Lipoprotein(a) : new insights into an atherogenic lipoprotein

Lipoprotein(a) constitutes a macromolecular complex in human plasma that combines structural features from the blood clotting and the lipoprotein systems. Aside from the discovery of lipoprotein(a) [Lp(a)] as a potential independent risk factor for premature cardiovascular disease its physiological role and activity remains obscure. Since the site of catabolism has not yet been fully characterized, there is intensive search for factors which influence plasma Lp(a) levels. Several clinical conditions and metabolic states have been identified to be added to the disorders of the lipid metabolism itself that modulate Lp(a) plasma levels. Diseases of the kidney and their accompanying factors (proteinuria and nephrotic syndrome) as well as end-stage renal disease and their treatment modalities (hemodialysis, peritoneal dialysis, and kidney transplantation) have all been found to increase Lp(a) plasma levels substantially. Fluctuations in Lp(a) also seem to occur in states of hormonal changes, such as in diabetes mellitus, after estrogen treatment, and during pregnancy. Recently a plausible mechanism for the atherogenic activity of Lp(a) has been ascribed to the inhibiting effect of Lp(a) on plasminogen activation, thus decreasing plasmin formation which in turn reduces the activation of transforming growth factor , a potent inhibitor of smooth muscle cell proliferation. Lp(a) exerts its pathological effect at plasma levels in the range of 20–30 mg/dl. Therefore, it seems mandatory to quantitate Lp(a) levels in patients who are at risk of developing progressive atherosclerotic disease to identify those with high levels of this unique atherogenic lipoprotein. Since plasma levels of Lp(a) are insensitive to diet, exercise, and most lipid-lowering drugs, the reduction of other risk factors that predispose to atherosclerotic disease is the only clinical strategy at present.Abbreviations apo(a) apolipoprotein(a) - apoB apolipoprotein B - CAPD continuous ambulatory peritoneal dialysis - ESRD end-stage renal disease - FCHL familial combined hyperlipidemia - FH familial hypercholesterolemia - HD hemodialysis - HGF hepatocyte growth factor - HMG-CoA 3-hydroxy-3-methyl glutaryl coenzyme A - LDL low-density lipoprotein - Lp(a) lipoprotein(a) - TGF-R transforming growth factor- - TGRLP triglyceride-rich lipoproteins     

Heparin-induced extracorporal low-density-lipoprotein precipitation (H. E. L. P.) to improve the recovery of hearing in patients with sudden idiopathic hearing loss

The pathogenesis of sudden hearing loss (SHL) is still not well understood. Possible causes include increased blood viscosity, microthrombosis or altered blood flow. Hypercholesterolemia, hyperfibrinogenemia and increased platelet aggregation are frequently observed in patients with SHL. The aim of this study was to investigate whether drastic lowering of plasma cholesterol and fibrinogen by selective extracorporal apheresis could have a beneficial effect on hearing recovery in these patients. Seven patients with SHL were treated with an extracorporal procedure removing fibrinogen and cholesterol from plasma. Six of the seven patients showed an immediate improvement in auditory thresholds following a single treatment of heparin-induced low-density lipoprotein precipitation. These findings indicate for the first time that acute and drastic removal of plasma fibrinogen and low-density lipoproteins may be an effective clinical method for the treatment of patients with SHL. Received: 19 February 1999 / Accepted: 6 May 1999     

The tolerability,pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability,in healthy volunteers

447C88 (N-Heptyl-N-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC₅₀ of 10.2 ng·ml^–1 (23 nM). It is poorly absorbed but 5 mg·kg^–1·day^–1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats.In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food.All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean C_max and AUC were 1.8 ng·ml^–1 and 9.0 ng·ml^–1·h after 200 mg rising to 5.4 ng·ml^–1 and 23.8 ng·ml^–1·h respectively after 800 mg; t_1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.     

