European Journal
of Clinical Iniiesiigation ( I 992) 22, 76 1-763
CONFERENCE REPORT
N e w horizons in the pathogenesis of coronary heart disease M. OLIVER, Wynn Institute for Metabolic Research, London, UK
A symposium was held recently in London on 22 June 1992 on this subject. A new perspective of the significance of risk factors is now possible as we enter this decade, since we have learnt during the last decade that rather less than 50% of the incidence ofcoronary heart disease in males, and in the region of 25% of the incidence in females, can be explained by the ‘orthodox’ risk factors of cigarette smoking, raised blood cholesterol and raised blood pressure. Thus, this conference was innovatory and informative in bringing together international experts who reported their research and that of others in fields which might be described as being beyond the ‘orthodox’ risk factors. Professor A. T. Diplock (London, UK) described pathways through which oxygen-derived free radicals and related active metabolites are formed and the effect these may have on various biological molecules related to atherosclerosis and the ischaemic myocardium. Iron and copper ions act as catalytic agents exacerbating the proliferation of free radicals. Unsaturated fatty acids in low density lipoproteins are particularly susceptible and can undergo peroxidation in the space beneath the arterial endothelium. This may be a primary event in the aetiogenesis of atheroma. What can we do to contain these self-destructive processes? Naturally-occurring antioxidants, such as selenium, betacarotene and the anti-oxidant vitamins E and C, may all play a role. The incidence of cardiovascular disease appears to be higher in populations with low levels of vitamin E and C and betacarotene and there is emerging evidence that some antioxidants may, at least experimentally, reduce the accumulation of cholesterol in the arterial wall. The concept of a recommended daily intake of anti-oxidant vitamins is now outmoded. It was originally defined to prevent deficiency diseases but the possibility that larger concentrations in the region of 60-100 mg daily of vitamin E may be protective now has to be considered seriously and an appropriately designed controlled trial against coronary heart disease needs to be initiated. Professor J. Witztum (San Diego, USA) demonstrated that low density lipoproteins (LDL) must be modified in some way or oxidized for them to accumulate in the macrophages within the arterial wall. Products of oxidized LDL are chemotactic for their Correspondence: Profcssor Michael Olivcr, Director. Wynn Institute for Metabolic Research. 21 Wellington Road. London NW89SQ.
precursor monocytes in the plasma, and stimulate the release of MCP- 1, another potent monocyte chemoattractant. Oxidised LDL promotes the atherogenic process by many mechanisms. It is cytotoxic for cells in the arterial wall, increases adherence of molecules for monocytes on endothelial surfaces, causes release of interleukin 1 b from macrophages, is chemotactic for T-cells and inhibits the actions of EDRF on smooth muscle cells, thereby possibly causing vasoconstriction of coronary arteries. Thus, inhibition of LDL oxidation might be beneficial for a number of reasons and the most favoured naturally-occurring antioxidant is a-tocopherol (vitamin E). Probucol, a pharmacological anti-oxidant, also has a profound inhibitory effect. Monounsaturated fatty acids may be inhibitory to the destructive activities of oxidized LDL. Low concentrations of linoleic acid may also be a marker of increased peroxidation and this might explain the inverse relationship between linoleic acid and coronary heart disease incidence. Professor J. Martin (London, UK) provided evidence that after myocardial infarction there is an increase in the size of platelets (which predict a second infarct and death) and also in large highly polyploid megakaryocytes. Fibrinogen binds with platelets at the GP IIb/III a receptors. Larger platelets have more of these receptors, thus giving a greater tendency to thrombosis. The initial hormonal stimulation of megakaryocyte changes is unclear. Nitric oxide is an ubiquitous mediator and is fundamental in maintaining blood flow through arteries by causing relaxation of vascular smooth muscle cells via an action on the enzyme soluble guanalate cyclase. It was reported that an enzyme that produces nitric oxide (NO synthase) can be induced in megakaryocytes by interleukin IB, which is secreted by macrophages in atheromatous plaques. This might be a defence reaction with the nitric oxide thus produced protecting against the effects of atheroma. Professor Martin described a further area of renewed interest-the possibility that ischaemia of the media may occur as a consequence of occlusion of the adventitial vasa vasorum. This might initiate proliferative changes in the intima leading to atheroma. The adventitia has a role in modulating the integrity of the intima of the artery. The focus then moved to a comprehensive review of the relationship between increased plasma fibrinogen and increased risk ofcoronary heart disease. A pioneer in the fundamentally important role of thrombosis in 76 I
762
M. OLIVER
