Cholesterol Journal Articles

Record 2561 to 2580

Cholesterol levels: coronary heart disease and mortality in men and women
Drown, D. J. (1996), Prog Cardiovasc Nurs 11(1): 41.

Cholesterol limits estrogen uptake by liposomes and erythrocyte membranes
Jacobsohn, M. K., S. Bauder, et al. (1994), Biochim Biophys Acta 1195(1): 131-40.
Abstract: Multilamellar vesicles (MLV) were prepared from phospholipids with and without cholesterol in equimolar amounts and 4-14Cestradiol. Unincorporated estrogen was removed by petroleum ether extraction or by aqueous buffer washes. In either case, cholesterol-containing vesicles incorporated one-half the estradiol as vesicles without sterol. Addition of estradiol to preformed vesicles followed by buffer washes showed that vesicles without cholesterol invariably retained more estradiol than those with the sterol. Reduction of the cholesterol content to one-half increased estradiol incorporation. The pattern of estradiol removal from MLV with successive buffer washes indicated that much of the steroid associated with cholesterol-containing vesicles was superficially bound to the membrane but vesicles without cholesterol incorporated the estrogen into the bilayer structure. To test the role of cholesterol in limiting the uptake of an estrogen by cells, right-side out resealed ghosts of ox erythrocytes were prepared. They were partially depleted of cholesterol by exposure to small unilamellar vesicles of dioleoylphosphatidyl choline. A decrease in cholesterol content correlates with an increase in estradiol uptake by red cell ghosts. The experiments described point to a central role of cholesterol in limiting the uptake of steroids. The loss of cholesterol of steroid producing cells caused by tropic hormones may be key to their mode of action in promoting secretion of steroid hormones. Likewise, the long-term genomic responses of steroid target cells may depend upon their cholesterol content and the ease by which the steroid can penetrate the membrane barrier.

Cholesterol lipoproteins, triglycerides, rural-urban differences and prevalence of dyslipidaemia among males in Rajasthan
Gupta, R., H. Prakash, et al. (1997), J Assoc Physicians India 45(4): 275-9.
Abstract: To develop profiles of serum cholesterol lipoproteins and triglycerides, influence of rural versus urban lifestyle in their levels and prevalence of dyslipidaemias, we studied cohorts of male population in Rajasthan. Fasting blood samples were obtained from 401 men (age range 20-73 years) randomly selected from a larger sample of 3397 during a comprehensive cardiovascular risk factor survey in rural (202 men) and urban (199 men) populations. Serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides (TG) were determined and correlated with age and anthropometric variables. The lipid levels were classified according to US National Cholesterol Education Program (NCEP) guidelines. The mean +/- SD levels in mg/dl were, total cholesterol 170.5 +/- 40, LDL cholesterol 102.1 +/- 36, HDL cholesterol 43.6 +/- 12 and TG 124.0 +/- 50. The mean levels in rural vs. urban population were total cholesterol 165 +/- 37 vs. 176 +/- 43 (p = 0.008), LDL cholesterol 97 +/- 33 vs. 108 +/- 39 (p = 0.003), HDL cholesterol 44 +/- 13 vs. 43 +/- 12 (p = 0.44) and TG 122 +/- 46 vs 126 +/- 55 (p = 0.41). There was significant positive correlation of age and body-mass index with total and LDL cholesterol and triglycerides but not with HDL cholesterol. When classified according to the NCEP guidelines high total cholesterol (> or = 240 mg/dl) and LDL cholesterol (> or = 160 mg/dl) was in 33 (8.3%). Borderline high total cholesterol (200-239) was in 64 (16%) and borderline high LDL cholesterol (130-159) in 55 (13.7%). Borderline high triglyceride (200-400 mg/dl) was in 33 (8.2%) and severe hypertriglyceridaemia in none. Low HDL cholesterol (< 35 mg/dl) was in 96 (23.9%) and protective level of HDL cholesterol (> or = 60 mg/dl) in 47 (11.7%). In urban as compared to rural men the prevalence of hypercholesterolaemia > 200 mg/dl (28% vs 22%) and hyper LDL cholesterolaemia (26% vs 18%) were significantly more.

