Normocholesterolemic Patients Research Articles

Identification of a Positive Association between Mammary Adipose Cholesterol Content and Indicators of Breast Cancer Aggressiveness in a French Population

BackgroundSeveral studies have recently highlighted important roles for adipose tissue in cancer. However, few have examined adipose tissue cholesterol, and no study has been performed in breast adipose tissue associated with breast tumors. ObjectivesThe present work was designed to determine if breast adipose tissue cholesterol from the tumor-surrounding area is associated with breast cancer aggressiveness. MethodsBetween 2009 and 2011, 215 breast adipose tissue samples were collected at the Tours University Hospital (France) during surgery of women (aged 28–89 y) with invasive breast cancer. Associations of free cholesterol (FC), esterified cholesterol (EC), and total cholesterol (TC) amounts with clinical variables (age, BMI, and treated or untreated hypercholesterolemia) and tumor aggressiveness parameters [phenotype, grade, presence of inflammatory breast cancer (IBC), and multifocality] were tested using Student’s t test and after ANOVA. ResultsThe predominant form of cholesterol in adipose tissue was FC, and 50% of patients had no detectable EC. The adipose tissue FC content (μg/mg total lipid) was 18% greater in patients >70 y old than in those 40–49 y old (P < 0.05) and the TC content tended to be 12% greater in untreated hypercholesterolemic patients than in normocholesterolemic patients (P = 0.06). Breast adipose cholesterol concentrations were increased in tissues obtained from patients with human-epidermal-growth-factor-receptor-2 (HER2) phenotype (+13% FC; P < 0.05 compared with luminal A), IBC (+15% FC; P = 0.06 compared with noninflammatory tumors), as well as with multifocal triple-negative tumors (+34% FC, P < 0.05; +30% TC, P < 0.05, compared with unifocal triple-negative tumors). Among patients with triple-negative tumors, hypercholesterolemia was significantly more common (P < 0.05) in patients with multifocal tumors (64%) than in patients with unifocal tumors (25%). ConclusionsThis study is the first of this magnitude that analyzes cholesterol concentrations in adipose tissue from female breast cancer patients. An increase in breast adipose tissue cholesterol content may contribute to breast cancer aggressiveness (HER2 phenotype, multifocality of triple-negative tumors, and IBC).

Pravastatin-induced changes in expression of long non-coding and coding RNAs in endothelial cells.

ObjectiveAtherosclerosis is the main cause of the cardiovascular disease (CVD). Elevated blood cholesterol and inflammation of the endothelium are two major mechanisms contributing to the establishment of atherosclerotic plaques. Statins, such as pravastatin, are blood‐cholesterol lowering drugs commonly prescribed for patients with or at risk for CVDs. In addition to lowering blood cholesterols, statins have recently been shown to improve endothelial function in both hyper‐ and normocholesterolemic patients with atherosclerosis. To understand the molecular mechanisms underlying the endothelial function improvement by statins, we assessed the RNA profile of pravastatin‐treated endothelial cells, particularly their mRNAs and long non‐coding RNAs (lncRNAs).MethodsHuman umbilical vein endothelial cells (HUVECs) treated with pravastatin (10 µM) for 24 hr were profiled for lncRNAs and mRNAs using the Arraystar Human lncRNA Expression Microarray V3.0.ResultsOf the 30,584 different lncRNAs screened, 95 were significantly upregulated, while 86 were downregulated in HUVECs responding to pravastatin. LINC00281 and BC045663 were the most upregulated (~8‐fold) and downregulated (~3.5‐fold) lncRNAs, respectively. Of the 26,106 different mRNAs screened in the pravastatin‐treated HUVEC samples, 190 were significantly upregulated, while 90 were downregulated. Assigning the differentially expressed genes by bioinformatics into functional groups revealed their molecular signaling involvement in the following physiological processes: osteoclast differentiation, Rap1 signaling pathway, hematopoiesis, immunity, and neurotrophin signaling pathway.ConclusionsThis is the first lncRNA and mRNA expression profiling of pravastatin‐mediated changes in human endothelial cells. Our results reveal potential novel targets and mechanisms for pravastatin‐mediated vascular protection in atherosclerosis.