the development of coronary heart disease, Professor T. Meade (London, UK) described five prospective studies indicating an independent association between plasma fibrinogen and coronary heart disease or stroke that it is about as strong as for cholesterol. High fibrinogen levels contribute to the development of atheroma in several ways-by increasing blood viscosity, by acting as a co-factor in platelet aggregability and by influencing the amount of fibrin deposited when coagulation is initiated. Plasma fibrinogen concentrations are lowered by moderate alcohol consumption and strenous physical activity, both of which have been shown to be associated with a reduced incidence of coronary heart disease. There is also growing evidence that the extrinsic coagulation system, the activity of which depends on the complexing of factor VII with tissue factor, influences the onset of CHD through thrombin production. More data are needed, however, concerning the importance of plasminogen-activator inhibitors and that of tPA in the onset and recurrence of CHD. There is increasing evidence for the effectiveness of anti-thrombotic treatment and prophylaxis. Professor U. Smith (Goteborg, Sweden) outlined the components of the insulin resistance syndrome (IRS). He used this description in preference to ‘Syndrome X’, which is also a term used by cardiologists to describe angina and myocardial ischaemia in the absence of definable coronary artery disease. It is also a preferable term to Reaven’s syndrome and should be more widely used to describe the combination of increased insulin resistance, high serum triglycerides, low HDL cholesterol and raised blood pressure. Most previous work has linked insulin resistance to a propensity for diabetes, where obesity particularly abdominal obesity may provide an intermediate link. Several extensive epidemiological studies have shown that hyperinsulinaemia is a risk factor for coronary heart disease and recent findings indicate that insulin resistance may be a cause of atherosclerosis and thrombosis. It may be a particularly important determination of racial differences, such as the high incidence of coronary heart disease in Indian Asians. Hyperinsulinaemia exerts effects on lipid and protein metabolism, the synthesis of several different functions of cellular enzymes and it is related to blood pressure regulation; but the link between hyperinsulinaemia and hypertension is not well understood. Central obesity is associated with marked insulin resistance and may be an important link with the lipid and other metabolic abberrations of the insulin resistance syndrome. This syndrome appears to be a common concomitant with the menopause and can also be elicited by cigarette smoking. Further understanding of the insulin resistance syndrome will add another dimension to the risk profile and provide an important link between metabolic risk factors for atherosclerosis and thrombogenesis. Professor R. Krauss (Berkeley) described new developments in our understanding of the transport of
cholesterol in the plasma by identifying subtypes of low density lipoproteins (LDL) focusing particularly on LDL sub-class 111(small, dense LDL). He indicated that predominance of small dense LDL is a common heritable phenotype influenced by an autosomal dominant gene. In comparison with subjects who have larger LDL subclasses (LDL I or II), individuals with small, dense LDL have higher levels of triglycerides and apoprotein B, lower concentrations of high density lipoprotein (HDL) and features of the insulin resistance syndrome, including increased systolic blood pressure. This phenotype may be present in as many as 30% of the American population, and might confer up to a 3-fold increased risk of myocardial infarction. Subjects with the small LDL trait show greater reductions in plasma LDL and LDL/HDL ratios in response to a reduced fat diet than to subjects with larger LDL. Discrimination of LDL subclass phenotypes might have important therapeutic implications in so far as treatment for raised LDL could be more focused in the future on those with raised small LDL. Dr Elizabeth Barrett-Connor (San Diego, USA) reviewed the role of hormone replacement therapy for postmenopausal women indicating that the beneficial effects were primarily related to the use of oestrogens and that at present we know insufficient about combined preparations of oestrogens and progestogens. The beneficial effects may amount to as much as 3050% reduction in the incidence of coronary heart disease with a smaller attributable adverse effect on breast and endometrial cancer. Despite the strong experimental evidence that in animal models oestrogens protect against induced atherosclerosis, no regression studies have been undertaken in women. Equally, no large randomized control trial of the effect of oestrogen or combined oestrogen progestogen preparations on cardiovascular disease have been established. Indeed, these will be difficult because of the large size of any study and problems of randomizing postmenopausal women to placebo treatment. Natural oestrogens have numerous effects on several biological systems that could influence the risk of coronary heart disease: these relate to lipid and lipoprotein metabolism (there is clear evidence that oestrogens lower LDL and raise HDL cholesterol), insulin resistance is improved and vasomotor tone affected towards a net reduction of vascular resistance. Exactly why this occurs is not clear but there are oestrogen receptors in vascular endothelium and more studies are needed to determine their function and their possible relation to other influences on vasoconstrictor. Precise estimates as to the benefit of hormone replacement therapy are difficult in view of the various selection factors that have operated in establishment of existing cohort studies but the overall estimate is that it is considerable. It is depressing that so little attention seems to be paid by primary care physicians to the potential protective benefits of hormone replacement
