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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of exercise on hypocholesterolemia, one of the risk factors of cerebrovascular disorders, were examined. 47-51-day-old stroke-prone spontaneously hypertensive rats (stroke-prone SHRs) were assigned to 2 groups, sedentary or exercise, and raised for 8 weeks. The total serum cholesterol level of the exercised group was 17-18% higher (P less than 0.01) than the control group, and the level of cholesterol synthesis in the liver of the former group significantly higher than in the latter. On the other hand, the level of intestinal cholesterol synthesis in the exercised group was significantly lower. The activity of HMG-CoA reductase in the liver microsomes was significantly increased by exercise, but the activity of this enzyme in the small intestine was not affected. A significant correlation was observed between the rate of cholesterol synthesis in the liver and the amount of radiolabeled cholesterol released into the serum. From these results, we conclude that the enhancement of the synthesis and the release of cholesterol in the liver by exercise is a major cause of the exercise-induced increase in serum cholesterol of stroke-prone SHRs.
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PMID:Effects of exercise on hypocholesterolemia of stroke-prone spontaneously hypertensive rats. 259 21

1. Recent outcome trials suggest that lipid-lowering with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors is justifiable on risk-benefit grounds in subjects with serum cholesterol > 5.5 mmol/l who have coronary heart disease, other forms of atherosclerotic vascular disease, or who are free of vascular disease but have a risk of major coronary events > or = 1.5% per year. Choice of an appropriate treatment policy will require (i) knowledge of the proportion of the population who will need treatment for secondary prevention, and (ii) targeting of treatment for primary prevention at a specified absolute risk of coronary heart disease events. Selection of an appropriate coronary heart disease risk for primary prevention requires consideration of the number needed to be treated to prevent one coronary heart disease event, the proportion of the population requiring treatment, the cost-effectiveness of treatment and the total cost of treatment. 2. In a random stratified sample of subjects aged 35-69 years from the Health Survey for England 1993 we first examined the prevalence of subjects with cardiovascular disease and serum cholesterol > 5.5 mmol/l who may be candidates for secondary prevention. In those free of cardiovascular disease we then examined the prevalence of subjects with serum cholesterol > 5.5 mmol/l who had three different levels of coronary heart disease risk: coronary heart disease event rates of 4.5% per year, 3.0% per year and 1.5% per year. These subjects may be candidates for primary prevention depending on the treatment policy selected. 3. For secondary prevention, 4.8% (95% confidence interval 4.3-5.3) of the U.K. population aged 35-69 years might be candidates for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor treatment, comprising 2.4% (2.0 to 2.7) with a history of myocardial infarction, 1.9% (1.6 to 2.2) with angina and 0.5% (0.3-0.7) with a history of stroke--all with total cholesterol > 5.5 mmol/l. The prevalence of these diagnoses with total cholesterol > 5.5 mmol/l increased with age, from 1.5% at age 35-39 years to 16.2% at age 65-69 years in men, and from 0.2% at age 35-39 years to 10.0% at age 65-69 years in women. Approximately 13 people would need treatment for 5 years to prevent one coronary event, at a cost of 36,000 pounds per event prevented. The number needing treatment for secondary prevention would increase substantially if treatment was extended to patients above 70 years of age or to those with serum cholesterol < or = 5.5 mmol/l. 4. Primary prevention aimed at a coronary event risk of 4.5% per year would lead to treatment of only 0.3% (0.2-0.4) of those aged 35-69 years, and those treated would be predominantly older men with additional risk factors for coronary heart disease. The number needed to be treated and cost per coronary event prevented would be similar to those for secondary prevention. 5. Primary prevention targeted at subjects with a coronary event rate of 3.0% per year would entail treating 3.4% (3.0-3.9) of all those aged 35-69 years. At this level of risk, 20 people would need treatment for 5 years to prevent one coronary event, at a cost of 55,000 pounds per event prevented. 6. Primary prevention aimed at a coronary event rate of 1.5% per year would entail treating 19.6% (18.7-20.6) of all subjects aged 35-69 years, and about 80% of men aged 60-69 years for primary or secondary prevention. At this level of risk, 40 people would need treatment for 5 years to prevent one event, at a cost of 111,000 pounds per event saved. 7. Guidelines for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor treatment should take into account the considerable workload and financial resources needed to implement secondary prevention of coronary heart disease, the accepted first priority. For primary prevention they need to consider the number needed to be treated to prevent one event, the number of subjects needing treatment, the cost-effectiveness of treatment and
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PMID:Lipid-lowering for prevention of coronary heart disease: what policy now? 917 44

