高密度脂蛋白颗粒大小与青年冠心病无症状性心肌缺血的关系

目的 探讨高密度脂蛋白(HDL)颗粒大小与青年冠心病无症状性心肌缺血(SMI)的相关性。方法 共纳入469例青年冠心病患者,其中无症状性心肌缺血组194例(SMI组,n=194),有症状性心肌缺血组275例(non-SMI组,n=275)。收集患者的一般资料,检测血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDLC)、载脂蛋白A1(ApoA1)水平及相关生化指标。计算HDL颗粒大小的量化指标HDLC/ApoA1,以及相关脂质参数TC/HDLC、non-HDLC、TG/HDLC、LDLC/HDLC。应用多因素Logistic回归分析明确HDL颗粒大小(HDLC/ApoA1)与青年冠心病SMI发生的关系。结果 与non-SMI组比较,SMI组患者血清TC、尿酸、LDLC、LDLC/HDLC、TC/HDLC、non-HDL水平偏低,HDLC、ApoA1、HDLC/ApoA1值更大(均P＜0.05)。相关分析结果显示,HDL颗粒大小(HDLC/ApoA1)与Gensini积分呈负相关(r=－0.405,P＜0.05)。多因素分析显示,HDL颗粒大小(HDLC/ApoA1)是青年冠心病患者SMI的独立预测因子(OR=0.697,95%CI:0.233~0.910,P=0.007)。受试者工作特征曲线显示,以0.36为HDL颗粒大小(HDLC/ApoA1)临界值预测青年冠心病SMI发生的灵敏度为92.1%,特异度为75.5%。结论 HDL颗粒大小(HDLC/ApoA1)与青年冠心病SMI患者冠状动脉病变严重程度呈负相关,对青年冠心病SMI具有较强的预测价值。     

Plasma high density lipoprotein cholesterol in thyroid disease.

The plasma levels of high density lipoprotein cholesterol (HDL-C) were reduced in 16 hyperthyroid female patients compared to 37 euthyroid women (33.5 +/- 8 vs. 51.5 +/- 13 mg/dl (mean +/- SD); P less than 0.001). When 5 patients were restudied after restoration of the euthyroid state, plasma HDL-C increased from 29 +/- 5 to 43 +/- 11.5 mg/dl (P less than 0.05). In addition, in 22 hypothyroid women, HDL-C levels were also diminished compared to the euthyroid group (43.4 +/- 15.5 vs. 51.5 +/- 13 mg/dl; P less than 0.05). Nine patients were restudied after L-T4 replacement therapy; their levels of HDL-C increased but not to a statistically significant degree. The daily administration of 0.3 mg L-T4 to eight normal male volunteers for 1 month did not significantly affect HDL-C levels.     

The effects of nicotinic acid treatment on high density lipoprotein particle size subclass levels in hyperlipidaemic subjects

Twenty-three consecutive hyperlipidaemic patients were treated with 4 g nicotinic acid daily for 6 weeks. The treatment resulted in the expected reduction of serum very low density (VLDL) and low density lipoproteins (LDL) and in the increase of high density lipoproteins (HDL). The cholesterol concentration of the latter fraction rose by 45%. The HDL fraction was isolated by ultracentrifugation and then subjected to gradient gel electrophoresis (gge), in order to determine the HDL particle size distribution, before and after treatment. The increase of HDL was almost exclusively confined to the largest HDL (gge) subclass HDL-2b, the protein content of which rose by 183%. In contrast, there was about a 25% decrease in the concentration of the smallest HDL(gge) subclasses, HDL-3b and HDL-3c. The levels of HDL-2b and VLDL triglycerides showed a significant inverse correlation before, as well as after, treatment. Multiple partial correlation analysis demonstrated, however, that the nicotinic acid induced increase in HDL-2b concentration showed a highly significant inverse correlation to the decrease in LDL cholesterol, but not to the decrease in VLDL triglyceride levels. Recent studies, in particular those regarding the negative correlation between both the degree and progression of coronary atherosclerosis and the HDL-2b concentration in young male myocardial infarct patients, suggest that the profound increase of HDL-2b levels by nicotinic acid treatment in hyperlipidaemic patients might be of considerable importance in the protection of coronary atherosclerosis.     

