Influence of cholesterol on survival after stroke: retrospective study.OBJECTIVE: To investigate the association between serum cholesterol concentration and cerebrovascular disease. DESIGN: Retrospective study. SETTING: Acute stroke unit of inner city general hospital. SUBJECTS: 977 patients with acute stroke. MAIN OUTCOME MEASURES: Serum total cholesterol concentration, type of stroke investigated by computed tomography or magnetic resonance imaging, three month outcome (good (alive at home) or bad (dead or in care)), long term mortality. RESULTS: After adjustment for known prognostic factors, higher serum cholesterol concentrations were associated with reduced long term mortality after stroke (relative hazard 0.91 (95% confidence interval 0.84 to 0.98) per mmol/l increase in cholesterol) independently of stroke type, vascular territory and extent, age, and hyperglycaemia. Three month outcome was also influenced independently by serum cholesterol (P = 0.024). CONCLUSIONS: Our data suggest an association between poor stroke outcome and lower serum cholesterol concentration. Until a prospective controlled study has confirmed the benefits of lowering cholesterol concentration in elderly subjects, the application of cholesterol lowering guidelines cannot be justified as secondary prevention of acute stroke.

Comparative cholesterol lowering properties of vegetable oils: beyond fatty acids.OBJECTIVE: Our laboratory has previously reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Although RBO has up to three times more serum cholesterol-raising saturated fatty acids (SATS) than some unsaturated vegetable oils, we hypothesized that its greater content of the unsaponifiables would compensate for its high SATS and yield comparable cholesterol-lowering properties to other vegetable oils with less SATS. METHODS: To study the comparative effects of different unsaturated vegetable oils on serum lipoprotein levels, nine cynomologus monkeys (Macaca fascicularis) were fed diets, for four weeks, in a Latin square design, containing rice bran, canola or corn oils (as 20% of energy) in a basal mixture of other fats to yield a final dietary fat concentration of 30% of energy. All animals were fed a baseline diet containing 36% of energy as fat with 15% SATS, 15% monounsaturated fatty acids (MONOS) and 6% polyunsaturated fatty acids (POLYS). RESULTS: Despite the lower SATS and higher MONOS content of canola oil and the higher POLYS content of corn oil, RBO produced similar reductions in serum total cholesterol (TC) (-25%) and low density lipoprotein cholesterol (LDL-C) (-30%). In addition, as compared to the baseline diet, the reduction in serum TC and LDL-C cholesterol with RBO was not accompanied by reductions in high density lipoprotein cholesterol (HDL-C) which occurred with the other two dietary oils. Using predictive equations developed from data gathered from several studies with non-human primates, we noted that the observed serum TC and LDL-C lowering capabilities of the RBO diet were in excess of those predicted based on the fatty acid composition of RBO. CONCLUSIONS: These studies suggest that non-fatty acid components (unsaponifiables) of RBO can contribute significantly to its cholesterol-lowering capability.

Crilvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, inhibits cholesterol absorption in genetically hypercholesterolemic rats.Crilvastatin is a new drug from the pyrrolidone family, which acts as a non-competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The long-term effects of oral crilvastatin treatment (200 mg per day per kg body weight for 4 and 10 weeks) were investigated on in vivo cholesterogenesis in male adult normocholesterolemic (SW) and genetically hypercholesterolemic (RICO) rats. In both strains of rats, the treatment had no effect on the plasma cholesterol level, but efficiently inhibited cholesterol synthesis in liver and intestine, as shown by the decreased incorporation of exogenous [14C]acetate into hepatic (3.5-fold in SW, 1.7-fold in RICO rats) and intestinal (2.5-fold in SW, 3.3-fold in RICO rats) sterols. In RICO rats in which the dietary cholesterol absorption coefficient was two-fold lower in treated (38%) than in untreated (78%) rats, this drug reduced intestinal cholesterol absorption. As a result, the total plasma cholesterol input (absorption + synthesis), measured by isotope analysis in RICO rats, was markedly lower in treated (11.3 mg per day) than in untreated animals (28.8 mg per day).