The biosynthesis of cholesterol is regulated mainly by HMG-CoA reductase, however, recent studies indicated the pivotal role of another enzyme in cholesterol homeostasis. A previous report showed a marked decrease in the activity of mevalonate pyrophosphate decarboxylase (MPD) in stroke-prone spontaneously hypertensive rats and its possible involvement in the pathogenesis of the disorder. In this study, we purified liver MPD from rats fed a diet containing cholestyramine and pravastatin (CP diet) using conventional chromatographic techniques. We obtained two electrophoretically homogeneous enzyme preparations; 45 and 37 kDa proteins with specific activities of 8.0 and 7.4 micromol/min/mg, respectively. The enzymes showed similar molecular weights of 90 kDa, as judged on gel permeation chromatography. A kinetic study indicated apparent Km values for mevalonate pyrophosphate and ATP of 22.7 microM and 0.71 mM, respectively, for the 45 kDa MPD, and 20.0 microM and 0.80 mM, respectively, for the 37 kDa MPD. Half maximum activities were observed at 1.5 mM and 1.1 mM Mg2+ for the 45 and 37 kDa MPDs, respectively. Both enzymes required ATP as a phosphate acceptor, and in addition Mg2+, Mn2+, and Co2+ were effective as divalent cations. The optimum pH for both enzymes was 7.0. The isoelectric points for the 45 and 37 kDa MPDs were 5.6 and 5.4, respectively. Polyclonal antiserum raised against the 45 kDa enzyme detected both the 45 and 37 kDa bands on immunoblots with CP diet-induced liver crude extract as an antigen. However, non-induced liver contained the 45 kDa protein but not the 37 kDa protein. These results indicated that the CP diet induced a new species, 37 kDa, of MPD which is characteristically and immunologically very similar to the well-known 45 kDa MPD.
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PMID:Purification and characterization of two mevalonate pyrophosphate decarboxylases from rat liver: a novel molecular species of 37 kDa. 934 97

Monumental advances in the field of lipid metabolism and its relationship to atherosclerotic cardiovascular disease have been achieved during the last half century. Epidemiologic studies have defined lipid disorders as highly significant independent risk factors for coronary heart disease, along with diabetes mellitus, hypertension and smoking. Primary and secondary prevention studies including the Coronary Primary Prevention Trial, Helsinki Heart Study, and the Coronary Drug Project have shown that lowering the atherogenic low density lipoproteins (LDL) and very low density lipoproteins (VLDL) whilst raising the high density lipoproteins (HDL) significantly decreases the risk for coronary disease. Striking evidence that aggressive therapy (to sharply lower LDL and raise HDL with newer drugs) prevents progression and induces regression of coronary narrowing has been obtained in numerous recent studies using quantitative coronary arteriography. An interesting and unexpected lesson learned from these arteriographic studies was that a highly significant reduction within months in several studies in coronary events was out of proportion to improvements in luminal narrowing. Recently, three major clinical trials to assess the effects of cholesterol reduction by the newly discovered HMG CoA reductase inhibitors (statins) have been published. Pravastatin significantly reduced coronary events in hypercholesterolemic patients [mean LDL-Chol. = 5.0 mM/L (192 mg/dl)] without a history of myocardial infarction. In a secondary prevention study, simvastatin also reduced coronary complications in hypercholesterolemic patients [mean LDL-Chol. = 4.9 mM/L (190 mg/dl)] with pre-existing coronary disease. Very recently, pravastatin treatment significantly reduced coronary events and stroke in patients with a history of myocardial infarction and average cholesterol levels [mean LDL-Chol. = 3.6 mM/L (139 mg/dl)], representing the majority of patients with coronary disease. In all these studies, reduction in cardiovascular events was approximately one-third. In subgroup analyses, men, women, elderly, smokers and hypertensives benefited from cholesterol lowering. There was no significant increase in non-cardiovascular causes of death. In the United States of America, the National Cholesterol Education Program (NCEP) Adult Treatment Panel, representing major health organizations, developed national guidelines on the detection, evaluation and treatment of high blood cholesterol in adults. In a given patient, the Panel recognizes the importance of weighing all cardiovascular disease risk factors including age (men > 45 years, postmenopausal women), family history of premature coronary disease, smoking, hypertension, diabetes and HDL-Cholesterol (< 35 mg/dl) in determining how aggressive therapy should be. The patient with manifest coronary heart disease (CHD) is given a special position as such patients are at highest risk for recurrent events. Major goals of therapy are to lower the LDL-Cholesterol to 2.6 mM/L (< 100 mg/dl) in the CHD patient. In non-CHD patients with two or more risk factors, the LDL-Cholesterol goal is 3.4 mM/L (130 mg/dl). In those with fewer risk factors, the goal is 4.2 mM/L (160 mg/dl). These guidelines should be modified as appropriate for Singapore. Patients with elevated triglycerides usually have low HDL-Cholesterol levels and often represent a heterogeneous group who may have other concurrent abnormalities including the presence of small dense LDL, insulin resistance, hypertension, obesity, overt diabetes and combined hyperlipidemia. Such patients merit individualized treatment. The prevalence of this syndrome may be more common in Singapore and requires further investigation. Current therapeutic guidelines emphasize the need for weight loss and dietary restriction of total and especially saturated fat (< 7% to 10% total calories), cholesterol (< 200 to 300 mg/day), and exercise. (ABSTRACT TRUNCATED)
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PMID:Cholesterol and atherosclerosis: a contemporary perspective. 939 24

