Managing Atherosclerotic Cardiovascular Risk in Young Adults: JACC State-of-the-Art Review.

There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians identify and address high-risk conditions in the 20- to 39-year age range (young adults). These include tobacco use, elevated blood pressure/hypertension, family history of premature ASCVD, primary severe hypercholesterolemia such as familial hypercholesterolemia, diabetes with diabetes-specific risk-enhancing factors, or the presence of multiple other risk-enhancing factors, including in females, a history of pre-eclampsia or menopause under age 40. The authors update current thinking on lipid risk factors such as triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, or lipoprotein (a) that are useful in understanding an individual's long-term ASCVD risk. The authors review emerging strategies, such as coronary artery calcium and polygenic risk scores in this age group, that have potential clinical utility, but whose best use remains uncertain. Finally, the authors discuss both the obstacles and opportunities for addressing prevention in early adulthood.

Chronic kidney disease and statin eligibility.

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 < 60 mL/min/1.73 m2. Overall prevalence of low, intermediate, and high 10-year risk for ASCVD was determined. 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 <7.5% (low risk); 31.7% had intermediate risk (7.5-< 20%), and 22.0% had high risk (≥20%). In participants with CKD, 62.5% were women. A total of 19.6% of all participants with CKD had diabetes. A total of 46.3% of participants with CKD at intermediate or high risk reported taking cholesterol-lowering drugs. CONCLUSION: A total of 46.3% of patients with CKD aged 40-75 years had 10-year risk <7.5% (low risk) and hence were statin eligible by European and Kidney Disease: Improving Global Outcomes (>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.

An Analysis of Individual Body Fat Depots and Risk of Developing Cancer: Insights From the Dallas Heart Study.

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.

Metabolic syndrome update.

The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease and type 2 diabetes. It is composed of atherogenic dyslipidemia, elevated blood pressure, insulin resistance and elevated glucose, a pro-thrombotic state, and a pro-inflammatory state. Excess energy intake and concomitant obesity are the major drivers of the syndrome. Lifestyle intervention can reverse metabolic risk factors, but at times, drug therapies or bariatric surgery may be required to control more overt risk factors.

National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report.

The leadership of the National Lipid Association convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. An Executive Summary of those recommendations was previously published. This document provides support for the recommendations outlined in the Executive Summary. The major conclusions include (1) an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins (non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol [LDL-C], termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical atherosclerotic cardiovascular disease (ASCVD) events; (2) reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies; (3) the intensity of risk-reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event; (4) atherosclerosis is a process that often begins early in life and progresses for decades before resulting a clinical ASCVD event. Therefore, both intermediate-term and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; (5) for patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD risk; (6) nonlipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus; and (7) the measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.

Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers.

UNLABELLED: Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P ≤ 0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327691.

Treatment targets in the management of dyslipidemias: which targets in whom?

The public health approach to prevention of atherosclerotic cardiovascular disease (ASCVD) continues to hold great potential for prevention. This approach includes diets low in saturated fats and cholesterol, maintaining desirable body weight, regular physical activity, and absence of cigarette smoking. But drug therapy is becoming more widely used. Statins have been available for treatment of elevated serum cholesterol for a quarter of a century. They have proven efficacious for reducing risk for atherosclerotic cardiovascular disease (ASCVD). They carry little toxicity, and now that some derivatives are generic, they are inexpensive. Statins have become standard of care for patients with established ASCVD. To achieve further reduction in ASCVD events through cholesterol lowering will require new combinations with older agents and development of new drugs. The future of secondary prevention lies in testing of old and new "add-on" agents. Indications for statin use in primary prevention is less clear-cut. But clinical-trial experience with statins point to enormous potential for reducing ASCVD in the population. At the same time, there are dangers of overuse and turning society into a "drug culture". To abandon the benefits of healthy lifestyles for excessive drug intervention would be unfortunate.

Cardiorespiratory fitness, LDL cholesterol, and CHD mortality in men.

