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Lipoprotein(a) [Lp(a)] contributes to cardiovascular disease risk. A genetically determined size polymorphism in apolipoprotein(a) [apo(a)], determined by the number of Kringle (K) repeats, inversely regulates Lp(a) levels. Nongenetic factors including dietary saturated fat influence Lp(a) levels. However, less is known about the effects of carbohydrates including dietary sugars. In this double-blind, parallel arm study among 32 overweight/obese adults, we investigated the effect of consuming glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks on Lp(a) level and assessed the role of the apo(a) size polymorphism. The mean (±SD) age of participants was 54 ± 8 years, 50% were women, and 75% were of European descent. Following the 10-week intervention, Lp(a) level was reduced by an average (±SEM) of -13.2% ± 4.3% in all participants (P = 0.005); -15.3% ± 7.8% in the 15 participants who consumed glucose (P = 0.07); and -11.3% ± 4.5% in the 17 participants who consumed fructose (P = 0.02), without any significant difference in the effect between the two sugar groups. Relative changes in Lp(a) levels were similar across subgroups of lower versus higher baseline Lp(a) level or carrier versus noncarrier of an atherogenic small (≤22K) apo(a) size. In contrast, LDL-C increased. In conclusion, in older, overweight/obese adults, consuming sugar-sweetened beverages reduced Lp(a) levels by ∼13% independently of apo(a) size variability and the type of sugar consumed. The Lp(a) response was opposite to that of LDL-C and triglyceride concentrations. These findings suggest that metabolic pathways might impact Lp(a) levels.

Reducing dietary saturated fatty acids (SFA) intake results in a clinically significant lowering of low-density lipoprotein cholesterol (LDL-C) across ethnicities. In contrast, dietary SFA's role in modulating emerging cardiovascular risk factors in different ethnicities remains poorly understood. Elevated levels of lipoprotein(a) [Lp(a)], an independent cardiovascular risk factor, disproportionally affect individuals of African descent. Here, we assessed the responses in Lp(a) levels to dietary SFA reduction in 166 African Americans enrolled in GET-READI (The Gene-Environment Trial on Response in African Americans to Dietary Intervention), a randomized controlled feeding trial. Participants were fed two diets in random order for 5 weeks each: 1) an average American diet (AAD) (37% total fat: 16% SFA), and 2) a diet similar to the Dietary Approaches to Stop Hypertension (DASH) diet (25% total fat: 6% SFA). The participants' mean age was 35 years, 70% were women, the mean BMI was 28 kg/m2, and the mean LDL-C was 116 mg/dl. Compared to the AAD diet, LDL-C was reduced by the DASH-type diet (mean change: -12 mg/dl) as were total cholesterol (-16 mg/dl), HDL-C (-5 mg/dl), apoA-1 (-9 mg/dl) and apoB-100 (-5 mg/dl) (all P < 0.0001). In contrast, Lp(a) levels increased following the DASH-type diet compared with AAD (median: 58 vs. 44 mg/dl, P < 0.0001). In conclusion, in a large cohort of African Americans, reductions in SFA intake significantly increased Lp(a) levels while reducing LDL-C. Future studies are warranted to elucidate the mechanism(s) underlying the SFA reduction-induced increase in Lp(a) levels and its role in cardiovascular risk across populations.

Lipoprotein(a) [Lp(a)] is an independent, causal, genetically determined risk factor for cardiovascular disease (CVD). We provide an overview of current knowledge on Lp(a) and CVD risk, and the effect of pharmacological agents on Lp(a). Since evidence is accumulating that diet modulates Lp(a), the focus of this paper is on the effect of dietary intervention on Lp(a). We identified seven trials with 15 comparisons of the effect of saturated fat (SFA) replacement on Lp(a). While replacement of SFA with carbohydrate, monounsaturated fat (MUFA), or polyunsaturated fat (PUFA) consistently lowered low-density lipoprotein cholesterol (LDL-C), heterogeneity in the Lp(a) response was observed. In two trials, Lp(a) increased with carbohydrate replacement; one trial showed no effect and another showed Lp(a) lowering. MUFA replacement increased Lp(a) in three trials; three trials showed no effect and one showed lowering. PUFA or PUFA + MUFA inconsistently affected Lp(a) in four trials. Seven trials of diets with differing macronutrient compositions showed similar divergence in the effect on LDL-C and Lp(a). The identified clinical trials show diet modestly affects Lp(a) and often in the opposing direction to LDL-C. Further research is needed to understand how diet affects Lp(a) and its properties, and the lack of concordance between diet-induced LDL-C and Lp(a) changes.