High dose rosuvastatin increases ABCA1 transporter in human atherosclerotic plaques in a cholesterol-independent fashion

BackgroundATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques. MethodsSeventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry. ResultsBoth rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein. ConclusionsHigh-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin.Trial registration: ISRCTN16590640

Lifestyle intervention enhances high-density lipoprotein function among patients with metabolic syndrome only at normal low-density lipoprotein cholesterol plasma levels

Metabolic syndrome (MetS) is associated with altered lipoprotein metabolism and impairment in the functionality of small, dense high-density lipoprotein (HDL) particles secondary to compositional alterations. The objective of this study was to investigate the capacity of a lifestyle program to improve the composition and antioxidative function (AOX) of small dense HDL3c in MetS. Patients with MetS (n=33) not taking lipid-lowering drugs were recruited to follow a 12-week educational program to reduce caloric intake and to increase physical activity. HDL subfractions were preparatively isolated by isopycnic density-gradient ultracentrifugation. AOX of HDL3c was assessed as its capacity to inhibit low-density lipoprotein oxidation induced by an azoinitiator. AOX of HDL3c was significantly improved (mean reduction in the propagation rate of low-density lipoprotein oxidation by HDL3c, -6.8%, P=.03) and systemic oxidative stress, assessed as plasma levels of 8-isoprostanes, tended to decrease in normocholesterolemic MetS patients (low-density lipoprotein cholesterol [LDL-C] < 130mg/dL) but not in patients with elevated LDL-C levels and in the whole study population. In both the whole study population and the normocholesterolemic subgroup, lifestyle intervention resulted in a significant degree of normalization of HDL3c composition, (enrichment in apolipoprotein A-I and cholesteryl esters, depletion in triglycerides), which was more pronounced at LDL-C < 130mg/dL. In patients with MetS, a lifestyle program improves AOX of small, dense HDL in subjects with normal LDL-C levels. Correction of HDL composition, involving partial normalization of apoA-I content and core lipid composition, 2 central features of the lipid hydroperoxide-inactivating capacity of HDL, may account for this effect.

Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease

This study compared the molecular lipidomic profile of LDL in patients with nondiabetic advanced renal disease and no evidence of CVD to that of age-matched controls, with the hypothesis that it would reveal proatherogenic lipid alterations. LDL was isolated from 10 normocholesterolemic patients with stage 4/5 renal disease and 10 controls, and lipids were analyzed by accurate mass LC/MS. Top-down lipidomics analysis and manual examination of the data identified 352 lipid species, and automated comparative analysis demonstrated alterations in lipid profile in disease. The total lipid and cholesterol content was unchanged, but levels of triacylglycerides and N-acyltaurines were significantly increased, while phosphatidylcholines, plasmenyl ethanolamines, sulfatides, ceramides, and cholesterol sulfate were significantly decreased in chronic kidney disease (CKD) patients. Chemometric analysis of individual lipid species showed very good discrimination of control and disease sample despite the small cohorts and identified individual unsaturated phospholipids and triglycerides mainly responsible for the discrimination. These findings illustrate the point that although the clinical biochemistry parameters may not appear abnormal, there may be important underlying lipidomic changes that contribute to disease pathology. The lipidomic profile of CKD LDL offers potential for new biomarkers and novel insights into lipid metabolism and cardiovascular risk in this disease.

Pro-inflammatory monocyte-macrophage polarization imbalance in human hypercholesterolemia and atherosclerosis

Monocyte-macrophages (MoMas) play a major role in atherosclerosis. In mice, hypercholesterolemia increases pro-inflammatory monocytes that promote plaque growth, but whether this is true also in humans in unknown. We herein analyzed monocyte subsets and MoMa phenotypes in familiar (FH, n = 22) and non-familiar (NFH, n = 20) hypercholesterolemic compared with normocholesterolemic (CTRL, n = 20) patients. We found that FH and NFH had higher circulating pro-inflammatory CD68+CCR2+ M1 MoMas than CTRL, while anti-inflammatory CX3CR1+CD163+/CD206+ M2 MoMas were reduced only in NFH. As a result, the M1/M2 polarization balance was increased in FH and, more markedly in NFH. M1 MoMas and the M1/M2 polarization ratio were directly correlated to pre-treatment LDL cholesterol levels and strongly associated with the presence of atherosclerotic plaques. In conclusion, we show for the first time that human hypercholesterolemia is associated with a pro-inflammatory imbalance of circulating monocytic cells, which can predispose to the development of atherosclerosis.

