Protective effect of lupeol and its ester on cardiac abnormalities in experimental hypercholesterolemia

Hyperlipidemia is a major risk factor for the premature development of coronary heart disease and it has been shown to increase the incidence of myocardial ischemia and cardiac events. Pentacyclic triterpenes possess antiatherosclerotic, antioxidant, anti-inflammatory and cytoprotective effects. To study the effect of plant derived triterpene, lupeol and its ester lupeol linoleate, on lipid status and biochemical changes on heart tissue, male albino Wistar rats were fed high-cholesterol diet (normal rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. There was a significant (p<0.001) increase in the levels of total cholesterol, triglycerides and phospholipids along with augmented activities of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase in the heart tissue. Triterpenes treatment reduced the above alterations produced in hypercholesterolemic rats. The transmembrane enzymes, namely Na(+), K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase showed a decrease in their activities. Triterpenes treatment reversed these levels, prevented the hypertrophic cardiac histology and restored the normal ultrastructural architecture. In conclusion, lupeol and lupeol linoleate intervention minimized the lipid abnormalities and abnormal biochemical changes induced by HCD fed rats. This shows that triterpenes possess cardioprotective effects which will be beneficial in hypercholesterolemic condition. Out of these two triterpenes tested, lupeol linoleate appeared to be even more effective than lupeol.     

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients

ABSTRACT

Objective: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses.

Research design and methods: Double-blind, multicenter, 6‐week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10?mg/day), the next highest (10/40 or 20?mg/day), and maximum doses (10/80 or 40?mg/day).

Results: At all doses and across doses, ezetimibe/simvastatin reduced LDL‐C levels significantly more (52–61%) than rosuvastatin (46–57%; p ≤ 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p ≤ 0.005) attained LDL‐C levels < 70?mg/dL (1.8?mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (?p < 0.001), non-high-density lipoprotein cholesterol (?p < 0.001), lipid ratios (?p ≤ 0.003), and apolipoprotein B (?p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (?p = 0.004) and next highest (?p = 0.006) doses, and across all doses (?p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10?mg versus 10/20?mg/day (?p = 0.004) and 40?mg versus 10/80?mg/day (?p < 0.001).

Conclusion: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL‐C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.     

Recent advances on Ilex paraguariensis research: Minireview

Ilex paraguariensis dried and minced leaves are made into a brewed tea, prepared in a sui generis manner by large populations in South America, having evolved from a tea drunk by the Guarani ethnic group to a beverage that has a social and almost ritualistic role in some South American modern societies. It is used both as a source of caffeine, in lieu or in parallel with tea and coffee, but also as a therapeutic agent for its alleged pharmacological properties. Although with some exceptions, research on biomedical properties of this herb has had a late start and strongly lags behind the impressive amount of literature on green tea and coffee. However, in the past 15 years, there was a several-fold increase in the literature studying Ilex paraguariensis properties showing effects such as antioxidant properties in chemical models and ex vivo lipoprotein studies, vaso-dilating and lipid reduction properties, antimutagenic effects, controversial association with oropharyngeal cancer, anti-glycation effects and weight reduction properties. Lately, promising results from human intervention studies have surfaced and the literature offers several developments on this area. The aim of this review is to provide a concise summary of the research published in the past three years, with an emphasis on translational studies, inflammation and lipid metabolism. Ilex paraguariensis reduces LDL-cholesterol levels in humans with Ilex paraguariensis dyslipoproteinemia and the effect is synergic with that of statins. Plasma antioxidant capacity as well as expression of antioxidant enzymes is positively modulated by intervention with Ilex paraguariensis in human cohorts. A review on the evidence implicating Ilex paraguariensis heavy consumption with some neoplasias show data that are inconclusive but indicate that contamination with alkylating agents during the drying process of the leaves should be avoided. On the other hand, several new studies confirm the antimutagenic effects of Ilex paraguariensis in different models, from DNA double breaks in cell culture models to mice studies. Novel interesting work has emerged showing significant effect on weight reduction both in mice and in rat models. Some mechanisms involved are inhibition of pancreatic lipase, activation of AMPK and uncoupling of electron transport. Intervention studies in animals have provided strong evidence of anti-inflammatory effects of Ilex paraguariensis, notably protecting cigarette-induced lung inflammation acting on macrophage migration and inactivating matrix-metalloproteinase. Research on the effects of Ilex paraguariensis in health and disease has confirmed its antioxidant, anti-inflammatory, antimutagenic and lipid-lowering activities. Although we are still waiting for the double-blind, randomized prospective clinical trial, the evidence seems to provide support for beneficial effects of mate drinking on chronic diseases with inflammatory component and lipid metabolism disorders.     