Heritability of LPA allele, apo(a) isoform sizes, and isoform-associated lipoprotein(a) [Lp(a)] levels was studied in 82 Caucasian and African-American families with two parents and two children (age: 6-74 years). We determined: 1) Lp(a) levels; 2) LPA allele sizes; 3) apo(a) isoform sizes; and 4) isoform-specific apo(a) levels (ISLs), the amount of Lp(a) carried by an individual apo(a) isoform. Trait heritability was estimated by mid-parent-offspring analysis. The ethnicity-adjusted heritability estimate for Lp(a) level was 0.95. Heritability for ISLs corresponding to the smaller LPA allele in a given allele-pair was higher than that corresponding to the larger LPA allele (0.91 vs. 0.59, P = 0.017). Although not statistically different, heritability for both apo(a) isoforms (0.90 vs. 0.70) and LPA alleles (0.98 vs. 0.82) was higher for the smaller versus larger sizes. Heritability was generally lower in African-Americans versus Caucasians with a 4-fold difference for the larger LPA allele (0.25 vs. 0.94, P = 0.001). In Caucasians, an overall higher heritability pattern was noted for the older (≥47 years) versus younger (

We previously demonstrated an association between lipoprotein (a) [Lp(a)] levels and atherosclerosis in human immunodeficiency virus (HIV)-seropositive women. The effects of antiretroviral therapy (ART) on Lp(a) levels in relation to apo(a) size polymorphism remain unclear. ART effects on allele-specific apo(a) level (ASL), an Lp(a) level associated with individual apo(a) alleles within each allele-pair, were determined in 126 HIV-seropositive women. ART effects were tested by a mixed-effects model across pre-ART and post-ART first and third visits. Data from 120 HIV-seronegative women were used. The mean age was 38 years; most were African-American (∼70%). Pre-ART ASLs associated with the larger (4.6 mg/dl vs. 8.0 mg/dl, P = 0.024) or smaller (13 mg/dl vs. 19 mg/dl, P = 0.041) apo(a) sizes were lower in the HIV-seropositive versus HIV-seronegative group, as was the prevalence of a high Lp(a) level (P = 0.013). Post-ART ASL and prevalence of high Lp(a) or apo(a) sizes and frequency of small size apo(a) (22 kringles) did not differ between the two groups. ART increased Lp(a) level (from 18 to 24 mg/dl, P < 0.0001) and both ASLs (P < 0.001). In conclusion, regardless of genetic control, Lp(a) can be modulated by HIV and its treatment. ART initiation abrogates HIV-induced suppression of Lp(a) levels and ASLs, contributing to promote CVD risk in HIV-seropositive individuals.

ObjectiveIn the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV)-related elevated cardiovascular disease risk remain unclear.Approach and resultsThe associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima-media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women's Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ≈31 years), with the majority being Blacks (≈70%). The prevalence of a small size apo(a) (≤22 Kringle repeats) or a high Lp(a) level (≥30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (P=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.022) were significantly associated with carotid artery intima-media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4+ T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (P=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima-media thickness.ConclusionsLp(a) and allele-specific apo(a) levels predict carotid artery intima-media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection.