Serum high density lipoprotein in hemodialysis patients.

Uremic patients on prolonged maintenance hemodialysis (hemodialysis patients) are at high risk for atherosclerotic cardiovascular complications. To investigate the serum lipoprotein (Lp) abnormalities in hemodialysis patients, high density Lp (HDL) concentration was determined using ultracentrifugal analysis and quantitative immunoelectrophoresis in 23 hemodialysis patients, 8 non-uremic hyperlipidemic subjects, and 12 normal subjects. Immunoreactive HDL as well as HDL-cholesterol (HDL-Ch) in hemodialysis patients was lower significantly than the level in patients with non-uremic hyperlipidemia or normolipidemic healthy persons. Taking the results of previous reports into counts, decrease in HDL and HDL-Ch seems to contribute to the development of dyslipoproteinemia (broad-midband lipoproteinemia; an accumulation of the intermediate Lp or the remnant Lps) in hemodialysis patients. The results of the present study suggest that protective function proposed by the previous workers of HDL against atherosclerosis may be operated by facilitating the elimination of the accumulated midband Lps.     

Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis.

Plasma high density lipoprotein (HDL) concentrations were increased in five hypercholesterolemic normoglyceridemic patients after removal of plasma low density lipoprotein (LDL) by LDL-pheresis. In each patient up to 80% of circulating LDL was removed by passing plasma through immunoadsorption columns containing antibody to apolipoprotein B immobilized to Sepharose. Rebound of LDL was slow after the procedure: 5-7 days in four non-familial hypercholesterolemic patients and greater than 14 days in one patient with homozygous familial hypercholesterolemia. Plasma HDL rose above the pretreatment baseline during the interval between treatments in four of the five patients. When treatments were repeated weekly, time-averaged plasma LDL was lowered by 40-70%, while plasma HDL cholesterol and apolipoprotein AI were increased up to 2-fold, depending on the degree of LDL lowering. Plasma HDL concentrations fell back to their baseline values when LDL-pheresis was stopped and rose again when treatment was restarted. Thus, LDL-pheresis may augment the therapeutic effectiveness of LDL lowering by raising plasma HDL levels and the concentration of HDL relative to LDL.     

Plasma testosterone,high density lipoprotein cholesterol and other lipoprotein fractions

High density lipoprotein (HDL) cholesterol levels are strongly related to risk of heart attack. Identification of determinants of high density lipoprotein cholesterol may provide important information concerning the cause of heart disease. The relation between one possible determinant, testosterone, and high density lipoprotein cholesterol and other lipoprotein fractions was evaluated in 247 middle-aged men. The results indicate that testosterone levels (both free and total) were positively correlated with high density lipoprotein cholesterol (r = +0.24, p < 0.01) and negatively correlated with triglycerides and very low density lipoprotein cholesterol. The association between testosterone and high density lipoprotein cholesterol could not be explained by intake of alcohol, obesity, age, smoking or physical activity. Furthermore, the relation of testosterone to HDL cholesterol was independent of the relation of testosterone to very low density lipoprotein (VLDL) cholesterol or triglycerides.     

Increased turnover of very low density lipoprotein triglyceride during treatment with cholestyramine in familial hypercholesterolaemia

Kinetics of very low density lipoprotein (VLDL) triglyceride were determined in seven patients with heterozygous familial hypercholesterolaemia, using a 3H-glycerol technique. The study was repeated after 5-7 weeks of therapy with the bile acid-binding resin, cholestyramine. The rate of synthesis of VLDL triglyceride was increased by 85% (P less than 0.05) during resin therapy. Simultaneously, the fractional catabolic rate of VLDL was increased by 40% (P less than 0.02), so that only a moderate increase in plasma concentration was observed. Repeated measurements of VLDL size by electron microscopy (before, 1 week, and 5-7 weeks after initiation of therapy) indicated that a transient increase in VLDL size occurred in response to cholestyramine. The results are consistent with a stimulatory effect of bile acid sequestrants on VLDL triglyceride production and indicate that, in most subjects, a compensatory increase in VLDL triglyceride removal occurs.     

