| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Statins and low-density lipoprotein cholesterol levels Cohen, J. S. (2003), Am J Med 115(1): 74-5; author reply 75-6. |
| Statins and stroke: evidence for cholesterol-independent effects Di Napoli, P., A. A. Taccardi, et al. (2002), Eur Heart J 23(24): 1908-21. |
| Statins do more than just lower cholesterol Vaughan, C. J., M. B. Murphy, et al. (1996), Lancet 348(9034): 1079-82. |
| Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice Frolkis, J. P., G. L. Pearce, et al. (2002), Am J Med 113(8): 625-9. Abstract: BACKGROUND: Statins have become a mainstay in the treatment of hyperlipidemia, based on their potency and favorable side-effect profile. Drug choice is presumed to be guided by the estimated degree of low-density lipoprotein (LDL) cholesterol lowering required in a particular patient and the projected efficacy of any drug-dose combination, as contained in the package inserts for each medication. We investigated whether these expectations were met in a clinical practice. METHODS: Data were analyzed for 367 hyperlipidemic patients in a preventive cardiology practice who were not taking statins at entry, who were given a standard statin dose at their first visit, and who had at least one follow-up visit on the same drug/dose. Expected LDL cholesterol reductions were calculated for each patient based on guidelines in the package inserts for each drug. RESULTS: The mean (+/-SD) observed LDL cholesterol reduction of 26% +/- 20% was significantly less than expected (34% +/- 7%, P < 0.001). The ratio of observed to expected reduction was not different for the three statins used (atorvastatin, 0.79 +/- 0.48; simvastatin, 0.88 +/- 0.61; pravastatin, 0.75 +/- 0.69; P = 0.39). CONCLUSIONS: The use of statins in a clinical practice led to observed reductions in LDL cholesterol level that were significantly less than those projected by package insert guidelines. We believe this gap reflects the reduced patient compliance frequently observed in clinical practice settings, rather than any inherent difference in statin responsiveness of a practice versus a trial population. Physicians should be aware of this disparity when using statins in the clinical setting. |
| Statins for cardiovascular prevention. Lowering LDL cholesterol, the primary objective Fruchart, J. C. (2002), Presse Med 31(30): 1428-33. Abstract: A MAJOR CARDIOVASCULAR RISK FACTOR: LDL-cholesterol is unquestionably the principle cardiovascular risk factor, showing a continuous relationship without threshold value with the incidence of cardiovascular events. Interventional studies conducted with statins showed a significant reduction in cardiovascular risk and total mortality, which was enhanced when the absolute risk was high in the population studied. Moreover, there was a linear relationship between the decrease in cholesterol and the reduction of coronary events. FOR OPTIMAL CARDIOVASCULAR PREVENTION: Many arguments are in favor of a drastic reduction in LDL-cholesterol (< 1 g/l) for secondary prevention and in patients at high vascular risk (absolute cardiovascular risk greater than 20% over 10 years), without the possibility, today, of clearly defining the optimal target level in these patients. However, in daily practice the therapeutic aims established by national and international recommendations are rarely reached, as is shown by several epidemiological surveys. NEW THERAPEUTIC STRATEGIES: To obtain even lower levels of LDL-cholesterol, two strategies are possible, either combined with other hypolipidemic substances, such as intestinal cholesterol absorption inhibitors, or administration of more potent statins (rosuvastatin, pitavastatin). Nonetheless, the other risk factors must also be treated in order to reduce the patients' global cardiovascular risk score. |
| Statins for heart failure: at the crossroads between cholesterol reduction and pleiotropism? von Haehling, S. and S. D. Anker (2005), Heart 91(1): 1-2. Abstract: Statins are being hailed as the new aspirin--but are they beneficial for patients with heart failure? |
| Statins in coronary artery disease: beyond cholesterol reduction Gambhir, D. S. and J. Gambhir (1997), Indian Heart J 49(3): 257-61. |