Reflex testing I: algorithm for lipid and lipoprotein measurement in coronary heart disease risk assessment

We reviewed the current literature in order to construct a reflex testing algorithm that maximizes clinical utility and cost-effectiveness of lipid and lipoprotein testing. The algorithm was based on the 2nd Report of the National Cholesterol Education Program Adult Treatment Panel guidelines for use of total cholesterol (TC), triglycerides (TG), HDL-C, and LDL-C, and published reports describing the clinical use of apolipoprotein B and lipoprotein (a). The success of this algorithm was tested in a low-risk general and a high-risk hyperlipidemic patient population. Lipid data and non-lipid risk factors were obtained from a national database and from patients seen at two lipid clinics. A total of 16 968 individuals from the National Health and Nutrition Examination Survey III database comprised the low-risk group, and 239 patients examined in the Hartford Hospital and Washington University Lipid Clinics comprised the high-risk group. We found a solid scientific base to support the NCEP guidelines and reasonable support for limited testing of apoB and Lp(a). According to the algorithm, the direct LDL-C assay was deemed unnecessary in 98% and 91% of low- and high-risk subjects, respectively, if one assumes that the Friedewald equation is adequate with TG≤4.00 g/l. With a more conservative cutoff of TG≤2.50 g/l, the algorithm canceled 92% and 81% of direct LDL tests, respectively. The algorithm also limited TG to 20 and 64%, apoB to 6 and 20%, and Lp(a) to 15 and 56%, of low- and high-risk groups, respectively. Use of a comprehensive, reflex algorithm for coronary heart disease risk assessment will substantially reduce the utilization of laboratory services without diminishing the clinical value of these tests. The algorithm will prevent the overuse of certain expensive tests (direct LDL) while promoting the limited use of underutilized tests [apoB and Lp(a)].     

Effect of metabolic acidosis on hyperlipidemia in uremia

Nine patients (aged 18±1 years) on maintenance hemodialysis with metabolic acidosis and hyperlipidemia were studied before and after 2 weeks of oral sodium bicarbonate (NaHCO₃) treatment to correct the acidosis. To control for the effect of additional sodium, they were also studied after 2 weeks of an equivalent amount of oral sodium chloride (NaCl). Oral NaHCO₃ treatment led to significant increases in venous pH, serum bicarbonate, and serum 1,25-dihydroxyvitamin D₃ concentrations, but no significant change in total and ionized calcium, phosphate, sodium, potassium, creatinine, blood urea nitrogen, and intact parathyroid hormone concentrations. Oral NaCl did not change any of the biochemical parameters. Before treatment of acidosis, these uremic patients had high serum triglycerides, low serum high-density lipoprotein (HDL) cholesterol, but normal total cholesterol compared with controls. Following 2 weeks of NaHCO₃ treatment, there was a significant decrease in the serum concentrations of triglycerides (P<0.01). HDL and total cholesterol did not change. There were no changes in triglycerides, HDL or total cholesterol from baseline values following 2 weeks of NaCl. Thus treatment of metabolic acidosis ameliorated hypertriglyceridemia but had no effect on HDL and total cholesterol in patients with uremia on hemodialysis. The underlying mechanism may involve 1,25-dihydroxyvitamin D3. Received: 3 August 1998 / Revised: 30 November 1998 / Accepted: 2 December 1998     

Cholesterol and other cardiovascular risk factors in a working population in Ile-De-France (France): First results of the PCV-METRA study

In 1989, the French PCV-METRA Group (PCV-METRA = Prévention Cardio-Vasculaire en Médecine du Travail) started a large prospective survey of cardiovascular (CDV) morbidity and mortality and of CVD risk factors, especially cholesterol, in a working population in Ile-de-France, a region including Paris. This report presents the first results of this study, based on a sample of 5758 men and 2603 women, aged 18–65 years. The variables examined included the levels of total cholesterol (TC), High-density-lipooprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and the other major CVD risk factors (smoking, sedentary way of life, hypertension, hypercholesterolemia, use of oral contraceptives and familial history of CVD risks). TC and LDL-C significantly increased with age. The changes with age were significantly different in men and women. The levels were similar in both sexes at less than 30 yrs, increased sharply for men after age 30 and were significantly higher in men than in women from 30 to 55 yrs. Beyond 55 yrs, no difference was obserbed between the two sexes. In contrast, HDL-C was higher in women at all age ranges. In the total sample, 35% of men and 21% of women were hypercholesterolemic (TC 2.4 g/ L). Our observations fully confirm and refine previous findings in the US and in other European countries. In addition, a substantial set of data on CVD risk factors for the working population in France, especially for female subjects for whom data are scanty, is now available.Corresponding author.     