家族性高胆固醇血症纯合子患者低密度脂蛋白受体缺陷的研究

目的：研究家族性高胆固醇血症纯合子患者的发病机理。方法：在临床研究和家系调查的基础上, 培养患者皮肤成纤维细胞, 采用放射性配体结合受体分析技术研究其低密度脂蛋白受体。结果：患者低密度脂蛋白受体对低密度脂蛋白的高亲和性结合为正常人的７８．２％，高亲和性内移和降解则分别为正常人的３．６％和１．７％。结论：本例家族性高胆固醇血症纯合子患者的发病机制为低密度脂蛋白受体内移功能障碍。     

Impaired coronary flow velocity reserve and aortic distensibility in patients with untreated hypercholesterolemia—an echocardiographic study

Introduction Hypercholesterolemia is a primary risk factor for the development of atherosclerosis and leading to severe stages of coronary artery disease (CAD) and aortic atherosclerosis (AA). The objective of this investigation was to measure elastic modulus [(E(p), in 10³ mmHg] and Young’s circumferential static elastic modulus [(E(s), in 10³ mmHg] as aortic distensibility indices and coronary flow velocity reserve (CFR) in untreated hypercholesterolemic (HC) patients in the course of the same stress transesophageal echocardiography (TEE) and to compare their results to normochole- sterolemic (NC) subjects. Patients and methods The following patient populations were compared: 17 NC subjects with negative coronary angiograms, 18 patients with untreated hypercholesterolemia with a negative coronary angiogram and 23 HC patients with significant left anterior descending coronary artery (LAD) disease. All patients underwent coronary angiography, transthoracic and stress TEE examinations. Results CFR was significantly reduced in patients of both groups with hypercholesterolemia as compared to NC subjects (1.99±0.76 and 1.79±0.32 vs. 2.58±0.63, P < 0.05, respectively). E(p) was significantly increased in HC patients with negative coronary angiograms as compared to NC subjects (0.39±0.18 vs. 0.67±0.19, P < 0.05), while further increase was found in HC patients with LAD disease (0.67±0.19 vs. 1.09±0.52, P < 0.05). E(s) behaved similarly (4.06±2.73 vs. 7.60±3.70 vs. 11.38±6.91, P < 0.05, respectively). Conclusion In conclusion it may be stated that CFR and aortic distensibility indices can be evaluated simultaneously by stress TEE in HC patients. CFR and aortic distensibility were impaired in HC patients as compared to NC subjects.     

Meaning of Low‐Density Lipoprotein‐Apheresis for Hypercholesterolemic Patients at High Risk for Recurrence of Coronary Heart Disease

Abstract: The goal of cholesterol‐lowering therapy in hypercholesterolemic patients at high risk for recurrence of coronary heart disease (CHD) is the prevention of acute coronary syndrome by stabilization of coronary atheromatous plaque. We often encounter patients in whom it is difficult to maintain the serum cholesterol level at a desirable level with dietary therapy and drug treatment, despite the development and use of statins. For secondary prevention in patients who are at high risk for the recurrence of CHD and whose cholesterol level cannot be controlled by drugs alone, low‐density lipoprotein (LDL)‐apheresis therapy, which involves removal of LDL through extracorporeal circulation, is now available. Many reports concerning improvement of vascular endothelial function, improvement of myocardial ischemia, regression of coronary atherosclerotic lesions, stabilization of coronary plaque, and reduction in the incidence of cardiac events as a result of LDL‐apheresis treatment have been published in various countries. We believe that LDL‐apheresis should be performed on hypercholesterolemic patients with existing CHD for whom diet and maximum cholesterol‐lowering drug therapies have been ineffective or not tolerated and whose LDL cholesterol level is 160 mg/dL or higher.     

A case report of the cascade filtration system: a safe and effective method for low-density lipoprotein apheresis during pregnancy

Women with familial hypercholesterolemia (FH) should be treated effectively during pregnancy, as elevated low-density lipoprotein cholesterol (LDL-C) levels may result in life-threatening consequences. Hydroxymethylglutaryl-coenzyme A reductase inhibitors are contraindicated during pregnancy, therefore LDL apheresis should be considered in the management of such pregnant cases. There are five different methods of selective LDL apheresis: heparin-induced extracorporeal LDL precipitation, double filtration plasmapheresis, direct adsorption of lipoproteins, dextran sulfate adsorption, and LDL immunoadsorption. The cascade filtration system is another modern and effective method for the extracorporeal elimination of LDL-C, although it is not as selective as the methods mentioned above. Herein, we present the case of a pregnant woman with heterozygous FH and extremely elevated LDL-C levels who has been successfully treated with the cascade filtration system until delivery. As far as we can ascertain, LDL apheresis with the cascade filtration system during pregnancy has not yet been reported in the literature.     

Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles

Given that combination therapy with statin plus fibrate confers a risk of myopathy, it is worthwhile to determine whether statin or fibrate monotherapy is associated with greater clinical benefit in individuals with combined hyperlipidemia. In this randomized double-blind study, we compared the efficacy of simvastatin and fenofibrate on indexes of endothelial function (flow-mediated dilation (FMD) of the brachial artery) and inflammatory markers (plasma high-sensitivity C-reactive protein (CRP), interleukin-1β (IL-1β), soluble CD40, and soluble CD40 ligand (sCD40L) levels), as surrogate indicators of future coronary heart disease (CHD), in patients with combined hyperlipidemia. A total of 70 patients with plasma triglyceride levels between 200 and 500 mg/dl and total cholesterol levels of >200 mg/dl were randomly assigned to receive either simvastatin (20 mg/day) (n=35) or micronized fenofibrate (200 mg/day) (n=35) for 8 weeks. Treatment with simvastatin was associated with significantly greater reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), while the decrease in triglycerides was significantly greater in patients receiving fenofibrate. Both fenofibrate and simvastatin markedly reduced plasma levels of high-sensitivity CRP, IL-1β, and sCD40L, and improved endothelium-dependent FMD without mutual differences. The changes in plasma inflammatory markers did not correlate with baseline clinical characteristics in both groups. However, the improvement in FMD with fenofibrate treatment correlated inversely with baseline high-density lipoprotein cholesterol (HDL-C) levels, whereas the improvement in FMD with simvastatin treatment was positively related to HDL-C levels. Accordingly, in the subgroup with a baseline HDL-C of ≤40 mg/dl, only fenofibrate significantly improved the endothelium-dependent FMD. On the other hand, in the subgroup with HDL-C >40 mg/dl, only treatment with simvastatin achieved significant improvement in FMD. The data here indicate that in patients with combined hyperlipidemia, both fenofibrate and simvastatin have comparative beneficial effects on various inflammatory markers and differential beneficial effects on endothelial function according to baseline HDL-C levels. These findings should be validated by additional prospective studies, in which patients are stratified by baseline HDL-C prior to randomization.     

Splenic extrafollicular reactions and BM plasma cells sustain IgM response associated with hypercholesterolemia

Hypercholesterolemia associated with atherosclerotic disease is known to be associated with increased total and oxidized (ox) low‐density lipoprotein (LDL)‐specific IgM antibodies in circulation. However, the B‐cell responses accounting for this increase remain to be elucidated. Here, we observed an association between total IgM and oxLDL‐specific IgM autoantibodies with cholesterol in the plasma of hypercholesterolemic apolipoprotein E deficient (apoE^?/?) mice. Our findings also indicated that oxLDL‐specific IgM autoantibodies production was restricted to the spleen, but not the lymph nodes. Further examination of the spleen revealed that the extrafollicular responses, but not germinal center reactions, were the dominant antibody‐producing pathway. A quiescent population of IgM⁺ plasma cells including oxLDL‐specific IgM antibody secreting cells in BM also sustained the elevated IgM antibodies response in circulation. We determined that IgM⁺ plasma cells in the BM were, at least in part, splenic derived by depleting CD11c⁺ DCs and plasmablasts to disrupt the humoral responses. In addition, lowering hypercholesterolemia reduced IgM response by interfering with extrafollicular and BM responses. By elucidating the mechanism underlying the elevated IgM response observed in hypercholesterolemia, this study provides insight into novel immunotherapeutic avenues.     

秦皇岛市北戴河区教师行业高胆固醇血症的发病情况

目的分析秦皇岛市北戴河区教师行业高胆固醇血症发病的逐年变化情况。方法分别筛选2009及2010年北戴河区城镇居民参加体检的教职工的体检结果,按照体检时间、年龄、性别进行分组,并对各组体检数据进行统计学处理,分析北戴河区教师行业高胆固醇血症的检出情况,分析其增长原因及其对策。结果 2010年教师行业总体的高胆固醇血症检出率明显高于2009年,差异有统计学意义(P0.01),不同性别及不同年龄组的高胆固醇血症检出率2010年均较2009年明显增多,差异有统计学意义(P0.01)。2009年男性的高胆固醇血症检出率高于女性,2010年女性高于男性,高胆固醇血症的逐年增长率女性多于男性。结论北戴河区教师行业高胆固醇血症的检出情况呈逐年增多趋势;女性增长多于男性。