Circulating plasma phospholipid fatty acid levels as a biomarker of habitual dietary fat intake: The INTERMAP/INTERLIPID Study.

BACKGROUND: Accurate assessment of fat intake is essential to examine relationships between diet and disease risk. However, estimating individual intakes of fat quantity by dietary assessment is difficult. OBJECTIVE: We assessed the association of plasma phospholipid fatty acid levels with dietary intake of fatty acids in the INTERMAP/INTERLIPID study, conducted with a standardized protocol. METHODS: The study participants were 1339 men and women ages 40-59 years from five Japanese populations one from Hawaii; four from Japan. Fatty acid intake was estimated from four standardized 24-hour dietary recalls. Plasma phospholipid fatty acid composition was analyzed by gas chromatography. We illustrated the relationship between intake and circulating fatty acid levels using Spearman's rank-correlation coefficients, mean, and median values. RESULTS: Spearman's rank-correlation coefficients between intake (g/d) and circulating fatty acid levels (µg/ml) were -0.03 to 0.21 for saturated fatty acids and monounsaturated fatty acids and -0.04 to 0.32 for trans fatty acids. The coefficients for essential n-3 and n-6 fatty acids were moderate to high, especially for eicosapentaenoic acid (EPA), 0.60; docosahexaenoic acid (DHA), 0.41; and EPA+DHA, 0.51. The circulating levels and intake of marine-derived n-3 fatty acids showed a linear association, at least for the intake of EPA+DHA up to 2.1 g/d. CONCLUSION: We observed high correlation between intake and circulating levels of marine-derived n-3 fatty acids in participants from Japanese and Japanese-American populations with high and low fish intake. Plasma phospholipid marine-derived n-3 fatty acid measurements are a simple and reliable biomarker for assessing dietary intake.

Adiposity and Smoking Mediate the Relationship Between Depression History and Inflammation Among Young Adults.

BACKGROUND: Depression is associated with inflammation, but the mechanisms underlying this association are unclear. We examined adiposity and smoking as potential pathways through which childhood depression may lead to an elevated inflammatory status among young adults. METHODS: The sample included 294 subjects with histories of depression (probands), 270 never-depressed siblings of probands (high-risk siblings), and 169 controls. C-reactive protein (CRP), interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1 (sICAM-1) were assessed in serum samples. An adiposity score was computed from body mass index and waist circumference. Smoking behavior was evaluated during an interview. Mixed-effects models were used to test whether adiposity and smoking mediate the relationship between depression and inflammation. RESULTS: Probands (p = .004), but not siblings (p = .071), had higher levels of sICAM-1 compared to controls. However, depression history and risk status had no direct effects on CRP (ps > .13) or IL-6 (ps > .16). Importantly, adiposity indirectly mediated the effect of group (probands vs. controls; siblings vs. controls) on all three inflammatory markers. Smoking indirectly mediated the effect of group (probands vs. controls; siblings vs. controls) on sICAM-1 only. CONCLUSIONS: Among young adults, the adverse inflammatory consequences of depression history are significant for sICAM-1. Adiposity and smoking are pathways through which depression can indirectly impact several inflammatory markers, suggesting possible preventive interventions to improve the immunologic and cardiovascular health of depression-prone individuals.

Childhood-onset depression and arterial stiffness in young adulthood.

