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Over the long-term, at least half of patients started on statins will discontinue them. Statin noncompliance can be defined as discontinuing therapy for whatever reason. This results from four causes: dysfunction of the health care system; fear of side effects (nocebo effect); disorders of the musculoskeletal system or other organs misconstrued as statin related; and true statin myotoxicity. Statin intolerance here represents discontinuation due to perceived side effects. For statin intolerance in patients with clinical atherosclerotic cardiovascular disease, the goal is an LDL level < 70 mg/dL Treatment includes maximally tolerated statin dosage, adding non-statin drugs, and if necessary, a PCSK9 inhibitor. For primary prevention in patients at intermediate risk, as determined by risk factors, coronary artery calcium should be measured for deciding on statin therapy. For patients having zero calcium, a statin can be withheld for a decade before rescanning. If original calcium score is 1-99 Agatston units, a statin can be delayed for five years before rescanning. When the score is ≥ 100, statin therapy is indicated.

Pooled cohort equations (PCEs) estimate 10-year risk for atherosclerotic cardiovascular disease (ASCVD) in US adults. One use is to guide statin eligibility. However, PCEs risk estimate is inaccurate in some US subpopulations.Recent cholesterol guidelines proposed addition of risk enhancing factors to improve risk assessment for selection of statin therapy. This study examines frequencies of several risk enhancing biomarkers in NHANES subjects at intermediate risk (7.5 -20% 10-year risk for ASCVD) and considers how they may be used to better assess risk for individuals.Prevalence of the following biomarkers were determined; elevations in apolipoprotein B-containing lipoproteins, i.e., LDL cholesterol (LDL-C) (160-189 mg/dL), non-HDL-cholesterol (non-HDL-C) (190-219 mg/dL), or total apolipoprotein B (apoB) (≥ 130 mg/dL), serum triglyceride (≥175 mg/dL), hemoglobin A1c (5.7-6.4%), high sensitivity C-reactive protein (2-10 mg/L), and waist circumference ≥ 102 cm, and abnormal estimated glomerular filtration rate (15 - ≤ 60 mg/min/1.73 m25% of NHANES population had intermediate risk. In this subpopulation, 85% had ≥ 1 biomarkers-similarly in women and men-with a third having ≥3 abnormal markers. Frequencies were not age-related, except in those 40-49 years, in whom40% had ≥3 abnormal biomarkers. It made little difference whether LDL-C, non-HDL-C or apoB was used as the atherogenic lipoprotein.Three or more enhancing risk factors in intermediate risk subjects can complement PCE-estimated 10-year risk and guide the patient-provider discussion toward use of lipid-lowering medication. Future research is needed to integrate risk estimates by PCE and multiple risk enhancers.

Statins effectively reduce risk for atherosclerotic cardiovascular disease (ASCVD) when 10-year risk is ≥ 7.5%. In many patients at intermediate risk (7.5-20% risk), there is uncertainty about reliability of risk assessment by current pooled cohort equations (PCE). A decision to initiate statin therapy is favored by several risk enhancing factors not employed in PCEs.This study examines the scope of the metabolic syndrome, a risk enhancing factor, and its principal sequala, diabetes, in 26,796 US adults age 40-75 years from the NHANES survey data, 1999-2016.The prevalence of metabolic syndrome without diabetes (MetS+) and of diabetes (DM+) were determined for 10-year risk categories estimated to be low (7.5%), intermediate (7.5% -20%) and high (≥20%). Data were weighted to account for complex study design.90.4% of the population was free of ASCVD. In subjects projected to be at low risk by PCEs, MetS+ was present in 15.0% and 17.6% of women and men, respectively. MetS + increased to 30.6% of women and 29.6% of men at intermediate risk, and to 21.5% of women and 32.2% of men at high risk. In addition, DM+ was present in 6.1%/5.3% (F/M) of low risk individuals, 20.1%/14.8% (F/M) of intermediate risk subjects, and 44.3%/39.4% (F/M) of high-risk persons. Prevalence of both MetS+ and DM + rose progressively with age in women and men.MetS+ and DM + are common multiplex risk factors that predispose to higher lifetime risk and support statin therapy in patients at intermediate and high risk.

Background Chronic kidney disease (CKD) is a risk factor for atherosclerotic cardiovascular disease (ASCVD). American cardiovascular societies consider CKD a risk-enhancing factor that supports statin therapy in intermediate-risk patients aged 40–75 years. In contrast, European cardiovascular societies recommend statins for all middle-aged adults with CKD. The Kidney Disease: Improving Global Outcomes lipid management guideline for CKD recommends statin therapy for all patients with CKD >50 years. Clinical implications for these differences have not been examined. Objective This study examines CKD prevalence and statin eligibility in non-ASCVD adults, representative of the US population, at 3 levels of 10-year risk of ASCVD estimated by pooled cohort equations. Methods National Health and Nutrition Examination Surveys 1999–2016 weighted data were evaluated for CKD defined as estimated glomerular filtration rate Results A total of 92.5% of all participants had estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2; 7.5% (confidence interval 6.9%, 8.1%) had CKD. Among participants with CKD, 46.3% had 10-year risk for ASCVD Conclusion A total of 46.3% of patients with CKD aged 40–75 years had 10-year risk 50 years) guidelines. US cardiovascular guidelines limit statin eligibility to intermediate- and high-risk CKD. Statin eligibility in lower-risk patients may be best determined by measuring coronary artery calcium.

By current guidelines, statin treatment decisions depend on multiple risk factor algorithms (e.g., pooled cohort equations [PCEs]). By available PCEs most older middle-aged women are statin eligible. But several studies cast doubt on reliability of available PCEs for ASCVD risk assessment. An alternative method for risk assessment is a coronary artery calcium (CAC) score. Many older women have zero CAC, which equates to low risk for ASCVD; these women can delay statin therapy for several years before re-scanning. When CAC is 1-99 Agatston units, risk is only borderline high and statin delay also is an option until re-scanning. When CAC is100 Agatston units, risk is high enough to warrant a statin. In most women, CAC is the best guide to treatment decisions. In high-risk women (e.g., diabetes and severe hypercholesterolemia), generally are indicated, but CAC can assist in risk assessment, but other risk factors also can aid in treatment decisions.

