Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Statins belong to a class of drugs known to inhibit 3-hydroxy 3-methylglutaryl coenzyme A reductase, and block hepatic cholesterol synthesis. Since the initial statin was approved by the Food and Drug Administration in 1987, these agents quickly became the gold standard for treatment of hypercholesterolemia. Effective lipid-lowering has been found to improve the long-term prognosis of patients with coronary artery disease. In addition, statins have also been found to be highly effective in primary and secondary stroke prevention among medically managed patients with cardiovascular disease, and it appears that this benefit is largely due to the non-cholesterol-lowering, so-called pleiotropic, effects of statins. During the past decade, agents such as beta-blockers, aspirin, or other antiplatelet medications have proven to reduce the incidence of adverse postoperative outcomes among vascular surgical patients, and have rightfully assumed a place in our overall therapeutic armamentarium. There is growing evidence that statins may be especially effective in reducing cardiovascular morbidity and improving outcomes after major vascular surgery. A recent study from Johns Hopkins Hospital demonstrated a threefold reduction in the rate of perioperative stroke (P < .05) and fivefold reduction of perioperative mortality (P < .05) among 1,566 patients undergoing carotid endarterectomy (CEA). This benefit was confirmed in a series of 3,360 CEAs performed at multiple hospitals throughout Western Canada. Statin use was independently associated with a 75% reduction (odds ratio [OR] = 0.25; 95% confidence interval [CI], 0.07-0.90) in the odds of death and 45% reduction (OR = 0.55; 95% CI, 0.32-0.95) in the odds of ischemic stroke or death among patients with symptomatic carotid disease. Further, there is some data indicating that statin use may reduce long-term incidence of restenosis following CEA. Preliminary work indicates that a similar benefit of statin use in reducing neurologic morbidity among patients undergoing carotid angioplasty and stent procedures. A number of the pleiotropic effects of statin medications may be responsible for these clinical observations. Further work is necessary to better elucidate these mechanisms, as well as to determine the optimal agents, dosing, and timing of drug administration among patients undergoing carotid interventions.
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PMID:The effect of statin medications on perioperative and long-term outcomes following carotid endarterectomy or stenting. 1808 42

It has been shown that HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) lower the incidence of a first stroke in patients with coronary heart disease, diabetes, or risk factors for cardiovascular disease. However, it is unknown whether statin therapy could reduce the incidence of a second stroke in patients without evidence of heart disease. This article reviews the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial, a prospective, randomized, multicentered, double-blind, placebo-controlled, international trial designed to examine the effect of high-dose atorvastatin on secondary stroke prevention. Trial participants (4,731) had experienced a stroke or transient ischemic attack within 1 to 6 months before randomization into the study. Over the 5-year follow-up period, incidence of second stroke or transient ischemic attack was significantly reduced in the atorvastatin treatment group compared with the placebo group. In addition, high-dose atorvastatin therapy significantly decreased major coronary artery and other negative cardiovascular events. The reduction in incidence of secondary stroke was specific to ischemic stroke as opposed to hemorrhagic stroke. Results of the trial are clinically significant and support extension of the latest secondary stroke prevention guidelines to include statin therapy for those patients without coronary heart disease.
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PMID:High-dose statin therapy for secondary prevention of stroke: stroke prevention by aggressive reduction in cholesterol levels study review. 1815

Cardiovascular risk factors, particularly low-density lipoproteins (LDL), give rise to atherosclerosis and its complications by triggering a dysfunctional endothelium, inflammation, and a procoagulant vascular surface. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibition by statins leads to a fall in circulating and plaque LDL concentrations and improvement in many cellular dysfunctions, but controlled trials only show partial benefit with regard to myocardial infarction, stroke, and cardiovascular death. Emerging clinical evidence now shows that these risk factors also stimulate the activation (isoprenylation) of small G-binding proteins and, through their effectors (Rho-associated kinase) they can activate many or most of the subcellular and vessel wall pathophysiology of atherosclerosis. Inhibition of Rho-kinase can improve these dysfunctions with no changes in LDL. Similarly, statins can diminish the activation of these small G-binding proteins and their downstream effectors in atherosclerosis. This review compares and contrasts the effects of statins on atherosclerosis that are related to changes in LDL with those effects occurring through these alternate lipid pathways, and suggests that the therapeutic control of these small G-binding proteins and their downstream effectors may significantly add to the partial benefits of using statins in patients with atherosclerotic heart disease.
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PMID:Antiatherosclerotic effects of statins: LDL versus non-LDL effects. 1817 55