| Statins inhibit synthesis of an oxysterol ligand for the liver x receptor in human macrophages with consequences for cholesterol flux Wong, J., C. M. Quinn, et al. (2004), Arterioscler Thromb Vasc Biol 24(12): 2365-71. Abstract: OBJECTIVE: Cholesterol efflux from macrophages in the artery wall, a key cardioprotective mechanism, is largely coordinated by the nuclear oxysterol-activated liver X receptor, LXRalpha. We investigated the effect of statins on LXR target gene expression and cholesterol efflux from human macrophages. METHODS AND RESULTS: In human macrophages (THP-1 cell line and primary cells), the archetypal statin, compactin, greatly reduced mRNA levels of 2 LXR target genes, ABCA1 and ABCG1 mRNA, as well as decreased cholesterol efflux. Commonly prescribed statins also downregulated LXR target gene expression in THP-1 cells. We provide several lines of evidence indicating that statins decrease expression of LXR target genes by inhibiting the synthesis of an oxysterol ligand for LXR, 24(S),25-epoxycholesterol. When THP-1 cells were cholesterol-loaded via incubation with acetylated low-density lipoprotein, synthesis of 24(S),25-epoxycholesterol was greatly reduced and the downregulatory effect of compactin on ABCA1 mRNA levels and cholesterol efflux was lost. CONCLUSIONS: Our results suggest that statins may downregulate cholesterol efflux from nonloaded human macrophages by inhibiting synthesis of an oxysterol ligand for LXR. Further work is needed to determine how relevant our observations are to arterial foam cells in vivo. |
| Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol Sukhova, G. K., J. K. Williams, et al. (2002), Arterioscler Thromb Vasc Biol 22(9): 1452-8. Abstract: OBJECTIVE: Some of the statin-induced reduction in cardiac events in patients with atherosclerosis may be derived from mechanisms independent of lipid lowering. This study tested in nonhuman primates whether statins can influence inflammation (indicated by vascular cell adhesion molecule-1, interleukin-1beta, tissue factor, and macrophages) and features of plaque stability (indicated by collagen and smooth muscle cells) independent of their effect on plasma cholesterol level. METHODS AND RESULTS: Adult male cynomolgus monkeys (n=12 per group) consumed an atherogenic diet for 12 months while receiving (1) no treatment (control), (2) pravastatin (Prava, 40 mg/kg per day), or (3) simvastatin (Simva, 20 mg/kg per day). Dietary cholesterol was adjusted to equalize plasma cholesterol levels among groups. Although the intima/media ratio in the abdominal aorta did not differ among groups, drug treatment reduced inflammation and features of plaque vulnerability. Macrophage content in the lesions of statin-treated animals was lowered (2.4-fold with Prava and 1.3-fold with Simva; both P<0.001 versus control). Furthermore, lesions had approximately 2-fold less vascular cell adhesion molecule-1, interleukin-1beta, and tissue factor expression in statin-treated versus control animals (P<0.005). Lesional smooth muscle cell and collagen content was 2.1-fold greater in the Prava-treated group (P<0.001) and 1.5-fold greater in the Simva-treated group (P<0.005) than in the control group. CONCLUSIONS: In primates, these results provide further support for the beneficial effect of statins on plaque inflammation and stability in addition to cholesterol lowering. |
| Statins, cholesterol, and mevalonate pathways? Lewis, L. S. (1996), Lancet 347(9000): 551. |
| Statins, cholesterol, Co-enzyme Q10, and Parkinson's disease Lieberman, A., K. Lyons, et al. (2005), Parkinsonism Relat Disord 11(2): 81-4. Abstract: 'Statins', drugs that lower cholesterol are widely used. Statins block cholesterol in the body and brain by inhibiting HMG-Co-A reductase. This pathway is shared by CoQ-10. An unintended consequence of the statins is lowering of CoQ-10. As CoQ-10 may play a role in PD, its possible statins may worsen PD. Such a report has appeared. Statins came into wide use in 1997-1998, 6 years before our study began. Thus 74% of our patients on a statin had a PD duration of 1-6 years versus 56% of our patients not on a statin. A direct comparison of patients on a statin and not on a statin would bias the study in favor of the statins: patients on a statin would have a shorter disease duration and less advanced PD. Therefore we divided the patients into two groups. Group I consisted of 128 patients on a statin, and 252 not on a statin who had PD for 1-6 years. In this group, disease severity (Hoehn & Yahr Stage), levodopa dose, Co-enzyme Q10 use, prevalence of 'wearing off', dyskinesia and dementia were similar. Group II consisted of 45 patients on a statin and 200 patients not on a statin who had PD for 7-22 years. In this group disease severity, levodopa dose, Co-enzyme Q10 use, prevalence of wearing off, dyskinesia and dementia were similar. Statins although they may affect Co-enzyme Q10 levels in the body and the brain, do not worsen PD at least as assessed by stage, and prevalence of wearing-off, dyskinesia, and dementia. |
