Kirk EA; Sutherland P; Wang SA; Chait A; LeBoeuf RC
Department of Medicine and the Nutritional Sciences Program, University of Washington, Seattle, WA 98195, USA.
J Nutr (United States) Jun 1998, 128 (6) p954-9

Susceptibility to atherosclerosis is determined by a combination of genetic and environmental factors, including diet. Consumption of diets rich in soy protein has been claimed to protect against the development of atherosclerosis. Potential mechanisms include cholesterol lowering, inhibition of lipoprotein oxidation and inhibition of cell proliferation by soy proteins or isoflavones, such as genistein , that are present in soy . This study was designed to determine whether soy isoflavones confer protection against atherosclerosis in mice and whether they reduce serum cholesterol levels and lipoprotein oxidation. C57BL/6 and LDL receptor-deficient (LDLr-null) mice were fed soy protein-based, high fat diets with isoflavones present (IF+, 20.85 g/100 g protein, 0.027 g/100 g genistein , 0.009 g/100 g daidzein) or diets from which isoflavones , and possibly other components, had been extracted (IF-, 20.0 g/100 g protein, 0.002 g/100 g genistein , 0.001 g/100 g daidzein). Because LDLr-null mice develop extensive atherosclerosis and hypercholesterolemia after minimal time on a high fat diet, they were fed the diets for 6 wk, whereas C57BL/6 mice were fed the diets for 10 wk. Plasma cholesterol levels did not differ between LDLr-null mice fed IF- and those fed IF+, but were 30% lower in C57BL/6 mice fed the IF+ diet than in those fed the IF- diet. Susceptibility of LDL to oxidative modification, measured as the lag phase of conjugated diene formation in LDLr-null mice, was not altered by isoflavone consumption. All LDLr-null mice developed atherosclerosis, and the presence or deficiency of dietary isoflavones did not influence atherosclerotic lesion area. In contrast, atherosclerotic lesion area was significantly reduced in C57BL/6 mice fed IF+ compared with those fed IF-. Thus, this study demonstrates that although the isoflavone-containing diet resulted in a reduction in cholesterol levels in C57BL/6 mice, it had no effect on cholesterol levels or on susceptibility of LDL to oxidative modification in LDLr-null mice. Further, dietary isoflavones did not protect against the development of atherosclerosis in LDLr-null mice but did decrease atherosclerosis in C57BL/6 mice. These findings suggest that soy isoflavones might lower cholesterol levels by increasing LDL receptor activity, and the reduction in cholesterol may offer some protection against atherosclerosis.

Barnes S.
S. Barnes, Dept. of Pharmacology and Toxicology, University of Alabama, Birmingham, AL 35294 United States
Proceedings of the Society for Experimental Biology and Medicine (United States), 1998, 217/3 (386-392)

Soy is a unique dietary source of the isoflavones , genistein and daidzein. It has been part of the Southeast Asian diet for nearly five millenia, whereas consumption of soy in the United States and Western Europe has been limited to the 20th century. Heavy consumption of soy in Southeast Asian populations is associated with reduction in the rates of certain cancers end cardiovascular disease. Recent experimental evidence suggests that phytochemicals in soy are responsible for its beneficial effects, which may also include prevention of osteoporosis, a hereditary chronic nose bleed syndrome, and autoimmune diseases. Exposure of soy formula-fed infants to the potential estrogenizing effects of the isoflavones is limited by the first pass effect of the liver following the uptake of isoflavones from the gut. Several mechanisms of action of isoflavones have been proposed-both through estrogen-dependent and estrogen-independent pathways.

Brouillard R; George F; Fougerousse A
Laboratoire de Chimie des Polyphenols, Universite Louis Pasteur, Faculte de Chimie, Strasbourg, France.
Biofactors (Netherlands) 1997, 6 (4) p403-10

Over the past few years, it has been accepted that a moderate red wine consumption is a factor beneficial to human health. Indeed, people of France and Italy, the two major wine-producing European countries, eat a lot of fatty foods but suffer less from fatal heart strokes than people in North-America or in the northern regions of Europe, where wine is not consumed on a regular basis. For a time, ethanol was thought to be the "good" chemical species hiding behind what is known as the "French paradox". Researchers now have turned their investigations towards a family of natural substances called "polyphenols", which are only found in plants and are abundant in grapes . It is well known that these molecules behave as radical scavengers and antioxidants, and it has been demonstrated that they can protect cholesterol in the LDL species from oxidation, a process thought to be at the origin of many fatal heart attacks. However, taken one by one, it remains difficult to demonstrate which are the best polyphenols as far as their antioxidant activities are concerned. The main obstacle in that kind of research is not the design of the chemical and biological tests themselves, but surprisingly enough, the limited access to chemically pure and structurally elucidated polyphenolic compounds. In this article, particular attention will be paid to polyphenols of red wine made from Vitis vinifera cultivars. With respect to the "French paradox", we address the following question: are wine polyphenolic compounds identical to those found in grapes (skin, pulp and seed), or are there biochemical modifications specifically taking place on the native flavonoids when a wine ages? Indeed, structural changes occur during wine conservation, and one of the most studied of those changes concerns red wine colour evolution, called "wine ageing". As a wine ages, it has been demonstrated that the initially present grape pigments slowly turn into new more stable red pigments. That phenomenon goes on for weeks, months and years. Since grape and wine polyphenols are chemically distinct, their antioxidant activities cannot be the same. So, eating grapes might well lead to beneficial effects on human health, due to the variety and sometimes large amounts of their polyphenolic content. However, epidemiological surveys have focused on wines,not on grapes .... (35 Refs.)

Crist DM; Peake GT; Stackpole PJ
Clin Exp Pharmacol Physiol (England) Jul 1986, 13 (7) p513-8

Testosterone cypionate administration in weight-trained subjects reduced serum high-density lipoprotein cholesterol (HDL-C) levels without affecting the total cholesterol (Total-C)/HDL-C ratio. Nandrolone decanoate administration also reduced HDL-C levels, but elevated the Total-C/HDL-C ratio. These findings could not be attributed to changes in exercise patterns, dietary intake, or alcohol consumption. It is concluded that the synthetic androgen employed in this study produced a worsening of potential lipid-related risk factors for ischemic heart disease and that exogenous testosterone has a much less pronounced effect on such risk factors.