Factors associated with the opinion of hypercholesterolemic patients on the duration of their treatment. Results of the FRACTION studyINTRODUCTION: The treatment of hypercholesterolemia is regularly limited by non compliance over the long-term. Studies conducted on the subject underline the interest of considering compliance as a behaviour composed of multiple determinants that require better knowledge. The patients' opinion concerning the severity and evolution of their health problem, as well as the use and duration of their treatment, are, in this context, essential. OBJECTIVES: Based on the hypothesis that hypercholesterolemic patients who believe that their problem only requires short-term treatment are "candidates" for poor compliance, we attempted to identify the factors that determine their opinion on the duration of treatment. METHODS: 1595 files of hypercholesterolemic patients, who had participated in a survey describing how they represented cholesterol and its impact on their health (the FRACTION study), were analyzed. Two groups of opposing opinion on the duration of treatment for hypercholesterolemia (limited or prolonged) were formed. Their socio-demographic and clinical characteristics and the way they represented their health were compared. The factors predicting their opinion on the duration of treatment were identified. RESULTS: The opinion that only short-term treatment was required was associated with younger age, lower education, the fact of not (or not yet) being treated pharmacologically, personal experience of the disease (presence of hypertension, cardiovascular family history or perception of diminished health), little correct knowledge on cholesterol and hypercholesterolemia and greater erroneous beliefs or prejudice with regard to treatment. After adjustment to the socio-demographic and clinical factors, many representations of health continue to predict the opinion in favor of short-term treatment. CONCLUSION: This study demonstrates, for the first time, the importance of knowledge on health, beliefs and personal judgement that are among the determinating factors of patients' opinion on the duration of their treatment. It shows the justification of their individual approach to compliance, behaviour highly influenced by the representation each patient has of his health. It emphasizes the interest of personalizing educative messages addressed to hypercholesterolemic patients, by taking into better account the potential factors of resistance to compliance.

Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption.(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

Lysine: arginine ratio of a protein influences cholesterol metabolism. Part 1--Studies on sesame protein having low lysine: arginine ratio.The effect of globulin fraction with a lysine: arginine (lys:arg) ratio 0.67, isolated from sesame (Sesamum Indicum) seeds on cholesterol metabolism was studied in rats fed cholesterol free and cholesterol containing diet and compared with casein (lys:arg ratio-2.0). Rats fed sesame seed globulin showed significantly lower concentrations of cholesterol in the serum and aorta. The decrease in serum was manifested in both HDL and LDL + VLDL fractions. There was increased cholesterogenesis in the liver as was evident from increased incorporation of labeled acetate into cholesterol and increased activity of 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Increased hepatic diversion of cholesterol to bile acid synthesis and increased fecal excretion of bile acids and sterols were also observed in rats fed sesame seed globulins. Rats fed sesame globulins also showed significantly higher activity of lipoprotein lipase in the heart and adipose tissue and that of plasma Lecithin: cholesterol acyltransferase (LCAT). These studies suggest that low lysine: arginine ratios of a protein exert hypocholesterolemic effects.

Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis.BACKGROUND: Reduced coronary flow reserve (CFR) in hypercholesterolemic patients without evidence of ischemia has been reported. However, it remains uncertain whether this abnormality occurs without overt coronary atherosclerosis. This study aimed to clarify whether CFR is impaired even in anatomically normal coronary arteries in hypercholesterolemic patients and to compare CFR between familial hypercholesterolemic (FH) patients and secondary hypercholesterolemic (SH) patients. METHODS AND RESULTS: Twenty-two patients with hypercholesterolemia (11 FH, 11 SH) and 11 control subjects were studied. Baseline myocardial blood flow (MBF) and MBF during dipyridamole loading were measured in segments perfused by angiographically normal coronary arteries with the use of positron emission tomography and 13N-ammonia, and CFR was calculated. Baseline MBF (mL/min per 100 g heart wt) in FH (81.3 +/- 31.4) and SH (70.0 +/- 20.7) patients was not different from that in control subjects (75.0 +/- 34.9). However, MBF during dipyridamole loading was significantly lower in FH patients (129 +/- 19.1) than in control subjects (322 +/- 174, P < .01) and SH patients (210 +/- 71.2, P < .01). CFR in FH patients (1.59 +/- 0.41) was also significantly lower compared with both control subjects (4.22 +/- 1.42, P < .01) and SH patients (3.00 +/- 0.96, P < .01). CFR in SH patients was also significantly lower than that in control subjects (P < .05). CFR correlated significantly with both plasma total cholesterol (r = .67, P < .01) and LDL cholesterol concentrations (r = .69, P < .01). CONCLUSIONS: CFR was decreased even in anatomically normal coronary arteries in hypercholesterolemic patients. This abnormality was more prominent in FH patients.

