Ethnic differences in HDL quantity, quality, and potential associations with coronary heart disease risk.

Reduced plasma HDL cholesterol concentration has been associated with an increased risk of coronary heart disease. However, a low HDL cholesterol concentration is usually not observed as an isolated disorder because this condition is often accompanied by additional metabolic alterations. The objective of this study was to document the relevance of assessing HDL particle size as another feature of the atherogenic dyslipidemia found among subjects with visceral obesity and insulin resistance. For that purpose, an average HDL particle size was computed by calculating an integrated HDL particle size using nondenaturing 4-30% gradient gel electrophoresis. Potential associations between this average HDL particle size versus morphometric and metabolic features of visceral obesity were examined in a sample of 238 men. Results of this study indicated that HDL particle size was a significant correlate of several features of an atherogenic dyslipidemic profile such as increased plasma TG, decreased HDL cholesterol, high apolipoprotein B, elevated cholesterol/HDL cholesterol ratio, and small LDL particles as well as increased levels of visceral adipose tissue (AT) (0.33 < or = absolute value of r < or = 0.61, P < 0.0001). Thus, men with large HDL particles had a more favorable plasma lipoprotein-lipid profile compared with those with smaller HDL particles. Furthermore, men with large HDL particles were also characterized by reduced overall adiposity and lower levels of visceral AT as well as reduced insulinemic-glycemic responses to an oral glucose load. In conclusion, small HDL particle size appears to represent another feature of the high TG- low HDL cholesterol dyslipidemia found in viscerally obese subjects characterized by hyperinsulinemia.

ATP III recognizes that detection of cholesterol disorders and other coronary heart disease (CHD) risk factors occurs primarily through clinical case finding. Risk factors can be detected and evaluated as part of a person's work-up for any medical problem. Alternatively, public screening programs can identify risk factors, provided that affected individuals are appropriately referred for physician attention. The identification of cholesterol disorders in the setting of a medical examination has the advantage that other cardiovascular risk factors—including prior CHD, PVD, stroke, age, gender, family history, cigarette smoking, high blood pressure, diabetes mellitus, obesity, physical inactivity—co-morbidities, and other factors can be assessed and considered prior to treatment. At the time of physician evaluation, the person's overall risk status is assessed. Thus, detection and evaluation of cholesterol and lipoprotein problems should proceed in parallel with risk assessment for CHD. The approach to both is described below. The guiding principle of ATP III is that the intensity of LDL-lowering therapy should be adjusted to the individual's absolute risk for CHD. In applying this principle, ATP III maintains that both short-term (≤10-year) and long-term (> 10-year) risk must be taken into consideration. Thus, treatment guidelines are designed to incorporate risk reduction for both short-term and long-term risk (composite risk). ATP III identifies three categories of risk for CHD that modify goals and modalities of LDL-lowering therapy: established CHD and CHD risk equivalents, multiple (2+) risk factors, and 0-1 risk factor (Table III.1-1). View this table: Table III.1-1. Categories of Risk for Coronary Heart Disease (CHD) ### a. Identification of persons with CHD and CHD risk equivalents Coronary heart disease . Persons with CHD are at very high risk for future CHD events (10-year risk >20 percent). Several clinical patterns constitute a diagnosis of CHD; these include history of acute myocardial infarction, evidence of silent myocardial infarction or myocardial ischemia, history of unstable angina and stable angina pectoris, and history …