Antihypertensive effect of rosuvastatin in normocholesterolemic hypertensive patients and its association with flow mediated dilation and oxidative stress

Antihypertensive effect of rosuvastatin in normocholesterolemic hypertensive patients and its association with flow mediated dilation and oxidative stress

Enhanced lipid peroxidation and platelet activation as potential contributors to increased cardiovascular risk in the low-HDL phenotype

Background Low high-density lipoprotein (HDL) levels are major predictors of cardiovascular (CV) events, even in patients on statin treatment with low-density lipoprotein (LDL) at target. In animal models HDLs protect LDL from oxidation and blunt platelet activation. Our study aimed to examine whether HDL levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis. Methods and Results Urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/dL, and in 47 CHD patients with HDL >35 mg/dL. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/dL showed significantly higher urinary 8-iso-PGF2α (median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine, P =0.019) and 11-dehydro-TXB2 (563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine, P =0.0001) than patients with higher HDL. A direct correlation was found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 in the entire group of patients (ρ=0.77, P <0.0001). HDL levels were inversely related to both 8-iso-PGF2α (ρ=−0.32, P =0.001) and 11-dehydro-TXB2 (ρ=−0.52, P <0.0001). On multiple regression, only 8-iso-PGF2α (β=0.68, P <0.0001) and HDL level (β=−0.29, P <0.0001) were associated with urinary 11-dehydro-TXB2 excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase. Conclusions A low HDL phenotype, both in CHD patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low HDL with increased CV risk.

Simvastatin, Atorvastatin, and Pravastatin are Equally Effective in Improving Acetylcholine‐Induced Relaxation in STZ‐Diabetic Rats

Statin therapy improves cardiovascular (CV) status in normocholesterolemic diabetic patients. To further clarify the underlying mechanisms, we studied and compared the effect of atorvastatin (AV), simvastatin (SV), and pravastatin (PV) (10 mg/kg/day) on acetylcholine (Ach)‐induced relaxation in the aortic rings of streptozotocin (STZ)‐induced diabetic rats. EMAX values for the Ach‐induced relaxation were lower in diabetic than in CT rats (53.70 ± 4.07 % vs. 74.61 ± 3.27 %, N=10, P&lt;0.05). Four weeks of statin treatment improved EMAX in diabetic rats (AV 82.13 ± 7.01 %, SV 84.63 ± 6.51 %, and PV 79.40 ± 9.10 %, N=8, P&lt;0.05), but EC50 values remained unchanged (from 0.41 ± 0.098 μM before treatment to an average across the three statins of 0.54 ± 0.252 μM after treatment, P&gt;;0.05). All statins produced a similar improvement in vascular relaxation. Moreover, this positive statin effect was abolished by 1 mM LNAME, suggesting that it is NO‐dependent. The reduction of CV events by statins in diabetic patients may be secondary to improved endothelial function, which by decreasing vascular tone and systemic vascular resistance, will reduce the workload on the heart. Supported by MBRS‐RISE Grant R25‐GM061838.

Enhanced Lipid Peroxidation and Platelet Activation as Potential Contributors to Increased Cardiovascular Risk in the Low‐HDL Phenotype

BackgroundLow high‐density lipoprotein (HDL) levels are major predictors of cardiovascular (CV) events, even in patients on statin treatment with low‐density lipoprotein (LDL) at target. In animal models HDLs protect LDL from oxidation and blunt platelet activation. Our study aimed to examine whether HDL levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis.Methods and ResultsUrinary 8‐iso‐PGF2α and 11‐dehydro‐TXB2, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/dL, and in 47 CHD patients with HDL >35 mg/dL. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/dL showed significantly higher urinary 8‐iso‐PGF2α (median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine, P=0.019) and 11‐dehydro‐TXB2 (563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine, P=0.0001) than patients with higher HDL. A direct correlation was found between urinary 8‐iso‐PGF2α and 11‐dehydro‐TXB2 in the entire group of patients (ρ=0.77, P<0.0001). HDL levels were inversely related to both 8‐iso‐PGF2α (ρ=−0.32, P=0.001) and 11‐dehydro‐TXB2 (ρ=−0.52, P<0.0001). On multiple regression, only 8‐iso‐PGF2α (β=0.68, P<0.0001) and HDL level (β=−0.29, P<0.0001) were associated with urinary 11‐dehydro‐TXB2 excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase.ConclusionsA low HDL phenotype, both in CHD patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low HDL with increased CV risk.

Hypercholesterolemia and in-vivo coronary plaque composition in patients with coronary artery disease: a virtual histology - intravascular ultrasound study.