Chronic ischemia alters prostate structure and reactivity in rabbits.PURPOSE: Autopsy studies performed in men older than 80 years old have demonstrated that 90% have histological evidence of benign prostatic hyperplasia. Despite this fact pressure flow studies in men of this age who are referred for the evaluation of lower urinary tract symptoms have shown that only 40% have evidence of bladder outlet obstruction. To our knowledge the specific features of benign prostatic hyperplasia responsible for bladder outlet obstruction are not known. To investigate the possible etiological factors responsible for bladder outlet obstruction we determined whether chronic ischemia alters the structural and functional properties of the prostate. MATERIALS AND METHODS: Male New Zealand White rabbits weighing 3.5 to 4 kg. were divided into a chronic prostate ischemia (12), hypercholesterolemia (8) and age matched control (8) group. The chronic prostate ischemia group underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet, the hypercholesterolemia group received a 0.5% cholesterol diet only and controls received a regular diet. After 12 weeks using anesthesia iliac artery and prostatic blood flow was measured by an ultrasonic and laser Doppler flowmeter, respectively. The animals were then sacrificed and the prostate was processed for histological evaluation, immunohistochemical staining for vascular endothelial growth factor expression and organ bath studies. RESULTS: Iliac artery and prostatic blood flow was significantly decreased in the chronic prostate ischemia compared with the hypercholesterolemia and control groups. Histological findings included thickening and fibrosis of the prostatic stroma and cystic atrophy of the epithelium in the chronic prostate ischemia group as well as minor thickening of the stroma in the hypercholesterolemia group. These structural changes correlated with decreased vascular endothelial growth factor expression. Organ bath studies showed that chronic ischemia and to a lesser extent hypercholesterolemia impaired electrical field stimulation induced neurogenic relaxation of the prostatic tissue. Neurogenic relaxation of the prostatic tissue was improved by combined treatment with indomethacin and L-arginine in the hypercholesterolemia but not in the chronic prostate ischemia group. Nitric oxide donor sodium nitroprusside produced comparable relaxation in all 3 groups. CONCLUSIONS: Chronic ischemia causes marked changes in prostatic structure and contractility. Ischemia induced glandular atrophy was consistently associated with decreased vascular endothelial growth factor expression. Decreased relaxation of the ischemic tissue to electrical field stimulation appears to involve the nitric oxide pathway. The nitric oxide precursor L-arginine reversed hypercholesterolemia induced impairment of prostatic tissue relaxation. Our study suggests that chronic ischemia results in thickening and fibrosis of the prostate, changing its mechanical properties. Chronic ischemia also impairs neurogenic relaxation in the prostate. We discuss the possible relationship of these changes to clinical bladder outlet obstruction.

Total cholesterol and high-density lipoprotein cholesterol in patients with non-insulin-dependent diabetes mellitusNon-insulin-dependent diabetics often have quantitative changes in plasma lipid profiles characterised by higher triglycerides and lower HDL-cholesterol than the average population. This paper summarises the cross-sectional data (reported by the general practitioners participating in Medicos-Sentinela) concerning total and HDL-cholesterol in a cohort of non-insulin-dependent diabetics treated at primary care settings in Portugal. Total cholesterol and High Density Lipoprotein (HDL) associated cholesterol were significantly higher in women. Total cholesterol increased significantly with age (in women), regular alcohol intake, body mass index, systolic blood pressure and diastolic blood pressure (in males). HDL-cholesterol showed significant increase with age (both sexes and males only), gender, and alcohol intake in males. The increase in total cholesterol found in patients with regular alcohol intake is an infrequently reported finding.

Effect of a synthetic androgen on biliary lipid secretion in the female hamster.This study was designed to elucidate the effect of the synthetic androgen, methyltestosterone, on bile flow and biliary lipid secretion in female hamsters. Animals were divided into four groups and fed the following diets: group 1, lithogenic diet for three weeks; group 2, lithogenic diet + 0.05% methyltestosterone for three weeks; group 3, lithogenic diet for six weeks; group 4, lithogenic diet + 0.05% methyltestosterone for six weeks. At the end of each experimental period, the hamsters were operated on to establish external biliary fistulas. During the depletion of the endogenous bile acid pool (for two hours), the basal bile flow of group 4 was significantly smaller than that of group 3. Basal bile acid output was significantly lower in the methyltestosterone-fed groups 2 and 4 than in control groups 1 and 3. In contrast, groups 2 and 4 secreted more cholesterol than groups 1 and 3. Group 4 had a higher ratio of cholesterol output to phospholipid output than group 3. Increasing doses of taurocholate were infused after the bile acid depletion period, and it was found that methyltestosterone did not change the bile acid independent bile flow. The increments in cholesterol or phospholipid output induced per increment of bile acid output (linkage coefficients) were analyzed by linear regression. The methyltestosterone-fed groups (groups 2 and 4) had a higher linkage coefficient of cholesterol output to bile acid output than the control groups (groups 1 and 3). The linkage coefficients of phospholipid output to bile acid output of groups 2 and 4 were also higher compared to groups 1 and 3. The linkage coefficient of cholesterol output to phospholipid output of group 2 was higher than that of group 1. These results suggest that methyltestosterone stimulated the cosecretion mechanism of cholesterol and phospholipid in bile associated with an increasing ratio of cholesterol to phospholipid. In conclusion, the synthetic androgen, methyltestosterone, caused a decrease in basal bile flow and bile acid secretion, and an increase in basal cholesterol secretion and the biliary cholesterol-to-phospholipid ratio. These findings explain, in part, how methyltestosterone intensifies the formation of cholesterol gallstones in female hamsters.