INTRODUCTION: There are no published data regarding the joint association of cardiorespiratory fitness (CRF) and LDL cholesterol concentration with subsequent CHD mortality in men. METHODS: A total of 40,718 healthy men received a comprehensive baseline clinical examination between 1971 and 2006. CRF was determined from a maximal treadmill exercise test. Participants were divided into categories of low (quintile 1), moderate (quintiles 2-3), and high (quintiles 4-5) CRF by age group, as well as by Adult Treatment Panel III-defined LDL categories. HRs for CHD mortality were computed with Cox regression analysis. RESULTS: A total of 557 deaths due to CHD occurred during 16.7 ± 9.0 yr (681,731 man-years) of follow-up. After adjustment for age, examination year, smoking status, family history, and body mass index, a significant positive trend in CHD mortality was shown across decreasing categories of CRF. HRs with 95% confidence interval were 1.0 (referent), 1.18 (0.94-1.47), and 2.10 (1.65-2.67) for high, moderate, and low fit groups, P trend <0.0001. Adjusted HRs were significantly higher across increasing LDL categories: 1.0 (referent), 1.30 (0.87-1.95), 1.54 (1.04-2.28), 2.16 (1.45-3.21), and 2.02 (1.31-3.13), P trend <0.0001. When grouped by CRF category as well as by LDL category, there was a significant positive trend (P < 0.02) in adjusted mortality across decreasing categories of CRF within each LDL category. CONCLUSIONS: CRF is strongly and inversely associated with CHD mortality in men. Compared with men with low CRF, at a moderate to high level of CRF, the risk of mortality within each LDL category is significantly attenuated. This study suggests that measurement of CRF should be considered for routine cardiovascular risk assessment and risk management.

Cardiorespiratory fitness and metabolic risk.

The present study sought to evaluate the relation between cardiovascular risk factors and cardiorespiratory fitness (CRF) in a large population. Low CRF has been associated with increased total mortality and cardiovascular mortality. The mechanisms underlying greater cardiovascular mortality have not yet been determined. A series of cardiovascular risk factors were measured in 59,820 men and 22,192 women who had undergone determinations of CRF with maximal exercise testing. The risk factor profiles were segregated into 5 quintiles of CRF. With decreasing CRF, increases occurred in obesity, triglycerides, non-high-density lipoprotein cholesterol, triglyceride/high-density lipoprotein ratios, blood pressure, metabolic syndrome, diabetes, and cigarette smoking. Self-reported physical activity declined with decreasing levels of CRF. In conclusion, it appears likely that the enrichment of cardiovascular risk factors, especially metabolic risk factors, account for a portion of the increased cardiovascular mortality in low-fitness subjects. The mechanisms responsible for this enrichment in subjects with a low CRF represent a challenge for future research.

Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease.

We determined the ability of in-trial measurements of triglycerides (TGs) to predict new cardiovascular events (CVEs) using data from the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) trials. The trials compared atorvastatin 80 mg/day with moderate-dose statin therapy (simvastatin 20 to 40 mg/day in IDEAL and atorvastatin 10 mg/day in TNT) in patients with clinically evident coronary heart disease or a history of myocardial infarction. The outcome measurement in the present research was CVE occurring after the first year of the trial. After adjusting for age, gender, and study, risk of CVEs increased with increasing TGs (p <0.001 for trend across quintiles of TGs). Patients in the highest quintile had a 63% higher rate of CVEs than patients in the lowest quintile (hazard ratio 1.63, 95% confidence interval 1.46 to 1.81) and the relation of TGs to risk was apparent even within the normal range of TGs. The ability of TG measurements to predict risk decreased when high-density lipoprotein cholesterol and apolipoprotein B:apolipoprotein A-1 were included in the statistical analysis, and it was abolished with inclusion of further variables (diabetes, body mass index, glucose, hypertension, and smoking; (p = 0.044 and 0.621, respectively, for trend across quintiles of TGs). Similar results were obtained in patients in whom low-density lipoprotein cholesterol had been lowered to guideline-recommended levels. In conclusion, even slightly increased TG levels are associated with higher risk of recurrence of CVEs in statin-treated patients and should be considered a useful marker of risk.

Sex differences in the relationship between C-reactive protein and body fat.

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/m(2)), 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 (R(2) 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.

Evaluation of coronary artery calcium screening strategies focused on risk categories: the Dallas Heart Study.