Cholesterol loading induces a block in the exit of VSVG from the TGN
Ying, M., S. Grimmer, et al. (2003), Traffic 4(11): 772-84.
Abstract: Recent work from our laboratory demonstrated that increased cellular cholesterol content affects the structure of the Golgi apparatus. We have now investigated the functional consequences of the cholesterol-induced vesiculation of the Golgi apparatus and the role of actin for these changes. The results showed that cholesterol-induced vesiculation and dispersion of the Golgi apparatus is a reversible process and that reversal can be inhibited by cytochalasin D, an actin-disrupting reagent. Furthermore, electron microscopy revealed that jasplakinolide, which stabilizes actin filaments, prevented the dispersion, but not the vesiculation of the Golgi cisternae. Importantly, the different Golgi markers seemed to be separated even after vesiculation. To investigate whether transport through the different steps of the exocytic pathway was affected in cholesterol-treated cells, we visualized ER to plasma membrane transport by using ts045-VSVG-GFP. In COS-1 cells expressing ts045-VSVG-GFP increased cholesterol levels did not affect transport of VSVG into the vesiculated Golgi apparatus. However, increased levels of cholesterol resulted in retention of the nascent G protein in vesicles with the TGN-marker TGN46. Biotinylation of cell surface molecules to quantify arrival of VSVG at the plasma membrane confirmed that cholesterol treatment inhibited export of the VSVG protein. In conclusion, the data show that transport of VSVG into/through a vesiculated Golgi is feasible, but that cholesterol loading inhibits exit of VSVG from the vesicles containing TGN markers. Furthermore, the data illustrate the importance of actin filaments for Golgi structure.

Cholesterol loading of macrophages leads to marked enhancement of native lipoprotein(a) and apoprotein(a) internalization and degradation
Bottalico, L. A., G. A. Keesler, et al. (1993), J Biol Chem 268(12): 8569-73.
Abstract: Lipoprotein(a) levels in the plasma are strongly correlated with atherosclerotic coronary artery disease. Although the mechanism of this effect is not known, the interaction of lipoprotein(a) with macrophages may be important. Previous work has shown that macrophages in culture internalize and degrade native lipoprotein(a) poorly. In the present study, the interaction of Lp(a) with mouse peritoneal and human monocyte-derived macrophages that were cholesterol-loaded, such as occur in atheromata, was investigated. 125I-Lp(a) degradation was increased 4-5-fold in macrophages that had been loaded with cholesterol by incubation with acetyl-LDL for 2-4 days. The enhanced degradation of Lp(a) by foam cells was chloroquine-sensitive and dependent upon the presence of calcium in the extracellular medium. Incubation of the macrophages with acetyl-LDL plus an inhibitor of acyl CoA:cholesterol acyltransferase, which increased the free cholesterol content and decreased the cholesteryl ester content of the cells, resulted in an even greater up-regulation of 125I-Lp(a) degradation (8-23-fold over control macrophages). The interaction of Lp(a) with cholesterol-loaded macrophages involved the apoprotein(a) moiety of Lp(a) since 125I-apoprotein(a), but not 125I-Lp(a-), was degraded to a much greater extent by foam cells compared to control macrophages. The uptake and degradation of Lp(a) in foam cells was not mediated by LDL, scavenger, LDL receptor-related protein (LRP), or plasminogen receptors. Thus, cholesterol loading of macrophages markedly enhances the internalization and lysosomal degradation of Lp(a) and apo(a) by a calcium-dependent receptor activity different from known lipoprotein receptors.

Cholesterol localization in ultrathin frozen sections in Schnyder's corneal crystalline dystrophy
Rodrigues, M. M., H. S. Kruth, et al. (1990), Am J Ophthalmol 110(5): 513-7.
Abstract: We examined a 57-year-old woman who had bilateral corneal crystalline deposits associated with xanthelasma. The patient's son had bilateral stromal haze. Plasma cholesterol and apolipoprotein A-I and B levels were normal. Histopathologic examination disclosed lipid deposits, particularly in the superficial stroma and Bowman's layer. These deposits stained with oil red O and filipin, a fluorescent probe that specifically detects unesterified cholesterol. Cryoultramicrotomy disclosed more specific ultrastructural localization of unesterified cholesterol with an array of crystals resembling multiple plates in extracellular corneal tissue.

