Elevated LDL Cholesterol Concentrations Research Articles

A-116 Evaluation of Lp(a) Ultra assay for the Immunoturbidimetric Quantitative Determination of Lipoprotein (a) in Human Serum and Plasma With Siemens Healthineers Atellica CH 930 Analyzer

Abstract Objective The aim of this study is to evaluate the analytical performances of the Lp(a) Ultra assay for the immunoturbidimetric quantitative determination of lipoprotein (a) in human serum and plasma on Siemens Healthineers Atellica CH 930 Analyzer. Background Lipoprotein (a) has been found in artery walls and can have atherogenic effects. Because of its structural similarity to plasminogen, it can also inhibit fibrinolysis and hence acts thrombogenically. High Lp(a) concentrations in serum correlate with premature manifestation of atherosclerosis and strokes. In combination with elevated LDL Cholesterol concentrations, the coronary risk increases approximately six-fold. Methods Lp(a) Ultra is a latex immunoassay manufactured by Sentinel Diagnostics and developed to measure Lp(a) levels. If the antigen-antibody reaction takes place between Lp(a) in the sample and the anti-Lp(a) antibodies, which have been adsorbed to latex particles, agglutination occurs. This agglutination is detected as an absorbance change, with the magnitude of the change being proportional to the quantity of Lp(a) contained in the sample. Results The Limit of Blank LOB (4 samples × 5 replicates × 3 runs) was ≤2.0 mg/dL. The Limit of Detection LOD (4 samples × 5 replicates × 3 runs) was ≤ 3.0 mg/dL. The Limit of Quantitation LOQ (8 dilution levels × 10 replicates × 3 runs) was ≤5.0 mg/dL at %CV lower than 20%. The Intra Assay (5 samples × 20 replicates × 3 runs) gave the following %CVs: 2.4% at 12.1 mg/dL, 0.8% at 30.3 mg/dL, 0.6% at 47.8 mg/dL, 0.5% at 58.8 mg/dL, 1.7% at 87.1 mg/dL. Total precision study (5 samples × 2 runs × 2 replicates × 20 runs) gave the following %CVs: 4.0% at 11.5 mg/dL, 3.6% at 21.7 mg/dL, 3.0% at 32.0 mg/dL, 2.8% at 42.2 mg/dL, 2.3% at 50.7 mg/dL. The test was linear up to 130 mg/dL. Calibration stability was up to 30 days. Reagent on board stability was up to 30 days. This application (y) was compared with the same test applied on Beckman Coulter AU680 Analyzer (x) and gave the following results: using Passing Bablok analysis: y = 0.8 + 1.0x; correlation coefficient (r) = 0.997; using Deming analysis: y = 1.0 + 1.0x; correlation coefficient (r) = 0.997; number of samples = 120. There is not Hook effect/antigen excess up to 600 mg/dL. Conclusions Analytical performances of Lp(a) Ultra assay on Siemens Healthineers Atellica CH 930 Analyzer meet the requirements for its use as immunoturbidimetric quantitative determination of lipoprotein (a) in human serum and plasma and make this assay very suitable for the routine measurement of this analyte.

PCSK9 inhibition in children with familial hypercholesterolaemia

Heterozygous familial hypercholesterolaemia is the most prevalent monogenic dyslipidaemia, affecting approximately 1 in 300 people worldwide.1 If left untreated, elevated LDL cholesterol concentrations in heterozygous familial hypercholesterolaemia are associated with a more than ten-fold increased risk of premature atherosclerotic cardiovascular disease.1 For children and adolescents with heterozygous familial hypercholesterolaemia, clinical guidelines recommend early intervention with lifestyle modification and statin drugs, with increasingly assertive targets for LDL cholesterol.