The Effect of Gastric Bypass on Cholesterol,HDL, and the Risk of Coronary Heart Disease

A review of 150 charts revealed that 36 patients had pre-operative serum cholesterol greater than 200 mg% prior to Roux-Y gastric bypass. The average pre-operative weight was 266 lb (121 kg) and at 1 year post-operative 166 lb (75 kg), or 100 lb (45 kg) lost (77% excess weight loss). We compared the following pre- and post- operative data and found that: (1) cholesterol was decreased by 24% and triglycerides decreased by 40%; (2) post-operative cholesterol/HDL-C ratio of 3.31 put our patients in the half of average risk category for a clinical pathological coronary event according to the SmithKline Beecham Laboratories risk ratio chart. We conclude that Roux-Y gastric bypass and its ability to produce a significant weight loss and markedly affect cholesterol and triglyceride metabolism will also reduce a patient's risk of myocardial infarction.     

Effect of carbon disulphide intoxication on fecal excretion of end products of cholesterol metabolism

Summary The aim of this study was to compare the time course of ¹⁴C-steroid excretion following administration of ¹⁴C-cholesterol in normal and CS₂intoxicated rats. The excretion of steroid with the feces was evaluated in the normal and CS₂ intoxicated rats at the end of 7 month exposure to CS₂. The results of the experiment indicated that in rats exposed to CS₂ excretion of ¹⁴C-steroid is lower. It was due to a reduced excretion of ¹⁴C-bile acid fraction while at the same time the share of sterol + rose. On the basis of our former results which excluded the influence of CS₂ on absorption of cholesterol and indicated its effect on cholesterol synthesis it was revealed in this experiment that intoxication with CS₂ also inhibits cholesterol degradation. Disturbances of both processes can be essential for accumulation of cholesterol in blood of animals intoxicated with CS₂.This investigation has been carried out under the Polish-American agreement No. 05-008-2 with the Occupational Health Program, U.S. Public Health Service     

针刺对去势雌性大鼠血脂的影响

目的　观察去势雌性大鼠模型血脂的变化及针刺对其的影响。方法　采用 6月龄 wistar雌性大鼠 80只 ,随机分成假手术组、针刺组和空白对照组。结果　去卵巢大鼠的血清胆固醇高于假手术组 ( P<0 .0 5 ) ,血清甘油三酯无明显差异。针刺组治疗后血清胆固醇低于空白对照组 ( P<0 .0 5 ) ,与假手术组对比无明显差异 ;针刺组血清甘油三酯治疗前后无明显差异 ;空白对照组血脂无明显变化。结论　去势后雌性大鼠血清胆固醇显著升高 ,血清甘油三酯无明显变化 ;针刺治疗能使去势后雌性大鼠升高的血清胆固醇水平降低到未去势大鼠血清胆固醇水平     

高效液相色谱法测定鸡蛋蛋黄中胆固醇含量

采用高效液相色谱法,以C18柱(3.9 mm×150 mm.5 μm)为固定相,乙腈-异丙醇(4:1,v/v)为流动相,流速1.0 ml/min;检测波长210 nm,测定鸡蛋蛋黄中胆固醇含量,结果胆固醇浓度在0.05-0.8 g/L范围内与色谱峰面积呈线性关系,相关系数r=0.999 2,高、中、低3个浓度的加样回收率为98.26%-100.2%,日内精密度(RSD)(3.8%)。4种鸡蛋蛋黄的胆固醇平均含量分别为11.61 mg/g蛋黄、10.49 mg/g蛋黄、9.82 mg/g 蛋黄和9.46 mg/g蛋黄,该方法适用于蛋黄胆固醇的快速测定.具有准确、快速、简便、重现性好等优点。