Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation has been postulated to be a major contributor to restenosis after angioplasty. We examined the correlation between inflammatory and coagulatory reactions and the occurrence of restenosis, and how treatment with statins influences this correlation. A total of 243 patients with stable angina who were scheduled for a percutaneous coronary intervention (PCI) and follow-up coronary angiography were enrolled in the study. Eighty-one of these patients were treated with statins for at least 1 month before their PCI and throughout the study period. Blood was withdrawn on the day of the PCI and on the day of the follow-up catheterization. Patients with the highest hs-CRP at the time of the initial PCI maintained elevated hs-CRP levels over time and showed significantly higher rates of restenosis or TLR after 6 +/- 1 months than subjects with low initial hs-CRP. Statin treatment abolished this difference. Fibrinogen levels were also increased in subjects with high initial hs-CRP, both at the time of the initial PCI and at follow-up. In an univariate analysis, both initial and follow-up levels of hs-CRP and fibrinogen correlated with restenosis. However, both the initial and follow-up levels of hs-CRP only were independent predictors of increased restenosis in a multivariate analysis, except in the statin-treated subgroup. In conclusions, the persistent increase in CRP is a risk factor for restenosis in patients with stable angina who have not been treated with statins.
Atherosclerosis 2004 Apr
PMID:A persistent increase in C-reactive protein is a risk factor for restenosis in patients with stable angina who are not receiving statins. 1506 3

Ezetimibe (Ezetrol), recently launched in Belgium by Merck Sharp& Dohme and Schering Plough, is presented as 10 mg tablets. It belongs to a new class of lipid-lowering agents that selectively inhibit the intestinal absorption of cholesterol and phytosterols. Its mechanism of action results in a synergistic cholesterol-lowering effect together with a statin that inhibits cholesterol synthesis by the liver. Ezetimibe, at a daily dose of 10 mg, is indicated, in combination with a statin, as adjuvant treatment to diet in patients with primary hypercholesterolaemia (homozygote or heterozygote familial form and non-familial polygenic form) not well controlled with a statin alone. In case of statin contra-indication or intolerance, ezetimibe can be used in monotherapy. Its tolerance profile is excellent. Statin-ezetimibe combination allows to significantly reduce total and LDL cholesterol levels and increases the percentage of hypercholesterolaemic patients who will reach the target levels recommended in the international guidelines against atherosclerosis. However, such a combination should still prove its efficacy in reducing cardiovascular morbidity and mortality in large prospective clinical trials.
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PMID:[Ezetimibe (Ezetrol)]. 1518 38

Adipose tissue expression of tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of obesity-linked insulin resistance and the dyslipoproteinemia of insulin resistance. This study has two aims: (1) to compare select inflammatory mediators in non-smoking, normoglycemic male subjects with and without the atherogenic dyslipoproteinemia (ADL), and (2) to determine the effects of statin therapy on select inflammatory mediators. ADL subjects had higher levels of insulin (16.7 +/- 7.5 versus 11.6 +/- 5.9 microIU/mL, P=0.008), soluble TNF receptor superfamily 1B (sTNFRSF1B) (3.3 +/- 0.7 versus 2.7 +/- 0.5 ng/mL, P=0.005), and interleukin-6 (IL-6) (2.6 +/- 2.2 versus 1.3 +/- 1.8 pg/mL, P=0.006) as compared to those of the non-ADL subjects. After adjustment for age, sTNFRSF1B (P=0.003) was more predictive of ADL than high-sensitivity C-reactive protein (hs-CRP) (P=0.047). Statin therapy did not change sTNFRSF1B, TNF-alpha, IL-6, hs-CRP, whereas soluble TNF receptor superfamily 1A (sTNFRSF1A) increased slightly (P=0.048). A high level of sTNFRSF1B is a strong marker of the pro-inflammatory state in this sample of male ADL subjects.
Atherosclerosis 2004 Nov
PMID:Elevated soluble tumor necrosis factor receptor levels in non-obese adults with the atherogenic dyslipoproteinemia. 1548 68

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg x kg(-1) x day(-1)) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7alpha-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7alpha-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.
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PMID:HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. 1550 47

