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)

To date, lipid-lowering therapy appears to be the most effective medical intervention to retard progression of coronary atherosclerosis. In spite of promising experimental results, clinical trials completed so far have failed to demonstrate that calcium channel blockers (CCBs) alone influence the evolution of established coronary atherosclerosis. To assess whether the two therapies may have an additive or synergistic beneficial effect on human atherosclerosis, we reviewed in this regard the data of the angiographic Regression Growth Evaluation Statin Study (REGRESS) trial. REGRESS was designed to determine the effect of lipid-lowering therapy with pravastatin in symptomatic patients with normal to moderately raised cholesterol levels. Angiographically, with respect to the minimum obstruction diameter, in the pravastatin group, patients had on average 0.05 mm (95% confidence interval [CI]: 0.01-0.09) less progression if cotreated with CCBs compared with no CCB treatment, whereas in the placebo (no pravastatin) group, no effect of CCB treatment was observed (interaction test for differential effect of CCB treatment in patients with pravastatin compared with patients receiving placebo: P=.0016). With respect to the mean segment diameter, similar although not significant (P=.33) results were found. With respect to new lesion formation, in the pravastatin group, there were 50% (CI: 25-83) fewer patients with new angiographic lesions if cotreated with CCBs compared with no CCB cotreatment, whereas in the placebo (no pravastatin) group, no significant effect of CCB treatment was observed (interaction test: P=.0026). No beneficial effects of CCB treatment on clinical events were observed. Although the REGRESS trial was not designed to evaluate combination therapy, the results suggest strongly that addition of CCBs to 3-hydroxy-3-methyl-glutaryl-coenzyme reductase inhibitor therapy (pravastatin) acts synergistically in retarding the progression of established coronary atherosclerosis.
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PMID:Evidence for a synergistic effect of calcium channel blockers with lipid-lowering therapy in retarding progression of coronary atherosclerosis in symptomatic patients with normal to moderately raised cholesterol levels. The REGRESS Study Group. 863 Jun 69

Although thrombolytic drugs, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting have provided major advances in the treatment of coronary artery disease, the use of lipid-lowering drugs for secondary prevention has significantly reduced cardiovascular events in the population with coronary artery disease. Secondary prevention trials using HMG-CoA reductase inhibitors include the Familial Atherosclerosis Treatment Study (FATS), the Monitored Atherosclerosis Regression Study (MARS), the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the Asymptomatic Carotid Artery Progression Study (ACAPS), the Multi Anti-Atheroma Study (MAAS), the Scandinavian Simvastatin Survival Study (4S), the Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC I), the Regression Growth Evaluation Statin Study (REGRESS), the Pravastatin Multinational Study, and the Pravastatin, Lipids, and Atherosclerosis in Carotids (PLAC II). Mean changes from baseline of lipid fractions in these trials included: total cholesterol 18 to 35% reduction; low-density lipoprotein (LDL) cholesterol 26 to 46% reduction; high-density lipoprotein (HDL) cholesterol 5 to 15% increase; and triglyceride 7 to 22% reduction. Angiographic regression or lack of progression was statistically demonstrated in the FATS, MARS, CCAIT, MAAS, PLAC I, and REGRESS trials. Cardiovascular events decreased 25 to 92% in all trials, and there was a significant reduction in both cardiovascular and total mortality in the 4S. The greater reduction in cardiovascular events than in anatomic changes suggests that the HMG-CoA reductase inhibitors stabilized the surface of plaques. Monotherapy with HMG-CoA reductase inhibitors provides the clinical opportunity to modify the natural history of coronary artery disease.
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PMID:Monotherapy with HMG-CoA reductase inhibitors and secondary prevention in coronary artery disease. 887 86