Survivors of childhood brain tumors may be at risk for early onset of metabolic syndrome, possibly secondary to surgery and/or radiation exposure. This study examines effects of radiation exposure to hypothalamus-pituitary-adrenal axis (HPA) on metabolic risk among survivors of childhood brain tumors. One hundred forty-two met inclusion criteria; 60 had tumor surgery plus radiation exposure (>1 Gray (Gy)) to HPA. The second subgroup of 82 subjects had surgery only and were not exposed to radiation. Both subgroups had survived for approximately 5 years at the time of study. All had clinical evaluation, vital signs, anthropometry, measurement of body composition by dual X-ray absorptiometry and fasting laboratory assays (metabolic panel, insulin, C-peptide, insulin-like growth factor-1, leptin and adiponectin). Body composition data for both subgroups was compared with the National Health and Nutrition Survey (NHANES) subgroup of similar age, gender and body mass index. Cranial surgery was associated with obesity of similar severity in both subgroups. However, survivors exposed to radiation to the HPA also had increased visceral fat mass and high prevalence of growth hormone deficiency and metabolic syndrome. Fat mass alone did not explain the prevalence of the metabolic syndrome in radiation exposure subgroup. Other factors such as growth hormone deficiency may have contributed to metabolic risk. We conclude that prevalence of metabolic syndrome among subjects exposed to hypothalamic radiation was higher than expected from hypothalamic obesity alone. Radiation exposure may exert untoward endocrinopathies due to HPA exposure that worsens metabolic risk. Early screening for metabolic syndrome in this population is indicated.

BACKGROUND Non-high-density lipoprotein cholesterol (non-HDL-C) includes atherogenic cholesterol and low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. Patients with diabetes frequently have elevations in non-HDL-C. OBJECTIVE This study examines temporal trends in the levels of non-HDL-C in free-living subjects with diabetes but a negative history of atherosclerotic cardiovascular disease. METHODS National Health and Nutrition Examination Surveys conducted between 1999 and 2016 had data from 3,219 adults (aged 40-75 years) with diabetes. Temporal trends in changes in the distribution of total cholesterol, non-HDL-C, LDL cholesterol (LDL-C), and HDL-C were evaluated. Data were weighted to account for complex survey design. RESULTS Significant decreases were observed in non-HDL-C (20.1%; P

AIMS/HYPOTHESIS: Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort. METHODS: A total of 1557 participants in the Dallas Heart Study without type 2 diabetes underwent measurements of metabolic biomarkers, fat depots by MRI, and plasma ceramides by liquid chromatography-mass spectrometry. Diabetes outcomes were assessed after 7 years. Associations of body fat and insulin resistance with ceramides at baseline and of ceramides with incident diabetes outcomes were analysed. RESULTS: The cohort had mean age 43 years, with 58% women, 45% African-Americans and mean BMI 28 kg/m(2). Total cholesterol levels were associated with all ceramides, but higher triacylglycerols and lower HDL-cholesterol and adiponectin were associated only with saturated fatty acid chain ceramides (p

Objective To examine the prospective relationships among cardiorespiratory fitness (CRF), fasting blood triglyceride to high density lipoprotein cholesterol ratio (TG:HDL-C), and coronary heart disease (CHD) mortality in men. Methods A total of 40,269 men received a comprehensive baseline clinical examination between January 1, 1978, and December 31, 2010. Their CRF was determined from a maximal treadmill exercise test. Participants were divided into CRF categories of low, moderate, and high fit by age group and by TG:HDL-C quartiles. Hazard ratios for CHD mortality were computed using Cox regression analysis. Results A total of 556 deaths due to CHD occurred during a mean ± SD of 16.6±9.7 years (669,678 man-years) of follow-up. A significant positive trend in adjusted CHD mortality was shown across decreasing CRF categories ( P for trend P for trend P =.04) in CHD mortality across decreasing CRF categories in each TG:HDL-C quartile. Conclusion Both CRF and TG:HDL-C are significantly associated with CHD mortality in men. The risk of CHD mortality in each TG:HDL-C quartile was significantly attenuated in men with moderate to high CRF compared with men with low CRF. These results suggest that assessment of CRF and TG:HDL-C should be included for routine CHD mortality risk assessment and risk management.

Context: Polycystic ovarian syndrome (PCOS) is often associated with obesity and diabetes. Objective: The present study measured body fat distribution and metabolic risk factors in women with features of PCOS. Design: Cross-sectional, multiethnic study of cardiovascular risks. Setting: General community. Study Participants: 145 PCOS and 344 non-PCOS women. Exposure Measures: Body composition by dual x-ray absorptiometry; abdominal fat masses measured by magnetic resonance imaging and hepatic triglyceride by magnetic resonance spectroscopy. Outcomes Measures: Body composition, liver fat content, homeostatic model assessment for insulin resistance (HOMA-IR), revised, and metabolic syndrome components. Results: PCOS women had a higher free androgen index compared with the non-PCOS women. Nonobese PCOS and non-PCOS women had a similar body fat content and distribution, HOMA-IR, and hepatic triglyceride content. Obese PCOS women had a similar total body fat percentage compared with their non-PCOS counterparts (41.4% and 41.4% respectively). Both obese groups had similar intraperitoneal fat (1.4% of total body mass in PCOS vs 1.4% in non-PCOS). However, obese PCOS women had a greater ratio of truncal/lower body fat (1.42 vs 1.27; P < 0.016). They also had greater insulin resistance (HOMA-IR: PCOS, 2.24% vs non-PCOS, 1.91%; P < 0.016), higher liver triglyceride content (6.96% in PCOS vs 4.44% in non-PCOS; P < 0.016), and a greater incidence of hypertension (33% vs 24%; P < 0.05). No differences were observed in other metabolic risk factors. Conclusions: Both obese and nonobese women with PCOS features had a greater free androgen index compared with non-PCOS women, but neither had greater intraperitoneal fat or abnormal lipid levels. Obese, but not nonobese, women with PCOS had a greater truncal/lower extremity fat ratio, HOMA-IR, and liver triglyceride content., Obese and non-obese PCOS women have a higher free androgen index than do non-PCOS women. Neither have high intraperitoneal fat. Only obese PCOS women have higher upper body fat, HOMA-IR, and liver fat content.

Background Registered dietitian nutritionists are trained to identify optimal food choices for clients based on medical state and lifestyle. Orthorexia nervosa (ON) is a proposed disorder related to obsessions about eating healthfully. Eating disorders (EDs) are serious mental illnesses with symptoms related to eating, body image, and self-esteem. Both ON and EDs are more common among RDNs than the general population. Objective This study examined the prevalence of ON and EDs in RDNs in the United States and, among this sample, assessed whether the presence of ON symptoms related to symptoms of EDs, including weight, shape, eating, and restraint. Design A cross-sectional design compared responses for participants after dividing into three groups: those scoring at-risk for ON, those with a current or past ED, and a comparison group. Participants A sample of 2,500 RDNs were invited to complete surveys electronically; 636 responses were received. Main outcome measures Scores on the Orthorexia Nervosa Questionnaire (ORTO-15) and Eating Disorder Examination Questionnaire (EDE-Q) determined prevalence of ON and EDs. Differences in these measures, and body mass index were compared among the three groups. Statistical analyses Analysis of variance and χ 2 analyses were used to compare the groups. Results For the entire sample, scores on the ORTO-15 suggested 49.5% were at risk for ON, and scores on the EDE-Q suggested 12.9% were at risk for an ED, with 8.2% of RDNs self-disclosing treatment for an ED. Both the group disclosing ED treatment and the group at risk for ON had a lower mean body mass index, lower scores on the ORTO-15, and higher scores on the EDE-Q and all its subscales than the comparison group. Conclusions Clarifying the relationship between ON and EDs is warranted because ON symptoms appear to be associated not only with disturbances in eating, but also with elevated shape and weight concerns.