OBJECTIVES: The literature on childhood-onset depression and future compromised vascular function is suggestive but limited. The objective of this study was to determine if arterial stiffness, a predictor of future cardiovascular disease (CVD), measured in young adulthood, is associated with childhood-onset depression. METHODS: Cardiometabolic risk factors and pulse wave velocity (PWV), a measure of arterial stiffness, were cross-sectionally assessed in young adults with a history of childhood-onset depression (clinical diagnosis of major depressive episode or dysthymic disorder; N = 294 probands; initially recruited via child mental health facilities across Hungary; mean age of first depressive episode = 10.4 years), their never-depressed full biological siblings (N = 269), and never-depressed controls (N = 169). The mean ages of probands, siblings, and controls at the PWV visit were 25.6, 25.0, and 21.7 years, respectively, and 8.8% of the probands were in a current depressive episode. RESULTS: Controlling for age, sex, age*sex, education, and family clusters, PWV (m/s) did not statistically differ across the groups (probands = 7.01; siblings = 6.98; controls = 6.81). However, after adjusting for key covariates, there were several across-group differences in CVD risk factors: compared to controls, probands and siblings had higher diastolic blood pressure and lower high-density lipoprotein cholesterol, probands had higher triglycerides, and siblings had higher body mass index (all p < 0.05). CONCLUSION: We found limited evidence of an association between a history of childhood-onset depression and young adulthood arterial stiffness. However, our findings of elevated cardiovascular risk factors in those with childhood-onset depression suggest that pediatric depression may predispose to increased CVD risk later in life and warrants further investigation.

Maternal Serum Antioxidants in Mid Pregnancy and Risk of Preterm Delivery and Small for Gestational Age Birth: Results from a Prospective Pregnancy Cohort.

Background: Preterm delivery (PTD) and poor fetal growth are major contributors to neonatal mortality and morbidity that can extend from birth onward. Although overt maternal nutrient deficiencies are associated with adverse pregnancy outcomes, such deficiencies are rare in developed countries. However, some evidence suggests that even within the normal range, higher levels of antioxidant nutrients are protective against adverse pregnancy outcomes. Materials and Methods: Using data from the prospective Pregnancy Outcomes and Community Health (POUCH) Study (n = 301 preterm; n = 246 term), we examined associations between maternal blood levels of selected antioxidants and pregnancy outcomes. Serum collected at 16-27 weeks' gestation was analyzed for carotenoids, retinol, and α- and γ-tocopherol. Using weighted polytomous regression, these nutrient concentrations were assessed in relation to (1) PTD (<37 weeks gestation) overall and grouped as spontaneous or medically indicated; and (2) small for gestational age (SGA) defined as birthweight-for-gestational age <10th percentile of a national reference population. Results: Women with total serum carotenoids in the upper quartile (Q4) had significantly lower odds of medically indicated PTD compared with women in the lower quartiles (Q1-Q3) even after adjustment for maternal characteristics (aOR = 0.4; 95% CI: 0.2-0.9). Odds ratios for SGA were consistently ≤0.5 among women with any of the serum nutrients in Q4 as compared with Q1-Q3, but final models did not reach statistical significance. Conclusion: Results support the possibility that high maternal serum antioxidants and/or the larger dietary or lifestyle pattern they represent may play a protective role in preventing adverse pregnancy outcomes.

The haptoglobin 2-2 genotype is associated with cardiac autonomic neuropathy in type 1 diabetes: the RETRO HDLc study.

AIM: The haptoglobin (Hp) 2-2 genotype has been shown to increase the risk of coronary artery disease, kidney dysfunction and mortality from cardiovascular and renal causes in type 1 diabetes (T1D). Similar associations, however, have not been observed in those without diabetes. As cardiac autonomic neuropathy (CAN) is a cardiovascular disease risk factor, we assessed the presence of an association between the Hp 2-2 genotype and CAN. METHODS: The study included 216 individuals with childhood-onset T1D and 200 individuals with normal glucose tolerance (NGT) of similar age and gender distribution to their counterparts with T1D. CAN was assessed using an electrocardiogram as an abnormal, age-specific, heart rate response to deep breathing. Multivariable logistic regression models were used to assess the association between the Hp 2-2 genotype and CAN. RESULTS: Compared with NGT, participants with T1D had a similar proportion of Hp 2-2 carriers (41.5% vs. 32.0%, p = 0.05) but a greater CAN prevalence (28.2% vs. 5.0%, p < 0.0001). In multivariable logistic regression models, those carrying the Hp 2-2 genotype had significantly higher odds of CAN compared with Hp 1-1 or Hp 2-1 carriers (OR = 2.27, p = 0.01). The presence of T1D (OR = 4.20, p = 0.0003), hypertension (OR = 2.08, p = 0.03), eGFR (OR = 0.98, p = 0.01) and WBC count (OR = 1.21, p = 0.02) were also associated with CAN. There was no T1D by Hp interaction (p = 0.92), although in stratified analyses, the Hp-CAN association was significant only in T1D. CONCLUSIONS: The Hp 2-2 genotype was independently associated with greater odds of CAN in T1D though no definitive conclusions could be made in NGT.