Ghafoorunissa
National Institute of Nutrition, Indian Council of Medical Research, Jamai Osmania, Hyderabad 500 007 India
Lipids (USA), 1996, 31/3 Suppl. (S287-S291)

To arrive at fat requirements for Indians, the contribution of invisible fat should be determined. Total lipids were extracted from common Indian foods, and their fatty acid compositions were determined. This data and information on intake of various foods were used to estimate the contents of 'invisible' fat and fatty acids in Indian diets. Taking into account World Health Organization (WHO) guidelines and the invisible fat intake of Indians, recommendations were made for lower and upper limits of visible fats. In the rural poor, the 'visible'-fat intakes are much lower than estimated minimum requirements. Therefore, to meet the energy needs of low income groups, particularly young children, visible-fat intakes must be increased to recommended levels. The urban high-income group, however, should reduce dietary fat. Data on intake of various fatty acids in total diet shows that even the recommended lower limit of oil can meet linoleic acid requirements. Intake of alpha-linolenic acid is low, however. Increase in dietary n-3 polyunsaturated fatty acid (PUFA) produces hypolipidemic, anti-inflammatory, and antithrombotic effects. Effects of n-3 PUFA on blood lipids, platelet fatty acid composition, and platelet aggregation were therefore investigated in Indian subjects consuming cereal based diets. Supplementation of fish oils (long-chain n-3 PUFA) as well as the use of rapeseed oil (alpha-linolenic acid) produced beneficial effects. Since the requirements of alpha-linolenic acid and/or long-chain n-3 PUFA are related to linoleic acid intake, use of more than one oil (correct choice) is recommended for providing a balanced intake of various fatty acids. Analysis of Indian food showed that some foods are good sources of alpha-linolenic acid. Regular consumption of these foods can also improve the quality of fat in Indian diets. Nonvegetarians, however, have the choice of eating fish to accomplish this.

Schoolfield D.J.; Behall K.M.; Kelsay J.L.; Prather E.S.; Clark W.M.; Reiser S.; Canary J.J.
Carbohydrate Nutrition Laboratory, Beltsville Human Nutrition Research Center, ARS, USDA, Beltsville, MD 20705 USA
Nutr. Res. (USA), 1990, 10/4 (367-378)

Diets high in fiber and oxalate may result in decreased mineral bioavailability. However, increased fiber intake can reduce risk factors for some diseases. Twelve men were fed diets containing 25 g or 5 g of neutral detergent fiber with 450 mg/day of oxalic acid for six weeks each in a crossover design to determine whether plasma minerals and other metabolites would be affected. High dietary oxalate levels were fed throughout the study. The fiber sources were fruit and vegetables or their juices and spinach was the source of oxalate. Five minerals and cholesterol , triglycerides, uric acid, glucose and urea nitrogen (BUN) were measured in fasting plasma and correlated with fecal oxalate, mineral intake and apparent mineral balance. Fiber level had no effect on the plasma constituents. Plasma inorganic phosphorus (P(i)) decreased (p = 0.002), while BUN, calcium and copper increased (p < 0.010), (p = 0.004), (p = 0.011) with time. BUN and P(i) changes which occurred may have been related to ingestion of high levels of oxalate for eighty-four days.

Sikand G; Kashyap ML; Yang I
Division of Cardiology, University of California-Irvine, Orange 92868-3298, USA.
J Am Diet Assoc (United States) Aug 1998, 98 (8) p889-94; quiz 895-6

This study was designed to evaluate whether medical nutrition therapy administered by registered dietitians could lead to a beneficial clinical and cost outcome in men with hypercholesterolemia. Ninety-five subjects participating in a cholesterol -lowering drug study took part in an 8-week nutrition intervention program before initiating treatment with a cholesterol -lowering medication, Patient records were reviewed via a retrospective chart review to determine plasma lipid levels at the beginning and end of the program and the number and length of sessions with a dietitian. Complete information was available for 74 subjects aged 60.8 n+/- 9.8 years (mean +/- SD). Medical nutrition therapy lowered total serum cholesterol levels 13% (P < .001), low-density lipoprotein cholesterol (LDL-C) 15% (P < .0001), triglyceride 11% (P < .05), and high-density lipoprotein- cholesterol (HDL-C) 4% (P < .05). Total dietitian intervention time was 144 +/- 21 minutes (range = 120 to 180 minutes) in 2.8 +/- 0.7 sessions (range = 2 to 4) during 6.81 +/- 0.7 weeks of medical nutrition therapy (range = 6 to 8 weeks). Analysis of covariance was conducted to examine whether mean change in LDL-C differed by number of dietitian visits. Results showed a marginal difference between the number of dietitian visits and change in LDL-C (f = 2.6, P < .084). However, the magnitude of LDL-C reduction was significantly higher with 4 dietitian visits (180 minutes) than with 2 visits (120 minutes) (21.9% vs 12.1%; P = .027). Lipid drug eligibility was obviated in 34 of 67 (51%) subjects per the National Cholesterol Treatment Program guidelines algorithm. The estimated annualized cost savings from the avoidance of lipid medications was $60,561.68. Therefore, we conclude that 3 or 4 individualized dietitian visits of 50 minutes each over 7 weeks are associated with a significant serum cholesterol reduction and a savings of health care dollars.

Borgia MC; Medici F
Universita Degli Studi di Roma La Sapienza, Italy.
Angiology (United States) May 1998, 49 (5) p339-48

In this review the indications for the available treatments for dyslipidemias in the prevention of coronary heart disease (CHD) are considered, and their efficacy according to the latest studies is analyzed. As data sources the authors used the main multicenter studies performed in the last twenty years to evaluate primary and secondary prevention of CHD by correcting dyslipidemias as well as the results of meta-analyses of these studies. All treatments considered were found effective in preventing CHD morbidity and mortality to some extent. In particular, the combination of diet with niacin or hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors seems to give the best results. These drugs induce a marked reduction of total and low-density lipoprotein (LDL) cholesterol and an increase of high-density lipoprotein (HDL) cholesterol concentrations. The use of diet, niacin , and HMG CoA reductase inhibitors reduces total as well as specific mortality. Treatment of dyslipidemia to prevent CHD depends on the pattern and severity of dyslipidemia, the presence of overt CHD, and the patient's response to diet. Pharmacologic treatment should be started only after dietary modifications have been tried and must be combined with diet. Drug side effects must also be considered, for they may affect patient compliance. High levels of total and LDL and low levels of HDL cholesterol are major risk factors for coronary atherosclerosis. Correcting lipid abnormalities can reduce the risk of development or progression of CHD. Diet and drugs are the main instruments available to normalize lipid levels. The choice of drug to combine with diet must be based on its specific effects on lipid metabolism, side effects, and efficacy in reducing CHD. (77 Refs.)

Tato F; Vega GL; Grundy SM
Department of Clinical Nutrition of the University of Texas Southwestern Medical Center and The Veterans Affairs Medical Center at Dallas, 75235-9052, USA.
Am J Cardiol (United States) Mar 15 1998, 81 (6) p805-7

Marked lowering of plasma total and low-density lipoprotein cholesterol levels that occur during treatment of dyslipidemia with pharmacologic doses of nicotinic acid result from hepatotoxicity. Therefore, a marked reduction in low-density lipoprotein may suggest generalized liver toxicity and drug treatment should be discontinued.

McKenney JM; McCormick LS; Weiss S; Koren M; Kafonek S; Black DM
Virginia Commonwealth University, Richmond, USA.
Am J Med (United States) Feb 1998, 104 (2) p137-43

BACKGROUND: To assess the lipid-lowering effects and safety of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia.

