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Objective: To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to determine whether a low dose of lovastatin will correct this abnormality.Design: In the first part of the study, turnover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placed-controlled, randomized, double-blind study using lovastatin as the therapeutic agent.Setting: The General Clinical Research Center of the University of Texas Southwestern Medical Center, Dallas, utilizing inpatient and outpatient facilities, and the Veterans Affairs Medical Center, Dallas, Tex.Patients: For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean +/- SD LDL cholesterol, 4.78 +/- 0.59 mmol/L [185 +/- 23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean +/- SD LDL cholesterol, 3.31 +/- 0.39 mmol/L [128 +/- 15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study.Interventions: In the drug study, patients received blindly both lovastatin (10 mg/d) and placebo.Main Outcome Measures: In the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy.Results: In the LDL turnover study, mean (+/- SD) input (production) rates for LDL apolipoprotein B (apo B) were similar for hypercholesterolemic women and control women (12.4 [+/- 3.2] mg/kg per day and 11.1 [+/- 2.2] mg/kg per day, respectively). In contrast, mean (+/- SD) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [+/- 0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [+/- 0.03] pools per day). In the drug trial, lovastatin therapy reduced mean (+/- SD) total cholesterol and LDL cholesterol from 7.03 (+/- 1.16) mmol/L (272 [+/- 45] mg/dL) and 4.42 (+/- 0.80) mmol/L (171 [+/- 31] mg/dL, respectively, to 5.70 (+/- 1.03) mmol/L (221 [+/- 40] mg/dL) and 3.46 (+/- 0.85) mmol/L (134 [+/- 33] mg/dL).Conclusions: The turnover data suggest that hypercholesterolemia in post-menopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause. [ABSTRACT FROM AUTHOR]

The novel enantiopure dipyridyl spacer 2,2'-dimethoxy-1,1'-binaphthyl-3,3'-bis(4-pyridyl-amido) (R)-L has been designed as a robust source of axial chirality to obtain helical coordination polymers. The reaction of (R)-L and the differently substituted dithiophosphato complexes [Ni((RO)2PS2)2] [R = Me (1), Et (2)] efficiently yielded coordination polymers (1⋅L)∞ and (2⋅L)∞, respectively, consisting of helical chains in which the nickel(II) ions of the [Ni((RO)2PS2)2] units are bridged by the enantiopure L ligands. The obtained polymers differ in terms of the configuration at the metal centres, which is trans and cis for (1⋅L)∞ and (2⋅L)∞, respectively. The cis configuration in (2⋅L)∞ generates a further element of chirality around the metal center, which occurs stereospecifically, as only one enantiomeric form is present, with homochiral helices packed with opposite screw sense in the crystal. The electronic and structural features of L, (1⋅L)∞, and (2⋅L)∞ have been investigated by means of DFT theoretical calculations, and the theoretical results have been compared with the experimental ones coming from single-crystal X-ray diffraction. The cis/trans isomerism displayed by the metal centers in (1⋅L)∞ and (2⋅L)∞ has been tentatively explained on the basis of the results of theoretical calculations performed on hypothetical pentacoordinated intermediates. [ABSTRACT FROM AUTHOR]

A comprehensive whole-body approach to noninvasive evaluation of coronary and extracoronary vasculature is currently not available. The objective of our study was to assess the potential of 64-slice computed tomography angiography (64-CTA) for whole-body evaluation of atherosclerosis burden. Seventy-eight patients referred for coronary imaging underwent whole-body 64-CTA using an adjusted strategy for the administration of contrast medium with dose-saving algorithms involving ECG modulation and reduced tube voltage. Arterial segments (15 coronary, 32 systemic) were evaluated for significant (> or =50%) steno-occlusive disease while arterovenous density was evaluated at seven extracoronary locations. Homogeneous attenuation (mean 321 +/- 20 HU) was obtained throughout the systemic vasculature. Atherosclerosis was observed in 238/995 (24%) coronary and 368/2441 (15%) systemic segments. Significant stenoses/occlusions were present in 214 (21%)/24 (2.5%) coronary segments while asymptomatic clinically relevant stenoses were present in 49 systemic segments. Sensitivity, specificity, positive and negative predictive values of coronary 64-CTA among 52 patients who also underwent quantitative coronary angiography were 92%, 95%, 81% and 98%, respectively. ECG modulation decreased radiation exposure to 14.1-15.4 mSv per patient. Comprehensive, noninvasive assessment of atherosclerosis can be performed by whole-body 64-CTA and may have a positive impact on secondary prevention. [ABSTRACT FROM AUTHOR]

