Jayme Diament

Risk factors for atherosclerosis in children and adolescents with family history of premature coronary artery disease

OBJECTIVES To identify the prevalence of dyslipidemia in a group of 109 children and adolescents with a family history of premature coronary artery disease and to investigate the association between dyslipidemia and other risk factors for atherosclerosis. METHODS Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides, body mass index, blood pressure, physical activity, smoking, per capita income and maternal schooling were investigated. RESULTS Total cholesterol and LDL-C levels were higher than desirable in 27.5% and 19.3%, respectively, of our patients; 13.8% had lower HDL-C values and 13.0% presented hypertriglyceridemia. Obesity and excess weight were observed in 25.7% of the cases. Out of these, 57.1% had abnormal lipid values. Dyslipidemia was observed in 38.5%, either alone or in combination with other risk factors. Smoking was observed in 3.6%, hypertension in 2.7% and physical inactivity in 72.5%. There was no relationship between dyslipidemia and per capita income, maternal schooling and physical inactivity. However, obesity and excess weight were identified as significantly associated with the occurrence of dyslipidemia (p = 0.02; odds ratio = 2.82, 95% CI = 1.6-6.81). CONCLUSION In children and adolescents with a family history of premature coronary artery disease, early identification of the risk factors for atherosclerosis is essential to allow the implementation of preventive measures.

Seven DNA polymorphisms at the candidate genes of atherosclerosis in Brazilian women with angiographically documented coronary artery disease.

The possible association of genetic markers at the apolipoprotein E (HhaI polymorphism), apolipoprotein B (XbaI, EcoRI and Ins/Del polymorphisms), and low-density lipoprotein receptor (LDLR) (AvaII, HincII and PvuII polymorphisms) with coronary artery disease (CAD) was evaluated in 50 Brazilian women with CAD diagnosed by angiography and in 100 healthy women (controls). The frequency of E3/E4 genotype for HhaI polymorphism at the Apo E gene was significantly higher in CAD patients than in controls (40% vs. 14%, respectively, P<0.001). Similarly, the X-X- genotype for XbaI polymorphism was more frequent in CAD individuals than controls (42% vs. 12%, P<0.0001). The A+A+ and P1P1 genotypes for AvaII and PvuII polymorphisms at the LDLR locus were also higher in CAD subjects than controls (44% vs. 16%, P<0.001 and 64% vs. 39%, P<0.05, respectively). The estimated relative risks for CAD in women carrying the E3/E4, X-X-, A+A+ and P1P1 genotypes were 4.1 [95% confidence interval (CI), 3.0-5.6], 5.3 (95% CI, 3.8-7.5), 4.1 (95% CI, 3.0-5.5), and 2.8 (95% CI, 2.2-3.6), respectively. This study demonstrates that Apo E, Apo B and LDLR gene polymorphisms are associated with CAD in Brazilian Caucasian women.

Leptin G-2548A promoter polymorphism is associated with increased plasma leptin and BMI in Brazilian women

Variants in leptin gene (LEP) have been implicated in the pathogenesis of obesity. The relationship between LEP G-2548A polymorphism and obesity-related traits was evaluated in a sample of Brazilian women (n = 228) who were randomly selected from two clinical centers in Sao Paulo city. Blood samples were collected for DNA extraction, plasma leptin and serum lipids measurements. LEP G-2548A genotypes were identified by a PCR- RFLP strategy using the endonuclease Alw44I. LEP G-2548A was associated with obesity after adjustment for covariates (age, hypertension, coronary artery disease, smoking and physical activity). Women carrying G allele had a four times higher risk of obesity than the A allele carriers (OR: 4.11, CI95%: 1.06-15.90, p = 0.041). G allele was also related to increased plasma leptin (p = 0.024) and body mass index (p = 0.027). Hypertension, hyperglycemia, dyslipidemia and coronary artery disease were associated with obesity. However LEP G-2548A polymorphism was not related to these variables. All together these data suggest that LEP G-2548A polymorphism has an important role in regulating plasma leptin levels and body mass index in women.