Elevated serum low-density lipoprotein cholesterol (LDL-C) and low serum high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic ischemic stroke. The National Cholesterol Education Panel and the American Heart Association have released guidelines for the treatment of dyslipidemia that stress LDL-C reduction using HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) and are applicable to individuals who have had or are at a high risk of having a stroke. Treatment of low HDL-C is a secondary goal of these guidelines and can be best achieved by using extended-release niacin (alone or in combination with statins) and fibrates. Early and aggressive treatment of dyslipidemia is an important component of a multimodality approach to stroke prevention.
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PMID:HDL-C and LDL-C: their role in stroke pathogenesis and implications for treatment. 1858 8

Iridodonesis or tremulous iris is a clinical sign of ectopia lentis which is frequently associated with homocystinuria. We present a forty-two-year-old woman victim of a left middle cerebral artery ischemic stroke. The clinical examination found bilateral iridodonesis and laboratory tests showed an increased level of serum homocysteine and homocystinuria. Homocystinuria was caused by a compound heterozygous I278T and D444N mutation of cystathionine beta-synthase (CBS) gene and also a C667T heterozygous polymorphism of methylene-tetrahydrofolate-reductase gene. This case was atypical because of the incomplete phenotype, development of complications in adulthood and the association of a rare compound heterozygous mutation of the CBS gene.
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PMID:[Stroke and iridodonesis revealing a homocystinuria caused by a compound heterozygous mutation of cystathionine beta-synthase]. 1880 5

Genes involved in the hemostatic mechanism are logical candidate genes for association studies in prothrombotic conditions such as stroke. Since the underlying etiology in pediatric strokes is different than adults, looking for genetic causes would be the logical thing to do in the pediatric stroke population. Fifty-eight Asian-Indian stroke patients below 15 years of age and equal number of age- and sex-matched healthy controls were the subjects for the study. The subjects were screened for 13 polymorphisms and three mutations spread across seven different candidate genes involved in the hemostatic system. Of the 13 polymorphisms and three mutations studied, four polymorphisms, HPA-I, TAFI 147Ala>Thr, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, and MTHFR 1298 A>C, showed significant association with the disease phenotype. MTHFR 677 C>T showed the strongest association and therefore may have a strong predisposing role for pediatric strokes. Gene-gene interaction studies showed a strong interaction between HPA-I and MTHFR 677 C>T polymorphism. The wild type of both these polymorphisms synergistically showed a strong protective effect [p < 0.0001, O.R: 10.06(4.26-23.71)]. Polymorphisms in HPA-I and MTHFR may have important predisposing roles in the development of pediatric stroke.
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PMID:Prothrombotic polymorphisms, mutations, and their association with pediatric non-cardioembolic stroke in Asian-Indian patients. 1883 20

Warfarin remains the drug of choice for long-term anticoagulation management in a variety of conditions. Despite an established role in prevention of thromboembolic events such as stroke, warfarin continues to be underutilized because of its association with serious drug-related adverse events. Lacking alternative therapeutic approaches, intensive research in the past decade has focused on making anticoagulation with warfarin safer. Much emphasis has been placed on defining factors associated with the wide individual variability in warfarin dose. Polymorphic sites in three genes, cytochrome P450 (CYP) 2C9, vitamin K 2,3 epoxide reductase complex 1 (VKORC1), and CYP4F2, have been shown to affect stable warfarin dose. An overview of the persistent issues related to warfarin therapy and our current understanding of the genetic and clinical factors affecting warfarin dosing is presented. Finally, unresolved issues in improving clinical care of warfarin patients and future directions are provided.
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PMID:Understanding the pharmacogenetic approach to warfarin dosing. 1899 6

Our goal was to analyze the effects of treatment with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (simvastatin, 40 mg/day) on serum S100BB and tau protein levels during the acute ischemic stroke (IS). Twenty four patients with IS were divided into two equal groups; treated and untreated with simvastatin. Blood was obtained four times during acute IS. Tau protein was noticed in six patients from treated group and in five patients from untreated group. The serum tau protein levels significantly increased on the 10th day only in patients untreated with simvastatin (p < 0.05). Simvastatin did not exert an effect on serum S100BB protein levels.
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PMID:Simvastatin inhibits the increase in serum tau protein levels in the acute phase of ischemic stroke. 1921 98

There is compelling evidence that treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors - "statins" - the most important class of lipid lowering agents, reduces ischemic stroke incidence independent on their effect on serum cholesterol levels. In this review, the non-lipid-mediated - "pleiotropic" - effects of statins as well as their potential implication in developing new treatment strategies for stroke prevention will be discussed.
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PMID:New insights into the pleiotropic effects of statins for stroke prevention. 1951 4

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function.
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PMID:Hyperhomocysteinemia in uremia--a red flag in a disrupted circuit. 1970 80


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