METHODS: We performed a randomized, open-label, parallel-design, active-controlled, study in eight centers in the United States. We enrolled 108 patients with total cholesterol (TC) of > or =200 mg/dL, serum triglycerides (TG) > or =200 and < or =800 mg/dL, and apolipoprotein B (apo B) > or =110 mg/dL. Patients were randomly assigned to receive atorvastatin 10 mg once daily (n=55) or immediate-release niacin 1 g three times daily for 12 weeks (n=53). Patients were stratified based on low-density lipoprotein cholesterol (LDL-C): Patients with LDL-C > or =135 mg/dL were considered to have combined hyperlipidemia and patients with LDL-C <135 mg/dL were considered to have isolated hypertriglyceridemia. The primary outcome measure was percent change from baseline in LDL-C. Other lipid levels were evaluated as secondary parameters.

RESULTS: Atorvastatin reduced LDL-C 30% and TC 26% from baseline, and increased high-density lipoprotein cholesterol (HDL-C) 4%. Total TG were reduced 17%. Niacin reduced LDL-C 2%, TC 7%, increased HDL-C 25%, and reduced total TG 29% from baseline. There was a significant difference in LDL-C reduction , the primary efficacy parameter, between the two treatment groups (P <0.05, favoring atorvastatin), as well as a significant difference in the improvement in HDL-C (P <0.05, favoring niacin). The effect of atorvastatin was relatively consistent between patients with combined hyperlipidemia and isolated hypertriglyceridemia, whereas there was more variability between these strata in the niacin treatment group. Atorvastatin was better tolerated than niacin .

CONCLUSION: Atorvastatin may allow patients with combined hyperlipidemia to be treated with monotherapy and offers an efficacious and well-tolerated alternative to niacin for the treatment of patients with isolated hypertriglyceridemia.

Brown BG; Zambon A; Poulin D; Rocha A; Maher VM; Davis JW; Albers JJ; Brunzell JD
Department of Medicine, University of Washington School of Medicine, Seattle 98195, USA.
Am J Cardiol (United States) Feb 26 1998, 81 (4A) p52B-59B

Patients in the original Familial Atherosclerosis Treatment Study (FATS) cohort were subgrouped into those with triglyceride levels < or = 120 mg/dL (n = 26) and those with triglyceride levels > or = 190 mg/dL (n = 40). Their therapeutic responses to niacin plus colestipol, lovastatin plus colestipol, colestipol alone, or placebo were determined. Therapeutic response was also determined in the same 2 triglyceride subgroups (n = 12 and n = 27, respectively) of patients selected for low levels of high-density lipoprotein (HDL) cholesterol and coronary artery disease. These triglyceride criteria were chosen to identify patient subgroups with high likelihood of "pattern A" (normal-size low-density lipoprotein [LDL] particles and triglyceride < or = 120 mg/dL) or "pattern B" (small dense LDL and triglyceride > or = 190 mg/dL). Our findings in these small patient subgroups are consistent with the emerging understanding that coronary artery disease patients presenting with high triglyceride levels have lower HDL-C, smaller less buoyant LDL-C, and greater very low-density lipoprotein (VLDL) cholesterol and VLDL apolipoprotein B, and are more responsive to therapy as assessed by an increase in HDL-C and reduction in triglycerides, VLDL-C, and VLDL apolipoprotein B. In the FATS high-triglyceride subgroup with these characteristics, a tendency toward greater therapeutic improvement in coronary stenosis severity was observed among those treated with either of the 2 forms of intensive cholesterol -lowering therapy. This improvement is associated with therapeutic reduction of LDL-C and elevation of HDL-C, but also appears to be associated with drug-induced improvement in LDL buoyancy. (20 Refs.)

Gotto A.M. Jr.
Dr. A.M. Gotto Jr., Weill Medical College, Olin Hall, 445 E. 69th Street, New York, NY 10021 United States
American Journal of Cardiology (United States), 1998, 82/9 A (22Q-25Q)

The data for an independent association between triglyceride concentrations and risk for coronary artery disease (CAD) are equivocal, unlike the data for low-density lipoprotein (LDL) cholesterol and high- density lipoprotein (HDL) cholesterol , which show strong, consistent, and opposing correlations with CAD risk. There is some evidence for triglyceride as an independent risk factor in certain subgroups, for example, women 50-69 years of age (Framingham Heart Study) and in patients with noninsulin- dependent diabetes. However, the evidence is stronger for triglyceride as a synergistic CAD risk factor. For example, patients with the 'lipid triad' of high LDL cholesterol , low HDL cholesterol , and high triglyceride accounted for most of the event reduction with lipid-lowering therapy in the Helsinki Heart Study. An important confounder of the correlation between triglyceride and CAD risk is the heterogeneity of triglyceride, rich lipoproteins: the larger triglyceride-rich particles are thought not to be associated with CAD risk, whereas the smaller (and denser) particles are believed to be atherogenic. At present, measurement of fasting triglyceride levels and triglyceride assessment in conjunction with LDL cholesterol and HDL cholesterol concentrations are the most practical methods of evaluating hypertriglyceridemia in CAD risk, although postprandial lipemia may prove a better indicator of atherogenicity. Management of hypertriglyceridemia should initially focus on nonpharmacologic therapy (i.e., diet, exercise, weight control, and alcohol reduction). In diabetic patients, meticulous glycemic control is also important. However, if this approach proves inadequate, there are several pharmacologic options. Fibrates may be effective in decreasing triglyceride and increasing HDL cholesterol . Nicotinic acid (niacin) has been shown to decrease triglyceride, increase HDL cholesterol , lower LDL cholesterol , and decrease lipoprotein(a); it also decreases fibrinogen. The statins appear to be effective in decreasing triglyceride and LDL cholesterol in hypertriglyceridemia; however, they do not normalize metabolism of apolipoprotein B, and HDL cholesterol may remain low. Therefore, combination with a fibrate or niacin may be appropriate. Attention to hypertriglyceridemia with respect to increased CAD risk represents an important step in assessing global risk for CAD development.

Kwiterovich P.O. Jr.
Dr. P.O. Kwiterovich Jr., Johns Hopkins Hospital, CMSC 604, 600 North Wolfe Street, Baltimore, MD 21287-3654 United States
American Journal of Cardiology (United States), 1998, 82/9 A (13Q-21Q)