| Statins, super-statins and cholesterol absorption inhibitors Brousseau, M. E. (2003), IDrugs 6(5): 458-63. Abstract: An elevated level of low-density lipoprotein cholesterol (LDL-C) is an independent risk factor for premature coronary heart disease (CHD), with a value of > or = 160 mg/dl designated as high-risk by the National Cholesterol Education Program Adult Treatment Panels I, II and III. Current goals of therapy for all patients with elevated LDL-C include reducing levels to: (i) < 160 mg/dl in those with < or = 1 CHD risk factor; (ii) < 130 mg/dl in those with more than or equal to 2 CHD risk factors; and (iii) < 100 mg/dl in patients with established CHD or CHD risk equivalents, one of which is diabetes. The discovery of drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis, constituted a major advance in the treatment of patients with elevated plasma concentrations of LDL-C. The efficacy of statins in LDL-lowering and CHD risk reduction has clearly been demonstrated in a number of primary and secondary intervention trials. Emerging options for the treatment of patients with elevated LDL-C include the super-statins rosuvastatin and pitavastatin, as well as the cholesterol absorption inhibitor ezetimibe. This article reviews large-scale clinical trials in which statins have been used to reduce LDL-C concentrations. Studies that have examined the efficacy and safety of rosuvastatin, pitavastatin and ezetimibe will also be discussed. |
| Status incongruence and serum cholesterol in an English general practice Dressler, W. W., P. Evans, et al. (1992), Soc Sci Med 34(7): 757-62. Abstract: The relationship between status incongruence and serum cholesterol was examined in a case-control study carried out in an English general practice population. Patients (n = 54) with elevated serum cholesterols (greater than or equal to 7.0 mmol/l) were compared to age and sex matched controls (n = 54). A specific type of status incongruence--lifestyle incongruity--was measured as the degree to which style of life (material consumption and status-enhancing behaviors) exceeded occupational status. Lifestyle incongruity was associated with higher serum cholesterol and an increased odds of being a case. This association was independent of age, sex, the body mass index, family history of cardiovascular disease, alcohol use, and, for women, menopausal status. Implications of these results for research on social inequality and the risk of cardiovascular disease are discussed. |
| Steady-state detection of cholesterol contained in the plasma membrane of a single cell using lipid bilayer-modified microelectrodes incorporating cholesterol oxidase Devadoss, A. and J. D. Burgess (2004), J Am Chem Soc 126(33): 10214-5. |
| Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure Sun, Y., M. Hao, et al. (2003), J Biol Chem 278(8): 5813-20. Abstract: Liver X receptor/retinoid X receptor (LXR/RXR) transcription factors have been found to induce a number of genes involved in the regulation of cellular cholesterol efflux, including the ATP-binding cassette transporter A1 (ABCA1), which mediates the active efflux of cellular cholesterol and phospholipids to extracellular acceptors, such as apolipoprotein A-I (apoA-I). In a screen for macrophage LXR/RXR target genes, we identified stearoyl-CoA desaturases 1 and 2 (Scd1 and Scd2), and subsequently tested the hypothesis that SCD activity might modulate cellular cholesterol efflux. In HEK 293 cells co-transfection of ABCA1 with either SCD1 or SCD2 inhibited ABCA1-mediated cholesterol efflux but not phospholipid efflux. In Chinese hamster ovary (CHO) cells with moderate stable overexpression of SCD1, cholesterol efflux to apoA-I was inhibited by 73%, whereas phospholipid efflux and ABCA1 protein levels were unchanged. In contrast, cholesterol efflux to HDL(2), which is not dependent on ABCA1, was increased 2-fold in CHO-SCD1 cells. The effect of SCD on cholesterol efflux to apoA-I was independent of acyl-CoA:cholesterol acyltransferase (ACAT) activity. SCD activity led to an increased content of plasma membrane monounsaturated fatty acids (18:1) at the expense of saturated fatty acids (18:0). As shown by confocal microscopy, SCD overexpression led to a decrease of Triton X-100-resistant domains in the plasma membrane, indicating a decrease in membrane-ordered regions. The data suggest that SCD changes membrane organization and depletes a specific pool of membrane cholesterol supporting ABCA1-mediated efflux, whereas increasing availability of cholesterol for passive efflux by HDL(2). ABCA1-mediated cholesterol and phospholipid efflux may be uncoupled in pathological states associated with high SCD activity, as in hyperinsulinemic obese mice, or in animals treated with LXR activators. |