Association of High-Sensitivity Troponin with Cardiac CT Angiography Evidence of Myocardial and Coronary Disease in a Primary Prevention Cohort of Men: Results from MACS.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) elevations are associated with incident cardiovascular disease events in primary prevention samples. However, the mechanisms underlying this association remain unclear. METHODS: We studied 458 men without known cardiovascular disease who participated in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study and had cardiac CT angiography. We used multivariable linear and logistic regression models to examine the cross-sectional associations between coronary artery stenosis, coronary artery plaque, indexed left ventricular mass (LVMi), and the outcome of hs-cTnI. We also evaluated the associations between HIV serostatus or use of highly active antiretroviral therapy (HAART) and hs-cTnI. RESULTS: The mean age was 54 years, 54% were white, and 61% were HIV infected. In multivariable-adjusted logistic models, comparing the highest quartile of LVMi with the lowest quartile, the odds ratio (OR) of hs-cTnI ≥75th percentile was 2.59 (95% CI, 1.20-5.75). There was no significant association between coronary stenosis severity or plaque type and hs-cTnI in linear models; however, in logistic regression models, coronary artery stenosis ≥70% (8% of sample) was marginally associated with a higher likelihood (OR, 2.75 [95% CI, 1.03, 7.27]) of having hs-cTnI ≥75th percentile. There were no associations between HIV serostatus or HAART use and hs-cTnI in either linear or logistic models. CONCLUSION: Among primary prevention men with or at risk for HIV, hs-cTnI concentrations were strongly associated with LVMi but were not associated with HIV infection or treatment status or with coronary plaque type or stenosis until the extremes of severity (≥70% stenosis).

Serum long-chain n-3 polyunsaturated fatty acids and aortic calcification in middle-aged men: The population-based cross-sectional ERA-JUMP study.

BACKGROUND AND AIM: Few studies have examined the association of long-chain n-3 polyunsaturated fatty acids (LCn-3PUFAs) with the measures of atherosclerosis in the general population. This study aimed to examine the relationship of total LCn-3PUFAs, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) with aortic calcification. METHODS AND RESULTS: In a multiethnic population-based cross-sectional study of 998 asymptomatic men aged 40-49 years (300 US-White, 101 US-Black, 287 Japanese American, and 310 Japanese in Japan), we examined the relationship of serum LCn-3PUFAs to aortic calcification (measured by electron-beam computed tomography and quantified using the Agatston method) using Tobit regression and ordinal logistic regression after adjusting for potential confounders. Overall 56.5% participants had an aortic calcification score (AoCaS) > 0. The means (SD) of total LCn-3PUFAs, EPA, and DHA were 5.8% (3.3%), 1.4% (1.3%), and 3.7% (2.1%), respectively. In multivariable-adjusted Tobit regression, a 1-SD increase in total LCn-3PUFAs, EPA, and DHA was associated with 29% (95% CI = 0.51, 1.00), 9% (95% CI = 0.68, 1.23), and 35% (95% CI = 0.46, 0.91) lower AoCaS, respectively. Results were similar in ordinal logistic regression analysis. There was no significant interaction between race/ethnicity and total LCn-3PUFAs, EPA or DHA on aortic calcification. CONCLUSIONS: This study showed the significant inverse association of LCn-3PUFAs with aortic calcification independent of conventional cardiovascular risk factors among men in the general population. This association appeared to be driven by DHA but not EPA.

Lipoprotein particles and coronary artery calcium in middle-aged US-White and Japanese men.