NEW HORIZONS IN CORONARY HEART DISEASE therapy against cardiovascular disease, as well as osteoporosis. Professor D. Barker (Southampton, UK) demonstrated that much of the incidence of coronary heart disease could be related to the small baby syndromein other words, many of the metabolic disturbances known to be present in middle aged patients with coronary heart disease and stroke originate through impaired growth and development during fetal life and infancy. These diseases may be a consequence of ‘programming’ in early life resulting in long-term changes in physiology and metabolism. Thus, there is a strong inverse relationship between body weight at birth and at 1 year with the incidence of CHD in middle and late middle-age and late life. Professor Barker has been able to draw on an unique database for measurement of weight and head circumference at birth and weight at 1 year with a follow-up of people into their late 50s and 60s. He put particular emphasis on the importance of the maturation of the pancreas. Failure of maturation of the pancreas during early life may be irretrievable and is in its turn related to nutritional deprivation in utero. Surely this conference on ‘New Horizons’ justifies its title when evidence is provided to suggest that the function of the pancreas at birth might influence subsequent coronary heart disease! Nutritional deprivation in early life can programme the size and DNA contents of many systems and organs. Little is known about the maternal influences which impair early growth but adult levels of blood pressure, lipids, glucose metabolism, haemostatic factors and even the distribution of body fat may all be determined in part by intra-uterine influences. It is an interesting speculation that one of the explanations of the decrease in coronary heart disease and stroke during the last 30-40 years may be related to improvement of fetal and neonatal nutrition in comparison with the years between the wars and before The First World War. This question of undernutrition and social impoverishment was taken up by Professor M. Marmot (London, UK) who indicated very clearly the steep inverse association which exists between social class and CHD mortality in the United Kingdom, drawing particularly on the Whitehall study of Civil Servants. An inverse association exists between employment grade and prevalence of angina, electrocardiographic evidence of ischaemia and symptoms of chronic bronchitis. There are striking employment grade differences with regard to smoking, diet and exercise. Monotonous work characterized by boredom and inability to control one’s destiny is associated with a high incidence of CHD. This may partly explain the alarming
763
increase in CHD incidence in many Eastern European countries, while there is a concurrent progressive fall in Western European countries. Professor Marmot proposed that one explanation for the low CHD rates in Japan (where CHD is actually decreasing) is the country’s increased prosperity and a more equitable distribution of income and opportunity; he did not believe that reduction in CHD in Japan over the last 20 years could be explained simply by changes in diet and, anyway, the Japanese smoke to excess. The message is obvious. One of the best investments for Government to reduce CHD in the United Kingdom is economic and social class policy directed at improving living and working conditions and improving opportunities in those socially impoverished. This was a stimulating conference, sponsored by the Butter Council, throwing out numerous new ideas, and going beyond the entrenchment of scientific thinking induced by the dominance of the cholesterol hypothesis, important that this may be. Government based research and health education programmes, pharmaceutical houses, basic and clinical scientists have a great deal more to address in this decade. Summing up, Professor M. Oliver (London) stated ‘It is not good enough simply to assume that measurement and control of the ‘orthodox’ risk factors is all that needs to concern us’. At last, new fields of endeavour are emerging and there are distinct possibilities that further research into a number of the themes developed in this conference may provide us with answers about the missing one half or more of the risk factors leading to coronary heart disease and consequently their eventual control. Representative references Diplock AT. Anti-oxidants nutrients and disease prevention: an overview. Am J Clin Nutr 1991;53:189 Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991;88:1785-92. Lelchuk R, Radomski M, Martin JF, Moncada S. Constitutive and inducible nitric oxide synthases in human megakaryoblastic cells. J Pharmacol Exp Therap 1992; (in press). Meade TW, Brozovic M, Mellows S, Miller G et a/. Haemostatic function and ischaemic heart disease: Principal results of the Northwich Park Heart Study. Lancet 1986; ii: 533-7. Smith U. Gudbjornsdottir S, Landin K. Hypertension as a metabolic disorder. J Int Med 1991;229:1-7. Austin MA, King MC, Vranizan KM, Krauss AM. Atherogenic lipoprotein phenotype: A proposed genetic marker for coronary heart disease risk. Circulation 1990;82(2):495-506. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991;265:1861-7. Barker DJP. Fetal and infant origin of adult disease. Br Med J Marmot MG. Davey-Smith G, StanfTeld S, Patel C e t a / .Inequalities in health twenty years on: The Whitehall I1 Study of British Civil Servants. Lancet 1991;337:1387-93.