Plasma high density lipoprotein subfractions in subjects with different coronary risk indices as assessed by plasma lipoprotein concentrations

The distribution of plasma high density lipoprotein (HDL) subfractions was determined in 2 groups of healthy male subjects with different coronary risk indices (CI) as assessed by the ratio of total plasma cholesterol/HDL-cholesterol. The subjects in the 2 groups were of similar age and fitness (as assessed by VO2max). The higher risk group (CI greater than 4.0) contained a lower relative concentration of a specific HDL subfraction, HDL2b, separated by gradient gel electrophoresis, and a lower level of an apo E-rich HDL fraction, isolated by affinity chromatography, than the lower risk group (CI less than 4.0). The concentration of total HDL-cholesterol was higher in the lower risk group due to a difference in HDL2-cholesterol when separation was achieved by polyanion precipitation, but not when separation was made by ultracentrifugation. These observations suggest that the level of these specific HDL subfractions might, when taken in conjunction with plasma cholesterol concentration, provide a better index of coronary risk than that of total HDL as conventionally employed.     

Effect of ezetimibe/simvastatin compared with atorvastatin on lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia

Aim: To evaluate the effects of the usual starting and next higher doses of ezetimibe/simvastatin and atorvastatin on the cholesterol content of lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia. Methods: This post hoc analysis compared the effects of treatment with ezetimibe/simvastatin 10/20 mg vs. atorvastatin 10 and 20 mg/day and ezetimibe/simvastatin 10/40 mg/day vs. atorvastatin 40 mg/day on the cholesterol content of lipoprotein subclasses in the modified intent‐to‐treat (mITT) population (n = 1013) and in subgroups of patients with triglyceride (TG) levels <200 mg/dl (n = 600) and ≥200 mg/dl (2.6 mmol/l) (n = 413). Results: Ezetimibe/simvastatin significantly reduced low‐density lipoprotein cholesterol (LDL‐C) subclasses LDL₁‐C, LDL₂‐C and LDL₃‐C; real LDL‐C (LDL‐C^r); intermediate‐density lipoprotein cholesterol (IDL‐C), IDL₁‐C, IDL₂‐C; very low‐density lipoprotein cholesterol (VLDL‐C), VLDL₃‐C; and remnant‐like lipoprotein cholesterol (RLP‐C) from baseline more than atorvastatin at all dose comparisons (p < 0.01) in the mITT population. Significant improvements were also observed in high‐density lipoprotein cholesterol (HDL‐C) subclass HDL₃‐C at the ezetimibe/simvastatin 10/20 mg vs. atorvastatin 20 mg and highest dose comparisons (p < 0.001) and in VLDL_{1 + 2}‐C at the lowest and highest dose comparisons (p < 0.001). Changes in LDL₄‐C and LDL‐C subclass patterns (A, B and I) were comparable for both treatments. Generally, similar results were observed for patients with TG levels <200 and ≥200 mg/dl (2.3 mmol). For both treatments, notable differences between TG subgroups were that patients with elevated TGs had smaller reductions in LDL₂‐C, slightly smaller decreases in all IDL subclasses and greater decreases in all VLDL‐C subclasses than those with lower TG levels. Frequency of pattern B was also reduced more in patients with higher TGs for both treatments. Conclusions: Ezetimibe/simvastatin reduced the cholesterol content of most lipoprotein subclasses from baseline with generally similar efficacy in patients with low and high TGs. Despite the different mechanism of action of ezetimibe, the response to ezetimibe/simvastatin and atorvastatin treatment related to these lipoprotein subclasses was generally consistent with the overall effects of these therapies on the major lipid/lipoprotein classes. The clinical significance of these results awaits further study.     

Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size.