Objective To examine the association between specific adipose tissue depots and the risk of incident cancer in the Dallas Heart Study. Patients and Methods Individuals without prevalent cancer in the Dallas Heart Study underwent quantification of adipose depots: visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, and liver fat by magnetic resonance imaging, and subcutaneous lower-body fat (LBF) by dual-energy X-ray absorptiometry from January 1, 2000, through December 31, 2002, and were observed for the development of cancer for up to 12 years. Multivariable Cox proportional hazards modeling was performed to examine the association between fat depots and cancer. Results Of 2627 participants (median age, 43 years; 69% nonwhite race), 167 (6.4%) developed cancer. The most common primary sites of cancer were the breast (in women) and the prostate (in men). In multivariable models adjusted for age, sex, race, smoking, alcohol use, family history of malignancy, and body mass index, a 1-SD increase in VAT was not associated with increased risk of cancer (hazard ratio [HR], 0.94; 95% CI, 0.77-1.14). In contrast, each 1-SD increase in LBF was associated with a reduced incidence of cancer (HR, 0.69; 95% CI, 0.52-0.92) in the fully adjusted model. Conclusions In this study, adiposity-associated cancer risk was heterogeneous and varied by fat depot: VAT was not independently associated with incident cancer, and LBF seemed to protect against cancer development. Further studies of the adiposity-cancer relationship, including serial assessments, are needed to better elucidate this relationship.

Evidence suggests that substantial testosterone therapy is occurring without checking levels of testosterone, presumably based on the presence of symptoms alone. We sought to explore the relationship between total testosterone level and non-specific symptoms, metabolic abnormalities, and sexual dysfunction associated with hypogonadism. This cross-sectional study included 2994 generally healthy men aged 50–79 years examined at a preventive medicine clinic in Dallas, TX from January 2012 to March 2016. Symptoms of hypogonadism were assessed. Screening morning total testosterone levels were measured and categorized into low (0.6). In this preventive medicine cohort, symptoms commonly attributed to testosterone deficiency were not associated with low total testosterone levels.

Background Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C) are targets for prevention of atherosclerotic cardiovascular disease (ASCVD). The American Heart Association and American College of Cardiology recently modified recommendations for clinical management of cholesterol in secondary and primary prevention. Accordingly, the present article examines the need for cholesterol-lowering drugs in the U.S. population with ASCVD. Objective This study examines trends in non–HDL-C and LDL-C levels in a free living population of ASCVD subjects between 1999 and 2016. Methods National Health and Nutrition Examination Surveys database included 4920 adults with ASCVD aged 40 to 85 years. Complete data were available for 4226. Trend analysis of changes in lipids is shown in box plots. Results Mean age was 67 years with 57% males. Over 17 years, LDL-C decreased significantly by 24% and non–HDL-C by 21%. Over the period of study, reported intake of cholesterol-lowering drugs rose from 37% in 1999-2000 to 69% in 2015 to 2016. Over this same period, serum triglycerides decreased by 29% (P Conclusions The changes in LDL-C and non–HDL-C in patients with ASCVD over a 17-year period probably are related to increased treatment with statins. However, the changes are too small to be explained by widespread use of high-intensity statins, which is the current recommendation for patients with ASCVD. These findings pose a challenge for professional education to support implementation of current guidelines for cholesterol-lowering therapies.

Serum concentrations of cholesterol are positively correlated with exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in humans. The associated change in cholesterol is small across a broad range of exposure to PFOA and PFOS. Animal studies generally have not indicated a mechanism that would account for the association in humans. The extent to which the relationship is causal is an open question. Nonetheless, the association is of particular importance because increased serum cholesterol has been considered as an endpoint to derive a point of departure in at least one recent risk assessment. To gain insight into potential mechanisms for the association, both causal and non-causal, an expert workshop was held Oct 31 and Nov 1, 2019 to discuss relevant data and propose new studies. In this report, we summarize the relevant background data, the discussion among the attendees, and their recommendations for further research.

Background Moderate hypertriglyceridemia is frequently associated with central obesity, insulin resistance, and atherogenic dyslipidemia. We showed previously that moderately obese men with hypertriglyceridemia have reduced fatty acid oxidation postabsorptively and postprandially. In the present study, we examined the oxidation of fatty acids in normotriglyceridemic men. Objective The study objective was to determine the relation between plasma triglyceride levels and fatty acid oxidation in normotriglyceridemic men. Study design Twenty-four healthy, nonobese White and African American men participated in a cross-sectional metabolic study for evaluation of fatty acid oxidation. Men were healthy, and none took hypolipidemic or hypoglycemic agents. They ingested 200 mg of fat/hour/kg of body weight over a 10-hour period. Plasma levels of triglyceride, nonesterified fatty acids, 3-β-hydroxybutyrate, insulin, and glucagon were measured postabsorptively and postprandially. Chylomicron-triglyceride halflife was also calculated. Results Nonobese White and African-American men had similar anthropometry, levels of plasma triglyceride, lipoprotein cholesterol, nonesterified fatty acids, 3-β-hydroxybutyrate, insulin, and glucagon postabsorptively and postprandially. For the group as a whole, there was a positive and significant correlation between plasma fatty acids and 3-β-hydroxybutyrate and an inverse association between plasma triglyceride levels and 3-β-hydroxybutyrate at baseline. All subjects had increased levels of metabolites of interest postprandially. However, there were no significant changes in plasma insulin, glucagon, or the ratio of insulin to glucagon. The postprandial levels of 3-β-hydroxybutyrate correlated positively with nonesterified fatty acids and inversely with the half-life of chylomicron triglyceride. Conclusion Normotriglyceridemia is strongly associated with oxidation of fatty acids by the liver suggesting the possibility that the fatty acid oxidation pathway is a potential target of intervention to prevent hypertriglyceridemia and concomitant fatty liver.