of Clinical Iniiesiigation ( I 992) 22, 76 1-763
CONFERENCE REPORT
N e w horizons in the pathogenesis of coronary heart disease M. OLIVER, Wynn Institute for Metabolic Research, London, UK
A symposium was held recently in London on 22 June 1992 on this subject. A new perspective of the significance of risk factors is now possible as we enter this decade, since we have learnt during the last decade that rather less than 50% of the incidence ofcoronary heart disease in males, and in the region of 25% of the incidence in females, can be explained by the ‘orthodox’ risk factors of cigarette smoking, raised blood cholesterol and raised blood pressure. Thus, this conference was innovatory and informative in bringing together international experts who reported their research and that of others in fields which might be described as being beyond the ‘orthodox’ risk factors. Professor A. T. Diplock (London, UK) described pathways through which oxygen-derived free radicals and related active metabolites are formed and the effect these may have on various biological molecules related to atherosclerosis and the ischaemic myocardium. Iron and copper ions act as catalytic agents exacerbating the proliferation of free radicals. Unsaturated fatty acids in low density lipoproteins are particularly susceptible and can undergo peroxidation in the space beneath the arterial endothelium. This may be a primary event in the aetiogenesis of atheroma. What can we do to contain these self-destructive processes? Naturally-occurring antioxidants, such as selenium, betacarotene and the anti-oxidant vitamins E and C, may all play a role. The incidence of cardiovascular disease appears to be higher in populations with low levels of vitamin E and C and betacarotene and there is emerging evidence that some antioxidants may, at least experimentally, reduce the accumulation of cholesterol in the arterial wall. The concept of a recommended daily intake of anti-oxidant vitamins is now outmoded. It was originally defined to prevent deficiency diseases but the possibility that larger concentrations in the region of 60-100 mg daily of vitamin E may be protective now has to be considered seriously and an appropriately designed controlled trial against coronary heart disease needs to be initiated. Professor J. Witztum (San Diego, USA) demonstrated that low density lipoproteins (LDL) must be modified in some way or oxidized for them to accumulate in the macrophages within the arterial wall. Products of oxidized LDL are chemotactic for their Correspondence: Profcssor Michael Olivcr, Director. Wynn Institute for Metabolic Research. 21 Wellington Road. London NW89SQ.
precursor monocytes in the plasma, and stimulate the release of MCP- 1, another potent monocyte chemoattractant. Oxidised LDL promotes the atherogenic process by many mechanisms. It is cytotoxic for cells in the arterial wall, increases adherence of molecules for monocytes on endothelial surfaces, causes release of interleukin 1 b from macrophages, is chemotactic for T-cells and inhibits the actions of EDRF on smooth muscle cells, thereby possibly causing vasoconstriction of coronary arteries. Thus, inhibition of LDL oxidation might be beneficial for a number of reasons and the most favoured naturally-occurring antioxidant is a-tocopherol (vitamin E). Probucol, a pharmacological anti-oxidant, also has a profound inhibitory effect. Monounsaturated fatty acids may be inhibitory to the destructive activities of oxidized LDL. Low concentrations of linoleic acid may also be a marker of increased peroxidation and this might explain the inverse relationship between linoleic acid and coronary heart disease incidence. Professor J. Martin (London, UK) provided evidence that after myocardial infarction there is an increase in the size of platelets (which predict a second infarct and death) and also in large highly polyploid megakaryocytes. Fibrinogen binds with platelets at the GP IIb/III a receptors. Larger platelets have more of these receptors, thus giving a greater tendency to thrombosis. The initial hormonal stimulation of megakaryocyte changes is unclear. Nitric oxide is an ubiquitous mediator and is fundamental in maintaining blood flow through arteries by causing relaxation of vascular smooth muscle cells via an action on the enzyme soluble guanalate cyclase. It was reported that an enzyme that produces nitric oxide (NO synthase) can be induced in megakaryocytes by interleukin IB, which is secreted by macrophages in atheromatous plaques. This might be a defence reaction with the nitric oxide thus produced protecting against the effects of atheroma. Professor Martin described a further area of renewed interest-the possibility that ischaemia of the media may occur as a consequence of occlusion of the adventitial vasa vasorum. This might initiate proliferative changes in the intima leading to atheroma. The adventitia has a role in modulating the integrity of the intima of the artery. The focus then moved to a comprehensive review of the relationship between increased plasma fibrinogen and increased risk ofcoronary heart disease. A pioneer in the fundamentally important role of thrombosis in 76 I
762
M. OLIVER