Oxidative modification of low density lipoproteins (LDL) has been implicated in the sequence of events leading to fatty streak formation in the arterial intima. Increased oxidative modifications of dense versus buoyant LDL particles could contribute to increased atherosclerosis associated with lipoprotein profiles enriched in small, dense LDL. In the present studies, we compared rates of copper-induced oxidative changes for six LDL subfractions ranging in density from 1.023 to 1.053 g/ml and mean particle diameter from 282 +/- 10 to 245 +/- 3. Rates of formation of thiobarbituric acid-reactive substances (TBARS), as indicated by the time required for half-maximal TBARS formation (T1/2max), decreased with increasing density and decreasing particle diameter to a minimum in fraction 5 (d = 1.046 g/ml, diameter = 250 +/- 5) (P = 0.007). In parallel studies using unfractionated LDL (d = 1.019-1.063 g/ml), T1/2max values were inversely correlated with the predominant LDL species diameter as determined by 2-16% gradient gel electrophoresis (P less than 0.05), consistent with the involvement of subclass composition in determining oxidative behavior. In separate experiments, subfraction differences in oxidation rates as assessed by TBARS formation were verified by the finding of similarly dispartate changes in fluorescence intensity and anionic electrophoretic mobility. T1/2max values were not related to LDL contents of alpha-tocopherol, beta-carotene, protein, triglycerides or phospholipids, but were significantly correlated with unesterified cholesterol content (r = 0.46; P less than 0.001) and were inversely associated with cholesteryl ester content (r = 0.28; P less than 0.05). The positive association of T1/2max with unesterified cholesterol suggests that this constituent may impart resistance to oxidative modification, possibly by altering properties of the surface monolayer where it resides.     

Serum high density lipoprotein in diabetic patients

Summary The purpose of the present investigation was the study of HDL lipoprotein changes in patients with diabetes mellitus. The comparison was made between 40 normal and 109 diabetic subjects and the following data was obtained: relative HDL concentration (polyacrylamide gel electrophoresis), HDL-cholesterol and apolipoprotein A concentrations. We found significant decreases in HDL (18–28%) and HDL-cholesterol (31–40 mg/ 100 ml) in most diabetics except in those with normalized serum levels of glucose and lipids (34% and 50 mg/100 ml respectively). There was a statistically significant difference in HDL and HDL-cholesterol concentrations between patients in the latter group and other diabetic patients. There was a negative correlation between HDL and HDL-cholesterol and serum glucose levels. No statistically significant difference was found when apolipoprotein A was compared in normal and diabetic subjects. Our results suggest that a deficient binding of cholesterol to apoprotein A might be present in diabetes.     

The influence of short-term treatment with simvastatin on the inflammatory profile of patients with hypercholesterolaemia

BACKGROUND: Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors can reduce cardiovascular mortality of patients with atherosclerosis. This effect is probably due not only to a decrease in concentration of cholesterol, but also to non-lipid-involving mechanisms elicited by the action of statin drugs. OBJECTIVE: To investigate the influence of short-term therapy with simvastatin on markers of inflammation and oxidation processes in patients with hypercholesterolaemia. DESIGN: We administered 20mg simvastatin daily for 12 weeks to 19 patients with hypercholesterolaemia (250-400 mg/dl). Peripheral blood samples for evaluation of plasma concentrations of thiobarbituric acid reactive substances (malonaldehyde), stable metabolites of nitric oxide (NOx) and interleukin 6 (11-6) were taken before and after the therapy. RESULTS: Plasma levels of malonaldehyde decreased significantly (from 4.533+/-0.428 versus 3.690+/-0.310 micromol/l, P = 0.04) during the study period. Similarly, there was a significant decrease in the plasma concentrations of NOx (from 33.477+/-4.352 micromol/l versus 25.919+/-2.561 micromol/l, P = 0.02). There were significant positive correlations between concentrations of total cholesterol and NOx in plasma (r = 0.4397, P = 0.008) and of low-density lipoprotein and NOx (r = 0.3987, P = 0.02). The plasma level of interleukin 6 remained unchanged by the intervention (1.837+/-0.200 versus 1.820+/-0.169 pg/ml, P = 0.54). CONCLUSIONS: Short-term therapy with simvastatin decreases the plasma concentrations of markers of peroxidation of lipids and of stable metabolites of nitric oxide in hypercholesterolaemic patients, but leaves levels of interleukin 6 unaffected.     