Levels of lipoprotein (a) [Lp(a)], a complex between an LDL-like lipid moiety containing one copy of apoB, and apo(a), a plasminogen-derived carbohydrate-rich hydrophilic protein, are primarily genetically regulated. Although stable intra-individually, Lp(a) levels have a skewed distribution inter-individually and are strongly impacted by a size polymorphism of the LPA gene, resulting in a variable number of kringle IV (KIV) units, a key motif of apo(a). The variation in KIV units is a strong predictor of plasma Lp(a) levels resulting in stable plasma levels across the lifespan. Studies have demonstrated pronounced differences across ethnicities with regard to Lp(a) levels and some of this difference, but not all of it, can be explained by genetic variations across ethnic groups. Increasing evidence suggests that age, sex, and hormonal impact may have a modest modulatory influence on Lp(a) levels. Among clinical conditions, Lp(a) levels are reported to be affected by kidney and liver diseases.

ObjectiveAge and inflammation are risk factors for cardiovascular disease but the impact of inflammation on cardiovascular risk across the lifespan is not understood. We investigated whether an inflammatory burden is modulated by age in healthy subjects.MethodsCaucasian and African-American families were recruited from the general population (age range: 6-74 years, n = 267). Systemic inflammation was assessed by C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, haptoglobin and α-acid glycoprotein, and vascular inflammation was assessed by pentraxin-3 (PTX-3), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM). To collectively assess systemic or vascular factors across the age spectrum, a composite z-score for each marker category was calculated.ResultsThere was a contrasting pattern in systemic versus vascular inflammatory burden over age with an increase in systemic but a decrease in vascular markers in both ethnic groups. The results remained unchanged after adjustments for the covariates and covariance. When looking at individual markers to examine which markers are most contributing factors to the composite scores, CRP and SAA were significantly and positively associated with age, while PTX-3 and sVCAM were significantly and negatively associated with age in both ethnic groups.ConclusionsThe composite z-score for systemic inflammation increased with age, while the composite z-score for vascular inflammation declined with age, irrespective of ethnicity. The findings illustrate a regulatory relationship between age and inflammation, and suggest that a perceived elevation of vascular markers among the very young may be an indication of physiological changes rather than reflecting a disease process.

BackgroundThe overall burden of chronic disease, inflammation and cardiovascular risk increases with age. Whether the relationship between age and inflammation is impacted by presence of an adverse metabolic burden is not known.MethodsWe determined inflammatory markers in humans (336 Caucasians and 224 African Americans) and in mice, representing a spectrum of age, weight and metabolic burden.ResultsIn humans, levels of inflammatory markers increased significantly with age in subjects without the metabolic syndrome, (P=0.009 and P=0.037 for C-reactive protein, P

BackgroundDiabetes educators and self-management programs are scarce in rural communities, where diabetes is the third highest-ranking health concern. The goal of this study was to evaluate the benefits of nurse telehealth coaching for persons with diabetes living in rural communities through a person-centered approach using motivational interviewing (MI) techniques.Materials and methodsA randomized experimental study design was used to assign participants to receive either nurse telehealth coaching for five sessions (intervention group) or usual care (control group). Outcomes were measured in both groups using the Diabetes Empowerment Scale (DES), SF-12, and satisfaction surveys. Mean scores for each outcome were compared at baseline and at the 9-month follow-up for both groups using a Student's t test. We also evaluated the change from baseline by estimating the difference in differences (pre- and postintervention) using regression methods.ResultsAmong the 101 participants included in the analysis, 51 received nurse telehealth coaching, and 50 received usual care. We found significantly higher self-efficacy scores in the intervention group compared with the control group based on the DES at 9 months (4.03 versus 3.64, respectively; p