Background: Excess visceral adipose tissue (VAT) is associated with an increased risk of prediabetes and type 2 diabetes (T2D) independent of body mass index (BMI). Whether expansion of VAT or other fat depots is associated with diabetes risk independent of weight gain is not fully known. Methods: Among participants without prevalent diabetes or cardiovascular disease enrolled in the Dallas Heart Study, we measured body fat distribution by dual energy x-ray absorptiometry and biomarkers of glycemia at baseline (2000-2002) and repeated 7 years later. The incidence of prediabetes and T2D per ADA definitions were assessed at follow-up. Results: The study included 1661 participants (mean age 44, 58% women, 45% black, 39% obese) with median weight gain of 3.0 (-1.1 to 7.2) kg. Eight percent of participants developed T2D and, among those with normal fasting glucose at baseline (n=1551), 36% developed prediabetes or T2D. Changes in fat depots are shown in the Table. VAT and SAT gain were associated with incident T2D and with prediabetes or T2D independent of traditional risk factors, baseline BMI, change in BMI, and baseline fat depot (Table). Increasing lower body fat was not associated with incident diabetes. Conclusions: Expansion of VAT and SAT are both associated with incident T2D independent of weight gain. Abdominal adiposity may be a modifiable target for diabetes prevention even in the absence of generalized weight loss. Disclosure I.J. Neeland: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Novo Nordisk A/S, National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Self; Advanced MR Analytics AB. C. Ayers: None. K.V. Patel: None. P.H. Joshi: Consultant; Self; Regeneron Pharmaceuticals, Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. S.M. Grundy: None. A. Rohatgi: Research Support; Self; Merck Sharp & Dohme Corp., American Heart Association. Consultant; Self; CSL Behring. Research Support; Self; National Heart, Lung, and Blood Institute. G.L. Vega: None.

Background Currently, exogenous hormone replacement is used in many men with hypogonadism without clear organic cause. This study examines the contribution of modifiable health behaviors, i.e., physical activity and weight control, to the maintenance of testosterone levels with aging. Methods In a cross-sectional study of 2994 healthy men aged 50–79 years examined at a preventive medicine clinic from January 2012 to March 2016, screening morning total testosterone levels were measured and categorized as low ( 400 ng/dL). Cardiorespiratory fitness (fitness) was estimated from a maximal exercise treadmill test. Multiple logistic regression models were used to test the associations between low testosterone levels and age, body mass index (BMI), and fitness. Findings Mean testosterone levels were in the normal range for each age group (50–59, 60–69, and 70–79). There was a similar prevalence of low testosterone in each age group (11·3%, 10%, and 10·5%, respectively). The prevalence of low testosterone was positively associated with BMI and negatively associated with fitness but was not associated with age. Interpretation This study found no evidence that low testosterone is an inevitable consequence of aging. Maintenance of healthy weight and fitness may help maintain normal testosterone levels.

To examine the additive effects of an increased number of positive adiposity exposures on all-cause mortality in men before and after stratification by cardiorespiratory fitness (CRF) level.A total of 36,836 men underwent a physical examination at the Cooper Clinic from January 1, 1971, through December 31, 2006. Exposures included body mass index, waist circumference, percentage of body fat, and CRF as determined by duration of a maximal exercise test. Participants were identified as being either obese (positive) or nonobese (negative) for each adiposity exposure and then grouped into 4 categories: group 1, negative for all adiposity exposures; group 2, positive for any 1 exposure; group 3, positive for any 2 exposures; and group 4, positive for all exposures. Then CRF was grouped as fit or unfit on the basis of the upper 80% and lower 20% of the age-standardized CRF distribution as previously reported in the Cooper Center Longitudinal Study. Hazard ratios were computed with Cox regression analysis.A total of 2294 deaths occurred during a mean ± SD of 15.5 ± 8.1 years of follow-up. Adjusted hazard ratios across adiposity groups were 1.0 (referent), 1.05, 1.37, and 1.87 for groups 1 through 4, respectively (P for trend.001). Mortality rates were significantly lower within each of the first 3 adiposity groups in fit compared with unfit men (P.009 for all comparisons).An increasing number of positive adiposity exposures were associated with increased mortality in men. Because moderate to high CRF attenuated mortality rates in all adiposity groups, measurement of CRF should be included for identifying men at increased risk for all-cause mortality.

Aggregation of metabolic risk factors-i.e., elevated plasma triglyceride (TG), reduced high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and raised plasma glucose-convey increased risk for atherosclerotic cardiovascular disease and type 2 diabetes.This study was carried out to determine the association of waist girth, ethnicity, and gender with susceptibility for metabolic risk. Included were 1671 adult women (50.7% black) and 1339 men (46.5% black) enrolled in the Dallas Heart Study. Subjects were stratified into three categories by waist girth-low, intermediate, and high, corresponding to BMI ranges of25 kg/m(2), 25-29.9 kg/m(2), and ≥30 kg/m(2).Risk factor prevalence rose progressively through each waist-girth category. However, even among those with high waist-girth, prevalence of three or more risk factors was less than 50%. Several differences among the ethnic groups were noted; for example, Hispanic men had a higher prevalence of elevated TG compared to whites; black men, on the other hand, had a lower frequency of high TG. There were also fewer black men with low HDL-C than in the other groups. Black and Hispanic men had a higher prevalence of elevated glucose and updated homeostasis model assessment of insulin resistance (HOMA2-IR) than whites. More black men had elevated blood pressure than other groups. These differences were less pronounced among ethnic groups of women.Although ethnic and gender differences in risk factor prevalence may exist, it is notable that the majority of subjects, even when obese, did not have elevated risk factors. This finding points to the need to focus largely on subjects with metabolic risk factors when implementing therapeutic interventions.

Background High triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) impart risk for heart disease. This study examines the relationships of TG/HDL-C ratio to mortality from all causes, coronary heart disease (CHD), or cardiovascular disease (CVD). Subjects and Methods Survival analysis was done in 39,447 men grouped by TG/HDL-C ratio cut point of 3.5 and for metabolic syndrome. National Death Index International Classification of Diseases ( ICD-9 and ICD-10) codes were used for CVD and CHD deaths occurring from 1970 to 2008. Incidence of type 2 diabetes mellitus (DM) according to ratio was estimated in 22,215 men. Triglyceride/HDL-C ratio and cross-product of TG and fasting blood glucose (TyG index) were used in analysis. Results Men were followed up for 581,194 person-years. Triglyceride/HDL-C ratio predicted CHD, CVD, and all-cause mortality after adjustment for established risk factors and non–HDL-C. Mortality rates were higher in individuals with a high ratio than in those with a low ratio. Fifty-five percent of men had metabolic syndrome that was also predictive of CHD, CVD, and all-cause mortality. Annual incidence of DM was 2 times higher in men with high TG/HDL-C ratio than in those with a low ratio. Individuals with high TG/HDL-C ratio had a higher incidence of DM than those with a low ratio. The TyG index was not equally predictive of causes of mortality to TG/HDL-C, but both were equally predictive of diabetes incidence. Conclusions Triglyceride/HDL-C ratio predicts CHD and CVD mortality as well as or better than do metabolic syndrome in men. Also, a high ratio predisposes to DM. The TyG index does not predict CHD, CVD, or all-cause mortality equally well, but like TG/HDL-C ratio, it predicts DM incidence.

