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Nutrition and atherogenic dyslipidemia
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
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