Landmark clinical studies in the past 5 years that demonstrated diminished mortality and first coronary events following lowering of low- density lipoprotein (LDL) cholesterol stimulated considerable interest in the medical community. Yet, high-density lipoprotein (HDL) cholesterol , which transports circulating cholesterol to the liver for clearance, clearly also exerts antiatherogenic effects. The Framingham Heart Study produced compelling epidemiologic evidence indicating that a low level of HDL cholesterol was an independent predictor of coronary artery disease (CAD). Emerging experimental and clinical findings are, collectively, now furnishing a solid scientific foundation for this relation. First, the reverse cholesterol transport pathway-including the roles of nascent (pre-beta) HDL, apolipoprotein A-I, lecithin-cholesterol acyltransferase (LCAT), cholesteryl ester transport protein, and hepatic uptake of cholesteryl ester from HDL by liver-is better understood. For example, the identification of a hepatic HDL receptor, SR-BI, suggests a mechanism of delivery of cholesteryl ester to liver that differs from the receptor-mediated uptake of LDL. Second, apolipoprotein A-I, the major protein component of HDL, and 2 enzymes on HDL, paraoxonase and platelet-activating factor acetylhydrolase appear to diminish the formation of the highly atherogenic oxidized LDL. Third, lower levels of HDL cholesterol are associated in a dose-response fashion with the severity and number of angiographically documented atherosclerotic coronary arteries. Fourth, low HDL cholesterol predicts total mortality in patients with CAD and desirable total cholesterol levels (<200 mg/dL). Fifth, low HDL cholesterol concentrations appear to be associated with increased rates of restenosis after percutaneous transluminal coronary angioplasty. In terms of elevating HDL cholesterol , cessation of cigarette smoking, reduction to ideal body weight, and regular aerobic exercise all appear important. Most medications used to treat dyslipidemias will raise HDL cholesterol levels modestly; however, niacin appears to have the greatest potential to do so, and can increase HDL cholesterol up to 30%. Recognizing these data, the most recent report of the National Cholesterol Education Program identified low HDL cholesterol as a CAD risk factor and recommended that all healthy adults be screened for both total cholesterol and HDL cholesterol levels.

Yee H.S.; Fong N.T.
H.S. Yee, Pharmacy Service, Dept. of Veterans Affairs Med. Ctr., 4150 Clement St., San Francisco, CA 94121 United States
Annals of Pharmacotherapy (United States), 1998, 32/10 (1030-1043)

OBJECTIVE: To review the efficacy and safety of atorvastatin in the treatment of dyslipidemias.

DATA SOURCES: A MEDLINE search (January 1960- April 1998), Current Contents search, additional references listed in articles, and unpublished data obtained from the manufacturer were used to identify data from scientific literature. Studies evaluating atorvastatin (i.e., abstracts, clinical trials, proceedings, data on file with the manufacturer) were considered for inclusion.

STUDY SELECTION: English- language literature was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of atorvastatin. Additional relevant citations were used in the introductory material and discussion.

DATA EXTRACTION: Open and controlled animal and human clinical studies published in English-language literature were reviewed and evaluated. Clinical trials selected for inclusion were limited to those in human subjects and included data from animals if human data were not available.

DATA SYNTHESIS: Atorvastatin is a recent hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of primary hypercholesterolemia, mixed dyslipidemias, and homozygous familial hypercholesterolemia. In patients who have not met the low-density lipoprotein cholesterol (LDL-C) goal as recommended by the National Cholesterol Education Program Adult Treatment Panel II guidelines, atorvastatin 10-80 mg/d may be used as monotherapy or as an adjunct to other lipid-lowering agents and dietary modifications. In placebo-controlled clinical trials, atorvastatin 10-80 mg/d lowered LDL-C by 35-61% and triglyceride (TG) concentrations by 14-45%. In comparative trials, atorvastatin 10-80 mg/d showed a greater reduction of serum total cholesterol (TC), LDL-C, TG concentrations, and apolipoprotein B-100 (apo B) compared with pravastatin, simvastatin, or lovastatin. In comparison, currently available HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin) lower LDL-C concentrations by approximately 20- 40% and TG concentrations by approximately 10-30%. In pooled placebo- controlled clinical trials of up to a duration of 52 weeks, atorvastatin in dosages up to 80 mg/d appeared to be well tolerated. The most common adverse effect of atorvastatin was gastrointestinal upset. The incidence of elevated serum hepatic transaminases may be greater at higher dosages of atorvastatin. The risk of myopathy and/or rhabdomyolysis is increased when an HMG-CoA reductase inhibitor is taken concomitantly with cyclosporine, gemfibrozil, niacin , erythromycin, or azole antifungals.

CONCLUSIONS: Atorvastatin appears to reduce TC, LDL-C, TG concentrations, and apo B to a greater extent than do currently available HMG-CoA reductase inhibitors. Atorvastatin may be preferred in patients requiring greater than a 30% reduction in LDL-C or in patients with both elevated LDL-C and TG concentrations, which may obviate the need for combination lipid-lowering therapy. Adverse effects of atorvastatin appear to be similar to those of other HMG-CoA reductase inhibitors and should be routinely monitored. Long-term safety data (>1 y) on atorvastatin compared with other HMG-CoA reductase inhibitors are still needed. Cost-effectiveness studies comparing atorvastatin with other HMG-CoA reductase inhibitors remain a subject for further investigation. Published clinical studies evaluating the impact of atorvastatin on cardiovascular morbidity and mortality are still needed. Additionally, clinical studies evaluating the impact of lipid-lowering therapy in a larger number of women, the elderly (>70 y), and patients with diabetes for treatment of primary and secondary prevention of coronary heart disease are needed.

Hilleman D.E.; Seyedroubari A.
Dr. D.E. Hilleman, Department of Pharmacy Practice, Creighton University, Sch. Pharm./Allied Hlth. Professions, 2500 California Plaza, Omaha, NE 68178 United States
Cardiovascular Reviews and Reports (United States), 1998, 19/5 (32-48)

Atorvastatin is the fifth HMG-CoA reductase inhibitor approved for use in the U.S. The mechanism of action of atorvastatin appears to be similar to other agents in the class. Atorvastatin is metabolized by cytochrome P450 3A4 to several active metabolites. Approximately 70% of the lipid lowering effect of atorvastatin is attributed to its metabolites. Atorvastatin's efficacy is greater than that of other available HMG-CoA reductase inhibitors. At 10 mg/day, atorvastatin reduces LDL cholesterol by 39% and triglycerides by 19%. At the highest FDA approved dose of 80 mg/day, atorvastatin reduces LDL cholesterol by 60% and triglycerides by 37%. Atorvastatin 10 mg/day produces LDL cholesterol reductions that are similar to or greater than the LDL cholesterol reductions achieved with all doses up to 40 mg/day with the other HMG-CoA reductase inhibitors. Atorvastatin is associated with a very low incidence of dose-limiting side effects with a discontinuation rate of less than 2%. The most common side effects are constipation, flatulence, dyspepsia, and abdominal pain. In comparative trials against other HMG-CoA reductase inhibitors, no significant differences in the incidence of side effects were observed. As with other HMG-CoA reductase inhibitors, combined use of atorvastatin with erythromycin, cyclosporin, fibric acid derivatives, niacin , and azole antifungals increases the risk of myopathy. Atorvastatin represents a highly effective HMG-CoA reductase inhibitor that produces greater reductions in LDL cholesterol and triglycerides than other currently available agents in this class. Based on NCEP treatment guidelines in which predetermined LDL cholesterol levels are the goal of therapy, atorvastatin appears to fill a major void that exists with current therapy. For patients requiring a 40% or greater reduction in LDL cholesterol , atorvastatin is the only agent capable of such reductions. The major unresolved issue with atorvastatin is its unknown impact on cardiovascular morbidity and mortality.