Although associations of cholesterol and coronary heart disease (CHD) are well accepted, the association between cholesterol and stroke has been a subject of some confusion. Epidemiologic evidence suggests no association between plasma concentrations of cholesterol and stroke, and earlier clinical trials were also negative. Two early meta-analyses of clinical trials designed to evaluate the effects of cholesterol lowering on CHD concluded that cholesterol lowering had no effect. More recently newer, more potent and better tolerated agents (HMG-CoA reductase inhibitors, reductase inhibitors) have become available and have been tested for their efficacy in reducing cholesterol and CHD in both primary prevention and secondary prevention trials. Meta-analyses of these trials, in contrast to the earlier trials, reveal a powerful statistically significant effect to reduce stroke as well as CHD in secondary prevention (30%); the direction of the effect is the same in trials of primary prevention or trials that randomized patients with and without CHD (mixed primary and secondary prevention trials) where the risk reductions for stroke, although not reaching statistical significance are 11 and 30%, respectively. An important difference in the newer analysis is the availability of several trials of secondary prevention in which low density lipoprotein cholesterol was lowered 25-30% and in which CHD event reduction was similarly reduced by 30%. Mechanisms for stroke reduction likely involve retardation of plaque progression in the intracranial and extracranial carotid arteries, plaque stabilization, and, in addition, stroke may be reduced partly as a consequence of CHD reduction.
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PMID:HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. 967 67

Hyperlipidemia is recognized as one of the major risk factors for the development of coronary artery disease and progression of atherosclerotic lesions. Dietary therapy together with hypolipidemic drugs are central to the management of hyperlipidemia, which aims to prevent atherosclerotic plaque progression, induce regression, and so decrease the risk of acute coronary events in patients with pre-existing coronary or peripheral vascular disease. In patients at high risk of coronary artery disease but without evidence of atherosclerosis, treatment is designed to prevent the premature development of coronary artery disease, whereas in those with hypertriglyceridemia, treatment aims to prevent the development of hepatomegaly, splenomegaly, and pancreatitis. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most potent lipid-lowering agents currently available, and their use in the treatment of hyperlipidemia provides the focus for this review. Particular emphasis is given to cerivastatin, a new HMG-CoA reductase inhibitor that combines potent cholesterol-lowering properties with significant triglyceride-reducing effects. Recently completed primary and secondary intervention trials have shown that the significant reductions in low-density lipoprotein (LDL) cholesterol achieved with statins result in significant reductions in morbidity and mortality associated with coronary artery disease as well as reductions in the incidence of stroke and total mortality. Such benefits occur early in the course of statin therapy and have led to suggestions that these drugs may possess antiatherogenic effects over and above their capacity to lower atherogenic lipids and lipoproteins. Experimental studies have also shown statin-induced improvements in endothelial function, decreased platelet thrombus formation, improvements in fibrinolytic activity, and reductions in the frequency of transient myocardial ischemia.
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PMID:Current and future treatment of hyperlipidemia: the role of statins. 973 40

