Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. (33/3532)

The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR-/-) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR-/- mice; and (3) hypercholesterolemic LDLR-/- mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR-/- mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; n=16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (n=18), or regular chow (n=7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849+/-268 versus 964+/-234 mg/dL) and much higher than in the chow-fed group (249+/-21 mg/dL). Final body weights in the Western diet group were higher (39+/-6.2 g) than in the fructose- (27.8+/-2.7 g) or chow-fed (26.7+/-3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187+/-16 versus 159+/-12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non-insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8+/-2.9% versus 7.8+/-2. 5% of aortic surface; P<0.01). These results suggest that (1) fructose-enriched diets do not induce IR in LDLR-/- mice; (2) the Western diets commonly used in LDLR-/- mice may not only induce atherosclerosis, but also IR, potentially complicating the interpretation of results; and (3) IR and hyperinsulinemia do not enhance atherosclerosis in LDLR-/- mice, at least under conditions of very high plasma cholesterol levels. The fact that various levels of hypercholesterolemia can be induced in LDLR-/- mice by fat-enriched diets and that such diets induce IR and hyperinsulinemia suggest that LDLR-/- mice may be used as models to elucidate the effect of IR on atherosclerosis, eg, by feeding them Western diets with or without insulin-sensitizing agents.  (+info)

Measuring serum total cholesterol: do vascular surgeons know what they are doing? (34/3532)

Raised serum total cholesterol (TC) is an accepted risk factor for both coronary and peripheral vascular disease and three landmark trials have shown the benefit of lowering TC using statins. Vascular surgeons tend to measure TC, but little is known about how they manage hypercholesterolaemia or whether they believe treatment will be of benefit. A questionnaire was sent to listed members of the Vascular Surgical Society of Great Britain and Ireland seeking responses to a range of questions on the measurement and management of raised TC. In all, 374 questionnaires were sent out. The response rate was 67%. Over 90% of respondents said they measured TC and considered a level below 5.5 mmol/l as normal. The cut-off for initiating drug therapy, referral to a dietician or to a lipid specialist varied from 5.5 to 7.5 mmol/l. Most (62%) believed that lowering TC improved coronary mortality, but fewer (26%) that it prevented worsening of claudication. Although most vascular surgeons check for raised TC, the level at which treatment begins and the form it takes varies; in many cases being at odds with recommendations. Few surgeons are convinced of the benefits of lowering TC for claudication and nearly one-fifth do not believe it improves coronary mortality.  (+info)

Genetic differences in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterol responsiveness. (35/3532)

This study compared the cholesterolemic response of two strains of mice with genetically determined differences in cholesterol absorption. When fed a basal low-cholesterol diet, 129/Sv mice absorbed cholesterol twice as efficiently as did C57BL/6 mice (44% vs. 20%). Total lipid absorption, in contrast, averaged 80-82% in both strains. The higher level of cholesterol absorption in the 129/Sv animals was reflected in an adaptive reduction in hepatic and intestinal sterol synthesis. When fed lipid-enriched diets, the 129/Sv mice became significantly more hypercholesterolemic and had twofold higher hepatic cholesterol concentrations than did the C57BL/6 animals even though the conversion of cholesterol to bile acids was stimulated equally in both strains. The difference in cholesterol absorption between these mouse strains was not the result of physicochemical factors relating to the size and composition of the intestinal bile acid pool but more likely reflects an inherited difference in one or more of the biochemical steps that facilitate the translocation of sterol across the epithelial cell.  (+info)

Ischemia-reperfusion induced microvascular responses in LDL-receptor -/- mice. (36/3532)