Nieuwenhuys CM; Beguin S; Offermans RF; Emeis JJ; Hornstra G; Heemskerk JW
Department of Human Biology, University of Maastricht, The Netherlands.
C.Nieuwenhuys@hb.unimaas.nl
Arterioscler Thromb Vasc Biol (United States) Sep 1998, 18 (9) p1480-9

We investigated the effects of dietary polyunsaturated fatty acids (PUFAs) on blood lipids and processes that determine hemostatic potential: platelet activation, coagulation, and fibrinolysis. For 8 to 10 weeks, Wistar rats were fed a high-fat diet containing various amounts (2% to 16%) of n-3 PUFAs derived from fish oil (FO) or a diet enriched in n-6 PUFAs from sunflower seed oil (SO). Only the FO diets caused a reduction in mean platelet volume, platelet arachidonate level, and formation of thromboxane B2 by activated platelets, but neither of the diets had a measurable effect on platelet activation. The FO-rich diets decreased the plasma concentrations of triglycerides and cholesterol , whereas the SO diet reduced triglycerides only. Parameters of fibrinolysis and standard coagulation times, ie, activated partial thromboplastin time and prothrombin time, were only marginally influenced by these diets. In contrast, dietary FO, but not SO, led to decreased levels of the vitamin K-dependent coagulation factors prothrombin and factor VII, while the level of antithrombin III was unchanged. The endogenous thrombin potential (ETP) was measured with an assay developed to detect the hypocoagulable state of plasma. After activation with tissue factor and phospholipids, the ETP was reduced by 23% or more in plasma from animals fed a diet with >4% FO. No significant effect of the SO diet on ETP was observed. Control experiments with plasma from warfarin-treated rats indicated that the ETP was more sensitive to changes in prothrombin concentration than in factor VII concentration. Taken together, these results indicate that in rats, prolonged administration of n-3 but not n-6 PUFAs can lead to a hypocoagulable state of plasma through a reduced capacity of vitamin K-dependent thrombin generation, with unchanged thrombin inactivation by antithrombin III.

van Vlijmen BJ; Mensink RP; van 't Hof HB; Offermans RF; Hofker MH; Havekes LM
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands.
J Lipid Res (United States) Jun 1998, 39 (6) p1181-8

Studying the effects of dietary fish oil on VLDL metabolism in humans is subject to both large intra- and interindividual variability. In the present study we therefore used hyperlipidemic apolipoprotein (APO) E*3-Leiden mice, which have impaired chylomicron and very low density lipoprotein (VLDL) remnant metabolism, to study the effects of dietary fish oil on serum lipids and VLDL kinetics under highly standardized conditions. For this, female APOE*3-Leiden mice were fed a fat- and cholesterol -containing diet supplemented with either 0, 3 or 6% w/w (i.e. 0, 6, or 12% of total energy) of fish oil . Fish oil -fed mice showed a significant dose-dependent decrease in serum cholesterol (up to -43%) and triglyceride levels (up to -60%), mainly due to a reduction of VLDL (-80%). LDL and HDL cholesterol levels were not affected by fish oil feeding. VLDL-apoB kinetic studies showed that fish oil feeding resulted in a significant 2-fold increase in VLDL-apoB fractional catabolic rate (FCR). Hepatic VLDL-apoB production was, however, not affected by fish oil feeding. VLDL-triglyceride turnover studies revealed that fish oil significantly decreased hepatic VLDL-triglyceride production rate (-60%). A significant increase in VLDL-triglyceride FCR was observed (+70%), which was not related to increased lipolytic activity. We conclude that APOE*3-Leiden mice are highly responsive to dietary fish oil . The observed strong reduction in serum very low density lipoprotein (VLDL) is primarily due to an effect of fish oil to decrease hepatic VLDL triglyceride production rate and to increase VLDL-apoB fractional catabolic rate.

Sorensen NS; Marckmann P; Hoy CE; van Duyvenvoorde W; Princen HM
Department of Biochemistry and Nutrition, Technical University of Denmark, Lyngby. ninas@mimer.be.dtu.dk
Am J Clin Nutr (United States) Aug 1998, 68 (2) p235-41

We investigated the effect of incorporating n-3 polyunsaturated fatty acids (PUFAs) into the diet on the lipid-class composition of LDLs, their size, and their susceptibility to oxidation. Forty-seven healthy volunteers incorporated 30 g sunflower-oil (SO) margarine/d into their habitual diet during a 3-wk run-in period and then used either SO or a fish -oil -enriched sunflower oil (FO) margarine for the following 4 wk. Plasma concentrations of total cholesterol , triacylglycerols, HDL cholesterol , LDL cholesterol , and apolipoproteins A-I and B did not differ significantly between the groups during intervention. The FO margarine increased the concentration of n-3 very-long-chain PUFAs in the LDL particles, showing 93% (P < or = 0.0001), 8% (P = 0.05), and 35% (P = < 0.0001) increases in eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid, respectively, in the FO group compared with 3%, 7%, and 7%, respectively, in the SO group during the intervention. The cholesterol content of the LDL particles increased in the FO group [total cholesterol : 6% (P = 0.008); cholesterol ester: 12% (P = 0.014)], although it was not significantly different from that in the control group, whereas the other lipid classes and the size of the LDL particles remained unchanged in both groups. A reduction in the alpha-tocopherol content in LDL (6%, P = 0.005) was observed in the FO group. Ex vivo oxidation of LDL induced with Cu2+ showed a significantly reduced lag time (from 91 to 86 min, P = 0.003) and lower maximum rate of oxidation (from 10.5 to 10.2 nmol x mg(-1) x min(-1), P = 0.003) after intake of the FO margarine. The results indicate that consumption of the FO compared with the SO margarine had no effect on LDL size and lipid composition and led to minor changes in LDL a-tocopherol content and oxidation resistance.

Corrigan FM; Horrobin DF; Skinner ER; Besson JA; Cooper MB
Argyll and Bute Hospital, Lochgilphead, UK.
Int J Biochem Cell Biol (England) Feb 1998, 30 (2) p197-207

The long-chain fatty acid composition of cholesterol esters, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) from parahippocampal cortex of Alzheimer's disease (AD) patients and control subjects was examined. In general the PC fraction contained less polyunsaturated long-chain fatty acids than did PE, PS or PI. Of the n-6 polyunsaturated long-chain fatty acids, PI contained the greatest incorporation of these acids followed by PE. There were significant differences between controls and AD patients in total n-6 EFAs. Arachidonic acid (C20:4n-6) was the predominant fatty acid of this family found to be present. In AD, PE and PS showed a deficit of adrenic acid (C22:4n-6) content and PE also contained less arachidonic acid. In AD subjects, the cholesterol esters contained significantly less n-3 polyunsaturated fatty acids with, specifically, a reduction in alpha-linolenic acid. Acetyl CoA content of hippocampal cortex was greater in AD patients than in control subjects indicating either an increased extent of oxidative metabolism or a failure to utilise acetyl CoA for anabolic processes. Abnormal magnitude of oxidative processes could give rise to the biosynthesis of PE and PS species containing less n-6 polyunsaturated fatty acids than occurs in control subjects.

de Lorgeril M; Salen P; Martin JL; Monjaud I; Boucher P; Mamelle N
Laboratoire de Physiologie and GIP-Exercice, Centre Hospitalo-Universitaire de Saint-Etienne and School of Medicine, France.
Arch Intern Med (United States) Jun 8 1998, 158 (11) p1181-7

BACKGROUND: The Mediterranean dietary pattern is thought to reduce the risk of cancer in addition to being cardioprotective. However, no trial has been conducted so far to prove this belief.