The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk

SFAs play the leading role in 1 of the greatest controversies in nutrition science. Relative to PUFAs, SFAs generally increase circulating concentrations of LDL cholesterol, a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, the purpose of regulatory mechanisms that control the diet-induced lipoprotein cholesterol dynamics is rarely discussed in the context of human adaptive biology. We argue that better mechanistic explanations can help resolve lingering controversies, with the potential to redefine aspects of research, clinical practice, dietary advice, public health management, and food policy. In this paper we propose a novel model, the homeoviscous adaptation to dietary lipids (HADL) model, which explains changes in lipoprotein cholesterol as adaptive homeostatic adjustments that serve to maintain cell membrane fluidity and hence optimal cell function. Due to the highly variable intake of fatty acids in humans and other omnivore species, we propose that circulating lipoproteins serve as a buffer to enable the rapid redistribution of cholesterol molecules between specific cells and tissues that is necessary with changes in dietary fatty acid supply. Hence, circulating levels of LDL cholesterol may change for nonpathological reasons. Accordingly, an SFA-induced raise in LDL cholesterol in healthy individuals could represent a normal rather than a pathologic response. These regulatory mechanisms may become disrupted secondarily to pathogenic processes in association with insulin resistance and the presence of other ASCVD risk factors, as supported by evidence showing diverging lipoprotein responses in healthy individuals as opposed to those with metabolic disorders such as insulin resistance and obesity. Corresponding with the model, we suggest alternative contributing factors to the association between elevated LDL cholesterol concentrations and ASCVD, involving dietary factors beyond SFAs, such as an increased endotoxin load from diet-gut microbiome interactions and subsequent chronic low-grade inflammation that interferes with fine-tuned signaling pathways.

Prevalence of dyslipidaemia among adults in Africa: a systematic review and meta-analysis.

The burden of dyslipidaemia in Africa remains inadequately characterised. We aimed to estimate the prevalence of dyslipidaemia in African adults from hospital-based and community-based studies. In this systematic review and meta-analysis, we searched MEDLINE via PubMed, Embase, African Journals Online, and African Index Medicus for studies published between Jan 1, 1980, and July 31, 2017, without language restriction. We assessed methodological quality of all cross-sectional studies reporting on the prevalence of elevated concentrations of total cholesterol, LDL cholesterol, or triglycerides, or low concentrations of HDL cholesterol in adults residing in African countries. We excluded reports on Africans living outside Africa, studies of individuals selected on the basis of existing dyslipidaemia or those including children and adolescents, and case series with a small sample size. The most frequently used cutoffs in the included studies were chosen for the subgroup analysis. We used random-effect model meta-analysis to derive the pooled prevalence of elevated total cholesterol, low HDL cholesterol, elevated LDL cholesterol, and elevated triglyceride concentrations. This study is registered with PROSPERO, number CRD42014015376. 181 studies (309 207 participants) were included in the meta-analysis. The pooled prevalence of dyslipidaemia in the general population from population-based studies was 23·6% (95% CI 18·4-29·2) for elevated concentrations of total cholesterol with a cutoff of at least 5·2 mmol/L, 41·1% (33·0-49·4) for low concentrations of HDL cholesterol with a cutoff of less than 1·0 mmol/L, 25·7% (16·2-36·6) for elevated concentrations of LDL cholesterol with a cutoff of at least 3·3 mmol/L, and 16·5% (11·8-21·6) for elevated concentrations of triglycerides with a cutoff of at least 1·7 mmol/L. The prevalence of dyslipidaemia is high in the general adult population in Africa. Ongoing efforts to reduce cardiovascular diseases in Africa should integrate effective detection and treatment of dyslipidaemia. None.

Homozygous familial hypercholesterolaemia in China: a genotype–phenotype analysis of cross-sectional data

BackgroundHomozygous familial hypercholesterolaemia is a rare life-threatening disease characterised by markedly elevated LDL cholesterol concentrations and accelerated atherosclerosis. Few studies have focused specifically on this group of patients, especially in China. We set out to investigate the phenotypical characteristics and the genotype–phenotype correlations of homozygous familial hypercholesterolaemia in China. MethodsIn this analysis of cross-sectional data, we collected data from patients with suspected homozygous familial hypercholesterolaemia from ten clinical hospitals in mainland China from 2003 to 2015. Inclusion criteria included total cholesterol greater than 10 mmol/L, presence of xanthomas, and a family history of premature coronary heart disease. Clinical data and DNA sequence of LDLR, APOB, and PCSK9 were obtained in all patients. All participants gave written informed consent using consent forms approved by the research ethics committee of Beijing Anzhen Hospital, China. FindingsWe collected data from 64 probands with suspected unrelated homozygous familial hypercholesterolaemia (mean age 13 years [range 2–37]). Molecular diagnosis showed that 15 had homozygous familial hypercholesterolaemia, 34 had compound heterozygous disease, nine had heterozygous disease, and six were mutation-negative. 66 LDLR mutations were found, and no APOB or PCSK9 mutations were found. Of the LDLR mutations, 26 were novel, and the most common mutation, occurring in 11 (17%) of 64 patients, was Trp462X (c1448G→A). The mean total cholesterol concentration was 16·6 mmol/L (SD 3·84; range 10·4–25·9), and the mean LDL cholesterol concentration was 13·86 mmol/L (SD 3·50; range 7·1–23·5). Total cholesterol and LDL cholesterol concentrations did not significantly differ between patients with homozygous familial hypercholesterolaemia, compound heterozygous familial hypercholesterolaemia, heterozygous familial hypercholesterolaemia, or those who were mutation-negative. InterpretationThis research provides important clinical and genetic information about suspected homozygous familial hypercholesterolaemia in mainland China. Our data suggest that diagnostic criteria need to be developed to screen patients with potential homozygous familial hypercholesterolaemia. FundingNational Natural Science Foundation of China (number 81471098).