We studied an extended family of similar genetic and environmental background to determine whether there is a difference in response to statin therapy in those subjects with heterozygous familial hypercholesterolaemia (FH Afrikaner-1 (FH1) or FH Afrikaner-2 (FH2)) compared to those with familial defective apo B-100 (FDB), or both FH plus FDB. Fasting lipid profiles and Lp(a) levels were done on 18 members of the family and then repeated following 6 weeks of therapy with simvastatin 20 mg daily. Statin therapy reduced LDL-cholesterol (LDL-C) by 31% in those with FH (n = 7); 29.8% in FDB (n = 5) and 25.4% in those with both FDB and FH (n = 5). There was no response to statin therapy in the single subject with both FH1, FH2, as well as FDB. Lp(a) levels did not change significantly either within or between any of the groups following statin therapy (FH from 6.5 (1.2-72.3) to 5.3 (1.2-52.3), FDB from 6.1 (4.70-71) to 8.2 (5.7 79) and FDB plus FH from 4.5 (2.6-17.4) to 3.1 (1.9-24) mg/dl). Statins are equally effective in lowering LDL-C in related subjects with heterozygous FH, FDB or both FDB plus FH. The ability of statins to lower LDL-C in FDB is probably due to increased hepatic uptake of lipoprotein precursors of LDL that can bind via apo E receptors. Lp(a) concentration is not reduced by drugs that stimulate LDL receptor activity implying that LDL receptors do not contribute greatly to normal clearance of Lp(a) in hypercholesterolaemic subjects with defects in receptor-mediated endocytosis of LDL.
Atherosclerosis 1997 Feb 28
PMID:Statin therapy in a kindred with both apolipoprotein B and low density lipoprotein receptor gene defects. 906 23

A large number of both primary and secondary preventive trials suggest that treatment of elevated plasma lipids may reduce the frequency of coronary heart disease (CHD) events. Meta-analyses indicate that for every 10% reduction of cholesterol, CHD mortality is lowered by 13% and all-cause mortality by 10%. Experience from several angiographic trials also suggests that coronary atherosclerosis can be retarded, and in some instances limited regression induced, by low-density lipoprotein (LDL)-cholesterol reduction and/or high-density lipoprotein (HDL)-cholesterol elevation. Coronary angiographic studies have shown that although the effects on retardation/regression of altherogenic lesions have been small, with luminal diameter changes of around 0.10 mm, the effects on clinical events were more substantial, with reductions of the order of 50%. There is also evidence that it is the mild and moderate lesions that are of particular concern with respect to the occurrence of clinical coronary events. The progression of atherosclerosis and the occurrence of coronary events are probably not exclusively dependent on a lowering of LDL-cholesterol concentrations. Analyses from the Monitored Atherosclerosis Regression Study (MARS), the Cholesterol Lowering Atherosclerotic Study (CLAS), and the Programs on the Surgical Control of the Hyperlipidaemias (POSCH) indicate that triglyceride-rich lipoproteins may also be of importance for the progression of mild/moderate lesions in subjects treated with cholesterol-lowering regimens. Recently, the results of the 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) demonstrated that bezafibrate significantly retarded the progression of coronary atheroma and coronary events in young male survivors of myocardial infarction, as assessed by changes in minimum lumen diameter. This positive outcome is most likely due to the beneficial treatment effects on the levels of serum triglycerides (-31%), plasma fibrinogen (-12%), and HDL cholesterol (+9%). The results of the BECAIT on progression of coronary atherosclerosis are comparable with those of two recent angiographic trials with HMG-CoA reductase inhibitors, the Multicenter Anti-Atheroma Study (MAAS), and the Regression Growth Evaluation Statin Study (REGRESS), despite different lipid and metabolic effects. BECAIT is the first controlled angiographic study to show that a fibrate can significantly retard the progression of coronary atherosclerosis. The exact mechanisms by which this occurs remain to be elucidated. However, the results of BECAIT illustrate the importance of factors other than LDL cholesterol in the progression of coronary atherosclerosis.
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PMID:Retardation of coronary atherosclerosis: the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and other angiographic trials. 921 Oct 18