METHODS: We compared overall survival and newly diagnosed cancer rate among 605 patients with coronary heart disease randomized in the Lyon Diet Heart Study and following either a cardioprotective Mediterranean-type diet or a control diet close to the step 1 American Heart Association prudent diet.

RESULTS: During a follow-up of 4 years, there were a total of 38 deaths (24 in controls vs 14 in the experimental group), including 25 cardiac deaths (19 vs 6) and 7 cancer deaths (4 vs 3), and 24 cancers (17 vs 7). Exclusion of early cancer diagnoses (within the first 24 months after entry into the trial) left a total of 14 cancers (12 vs 2). After adjustment for age, sex, smoking, leukocyte count, cholesterol level, and aspirin use, the reduction of risk in experimental subjects compared with control subjects was 56% (P=.03) for total deaths, 61% (P=.05) for cancers, and 56% (P=.01) for the combination of deaths and cancers. The intakes of fruits, vegetables, and cereals were significantly higher in experimental subjects, providing larger amounts of fiber and vitamin C (P<.05). The intakes of cholesterol and saturated and polyunsaturated fats were lower and those of oleic acid and omega - 3 fatty acids were higher (P<.001) in experimental subjects. Plasma levels of vitamins C and E (P<.05) and omega -3 fatty acids (P<.001), measured 2 months after randomization, were higher and those of omega-6 fatty acids were lower (P<.001) in experimental subjects.

CONCLUSIONS: This randomized trial suggests that patients following a cardioprotective Mediterranean diet have a prolonged survival and may also be protected against cancer. Further studies are warranted to confirm the data and to explore the role of the different lipids and fatty acids in this protection.

Fickova M; Hubert P; Cremel G; Leray C
Institute of Experimental Endocrinology, Slovak Academy of Sciences, 83306 Bratislava, Slovakia.
J Nutr (United States) Mar 1998, 128 (3) p512-9

The influence of dietary (n-3) compared with (n-6) polyunsatured fatty acids (PUFA) on the lipid composition and metabolism of adipocytes was evaluated in rats over a period of 1 week. Isocaloric diets comprised 16.3 g/100 g protein, 53.8 g/100 g carbohydrate and 21.4 g/100 g lipids, the latter containing either (n-3) PUFA (32.4 mol/100 mol) or (n-6) PUFA (37.8 mol/100 mol) but having identical contents of saturated, monounsaturated and total unsaturated fatty acids and identical polyunsaturated to saturated fatty acid ratios and double bond indexes. Despite comparable food intake, significantly smaller body weight increments and adipocyte size were observed in rats of the (n-3) diet group after feeding for 1 wk. Rats fed the (n-3) diet also had significantly lower concentrations of serum triglycerides, cholesterol and insulin compared with those fed the (n-6) diet, although levels of serum glucose and free fatty acids did not differ in the two dietary groups. In the (n-6) diet group, the (n-6) and (n-3) PUFA contents of plasma triglycerides, free fatty acids and phospholipids were 30-60% higher and 60-80% lower, respectively, than in the (n-3) diet group, whereas adipocyte plasma membrane phospholipids showed a significantly higher unsaturated to saturated fatty acid ratio and greater fluidity. Glycerol release in response to noradrenaline was significantly higher in the adipocytes of rats fed the (n-3) diet, whereas the antilipolytic effect of insulin generally did not differ in the two groups. Finally, insulin stimulated the transport of glucose and its incorporation into fatty acids to a lesser extent in adipocytes of (n-3) diet fed rats compared with (n-6) diet fed rats. This reduction in the metabolic effects of insulin in rats fed a (n-3) diet for 1 wk could be related to smaller numbers and a lower binding capacity of the insulin receptors on adipocytes and/or to a lesser degree of phosphorylation of the 95 kDa beta subunit of the receptor. In conclusion, dietary intake for 1 wk of (n-3) rather than (n-6) PUFA is sufficient to induce significant differences in the lipid composition and metabolic responses to insulin of rat adipocytes.

Brun J.F.; Khaled S.; Raynaud E.; Bouix D.; Micallef J.P.; Orsetti A.
J.F. Brun, Svc. d'Explor. Phys. Hormones Metab., CHRU de Montpellier, F-34059 Montpellier France
Clinical Hemorheology and Microcirculation (United States), 1998, 19/2 (89-104)

The life-extending effects of regular exercise are related to a decrease in both coronary and peripheral vascular morbidity, associated with some improvements in cardiovascular risk factors. A possible link between the beneficial metabolic and hemodynamic effects of exercise could be blood rheology, which is markedly affected by exercise. We propose here a description of the hemorheological effects of exercise as a triphasic phenomenon. Short-term effects of exercise are an increase in blood viscosity resulting from both fluid shifts and alterations of erythrocyte rheologic properties (rigidity and aggregability). Increased blood lactate, stress, and acute phase play a role in this process. Middle-term effects of regular exercise are a reversal of these acute effects with an increase in blood fluidity, explained by plasma volume expansion (autohemodilution) that lowers both plasma viscosity and hematocrit. Long-term effects further improve blood fluidity, parallel with the classical training-induced hormonal and metabolic alterations. While body composition, blood lipid pattern, and fibrinogen improve (thus decreasing plasma viscosity), erythrocyte metabolic and rheologic properties are modified, with a reduction in aggregability and rigidity. On the whole, these improvements reflect a reversal of the so- called 'insulin-resistance syndrome' induced by a sedentary lifestyle. Since impaired blood rheology has been demonstrated to be at risk for vascular diseases, the hemorheologic effects of exercise can be hypothesized to be a mechanism (or at least a marker) of risk reversal. This latter point requires further investigation. The physiological meaning of the tripbasic pattern of exercise-induced alterations of blood theology is uncompletely understood, but increased blood fluidity may improve several steps of oxygen transfer to muscle, as clearly demonstrated in hypoxic conditions. Increasing evidence emerges from the literature, that blood fluidity is a physiological determinant of fitness.

