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Dietary fatty acids and cholesterol: effects on plasma lipids and lipoproteins
Monday IO October 1994: Workshop Abstracts W6 Nutrition, lipoproteins and atherosclerosis
87
W6 NUTRITION, LIPOPROTEINS AND ATHEROSCLEROSIS Trans fatty acids and lipoproteins
m,
Mensink RP, van To1 A*, Zock PL, Dept. of Human
Nutrition, Anricultural Univ., Bomenwen 2. 6703 HD Waneningen; *Dept. >f Biochem., Erasmus Univ.: Rotterdam, The Netherlands
Isomeric fatty acids are unsaturated fatty acids with one or more double bonds in an unusual configuration (trans instead of cis) or position (positional cis isomers). The term trans is loosely used to refer to both types. Trans fatty acids arise through biohydrogenation in the rumen of cows and sheep or catalytic hydrogenation in oil-processing factories. The effects of trans monounsaturates on lipoproteins in man are opposite to those of the natural cis acid, oleic acid. Our own experiments in healthy volunteers employed 11% or 7.5% of energy as trans in strictly controlled diets. Trans fatty acids raised LDL and Lp(a) and lowered HDL, all in dosedependent fashion; raised serum cholesteryl ester transfer activity in 52/55 volunteers (mean change 18%, p < 0.02) and significantly lowered the HDL ratio of cholesteryl esters to triglycerides. LCAT was unchanged. Thus, trans fatty acids raise LDL, lower HDL and raise Lp(a) in man. The effects on HDL and LDL may be mediated through CETP. Effect of monounsaturated fatty acids on lipoprotein metabolism Jacotot, Sola R, Service Mddecine Inteme 5, HGpital Henri Mondor, 94010 Cretei CJdex, France
The increased consumption of monounsaturated fatty acids (MUFA) is associated with a low incidence of cardiovascular diseases, but the mechanisms of this relation are unclear. We investigated the role of dietary MUFA on the reverse transport of cholesterol mediated by HDL3 and on the subsequent regulation of intracellular cholesterol homeostasis. The study revealed that HDL3 obtained from the subjects fed the MUFA diet (compared with saturated or polyunsaturated fats diet) induced the highest [3H]free cholesterol efflux from cultured tibroblasts coupled with a reduced content of intracellular cholesterol and a higher LDL receptor activity in the cells. These variations of cholesterol efflux appear to be the consequence of modifications of HDW physicochemical parameters, particularly of HDW phospholipid fatty acid composition, fluidity and size. In conclusion, dietary fats induce physicochemical changes in HDW that can modulate cellular cholesterol metabolism. Sola et al. Arteriosclerosis Thrombosis 1993; 13: 958-966. Dietary cholesterol and plasma lipoproteins wPJ, CSIRO Division of Human Nutrition, PO Box 10041, Gouger Street, Adelaide SA 5000, Australia
It is not clear whether dietary cholesterol (DCh) directly contributes to coronary heart disease or only by influencing the lipoprotein profile. In specific situations DCh raises cholesterol in LDL, HDh and VLDUIDL. However the variability in responses is a classic example of genetic and nutritional factors interacting. The more desirable rise in HDb rather than in LDL occurs more in women, in younger people, in those with low LDL and in people with low waist-hip ratios (female fat distribution). Maleness, age and raised LDL predispose to a rise in LDL with DCh. One effect of the square root relationship between dietary and plasma cholesterol is that the effect of change in DCh is less when intake is high than when it is low, thus obscuring an effect at current ‘Western’ intakes. We have found good reproducibility in individuals. We have not found an effect of background dietary fatty acid profile on
response to DCh; but others have. While apo E genotype influences response to DCh (highest with E4), we have not found an effect of apo B gene polymorphism @co Rl or Xbal); in studies where this has been shown, the polymorphism accounts for a low percentage of LDL variability. Although diminished hepatic LDL receptor function has not been shown directly in humans, this is a likely major effect of DCh. Increased lipoprotein production has also been demonstrated for IDL and LDL. Changed hepatic lipase and lipid transfer protein activities may contribute to the HDb cholesterol rise. Compensatory responses involving cholesterol metabolism (decreased synthesis and increased excretion of ster01s) are well documented. It may become possible and certainly desirable to identify people whose genetic makeup predisposes them to DCh-induced hypercholesterolemia. Such improved targeting strengthens public health recommendations. Genetic factors in lipoprotein responsiveness to diet Schaefer EJ, Ordovas JM, Lichtenstein AH, Lipid Metabolism Lab., USDA Human Nutrition Research Center on Aging at Tufts Univ., Boston, MA, USA