BACKGROUND: A strategy using coronary artery calcium (CAC) screening to refine coronary heart disease risk assessment in moderately high risk (MHR) subjects (10-year risk 10%-20%) has been suggested. The potential impact of this strategy is unknown. METHODS: Coronary artery calcium screening strategies focused on MHR subjects were modeled in 2,610 subjects aged 30 to 65 years undergoing Framingham risk scoring and CAC assessment in the Dallas Heart Study. The proportions of subjects eligible for imaging and reclassified from MHR to high risk (HR) (10-year risk >20%) based upon CAC scores were determined. RESULTS: Only 1.0% of women and 15.4% of men were at MHR by Framingham risk scoring and thus eligible for imaging, and <0.1% and 1.1% respectively, changed from MHR to HR using a CAC threshold > or = 400. Coronary artery calcium imaging targeting MHR subjects was also relatively inefficient (>100 women, 14.3 men scanned per subject reclassified). Restricting to an older age range (45-65 years) or expanding the MHR group to 6% to 20% risk had virtually no impact on risk assessment in women. In a secondary analysis, a proposed imaging strategy targeting promotion of subjects from lower risk to MHR was more efficient and had greater yield than current recommendations targeting promotion from MHR to HR. CONCLUSIONS: Coronary artery calcium screening strategies focused on MHR subjects will have a negligible impact on risk assessment in women and a modest impact in men. Further studies are needed to optimize the use of CAC screening as an adjunct to coronary heart disease risk assessment, especially for women and those at seemingly lower risk.

Comparison of effectiveness of atorvastatin 10 mg versus 80 mg in reducing major cardiovascular events and repeat revascularization in patients with previous percutaneous coronary intervention (post hoc analysis of the Treating to New Targets [TNT] Study).

The Treating to New Targets (TNT) study demonstrated that intensive atorvastatin therapy to achieve low-density lipoprotein cholesterol concentrations well below recommended target levels provides an incremental clinical benefit in patients with stable coronary artery disease. This post hoc analysis of the TNT study was conducted to investigate whether this benefit extends to patients with previous percutaneous coronary intervention (PCI). A total of 10,001 patients with clinically evident coronary artery disease, including 5,407 patients with previous PCI, were randomized to atorvastatin 10 or 80 mg/day and followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event. Revascularization, a component of a secondary end point, was also examined. In patients with previous PCI, mean low-density lipoprotein cholesterol levels at study end were 79.5 mg/dl in the 80-mg arm and 100.8 mg/dl in the 10-mg arm. First major cardiovascular events occurred in 230 patients (8.6%) receiving high-dose atorvastatin and 289 patients (10.6%) receiving low-dose atorvastatin (hazard ratio 0.79, 95% confidence interval 0.67 to 0.94, p = 0.008). Repeat revascularization during follow-up (PCI or coronary artery bypass grafting) was performed in 466 patients (17.3%) in the 80-mg arm and 624 patients (22.9%) in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.65 to 0.82, p <0.0001). In conclusion, intensive lipid lowering to a mean low-density lipoprotein cholesterol level of 79.5 mg/dl (2.1 mmol/L) with atorvastatin 80 mg/day in patients with previous PCI reduces major cardiovascular events by 21% and repeat revascularizations by 27% compared with a less intensive lipid-lowering regimen.

Independent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study.

Diabetes mellitus (DM) has been termed a "coronary disease equivalent", yet data suggest that only those DM subjects with metabolic syndrome (MetS) are at increased coronary risk. Using data from the Dallas Heart Study, a large, probability-based population study, we assessed the individual and joint associations between MetS, DM and atherosclerosis, defined as coronary artery calcium (CAC) detected by electron-beam computerised tomography (EBCT) and abdominal aortic plaque (AAP) detected by magnetic resonance imaging. Among 2,735 participants, the median age was 44 years; 1,863 (68%) were non-white; 1,509 (55%) were women; 697 (25.5%) had MetS without DM; 53 (1.9%) had DM without MetS; and 246 (9.0%) had both DM and MetS. The prevalence of CAC increased from those with neither MetS nor DM (16.6%) to MetS only (24.0%) to DM only (30.2%) to both MetS and DM (44.7%) (ptrend <0.0001). The prevalence of CAC was higher in those with both DM and MetS versus either alone (p<0.0001). After adjustment, MetS and DM were each independently associated with CAC (odds ratio [OR] 1.4, 95% confidence intervals [CI] 1.1-1.8; OR 1.8, 95% CI 1.3-2.5, respectively). Compared with the group without DM or MetS, those with both MetS and DM had the most CAC (adjusted OR 2.3; 95% CI 1.6-3.2). All analyses of AAP yielded qualitatively similar results. In conclusion, both MetS and DM are independently associated with an increased prevalence of atherosclerosis, with the highest observed prevalence in subjects with both DM and MetS.