Epicardial fat is associated with severity of subclinical coronary atherosclerosis in familial hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is a common genetic disorder characterized by elevated blood cholesterol, increased prevalence of subclinical atherosclerosis and high risk of premature coronary heart disease. However, this risk is not explained solely by elevated LDL-cholesterol concentrations, and other factors may influence atherosclerosis development. There is evidence that increased adiposity may predispose to atherosclerosis in FH. Epicardial fat has been associated with subclinical coronary atherosclerosis in the general population. This study evaluated the association of epicardial fat (EFV) volume with the presence and extent of subclinical coronary atherosclerosis detected by computed tomography angiography in FH patients. MethodsNinety-seven FH subjects (35% male, mean age 45 ± 13 years, LDL-C 281 ± 56 mg/dL, 67% with proven molecular defects) underwent computed tomography angiography and coronary artery calcium (CAC) scoring. EFV was measured in non-contrast images using a semi-automated method. Segment-stenosis score (SSS) and segment-involvement score (SIS) were calculated. Multivariate Poisson regression was utilized to assess an independent association of EFV with coronary atherosclerotic burden. ResultsEFV was positively associated with age, body mass index, waist circumference, blood glucose, the presence of the metabolic syndrome components, but not with LDL-C. After adjusting for confounders and abdominal circumference, an independent association (shown as β coefficients and 95% confidence intervals) of EVF with CAC scores [β = 0.263 (0.234; 0.292), p=0.000], SIS [β = 0.304 (0.141; 0.465) p=0.000] and SSS [β = 0.296 (0.121; 0.471), p=0.001] was found. ConclusionsIn FH, EFV was independently associated with coronary atherosclerotic presence and severity.

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters1–3

Background: Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs).Objective: This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs).Methods: Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion.Results: The STs and the PEs and SEs were poorly hydrolyzed (1.69–4.12%). In contrast, OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r = −0.85; P < 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P < 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE.Conclusions: Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation.

The life cycle of the low-density lipoprotein receptor: insights from cellular and in-vivo studies.

Long-term exposure to elevated concentrations of LDL cholesterol increases the risk of cardiovascular events. The main player in clearing LDL cholesterol is the LDL receptor (LDLR) trafficking pathway; however, our fundamental knowledge about the mechanisms regulating this pathway is still incomplete. The LDLR pathway is very complex and involves multiple proteins. Endocytosis is regulated by two different adaptor proteins, that is, autosomal recessive hypercholesterolemia and Disabled-2. The proteolysis of the LDLR is regulated by inducible degrader of the LDLR and proprotein convertase subtilisin/kexin type 9. However, only a few proteins have been identified that provide insights into the endosomal sorting and recycling of the LDLR. Since the discovery of LDLR, knowledge about its function has greatly expanded. As a result of its importance in maintaining homeostatic LDL levels, the LDLR pathway has emerged as a key therapeutic target to reduce circulating cholesterol. In order to be able to treat and diagnose individuals with hypercholesterolemia in the future, it is important to learn more about the LDLR trafficking pathway, as we still lack a full mechanistic understanding of how LDLR trafficking is controlled.