The only common mutations within the population known to affect lipoprotein metabolism are apo E and apo A-N isoforms. Apo E2 differs from apo E3 by having a cysteine instead of an arginine at residue 158, while apo E4 differs from apo E3 by having an arginine at residue 112 instead of a cysteine. In participants in the Framingham Offspring Study that have had apo E isoforms assessed (n = 2258) the allele frequencies of epsilon 2, 3 and 4 were 0.08, 0.79 and 0.13, respectively. These alleles accounted for 1.0% of the variability in LDL-C in men, 0.5% in premenopausal women, and 5.0% in post-menopausal women. Apo A-IV-2 differs from apo A-IV-l by having a histidine instead of a glutamine at residue 360. The allele frequencies of apo A-N1 and apo A-IV-2 in the population are approximately 0.9 and 0.1, respectively, with the latter allele being associated with somewhat higher HDL-C levels in some studies. We studied LDL-C lowering in response to diets restricted in total fat (<30%), saturated fat (
Dietary saturated fatty acids and cholesterol, both individually and together, decrease LDL receptor activity in the liver. This impairs LDL removal from the plasma and hence increases plasma LDL concentrations. The capacity of a food or diet to affect plasma LDL concentration can be. denoted by a single number, the cholesterol saturated fat index (CSI). Fruits, grains, beans
Atherosclerosis X, Montreal, October I994
88
Monday 10 October 1994: Workshop Abstracts W7 Treatment advances: I - Dyslipoproteinemias
and vegetables are devoid of cholesterol and extremely low in saturated fat; their CSIs are almost zero, whereas eggs, butter, cheese and fatty meat have CSIs of 10-25. Not all saturated fats are hypercholesterolemic; only those from Cl2 to C16. Low amounts of dietary cholesterol (below 100 mg/day) do not have a plasma LDL elevating effect, but usual intakes of 300-500 mg/ day have a definite effect, even when saturated fat intake is controlled. However, very large quantities of dietary cholesterol, two or more times the usual intake, do not further increase the plasma LDL level (the ceiling effect). Dietary fatty acids with an especially potent hypotriglyceridemic effect are the very long chained polyunsaturated omega3 fatty acids from fish and fish oil. Such fatty acids (20:5 and 22:6) depress the synthesis of triglyceride-rich lipoproteins, especially VLDL, and improve the clearance of chylomicrons and VLDL from the blood. Thus, these omega-3 fatty acids lower the plasma triglyceride and VLDL levels and flatten greatly the usual fat tolerance curve after the consumption of a high-fat test breakfast. A diet low in saturated fat and cholesterol but high in the omega-3 fatty acids from fish and fish oil would have maximal plasma lipid-lipoprotein lowering effects for both LDL and VLDL. Nutrition and atherogenic dyslipidemia Univ. ofTexas Southwestern Med. W Center at DalwSM, las, 5323 Harry Hines Blvd., Dallas ‘Ix 75235, USA
Two major types of plasma lipid disorder contribute to coronary heart disease (CHD): hypercholesterolemia (elevated LDLcholesterol), and a lipid pattern that can be called atherogenic dyslipidemia (elevated VLDL remnants, increased small dense LDL particles, and low HDL levels). In the past, much attention has been given to the role of nutrition in the control of hypercholesterolemia. Much less attention has been given to the use of nutrition in the management of atherogenic dyslipidemia. To understand the potential utility of diet, we must first understand the mechanisms underlying atherogenic dyslipidemia. Recent studies indicate that the following factors contribute: increased production of VLDL triglycerides, reduced lipoprotein lipase, increased hepatic triglyceride lipase, increased cholesteryl ester transfer protein, and reduced synthesis of apolipoprotein A-I. Dietary factors seem to affect all these processes. Obesity and a high carbohydrate intake appear to produce the greatest adverse effects. For optimal dietary prevention of CHD, attention will have to be given to control of atherogenic dyslipidemia as well as of hypercholesterolemia. Nutrition and atherosclerosis regression wB, Watts GF, Lewis ES, St Thomas’ Hospital, London SE1 7EH, UK