Relationship between body mass index, waist circumference, and waist-to-hip ratio and mortality in elderly women: a 5-year follow-up study

This study examines the association between body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC) and all-cause and cardiovascular mortality in elderly women in a 5-year longitudinal study of 575 female outpatients 60 years and over. The highest BMI, WHR, and WC quartiles and predefined BMI categories were analyzed as predictive variables. Death occurred in 88 (15.4%). Underweight (BMI < 18.5 kg/m2) was associated with all-cause mortality in uni- and multivariate analyses, regardless of age bracket. The survival curves and univariate analysis showed that the highest WHR quartile (> or = 0.97) was associated with all-cause mortality. However, after adjustment for age, smoking, and previous cardiovascular diseases, the increase in WHR was positively associated only in women from 60 to 80 years of age. None of the anthropometric measurements was associated with cardiovascular mortality. The results indicate that underweight and increased waist-to-hip ratio were predictors of all-cause mortality in elderly women, mainly among those under 80 years.

High-Density Lipoproteins: Metabolic, Clinical, Epidemiological and Therapeutic Intervention Aspects. An Update for Clinicians

Summary High density lipoproteins (HDL) constitute a class of heterogeneous lipoproteins with a complex, not fully understood metabolism, particularly concerning cholesteryl ester transfer protein (CETP) action and catabolism. HDLs are anti-atherogenic due to reverse cholesterol transport and to antioxidant, anti-inflammatory, anticoagulant, profibrinolytic and endothelial protection properties, (shown in vitro and in animals). Experimental, clinical, epidemiologic, and therapeutic intervention studies have shown that there is an inverse relationship between blood levels of these lipoproteins and the development of atherosclerotic disease in coronary arteries.Measures to increase plasma HDL-C levels, besides changes in lifestyle habits (an adequate selection of diet components, smoking cessation, regular practice of aerobic exercises) include lipid lowering drugs (LLDs). Drugs capable of inhibiting CETP are currently in advanced stages of development. Research is also being conducted with other drugs that act on different points of lipid metabolism.

Postprandial Lipemia: Influence of Aging

OBJECTIVE To investigate the behavior of postprandial lipemia assessed by means of repeated measurements of triglyceride levels in healthy individuals aged from 20 to 50 years, divided into the following 3 age groups: GI--from 20 to 30 years; GII--from 31 to 40 years; and GIII--from 41 to 50 years. METHODS Triglyceride levels were measured in 3 conditions: after a 12-hour fast, and 2 and 6 hours after a standard meal containing 40 g of fat. RESULTS The repeated-measures analysis of triglyceride levels showed a distinct behavior of the age groups throughout the 6 hours. The younger participants (GI) had a reduction in the triglyceride levels in the sixth hour; the elderly (GIII) had increasing values in the sixth hour; and those in the intermediate age group (GII) maintained their triglyceride levels, when comparing the second and sixth hours of blood collection. The differences in behavior were significant (P=0.01). CONCLUSION In a healthy adult population sample, aging influences the postprandial lipemia behavior.

Lipid Metabolism in Subclinical Hypothyroidism: Plasma Kinetics of Triglyceride-Rich Lipoproteins and Lipid Transfers to High-Density Lipoprotein Before and After Levothyroxine Treatment

BACKGROUND Subclinical hypothyroidism (SCH) has been associated with atherosclerosis, but the abnormalities in plasma lipids that can contribute to atherogenesis are not prominent. The aim of this study was to test the hypothesis that patients with normocholesterolemic, normotriglyceridemic SCH display abnormalities in plasma lipid metabolism not detected in routine laboratory tests including abnormalities in the intravascular metabolism of triglyceride-rich lipoproteins, lipid transfers to high-density lipoprotein (HDL), and paraoxonase 1 activity. The impact of levothyroxine (LT4) treatment and euthyroidism in these parameters was also tested. METHODS The study included 12 SCH women and 10 matched controls. Plasma kinetics of an artificial triglyceride-rich emulsion labeled with radioactive triglycerides and cholesteryl esters as well as in vitro transfer of four lipids from an artificial donor nanoemulsion to HDL were determined at baseline in both groups and after 4 months of euthyroidism in the SCH group. RESULTS Fractional clearance rates of triglycerides (SCH 0.035 ± 0.016 min⁻¹, controls 0.029 ± 0.013 min⁻¹, p = 0.336) and cholesteryl esters (SCH 0.009 ± 0.007 min⁻¹, controls 0.009 ± 0.009 min⁻¹, p = 0.906) were equal in SCH and controls and were unchanged by LT4 treatment and euthyroidism in patients with SCH, suggesting that lipolysis and remnant removal of triglyceride-rich lipoproteins were normal. Transfer of triglycerides to HDL (SCH 3.6 ± 0.48%, controls 4.7 ± 0.63%, p = 0.001) and phospholipids (SCH 16.2 ± 3.58%, controls 21.2 ± 3.32%, p = 0.004) was reduced when compared with controls. After LT4 treatment, transfers increased and achieved normal values. Transfer of free and esterified cholesterol to HDL, HDL particle size, and paraoxonase 1 activity were similar to controls and were unchanged by treatment. CONCLUSIONS Although intravascular metabolism of triglyceride-rich lipoproteins was normal, patients with SCH showed abnormalities in HDL metabolism that were reversed by LT4 treatment and achievement of euthyroidism

Pvu II intron 15 polymorphism at the LDL receptor gene is associated with differences in serum lipid concentrations in subjects with low and high risk for coronary artery disease from Brazil.