ObjectivesThe goal of this study was to investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort.BackgroundNatriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models, but data are lacking in humans.MethodsA total of 2,619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP); and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index.ResultsMedian BNP and NT-proBNP levels in the study cohort (mean age 44 years; 56% women, 48% African Americans, 32% obese) were 3.0 and 28.1 pg/ml, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance, including lower visceral fat, liver fat, and homeostasis model assessment of insulin resistance index, and increased lower body fat and higher adiponectin (p < 0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral fat (beta coefficient = −0.08; p < 0.0001) and liver fat (beta coefficient = −0.14; p < 0.0001) and positively associated with lower body fat (beta coefficient = 0.07; p < 0.0001) independent of age, sex, race, and obesity status; findings were similar with BNP. Adjustment for body composition, homeostasis model assessment of insulin resistance index, circulating androgens, and adipocytokines did not attenuate the associations.ConclusionsHigher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides.

Objective Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population-based cohort of obese adults. Design and methods Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. Results In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p Conclusion VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk.

Objectives: Although psychosocial stress can result in adverse health outcomes, little is known about how perceptions of neighborhood conditions, a measure of environment-derived stress, may impact obesity. The association between perceptions of neighborhood environment and obesity (defined as body mass index [BMI] ≥ 30 kg/m2) among 5,907 participants in the Dallas Heart Study, a multi-ethnic, probability-based sample of Dallas County residents was examined. Design and Methods: Participants were asked to respond to 18 questions about perceptions of their neighborhood. Factor analysis was used to identify three factors associated with neighborhood perceptions: neighborhood violence, physical environment, and social cohesion. Logistic regression analyses were performed to determine the relationship between each factor (higher quintile = more unfavorable perceptions) and the odds of obesity. Results: Decreasing age, income, and education associated with unfavorable overall neighborhood perceptions and unfavorable perceptions about specific neighborhood factors (P trend

Background Centenarians with normal cognitive function have a "longevity phenotype" characterized by large low-density lipoproteins (LDL) and high-density lipoproteins (HDL) and low incidence of metabolic syndrome, hypertension, and cognitive impairment. Alzheimer's disease (AD) is associated with a number of cardiovascular risk factors, but it is not known if they have or lack the "longevity phenotype". Objective The study was designed to determine LDL size and body fat content and distribution in subjects with mild cognitive impairment (MCI) and AD. Results Fifty-eight persons with MCI or AD (cases) and 42 control subjects of similar age had measurement of LDL size and lipoprotein lipids after a 12 h fast and analysis of body composition by dual x-ray absorptiometry. Cases had small LDL size more often than controls (73% versus 66%) associated with significantly higher triglycerides, lower HDL cholesterol, and higher triglyceride/HDL cholesterol ratio (p ≤ 0.02). Cases with large LDL had a better lipoprotein profile than those with small LDL. Cases and controls had similar percent body fat, fat index, and lean mass index. Forty-seven percent of cases and 39% of controls were obese. Conclusion The prevalence of small LDL phenotype in MCI and AD cases contrasts with the "longevity phenotype" reported for centenarians with preserved cognitive function. The small LDL phenotype is an atherogenic lipoprotein profile found in metabolic syndrome, type 2 diabetes, and insulin resistance. It is now also reported in persons with MCI and AD.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can improve dyslipidemia in patients with diabetes and albuminuria. Whether combined ACEi+ARB or ACEi+mineralocorticoid receptor blockade improves dyslipidemia is not known. We hypothesized long-term administration of either losartan 100 mg or spironolactone 25 mg once daily added onto lisinopril 80 mg once daily would improve dyslipidemia in diabetic nephropathy (DN). We measured lipid levels, very-low-density (V), intermediate-density (I), low-density (LDL), high-density (HDL) lipoprotein, LDL particle size with their respective cholesterol (C) and apolipoprotein B levels (ApoB), and urine albumin/creatinine ratio (UACR) at 12-week interval during a 48-week randomized, double-blind placebo-controlled trial in 81 patients with DN. Plasma lipids and lipoprotein C were analyzed enzymatically and Apo B was determined chemically. Data were analyzed by mixed model repeated measures. ΔUACR differed among treatment arms (placebo −24.6%, los −38.2%, spiro −51.6%, p=0.02). No correlation existed between ΔUACR and ΔTG or any of the lipid or lipoprotein measurements. Compared with placebo losartan, but not spironolactone, decreased TG (−20.9% vs +34.3%, pTrial registration number NCT00381134; Results.

Survivors of childhood acute lymphoblastic leukemia (ALL) have an increased risk of cardiovascular disease. Small density lipoproteins are atherogenic but have not been studied in this population. We conducted a cross-sectional analysis of 110 ALL survivors (mean age, 24.3 years) to determine prevalence of small dense LDL (pattern B) phenotype in ALL survivors and identify associated factors. Lipid subfractions were measured using Vertical Auto Profile-II. Participants with greater than 50% of LDL-cholesterol (LDL-c) in small dense LDL fractions (LDL(3+4)) were classified as LDL pattern B. Visceral and subcutaneous adipose tissue (VAT, SAT) volumes were also measured by computed tomography. While the mean LDL-c level of ALL survivors was 108.7 ± 26.8 mg/dl, 36% (40/110) of survivors had atherogenic LDL pattern B. This pattern was more common in males (26/47; 55%) than in females (14/63; 22%, P = 0.001) and more common in survivors treated with cranial radiotherapy (15/33; 45%) than in those who were treated with chemotherapy alone (25/77; 33%; P = 0.04, adjusted for age, gender, history of hypertension, and smoking history). VAT was associated with atherogenic lipids: LDL pattern B and LDL(3+4) levels. This association was independent of other measures of body fat. We conclude that a substantial proportion of ALL survivors had an atherogenic LDL phenotype despite normal mean LDL-c levels. An atherogenic LDL phenotype may contribute to the increase in cardiovascular mortality and morbidity in this population.

Background To determine risk for type 2 diabetes in subjects with fasting glucose levels in the ranges of normoglycemia, mild hyperglycemia, and intermediate hyperglycemia and to assess the effect of obesity and metabolic syndrome on this risk. Subjects and Methods Incidence of type 2 diabetes mellitus was evaluated in 28,209 relatively healthy subjects participating in the Cooper Center Longitudinal Study. They were included in the study if they had more than 1 fasting plasma glucose measurement, anthropometry, and other parameters of interest. Three subgroups were identified: normoglycemic (Results Thirty-one percent of men and 15.9% of women had mild hyperglycemia and 11.9% of men and 3.6% of women had intermediate hyperglycemia. Yearly conversion rates to diabetes were low in individuals with normoglycemia and mild hyperglycemia but were strikingly higher in those with intermediate hyperglycemia. In subjects with intermediate hyperglycemia, presence of obesity and/or metabolic syndrome doubled conversion rates to diabetes. Conclusions This study showed a marked difference in outcomes in subjects with mild and intermediate hyperglycemia. Moreover, obesity and metabolic syndrome were associated with strikingly elevated risk for diabetes in subjects with intermediate hyperglycemia. Thus intermediate hyperglycemia plus obesity/metabolic syndrome seemingly justifies intensive clinical intervention for prevention of both diabetes and cardiovascular disease.