Background and ObjectivesHypercholesterolemia is a key factor in the development of atherosclerosis. We sought to evaluate the relation between hypercholesterolemia and plaque composition in patients with coronary artery disease.Subjects and MethodsStudy subjects consisted of 323 patients (mean 61.5 years, 226 males) who underwent coronary angiography and virtual histology-intravascular ultrasound examination. Patients were divided into two groups according to total cholesterol level: hypercholesterolemic group (≥200 mg/dL, n=114) and normocholesterolemic group (<200 mg/dL, n=209).ResultsHypercholesterolemic patients were younger (59.7±13.3 years vs. 62.6±11.5 years, p=0.036), than normocholesterolemic patients, whereas there were no significant differences in other demographics. Hypercholesterolemic patients had higher corrected necrotic core volume (1.23±0.85 mm3/mm vs. 1.02±0.80 mm3/mm, p=0.029) as well as percent necrotic core volume (20.5±8.5% vs. 18.0±9.2%, p=0.016) than normocholesterolemic patients. At the minimal lumen area site, percent necrotic core area (21.4±10.5% vs. 18.4±11.3%, p=0.019) and necrotic core area (1.63±1.09 mm2 vs. 1.40±1.20 mm2, p=0.088) were also higher than normocholesterolemic patients. Multivariate linear regression analysis showed that total cholesterol level was an independent factor of percent necrotic core volume in the culprit lesion after being adjusted with age, high density lipoprotein-cholesterol , hypertension, diabetes mellitus, smoking and acute coronary syndrome (beta 0.027, 95% confidence interval 0.02-0.053, p=0.037).ConclusionHypercholesterolemia was associated with increased necrotic core volume in coronary artery plaque. This study suggests that hypercholesterolemia plays a role in making plaque more complex, which is characterized by a large necrotic core, in coronary artery disease.

Impact of Metabolic Syndrome on Progression of Aortic Stenosis: Influence of Age and Statin Therapy

The aims of this study were to examine prospectively the relationship between metabolic syndrome (MetS) and aortic stenosis (AS) progression and to evaluate the effect of age and statin therapy on AS progression in patients with or without MetS. Despite the clear benefits of statin therapy in primary and secondary coronary heart disease prevention, several recent randomized trials have failed to demonstrate any significant effect of this class of drugs on the progression of AS. Previous retrospective studies have reported an association between MetS and faster AS progression. This predefined substudy included 243 of the 269 patients enrolled in the ASTRONOMER (AS Progression Observation: Measuring Effects of Rosuvastatin) trial. Follow-up was 3.4 ± 1.3 years. AS progression rate was measured by calculating the annualized increase in peak aortic jet velocity measured by Doppler echocardiography. Patients with MetS (27%) had faster stenosis progression (+0.25 ± 0.21 m/s/year vs. +0.19 ± 0.19 m/s/year, p = 0.03). Predictors of faster AS progression in multivariate analysis were older age (p = 0.01), higher degree of valve calcification (p = 0.01), higher peak aortic jet velocity at baseline (p = 0.007), and MetS (p = 0.005). Impact of MetS on AS progression was most significant in younger (< 57 years) patients (MetS: +0.24 ± 0.19 m/s/year vs. no MetS: +0.13 ± 0.18 m/s/year, p = 0.008) and among patients receiving statin therapy (+0.27 ± 0.23 m/s/year vs. +0.19 ± 0.18 m/s/year, p = 0.045). In multivariate analysis, the MetS-age interaction was significant (p = 0.01), but the MetS-statin use interaction was not. MetS was found to be a powerful and independent predictor of faster AS progression, with more pronounced impact in younger patients. These findings emphasize the importance of routinely identifying and treating MetS in AS patients. The apparent faster stenosis progression in the subset of normocholesterolemic patients with MetS receiving the statin will need to be confirmed by future studies.