Objective: This cross-sectional study examined whether contrasting distributions of nuclear magnetic resonance (NMR)-measured lipoproteins contribute to differences in the prevalence of subclinical atherosclerosis measured using coronary artery calcium (CAC) between the two groups of middle-aged males: the US-residing Caucasian (US-White) and Japan-residing Japanese (Japanese). Methods: In a population-based study of 570 randomly selected asymptomatic men aged 40-49 years (270 US-White and 300 Japanese), we examined the relationship between race/ethnicity, NMR-measured lipoproteins and CAC (measured by Electron Beam CT and quantified using the Agatston method) using multivariable robust Poisson regression adjusting for traditional and novel risk factors for coronary heart disease (CHD). Results: The US-White compared with the Japanese had significantly different NMR-measured lipoprotein particle distributions. The US-White had a significantly higher prevalence of CAC≥10 (CAC-prevalence) compared with the Japanese adjusting for CHD risk factors (prevalence ratio (PR)=2.10; 95% CI=1.24 to 3.48), and this difference was partially attenuated (~18%) with further adjustment for lipoprotein levels (PR=1.73; 95% CI=1.02 to 3.08). There was no reclassification improvement with further addition of lipoproteins particle concentrations/size to a model that already included traditionally measured lipids (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), cardiovascular risk factors, and inflammatory markers (net reclassification improvement index=-2% to 3%). Conclusions: Variations in the distribution of NMR-measured lipoprotein particles partially accounted for the difference in the CAC-prevalence between middle-aged US-White and Japanese men.

Data on alcohol consumption and coronary artery calcification among asymptomatic middle-aged men for the ERA-JUMP study.

Data presented in this article are supplementary data to our primary article 'Association of Alcohol Consumption and Aortic Calcification in Healthy Men Aged 40-49 Years for the ERA JUMP Study' [1]. In this article, we have presented supplementary tables showing the independent association of alcohol consumption with coronary artery calcification using Tobit conditional regression and ordinal logistic regression.

Comparison of carotid plaque burden among healthy middle-aged men living in the US, Japan, and South Korea.

BACKGROUND: Carotid plaque has emerged as a marker of coronary heart disease (CHD) risk. Comparison of carotid plaque burden between different race/ethnic groups may provide a relative estimate of their future CHD risk. METHODS: We conducted a population-based study among apparently healthy middle-aged men aged 40-49 years (ERA JUMP study (n = 924)) and recruited 310 Whites in Pittsburgh, US, 313 Japanese in Otsu, Japan, and 301 Koreans in Ansan, South Korea. The number of carotid plaque and CHD risk factors was assessed using a standardized protocol across all centers. The burden of carotid plaque was compared between race/ethnic groups after adjustment for age and BMI, and after multivariable adjustment for other CHD risk factors using marginalized zero-inflated Poisson regression models. Cross-sectional associations of risk factors with plaque were examined. RESULTS: Whites (22.8%) had more than four-fold higher prevalence (p < 0.01) of carotid plaque than Japanese men (4.8%) while the prevalence among Koreans was 10.6%. These differences remained significant after adjustment for age, BMI as well as other risk factors - incidence density ratio (95% confidence interval) for plaque was 0.13 (0.07, 0.24) for Japanese and 0.32 (0.18, 0.58) for Koreans as compared to Whites. Age, hypertension and diabetes were the only risk factors significantly associated with presence of carotid plaque in the overall population. CONCLUSION: Whites have significantly higher carotid plaque burden than men in Japan and Korea. Lower carotid plaque burden among Japanese and Koreans is independent of traditional CVD risk factors.

Is Magnetic Resonance Imaging Detection of Kidney Iron Deposition Increased in Haptoglobin 2-2 Genotype Carriers with Type 1 Diabetes?