Existing methods to analyse data from repeated arteriographic progression/regression studies are restrictive and do not fully explore the dynamics of coronary artherosclerosis. We present a new approach making a distinction between new occlusions, new lesions, and growth of existing lesions. Random effect models, based on the logistic, the Poisson, and the normal distribution are proposed with correlation depending on distance. The data from the Regression Growth Evaluation Statin Study (REGRESS) are used to validate the model. Lipid lowering treatment of pravastatin resulted in less growth of existing lesions and fewer new lesions than when placebo was given. Fewer new lesions were found in segments influenced by percutaneous transluminal coronary angioplasty (PTCA) than in segments not influenced by PTCA. Similarly, the growth of lesions influenced by PTCA was smaller than lesions not influenced by PTCA. More new occlusions were found in segments influenced by coronary arterial bypass grafting (CABG) than in segments not influenced by CABG, but 98 per cent of the new occlusions were located proximal to the bypass anastomosis. Similarly, existing lesions proximal to the bypass anastomosis showed larger growth (p < 0.001). We conclude that our new approach for analysing the arteriographic data from repeated coronary arteriographic studies appeared a fruitful way to analyse the dynamics of coronary atherosclerosis.
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PMID:On the statistical modelling of coronary arteriographic data: dynamics of coronary atherosclerosis related to systemic and focal parameters. REGRESS Study Group. Regression Growth Evaluation Statin Study. 948 17

It has proved difficult to identify high-risk patients for atherosclerosis and to determine how they might respond to medication. Recently, a common promoter variant of the human stromelysin-1 gene has been reported, which has been shown to affect the transcription. We investigated whether this polymorphism had any impact on the risk of events, especially restenosis and progression of coronary artery disease and whether the effect was modulated by treatment with pravastatin. The stromelysin-1 genotype was determined for 496 men with coronary artery disease and cholesterol levels between 4.0 and 8.0 mmol/L, participating in the Regression Growth Evaluation Statin Study (REGRESS) study, a clinical trial assessing the effect of the lipid-lowering drug pravastatin on the progression of atherosclerosis. Patients in the placebo group with 5A6A or 6A6A genotypes had more clinical events than patients with the 5A5A genotype (26% and 12%, respectively, p = 0.03). In the pravastatin group, the risk of clinical events in patients with 5A6A or 6A6A genotypes was lower, compared with placebo, whereas it was unchanged in those with a 5A5A genotype (p value for interaction: 0.038). Also, the incidence of repeat angioplasty in the placebo group was greater in patients with the 6A6A or 5A6A genotypes, compared with 5A homozygotes (38% and 40%, respectively, vs 11%, p = 0.09). Again, treatment substantially reduced the incidence in heterozygotes and 6A homozygotes (0% and 15%, respectively), whereas it was unchanged in 5A homozygotes (28%, p for interaction: 0.002). These effects were independent of the effects of pravastatin on the lipid levels. Thus, this study suggests that the stomelysin-1 promoter polymorphism confers a genotype-specific response to medication in determining clinical event-free survival and the risk for symptom-driven repeat angioplasty. This variant may therefore act as a predictor, not only of disease progression, but also of response to therapy and risk of restenosis.
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PMID:Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis. 1019 Mar 98

Elevated factor VII coagulant activity (FVII:C) has been associated with an increased risk of ischaemic heart disease, particularly for fatal events. Results of studies on the association between FVII:C and atherosclerosis are not consistent. FVII:C levels are influenced by several environmental factors and by genetic factors. One of the genetic factors is the -323Ins10 polymorphism in the promoter region of the factor VII gene, which is strongly related to FVII:C, and thus may be associated with ischaemic heart disease. We studied the association of this polymorphism with the severity and progression of atherosclerosis. In 511 male patients of the Regression Growth Evaluation Statin Study, the genotype for the -323Ins10 polymorphism was determined. The minimum obstruction diameter and the mean segment diameter were determined at baseline and after a 2-year follow-up period, and new lesion formation was assessed as well. Cardiovascular events were recorded. No relationship was observed between the -323Ins10 polymorphism and angiographic measures of disease progression, nor on the risk of new cardiovascular events. The results suggest that there is no association between the -323Ins10 polymorphism for factor VII and the severity or progression of coronary atherosclerosis in male patients with symptomatic coronary artery disease.
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PMID:The -323Ins10 polymorphism for factor VII is not associated with coronary atherosclerosis in symptomatic men. The REGRESS study group. 1070 2