CHD (coronary heart disease) is a complex disorder which is, in part, related to serum cholesterol levels. The rate-limiting enzyme in the catabolism of cholesterol into bile acids is CYP7A1 (cholesterol 7alpha-hydroxylase). The effect of the CYP7A1 A-278C promoter polymorphism on the progression of atherosclerosis, risk of a new clinical event and the influence of this variant on cholesterol-lowering therapy was investigated in 715 male patients with coronary atherosclerosis participating in REGRESS (Regression Growth Evaluation Statin Study). Genotype distributions were as follows: 283 with AA; 330 with AC and 102 with CC. There were no significant differences in baseline characteristics and serum lipids between genotypes. After 2 years, CC carriers had more progression of diffuse and focal atherosclerosis compared with AA carriers, as indicated by a larger decrease in MSD (mean segment diameter; 0.09 mm compared with 0.06 mm respectively; P=0.009) and MOD (minimum obstruction diameter; 0.09 mm compared with 0.05 mm respectively; P=0.024). Inclusion of risk factors for CHD in the model showed the same trend, although not significant for MOD (P=0.01 for MSD, and P=0.06 for MOD). In addition, CC carriers had an almost 2-fold higher risk of a new clinical event compared with AA carriers [RR (95% CI) 1.93 (1.11-3.36); P=0.02; where RR is relative risk and CI is confidence interval]. Inclusion of risk factors for CHD in the model showed the same trend, although not significant [RR (95% CI), 1.74 (0.96-3.12); P=0.06]. In conclusion, we present evidence that the CC variant of the A-278C polymorphism in the rate-limiting enzyme in the catabolism of cholesterol, CYP7A1, increases the progression of atherosclerosis and possibly the risk of a new clinical event.
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PMID:Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7alpha-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events. 1570 88

Statin drugs represent the major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Besides tremendous beneficial effects of statins, various forms of muscular toxicity (myalgia, cramp, exercise intolerance, and fatigability) occur frequently. We hypothesized that the iatrogenic effects of statins could result from alterations in Ca(2+) homeostasis. Acute applications of simvastatin on human skeletal muscle fibers triggered a Ca(2+) wave of intra-cellular Ca(2+) that mostly originates from sarcoplasmic reticulum (SR) Ca(2+)-release. In addition, simvastatin increased mitochondrial NADH content and induced mitochondrial membrane depolarization (EC(50)=1.96 microM) suggesting an altered mitochondrial function. Consequently on simvastatin application, a weak mitochondrial Ca(2+) efflux (EC(50)=7.8 microM) through permeability transient pore and Na(+)/Ca(2+) exchanger was triggered, preceding the large SR-Ca(2+) release. Increased SR Ca(2+) content after acute application of statin is also suggested by the increased Ca(2+) spark amplitude and by the effect of cyclopiazonic acid. We thus conclude that simvastatin induced alterations in mitochondrial function which lead to an increase in cytoplasmic Ca(2+), SR-Ca(2+) overload, and Ca(2+) waves. Taken together, these statin-induced muscle dysregulations may contribute to myotoxicity.
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PMID:Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle. 1575 63

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease characterized by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and ischaemic heart disease early in life. Early diagnosis and treatment are essential to prevent premature atherosclerosis in FH patients. The aim of our study was the evaluation of the effects of genetic [class of the LDL receptor (LDLR) gene mutation, apolipoprotein (apo)E, apoA-IV and cholesterol ester transfer protein gene polymorphisms] and environmental factors (age, sex, smoking habit and body mass index) on the lipid-lowering response to statin therapy in patients with molecularly defined FH. Atorvastatin 20 mg/day was prescribed in 49 patients with heterozygous FH. The lipid profile was examined before and after 12 weeks of therapy. Statin therapy resulted in a decrease of 37% and 36% in LDL-C and apoB levels, respectively. The study population was then divided into 2 groups according to the class of the LDLR mutation [patients sharing a class V mutation (the G1775A mutation, n=21) and patients sharing class II mutations (the G1646A and the C858A mutations, n=28)]. In both groups, the percentage decrement in LDL-C and apoB levels were correlated with the initial LDL-C and apoB levels, respectively. The class of the LDLR mutation affected the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. In detail, heterozygotes sharing a class V mutation of the LDLR showed a higher percentage decrement in LDL-C and apoB levels after atorvastatin administration compared to patients sharing class II mutations (49+/-9% versus 34+/-9%, P=0.001 for LDL-C and 42+/-16% versus 35+/-20%, P=0.001 for apoB). The influence of the classes of the LDLR gene mutations on the change of LDL-C and apoB levels to atorvastatin was still significant in a multivariate analysis. None of the other genetic and environmental factors studied affected the lipid-lowering response to atorvastatin therapy in patients with heterozygous FH in a multivariate analysis. Our data indicate that the class of the LDLR gene mutation affects the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. Specifically, patients with a class V mutation exhibit higher percentage decrease in LDL-C and apoB levels after statin therapy compared to patients sharing class II mutations.
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PMID:Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. 1586 14