Haptoglobin's (Hp) main role is to bind free hemoglobin (Hb), reducing its oxidative potential. The Hp-Hb complex formed is cleared from the circulation by macrophage receptor CD163. In diabetes, impaired Hp 2-2-Hb CD163 clearance and abnormal glomerular permeability allow the large Hp 2-2-Hb complex to cross the barrier, where its redox active iron leads to cellular toxicity. Although Hp 2-2 predicts renal function decline, whether renal iron deposition differs by Hp is unknown. We used renal quantitative T2* magnetic resonance imaging to estimate iron level in the cortex and medullar of type 1 diabetes (T1D) adults [15 Hp 1-1 and 15 Hp 2-2 carriers of similar age (53 years), duration (45 years), and gender]. Total kidney iron level was estimated as the sum of the cortex and medullar iron. Albuminuria was defined as urinary albumin to creatinine ratio >30 mg/g in two of three samples. Total kidney iron did not differ by gender or Hp but was higher in those with albuminuria (p = 0.05), an association confined to Hp 2-2 carriers (p = 0.04 vs. p = 0.51 in Hp 1-1). These data lead to the hypothesis that kidney iron deposition is increased among Hp 2-2 carriers with albuminuria in T1D. Antioxid. Redox Signal. 29, 735-741.

Association of alcohol consumption and aortic calcification in healthy men aged 40-49 years for the ERA JUMP Study.

BACKGROUND AND AIMS: Several studies have reported a significant inverse association of light to moderate alcohol consumption with coronary heart disease (CHD). However, studies assessing the relationship between alcohol consumption and atherosclerosis have reported inconsistent results. The current study was conducted to determine the relationship between alcohol consumption and aortic calcification. METHODS: We addressed the research question using data from the population-based ERA-JUMP Study, comprising of 1006 healthy men aged 40-49 years, without clinical cardiovascular diseases, from four race/ethnicities: 301 Whites, 103 African American, 292 Japanese American, and 310 Japanese in Japan. Aortic calcification was assessed by electron-beam computed tomography and quantified using the Agatston method. Alcohol consumption was categorized into four groups: 0 (non-drinkers), ≤1 (light drinkers), >1 to ≤3 (moderate drinkers) and >3 drinks per day (heavy drinkers) (1 drink = 12.5 g of ethanol). Tobit conditional regression and ordinal logistic regression were used to investigate the association of alcohol consumption with aortic calcification after adjusting for cardiovascular risk factors and potential confounders. RESULTS: The study participants consisted of 25.6% nondrinkers, 35.3% light drinkers, 23.5% moderate drinkers, and 15.6% heavy drinkers. Heavy drinkers [Tobit ratio (95% CI) = 2.34 (1.10, 4.97); odds ratio (95% CI) = 1.67 (1.11, 2.52)] had significantly higher expected aortic calcification score compared to nondrinkers, after adjusting for socio-demographic and confounding variables. There was no significant interaction between alcohol consumption and race/ethnicity on aortic calcification. CONCLUSIONS: Our findings suggest that heavy alcohol consumption may be an independent risk factor for atherosclerosis.

Significant inverse association of equol-producer status with coronary artery calcification but not dietary isoflavones in healthy Japanese men.

Equol, a metabolite of the dietary isoflavone daidzein, is produced by the action of gut bacteria in some individuals who are termed as equol-producers. It is proposed to have stronger atheroprotective properties than dietary isoflavones. We examined a cross-sectional association of dietary isoflavones and equol-producer status with coronary artery calcification (CAC), a biomarker of coronary atherosclerosis, among men in Japan. A population-based sample of 272 Japanese men aged 40-49 years recruited from 2004 to 2007 was examined for serum isoflavones, serum equol, CAC and other factors. Equol-producers were classified as individuals having a serum level of equol >83 nm. The presence of CAC was defined as a coronary Ca score ≥10 Agatston units. The associations of dietary isoflavones and equol-producers with CAC were analysed using multiple logistic regression. The median of dietary isoflavones, equol and CAC were 512·7 (interquartile range (IQR) 194·1, 1170·0), 9·1 (IQR 0·10, 33·1) and 0·0 (IQR 0·0, 1·0) nm, respectively. Prevalence of CAC and equol-producers was 9·6 and 16·0 %, respectively. Dietary isoflavones were not significantly associated with CAC. After multivariable adjustment, the OR for the presence of CAC in equol-producers compared with equol non-producers was 0·10 (95 % CI 0·01, 0·90, P<0·04). Equol-producers had significantly lower CAC than equol non-producers, but there was no significant association between dietary isoflavones and CAC, suggesting that equol may be a key factor for atheroprotective properties of isoflavones in Japanese men. This finding must be confirmed in larger studies or clinical trials of equol that is now available as a dietary supplement.