Atorvastatin Improves Cardiovascular Status, but Does Not Prevent the Development of Dilated Cardiomyopathy in Streptozotocin‐induced Diabetic Rats

Therapy with statins is associated with a significant reduction of cardiovascular (CV) events in normo‐cholesterolemic diabetic patients. The mechanisms, however, remain unclear. We assessed the effects of 4‐week administration of atorvastatin (ATV, 10 mg/kg/day) on CV function in streptozotocin‐induced diabetic rats. Age‐matched, non‐diabetic rats were used as controls (CT). Systolic blood pressure (SBP) and echocardiographic parameters were evaluated. Previous reports from our laboratory showed that SBP is significantly higher in diabetic rats than in non‐diabetic rats. In the current study, ATV decreased SBP in diabetic rats by 14% (P&lt;0.05), whereas the drug did not modify this parameter in CT rats. ATV also increased stroke volume (from 0.20±0.02 to 0.51±0.06 ml, n=5, P&lt;0.05), ejection fraction (from 44.9±3 to 59.9%, n=5, P&lt;0.05), and cardiac output (from 63.6 ±7 to 145.5 ±17 ml/min, n=5, P&lt;0.05) in diabetic rats. In addition, ATV reduced left ventricular end systolic volume by 27% (P&lt;0.05), but failed to reduce left ventricular end diastolic volume. These results indicate that although ATV does not reverse ventricular dilatation, it has a positive hemodynamic effect on the CV system of diabetic rats. Thus, type 1 diabetic patients may benefit from ATV treatment beyond the reduction of cholesterol levels. Supported by MBRS‐RISE Grant R25‐GM061838.

Search and rescue for hypotheses surviving AIM-HIGH, the niacin therapy earthquake: Still problematic after the primary publication

Search and rescue for hypotheses surviving AIM-HIGH, the niacin therapy earthquake: Still problematic after the primary publication

Lipid transfers to HDL are predictors of precocious clinical coronary heart disease

Background High-density-lipoprotein (HDL) has several antiatherogenic properties and, although the concentration of HDL-cholesterol negatively correlates with incidence of coronary artery disease (CAD), this is not sufficient to evaluate the overall HDL protective role. The aim was to investigate whether precocious CAD patients show abnormalities in lipid transfers to HDL, a fundamental step in HDL metabolism and function. Methods Thirty normocholesterolemic CAD patients aged < 50 y and 30 controls paired for sex, age and B.M.I. were studied. Fasting blood samples were collected for the in vitro lipid transfer assay and plasma lipid determination. A donor nanoemulsion labeled with radioactive free-cholesterol, cholesteryl esters, phospholipids and triglycerides was incubated with whole plasma and after chemical precipitation of non-HDL fractions, supernatant was counted for radioactivity in HDL. Results LDL and HDL-cholesterol and triglycerides were equal in both groups. Transfers of free-cholesterol (3.8 ± 1.2%vs 7.0 ± 3.3%,p < 0.0001) and triglycerides (3.7 ± 1.7%vs 4.9 ± 1.9%, p = 0.0125) were diminished in CAD patients whereas cholesteryl ester transfer increased (6.5 ± 1.9%vs 4.8 ± 1.8%, p = 0.0008); phospholipid transfer was equal (17.8 ± 3.5% vs19.5 ± 3.9%). Conclusion Alterations in the transfer of lipids to HDL may constitute a new marker for precocious CAD and relation of this metabolic alteration with HDL antiatherogenic function should be investigated in future studies.

Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.

Statins Improve Cardiovascular Status in STZ‐Diabetic Rats

Statin therapy has been associated with improved cardiac status in normocholesterolemic diabetic patients. The underlying mechanisms remain unknown. We compared the effects of daily administration of 10mg/kg atorvastatin (AV), simvastatin (SV), or pravastatin (PV) on CV function of streptozotocin (STZ)-diabetic rats. Systolic blood pressure (SBP), and echocardiographic parameters were evaluated after 4 weeks of treatment. The effect of acute incubation with statins on the Ach-induced relaxation was also evaluated in NE-precontracted aortic rings. SBP was significantly higher in diabetic than in age-matched non-diabetic rats (CT). SV decreased SBP in diabetic rats by 21% (N=10, P<0.05), whereas AV and PV did not modify this parameter. Statins increased cardiac output (CO) by 112 % (AV), 137% (SV), and 75% (PV) (N=10, P<0.05). Stroke volume and ejection fraction were also significantly increased by all the statins. Furthermore, the EMAX value for the Ach-induced relaxation was reduced in diabetic rats (53.7±4%) when compared to CT (74.6±3%) (N=10, P<0.05), and acute incubation of aortic rings with AV (5μM, 45 min) increased EMAX to 71.5±5% (N=4, P<0.05). These results indicate that statins have positive hemodynamic effects in diabetic rats which may be secondary to improvement on endothelial function and reduction on vascular tone and systemic peripheral resistance. Supported by RCMI Grant G12RR03051