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Conventional risk factors for coronary heart disease (CHD) do not completely account for the observed increase in premature CHD in people from the Indian subcontinent or for Asian Indians who have immigrated to the USA. The objective of this study was to determine the effect of immigration to the USA on plasma levels of lipoprotein [a] (Lp[a]) and other independent risk factors for CHD in Asian Indians. Three subject groups were studied: group 1, 57 subjects living in India and diagnosed with CHD (CHD patients); group 2, 46 subjects living in India and showing no symptoms of CHD (control subjects); group 3, 206 Asian Indians living in the USA. Fasting blood samples were drawn to determine plasma levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein [LDL cholesterol (LDL-Chol)], high density lipoprotein [HDL cholesterol (HDL-Chol)], apolipoprotein B-100 (apoB-100), and Lp[a]. Apolipoprotein [a] (apo[a]) size polymorphism was determined by immunoblotting. Plasma TG, apoB-100, and Lp[a] concentrations were higher in CHD patients than in control and USA groups. CHD patients had higher levels of TC and LDL-Chol and lower HDL-Chol than control subjects. However, the USA population had higher levels of TC, LDL-Chol, and apoB-100 and lower HDL-Chol than control subjects. Plasma Lp[a] levels were inversely correlated with the relative molecular weight of the more abundant of each subject's two apo[a] isoforms (MAI), and CHD patients showed higher frequencies of lower relative molecular weights among MAI. Our observed changes in lipid profiles suggest that immigrating to the USA may place Asian Indians at increased risk for CHD. This study suggests that elevated plasma Lp[a] confers genetic predisposition to CHD in Asian Indians, and nutritional and environmental factors further increase the risk of CHD. This is the first report implicating MAI size as a predictor for development of premature CHD in Asian Indians. Including plasma Lp[a] concentration and apo[a] phenotype in screening procedures may permit early detection and preventive treatment of CHD in this population.

The Framingham Heart Study has contributed importantly to understanding of the causes of coronary heart disease (CHD), stroke, and other cardiovascular diseases. Framingham research has helped define the quantitative and additive nature of these causes or, as they are now called, “cardiovascular risk factors.”1 The National Cholesterol Education Program (NCEP)2 3 has made extensive use of Framingham data in developing its strategy for preventing CHD by controlling high cholesterol levels. The NCEP guidelines2 3 adjust the intensity of cholesterol-lowering therapy with absolute risk as determined by summation of risk factors. The National High Blood Pressure Education Program (NHBPEP) has set forth a parallel approach for blood pressure control. In contrast to the NCEP,2 however, earlier NHBPEP reports issued through the Joint National Committee4 did not match the intensity of therapy to absolute risk for CHD. “Normalization” of blood pressure is the essential goal of therapy regardless of risk status. Blood pressure–lowering therapy is carried out as much for prevention of stroke and other cardiovascular complications as for reduction of CHD risk. Nonetheless, risk assessment could be important for making decisions about type and intensity of therapy for hypertension. Thus, the most recent Joint National Committee report5 gives more attention to risk stratification for adjustment of therapy for hypertension. Although Framingham data have already been influential in the development of national guidelines for risk factor management, the opportunity may exist for both cholesterol and blood pressure programs to draw more extensively from Framingham results when formulating improved risk assessment guidelines and recommending more specific strategies for risk factor modification. The American Heart Association has previously used Framingham risk factor data to prepare charts for estimating CHD risk. Framingham investigators of the National Heart, Lung, and Blood Institute prepared the original charts and have now revised …