Increased Aortic Calcification Is Associated With Arterial Stiffness Progression in Multiethnic Middle-Aged Men.

Arterial stiffness is established as an independent predictor of cardiovascular morbidity and mortality. The objective was to prospectively evaluate association of aortic calcification burden with progression of arterial stiffness in population-based samples of healthy middle-aged men from ERA JUMP cohort (Electron-Beam Computed Tomography and Risk Factor Assessment in Japanese and US Men in the Post-World War II Birth Cohort). Men (n=635) aged 40 to 49 years (207 white American, 45 black American, 142 Japanese American, and 241 Japanese in Japan) were examined at baseline and 4 to 7 years later. Aortic calcification was evaluated from level of aortic arch to iliac bifurcation. Arterial stiffness progression was measured as annual change in brachial-ankle pulse wave velocity. Multivariable-adjusted general linear models were applied to investigate associations of longitudinal change in aortic calcification with arterial stiffness progression in participants overall, as well as in subgroups without or with prevalent aortic calcification at baseline. Annual change in aortic calcification was positively and significantly associated with arterial stiffness progression. In participants with annual changes in aortic calcium score of ≤0, 1 to 10, 11 to 100, and >100, the adjusted means (SD) for the annual change in brachial-ankle pulse wave velocity were 3.8 (2.2), 7.2 (2.2), 12.2 (1.8), and 15.6 (2.6) cm/s, respectively (P for trend <0.01) adjusted for baseline aortic calcification, arterial stiffness, and standard cardiovascular risk factors. Arterial stiffness was associated with the incidence of aortic calcification over the follow-up period among participants without aortic calcification (n=297) and with an increase in aortic calcification among participants with prevalent aortic calcification at baseline (n=388). Our findings suggest aortic calcification may be causally linked to arterial stiffness.

The role of initial and longitudinal change in blood pressure on progression of arterial stiffness among multiethnic middle-aged men.

OBJECTIVE: A few studies have examined the longitudinal association of blood pressure (BP) with arterial stiffness progression, and the results were inconsistent. The objective of this study was to investigate the roles of initial BP and its longitudinal change on the progression of arterial stiffness measured using brachial-ankle pulse wave velocity (baPWV). METHOD: Study participants (n = 656) were from population-based samples of healthy men aged 40-49 years at baseline (213 White Americans, 47 African-Americans, 152 Japanese Americans and 244 Japanese in Japan). BP measures, baPWV and other factors were examined at baseline and 4-7 years later. General linear regression was applied for statistical analyses. RESULT: Annual change in SBP (standardized coefficient: 0.33, P < 0.001), but not its baseline level (standardized coefficient: 0.03, P = 0.495), had a positive significant association with the progression of baPWV after adjusting for a wide range of standard cardiovascular risk factors. Similarly, annual changes in DBP (standardized coefficient: 0.35, P < 0.001), pulse pressure (standardized coefficient: 0.15, P = 0.001) and mean arterial pressure (standardized coefficient: 0.37, P < 0.001) were positively associated with the progression of baPWV. None of the baseline measures were related to the progression of baPWV. CONCLUSION: Our findings imply that, regardless of initial BP, effective monitoring and controlling of BP is important to slow down arterial wall stiffening and hence reduce cardiovascular risk.

The impact of equol-producing status in modifying the effect of soya isoflavones on risk factors for CHD: a systematic review of randomised controlled trials.