Low‐Dose Statin Therapy Improves Endothelial Function in Type 2 Diabetic Patients With Normal Serum Total Cholesterol: A Randomized Placebo‐Controlled Study

The authors sought to explore the effect of low-dose atorvastatin on endothelial function in normocholesterolemic patients with type 2 diabetes mellitus without evidence of coronary disease. Sixty patients with type 2 diabetes mellitus, normal serum cholesterol, and normal exercise test results were enrolled. Initial assessment was performed by measurement of the brachial artery diameter and flow velocity both at baseline and after induced hyperemia. Patients were randomly assigned to receive either atorvastatin 10 mg daily for 4 weeks (atorvastatin group=30 patients) or matched placebo for the same period (placebo group=30 patients). Follow-up assessment of the brachial artery diameter and flow velocity (both baseline and hyperemic) was performed after 4 weeks. Initially, no significant difference was found between the two groups regarding brachial artery diameter or flow velocity, both at baseline and at peak hyperemia (P>.05 for all). At follow-up, there was a significantly higher flow velocity at baseline (P<.05) and a significantly higher percent increase of brachial artery diameter (from baseline to peak hyperemia) in the atorvastatin group (P<.05). In patients with type 2 diabetes mellitus and normal serum cholesterol without evidence of coronary disease, low-dose atorvastatin improves endothelial function.

Effect of Atorvastatin on Haemostasis, Fibrinolysis and Inflammation in Normocholesterolaemic Patients with Coronary Artery Disease

Treatment with HMG-CoA reductase inhibitors (statins) reduces the morbidity and mortality of coronary artery disease (CAD). In addition to their lipid-lowering actions, pleiotropic effects of statins have been demonstrated. The aim of the present study was to assess if atorvastatin therapy has an impact on haemostasis, fibrinolysis and inflammation in normocholesterolaemic patients with CAD. Fifty-four patients with CAD who had received atorvastatin treatment for at least 8 weeks (mean dosage 30 mg/day) and 54 patients with CAD who had not received atorvastatin therapy were selected from a larger prospective, randomized, double-blind study for inclusion in this post hoc analysis. Patients were matched by their total cholesterol levels. All patients were normocholesterolaemic. In the atorvastatin-treated patients significantly lower plasma levels of thrombin-antithrombin complexes (p < 0.05), plasminogen activator inhibitor-1 activity (PAI-1) [p < 0.05], soluble vascular cell adhesion molecule-1 (p < 0.05), soluble platelet selectin (p < 0.05) and high-sensitivity C-reactive protein (p < 0.05) were measured compared with patients not on atorvastatin therapy. Additionally, a strong trend towards lower soluble intercellular adhesion molecule-1 plasma levels was detected in patients treated with atorvastatin. No differences were found in tissue-type plasminogen activator antigen, plasmin-plasmin inhibitor complexes, fibrinogen, D-dimer and activated factor XII values. Atorvastatin appears to have an effect on coagulation activation, fibrinolysis and inflammation in patients with CAD. Reduction in PAI-1 and reduced thrombin formation may have an impact on cardiovascular morbidity and mortality in patients with CAD.

Standard-Dose Statin Therapy Provides Incremental Clinical Benefits in Normocholesterolemic Diabetic Patients

Randomized trials have established statins as an agent for prevention of coronary heart disease (CHD). The purpose of this study was to assess the hypothesis that standard-dose statin therapy has a beneficial effect in normocholesterolemic diabetic patients with CHD. A prospective, randomized, open, blinded-endpoint trial was conducted from 2002 to 2004 at 55 hospitals in Japan to evaluate the effect of statins on subsequent cardiovascular events. A total number of 1,016 CHD patients (301 patients with type 2 diabetes mellitus [DM] and 715 non-DM patients) with serum total cholesterol levels of 180-240 mg/dl were randomly divided into non-statin and statin treatments. Clinical parameters were comparable between DM and non-DM groups. Serum low-density lipoprotein (LDL)-cholesterol levels were equally decreased after statin treatment in the 2 groups. Statin treatment improved prognosis in both the DM and non-DM groups; however, the number needed to treat (NNT) and relative risk reduction (RRR) were remarkable especially in the DM group (NNT=8, RRR=67%) compared with the non-DM group (NNT=30, RRR=24%). Standard-dose statin therapy provides incremental clinical benefits in DM patients with normal cholesterol levels compared with non-DM patients. The data suggest that DM patients may enjoy the pleiotropic effects of statins, independent of the LDL-cholesterol lowering effects of these agents.