Obesity and diabetes are more common in African-Americans than whites. Because free fatty acids (FFA) participate in the development of these conditions, studying race differences in the regulation of FFA and glucose by insulin is essential.The objective of the study was to determine whether race differences exist in glucose and FFA response to insulin.This was a cross-sectional study.The study was conducted at a clinical research center.Thirty-four premenopausal women (17 African-Americans, 17 whites) matched for age [36 ± 10 yr (mean ± sd)] and body mass index (30.0 ± 6.7 kg/m²).Insulin-modified frequently sampled iv glucose tolerance tests were performed with data analyzed by separate minimal models for glucose and FFA.Glucose measures were insulin sensitivity index (S(I)) and acute insulin response to glucose (AIRg). FFA measures were FFA clearance rate (c(f)).Body mass index was similar but fat mass was higher in African-Americans than whites (P0.01). Compared with whites, African-Americans had lower S(I) (3.71 ± 1.55 vs. 5.23 ± 2.74 [×10⁻⁴ min⁻¹/(microunits per milliliter)] (P = 0.05) and higher AIRg (642 ± 379 vs. 263 ± 206 mU/liter⁻¹ · min, P0.01). Adjusting for fat mass, African-Americans had higher FFA clearance, c(f) (0.13 ± 0.06 vs. 0.08 ± 0.05 min⁻¹, P0.01). After adjusting for AIRg, the race difference in c(f) was no longer present (P = 0.51). For all women, the relationship between c(f) and AIRg was significant (r = 0.64, P0.01), but the relationship between c(f) and S(I) was not (r = -0.07, P = 0.71). The same pattern persisted when the two groups were studied separately.African-American women were more insulin resistant than white women, yet they had greater FFA clearance. Acutely higher insulin concentrations in African-American women accounted for higher FFA clearance.

Plasma levels of adiponectin are inversely associated with body mass. We hypothesised that adipose tissue distribution and body composition influences adiponectin levels.We assessed plasma adiponectin concentrations and dual-energy X-ray absorptiometry (DEXA) measurements of body composition among 2,820 participants from the Dallas Heart Study.Among both women and men, adiponectin levels were higher in whites than in either Hispanics or African-Americans (for women: median 9.99 μg/ml [25th,75th percentile 7.11, 13.77] vs 7.56 μg/ml [5.05, 9.98] vs 6.39 μg/ml [4.37, 9.41], respectively, p 0.0001; for men: 6.43 μg/ml [4.66, 9.19] vs 5.55 μg/ml [3.64, 7.50] vs 5.03 μg/ml [3.39, 7.28], p 0.0001). In univariate analysis, each individual component of body mass was inversely associated with adiponectin. After multivariate analysis, adiponectin levels were found to be positively associated with lower extremity fat, whether expressed in absolute mass (for women: β = 0.055, p 0.0001; for men: β = 0.061, p 0.0001), or as a relative proportion (for women: β = 0.035, p 0.0001; for men: β = 0.034, p 0.0001). This association was consistent across ethnicities. Conversely, adiponectin was negatively correlated with truncal fat, both in absolute (for women: β = -0.039, p 0.0001; for men: β = -0.044, p 0.0001) and relative terms (for women: β = -0.027, p 0.0001; for men β = -0.033, p 0.0001). At the extreme of body mass, higher degrees of lower extremity and truncal adiposity were associated with higher levels of adiponectin.These data suggest that the location of adipose depots differentially influences circulating adiponectin concentrations-a finding observed across ethnicity and sex. Gross measures of body mass alone do not adequately account for adiponectin levels. This supports a role of adiponectin as a mediator of the positive effects of lower extremity adiposity on improvements in insulin sensitivity.

Background Following our previous reports of an increased prevalence of insulin resistance and adiposity among acute lymphoblastic leukemia (ALL) survivors, particularly women treated with cranial radiotherapy (CRT), we aimed to (1) assess the relationships between adipokines (leptin and adiponectin), CRT, and measures of body fatness and (2) determine correlates of insulin resistance, by gender. Methods We conducted cross-sectional evaluation of 116 ALL survivors (median age: 23.0 years; range: 18–37; average time from treatment: 17.5 years), including fasting laboratory testing (adiponectin, leptin, insulin, and glucose), anthropometric measurements (weight, height, and waist circumference), DXA (total body fat and truncal-to-lower-body-fat ratio), and abdominal CT (visceral fat). We estimated insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR). Analytic approaches included regression models and Wilcoxon rank sum testing. Results Mean leptin per kilogram fat mass was higher for females (0.7 ng/ml/kg) than males (0.4 ng/ml/kg, P

Background The metabolic syndrome is a constellation of risk factors including dyslipidemia, dysglycemia, hypertension, a pro‐inflammatory state, and a prothrombotic state. All of these factors are accentuated by obesity. However, obesity can be defined by body mass index (BMI), percent body fat, or by body fat distribution. The latter consists of upper body fat (subcutaneous and visceral fat) and lower body fat (gluteofemoral fat). Waist circumference is a common surrogate marker for upper body fat. Methods Data from the National Health and Nutrition Examination Survey (NHANES) for the years 1999‐2006 was examined for associations of metabolic risk factors with percent body fat, waist circumference, and BMI. Results Associations between absolute measures of waist circumference and risk factors were similiar for men and women. The similarities of associations between waist circumference and risk factors suggests that greater visceral fat in men does not accentuate the influence of upper body fat on risk factors. Conclusions Different waist concumference values should not be used to define abdominal obesity in men and women.

Background: C-reactive protein (CRP) levels are significantly influenced by adiposity and are higher in women compared with men. We postulated that there may be sex differences in the relationship between CRP and body fat. Methods: We measured CRP and body fat parameters in 1166 men and 1413 women ages 30–65 in the population-based Dallas Heart Study. Total fat mass (TFM) was measured using dual-energy x-ray absorptiometry scanning and was subdivided into truncal fat (TrF) and lower body fat (LBF). The TrF/LBF ratio was used to measure fat distribution. Abdominal fat compartments (ip and sc) were measured using magnetic resonance imaging. Log-transformed CRP was used as the outcome variable in sex-combined models with interaction tests. Results: Median body mass index was higher in women than in men (29.9 vs. 28.2 kg/m2), as was TFM (29.7 vs. 20.5 kg) (P < 0.001 each). TFM was linearly associated with log CRP in both sexes, with a steeper slope of association in women (P interaction = 0.003). CRP increased to a greater degree with increasing TrF (P interaction = 0.0004) in women compared with men, even after adjustment for TFM; values were similar across sexes for LBF. Fat distribution (TrF/LBF ratio) was more strongly associated with CRP levels in women vs. men (R2 adjusted for TFM = 0.04 vs. 0.008). Greater increases in CRP were also observed with increasing ip and sc fat in women compared with men. Conclusions: The quantity and distribution of body fat influence CRP to a greater extent in women compared with men. Adiposity as a contributor to subclinical inflammation may be particularly relevant in women.