Atorvastatin compared with simvastatin in patients with severe LDL hypercholesterolaemia treated by regular LDL apheresis

OBJECTIVES: Atorvastatin is a new potent HMG-CoA reductase inhibitor. We evaluated whether patients with coronary heart disease and severe hypercholesterolaemia showing insufficient LDL (low-density lipoprotein) cholesterol reduction despite combined therapy with simvastatin and regular LDL apheresis will benefit from atorvastatin therapy. SETTING: Tertiary care centre, university hospital. METHODS: In 21 patients treated by LDL apheresis, concomitant simvastatin therapy (40 mg day-1) was replaced by atorvastatin (40 mg day-1) and increased to 60 and 80 mg day-1 (each for 3 months) if no side-effects were reported and NCEP treatment goals were not reached. RESULTS: In 20 of 21 patients (95%), atorvastatin resulted in significant reduction of LDL cholesterol compared with simvastatin (by 10%, additional 8% and additional 1%, with 40, 60 and 80 mg day-1, respectively). In four patients, NCEP treatment goals were reached (in three by atorvastatin alone, and in one by atorvastatin and apheresis). Patients with little reduction in LDL cholesterol to 40 mg day-1 atorvastatin benefited most by increasing the dose to 60 mg day-1 (additional 13% reduction), whilst those responding to atorvastatin 40 mg day-1 benefited less (additional 1.9% reduction). During atorvastatin therapy, significantly less plasma had to be treated during apheresis resulting in shorter apheresis time. Eight patients (38%) reported side-effects, resulting in discontinuation of atorvastatin in three (14%) and dose reduction in five patients (24%), whilst no elevation of biochemical markers was observed. CONCLUSION: Concomitant atorvastatin therapy is superior to simvastatin therapy in patients with severe hypercholesterolaemia treated with regular LDL apheresis, but is associated with a high rate of subjective side-effects.     

Effects of simvastatin on plasma lipid, lipoprotein and apolipoprotein concentrations in hypercholesterolaemia

The effect of 24 weeks of treatment with simvastatin, a newHMG coenzyme A reductase inhibitor (dosages of 20 and40 mg day^–1)on serum lipid, lipoprotein and apolipoprotein A-I and B concentrationsas well as safety parameters and subjective side effects werestudied in 11 patients with familial (FH) and 10 patients withpolygenic hypercholesterolaemia (P-HC). The effects on plasmalipoprotein and apolipoprotein concentrations had already beenachieved after four weeks in both groups and then remained duringthe study. In FH, mean fasting plasma total cholesterol concentrationdecreased from 10·51 to 6·71 mmol l^–1 (36%),and in P-HC from 6·55 to 4·54 mmol l^–1 (31%)at 24 weeks (P<0·001). Mean plasma low density lipoprotein(LDL) cholesterol concentrations also decreased, in FH from8·87 to 5·05 mmol l^–1 (43%) and in P-HCfrom 4–97 to 3–12 mmol l^–1 (37%) at 24 weeks(P<0·001). Furthermore, apolipoprotein B concentrationsdecreased significantly from 2·21 to 1·57 g l^–1(29%)(P<0·001) in FH and from 1·53 to 1·09g l^–1 (29%) (P<0·01) in P-HC. Plasma high densitylipoprotein (HDL) cholesterol increased in both FH and P-HCduring treatment. Increases were seen in both the subfractionsHDL₂ and HDL₃. Simvastatin was well tolerated. No serious clinicalor laboratory adverse effects were observed. It is concludedthat 24 weeks of treatment with simvastatin in doses up to 40mg day^–1 effectively reduces plasma total and LDL cholesterolconcentrations without causing subjective or significant objectiveside effects. Thus, simvastatin may be of great interest infuture studies for prevention of coronary heart disease dueto hypercholesterolaemia.     