Application of the screening for Heart Attack Prevention and Education Task Force recommendations to an urban population: observations from the Dallas Heart Study.

BACKGROUND: The Screening for Heart Attack Prevention and Education (SHAPE) Task Force recommends noninvasive atherosclerosis imaging of all asymptomatic men (aged 45-75 years) and women (aged 55-75 years), except those at very low risk, to augment conventional cardiovascular risk assessment algorithms. METHODS: Among 2611 participants in the Dallas Heart Study aged 30 to 65 years who underwent computed tomography to measure coronary artery calcification, low-density lipoprotein cholesterol (LDL-C) therapeutic targets were calculated using both National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and SHAPE algorithms. The proportion of subjects reclassified as being "at goal" for LDL-C vs "not at goal" after implementation of the SHAPE recommendations was determined. RESULTS: More subjects were identified with LDL-C levels greater than or equal to goal based on SHAPE than on NCEP-ATP III (27.4% vs 21.6%), with 7.0% of individuals reclassified as having unmet LDL-C goals and 1.1% of individuals reclassified as at goal. When more aggressive optional LDL-C goals were implemented, 31.7% had LDL-C levels greater than or equal to goal using SHAPE recommendations vs 28.1% using NCEP-ATP III recommendations, with 6.3% of subjects reclassified as being not at goal and 2.7% as being at goal. CONCLUSIONS: The SHAPE recommendations resulted in bidirectional reclassification of eligibility for lipid-lowering therapy in subjects aged 30 to 65 years. While broad implementation of these recommendations would modestly increase cholesterol-lowering drug use in this age range, the magnitude of the increase depends on whether standard or optional LDL-C goals are targeted.

Cardiovascular and metabolic risk factors: how can we improve outcomes in the high-risk patient?

Risk assessment algorithms, such as that used in the third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) for treating low-density lipoprotein cholesterol, can be used to classify patients' risk for cardiovascular and metabolic problems and to determine the appropriate level of therapeutic intervention. Patients at highest risk should receive the most intensive therapy. The presence of the metabolic syndrome, a clustering of atherogenic risk factors including dyslipidemia, elevated blood pressure, elevated blood glucose, and other problems, confers additional risk for diabetes mellitus and atherosclerotic cardiovascular disease at every level of risk. Pharmacotherapy with lipid-lowering, antiplatelet, antihypertensive, or insulin-sensitizing agents to modify specific risk factors is indicated in patients at higher risk, but lifestyle change (e.g., smoking cessation, weight reduction, increased physical activity, and "heart-healthy" dietary modifications) and blood pressure control can be used across all categories of risk.

Safety and efficacy of Atorvastatin-induced very low-density lipoprotein cholesterol levels in Patients with coronary heart disease (a post hoc analysis of the treating to new targets [TNT] study).