Arterial endothelial dysfunction in baboons fed a high-cholesterol, high-fat diet

Endothelial dysfunction signals the initiation and progression of atherosclerosis. Elevated LDL-cholesterol concentrations have been suggested to induce endothelial dysfunction, but direct in vivo evidence for the relation is still lacking. We examined the hypothesis that a high-cholesterol, high-fat (HCHF) diet can directly cause endothelial dysfunction in vivo. We measured inflammatory and endothelial dysfunctional markers in circulating blood and directly in endothelial cells, which were collected by femoral artery biopsies, in 10 baboons before and after a 7-wk HCHF dietary challenge. We found that the HCHF diet induced a high inflammatory status, as indicated by increased concentrations of interleukin 6, tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant protein 1. Although the concentrations of endothelial dysfunctional markers, such as soluble vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1, were not increased by the HCHF diet, membrane-bound VCAM-1 and membrane-bound E-selectin on endothelial cells were highly increased after 7 wk of the HCHF diet (P < 0.01). In contrast, the concentrations of endothelial nitric oxide synthase in endothelial cells were significantly reduced by the 7-wk HCHF diet (P < 0.01). Furthermore, the dietary challenge attenuated endothelial cell responses to TNF-alpha, lipopolysaccharide, native LDL cholesterol, and oxidized LDL-cholesterol stimulation. Our results show that an HCHF diet can directly induce inflammation and endothelial dysfunction. Prior in vivo exposure to an HCHF diet attenuates the in vitro responses of endothelial cells to atherogenic risk factors. This preconditioning phenomenon may have significant clinical relevance.

Study of a new PPARγ2 promoter polymorphism and haplotype analysis in a French population

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a role in adipocyte differentiation and insulin sensitization. We identified and characterized a new C/T substitution at position −689 (−689C > T) in the P2 promoter of PPARγ in a putative GATA binding site. By electrophoretic mobility shift assay, both GATA2 and GATA3 proteins could bind weakly to the wild-type P2 −689 GATA binding site but not to the mutated site. Neither GATA2 nor GATA3 was able to regulate significantly the P2 promoter activity in a reporter-luciferase assay, whatever the allele at position −689 was, suggesting that the −689 putative GATA site was probably not a functional target for GATAs. However, the presence of the −689T allele rendered the P2 promoter less active at the basal state. We genotyped a population of 1155 men and women for the −689C > T polymorphism and looked for possible associations with anthropometric and lipid variables. The carriers of the −689T allele had elevated body weight and LDL-cholesterol concentrations compared with the homozygous for the common allele. Haplotype analyses including the −681C > G (P3 promoter), −689C > T (P2 promoter), and Pro12Ala (exon B) polymorphisms were performed. Carriers of the G-T-Ala haplotype (corresponding to the P3 −681C > G, P2 −689C > T and Pro12Ala polymorphisms in this order) had elevated LDL-cholesterol concentrations and body weight compared with C-C-Pro individuals. In conclusion, we identified a new polymorphism in the P2 promoter of PPARγ. The P3 −681C > G, P2 −689C > T, and Pro12Ala polymorphisms and related haplotypes were associated with higher body weight and plasma LDL-cholesterol concentrations.

Homocysteine as a risk factor for CVD mortality in men with other CVD risk factors: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study

Based on case-control and prospective studies elevated blood total homocysteine (tHcy) has been suggested to be an independent risk factor for cardiovascular diseases (CVD). The purpose of the study was to explore the joint effect of increased serum tHcy concentration and other risk factors on the risk of CVD mortality in middle-aged men without a history of heart disease or stroke. A prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Eastern Finland. Subjects. A total of 802 men aged 46-64 years, examined in 1991-93. CVD mortality event. The mean serum tHcy concentration was 10.8 micromol L(-1) (SD 3.3). During the average follow-up time of 10.8 years 50 men experienced a CVD death. The hazard rate ratio for CVD mortality was 1.80 (95% confidence interval: 1.02-3.19) in men in the highest serum tHcy third versus lower thirds after adjustment for cardiovascular risk factors. Furthermore, elevated serum tHcy concentration appeared to increase the risk of CVD death in men who smoke or who have high circulating concentrations of serum total or LDL cholesterol, apo-B apolipoprotein or plasma fibrinogen. We conclude that homocysteine may increase the risk of CVD mortality in middle-aged men from Eastern Finland, and it may especially increase the risk when present with other risk factors for CVD.