Four clinical trials based on serial quantitative angiography have suggested that dietary change favorably modifies the course of coronary atherosclerosis. Two used multiple interventions and one was uncontrolled. The remaining trial, the St Thomas’ Atherosclerosis Regression Study, included diet as a single intervention in its randomized controlled design. 26 subjects in the diet group (D) and 24 on usual care (UC), all with symptomatic coronary artery disease, completed the 39-month trial, during which two or more food frequency lists, food consumption interviews, and 3-day records were used to compute nutrient intake. Change in the minimum width (MW) in mm of up to 10 proximal coronary segments was estimated, with appropriate blinding. The design provided an opportunity to seek, by univariate and multivariate analysis, relationships between nutrient intakes and the course of coronary atherosclerosis, in the context of a clinically practicable lipid-lowering diet. The main observed differences in nutrient intake (g/day) for D and UC respectively were in saturated fat: 21 vs. 42, in polyunsaturated fat: 17 vs. 12, in monounsaturated fat: 21 vs. 41, in cholesterol: 0.215 vs. 0.341, and in fiber: 28 vs. 18 (the diet emphasized sources of soluble fiber). In D, serum cholesterol was lowered 14.3%, triglyceride by 18.5%, LDL-cholesterol by 14.92, with no change in HDL. Body weight did not change significantly. Decrease in MW (= progression, defined as a mean decrease of >0.3 mm) was directly related to fat intake (r = 0.55) and saturated fat intake (r = 0.44), p = 0.001 for both. We compared nutrient intakes among subjects showing progression, no change, and regression respectively (the latter defined as an increase of MW of >0.3 mm). These groups showed significant differences in intakes (g/day) of fat (97, 72, and 61), saturated fat (42, 30, and 21), and monounsaturated fat (41, 30, and 22); differences in intake of cholesterol (0.349, 0.258. and 0.255) were not formallv sienificant (p = 0.069). Energy intakes differed significantly (2302, 2074, and 2015 kcal). To examine individual effects on change in MW, multiple regression analysis was used; intake of saturated fat and plasma LDL-cholesterol level were independently related to progression after adjustment for age, group assignment, and risk factor levels. The study provides evidence that intake of saturated fat is a determinant of directly measured progression of coronary artery disease in man; such progression was in our earlier studies related to the incidence of clinical coronary events. The effect of saturated fat was not fully explained by its influence on LDLcholesterol levels, and possibly involves further mechanisms such as fatty acid effects on LDL oxidation or on thrombogenic mechanisms. The higher intake of monounsaturated fat in those showing progression may reflect its coexistence, in several foods, with saturated fats. Our data favor recommendation of a saturated fat intake of ~8% of energy.
W7 TREATMENT ADVANCES: I - DYSLIPOPROTEINEMIAS Investigations of the effects of synthetic saponins terol absorption and serum cholesterol levels
on choles-
pyiovne C$*, Harris WS*, Morehouse LA#, McCarthy PA#, Gelfand RA , Shear CL#, Chandler CE’, DeNinno MP’, Harwood HJ’, *Lipid and Arteriosclerosis Prevention Clinic, Univ. of Kansas Med. Center, 3901 Rainbow Blvd., Kansas City, KS, 661607374; #Central Research, Pjizer, Inc., Eastern Point Road, Groton, CT 06340, USA Plant saponins are widely distributed natural biological agents which have been shown to inhibit cholesterol absorption from the intestinal lumen. Recently, the desirable effects of plant saponins have been mimicked by synthetic saponins such as tiqueside (CP88,818). This effect has been shown to reduce serum cholesterol
(J Lipid Res 1993; 34: 377-395). The over 60% inhibition of cholesterol absorption in experimental animals appears to be due to a non-systemic effect on both dietary and biliary cholesterol. Fecal neutral sterol excretion is increased by tiqueside administration in a dose-dependent fashion. Changes in fecal neutral stem1 excretion axe correlated with decreased hepatic and plasma cholesterol. Synthetic saponins, if sufficiently safe and effective, may be a novel approach for the treatment of lipidrelated cardiovascular risk. concentrations
Atorvastatin: a step ahead for HMG-CoA reductase inhibitors Parke-Davis Pharmaceutical Research. Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, LISA