Plasma lipoprotein distribution and lipid transfer activities in patients with type IIb hyperlipidemia treated with simvastatin

The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL. Whereas simvastatin significantly increased PLTP activity in an endogenous lipoprotein-dependent assay (P < 0.01), no variation was observed in a lipoprotein-independent assay. Simvastatin significantly decreased plasma CETP activity in an endogenous lipoprotein-dependent assay (P < 0.01), and the reduction in plasma cholesteryl ester transfer rates was explained by a 16% drop in CETP mass concentration (P < 0.01). In contrast, the specific activity of CETP was unaffected by the simvastatin treatment reflecting at least in part the lack of significant alteration in plasma triglyceride-rich lipoprotein acceptors. The simvastatin-induced changes in plasma CETP mass levels correlated positively with changes in plasma CETP activity (r = 0.483, P = 0.0561), in total cholesterol levels (r = 0.769; P < 0.01), and in LDL-cholesterol levels (r = 0.736; P < 0.01). Whereas the observations suggest that simvastatin might exert concomitant beneficial effects on plasma CETP and LDL levels, neither plasma cholesteryl ester transfer activity nor plasma phospholipid transfer activity appeared as the main determinants of the LDL and HDL distribution profiles in type IIb hyperlipidemic patients.     

The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia

In a genetically heterogeneous group of 109 patients with a clinical diagnosis of heterozygous familial hypercholesterolaemia (FH), the influence of gender, apolipoprotein (apo) E genotype and the type of molecular defect in the LDL-receptor (LDLR) gene on the reduction of plasma LDL-cholesterol levels to treatment with a HMG-CoA reductase inhibitor (simvastatin) were studied. Response was determined as the percentage fall in LDL-cholesterol from untreated levels and as the proportion of patients where levels fell below 4.9 or 4.1 mmol/l. Of the patients, 86 individuals had tendon xanthomata (TX+) and a diagnosis of 'definite' FH and these individuals presented with a significantly higher untreated LDL-cholesterol compared to the 23 individuals who did not have xanthomas (TX-) and a diagnosis of 'probable' FH (8.14+/-0.19 vs. 6.81+/-0.25, P= 0.001). Overall, HMG-CoA reductase inhibitor doses of 10, 20 or 40 mg/day resulted in a significant fall of LDL-cholesterol levels of 29, 39 and 49%, but at all doses those with TX had significantly higher levels than those without, and significantly fewer TX + patients achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l than the TX - group (P < 0.05 at each dose). In the TX+ group the response to treatment was of similar magnitude in men and women and in patients with different apoE genotype. In the 'probable' FH probands only three mutations were identified (detection rate 13%), one in the LDLR gene and two in the APOB gene, a detection rate significantly lower (P= 0.02) than in the 'definite' FH probands where 28 mutations were detected (detection rate 37%). In the TX + patients where no mutation was detected, treatment resulted in a greater proportion achieving LDL-cholesterol levels below 4.9 and 4.1 mmol/l compared to those with any LDLR mutation, this difference was close to statistical significance at the 4.9 mmol/l threshold at 10 mg/day (41 vs. 13%, P = 0.058). For the 14 patients with an LDLR mutation that was predicted to be 'severe', fewer achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l at each dosage compared to the 16 individuals with 'mild' mutations, and this difference was statistically significant at the maximal dosage of 40 mg/day (P = 0.018). Thus although characterisation of the molecular defect in FH patients may not be relevant to their immediate clinical management, those with a particular mutation may need more aggressive lipid-lowering treatment to reach LDL-cholesterol levels recommended to reduce the risk of coronary heart disease (CHD).     

