cases and controls were randomly frequency-matched, one-to-one. The control group was randomly divided into 5 sets of an equal number of records. Five sets of an equal number of cases were then randomly selected from the total number of cases. Each test data set included 1 case group and 1 control group, resulting in 5 independent data sets.

Results: In total, 5040 patient records met the case definition in the diabetes registry. Records of 15 patients who were prescribed metformin only, but did not meet any other case criteria, were reviewed and excluded after determining the patients were not diabetic. The control group consisted of 5 sets of 616 records each (totaling 3080 records), and the case group consisted of 5 sets of 616 records each (totaling 3080 records). Thus, each of the 5 independent data sets of 1 case group and 1 control group contained 1232 records. The case group was predominantly composed of white men (mean age, 69 years; mean body mass index, 31 kg/m2). Demographic data were similar for control patients. The ROC curve revealed that a HbA1c > or = 6.3% (mean + 1 SD) offered the most accurate cutoff value for diagnosing type 2 diabetes mellitus, with the following statistical values: C statistic, 0.78; sensitivity, 70%; specificity, 85%; and positive likelihood ratio, 4.6 (95% confidence interval, 4.2-5.0).

Conclusion: A HbA1c value > or = 6.3% may be a useful benchmark for diagnosing diabetes mellitus within a chronic disease management system and may be a useful tool for monitoring high-risk populations.
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http://dx.doi.org/10.4158/EP09135.ORDOI Listing
April 2010

Red blood cell fatty acid patterns and acute coronary syndrome.

PLoS One 2009 6;4(5):e5444. Epub 2009 May 6.

Sanford Research/USD, Cardiovascular Health Research Center, Sioux Falls, SD, USA.

Background: Assessment of coronary heart disease (CHD) risk is typically based on a weighted combination of standard risk factors. We sought to determine the extent to which a lipidomic approach based on red blood cell fatty acid (RBC-FA) profiles could discriminate acute coronary syndrome (ACS) cases from controls, and to compare RBC-FA discrimination with that based on standard risk factors.

Methodology/principal Findings: RBC-FA profiles were measured in 668 ACS cases and 680 age-, race- and gender-matched controls. Multivariable logistic regression models based on FA profiles (FA) and standard risk factors (SRF) were developed on a random 2/3(rds) derivation set and validated on the remaining 1/3(rd). The area under receiver operating characteristic (ROC) curves (c-statistics), misclassification rates, and model calibrations were used to evaluate the individual and combined models. The FA discriminated cases from controls better than the SRF (c = 0.85 vs. 0.77, p = 0.003) and the FA profile added significantly to the standard model (c = 0.88 vs. 0.77, p<0.0001). Hosmer-Lemeshow calibration was poor for the FA model alone (p = 0.01), but acceptable for both the SRF (p = 0.30) and combined models (p = 0.22). Misclassification rates were 23%, 29% and 20% for FA, the SRF, and the combined models, respectively.

Conclusions/significance: RBC-FA profiles contribute significantly to the discrimination of ACS cases, especially when combined with standard risk factors. The utility of FA patterns in risk prediction warrants further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673680PMC
June 2009

Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects.

Thromb Haemost 2008 Oct;100(4):634-41

Sanford Research/USD, 1100 E. 21st Street, Sioux Falls, SD 57105, USA.