Cholesterol lowering action of HOE 402 in the normolipidemic and hypercholesterolemic golden Syrian hamster
Hoffmann, A., M. Schmalz, et al. (1996), Biochim Biophys Acta 1299(1): 95-102.
Abstract: The potent hypolipidemic activity of HOE 402 (4-amino-2-(4, 4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl) carboxamide monohydrochloride), which was previously demonstrated in rat and rabbit, was investigated in noncholesterol and cholesterol fed male hamsters. In normolipidemic hamsters fed a low cholesterol chow diet containing 0.10% or 0.15% HOE 402 for 3 weeks, the plasma total cholesterol level fell by 13% and 20% respectively, but no effect on hepatic total cholesterol content was detected. Hepatic sterol synthesis was increased 3-fold in hamsters fed 0.15% HOE 402. In hamsters fed a chow diet containing 0.25% cholesterol for 3 weeks, the plasma cholesterol level increased to 226 mg/dl (compared to 123 mg/dl in their chow fed controls) and the liver cholesterol content was 26.2 mg/g compared to 2.3 mg/g in the control group. However, 0.15% HOE 402 led to a 48% reduction and 0.20% HOE 402 to a 80% reduction, in total hepatic cholesterol concentration. There was a 43% fall in plasma cholesterol level being observed with the higher HOE 402 dose. Using the dual isotope plasma ratio method, no inhibition of intestinal cholesterol absorption by HOE 402 was found, either in the noncholesterol fed or in the cholesterol fed hamsters. Cholesterol feeding diminished the whole LDL animal clearance to 393 +/- 17 microliters/h per 100 g animal (control 666 +/- 81 microliters/h per 100 g). When treated with 0.20% HOE 402, the whole animal LDL clearance rate was enhanced 2.3-fold to 824 +/- 66 microliters/h per 100 g. In the hamsters fed 0.25% cholesterol alone whole liver LDL receptor activity was suppressed to 63 +/- 5%, compared to that in the untreated controls (100%). The addition of 0.20% HOE 402 to the cholesterol enriched diet not only reversed this suppression, but resulted in a marked stimulation of liver receptor activity to 165 +/- 15% (whole body LDL receptor activity 141 +/- 10%). These results indicate that HOE 402 exerts its lipid lowering effect by a more direct activation on hepatic LDL receptor activity rather than by an indirect intestinal effect on cholesterol absorption.

Cholesterol lowering after participation in the Scandinavian Simvastatin Survival Study (4S) in Finland
Strandberg, T. E., S. Lehto, et al. (1997), Eur Heart J 18(11): 1725-7.
Abstract: BACKGROUND: Patient compliance is crucial for the effectiveness of preventive medication. The aim of the study was to investigate changes in serum cholesterol levels and the use of cholesterol lowering drugs one year after the end of the Scandinavian Simvastatin Survival Study (4S), a randomized secondary prevention study of coronary heart disease with simvastatin and placebo. METHODS AND RESULTS: A questionnaire asking the current use of cholesterol lowering drugs, most recent serum cholesterol value and attitudes towards cholesterol lowering was sent to 785 surviving 4S participants in four 4S centres in Finland. The response rate was 94%. The current use of cholesterol lowering drugs and the reported mean serum cholesterol values were similar to the original simvastatin and placebo groups. In all, 74% (n = 546) reported that they had used cholesterol lowering drugs after the study, and 63% (n = 467) were currently using them, mostly simvastatin (96%) with an average dose of 14 (SD 5) mg.day-1. Cholesterol lowering was considered to be 'very important' by 53% and 'important' by 37% of the respondents. The most frequent reasons for discontinuation were 'drug costs' (38%) and 'normal cholesterol values' (30%). The reported mean serum cholesterol levels were 5.1 (SD 1.0) and 5.7 (SD 1.1) mmol-1 in the current cholesterol lowering drug users and non-users, respectively (P < 0.0001). The in-trial treatment goal of serum cholesterol (< or = 5.2 mmol-1) was not met in 38% of the users and in 68% of the non-users of cholesterol lowering drugs. CONCLUSION: One year post-trial the original simvastatin and placebo groups of the 4S had become similar with regard to the use of cholesterol lowering drugs and serum cholesterol levels. The adherence to medication, however, still remained relatively high, but there was a shift toward lower doses, and consequently toward higher post-trial serum cholesterol levels.

Cholesterol lowering and bile acid excretion in the hamster with cholestyramine treatment
Suckling, K. E., G. M. Benson, et al. (1991), Atherosclerosis 89(2-3): 183-90.
Abstract: Cholestyramine was administered to hamsters at 6 doses in the diet for 1 week. Plasma cholesterol, LDL + VLDL cholesterol and HDL cholesterol were measured after this period. Bile acid excretion was measured in faeces collected over the final 24 h of the experiment. A dose-response curve for each parameter measured was constructed using data from individual hamsters. For the bile acid and the cholesterol measurements a maximum response was observed at the highest doses. A correlation between the bile acids excreted over 24 h and the LDL + VLDL cholesterol showed that the maximum effect of cholestyramine on lowering plasma and lipoprotein cholesterol occurred at a submaximal excretion level of bile acids. Comparison of the efficiency of cholestyramine in reducing plasma cholesterol in the hamster with limited data in the dog and in man suggest that a greater lowering of plasma cholesterol is achieved in the dog and in man for an equivalent increase in bile acid excretion caused by the sequestrant. As is already known, cholestyramine treatment caused an increase in hepatic cholesterol 7 alpha-hydroxylase and HMG-CoA reductase activity. Interestingly in this study the novel observation was made that the bile acid sequestrant reduced the activity of hepatic acyl-CoA: cholesterol acyltransferase.