Introduction: South Asian individuals have high risk of atherosclerotic cardiovascular disease (ASCVD). Some investigators suggest smaller coronary artery size may be partially responsible. Hypothesis: We hypothesized that South Asian participants would have smaller left anterior descending artery (LAD) cross sectional area (CSA) than Black and White participants, and that this association would be attenuated after adjusting for body size (BMI and height) and cardiovascular risk factors. Methods: We compared the LAD CSA (lumen and arterial wall) among South Asians in the Mediators of Atherosclerosis in South Asians Living in America study with White and Black participants in the Coronary Artery Risk Development in Young Adults study, adjusting for BMI, height, and other ASCVD risk factors. We used thin-slice non-contrast cardiac computed tomography to measure LAD CSA. We used linear regression models to explore differences by race/ethnicity in LAD CSA after adjusting for demographic, BMI, height, coronary artery calcium (CAC), and ASCVD risk factors. Results: We included 3,353 participants: 513 South Asian (44% women), 1286 Black (60% women), and 1554 White (54% women). After adjusting for age, BMI, height, there was no difference in LAD CSA between South Asian and White participants by sex. However, South Asian participants had smaller LAD CSA compared to Black participants by sex. After full adjustment for ASCVD risk factors, LAD CSA values were: South Asian women (19.9 mm 2 , 95% CI [18.8 - 20.9]) and men (22.3 mm 2 , 95% CI [21.4 - 23.2]; White women (20.0 mm 2 , 95% CI [19.4 - 20.5]) and men (23.6 mm 2 , 95% CI [23.0 - 24.2]); and Black women (21.6 mm 2 , 95% CI [21.0 - 22.2]) and men (26.0 mm 2 , 95% CI [25.3 - 26.7]) ( Figure 1 ). Conclusions: After accounting for differences in body size, South Asian participants had smaller LAD CSA compared to Black participants, but similar to White participants. Future studies should determine whether LAD CSA is associated with future ASCVD events.

This report was derived from a workshop on cardiovascular risk assessment sponsored by the National Heart, Lung, and Blood Institute, which addressed whether risk equations developed in the Framingham Heart Study (FHS) for predicting new-onset coronary heart disease (CHD) apply to diverse population groups. Preparation for the workshop included a reanalysis and comparison of prospective studies in several different populations in which risk factors were related to cardiovascular outcomes. Some studies included fatal and nonfatal CHD end points, whereas others contained only CHD mortality. Extensive collaboration provided as much uniformity as possible with respect to both risk factors and CHD end points. The FHS has led in defining the quantitative impact of risk factors.1 Many potential risk factors were measured and related to cardiovascular outcomes. Several risk factors proved to be strong, largely independent predictors of cardiovascular disease (CVD). These factors—advancing age, cigarette smoking, blood pressure (particularly systolic), cholesterol in total serum and HDL, and diabetes—served as the basis for the development of risk prediction equations.1 If FHS risk estimates are to be widely used, they must apply widely in the US population. To document their transportability, they must be compared with prospective studies in other populations. Although the FHS is the longest running prospective study, there are other major studies. The cardiovascular end points of these other studies have varied. Some include cardiovascular morbidity and mortality; others have only cardiovascular mortality. Among the end points, CHD is the most extensively reported; for this reason, CHD was the primary focus of the workshop. ### Multivariate Relative Risk Comparisons In preparation for the workshop, multivariate regression coefficients for each risk factor were compared in different populations with those of the FHS. Adjusted relative risk estimates make it possible to determine whether each independent risk factor confers a similar or different relative risk among different …

Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Low density lipoprotein cholesterol (LDL-C) is the appropriate focus of primary and secondary prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Basic investigation and evidence from animal models and epidemiological studies lend robust support to its role as a major risk factor for CHD. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors reduce plasma concentrations of LDL-C and have consistently shown substantial benefits in primary and secondary prevention. However, although treatment has dramatically reduced the risk of recurrent CHD in secondary prevention trials, it is becoming increasingly evident that even reduction of LDL-C to 100 mg/dL may not be adequate to restore the risk levels of such patients to the risk levels of those individuals free of CHD. Despite mean on-treatment LDL-C concentrations ranging from 97 to 113 mg/dL, recurrent CHD event rates in 3 secondary prevention trials were all ≈2% per year.1 2 3 The CHD event rate in the 40% subset of participants in the Scandinavian Simvastatin Survival Study who lowered their LDL-C levels to <100 mg/dL (mean 95 mg/dL) was also 2% per year.4 These event rates are unacceptably high, and 2 approaches are being explored to determine whether there is room for improvement: (1) more aggressive lowering of LDL-C and (2) treatment of the “lipoprotein complex.” Although the first of these appears intuitively attractive, careful examination of curves relating CHD event rates to on-treatment LDL-C in the trials outlined above suggests an asymptotic relationship. The CHD risk appears to “flatten out” at 2% per year for LDL-C levels <120 mg/dL. In addition, although there are no data to show that dramatic reduction of LDL-C (eg, <50 mg/dL) might lead to increased risk of adverse events, subgroup analysis from the Multiple Risk Factor Intervention Trial (MRFIT) suggests an increased risk of hemorrhagic stroke in individuals with …