Omega-3 fatty acids (n-3 FA) from oily fish are clinically useful for lowering triglycerides and reducing risk of heart attacks. Accordingly, patients at risk are often advised to take both aspirin and n-3 FA. However, both of these agents can increase bleeding times, and the extent to which the combination inhibits platelet function is unknown. The purpose of this pilot study was to determine the effects of a prescription omega-3 FA product (P-OM3) and aspirin, alone and in combination, on platelet aggregation assessed by whole blood impedance aggregometry (WBA). Ten healthy volunteers provided blood samples on four separate occasions: Day 1, baseline; Day 2, one day after taking aspirin (2 x 325 mg tablets); Day 29, after 28 days of P-OM3 (4 capsules/day); and Day 30, after one day of combined P-OM3 and aspirin. WBA was tested with two concentrations of collagen, with ADP and with a thrombin receptor activating peptide (TRAP). Compared to baseline, aspirin alone inhibited aggregation only with low-dose collagen stimulation; P-OM3 alone did not inhibit aggregation with any agonist; and combined therapy inhibited aggregation with all agonists but TRAP. Significant interactions between interventions were not observed in response to any agonist. In conclusion, P-OM3 alone did not inhibit platelet aggregation, but did (with two agonists) when combined with aspirin. Since previous studies have not reported a clinically significant risk for bleeding in subjects on combined therapy, P-OM3 may safely enhance the anti-platelet effect of aspirin.
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October 2008

Serum thyroid hormone levels may not accurately reflect thyroid tissue levels and cardiac function in mild hypothyroidism.

Am J Physiol Heart Circ Physiol 2008 May 29;294(5):H2137-43. Epub 2008 Feb 29.

Cardiovascular Research Center, Sanford Research/University of South Dakota, 1100 East 21st Street, Sioux Falls, SD 57105, USA.

The link between thyroid dysfunction and cardiovascular diseases has been recognized for more than 100 years. Although overt hypothyroidism leads to impaired cardiac function and possibly heart failure, the cardiovascular consequences of borderline low thyroid function are not clear. Establishment of a suitable animal model would be helpful. In this study, we characterized a rat model to study the relationship between cardiovascular function and graded levels of thyroid activity. We used rats with surgical thyroidectomy and subcutaneous implantation of slow release pellets with three different T(4) doses for 3 wk. In terminal experiments, cardiac function was evaluated by echocardiograms and hemodynamics. Myocardial arteriolar density was also quantified morphometrically. Thyroid hormone levels in serum and heart tissue were determined by RIA assays. Thyroidectomy alone led to cardiac atrophy, severe cardiac dysfunction, and a dramatic loss of arterioles. The low T(4) dose normalized serum T(3) and T(4) levels, but cardiac tissue T(3) and T(4) remained below normal. Low-dose T(4) failed to prevent cardiac atrophy or restore cardiac function and arteriolar density to normal values. All cardiac function parameters and myocardial arteriolar density were normalized with the middle dose of T(4), whereas the high dose produced hyperthyroidism. Our results show that thyroid hormones are important regulators of cardiac function and myocardial arteriolar density. This animal model will be useful in studying the pathophysiological consequences of mild thyroid dysfunction. Results also suggest that cardiac function may provide valuable supplemental information in proper diagnosis of mild thyroid conditions.
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http://dx.doi.org/10.1152/ajpheart.01379.2007DOI Listing
May 2008

Determinants of Blood Cell Omega-3 Fatty Acid Content.

Open Biomark J 2008 ;1:1-6

Division of Epidemiology, Department of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry.

BACKGROUND: Although red blood cell eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) content (the Omega-3 Index) predicts cardiovascular death, the factors determining the Index are unknown. METHODS: In 704 outpatients, we undertook an investigation of the clinical determinants of the Index. RESULTS: Factors associated with the Index in decreasing order were: EPA+DHA supplement use, fish consumption frequency, triglyceride level, age, high cholesterol history, and smoking. These factors explained 59% of Index variability, with capsules/fish intake together accounting for 47%. The Index increased by 13% (p< 0.0001) for each serving level increase in fish intake and EPA+DHA supplementation correlated with a 58% increase (p< 0.0001) regardless of background fish intake (p=0.25; test for interaction). A 100 mg/dL decrease in serum triglycerides was associated with a 15% higher (p<0.0001) Index. CONCLUSIONS: The intake of EPA+DHA-rich foods and supplements principally determined the Omega-3 Index, but explained only about half of the variability.
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http://dx.doi.org/10.2174/1875318300801010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785093PMC
January 2008