| Stereology of the myocardium and blood biochemistry in aged rats fed with a cholesterol-rich and canola oil diet (n-3 fatty acid rich) Aguila, M. B., M. I. Rodrigues-Apfel, et al. (1998), Basic Res Cardiol 93(3): 182-91. Abstract: The myocardial changes brought about by canola oil (n-3 fatty acid rich) and hyperlipidic diets were studied in 45 rats. Three groups each consisting of 15 animals was separated into (A) which receiving a normal balanced diet; and in groups (CHO) and (O) the animals receiving hyperlipidic and canola oil diet, respectively. These diets were fed to the animals from 21 days until 15 months old, then a blood analysis was performed, after which they were sacrificed and the hearts taken for light microscopic studies. The total lipids serum was extracted and the low density lipoproteins (LDL-C and VLDL-C) and chylomicron fractions were determined as well as the cholesterol concentration in the high density lipoprotein fraction (HDL-C). The myocardium was composed of myocytes and cardiac interstitium, which is made up of connective tissue and blood vessels. The following stereological parameters were determined: a) from myocyte: volume density of myocyte, total volume of myocytes surface density of myocyte, total surface of myocyte and cross sectional area of myocyte; b) from blood vessels: volume density of blood vessels, total volume of blood vessels, length density of blood vessels, surface density of blood vessels, total surface of blood vessels and cross sectional area of vessels; c) from connective tissue: volume density of connective tissue and total volume of connective tissue. The differences were tested by the analysis of variance and Tukey test. The Mantel-Haenezel test analyzed the survival curve test comparing the different groups. Many stereological parameters had significant differences: cardiac weight, thickness of the right and left ventricular wall, aorta and pulmonary artery inner diameters. HDL-C, LDL-C, volume density of myocyte, total surface of myocyte, surface density of myocyte, total surface of myocyte, total volume of blood vessel, length density of blood vessels, surface density of blood vessels, total surface of blood vessels, volume density of connective tissue, total volume of connective tissue. Differences in survival curves were significant between groups CHO x A and CHO x O (p < 0.05) but not between groups A x O (p = 0.48). For the cardiac weight, the smallest values were found in group O. The aorta and artery pulmonary internal diameters were smaller in group CHO. The HDL-C serum was about 40% greater in group O. The LDL-C serum was more than 80% less in the same group. The average of volume density of myocyte was less in group CHO, while the average of volume density of connective tissue was greater in group CHO in comparison to groups A and O. The length density of blood vessels was greater in group O than in groups A and CHO. The surface density of myocyte and surface density of blood vessels were smaller in group CHO and greater in group A. The total surface of myocyte and total surface of blood vessels were greater in group CHO and smaller in group O. Differences were significant between groups A x CHO. The total volume of myocytes was greater in group A, while the total volume of connective tissue was greater in group CHO. The cross sectional area of myocyte and cross sectional area of vessels were greater in group CHO and smaller in group O suggesting that the canola oil diet (n-3 fatty acid rich) preserves the myocardium more than the standard and cholesterol-rich diets. |
| Stereoselective interactions of a specialized antibody with cholesterol and epicholesterol monolayers Izhaky, D. and L. Addadi (2000), Chemistry 6(5): 869-74. Abstract: The stereoselective recognition by monoclonal antibodies of two-dimensional monolayers of cholesterol spread at the air-water interface is presented. Using immunofluorescence, we show that one antibody, raised and selected against crystals of cholesterol monohydrate, specifically recognizes monolayers of cholesterol, but not monolayers of epicholesterol--its epimeric form. This demonstrates that stereoselective recognition also applies to protein-surface interactions. |