Guidelines have recommended non-high-density lipoprotein (non-HDL) cholesterol as a secondary target for therapy after the low-density lipoprotein (LDL) cholesterol goals have been met in patients with hypertriglyceridemia; non-HDL cholesterol is viewed as a surrogate for apolipoprotein (Apo)B, an alternate end point of treatment. The present analysis of the previously reported Simvastatin plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial assessed the associations of non-HDL cholesterol and LDL cholesterol with ApoB levels in patients with combined hyperlipidemia treated with combination simvastatin (20 mg) and fenofibrate (160 mg) or simvastatin monotherapy (20 mg). The correlations of these factors were analyzed in the overall modified intent-to-treat population (n = 594) and in patient subgroups stratified by triglyceride (TG) tertiles. Simvastatin plus fenofibrate and simvastatin alone significantly reduced LDL cholesterol, TG, non-HDL cholesterol and ApoB levels and non-HDL cholesterol/ApoB ratio (por =0.0004), regardless of the TG level. The greatest reductions occurred with combination treatment. The baseline levels of non-HDL cholesterol and LDL cholesterol correlated highly with ApoB and were stronger in the lower TG tertiles than in the higher TG tertiles. After 12 weeks, the correlations had changed little with simvastatin monotherapy but had increased substantially with combination therapy and were most improved at high TG levels. In conclusion, these results suggest that both non-HDL cholesterol and ApoB provide similar information in relation to treatment response in patients with combined hyperlipidemia and hypertriglyceridemia, and that non-HDL cholesterol is a good indicator of ApoB-containing lipoproteins, supporting its recommended use as a secondary therapeutic target in these patients.

Low density lipoprotein (LDL) is probably the most atherogenic of all the lipoproteins. Several abnormalities in LDL metabolism seem to be associated with coronary heart disease (CHD) one of them being an elevation of plasma LDL concentration. Recent findings suggest that disorders in the metabolism of LDL could be associated with accelerated atherosclerosis even without elevated LDL levels such as increased flux of LDL and changes in the LDL composition. Elevation of plasma LDL levels can be caused by two factors, first, a decrease in the clearance of LDL and second, an overproduction of this lipoprotein. Catabolism of LDL is largely determined by the LDL receptors as clearly shown in patients with familial hypercholesterolemia (FH). In this inherited disease the patients do not have normal LDL receptors and their LDL levels are remarkably elevated. LDL production is also increased in these subjects. In the rest of the population LDL levels are regulated by both the LDL clearance and production rate. The latter also seems to be related to the LDL receptor activity. The conversion of the LDL precursor, very low density lipoprotein (VLDL) to LDL is the most important factor regulating LDL synthesis. When the LDL receptor activity is low a large fraction of VLDL apolipoprotein B (apoB), the major structural protein in VLDL, is converted to LDL, and LDL production is high. On the other hand, only a small part of VLDL apoB is converted to LDL resulting in low LDL synthesis rate in conditions with high LDL receptor activity. The relationships between production and clearance of LDL are, however, more complex. There are individuals who produce a large number of VLDL and LDL particles but maintain LDL concentrations at a normal level by clearing their LDL very effectively. These subjects obviously have another abnormality in lipoprotein metabolism namely an overproduction of apoB. This disorder has been observed in several conditions like obesity, adult-onset diabetes mellitus, several patients with familial combined hyperlipidemia and some normolipidemic subjects with premature coronary heart disease. In all these conditions increased transport of LDL can be associated with coronary artery disease even in the absence of hypercholesterolemia. This raises the possibility that increased flux of LDL could itself be atherogenic possibly by overloading reverse cholesterol transport. Finally, there is some evidence that LDL particle composition may be important in the process of atherogenesis. High LDL apoB but normal LDL cholesterol levels, hyperapobetalipoproteinemia, has been associated with premature coronary heart disease. Furthermore, variability in LDL composition and particle size indicates that LDL can be heterogenous and raises the possibility that some forms of LDL are more atherogenic than others. In conclusion, the metabolic basis of coronary heart disease, particularly the abnormalities associated with the most atherogenic lipoprotein, LDL, seem to be multiple and indicate a need to expand our views of causal factors in coronary heart disease.

Background: Previous reports indicate that both distribution and amount of body fat confers susceptibility to metabolic syndrome. However, the relative contributions of these two different parameters of body fat to the various components of the metabolic syndrome have not been well defined. Methods: Dual-energy X-ray absorptiometry (DXA) was used to measure and compare the relative amounts of total body fat, truncal fat, and lower body fat in a representative sample of 2587 black, white, and Hispanic men and women from the Dallas Heart Study (DHS). The relationships among these variables and fasting plasma levels of lipids, glucose, insulin, C-reactive protein (CRP), and leptin as well as blood pressure were analyzed. Results: Beyond total body fat, fat distribution had the greatest impact on plasma triglycerides in all subjects and on high-density lipoprotein cholesterol (HDL-C) levels in women only. An intermediate effect of fat distribution was observed for homeostasis model assessment of insulin resistance (HOMA-IR) and for blood pressure. Plasma CRP levels were much more sensitive to body fat content than to body fat distribution and leptin levels were determined almost exclusively by body fat content. Although there were minor differences among the different ethnic groups, the major relationship patterns between these variables were similar. Conclusion: For most metabolic risk factors, both body fat content and distribution independently contributed to levels, although significant differences were seen between the relative contributions of each variable to individual risk factors.

The effects of insulin on the suppression of lipolysis are neither fully understood nor quantified. We examined a variety of mathematical models analogous to the minimal model of glucose disposal (MMG) to quantify the combined influence of insulin on lipolysis and glucose disposal during an insulin-modified frequently sampled intravenous glucose tolerance test. The tested models, which include two previously published ones, consisted of separate compartments for plasma free fatty acids (FFA), glucose, and insulin. They differed in the number of compartments and in the action of insulin to suppress lipolysis that decreased the plasma FFA level. In one category of models, a single insulin compartment acted on both glucose and FFA simultaneously. In a second category, there were two insulin compartments, each acting on FFA and glucose independently. For each of these two categories, we tested 11 variations of how insulin suppressed lipolysis. We also tested a model with an additional glucose compartment that acted on FFA. These 23 models were fit to the plasma FFA and glucose concentrations of 102 subjects individually. Using Bayesian model comparison methods, we selected the model that best balanced fit and minimized model complexity. In the best model, insulin suppressed lipolysis via a Hill function through a remote compartment that acted on both glucose and FFA simultaneously, and glucose dynamics obeyed the classic MMG.

