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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular disease is a major cause of morbidity and mortality worldwide. During the last decade huge amount of laboratory and clinical evidence proved link between serum lipid concentration and the development of coronary heart disease. The Adult Treatment Panel III of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management. Since the publication of these guidelines numbers of new clinical trials and experimental results have been published. Recently completed clinical trials have indicated that reduction of low-density lipoprotein cholesterol to goals lower than the previously considered appropriate 2,6 mmol/l, produce further cardiovascular risk reduction in high risk individuals. There is growing evidence of the role of inflammation in the development of atherosclerosis and cardiovascular disease. Numerous studies have demonstrated that elevated C-reactive protein may be an independent cardiovascular risk factor. Statin therapy has produced a greater cardiovascular risk reduction in those patients whose C-reactive protein level was high. Ezetimibe is a new intestinal cholesterol uptake inhibitor, which reduces LDL cholesterol in monotherapy or in combination with statins. Lately a variety of new antilipemic agents are being developed. The present review summarizes some of these new results and their effect on cholesterol lowering therapy.
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PMID:[New results in the management of hypercholesterolemia]. 1626 67

Ezetimibe, a cholesterol absorption inhibitor, can be combined with statins to lower low-density lipoprotein (LDL) cholesterol. We have previously shown that ezetimibe can decrease LDL cholesterol by 16% even in patients treated by regular LDL apheresis and statins (Atherosclerosis. 2005;180:107-112). However, it is unclear whether ezetimibe decreases all LDL subfractions equally in patients with hypercholesterolemia. We therefore evaluated the effect of ezetimibe (5 weeks, 10 mg/d) on LDL subtype distribution in a placebo-controlled, double-blind randomized crossover study in 20 patients (age, 56+/-9 years; body mass index, 27.5+/-4 kg/m2) with severe hyperlipoproteinemia and coronary heart disease who are treated by statins and regular LDL apheresis. Both treatment periods (placebo and ezetimibe) were separated by a 5-week washout period. Low-density lipoprotein subtype distribution was determined at the end of each treatment period before apheresis by density gradient ultracentrifugation (LDL1, 1.020-1.024; LDL2, 1.025-1.029; LDL3, 1.030-1.034; LDL4, 1.035-1.040; LDL5, 1.041-1.047; LDL6, 1.048-1.057; LDL7, 1.058-1.066 g/mL). Overall, the LDL subtype distribution did not change significantly (large-buoyant LDL [LDL1+LDL2], 17.2%+/-6.4% vs 16.3%+/-7.1%; intermediate LDL [LDL3+LDL4], 49.3%+/-4.5% vs 48.2%+/-5.2%; small-dense LDL [LDL5+LDL6+LDL7], 33.5%+/-8.0% vs 35.5%+/-10% during placebo and ezetimibe treatments, respectively). With respect to the individual LDL subfractions, cholesterol was significantly (P<.05, Wilcoxon test) reduced by ezetimibe in LDL1 to LDL5 with a somewhat more pronounced reduction in larger LDL (mean+/-SD, -20%+/-28%, -17%+/-32%, -14%+/-25%, -13%+/-27%, -11%+/-21%, -7%+/-21%, -4%+/-19%; median, -28%, -12%, -18%, -16%, -4%, -4%, -2% for LDL subfractions 1-7, respectively). We therefore conclude that ezetimibe decreases cholesterol in nearly all LDL subfractions. Although this was established in patients concomitantly treated with statins and apheresis, this may also hold true in other clinically relevant situations.
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PMID:Effect of ezetimibe on low-density lipoprotein subtype distribution: results of a placebo-controlled, double-blind trial in patients treated by regular low-density lipoprotein apheresis and statins. 1663 35

Sitosterolemia is a rare, recessively inherited disorder characterized by increased absorption and delayed removal of noncholesterol sterols, which is associated with accelerated atherosclerosis, premature coronary artery disease, hemolysis, and xanthomatosis. Treatments include low-sterol diet and bile salt-binding resins; however, these often do not reduce the xanthomatosis. We examined the effects of the intestinal cholesterol/phytosterol transporter inhibitor ezetimibe added to cholestyramine in a young female patient with sitosterolemia and associated xanthomatosis. The patient was an 11-year-old female with sitosterolemia presenting with prominent xanthomas in the subcutaneous tissue of both elbows who was receiving treatment with cholestyramine 2 g once daily. Bilateral carotid bruits were audible, and a grade II/VI systolic murmur was detected at the left upper sternal border. She also had a low platelet count of 111,000/microL. Ezetimibe 10 mg once daily was added to the patient's ongoing cholestyramine regimen, and she was evaluated for 1 year. The patient followed an unrestricted diet during the 1-year treatment period. After 1 year of treatment with ezetimibe added to ongoing cholestyramine therapy, the patient's plasma sitosterol and campesterol levels decreased by approximately 50%. Her carotid bruits completely resolved, her systolic murmur diminished, and her platelet count rose to 268,000/microL. More remarkably, the tuberous xanthomas on her elbows had completely regressed. Ezetimibe added to ongoing low-dose cholestyramine therapy led to a marked improvement in plasma sterol concentrations, complete regression of xanthomatosis, resolution of carotid bruits, and improvement in cardiac murmur in a young female patient with sitosterolemia.
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PMID:Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. 1669 47