O'Brien T.; Nguyen T.T.; Zimmerman B.R.
Dr. T. O'Brien, Div. of Endocrinol., Metabol./Nutri., Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905 United States
Mayo Clinic Proceedings (United States), 1998, 73/10 (969-976)

The increased risk of coronary artery disease in subjects with diabetes mellitus can be partially explained by the lipoprotein abnormalities associated with diabetes mellitus. Hypertriglyceridemia and low levels of high-density lipoprotein are the most common lipid abnormalities. In type 1 diabetes mellitus, these abnormalities can usually be reversed with glycemic control. In contrast, in type 2 diabetes mellitus, although lipid values improve, abnormalities commonly persist even after optimal glycemic control has been achieved. Screening for dyslipidemia is recommended in subjects with diabetes mellitus. A goal of low-density lipoprotein cholesterol of less than 130 mg/dL and triglycerides lower than 200 mg/dL should be sought. Several secondary prevention trials, which included subjects with diabetes, have demonstrated the effectiveness of lowering low-density lipoprotein cholesterol in preventing death from coronary artery disease. The benefit of lowering triglycerides is less clear. Initial approaches to lowering the levels of lipids in subjects with diabetes mellitus should include glycemic control, diet, weight loss, and exercise. When goals are not met, the most common drugs used are hydroxymethylglutaryl coenzyme A reductase inhibitors or fibrates.

Jabbar M.A.; Zuhri-Yafi M.I.; Larrea J.
Dr. M.A. Jabbar, Department of Pediatrics, Hurley Medical Center, 1 Hurley Plaza, Flint, MI 48502 United States
Journal of the American College of Nutrition (United States), 1998, 17/5 (458-461)

Objective: To compare the short and long term effectiveness of fish oil , insulin, and gemfibrozil in a non-diabetic patient with severe hypertriglyceridemia.

Method: An adolescent male with hypertriglyceridemia (triglyceride level 4575 mg/dl) and abdominal pain was treated with the goal of immediate reduction and maintenance of triglyceride (TG) level below 1000 mg/dl. Fish oil , insulin and gemfibrozil were administered sequentially, in separate time blocks, for a duration of 3, 6, and 6 months, respectively.

Results: Fish oil took several weeks to lower TG level, and patient compliance during 3 months of therapy was inadequate. Insulin was effective in immediately lowering the TG level, but was unable to maintain the level below 1000 mg/dl. Gemfibrozil was ineffective in achieving the immediate reduction of TG level; however, it was adequate in maintaining the desired level in the long-term and patient compliance was better than with the fish oil .

Conclusion: In patients with risk of pancreatitis due to severe hypertriglyceridemia, immediate reduction of the triglyceride level is achievable by using a single dose of regular insulin (0.1 unit/kg, subcutaneous) while long-term maintenance therapy can be provided by gemfibrozil.

Seljeflot I.; Arnesen H.; Brude I.R.; nenseter M.S.; Drevon C.A.; Hjermann I.
I. Seljeflot, Medical Outpatient Clinic, Department of Medicine, Ulleval University Hospital, N-0407 Oslo Norway
European Journal of Clinical Investigation (United Kingdom), 1998, 28/8 (629-635)

Background. Increased expression of cell adhesion molecules and increased procoagulant activity of the vascular endothelium have been postulated to characterize dysfunctional endothelium. The cellular effects of n-3 fatty acids (n-3 FAs) and antioxidants are still not clarified.

Methods. In a randomized, factorial two-by-two design study, we have investigated 41 male smokers with hyperlipidaemia before and after 6 weeks of supplementation with either n-3 FAs (4.8 g daily) or placebo with the addition of antioxidants (1.50 mg of vitamin C, 75 mg of vitamin E and 15 mg of p-carotene daily) or placebo with regard to the effects on some endothelial cell markers: thrombomodulin (sTM), von Willebrand factor (vWF), tissue plasminogen activator antigen (tPAag) and soluble forms of the cell adhesion molecules E-selectin, P-selectin and vascular cell adhesion molecule 1 (VCAM-1).

Results. In the n-3 FA group, significant reductions in the plasma levels of vWF (P = 0.034) and sTM (P<0.001) were demonstrated compared with placebo, whereas increased levels were found for E-selectin (P = 0.001) and VCAM-1 (P = 0.010). In the antioxidant group, no differences in changes were noted for any of the variables.

Conclusion. The reduction in the levels of sTM and VWF with n-3 FA supplementation could indicate an improvement with regard to the haemostatic markers of endothelial dysfunction, whereas the simultaneous increase in the soluble forms of E-selectin and VCAM-1 may suggest an adverse effect on the inflammatory system. The antioxidants seem to be neutral in their effect on these endothelial cell markers in our study population of smokers. The interpretation of the soluble forms of these molecules are, however, still debatable.

Swahn E.; von Schenck H.; Olsson A.G.
Dr. E. Swahn, Department of Cardiology, Institution of Internal Medicine, University Hospital, S-581 85 Linkoping Sweden
Clinical Drug Investigation (New Zealand), 1998, 15/6 (473-482)

This study investigated whether an ethyl ester preparation of fish oil (omega-3) could normalise raised plasma concentrations of triglycerides, apolipoprotein CIII on apolipoprotein B-containing particles (LP CIII:B) found in patients with recent acute myocardial infarction. We also studied the effect of fish oil on antithrombin III levels. Out of 75 patients with a plasma triglyceride value less than or equal to 2.0 mmol/L, 22 normalised their triglycerides during diet and were therefore not randomised. The remaining patients were randomly assigned to 12 weeks' treatment with a daily dose of 4g omega-3 or placebo. Mean plasma triglyceride concentrations were reduced by 24% from 3.10 plus or minus 1.15 (SD) to 2.53 plus or minus 0.94 mmol/L (p < 0.001) on omega-3 (p < 0.001 vs placebo). The reduction was due to decreases in very low density lipoprotein concentrations. Total apolipoprotein CIII decreased significantly. This was due to reductions in LP CIII:non B concentrations, but the ratio LP CIII:non B/LP CIII:B was unaffected because of a slight insignificant decrease in LP CIII:B. The plasma triglyceride decreasing effect of omega-3 could therefore not be due to redistribution of CIII between lipoproteins. Low density lipoprotein (LDL) cholesterol increased significantly with omega-3 by 7%, and antithrombin III increased significantly with fish oil . In conclusion, omega-3 had a moderate plasma triglyceride lowering effect and increased LDL cholesterol slightly, while antithrombin III increased in patients with hypertriglyceridaemia who had recently experienced a myocardial infarction. Myocardial infarction starts via a thrombotic process at an atherosclerotic lesion in a coronary artery. Most patients developing this disease have an abnormal plasma lipoprotein pattern consisting of slightly raised triglycerides (TGs), moderately elevated total cholesterol , and low high density lipoprotein (HDL) cholesterol values predisposing to atherosclerosis. Hypertriglyceridaemia may be associated with a greater risk for thrombosis in postmyocardial infarction patients because of a reduced fibrinolytic capacity. The dyslipidaemia may also indicate an unfavourable distribution of plasma lipoprotein particles in patients with myocardial infarction. Dietary changes normalise the dyslipidaemia in some patients but are inadequate in others. In these latter patients pharmacological lipid-lowering treatment is necessary. The myocardial infarction patient with an athero-thrombogenic syndrome could theoretically therefore benefit from a pharmacological agent acting on both the thrombotic and lipidaemic pathophysiological pathways. The pharmacological potency of the omega -3 -fatty acids allows for this possibility. It has been known since the mid 1970s that omega -3 -fatty acids are effective in lowering plasma triglyceride concentrations. They also increase the concentration of HDL cholesterol slightly. Their effects on cholesterol have varied, with some studies showing increases and others decreases. These fatty acids also inhibit platelet aggregation. It was therefore of interest to expand the experience of this type of treatment to effects on plasma lipoprotein particle distribution. We also studied parameters of fibrinolysis since the literature shows diverging results of omega - 3 - fatty acids on these parameters. In the present study we tested a new compound, omega-3, an oil consisting of ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with the aim of normalising dyslipidaemia, and reducing the thrombotic tendency in a potentially important target population for such treatment, postmyocardial infarction patients. The high EPA and DHA concentration in omega-3 made a convenient intake of only four capsules daily possible. The design of the study followed the current guidelines for secondary prevention of ischaemic heart disease.