Coronary artery disease (CAD) has a high prevalence in the Brazilian population. Nevertheless, studies of genetic risk factors for CAD in this country have not been sufficiently conducted. We used the Pvu II polymorphism (intron 15) at the low-density lipoprotein receptor (LDLR) gene to study the effect of variation at this locus in determining plasma lipid concentrations in 128 white subjects presenting a lipid profile suggesting high risk for CAD (HRG) and 100 white normolipidemic individuals (controls, CG). The Pvu II polymorphism was detected by PCR-RFLP. The P1P1 genotype for Pvu II polymorphism (homozygous for absence of restriction site) was greater in HRG individuals than in CG subjects (57% vs. 38%, P<0.05). Moreover, the P1P1 genotype was strongly associated with high concentrations of total cholesterol (P=0.0001), triglycerides (P=0. 0295), LDL-C (P=0.0001), and VLDL-C concentrations (P=0.0280) and lower HDL-C concentrations (P=0.0051) in HRG subjects. Similarly, the CG individuals with P1P1 genotype presented high concentrations of total cholesterol and LDL-C compared to other genotypes (P=0. 0001). This study demonstrates the influence of Pvu II polymorphism of the LDLR on serum lipid concentrations of individuals with low and high risk for CAD from Brazil.

Effects of Ava II and Hinc II polymorphisms at the LDL receptor gene on serum lipid levels of Brazilian individuals with high risk for coronary heart disease.

Coronary heart disease (CHD) has presented high prevalence in the Brazilian population. Nevertheless, studies of genetic risk factors for CHD in our country are insufficiently carried out. We have investigated the effects of Ava II (exon 13) and Hinc II (exon 12) polymorphisms at the low‐density lipoprotein receptor (LDLR) gene on circulating lipids of 170 white unrelated individuals presenting a lipid profile with high risk for CHD (HRG) and 130 controls (CG) from São Paulo City, Brazil. Ava II and Hinc II polymorphic regions at the LDLR gene were amplified by PCR and analyzed by enzymatic isotyping. The frequency of the genotypes A+A+ (Ava II) and H+H+ (Hinc II) was greater in HRG group compared to that of the controls (32 vs. 16% and 32 vs. 18%, respectively). Moreover, in the HRG group, A+A+ and H+H+ genotypes were associated with high concentrations of total cholesterol and LDL‐C in serum (P = 0.0001). Our results indicate that Ava II and Hinc II polymorphisms at the LDLR locus contribute to the variability of total cholesterol and LDL‐C levels in HRG individuals. These data suggest that the LDLR polymorphism remains a useful genetic marker for predicting CHD risk. J. Clin. Lab. Anal. 13:251–258, 1999.

reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions

Objectives Cholesterol-rich nanoemulsions (LDE) bind to low-density lipoprotein (LDL) receptors and after injection into the bloodstream concentrate in aortas of atherosclerotic rabbits. Association of paclitaxel with LDE markedly reduces the lesions. In previous studies, treatment of refractory cancer patients with etoposide associated with LDE had been shown devoid of toxicity. In this study, the ability of etoposide to reduce lesions and inflammatory factors in atherosclerotic rabbits was investigated. Methods Eighteen New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, nine animals were treated with four weekly intravenous injections of etoposide oleate (6 mg/kg) associated with LDE, and nine control animals were treated with saline solution injections. Results LDE-etoposide reduced the lesion areas of cholesterol-fed animals by 85% and intima width by 50% and impaired macrophage and smooth muscle cell invasion of the intima. Treatment also markedly reduced the protein expression of lipoprotein receptors (LDL receptor, LDL-related protein-1, cluster of differentiation 36, and scavenger receptor class B member 1), inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), matrix metallopeptidase-9, and cell proliferation markers (topoisomerase IIα and tubulin). Conclusion The ability of LDE-etoposide to strongly reduce the lesion area and the inflammatory process warrants the great therapeutic potential of this novel preparation to target the inflammatory-proliferative basic mechanisms of the disease.