Background Because dietary N-3 fatty acids reduce plasma triglycerides, they may also decrease hepatic triglyceride content. If so, N-3 fatty acids might constitute a therapy for fatty liver. Methods Twenty-two subjects were recruited into a study designed to test the effects of N-3 fatty acids on liver fat content. Seventeen completed the trial that had a sequential design of 4-week placebo followed by an 8-week treatment with 9 g/d of fish oil. Liver fat was measured during placebo and treatment by magnetic resonance spectroscopy. Compliance was assessed by capsule count at the end of each study phase and measurement of fatty acid composition in plasma triglyceride and phospholipid. Plasma lipoproteins and adiponectin were also measured. Results Treatment with fish oils reduced significantly levels of plasma triglyceride by 46% ( P Conclusions N-3 fatty acids at high doses lower plasma triglyceride levels, but there are no significant decreases in hepatic content of triglyceride for the group as a whole. Whereas the triglyceride lowering is uniform, the liver response is more variable.

Objective— Although IL-18 promotes atherogenesis in animal studies and predicts cardiovascular risk in humans, it is unknown whether elevated IL-18 levels are associated with coronary atherosclerosis in the general population. Methods and Results— IL-18 plasma levels were determined by ELISA in 2231 subjects from the Dallas Heart Study. In univariable analysis, IL-18 levels associated with traditional cardiovascular risk factors and particularly with components of the metabolic syndrome (MS, P P Conclusions— In a large population-based sample, elevated IL-18 plasma levels associated with risk factors for atherosclerosis and with the metabolic syndrome. The association between IL-18 and atherosclerosis diminished after accounting for traditional cardiovascular risk factors. These data suggest that IL-18 does not add independently to detection of atherosclerotic burden in asymptomatic individuals.

Background African Americans commonly have normal high-density lipoprotein cholesterol (HDL-C) and low triglyceride levels despite having insulin resistance and obesity. The higher than expected HDL-C levels are usually attributed to low levels of hepatic triglyceride lipase (HTGL) activity. Factors that regulate HTGL in African Americans are not well delineated. Methods In the current study, HTGL activity was examined in relation to indices of body fat (body mass index [BMI] and waist circumference [WC]), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR] index), and adipokines (adiponectin and leptin). Sixty-three African Americans (33 men, 30 women; median age 31 years, range 20-50 years; median BMI 28.6 kg/m2, range 19.7-54.7 kg/m2) had anthropometry and measurement of postheparin lipase activities (HTGL), plasma HDL-C, triglycerides, and plasma adiponectin. Results HTGL correlated strongly with HDL-C ( r = −.52, p < .0001) and adiponectin ( r = −.49, p < .001). HTGL increased with BMI and WC ( r = .297, p = .018 and r = .301, p = .016, respectively). Adiponectin correlated strongly with HDL-C ( r = .50, p < .0001) and triglycerides ( r = −.493, p < .001). From multiple regression models, 28% of HTGL variability among African Americans can be explained by adiponectin levels in combination with gender and 35% of HTGL is explained with HDL-C included in the model. Conclusion The data suggest that adiponectin is a significant metabolic concomitant of HTGL activity in African Americans.

Severe obesity is increasingly common in the United States. Very obese persons are at increased risk for the metabolic consequences of obesity. A common multidimensional risk condition associated with obesity is the metabolic syndrome. It is accompanied by increased risk for cardiovascular disease and type 2 diabetes. Clinical manifestations of the metabolic syndrome can vary among obese individuals depending on ethnicity and gender. This study was carried out to determine the pattern of metabolic risk factors in very obese women who were considered candidates for bariatric surgery. Twenty-eight women of this type were compared to 28 nonobese women. Among the former, 11 had categorical hyperglycemia (type 2 diabetes), and 26 had metabolic syndrome by current criteria. Both those with and without diabetes had higher triglycerides and lower high-density lipoprotein (HDL) cholesterol levels than nonobese, but their levels were not categorically abnormal. These changes may have been related to observed lower postheparin lipoprotein lipase activities and higher hepatic lipase activities. In spite of lipid changes, apolipoprotein B levels were only marginally higher in very obese women. In contrast to small changes in lipoprotein metabolism, the obese women were severely insulin resistant, as indicated by hyperglycemia and elevated insulin levels. In addition, they had very high C-reactive protein levels. Thus, the metabolic syndrome, which appears to be typical of very obese women, is characterized by insulin resistance, glucose intolerance and a proinflammatory state. Atherogenic dyslipidemia as a metabolic risk factor in contrast is relatively mild. This pattern is more likely to lead to type 2 diabetes prior to development of clinically evident cardiovascular disease.

Summary Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results. We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06). Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.

Objectives: Several reports indicate that the body fat compartments, especially ip fat, predict metabolic risk better than total body fat. The objective of the study was to determine whether this can be confirmed and generalized throughout the population.Participants: A representative sample of 1934 Black and White women and men of the Dallas Heart Study participated in the study.Design: We measured the fat in total body, trunk, and lower body with dual-energy x-ray absorptiometry and in abdominal compartments (sc, ip, and retroperitoneal) with magnetic resonance imaging. Other measurements included body mass index (BMI), waist circumference, blood pressure, plasma lipids, glucose, insulin (including homeostasis model), and C-reactive protein.Results: In all groups, total body fat correlated positively with key metabolic risk factors, i.e. homeostasis model, triglyceride/high-density lipoprotein-cholesterol ratios, C-reactive protein, and blood pressure; however, it explained less than one third of the variability of all the risk factors. After adjustment for total body fat, truncal fat conferred additional positive correlation with risk factors. Furthermore, with multivariable regression analysis, ip fat conferred independent correlation with plasma lipids beyond a combination of other compartments including truncal fat. Still, except for insulin levels, all combinations including ip fat still explained less than one third of the variability in risk-factor levels. Conversely, lower body fat correlated negatively with risk factors; i.e. lower body fat appeared to offer some protection against risk factors.Conclusions: Body fat distribution has some influence on risk factors beyond total body fat content. Both waist circumference and BMI significantly predicted risk factors after adjustment for total body fat, and for clinical purposes, most of the predictive power for men was contained in waist circumference, whereas for women, BMI and waist circumference were similarly predictive. Finally, even though the correlations between combined body fat parameters and risk factors explained only a portion of the variation in the latter, the average number of categorical metabolic risk factors increased progressively with increasing obesity. Hence, obesity seemingly has more clinical impact than revealed in these correlative studies.