Sirtori C.R.; Crepaldi G.; Manzato E.; Mancini M.; Rivellese A.; Paoletti R.; Pazzucconi F.; Pamparana F.; Stragliotto E.
C.R. Sirtori, Center E. Grossi Paoletti, University of Milano, Milan Italy
Atherosclerosis (Ireland), 1998, 137/2 (419-427)

n-3 Fatty acids in the form of ethyl esters (EE) allow lower daily doses and improved compliance. Administration of n-3 fatty acids to patients with glucose intolerance has led to controversial findings, some studies indicating worsening of the disorder, others no effect, or an improvement. A total of 935 patients with hypertriglyceridemia, associated with additional cardiovascular risk factors, i.e. glucose intolerance, NIDDM and/or arterial hypertension were entered a double blind (DB) protocol lasting 6 months with n-3 BE versus placebo, followed by a further 6 months of open study (n = 868) on 2 g a day of n-3 EE. At the end of the DB period, triglyceridemia in the total group was reduced significantly more by n-3 EE, without alterations in glycemic parameters. In the 6 months open follow up, patients on n-3 EE with type IIB hyperlipoproteinemia showed a significant reduction of total cholesterol , both in cases with (- 4.15% vs. the 6 month levels) and without NIDDM (- 3.8%). HDL-cholesterol had an overall mean rise of 7.4%, maximal in type IV patients with (+9.1%) and without (+ 10.1%) NIDDM. No alterations in glycemic parameters were detected in treated patients. Administration of n-3 EE to patients with hypertriglyceridemia associated with NIDDM or impaired glucose tolerance appears safe and effective.

Abe Y.; El-Masri B.; Kimball K.T.; Pownall H.; Reilly C.F.; Osmundsen K.; Smith C.W.; Ballantyne C.M.
Dr. C.M. Ballantyne, Baylor College of Medicine, 6565 Fannin, MS A-601, Houston, TX 77030 United States
Arteriosclerosis, Thrombosis, and Vascular Biology (United States), 1998, 18/5 (723-731)

Hypertriglyceridemia may contribute to the development of atherosclerosis by increasing expression of cell adhesion molecules (CAMs). Although the cellular expression of CAMs is difficult to assess clinically, soluble forms of CAMs (sCAMs) are present in the circulation and may serve as markers for CAMs. In this study, we examined the association between sCAMs and other risk factors occurring with hypertriglyceridemia, the effect of triglyceride reduction on sCAM levels, and the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in monocyte adhesion in vitro. Compared with normal control subjects (n=20), patients with hypertriglyceridemia and low HDL (n=39) had significantly increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) (316plus or minus28.8 versus 225plus or minus16.6 ng/mL), sVCAM-1 (743plus or minus52.2 versus 522plus or minus43.6 ng/mL), and soluble E-selectin (83plus or minus5.9 versus 49three-quarter.6 ng/ml). ANCOVA showed that the higher sCAM levels in patients occurred independently of diabetes mellitus and other risk factors. In 27 patients who received purified n-3 fatty acid (Omacor) 4 g/d for less than or equal to7 months, triglyceride level was reduced by 47plus or minus4.6%, sICAM-1 level was reduced by 9plus or minus3.4% (P=.02), and soluble E-selectin level was reduced by 16plus or minus3.2% (P<.0001), with the greatest reduction in diabetic patients. These results support previous in vitro data showing that disorders in triglyceride and HDL metabolism influence CAM expression and treatment with fish oils may alter vascular cell activation. In a parallel-plate flow chamber, recombinant sVCAM-1 at the concentration seen in patients significantly inhibited adhesion of monocytes to interleukin-1-stimulated cultured endothelial cells under conditions of flow by 27.5plus or minus7.2%. Thus, elevated sCAMs may negatively regulate monocyte adhesion.

Borthwick L.
Dr. L. Borthwick, Lister Hospital, Correy's Mill Lane, Stevenage SG1-4AB United Kingdom
Clinical Drug Investigation (New Zealand), 1998, 15/5 (397-404)

The objective of this study was to investigate the effects and tolerability of an omega-3 ethyl ester concentrate (Omacor (R)) on serum lipid concentrations in patients with hyperlipidaemia. A multicentre, double-blind, randomised, placebo-controlled trial was performed in the hospital and general practice setting. 84 patients with hyperlipidaemia were given a therapeutic lipid-lowering diet for 10 weeks. Of these, 55 patients were randomised to a 12-week treatment period. 47 patients completed the study and two patients withdrew because of adverse events. Randomised patients received omega-3 ethyl ester concentrate or corn oil (placebo), both administered at a dose of 2 g twice daily in soft gelatin capsules. Main outcome measures included changes in eicosapentaenoic acid (EPA)/ docosahexaenoic acid (DHA) content of serum phospholipids, total serum triglycerides, total serum cholesterol , and high density lipoprotein (HDL) cholesterol between baseline (week 10) and the end of treatment (week 22). After 12 weeks of treatment, patients receiving the omega-3 ethyl ester concentrate showed a significant increase in the EPA/DHA content of serum phospholipids (p < 0.0001). No significant changes in serum phospholipids were observed in the patients given placebo. A mean [standard deviation (SD)] reduction in serum triglyceride of 28.3 (19.1)% (p = 0.0001) occurred in patients given the omega-3 ethyl ester concentrate. Patients receiving corn oil showed a nonsignificant mean (SD) increase in serum triglyceride of 9.1 (24.8)%. Therefore, a difference between the groups of 37.4% in favour of active treatment was found (p < 0.0001). Total serum cholesterol did not change significantly in either treatment group. Mean (SD) HDL cholesterol concentrations showed an increase of 0.9 (21.6)% in patients receiving omega-3 ethyl ester concentrate and 3.6 (24.3)% in the corn-oil group; however, neither increase was significant. In conclusion, omega-3 ethyl ester concentrate, 4 g/day, produced a significant reduction in mean serum triglyceride concentration in patients with hyperlipidaemia and was well tolerated.

Willumsen N.; Vaagenes H.; Holmsen H.; Berge R.K.
R.K. Berge, Department of Clinical Biology, Division of Biochemistry, University of Bergen, N-5021 Bergen Norway
Biochimica et Biophysica Acta - Biomembranes (Netherlands), 1998, 1369/2 (193-203)

A series