ObjectivesLipoprotein(a), Lp(a), represents an apolipoprotein (apo) B-carrying lipoprotein, yet the relationship between Lp(a) and apoB levels has not been fully explored.MethodsWe addressed the relationship between Lp(a) and apoB-containing lipoprotein levels in 336 Caucasians and 224 African-Americans. Our approach takes unique molecular properties of Lp(a) as well as contribution of Lp(a) to the levels of these lipoproteins into account.ResultsLevels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apoB and apoB/apoA-1 did not differ across ethnicity. African-Americans had higher levels of Lp(a) and high-density lipoprotein cholesterol and lower triglyceride levels compared to Caucasians. Lp(a) levels were correlated with levels of TC (p < 0.005), LDL-C (p < 0.001), apoB (p < 0.05) or apoB/apoA-1 (p < 0.05) in both ethnic groups. These associations remained significant only in African-Americans after adjustments for the contribution of Lp(a)-cholesterol or Lp(a)-apoB. Furthermore, taking Lp(a)-apoB into account, allele-specific apo(a) levels were significantly associated with apoB levels and the apoB/apoA-1 ratio in African-Americans. The latter associations in African-Americans remained significant for allele-specific apo(a) levels for smaller apo(a) sizes (

A marked increase in the frequency of obesity at the population level has resulted in an increasing number of obese women entering pregnancy. The increasing realization of the importance of the fetal environment in relation to chronic disease across the lifespan has focused attention on the role of maternal obesity in fetal development. Previous studies have demonstrated that obesity during adolescence and adulthood can be traced back to fetal and early childhood exposures. This review focuses on factors that contribute to early developmental events, such as epigenetic modifications, the potential for an increase in inflammatory burden, early developmental programming changes such as the variable development of white versus brown adipose tissue, and alterations in organ ontogeny. We hypothesize that these mechanisms promote an unfavorable fetal environment and can have a long-standing impact, with early manifestations of chronic disease that can result in an increased demand for future health care. In order to identify appropriate preventive measures, attention needs to be placed both on reducing maternal obesity as well as understanding the molecular, cellular, and epigenetic mechanisms that may be responsible for the prenatal onset of chronic disease.

ObjectiveThe effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined.Design and methodsThirty two overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8, and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks.ResultsFasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. The 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels.ConclusionsThe consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin, and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption.

ContextResults from animal studies suggest that consumption of large amounts of fructose can promote inflammation and impair fibrinolysis. Data describing the effects of fructose consumption on circulating levels of proinflammatory and prothrombotic markers in humans are unavailable.ObjectiveOur objective was to determine the effects of 10 wk of dietary fructose or glucose consumption on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), E-selectin, intercellular adhesion molecule-1, C-reactive protein, and IL-6.Design and settingThis was a parallel-arm study with two inpatient phases (2 wk baseline, final 2 wk intervention), conducted in a clinical research facility, and an outpatient phase (8 wk) during which subjects resided at home.ParticipantsParticipants were older (40-72 yr), overweight/obese (body mass index = 25-35 kg/m(2)) men (n = 16) and women (n = 15).InterventionsParticipants consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wk. Blood samples were collected at baseline and during the 10th week of intervention.Main outcome measuresFasting concentrations of MCP-1 (P = 0.009), PAI-1 (P = 0.002), and E-selectin (P = 0.048) as well as postprandial concentrations of PAI-1 (P < 0.0001) increased in subjects consuming fructose but not in those consuming glucose. Fasting levels of C-reactive protein, IL-6, and intercellular adhesion molecule-1 were not changed in either group.ConclusionsConsumption of fructose for 10 wk leads to increases of MCP-1, PAI-1, and E-selectin. These findings suggest the possibility that fructose may contribute to the development of the metabolic syndrome via effects on proinflammatory and prothrombotic mediators.

BackgroundConsumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI).ObjectiveWe determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures.DesignThe subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption.ResultsConsumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups.ConclusionThe results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853.

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

The hypothesis was tested that plasma levels of adiponectin would be associated with coronary artery disease (CAD) across African-American and Caucasian ethnicity and gender. Adiponectin levels, cardiovascular risk factors, and extent of CAD were measured in 453 subjects (173 African-American and 280 Caucasian men and women). The distribution of adiponectin levels differed significantly between African-Americans and Caucasians (P