The objective of this study was to determine whether the microvascular responses to ischemia and reperfusion (I/R) are altered in an animal model of atherosclerosis, the low-density lipoprotein-receptor knockout (LDLr -/-) mouse. Intravital video microscopy was used to monitor venular wall shear rate, leukocytes rolling velocity, the number of rolling, adherent and emigrated leukocytes, and albumin leakage in cremasteric postcapillary venules of wild-type (B6129) and LDLr -/- mice exposed to 60 min of ischemia and 60 min of reperfusion. The postcapillary venules of LDLr -/- mice exhibited two- to threefold larger increments in the number of adherent leukocytes and a more profound albumin leakage response to I/R than venules in wild-type mice. The exaggerated inflammatory responses noted in LDLr -/- mice placed on a normal diet were not exacerbated by a high-cholesterol diet. Treatment of LDLr -/- mice with either a platelet-activating factor (PAF) receptor antagonist (WEB-2086) or a monoclonal antibody (YN-1) against the endothelial cell adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), markedly attenuated the I/R-induced leukocyte adherence and albumin leakage. These findings indicate that atherogenic mice are more vulnerable to the deleterious microvascular effects of I/R and that PAF-mediated, ICAM-1-dependent leukocyte adhesion contributes to this exaggerated response to I/R.  (+info)

Effect of 17beta-estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction. (37/3532)

17beta-Estradiol prevents early vascular lesion development and may also affect advanced atherosclerosis. To test the antiatherosclerotic effect of estrogen under conditions that resemble more advanced human atherosclerosis with severe endothelial dysfunction, we have investigated the effect of 17beta-estradiol in hypercholesterolemic rabbits treated with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). Chronic L-NAME administration attenuated endothelial nitric oxide (EDNO)-mediated vascular responses leading to significantly accelerated atherosclerotic plaque development. 17beta-Estradiol treatment alone inhibited aortic lesion formation with concurrent increase in EDNO-mediated responses. The beneficial effect of estrogen persisted in the L-NAME-treated rabbits, suggesting that the antiatherogenic action of 17beta-estradiol involves NO-independent mechanisms as well. Serum cholesterol levels were not altered by any of the treatments. 17beta-Estradiol treatment significantly increased EDNO production under these conditions as well. The reduction in plaque size by 17beta-estradiol was always accompanied by increased EDNO production, suggesting a strong association between these two events. The results demonstrate that estrogen treatment may exert protection against atherosclerosis even in patients with severe endothelial dysfunction.  (+info)

Improvement of endothelial vasomotor dysfunction by treatment with alpha-tocopherol in patients with high remnant lipoproteins levels. (38/3532)

OBJECTIVES: This study sought to examine whether oral intake of alpha-tocopherol, an antioxidant, could improve endothelium-dependent vasorelaxation in patients with high remnant lipoproteins levels. BACKGROUND: Remnant lipoproteins are known to be atherogenic and impair endothelium-dependent arterial relaxation, but the underlying mechanisms remain unclear. Oxidative stress is a common feature of various risk factors for atherosclerosis. METHODS: Flow-mediated vasodilation of the brachial artery during reactive hyperemia was examined by high resolution ultrasound technique before and at the end of 4 weeks treatment with oral administration of alpha-tocopherol acetate (300 IU/day) or placebo, which was randomly assigned, in 40 patients with high serum levels of remnants and in 30 patients with low remnants levels in the fasting state (>75th percentile and <25th percentile, respectively, of the distribution of remnants levels in 150 consecutive hospitalized patients). RESULTS: Before treatment, flow-mediated vasodilation was lower in patients with high remnants levels than in those with low levels (4.1 +/- 0.3% vs. 6.0 +/- 0.5%, p < 0.01). Treatment with alpha-tocopherol but not with placebo significantly increased flow-mediated dilation in patients with high remnants levels (7.5 +/- 0.4% after alpha-tocopherol vs. 4.2 +/- 0.4% after placebo, p < 0.01). In patients with low remnants levels, alpha-tocopherol was not effective. The beneficial effect with alpha-tocopherol in high remnants patients was associated with decrease in plasma levels of thiobarbituric acid reactive substances, an indicator of lipid peroxidation (6.6 +/- 0.3 nmol/ml before alpha-tocopherol vs. 4.6 +/- 0.3 after alpha-tocopherol, p < 0.05). CONCLUSIONS: Alpha-tocopherol improved impairment of endothelium-dependent vasodilation in patients with high remnants levels. The increase in oxidative stress may at least partly contribute to endothelial vasomotor dysfunction, in patients with high remnants levels.  (+info)