&I&&
Atherosclerosis X, Montreal, October 1994
87
W6 NUTRITION, LIPOPROTEINS AND ATHEROSCLEROSIS Trans fatty acids and lipoproteins
m,
Mensink RP, van To1 A*, Zock PL, Dept. of Human
Nutrition, Anricultural Univ., Bomenwen 2. 6703 HD Waneningen; *Dept. >f Biochem., Erasmus Univ.: Rotterdam, The Netherlands
Isomeric fatty acids are unsaturated fatty acids with one or more double bonds in an unusual configuration (trans instead of cis) or position (positional cis isomers). The term trans is loosely used to refer to both types. Trans fatty acids arise through biohydrogenation in the rumen of cows and sheep or catalytic hydrogenation in oil-processing factories. The effects of trans monounsaturates on lipoproteins in man are opposite to those of the natural cis acid, oleic acid. Our own experiments in healthy volunteers employed 11% or 7.5% of energy as trans in strictly controlled diets. Trans fatty acids raised LDL and Lp(a) and lowered HDL, all in dosedependent fashion; raised serum cholesteryl ester transfer activity in 52/55 volunteers (mean change 18%, p < 0.02) and significantly lowered the HDL ratio of cholesteryl esters to triglycerides. LCAT was unchanged. Thus, trans fatty acids raise LDL, lower HDL and raise Lp(a) in man. The effects on HDL and LDL may be mediated through CETP. Effect of monounsaturated fatty acids on lipoprotein metabolism Jacotot, Sola R, Service Mddecine Inteme 5, HGpital Henri Mondor, 94010 Cretei CJdex, France
The increased consumption of monounsaturated fatty acids (MUFA) is associated with a low incidence of cardiovascular diseases, but the mechanisms of this relation are unclear. We investigated the role of dietary MUFA on the reverse transport of cholesterol mediated by HDL3 and on the subsequent regulation of intracellular cholesterol homeostasis. The study revealed that HDL3 obtained from the subjects fed the MUFA diet (compared with saturated or polyunsaturated fats diet) induced the highest [3H]free cholesterol efflux from cultured tibroblasts coupled with a reduced content of intracellular cholesterol and a higher LDL receptor activity in the cells. These variations of cholesterol efflux appear to be the consequence of modifications of HDW physicochemical parameters, particularly of HDW phospholipid fatty acid composition, fluidity and size. In conclusion, dietary fats induce physicochemical changes in HDW that can modulate cellular cholesterol metabolism. Sola et al. Arteriosclerosis Thrombosis 1993; 13: 958-966. Dietary cholesterol and plasma lipoproteins wPJ, CSIRO Division of Human Nutrition, PO Box 10041, Gouger Street, Adelaide SA 5000, Australia
It is not clear whether dietary cholesterol (DCh) directly contributes to coronary heart disease or only by influencing the lipoprotein profile. In specific situations DCh raises cholesterol in LDL, HDh and VLDUIDL. However the variability in responses is a classic example of genetic and nutritional factors interacting. The more desirable rise in HDb rather than in LDL occurs more in women, in younger people, in those with low LDL and in people with low waist-hip ratios (female fat distribution). Maleness, age and raised LDL predispose to a rise in LDL with DCh. One effect of the square root relationship between dietary and plasma cholesterol is that the effect of change in DCh is less when intake is high than when it is low, thus obscuring an effect at current ‘Western’ intakes. We have found good reproducibility in individuals. We have not found an effect of background dietary fatty acid profile on
response to DCh; but others have. While apo E genotype influences response to DCh (highest with E4), we have not found an effect of apo B gene polymorphism @co Rl or Xbal); in studies where this has been shown, the polymorphism accounts for a low percentage of LDL variability. Although diminished hepatic LDL receptor function has not been shown directly in humans, this is a likely major effect of DCh. Increased lipoprotein production has also been demonstrated for IDL and LDL. Changed hepatic lipase and lipid transfer protein activities may contribute to the HDb cholesterol rise. Compensatory responses involving cholesterol metabolism (decreased synthesis and increased excretion of ster01s) are well documented. It may become possible and certainly desirable to identify people whose genetic makeup predisposes them to DCh-induced hypercholesterolemia. Such improved targeting strengthens public health recommendations. Genetic factors in lipoprotein responsiveness to diet Schaefer EJ, Ordovas JM, Lichtenstein AH, Lipid Metabolism Lab., USDA Human Nutrition Research Center on Aging at Tufts Univ., Boston, MA, USA