The benefits of long-term statin (HMG-CoA reductase inhibitor) treatment for preventing coronary events have been well documented in several large-scale prospective clinical trials. By influencing the determinants of myocardial injury, statins may produce direct cardioprotective effects in the ischemic myocardium and prevent further damaging recurrent events. Although not proven fully in a clinical setting, cholesterol-independent or 'pleiotropic' effects of statins are thought to protect against myocardial injury and may occur via a number of mechanisms. Endothelial dysfunction occurs early in the development of atherosclerosis and is associated with a reduction in endothelial nitric oxide (NO) production. Statins have been shown to increase the expression of endothelial NO synthase, with subsequent augmentation of NO in the vasculature. Statins have also been reported to have anti-inflammatory effects, reducing the release of cytokines and chemokines, decreasing the expression of pro-inflammatory cell adhesion molecules, and reducing the accumulation of neutrophils in myocardial tissue following ischemia and reperfusion. Indeed, the role of statins in reducing infarct size is supported by data from a number of preclinical studies. Statin treatment, administered at the onset of reperfusion, has been shown to reduce infarct size by approximately 50% following ischemia in various animal models, and this may be an NO-dependent effect. Randomized clinical trials have indicated that early initiation of statin treatment is associated with a reduction in both the rate of recurrence of cardiovascular events and death in patients with acute coronary syndrome. In addition, decreased rates of myocardial infarction and mortality were demonstrated in several retrospective studies where statin treatment was administered before an interventional procedure. There is a need for further clinical trials to fully elucidate the importance of pre-procedural statin therapy and to determine the extent and mechanisms by which statins exert their cardioprotective effects.
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PMID:Statins and the response to myocardial injury. 1590 Dec 4

Atherosclerosis is a multifactorial condition that can result in cardiovascular disease. Statin therapy is thought to mediate cardioprotective effects that influence endothelial function, inflammatory responses, plaque stability and thrombus formation, processes involved in atherosclerosis. Although reduction in low-density lipoprotein cholesterol (LDL-C) potentially plays a role in all of these effects, several lines of evidence also implicate nonlipidmediated 'pleiotropic' effects. For example, statin therapy confers a lower risk for coronary heart disease than placebo in patients with comparable serum cholesterol levels, and confers a greater magnitude of clinical benefit than expected based on LDL-C levels alone. Moreover, while nonstatin lipid-lowering therapy does not necessarily reduce stroke risk, statins have shown a significant reduction in stroke. Statins exert their pleiotropic effects, in part, by improving endothelial function via up-regulation of endothelial nitric oxide synthase enzyme activity. Markers of inflammation such as high sensitivity C-reactive protein have been also shown to add further prognostic information about patients at risk of cardiovascular disease who may benefit from statin therapy. Further studies are still needed to determine whether statins have direct effects on inflammatory pathways.
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PMID:Statins: potent vascular anti-inflammatory agents. 1603 95

Statins have been linked to a wide range of vascular benefits, many of them are likely to be due to attenuation of chronic vascular inflammation. Nuclear factor kappaB (NF-kappaB) is one of the key regulators of transcription of a variety of genes involved in immune and inflammatory responses. Therefore, we investigated the effect of statins on TNF-alpha-induced NF-kappaB signaling in human endothelial cells (EC). ECs were pre-incubated for 16 h with cerivastatin (10(-9) to 10(-7) M) or vehicle in the presence or absence of mevalonate, followed by stimulation with 20 ng/ml TNF-alpha. Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC. IkappaBalpha phosphorylation and IkappaBalpha degradation, however, still occurred in statin-treated cells. TNF-alpha also activated phosphatidylinositol (PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated TNF-alpha-induced Akt phosphorylation and p65 nuclear translocation. As observed with statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-alpha-induced p65 translocation, but did not prevent IkappaBalpha phosphorylation nor IkappaBalpha degradation. These studies demonstrate that TNF-alpha-induced NF-kappaB activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling.
Atherosclerosis 2006 Apr
PMID:Statins prevent NF-kappaB transactivation independently of the IKK-pathway in human endothelial cells. 1605 Dec 51


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