Fruit and vegetable consumption and LDL cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study

An elevated LDL-cholesterol concentration is associated with an increased risk of cardiovascular disease. The association between fruit and vegetable consumption and LDL has been inconsistent. The objective was to determine whether a high intake of fruit and vegetables is inversely associated with LDL concentrations. We used data collected from 4466 subjects in the National Heart, Lung, and Blood Institute Family Heart Study to study the association between fruit and vegetable consumption and serum LDL. We used a food-frequency questionnaire to assess fruit and vegetable intakes and regression models to estimate adjusted mean LDL according to fruit and vegetable consumption. The mean (+/-SD) age of the men (n = 2047) was 51.5 +/- 14.0 y and that of the women (n = 2419) was 52.2 +/- 13.7 y. The average daily serving of fruit and vegetables was 3.2 +/- 1.7 for men and was 3.5 +/- 1.8 for women. Fruit and vegetable consumption was inversely related to LDL: in the categories 0-1.9, 2.0-2.9, 3.0-3.9, and > or = 4 servings/d, multivariate-adjusted mean (95% CI) LDL concentrations were 3.36 (3.28, 3.44), 3.35 (3.27, 3.43), 3.26 (3.17, 3.35), and 3.17 (3.09, 3.25) mmol/L, respectively, for men (P for trend < 0.0001) and 3.35 (3.26, 3.44), 3.22 (3.14, 3.30), 3.21 (3.13, 3.29), and 3.11 (3.04, 3.18), respectively, for women (P for trend < 0.0001). This association was observed across categories of age, education, smoking status, physical activity, and tertiles of Keys score. Exclusion of subjects with prevalent diabetes mellitus or coronary artery disease did not alter these results significantly. Consumption of fruit and vegetables is inversely related to LDL in men and women.

New aspects of normolipidemic dyslipoproteinemias

Normolipidemic dislipoproteinemias include various disorders of different lipoproteins, of their subfractions or some apolipo-proteins, of primary or secondary origin, which are widespread among general population and, like hyperlipoproteinemias, they are associated with the risk for premature atherosclerosis. It is a primary, familial hypoalphalipoproteinemia, which is commonly associated with obesity, diet rich in carbohydrates, decreased physical activity and excessive use of coffee and some drugs. It is characterized by increase of apo B-100 in LDL particles, most probably as a consequence of increased hepatic synthesis. Apolipoprotein E isoforms ApoE4 isoform is associated with elevated LDL-cholesterol concentration due to rapid IDL to LDL conversion. The most important is the latent type IV (pre-beta) or IVb (pre-beta1) with decreased VLDL clearance. It is common in obesity, NIDDM and coronary heart disease, as an independent risk factor for premature atherosclerosis. Oxidatively modified LDL may have a key role in the pathogenesis of atherosclerosis and oxidative modification of HDL reduces its transport capacity and its inhibition of LDL oxidation. INCREASED LEVEL OF LP(A) Lp(a) is an independent risk factor for premature atherosclerosis, primarily in young and middle-aged men, in persons with elevated global cardiovascular risk factor profile, decreased HDL-cholesterol, and hypertension. The risk is smaller in persons taking hypocholesterolemic drugs. Also, it is elevated in NIDDM, hypothyroidism and kidney disease.

Men and Women Differ in Lipoprotein Response to Dietary Saturated Fat and Cholesterol Restriction

A diet restricted in saturated fat and cholesterol is recommended for subjects with elevated LDL cholesterol concentrations before and during drug therapy. Gender differences in lipoprotein subspecies response to such diets have not been studied in detail. We examined the effects of a diet low in total fat, saturated fat and cholesterol (Therapeutic Lifestyle Changes, TLC, diet: 26% of energy as fat, 4% as saturated fat, and 45 mg cholesterol/4.2 MJ), compared with an average American diet (AAD: 35% of energy as fat, 14% as saturated fat, and 147 mg cholesterol/4.2 MJ), on plasma lipoprotein subspecies in men and women. Each diet period lasted 6 wk. Body weight was kept constant during each diet period. Men (n = 19) and postmenopausal women (n = 14) >40 y old with moderate hypercholesterolemia participated in this study. Plasma lipoprotein concentrations were assessed by standardized methodology, and lipoprotein sizes were determined by gradient gel electrophoresis and NMR spectroscopy. The TLC diet resulted in greater reductions in total cholesterol and plasma apolipoprotein B concentrations in men than in women (-19% vs. -12%, P < 0.05, and -18% vs. -9%, P < 0.05, respectively). Postprandial triacylglycerol and LpAI:AII concentrations were reduced in men, but not in women (-15% vs. 8%, P < 0.05, and -9% vs. -2%, respectively, P < 0.05). Similar decreases in LpAI concentrations and LDL and HDL particle size were observed in men and women. These data are consistent with the concept that middle aged/elderly men may have a more favorable lipoprotein response to a low fat, low cholesterol diet than postmenopausal women.