For DNA-based tests that assess genetic predisposition to coronary heart disease (CHD) to be of clinical value, they need to provide information over and above conventional risk factors (CRFs) currently used in risk algorithms, such as the Framingham Risk Score,1 which incorporates CRFs such as age, gender, blood lipid concentrations, blood pressure, body mass index, family history, and smoking habit. To achieve this, several hurdles must be passed. The first challenge is to identify a set of common single-nucleotide polymorphisms (SNPs) at loci associated with CHD risk. Over the last 10 to 15 years, this has been done by use of a “candidate gene” approach through association studies in prospective analysis or case-control studies, ie, comparing SNP genotype or allele frequency between groups of individuals with CHD and healthy subjects. Several of the genes, chosen because of their key role in processes that predispose to atherosclerosis, have meta-analysis–confirmed effects on risk of CHD,2 the best example of which is the APOE gene, which encodes apolipoprotein E, with 3 common isoforms that are associated with strong effects on plasma lipids and more modest effects on risk of CHD.3 This “hypothesis-driven” search for useful genetic variants provides the foundation for the development of genetic CHD risk profiles, and in the last 2 years, it has been enhanced by technical advances that have allowed “hypothesis-free” genome-wide association studies (GWASs), primarily in a case-control setting. Although the list of identified CHD-risk loci and SNPs will clearly grow, we have at least the basis to start the examination of their potential clinical utility. The second set of challenges is to obtain a robust estimate of the size of the risk effects associated with these SNPs. This requires population-based prospective studies to avoid bias, because estimates in the case-control setting, although efficient for …

Ethnic and sex differences in circulating endotoxin levels: A novel marker of atherosclerotic and cardiovascular risk in a British multi-ethnic population

Case Presentation: E.C. is a 53-year-old postmenopausal female, referred for treatment of hypertension, with a family history of type 2 diabetes, hypertension, and coronary heart disease (CHD). Until learning that her blood pressure was “too high” during a routine physical examination, she felt well, and her postmenopausal symptoms had responded to hormone replacement therapy. She was not overweight (her body mass index [BMI] was 23.7 kg/m2), and the only abnormality on physical examination was a blood pressure of 145/95 RAR. Laboratory results revealed a normal blood count and urinalysis, with the following fasting plasma concentrations of relevant metabolic variables (in mg/dL): glucose 102, triglycerides (TG) 238, low-density lipoprotein cholesterol (LDL-C) 147, and high-density lipoprotein cholesterol (HDL-C) 52. E.C. is hypertensive and hypertriglyceridemic and at increased risk for CHD. Less obvious is that these metabolic abnormalities are highly likely to be the manifestations of a more fundamental defect—resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia, changes that greatly increase CHD risk.1,2⇓ The importance of insulin resistance as a CHD risk factor was first explicated in 1998, and the cluster of abnormalities likely to appear as manifestations of the defect in insulin action designated as syndrome X.1 Support for this notion has grown almost as fast as the names used to describe the phenomenon. The Adult Treatment Panel III (ATP III) has recently3 recognized the importance as CHD risk factors of a “constellation of lipid and nonlipid risk factors of metabolic origin,” designated this cluster of abnormalities as “the metabolic syndrome,” and indicated that “this syndrome is closely linked to insulin resistance.” Table 1 lists the criteria the ATP III stipulated be used to diagnose the metabolic syndrome, and a recent report4 has applied these criteria to the database of the Third National Health and Nutrition …