Abstract Background The present study evaluated the role of the PON1 L55M polymorphism independently and in conjunction with the Q192R polymorphism on the risk of coronary atherosclerosis in an Italian population. Materials and methods Three hundred and ninety-one subjects with significant coronary stenosis (> 50%) (coronary artery disease-positive; CAD+ ), 196 subjects with normal coronary arteries (< 10% stenosis) (CAD- ) and 178 healthy controls were screened using a combination of polymerase chain reaction and restriction enzyme digestion. Results In the pooled population, the frequencies of L and M alleles were 0·63 and 0·37, respectively; the most common haplotypes were QQ/LM (24·2%) and QR/LL (21·8%) and a strong linkage disequilibrium between L/55 and R/192 alleles was observed (D′ = -0·91; P < 0·0001). CAD+ subjects did not show any significant differences in the distribution of PON1–55 genotypes as compared to CAD- subjects and population controls (χ2 = 1·5, P = 0·8). After controlling for other risk factors, the low-concentration M allele was not associated with a significant change of CAD risk (OR 1·02; 95% CI 0·80–1·29; P = 0·87). Moreover, the L55M polymorphism did not show any interaction with other risk factors such as smoking, diabetes, hypertension, low levels of high-density lipoprotein (HDL) or high ratios of low-density to high-density lipoproteins. The combination of L55M with the Q192R polymorphism did not show any effect on CAD risk. However, a marginal decrease in myocardial infarction risk was detected when QQ/MM carriers (OR 0·51; 95% CI 0·26–0·99; P = 0·048), but not LL/RR carriers, were compared with subjects not homozygous for an L or R allele. Conclusions These findings did not indicate a major effect of the PON1 L55M polymorphism, either alone or in combination... [ABSTRACT FROM AUTHOR]

The anti-atherogenic effect of cholesteryl ester transfer protein (CETP) genetic variants associated with lowered enzyme activity is controversial. Moreover, in a few studies, this effect has been evaluated in the presence of a certain risk factor constellation. We addressed this issue in a case–control study, where 415 subjects with angiographically documented coronary artery disease (CAD+), 397 subjects without CAD (in 215, CAD was excluded by coronarography (CAD-)), and 188 healthy population controls, were screened for the CETP TaqIB polymorphism. The prevalence of the low-activity TaqIB2 allele was 0.396 in CAD+, and 0.428 and 0.416 in CAD- and population controls, respectively (p=0.40). Its presence was significantly associated with increased high-density lipoprotein cholesterol (HDL-C) in population controls (1.40±0.40 mmol/l in B1B1, 1.52±0.39 mmol/l in B1B2 and 1.58±0.46 mmol/l in B2B2; p<0.03 for trend), but not in the other groups. The CETP TaqIB polymorphism accounted for <1% of the HDL-C variance in the whole cohort (p=0.048). After adjustment for other risk factors, the CETP TaqIB2 allele was found not to be associated with significant changes in CAD risk independently of an assumed either dominant (odds ratio (OR) 0.97; 95% confidence interval (CI) 0.66–1.44; p=0.89) or recessive effect (OR 0.68; 95% CI 0.42–1.12; p=0.13). The CETP TaqIB polymorphism did not show a significant interaction with other risk factors in influencing CAD risk. Our findings do not support the hypothesis that a genetic variant resulting in lowered CETP activity is associated with reduced risk of coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Insulin resistance is recognised as the core factor in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, hypertension and atherosclerosis. Several studies indicate the possible role of mutations of the insulin receptor substrate-1 (IRS-1) gene in the pathogenesis of insulin-resistance and suggest a possible interaction between the IRS-1 gene and obesity, either by an effect on the development of obesity or by causing or aggravating the obesity-associated insulin resistance. Therefore, the prevalence of the G972R mutation of the IRS-1 gene was compared in 157 non-diabetic obese subjects (BMI > 30 m/kg2) and in 157 lean subjects (BMI < 28 m/kg2). By investigating the relation between this IRS-1 mutation, measures of obesity and metabolic parameters, we explored the possible influence of this mutation on body fat distribution and insulin resistance. Methods. The G972R mutation was detected by PCR amplification and BstN-1 restriction enzyme digestion. Data were analysed by univariate and multivariate analysis. Results. The G972R allele was significantly more frequent in obese subjects than in lean subjects (p < 0.002); however, no difference was found between centrally and peripherally obese subjects. Obese G972R carriers had significantly higher BMI (p < 0.001), fasting insulin (p < 0.01), triglycerides (p < 0.03) and HOMAIR (p < 0.001) than obese non-carriers. No differences were observed between G972R carriers and non-carriers among control subjects. Multivariate analysis confirmed that the IRS-1 G972R mutation was significantly and independently associated with reduced insulin sensitivity (p < 0.009) in the obese group. Conclusion/interpretation. The G972R mutation of the IRS-1 gene associates with obesity, but not with fat distribution, in this Italian cohort, and within the obese subjects this IRS-1 variant strongly associates with metabolic parameters suggesting greater insulin-resistance. These findings indicate a possible interaction between the IRS-1 variant and obesity in worsening insulin sensitivity. [Diabetologia (2001) 44: 367–372] [ABSTRACT FROM AUTHOR]