The athero-thrombotic and inflammatory profile of visceral obesity

The prevalence of type 2 diabetes has substantially increased in North America largely due to the fact that obesity has reached epidemic proportions in our society. Although obesity increases the likelihood of developing type 2 diabetes, hypertension and coronary heart disease (CHD), not every obese patient is characterized by these complications, emphasizing the fact that obesity is a heterogeneous condition. Evidence reviewed in this short paper supports the notion that body fat distribution, especially visceral adipose tissue accumulation, is a critical correlate of a cluster of diabetogenic, atherogenic, thrombotic and inflammatory metabolic abnormalities. This “dysmetabolic cluster”, referred to as the insulin resistance or metabolic syndrome, is associated with a substantially increased risk of CHD, even in the absence of hyperglycemia or elevated LDL cholesterol concentrations. From a risk assessment standpoint, we have reported that the “hypertriglyceridemic waist” phenotype (waist circumference ≥90 cm combined with triglycerides ≥2.0 mmol/l) was associated with a high likelihood (80%) of finding the cluster of metabolic abnormalities of abdominal obesity. Since waist circumference has been suggested to be a useful index of abdominal visceral obesity and of related metabolic complications, it is suggested that waist girth should be systematically measured in all patients. Finally, it is proposed that until abdominal obesity is identified as a therapeutic target, clinicians will not optimally manage cardiovascular disease risk in abdominally obese patients with type 2 diabetes or the metabolic syndrome.

Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.

This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.” The most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic β-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.1 2 Insulin secretion declines with advancing age,3 4 and this decline may be accelerated by genetic factors.5 6 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.7 8 The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)9 even when they do not have overt diabetes mellitus.10 The metabolic syndrome commonly precedes the development of type 2 diabetes by many years11 ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk. Recently, new criteria have been accepted for the diagnosis of diabetes.9 The upper threshold of fasting plasma glucose for the …

The apolipoprotein E4 allele is not associated with an abnormal lipid profile in a Native American population following its traditional lifestyle

The apolipoprotein E4 allele is associated in industrialized countries with an elevated LDL cholesterol concentration and an increased cardiovascular risk. Our purpose in this study was to assess the influence of the genetic variation at the APOE gene locus on the lipid profile of a Native American rural population. We examined plasma lipid levels and the common apo E alleles in 142 healthy randomly selected adults living in their native communities in western México. Their age was 38±17 years and the BMI 25.7±4.5 kg/m 2. Plasma cholesterol, triglycerides, LDL C and HDL C were 165±29.6, 126±83, 98±26 and 42±12.7 mg/dl respectively. Ninety-one per cent of the subjects had Lp(a) concentrations below 20 mg/dl and 30% had levels lower than 2 mg/dl. The most common APOE genotype was E3/3 (63%), followed by E3/4 (30.1%). The prevalence of the E2 allele was very low (2.3%). No difference was observed in LDL C concentrations between the E3/E3 and E3/E4 subjects; however carriers of the E2/3 genotype had lower LDL C levels. Similar results were obtained for cholesterol and apo B levels. In summary, the increased LDL C levels associated with the E4 allele in previous studies were not observed in a population with non-westernized habits. Environmental factors, such as diet and lifestyle, could outweigh the hypercholesterolemic predisposition resulting from the presence of the apo E4 allele

Low density lipoprotein ligand-receptor interactions in normal healthy individuals characterized by their XbaI apolipoprotein B DNA polymorphism

A DNA restriction fragment length polymorphism (RFLP), observed with the XbaI restriction enzyme digestion of peripheral lymphocyte genomic DNA and a 3.5 kb probe 3′ end of the apolipoprotein B gene, was investigated in 228 normal healthy males. Lipoprotein measurements were conducted on fasting plasma and related to the genotype; the X2X2 homozygotes (the X2 allele contains the enzyme cutting site) had significantly higher plasma cholesterol, low density (LDL) cholesterol and LDL apolipoprotein B. Thirty subjects (10 from each of the X1X1, X1X2 and X2X2 groups) were recalled and the LDL receptor activity measurements, conducted on peripheral venous blood lymphocytes, indicated no significant differences between the genotypes. However, when LDLs isolated from these individuals were assayed for ligand-receptor interaction with a human embryonic lung fibroblast cell line, significantly different maximum binding (B max) values in the X2 allele-bearing individuals were observed. This paradoxically elevated in vitro binding and degradation of LDL from X2X2 subjects suggests that the elevated concentrations of LDL cholesterol observed with this genotype in vivo does not result from a defective ligand-receptor interaction directly related to this polymorphism.