Cholesterol lowering and cerebrospinal fluid neurotransmitters: increased levels of the anxiogenic cholecystokinin-tetrapeptide during simvastatin administration to healthy male volunteers
Eriksson, M., T. Eklundh, et al. (1996), Biol Psychiatry 40(4): 302-4.

Cholesterol lowering and CHD prevention: time to get on with it
Betteridge, D. J. (1994), Br J Clin Pract 48(3): 115-7.

Cholesterol lowering and coronary artery disease: mechanisms of risk reduction
Archbold, R. A. and A. D. Timmis (1998), Heart 80(6): 543-7.

Cholesterol lowering and endothelial function
Vogel, R. A. (1999), Am J Med 107(5): 479-87.
Abstract: The pathophysiology of the association between cholesterol and atherosclerosis has been thought to involve the deposition, modification, and cellular uptake of cholesterol. We now believe that the process begins with vascular injury and involves inflammation and vessel remodeling. The vascular endothelium actively regulates vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth, all of which are important factors in the development of atherosclerosis. Endothelial dysfunction promotes atherosclerosis through vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and cytokine and growth factor stimulation and release. An important component of endothelial dysfunction is reduced availability of nitric oxide, which is caused by low-density lipoproteins, especially if they are oxidized. This reduced availability appears to occur through a combination of decreased production, abnormal signaling, and increased destruction by oxygen-free radicals. Concurrently, endothelium-mediated vasoconstrictors, adhesion molecules, cytokines, growth factors, and thrombogenic factors, such as endothelin, are increased by oxidized low-density lipoprotein. Several studies have shown improvements in endothelial function with cholesterol lowering, which may explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.

Cholesterol lowering and life expectancy: a critical evaluation
Klepzig, H., Jr. and M. Kaltenbach (1992), Z Kardiol 81(7): 347-53.
Abstract: Numerous studies have confirmed a positive correlation between serum cholesterol levels and the occurrence of coronary artery disease. Lowering cholesterol by 1% is accompanied by a reduction of coronary events by 2%. The rate of fatal coronary events is not significantly influenced. Coronary angiography demonstrated only a mild average reduction of coronary lesions after cholesterol-lowering therapy. This might be explained by the low lipid content of a coronary plaque (5-15%). The majority of intervention trials revealed an increase of the extracardiac mortality in treatment groups. Thus, up to the present, it remains unproven that cholesterol-lowering therapy leads to an increase in life expectancy.

Cholesterol lowering and morbidity and mortality
LaRosa, J. C. (1995), Curr Opin Lipidol 6(1): 62-5.
Abstract: Circulating cholesterol is causative in coronary atherosclerosis. Moreover, cholesterol lowering has been demonstrated to prevent the progression of atherosclerosis. Concern has been expressed, based on primary prevention trials and population studies, that cholesterol lowering might cause noncardiovascular mortality. When carefully analyzed, however, neither clinical trial data nor observational data supported this concern.

Cholesterol lowering and mortality: the importance of considering initial level of risk
Smith, G. D., F. Song, et al. (1993), Bmj 306(6889): 1367-73.
Abstract: OBJECTIVE--To investigate the level of risk of death from coronary heart disease above which cholesterol lowering treatment produces net benefits. DESIGN--Meta-analysis of results of randomised controlled trials of cholesterol lowering treatments. METHODS--Published and unpublished data from all identified randomised controlled trials of cholesterol lowering treatments with six months or more follow up and with at least one death were included in the meta-analysis. The analyses were stratified by the rate of death from coronary heart disease in the control arms of the trials. MAIN OUTCOME MEASURES--Death from all causes, from coronary heart disease, and from causes other than coronary heart disease. RESULTS--In the pooled analysis, net benefit in terms of total mortality from cholesterol lowering was seen only for trials including patients at very high initial risk of coronary heart disease (odds ratio 0.74; 95% confidence interval 0.60 to 0.92). In a medium risk group no net effect was seen, and in the low risk group there were adverse treatment effects (1.22; 1.06 to 1.42). In a weighted regression analysis a significant (p < 0.001) trend of increasing benefit with increasing initial risk of coronary heart disease was shown. Raised mortality from causes other than coronary heart disease was seen in trials of drug treatment (1.21; 1.05 to 1.39) but not in the trials of non-drug treatments (1.02; 0.88 to 1.19). Cumulative meta-analysis showed that these results seem to have been stable as new trials appeared. CONCLUSION--Currently evaluated cholesterol lowering drugs seem to produce mortality benefits in only a small proportion of patients at very high risk of death from coronary heart disease. Population cholesterol screening could waste resources and even result in net harm in substantial groups of patients. Overall risk of coronary heart disease should be the main focus of clinical guidelines, and a cautious approach to the use of cholesterol lowering drugs should be advocated. Future trials should aim to clarify the level of risk above which treatment is of net benefit.