| Stereoselective recognition of monolayers of cholesterol, ent-cholesterol, and epicholesterol by an antibody Geva, M., D. Izhaky, et al. (2001), Chembiochem 2(4): 265-71. Abstract: The interaction between a monoclonal antibody and four distinct monolayers with varying degrees of structural, chemical, and stereochemical similarity were studied and quantified. The antibody, raised and selected against cholesterol monohydrate crystals, interacts with cholesterol monolayers stereospecifically, but not enantiospecifically. Monolayers of ent-cholesterol molecules, which are chemically identical to cholesterol and whose structure is the exact mirror image of the cholesterol monolayer, interact with the antibody to the same extent as the cholesterol monolayers. The affinity of the antibody for both enantiomeric monolayers is extremely high. However, the antibody does not interact with monolayers of epicholesterol, which is an epimer of cholesterol: The hydroxy group in epicholesterol is in the 3alpha position rather than in the 3beta position, imposing a different angle between the hydroxy group and the rigid steroid backbone, and a different packing of the molecules. Monolayers of triacontanol, a long-chain primary aliphatic alcohol, interact with the antibody to a lesser extent than the cholesterol and ent-cholesterol monolayers, presumably due to the structural flexibility of the triacontanol molecule. The lack of chiral discrimination by the antibody is thus correlated to the level at which the chirality is exposed at the surface of the monolayers. |
| Stereospecificity of the inhibition by etomoxir of fatty acid and cholesterol synthesis in isolated rat hepatocytes Agius, L., E. J. Meredith, et al. (1991), Biochem Pharmacol 42(9): 1717-20. Abstract: The racemates of substituted 2-oxiranecarboxylates are potent inhibitors of fatty acid oxidation and fatty acid and cholesterol synthesis. We show in the accompanying paper Agius L, Peak M and Sherratt HSA, Biochem Pharmacol 42: 1711-1715, 1991 that only the R-enantiomer of etomoxir, a potent hypoglycaemic compound, inhibits fatty acid oxidation in hepatocytes. We demonstrate in this paper that although the R-enantiomer of etomoxir is esterified to its CoA-ester more readily than the S-enantiomer, both the R- and S-enantiomers are equally potent inhibitors of fatty acid and cholesterol synthesis from acetate in rat hepatocytes. The inhibition of fatty acid synthesis is not due to direct inhibition of fatty acid synthetase and the inhibition of cholesterol synthesis occurs at a site proximal to formation of mevalonate. Since the S-enantiomer inhibits fatty acid and cholesterol synthesis but not fatty acid oxidation the inhibition of the biosynthetic pathways is not coupled to inhibition of fatty acid oxidation. |
| Steroid saponins from fenugreek seeds: extraction, purification, and pharmacological investigation on feeding behavior and plasma cholesterol Petit, P. R., Y. D. Sauvaire, et al. (1995), Steroids 60(10): 674-80. Abstract: The seeds of fenugreek (Trigonella foenum graecum L.) are traditionally assumed to have restorative properties. We have recently shown that a fenugreek seed extract containing steroid saponins increased food consumption and induced hypocholesterolemia in rats. This study aims to investigate the specific role of purified steroid saponins in these properties. For this purpose, an original technique for extraction and purification of steroid saponins was carried out. Thereafter, the effects of these steroid saponins were investigated on feeding behavior and metabolic endocrine changes in normal and diabetic rats. All the steroid saponins (furostanol type) were extracted from the seeds and separated from all other constituents of the entire extract by using several purification procedures to give an extract containing at least 90% of steroid saponins. Pharmcological experiments were performed in vivo in normal and streptozotocin diabetic rats: steroid saponins were administered chronically mixed with food (12.5 mg/day per 300 g body weight). Our data show that the treatment with steroid saponins significantly increased food intake and the motivation to eat in normal rats, while modifying the circadian rhythm of feeding behavior; it also stabilized the food consumption in diabetic rats, which resulted in a progressive weight gain in these animals, in contrast to untreated diabetic controls. Both in normal and diabetic rats, steroid saponins decreased total plasma cholesterol without any change in triglycerides. In conclusion, the present work reports a clear methodology to obtain all the steroid saponins and demonstrates that these saponins enhance food consumption and motivation to eat, and reduce plasma cholesterol levels in rats. |