HMG-CoA reductase inhibitors are potent cholesterol-lowering drugs. Recent clinical trials and meta-analyses show a 30% stroke reduction after treatment with HMG-CoA reductase inhibitors. Subgroup analyses and experimental findings support the notion that HMG-CoA reductase inhibitors improve endothelial function directly by mechanism(s) independent of cholesterol-lowering. They reduce inflammatory, proliferative and thrombogenic processes in atherosclerotic plaques and improve endothelial dysfunction. Recent findings demonstrate an enhanced production of endothelium-derived nitric oxide (NO) by HMG-CoA reductase inhibitors. Endothelial NO is an important vasodilator and plays a beneficial role in cerebral ischemic injury. Prophylactic treatment with HMG-CoA reductase inhibitors in mice selectively upregulates endothelial NO synthase expression and activity, increases cerebral blood flow at resting state and during ischemia, and reduces cerebral infarct size after experimental stroke. These findings provide a novel mechanism for the prophylactic treatment of ischemia-induced cerebral injury under non-hypercholesterolemic conditions.
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PMID:[HMG-CoA reductase inhibitor and risk of stroke]. 975 26

The use of lipid-altering drugs has been shown to reduce the progression of atherosclerotic lesions and reduce the risk of atherosclerotic events (such as myocardial infarction and stroke). In general, these lipid-altering drugs are well tolerated but there is the potential for drug interactions. For example, HMG-CoA reductase inhibitors may interact with macrolides, azalides, azole antifungals and cyclosporin. Resins (such as cholestyramine and colestipol) may impair the absorption of many concurrent medications. Fibrates have potential drug interactions with warfarin, furosemide (frusemide), oral hypoglycaemics and probenecid. Nicotinic acid (niacin) may have potential drug interactions with high dose aspirin (acetylsalicylic acid), uricosuric agents (such as sulfapyrazone) and alcohol (ethanol). Finally, probucol may have potential drug interactions with antidysrhythmics, tricyclic antidepressants and phenothiazines. In addition, lipid-altering drugs, used in combination, may have the potential for drug interactions, enhancing some of the risks of adverse effects, such as myositis and hepatotoxicity. Therefore, in order to use lipid-altering drugs in the most effective, and safest manner, it is important for the clinician to have an understanding of the mechanisms of potential drug interactions, which drug interactions may theoretically occur, and specifically, which spe cific drug interactions have already been described.
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PMID:Drug interactions of lipid-altering drugs. 982 49

The importance of lowering plasma cholesterol to reduce the incidence of coronary events is well established. However, in the prevention of stroke disease, control of hypertension has been the main aim of treatment and lipid lowering therapy has not hitherto been considered to be desirable or necessary. In this review, the evidence from large multicentre trials, imaging studies and meta-analyses is presented. It shows convincingly that HMG-CoA reductase inhibitors (Statins) reduce stroke risk.
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PMID:Does cholesterol lowering prevent stroke? 987 81

Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (statins) improve endothelial function and reduce the incidence of stroke and myocardial infarction. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins increased eNOS mRNA half-life but did not change eNOS gene transcription. Inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol but also of isoprenoids. The upregulation of eNOS expression by statins was independent of cholesterol but mediated via the inhibition of the isoprenoid geranylgeraniol, whereas farnesiol had no effect on eNOS. Immunoblot analyses, (35S)-GTP gamma S-binding assays and transfection studies revealed that statins upregulate eNOS expression by blocking the geranylgeranylation of the GTPase Rho which is necessary for its membrane-associated activity. Studies with mice showed, that statin treatment upregulates eNOS expression and function independent of serum cholesterol levels. Prophylactic treatment with statins augmented cerebral blood flow and reduced cerebral infarcts in normocholesterolemic mice. These effects of statins were completely absent in eNOS-deficient mice indicating that enhanced eNOS activity by statins is the predominant mechanism by which these agents protect against cerebral injury. Our results suggest that statins provide a novel prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia. Upregulation of eNOS by inhibiting Rho may provide a new pharmacologic target for the treatment of arteriosclerosis, pulmonary hypertension, and heart failure.
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PMID:[Regulation of endothelial NO production by Rho GTPase]. 1037 57


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