Cholesterol lowering and the reduction of CHD incidence and total mortality: results from a meta-analysis of randomized trials
Holme, I. (1992), Cardiovasc Drugs Ther 6(2): 101-2.
Abstract: This editorial reports on a meta-analysis done on cholesterol-lowering trials. Coronary heart disease incidence is reported for 16 trials and total mortality for 19 trials. The cholesterol benefit ratio, i.e., the percent risk reduction divided by the percent cholesterol reduction, was analyzed in terms of total vs. potential modifying factors. For coronary heart disease the benefit ratio was 2.8 (95% CL: 1.5, 4.2), and for total mortality it was 1.2 (95% CL: -0.1, 2.3). Cholesterol reduction had to be at least 8-9% to outweigh the negative impact of treatment on total mortality.

Cholesterol lowering and the use of healthcare resources. Results of the Scandinavian Simvastatin Survival Study
Pedersen, T. R., J. Kjekshus, et al. (1996), Circulation 93(10): 1796-802.
Abstract: BACKGROUND: Advances in the treatment of cardiovascular disease have increased costs; annual cardiovascular healthcare expenditure in the United States currently exceeds $100 billion. Physicians and third-party payers need to assess the economic impact of treatments that reduce cardiovascular morbidity and mortality. METHODS AND RESULTS: The Scandinavian Simvastatin Survival Study is a randomized, double-blind, placebo-controlled trial in which simvastatin reduced the risk of death by 30% (P=.0003) over the median follow-up period of 5.4 years in patients with previous myocardial infarction or stable angina pectoris as a result of a 42% reduction in the risk of coronary deaths (P=.00001). In the present report, data prospectively collected from hospital admissions were analyzed to evaluate the impact of simvastatin on healthcare resource use and perform a cost-minimization analysis. In the placebo group (n=2223), there were 1905 hospitalizations (average duration, 7.9 days) for acute cardiovascular events or coronary revascularization procedures among 937 patients, whereas in the simvastatin group (n=2221), there were 1403 such hospitalizations (average duration, 7.1 days) among 720 patients (all differences, P<.0001). The corresponding number of hospital days was 15089 and 9951 in the two groups, respectively (34% reduction,P<.0001). In the United States, the resulting reduction in hospitalization costs over the 5.4 years of the trial would be $3872 per patient, reducing the effective cost of simvastatin by 88% to $0.28 per day. CONCLUSIONS: In addition to reducing mortality and morbidity in coronary heart disease patients, simvastatin markedly reduces use of hospital services, thus offsetting most of its cost.

Cholesterol lowering and the vessel wall: new insights and future perspectives
Stulc, T. and R. Ceska (2001), Physiol Res 50(5): 461-71.
Abstract: The basis for most acute coronary events is either rupture or fissuring of unstable atherosclerotic plaques with subsequent thrombosis leading to coronary artery occlusion. The development of atherosclerotic plaques takes several decades, but the mechanical features determining its stability and the risk of rupture can change very rapidly depending on a number of internal factors. Unstable plaques have a large lipid core, a thin overlying fibrous cap and an abundance of inflammatory cells. The most important factor determining the plaque stability is the plasma level of atherogenic LDL particles. Increased levels of these particles cause endothelial dysfunction with impaired vasodilatation capacity and prevalence of vasoconstriction, maintain inflammatory infiltration of the plaque, impair the strength of the fibrous cap and facilitate aggregation and coagulation. Effective lowering of plasma cholesterol by pharmacological and non-pharmacological means can revert most of these processes and increase the plaque's mechanical stability within several hours to days. Lipid lowering therapy can therefore decrease the risk of acute coronary events within a very short space of time. Thus a radical decrease in lipid levels, along with modification of other risk factors, may become the cornerstone for treatment of acute coronary syndromes, in addition to being an effective treatment in primary and secondary prevention of coronary heart disease (CHD).

Cholesterol lowering as a treatment for established coronary heart disease
LaRosa, J. C. and J. I. Cleeman (1992), Circulation 85(3): 1229-35.

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