High-dose statin therapy has been demonstrated to provide incremental benefit when low-density lipoprotein (LDL) cholesterol concentrations are lowered well below recommended target levels. This secondary analysis of the Treating to New Targets (TNT) study was conducted to investigate whether the attainment of very low LDL cholesterol levels was associated with a further reduction in major cardiovascular events compared with higher LDL cholesterol concentrations and whether any incremental benefit was achieved without additional safety risk. Patients with coronary heart disease and LDL cholesterol levels <130 mg/dl (3.4 mmol/L) were randomized to therapy with atorvastatin 10 mg/day (n = 5,006) or 80 mg/day (n = 4,995). The primary end point was the occurrence of a first major cardiovascular event. Clinical outcomes and safety data were compared across on-treatment LDL cholesterol quintiles. There was a highly significant reduction in the rate of major cardiovascular events with descending achieved levels of on-treatment LDL cholesterol (p <0.0001 for trend across LDL cholesterol). Analysis of individual components of the primary end point demonstrated similar results. Death from any cause and from noncardiovascular causes was lowest in patients with the lowest on-treatment LDL cholesterol levels. Cardiovascular deaths were also reduced with lower levels of on-treatment LDL cholesterol. There were no clinically important differences in adverse event rates across quintiles. Specifically, no increase in muscle complaints, suicide, hemorrhagic stroke, or cancer deaths was observed at the lowest LDL cholesterol levels. In conclusion, the present analysis adds support to the concept that for patients with established atherosclerotic cardiovascular disease, a further risk reduction without sacrifice of safety can be achieved by reducing LDL cholesterol to very low levels.

Insulin resistance and body fat distribution in South Asian men compared to Caucasian men.

OBJECTIVE: South Asians are susceptible to insulin resistance even without obesity. We examined the characteristics of body fat content, distribution and function in South Asian men and their relationships to insulin resistance compared to Caucasians. RESEARCH DESIGN AND METHODS: Twenty-nine South Asian and 18 Caucasian non-diabetic men (age 27+/-3 and 27+/-3 years, respectively) underwent euglycemic-hyperinsulinemic clamp for insulin sensitivity, underwater weighing for total body fat, MRI of entire abdomen for intraperitoneal (IP) and subcutaneous abdominal (SA) fat and biopsy of SA fat for adipocyte size. RESULTS: Compared to Caucasians, in spite of similar BMI, South Asians had higher total body fat (22+/-6 and 15+/-4% of body weight; p-value<0.0001), higher SA fat (3.5+/-1.9 and 2.2+/-1.3 kg, respectively; p-value = 0.004), but no differences in IP fat (1.0+/-0.5 and 1.0+/-0.7 kg, respectively; p-value = 0.4). SA adipocyte cell size was significantly higher in South Asians (3491+/-1393 and 1648+/-864 microm2; p-value = 0.0001) and was inversely correlated with both glucose disposal rate (r-value = -0.57; p-value = 0.0008) and plasma adiponectin concentrations (r-value = -0.71; p-value<0.0001). Adipocyte size differences persisted even when SA was matched between South Asians and Caucasians. CONCLUSIONS: Insulin resistance in young South Asian men can be observed even without increase in IP fat mass and is related to large SA adipocytes size. Hence ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat.

The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study.

OBJECTIVES: This study sought to evaluate the associations between different measures of obesity and prevalent atherosclerosis in a large population-based cohort. BACKGROUND: Although obesity is associated with cardiovascular mortality, it is unclear whether this relationship is mediated by increased atherosclerotic burden. METHODS: Using data from the Dallas Heart Study, we assessed the association between gender-specific obesity measures (i.e., body mass index [BMI]; waist circumference [WC]; waist-to-hip ratio [WHR]) and prevalent atherosclerosis defined as coronary artery calcium (CAC) score >10 Agatston units measured by electron-beam computed tomography and detectable aortic plaque measured by magnetic resonance imaging. RESULTS: In univariable analyses (n = 2,744), CAC prevalence was significantly greater only in the fifth versus first quintile of BMI, whereas it increased stepwise across quintiles of WC and WHR (p trend <0.001 for each). After multivariable adjustment for standard risk factors, prevalent CAC was more frequent in the fifth versus first quintile of WHR (odds ratio 1.91, 95% confidence interval 1.30 to 2.80), whereas no independent positive association was observed for BMI or WC. Similar results were observed for aortic plaque in both univariable and multivariable-adjusted analyses. The c-statistic for discrimination of prevalent CAC was greater for WHR compared with BMI and WC in women and men (p < 0.001 vs. BMI; p < 0.01 vs. WC). CONCLUSIONS: We discovered that WHR was independently associated with prevalent atherosclerosis and provided better discrimination than either BMI or WC. The associations between obesity measurements and atherosclerosis mirror those observed between obesity and cardiovascular mortality, suggesting that obesity contributes to cardiovascular mortality via increased atherosclerotic burden.