The prevention of coronary artery disease (CAD) involves therapeutic lifestyle changes such as smoking cessation, diet, weight reduction and exercise. In patients with established CAD or atherosclerosis in other vascular beds, or in patients at high risk of developing CAD, lowering serum total and low-density lipoprotein cholesterol (LDL-C) has been associated with a reduction in cardiovascular morbidity and mortality, and total mortality. Recently, large-scale studies have shown that lowering the LDL-C to less than 2.0 mmol/L is associated with a reduction of major cardiac events in patients with established CAD. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has had a major impact on preventive cardiology. Not all patients reach recommended LDL-C targets on currently available statins. Ezetimibe is a selective inhibitor of intestinal cholesterol absorption that results in an additional 15% to 25% reduction of LDL-C. The recommended dosage is 10 mg once daily; it is safe and well tolerated. Elevations in transaminase and creatine kinase occur in approximately 1% of subjects. Ezetimibe is suggested for patients who do not reach recommended LDL-C targets on an optimal dosage of statins alone. While the effects of ezetimibe on atherosclerosis have not been ascertained, clinical trials have consistently shown that the reduction in serum cholesterol correlates with a decrease in major cardiovascular events, irrespective of the method used to reduce cholesterol.
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PMID:Combination of statin and ezetimibe for the treatment of dyslipidemias and the prevention of coronary artery disease. 1695 4

Hypercholesterolemia is a major risk factor for atherosclerosis. HMG-CoA Reductase inhibitors (statins), which block hepatic synthesis of cholesterol, are the mainstay of therapy of hypercholesterolemia. Recent trials have demonstrated the importance of maintaining very low LDL-cholesterol levels in high-risk patients. Such low levels are sometimes hard to reach with statin monotherapy. Another source of cholesterol is intestinal absorption of dietary cholesterol and bile salts. Recent studies have elucidated the mechanism of intestinal cholesterol absorption. Ezetimibe, a specific inhibitor of cholesterol absorption can be used as an add-on therapy to statins in order to achieve treatment goals.
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PMID:[Cholesterol absorption as a target for the treatment of hypercholesterolemia]. 1718 57

SR-BI/apoE double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including hypercholesterolemia, occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, cardiac dysfunction and premature death. Ezetimibe is a FDA-approved, intestinal cholesterol absorption inhibitor that lowers plasma LDL cholesterol in humans and animals and inhibits aortic root atherosclerosis in apoE KO mice, but has not been proven to reduce CHD. Three-week-ezetimibe treatment of dKO mice (0.005% (w/w) in standard chow administered from weaning) resulted in a 35% decrease in cholesterol in IDL/LDL-size lipoproteins, but not in VLDL- and HDL-size lipoproteins. Ezetimibe treatment significantly reduced aortic root (57%) and coronary arterial (68%) atherosclerosis, cardiomegaly (24%) and cardiac fibrosis (57%), and prolonged the lives of the mice (27%). This represents the first demonstration of beneficial effects of ezetimibe treatment on CHD. The dKO mice were similarly treated with SC-435 (0.01% (w/w)), an apical sodium codependent bile acid transporter (ASBT) inhibitor, that blocks intestinal absorption of bile acids, lowers plasma cholesterol in animals, and reduces aortic root atherosclerosis in apoE KO mice. The effects of SC-435 treatment were similar to those of ezetimibe: 37% decrease in ILD/LDL-size lipoprotein cholesterol and 57% prolongation in median lifespan. Thus, inhibition of intestinal absorption of either cholesterol (ezetimibe) or bile acids (SC-435) significantly reduced plasma IDL/LDL-size lipoprotein cholesterol levels and improved survival of SR-BI/apoE dKO mice. The SR-BI/apoE dKO murine model of atherosclerotic occlusive, arterial CHD appears to provide a useful system to evaluate compounds that modulate cholesterol homeostasis and atherosclerosis.
Atherosclerosis 2008 May
PMID:Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice. 1805 57

To outward appearances, the publication of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial has led to a monolithic backlash against the use of ezetimibe by cardiologists for the treatment of hyperlipidemia. Rather than be swayed by popular opinion, we should each put the results of ENHANCE into context and ask the questions: should I put my trust in an imaging surrogate or in low-density lipoprotein (LDL) cholesterol (LDL-C), and how do the safety and efficacy of ezetimibe compare with other nonstatin lipid-lowering agents?
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PMID:The implications of the ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression trial: a return to first principles. 1854 13