The only common mutations within the population known to affect lipoprotein metabolism are apo E and apo A-N isoforms. Apo E2 differs from apo E3 by having a cysteine instead of an arginine at residue 158, while apo E4 differs from apo E3 by having an arginine at residue 112 instead of a cysteine. In participants in the Framingham Offspring Study that have had apo E isoforms assessed (n = 2258) the allele frequencies of epsilon 2, 3 and 4 were 0.08, 0.79 and 0.13, respectively. These alleles accounted for 1.0% of the variability in LDL-C in men, 0.5% in premenopausal women, and 5.0% in post-menopausal women. Apo A-IV-2 differs from apo A-IV-l by having a histidine instead of a glutamine at residue 360. The allele frequencies of apo A-N1 and apo A-IV-2 in the population are approximately 0.9 and 0.1, respectively, with the latter allele being associated with somewhat higher HDL-C levels in some studies. We studied LDL-C lowering in response to diets restricted in total fat (<30%), saturated fat (
Dietary saturated fatty acids and cholesterol, both individually and together, decrease LDL receptor activity in the liver. This impairs LDL removal from the plasma and hence increases plasma LDL concentrations. The capacity of a food or diet to affect plasma LDL concentration can be. denoted by a single number, the cholesterol saturated fat index (CSI). Fruits, grains, beans
Atherosclerosis X, Montreal, October I994
88
Monday 10 October 1994: Workshop Abstracts W7 Treatment advances: I - Dyslipoproteinemias
and vegetables are devoid of cholesterol and extremely low in saturated fat; their CSIs are almost zero, whereas eggs, butter, cheese and fatty meat have CSIs of 10-25. Not all saturated fats are hypercholesterolemic; only those from Cl2 to C16. Low amounts of dietary cholesterol (below 100 mg/day) do not have a plasma LDL elevating effect, but usual intakes of 300-500 mg/ day have a definite effect, even when saturated fat intake is controlled. However, very large quantities of dietary cholesterol, two or more times the usual intake, do not further increase the plasma LDL level (the ceiling effect). Dietary fatty acids with an especially potent hypotriglyceridemic effect are the very long chained polyunsaturated omega3 fatty acids from fish and fish oil. Such fatty acids (20:5 and 22:6) depress the synthesis of triglyceride-rich lipoproteins, especially VLDL, and improve the clearance of chylomicrons and VLDL from the blood. Thus, these omega-3 fatty acids lower the plasma triglyceride and VLDL levels and flatten greatly the usual fat tolerance curve after the consumption of a high-fat test breakfast. A diet low in saturated fat and cholesterol but high in the omega-3 fatty acids from fish and fish oil would have maximal plasma lipid-lipoprotein lowering effects for both LDL and VLDL. Nutrition and atherogenic dyslipidemia Univ. ofTexas Southwestern Med. W Center at DalwSM, las, 5323 Harry Hines Blvd., Dallas ‘Ix 75235, USA
Two major types of plasma lipid disorder contribute to coronary heart disease (CHD): hypercholesterolemia (elevated LDLcholesterol), and a lipid pattern that can be called atherogenic dyslipidemia (elevated VLDL remnants, increased small dense LDL particles, and low HDL levels). In the past, much attention has been given to the role of nutrition in the control of hypercholesterolemia. Much less attention has been given to the use of nutrition in the management of atherogenic dyslipidemia. To understand the potential utility of diet, we must first understand the mechanisms underlying atherogenic dyslipidemia. Recent studies indicate that the following factors contribute: increased production of VLDL triglycerides, reduced lipoprotein lipase, increased hepatic triglyceride lipase, increased cholesteryl ester transfer protein, and reduced synthesis of apolipoprotein A-I. Dietary factors seem to affect all these processes. Obesity and a high carbohydrate intake appear to produce the greatest adverse effects. For optimal dietary prevention of CHD, attention will have to be given to control of atherogenic dyslipidemia as well as of hypercholesterolemia. Nutrition and atherosclerosis regression wB, Watts GF, Lewis ES, St Thomas’ Hospital, London SE1 7EH, UK