Lipoprotein substrates for plasma cholesterol esterification. Influence of particle size and composition of the high density lipoprotein subfraction 3

Subpopulations of lipoproteins within the high density lipoprotein subfraction 3 (HDL3) have been isolated from human plasma and characterized in terms of their chemical composition and particle size. Since HDL3 are the major substrates for the esterification of plasma cholesterol, and thus play a central role in the transport of cholesterol through the plasma, these studies also examined the relative capacities of different HDL3 subpopulations to interact with lecithin: cholesterol acyltransferase. Substrate reactivity of a given preparation of lipoproteins was defined in terms of the Vmax of the cholesterol esterification reaction in incubations containing a fixed amount of human lipoprotein-free plasma as a source of the enzyme. Substrate reactivity was found to correlate inversely with the radius of HDL3 particles. This inverse relationship between particle size and substrate reactivity was independent of the particle content of cholesteryl ester.     

Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in Type IIa hypercholesterolemia

Summary Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL₂ 17%; HDL₃ 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.     

Impaired myocardial vasodilatation during hyperaemic stress is improved by simvastatin but not by pravastatin in patients with hypercholesterolaemia.

AIMS: Impaired myocardial vasodilatation during hyperaemic stress with dipyridamole has been documented in hypercholesterolaemics without evidence of ischaemia. This study investigated whether two commonly used hydroxymethylglutaryl coenzyme A reductase inhibitors, simvastatin and pravastatin, are equally effective in restoring myocardial vasodilatation. METHODS AND RESULTS: Forty-four hypercholesterolaemics with a low probability of coronary artery disease and 22 controls were studied. Before and after lipid-lowering therapy with simvastatin (n = 22) or pravastatin (n = 22), myocardial blood flow at rest and during dipyridamole loading was measured using positron emission tomography with [(13)N]ammonia, and myocardial vasodilatation was assessed. Treatments with simvastatin and pravastatin similarly reduced plasma total cholesterol and plasma low-density lipoprotein cholesterol. Resting myocardial blood flow was comparable in the controls, simvastatin group, and pravastatin group and unchanged after therapy. Myocardial blood flow during dipyridamole loading and myocardial vasodilatation was lower in the two therapy groups before treatment than in the controls. These parameters improved significantly after therapy with simvastatin, whereas no improvement was observed after pravastatin therapy. The per cent change in myocardial vasodilatation after simvastatin therapy was significantly and inversely correlated with per cent changes in plasma lipid fractions. CONCLUSION: Diminished myocardial vasodilatation in hypercholesterolaemics is improved by simvastatin but not by pravastatin, suggesting differences in vascular effects among statins.     

Low density lipoprotein particle size and risk factors of insulin resistance syndrome

The present study aimed to examine the association between low density lipoprotein (LDL) particle size and glucose and insulin variables and with other risk factors that have been related to insulin resistance syndrome. LDL particle size was determined in two groups of subjects who participated in the first examination of the Jerusalem Diabetes Study and who were invited to be re-examined after 8-10 years. The first group were non-diabetic subjects who were found to have at the first examination high insulin levels (above the sex and age specific 90th percentile of the 2 h post-glucose load insulin distribution). The second group was a random sample of individuals who had normal insulin and glucose levels at baseline. Sex-, Age- and body mass index (BMI) mean adjusted LDL-cholesterol (C), triglyceride (TG) and high density lipoprotein cholesterol (HDL-C) levels were significantly different among the LDL subclass groups. Fasting glucose levels and hemoglobin A(1c) did not differ statistically by LDL subclasses. Fasting and 2-h post load insulin levels were significantly higher in persons with LDL subclasses III and IV (small LDL), intermediate in those with LDL subclass II, and lowest in those with LDL subclass I (large LDL). Insulin resistance had an effect on the association between lipids, lipoproteins and LDL particle size. Multivariate analyses indicated that LDL-C, HDL-C and TG were independently associated with LDL particle size variability. The addition of 'insulin resistance' or insulin and glucose levels had no independent effects on LDL particle size. In conclusion, an association of LDL particle size with the cluster of risk factors that characterize the insulin resistance syndrome has been demonstrated. The association of 'insulin resistance' and LDL particle diameter, however, is not mediated directly through the level of insulinemia but via alterations in lipid metabolism.