Use of dexfenfluramine, fenfluramine and phentermine and the risk of stroke. (39/3532)

AIMS: To estimate the incidence of newly diagnosed idiopathic stroke among users of fenfluramine, dexfenfluramine and phentermine compared to obese nonusers. METHODS: We conducted a cohort study with nested case-control analysis utilizing data from the General Practice Research Database in the UK. Eight thousand four hundred and twenty-three subjects aged 69 years or less at the start of follow-up were exposed to at least one of the three study drugs and 17 225 similarly obese subjects were not exposed to any of the study drugs. RESULTS: We identified 45 incident cases of idiopathic CVA in this cohort of subjects. The incidence of CVA among all current users of a diet drug was 1.3/1000 person-years (95% CI 0.5, 3.5). The incidence for current fenfluramine users (n=2) was 2.6/1000 person-years (95% CI 0.7, 9.6), for current dexfenfluramine users (n=1) 1.1/1000 person-years (95% CI 0.3, 3.8), and for current phentermine users 0/1000 person-years (95% CI 0.0, 12.9). The incidence in obese nonusers was 0.6/1000 person-years (95% CI 0.4, 0. 9). The adjusted matched odds ratio (OR) for thrombotic stroke from the case-control analysis comparing current use of a diet drug to nonuse was 2.4 (95% CI 0.6, 9.1). There was only one exposed subject among seven who had haemorrhagic stroke. CONCLUSIONS: The incidence of CVA in generally young obese subjects during use of fenfluramine, dexfenfluramine or phentermine is low. Although we found an OR of 2. 4 comparing users of any of the anorexiants with nonusers, this is based on only three exposed cases and the confidence limits are wide. We conclude that our study does not support a substantial increased risk of stroke attributable to the use of fenfluramine, dexfenfluramine or phentermine.  (+info)

Effect of postal prompts to patients and general practitioners on the quality of primary care after a coronary event (POST): randomised controlled trial. (40/3532)

OBJECTIVES: To determine whether postal prompts to patients who have survived an acute coronary event and to their general practitioners improve secondary prevention of coronary heart disease. DESIGN: Randomised controlled trial. SETTING: 52 general practices in east London, 44 of which had received facilitation of local guidelines for coronary heart disease. PARTICIPANTS: 328 patients admitted to hospital for myocardial infarction or unstable angina. INTERVENTIONS: Postal prompts sent 2 weeks and 3 months after discharge from hospital. The prompts contained recommendations for lowering the risk of another coronary event, including changes to lifestyle, drug treatment, and making an appointment to discuss these issues with the general practitioner or practice nurse. MAIN OUTCOME MEASURES: Proportion of patients in whom serum cholesterol concentrations were measured; proportion of patients prescribed beta blockers (6 months after discharge); and proportion of patients prescribed cholesterol lowering drugs (1 year after discharge). RESULTS: Prescribing of beta bockers (odds ratio 1.7, 95% confidence interval 0.8 to 3.0, P>0.05) and cholesterol lowering drugs (1.7, 0. 8 to 3.4, P>0.05) did not differ between intervention and control groups. A higher proportion of patients in the intervention group (64%) than in the control group (38%) had their serum cholesterol concentrations measured (2.9, 1.5 to 5.5, P<0.001). Secondary outcomes were significantly improved for consultations for coronary heart disease, the recording of risk factors, and advice given. There were no significant differences in patients' self reported changes to lifestyle or to the belief that it is possible to modify the risk of another coronary event. CONCLUSIONS: Postal prompts to patients who had had acute coronary events and to their general practitioners in a locality where guidelines for coronary heart disease had been disseminated did not improve prescribing of effective drugs for secondary prevention or self reported changes to lifestyle. The prompts did increase consultation rates related to coronary heart disease and the recording of risk factors in the practices. Effective secondary prevention of coronary heart disease requires more than postal prompts and the dissemination of guidelines.  (+info)