The relationship between obesity and coronary atherosclerosis (and coronary heart disease [CHD]) has been a subject of some dispute for many years. Data from early investigations suggested that obesity is not an important contributing cause of coronary atherosclerosis and CHD. For example, results of the Seven Countries Study1 revealed little correlation between body weight and incidence of CHD. Moreover, in the massive autopsy study called “The Geographic Pathology of Atherosclerosis,” edited by Henry C. McGill, Jr,2 the relationship between body weight and atherosclerosis was weak at best. This study included a detailed examination of arteries from a large number of autopsies carried out in New Orleans, Sao Paulo, Puerto Rico, Lima, and Santiago; by and large, the results uncovered no association between extent of arterial fatty streaks or raised atherosclerotic lesions in either the coronary arteries or the aorta for any measure of body weight, height, or obesity.3 It was noted that this study had the advantage of including several groups that differed greatly in geographic origin, ethnicity, CHD morbidity, and severity of atherosclerosis. Although the authors3 conceded that obesity is a factor contributing to risk factors for CHD such as hypertension, they surmised that the relationship between obesity and other risk factors is too weak for obesity to have a detectable effect on the severity of atherosclerosis. See p 2712 In spite of these earlier negative findings, the Framingham Heart Study in the United States has consistently shown that increasing degrees of obesity are accompanied by greater rates of CHD.4,5⇓ Even so, multivariate analysis of Framingham data strongly suggests that most of the relationship between body weight and CHD risk is mediated through the standard, major risk factors, ie, blood pressure, total cholesterol, HDL cholesterol, and diabetes.6 Their own data led Framingham …

Objectives: African Americans (AA) have higher risk for coronary heart disease (CHD) outcomes than Whites. This racial disparity has been attributed to differences in risk factors such as hypertension, diabetes, smoking, and inactivity. Depression has been associated with CHD risk, both through behavioral factors and possibly through more direct mechanisms. Yet, the role of depressive symptoms in racial disparities in risk of CHD is not clear. Using the REGARDS Study, we examined the association between depressive symptoms and incident CHD. Hypothesis: Depressive symptoms are associated with incident CHD among AA, but not Whites. Methods: REGARDS is a national cohort of US community-dwelling adults aged &gt;45 recruited from 2003 to 2007. Longitudinal associations of depressive symptoms with incident acute CHD (fatal CHD or nonfatal myocardial infarction or coronary revascularization) by race were examined among 24,261 participants (AA = 10,265; Whites =13,996) free of CHD at baseline, and observed through 12/31/09. Baseline depressive symptoms were defined by the 4-item Centers for Epidemiological Studies Depression Scale (CES-D), with continuous scores (0-12 range) dichotomized as normal (&lt;4) or depressive symptoms (≥4). We estimated multivariable Cox proportional hazards models of incident CHD with depressive symptoms, adjusting for sociodemographics, CHD risk factors and health behaviors. Results: Overall mean follow-up was 4.2+1.5 years, CHD incidence was 8.3 events per 1000 person-years (n=366 events) among AA and 8.8 events per 1000 person-years (n=613 events) among Whites, p=0.0015. Depressive symptoms were more prevalent among AA (13.1%) than among Whites (8.5%), p&lt;0.001. There was a significant interaction between race and depressive symptoms, thus models were stratified on race. After adjustment for age, sex, marital status and region, depressive symptoms were significantly associated with incident CHD among AA (HR 1.57 {95% CI 1.18-2.09}) but not among Whites (HR 1.11 {0.80-1.56}). After adding education, income, physical activity, smoking, alcohol consumption, diabetes, BMI, CRP, systolic blood pressure, cholesterol, albuminuria, use of blood pressure or statin medications, the relationship for AA was modestly attenuated but still significant (HR 1.35 {95% CI 1.01-1.81}). Conclusions: Depressive symptoms were associated with risk of incident CHD among AA but not Whites. Efforts to reduce racial disparities in CHD may need to address environmental and psychosocial factors that place AA at higher risk.