Four clinical trials based on serial quantitative angiography have suggested that dietary change favorably modifies the course of coronary atherosclerosis. Two used multiple interventions and one was uncontrolled. The remaining trial, the St Thomas’ Atherosclerosis Regression Study, included diet as a single intervention in its randomized controlled design. 26 subjects in the diet group (D) and 24 on usual care (UC), all with symptomatic coronary artery disease, completed the 39-month trial, during which two or more food frequency lists, food consumption interviews, and 3-day records were used to compute nutrient intake. Change in the minimum width (MW) in mm of up to 10 proximal coronary segments was estimated, with appropriate blinding. The design provided an opportunity to seek, by univariate and multivariate analysis, relationships between nutrient intakes and the course of coronary atherosclerosis, in the context of a clinically practicable lipid-lowering diet. The main observed differences in nutrient intake (g/day) for D and UC respectively were in saturated fat: 21 vs. 42, in polyunsaturated fat: 17 vs. 12, in monounsaturated fat: 21 vs. 41, in cholesterol: 0.215 vs. 0.341, and in fiber: 28 vs. 18 (the diet emphasized sources of soluble fiber). In D, serum cholesterol was lowered 14.3%, triglyceride by 18.5%, LDL-cholesterol by 14.92, with no change in HDL. Body weight did not change significantly. Decrease in MW (= progression, defined as a mean decrease of >0.3 mm) was directly related to fat intake (r = 0.55) and saturated fat intake (r = 0.44), p = 0.001 for both. We compared nutrient intakes among subjects showing progression, no change, and regression respectively (the latter defined as an increase of MW of >0.3 mm). These groups showed significant differences in intakes (g/day) of fat (97, 72, and 61), saturated fat (42, 30, and 21), and monounsaturated fat (41, 30, and 22); differences in intake of cholesterol (0.349, 0.258. and 0.255) were not formallv sienificant (p = 0.069). Energy intakes differed significantly (2302, 2074, and 2015 kcal). To examine individual effects on change in MW, multiple regression analysis was used; intake of saturated fat and plasma LDL-cholesterol level were independently related to progression after adjustment for age, group assignment, and risk factor levels. The study provides evidence that intake of saturated fat is a determinant of directly measured progression of coronary artery disease in man; such progression was in our earlier studies related to the incidence of clinical coronary events. The effect of saturated fat was not fully explained by its influence on LDLcholesterol levels, and possibly involves further mechanisms such as fatty acid effects on LDL oxidation or on thrombogenic mechanisms. The higher intake of monounsaturated fat in those showing progression may reflect its coexistence, in several foods, with saturated fats. Our data favor recommendation of a saturated fat intake of ~8% of energy.
W7 TREATMENT ADVANCES: I - DYSLIPOPROTEINEMIAS Investigations of the effects of synthetic saponins terol absorption and serum cholesterol levels
on choles-
pyiovne C$*, Harris WS*, Morehouse LA#, McCarthy PA#, Gelfand RA , Shear CL#, Chandler CE’, DeNinno MP’, Harwood HJ’, *Lipid and Arteriosclerosis Prevention Clinic, Univ. of Kansas Med. Center, 3901 Rainbow Blvd., Kansas City, KS, 661607374; #Central Research, Pjizer, Inc., Eastern Point Road, Groton, CT 06340, USA Plant saponins are widely distributed natural biological agents which have been shown to inhibit cholesterol absorption from the intestinal lumen. Recently, the desirable effects of plant saponins have been mimicked by synthetic saponins such as tiqueside (CP88,818). This effect has been shown to reduce serum cholesterol
(J Lipid Res 1993; 34: 377-395). The over 60% inhibition of cholesterol absorption in experimental animals appears to be due to a non-systemic effect on both dietary and biliary cholesterol. Fecal neutral sterol excretion is increased by tiqueside administration in a dose-dependent fashion. Changes in fecal neutral stem1 excretion axe correlated with decreased hepatic and plasma cholesterol. Synthetic saponins, if sufficiently safe and effective, may be a novel approach for the treatment of lipidrelated cardiovascular risk. concentrations
Atorvastatin: a step ahead for HMG-CoA reductase inhibitors Parke-Davis Pharmaceutical Research. Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, LISA
&I&&
Atherosclerosis X, Montreal, October 1994