Cholesterol lowering involving different therapies improves the clinical outcome of patients. To define the underlying pathomechanism, we studied whether treatment with statins was associated with changes in blood thrombogenicity, endothelial dysfunction and soluble adhesion molecule levels. Fifty hypercholesterolemic patients were treated with pravastatin (40 mg/day, n=24) or simvastatin (20 mg/day, n=26). Lipid profile and blood thrombogenicity were assessed in all patients before and after 3 months of cholesterol reducing therapy. Blood thrombogenicity was assessed as thrombus formation, perfusing non-anticoagulated blood directly from the patients' vein through the Badimon perfusion chamber (shear rate 1690/s). Endothelial-dependent vasomotor response was tested by laser-Doppler flowmeter. Soluble adhesion molecule level were measured by ELISA. Total and LDL cholesterol were reduced in the two treatment groups by statin therapy. Statin therapy was associated with a significant reduction in blood thrombogenicity and endothelium-dependent vasoresponse. No differences were observed between simvastatin or pravastatin treatment. Lipid lowering by statins had no effect on plasma levels of fibrinogen, sL-selectin, sP-selectin and sICAM-1 antigen. Cholesterol lowering by both statins reduced the increased blood reactivity and endothelial dysfunction present under hypercholesterolemia. The multiple effects of lipid lowering therapy by statins may explain the benefits observed in recent epidemiological trials.
Atherosclerosis 2000 Nov
PMID:Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins. 1105 14

Effective treatment of dyslipidemia improves prognosis. Statin therapy has been documented to decrease the cardiovascular event rate in the setting of elevated low-density lipoprotein (LDL) cholesterol levels and coronary heart disease, but most patients are not treated to the target (LDL <or=100 mg/dL) set by the National Cholesterol Education Program. The triglyceride level is also being increasingly recognized as an important mediator in the process of progressive atherosclerosis and cardiovascular events. Studies suggest the target level for triglycerides should be the same as for LDL cholesterol levels-- no more than 100 mg/dL. In order to achieve these LDL and triglyceride levels, combination therapy is required frequently. Probably the most effective combination for mixed dyslipidemia is a statin with niacin. The use of adjunctive omega-3 supplementation also should be considered especially for patients with elevated triglyceride levels. Other adjunctive agents including sitostanol ester (in the form of a margarine) and a well-tolerated second generation bile acid sequestrant that will lower LDL cholesterol an additional 10% to 18% and will be available soon.
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PMID:Combination drug therapy for dyslipidemia. 1112 91

To date, there are no evidence-based data to support specific drug therapy for a patient with atheroembolism. It makes sense to use HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) in any patient with atherosclerosis, as these drugs have been shown to reduce the risk of myocardial infarction and stroke, and have a theoretical benefit on plaque stabilization. Surgical treatment should be considered for patients with abdominal aortic or popliteal artery aneurysms and downstream atheroembolism. There are case reports of atheroemboli in patients worsening after given warfarin or heparin. For this reason, some institutions are reluctant to prescribe these drugs for patients with atheroemboli or thromboemboli from aortic plaque. However, the incidence of this complication is quite low. Anticoagulation probably should be stopped if a patient develops atheroembolism. Similarly, the current state of knowledge does not allow for selecting specific pharmacologic intervention in patients with thromboemboli from aortic plaque. Statin therapy does make sense, as these drugs theoretically stabilize plaques and prevent plaque hemorrhage, thrombosis, and subsequent embolization. Unstable aortic plaques may develop superimposed thrombi (red thrombi on pathologic examination), easily seen as mobile elements on transesophageal echocardiography. Therefore, it is possible that anticoagulation with warfarin might prevent embolic events in these patients. For this reason, we are often in the position of recommending warfarin therapy for patients with emboli and severe atheromas seen on transesophageal echocardiography, especially when superimposed mobile thrombi are seen. There are small series in the literature that indicate the potential benefit of warfarin. However, until a large multicenter randomized clinical trial is done, the use of warfarin can not be definitively recommended. Antiplatelet agents, although safer than warfarin (less risk of hemorrhage), have not been proven beneficial in patients with thromboembolism from the aorta. Surgery (endarterectomy) of the aortic arch is a very risky procedure that should not be performed routinely, but may be used in highly selected patients.
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PMID:Embolism from the Aorta: Atheroemboli and Thromboemboli. 1134 63


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