Ezetimibe is a selective cholesterol absorption inhibitor, which potently inhibits the uptake and absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Identification and characterization of Niemann-Pick C1 Like 1 (NPC1L1) has established NPC1L1 as an essential protein in the intestinal cholesterol absorption process. While otherwise phenotypically normal, Npc1l1 null mice exhibit a significant reduction in the intestinal uptake and absorption of cholesterol and phytosterols. Characterization of the NPC1L1 pathway revealed that ezetimibe specifically binds to NPC1L1 and inhibits its sterol transport function. Npc1l1 null mice were resistant to diet-induced hypercholesterolemia, and when crossed with apoE null mice, were completely resistant to the development of atherosclerosis. In Npc1l1/apoE null mice or apoE null mice treated with ezetimibe plasma cholesterol levels were reduced primarily in the apoB48 containing chylomicron remnant lipoproteins relative to untreated apoE null mice. SR-B1 has been proposed to play a role in intestinal cholesterol uptake, but in Npc1l1/SR-B1 double null mice intestinal cholesterol absorption was not different than Npc1l1 null alone mice. Therefore, NPC1L1 is the critical intestinal sterol transporter which influences whole body cholesterol homeostasis, and is the molecular target of ezetimibe.
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PMID:Cholesterol homeostasis by the intestine: lessons from Niemann-Pick C1 Like 1 [NPC1L1). 1858 81

One of the major risk factors for ischemic disease is hyperlipidemia, which is mainly regulated by endogenous cholesterol synthesis in the liver and dietary absorption in the small intestine. In this study, we evaluated the vascular protective effects of a potent cholesterol absorption inhibitor, ezetimibe. ApoE-deficient mice were fed a chow or high-fat diet with or without ezetimibe (5mg/(kgday)) for 3 months. Co-treatment with ezetimibe significantly reduced plasma cholesterol (by 76%; from 1592 to 381mg/dL) and LDL cholesterol (by 78%; from 1515 to 319mg/dL), and increased HDL cholesterol (by 187%; from 16 to 46mg/dL) in high-fat diet mice. Consistently, a marked inhibitory effect of ezetimibe on the development of lipid-rich plaque was observed, as assessed by oil red O staining. Of importance, treatment with ezetimibe significantly improved endothelial dysfunction as assessed by the vasodilator response to acetylcholine, accompanied by inhibition of interleukin-6 mRNA and an increase in endothelial nitric oxide synthase (eNOS) mRNA in the aorta. Ezetimibe also suppressed oxidative stress and the ubiquitination-proteasome system in the aorta. Although changes in body weight and several tissue weights were similar in the groups with and without ezetimibe administration, only liver weight was significantly decreased in the ezetimibe-treated group. Interestingly, ezetimibe markedly inhibited lipid accumulation in the liver. Furthermore, ezetimibe increased the mRNA expression of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) synthase as a counteraction in the liver, but not in the aorta. Overall, ezetimibe significantly prevented atherosclerosis through not only lipid-lowering effects, but also other direct and/or indirect vascular protective actions in ApoE-deficient mice.
Atherosclerosis 2009 Mar
PMID:Vascular protective effects of ezetimibe in ApoE-deficient mice. 1860 52

Ezetimibe (EZE), an inhibitor of cholesterol absorption, reduces atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. The matrix protein ED-B fibronectin (ED-B) is upregulated in atherosclerotic lesions. Using a novel conjugate for near-infrared fluorescence (NIRF) imaging targeting ED-B, we studied the effect of EZE on plaque lesion formation in apoE(-/-) mice. ApoE(-/-) mice received EZE (5 mug/kg/d) or chow up to the age of 4, 6, and 8 months. NIRF imaging of aortic lesions was performed 24 hours after intravenous application ex vivo and in vivo. Plaque lesion formation was analyzed by histology and immunohistochemistry. Aortic lesion formation detected by Sudan staining and NIRF imaging was significantly reduced at 6 and 8 months (p < .001). Plaque areas determined by NIRF imaging significantly correlated with Sudan staining (p < .001). EZE treatment resulted in a significant reduction in plaque macrophage and ED-B immunoreactivity (both p < .05) in brachiocephalic lesions. There was a significant reduction in plaque size in brachiocephalic arteries in 8-month-old mice treated with EZE compared with mice during short-term treatment (p < .05), indicating EZE plaque regression. Targeted NIRF imaging showed a correlation to histologic lesion extension during therapeutical intervention in experimental atherosclerosis.
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PMID:Monitoring therapeutical intervention with ezetimibe using targeted near-infrared fluorescence imaging in experimental atherosclerosis. 1870 89


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