Recent studies suggest that the ability to produce equol, a metabolite of the soya isoflavone daidzein, is beneficial to coronary health. Equol, generated by bacterial action on isoflavones in the human gut, is biologically more potent than dietary sources of isoflavones. Not all humans are equol producers. We investigated whether equol-producing status is favourably associated with risk factors for CHD following an intervention by dietary soya isoflavones. We systematically reviewed randomised controlled trials (RCT) that evaluated the effect of soya isoflavones on risk factors for CHD and that reported equol-producing status. We searched PubMed, EMBASE, Ovid Medline and the Cochrane Central Register for Controlled Trials published up to April 2015 and hand-searched bibliographies to identify the RCT. Characteristics of participants and outcomes measurements were extracted and qualitatively analysed. From a total of 1671 studies, we identified forty-two articles that satisfied our search criteria. The effects of equol on risk factors for CHD were mainly based on secondary analyses in these studies, thus with inadequate statistical power. Although fourteen out of the forty-two studies found that equol production after a soya isoflavone intervention significantly improved a range of risk factors including cholesterol and other lipids, inflammation and blood pressure variables, these results need further verification by sufficiently powered studies. The other twenty-eight studies primarily reported null results. RCT of equol, which has recently become available as a dietary supplement, on CHD and its risk factors are awaited.

A Significant Positive Association of Vitamin D Deficiency with Coronary Artery Calcification among Middle-aged Men: For the ERA JUMP Study.

OBJECTIVE: Although a significant positive association of vitamin D deficiency with coronary heart disease has been demonstrated in cross-sectional as well as prospective studies, only a few studies have examined the association of vitamin D deficiency with subclinical atherosclerosis. We examined whether vitamin D deficiency is associated with subclinical atherosclerosis, as measured by coronary artery calcification (CAC) in asymptomatic adults. METHODS: In a population-based cross-sectional study, 195 men aged 40 to 49 years without cardiovascular disease were randomly selected (98 Caucasian and 97 Japanese American men). Liquid chromatography-tandem mass spectrometry was utilized to measure serum vitamin D. CAC was examined by electron beam computed tomography using standardized protocols and read centrally at the University of Pittsburgh using Agatston's methods. To investigate an association between vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL) and CAC (defined as Agatston score ≥ 10), we utilized multivariable logistic regression models. RESULTS: Prevalence of CAC and vitamin D deficiency was 27.2% and 10.3%, respectively. Participants with CAC were significantly older, had significantly higher body mass index (BMI), and had higher rates of smoking. Those with CAC were 3.31 times likely to be vitamin D deficient, after adjusting for traditional cardiovascular risk factors (odds ratio [OR] = 3.31, 95% confidence interval [CI], 1.12-9.77). CONCLUSIONS: In this population-based study of healthy middle-aged men, vitamin D deficiency had a significant positive association with the presence of CAC.

Association of Lipopolysaccharide-Binding Protein With Aging-Related Adiposity Change and Prediabetes Among African Ancestry Men.

OBJECTIVE: Cross-sectional studies suggest that lipopolysaccharide-binding protein (LBP) may be associated with obesity and metabolic disorders. However, prospective studies examining LBP are lacking. This prospective study investigated the association between LBP and metabolic abnormalities in 580 African ancestry men (mean age, 59.1 ± 10.5 years). RESEARCH DESIGN AND METHODS: We measured fasting serum LBP at baseline. Changes in adiposity and glucose homeostasis as well as case subjects with new type 2 diabetes and impaired fasting glucose (IFG) were assessed at a follow-up visit ~6 years later. Baseline LBP values were tested across quartiles for linear trend with metabolic measures. Multivariable logistic regression was used to determine the odds of new cases of IFG or diabetes per 1-SD greater baseline LBP. RESULTS: LBP was significantly associated with baseline BMI, waist circumference, whole-body and trunk fat, skeletal muscle density, fasting serum insulin, and HOMA-insulin resistance (IR) (all P < 0.01). Greater baseline LBP was significantly associated with longitudinal increases in the percentage of trunk fat (P = 0.025) and HOMA-IR (P = 0.034), but only borderline so with a decrease in skeletal muscle density (P = 0.057). In men with normal glucose, baseline LBP was associated with increased odds of having IFG at follow-up after adjustment for age, baseline trunk fat, and lifestyle factors (odds ratio per 1-SD LBP: 1.51; 95% CI 1.02-2.21). This association was attenuated after additional adjustment for change in trunk fat (P = 0.067). CONCLUSIONS: LBP may be a marker of prediabetes. Some of this association appears to be mediated through increased central and ectopic skeletal muscle adiposity.

Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial.

AIMS: Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, α-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized crossover pilot of α-tocopherol supplementation on HDL function [i.e., cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)] and lipoprotein subfractions in type 1 diabetes. METHODS: Hp genotype was assessed in members of two Allegheny County, PA, type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily α-tocopherol or placebo for 8 weeks with a 4-week washout. RESULTS: Baseline CE decreased with the number of Hp 2 alleles (p-trend = 0.003). There were no differences in LP or lipoprotein subfractions. In intention-to-treat analysis stratified by Hp, α-tocopherol increased CE in Hp 2-2 (ß = 0.79, p = 0.03) and LP in Hp 1 allele carriers (ß Hp 1-1 = 0.18, p = 0.05; ß Hp 2-1 = 0.21, p = 0.07); reduced HDL particle size (ß = -0.07, p = 0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1; and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp. CONCLUSIONS: In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. α-Tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies.

The association between maternal antioxidant levels in midpregnancy and preeclampsia.

OBJECTIVE: We sought to determine whether midpregnancy antioxidant levels are associated with preeclampsia, overall and by timing of onset. STUDY DESIGN: We carried out a case-control study, nested within a cohort of 5337 pregnant women in Montreal, Quebec, Canada. Blood samples obtained at 24-26 weeks were assayed for nonenzymatic antioxidant levels among cases of preeclampsia (n = 111) and unaffected controls (n = 441). We excluded women diagnosed with gestational hypertension only. We used logistic regression with the z-score of each antioxidant level as the main predictor variable for preeclampsia risk. We further stratified early-onset (<34 weeks) and late-onset preeclampsia and carried out multinomial logistic regression. Finally, we assessed associations between antioxidant biomarkers and timing of onset (in weeks) by Cox regression, with appropriate selection weights. We summed levels of correlated biomarkers (r(2) > 0.3) and log-transformed positively skewed distributions. We adjusted for body mass index, nulliparity, preexisting diabetes, hypertension, smoking, and proxies for ethnicity and socioeconomic status. RESULTS: The odds ratios for α-tocopherol, α-tocopherol:cholesterol, lycopene, lutein, and carotenoids (sum of α-carotene, ß-carotene, anhydrolutein, α-cryptoxanthin, and ß-cryptoxanthin) suggested an inverse association between antioxidant levels and overall preeclampsia risk; however, only lutein was significantly associated with overall preeclampsia in adjusted models (odds ratio, 0.60; 95% confidence interval, 0.46-0.77) per SD. In multinomial logistic models, the relative risk ratio (RRR) estimates for the early-onset subgroup were farther from the null than those for the late-onset subgroup. The ratio of α-tocopherol to cholesterol and retinol were significantly associated with early- but not late-onset preeclampsia: RRRs (95% confidence intervals) for early-onset preeclampsia 0.67 (0.46-0.99) and 1.61 (1.12-2.33), respectively. Lutein was significantly associated with both early- and late-onset subtypes in adjusted models; RRRs 0.53 (0.35-0.80) and 0.62 (0.47-0.82), respectively. Survival analyses confirmed these trends. CONCLUSION: Most antioxidants were more strongly associated with early-onset preeclampsia, suggesting that oxidative stress may play a greater role in the pathophysiology of early-onset preeclampsia. Alternatively, reverse causality may explain this pattern. Lutein was associated with both early- and late-onset preeclampsia and may be a promising nutrient to consider in preeclampsia prevention trials, if this finding is corroborated.