the development of coronary heart disease, Professor T. Meade (London, UK) described five prospective studies indicating an independent association between plasma fibrinogen and coronary heart disease or stroke that it is about as strong as for cholesterol. High fibrinogen levels contribute to the development of atheroma in several ways-by increasing blood viscosity, by acting as a co-factor in platelet aggregability and by influencing the amount of fibrin deposited when coagulation is initiated. Plasma fibrinogen concentrations are lowered by moderate alcohol consumption and strenous physical activity, both of which have been shown to be associated with a reduced incidence of coronary heart disease. There is also growing evidence that the extrinsic coagulation system, the activity of which depends on the complexing of factor VII with tissue factor, influences the onset of CHD through thrombin production. More data are needed, however, concerning the importance of plasminogen-activator inhibitors and that of tPA in the onset and recurrence of CHD. There is increasing evidence for the effectiveness of anti-thrombotic treatment and prophylaxis. Professor U. Smith (Goteborg, Sweden) outlined the components of the insulin resistance syndrome (IRS). He used this description in preference to ‘Syndrome X’, which is also a term used by cardiologists to describe angina and myocardial ischaemia in the absence of definable coronary artery disease. It is also a preferable term to Reaven’s syndrome and should be more widely used to describe the combination of increased insulin resistance, high serum triglycerides, low HDL cholesterol and raised blood pressure. Most previous work has linked insulin resistance to a propensity for diabetes, where obesity particularly abdominal obesity may provide an intermediate link. Several extensive epidemiological studies have shown that hyperinsulinaemia is a risk factor for coronary heart disease and recent findings indicate that insulin resistance may be a cause of atherosclerosis and thrombosis. It may be a particularly important determination of racial differences, such as the high incidence of coronary heart disease in Indian Asians. Hyperinsulinaemia exerts effects on lipid and protein metabolism, the synthesis of several different functions of cellular enzymes and it is related to blood pressure regulation; but the link between hyperinsulinaemia and hypertension is not well understood. Central obesity is associated with marked insulin resistance and may be an important link with the lipid and other metabolic abberrations of the insulin resistance syndrome. This syndrome appears to be a common concomitant with the menopause and can also be elicited by cigarette smoking. Further understanding of the insulin resistance syndrome will add another dimension to the risk profile and provide an important link between metabolic risk factors for atherosclerosis and thrombogenesis. Professor R. Krauss (Berkeley) described new developments in our understanding of the transport of
cholesterol in the plasma by identifying subtypes of low density lipoproteins (LDL) focusing particularly on LDL sub-class 111(small, dense LDL). He indicated that predominance of small dense LDL is a common heritable phenotype influenced by an autosomal dominant gene. In comparison with subjects who have larger LDL subclasses (LDL I or II), individuals with small, dense LDL have higher levels of triglycerides and apoprotein B, lower concentrations of high density lipoprotein (HDL) and features of the insulin resistance syndrome, including increased systolic blood pressure. This phenotype may be present in as many as 30% of the American population, and might confer up to a 3-fold increased risk of myocardial infarction. Subjects with the small LDL trait show greater reductions in plasma LDL and LDL/HDL ratios in response to a reduced fat diet than to subjects with larger LDL. Discrimination of LDL subclass phenotypes might have important therapeutic implications in so far as treatment for raised LDL could be more focused in the future on those with raised small LDL. Dr Elizabeth Barrett-Connor (San Diego, USA) reviewed the role of hormone replacement therapy for postmenopausal women indicating that the beneficial effects were primarily related to the use of oestrogens and that at present we know insufficient about combined preparations of oestrogens and progestogens. The beneficial effects may amount to as much as 3050% reduction in the incidence of coronary heart disease with a smaller attributable adverse effect on breast and endometrial cancer. Despite the strong experimental evidence that in animal models oestrogens protect against induced atherosclerosis, no regression studies have been undertaken in women. Equally, no large randomized control trial of the effect of oestrogen or combined oestrogen progestogen preparations on cardiovascular disease have been established. Indeed, these will be difficult because of the large size of any study and problems of randomizing postmenopausal women to placebo treatment. Natural oestrogens have numerous effects on several biological systems that could influence the risk of coronary heart disease: these relate to lipid and lipoprotein metabolism (there is clear evidence that oestrogens lower LDL and raise HDL cholesterol), insulin resistance is improved and vasomotor tone affected towards a net reduction of vascular resistance. Exactly why this occurs is not clear but there are oestrogen receptors in vascular endothelium and more studies are needed to determine their function and their possible relation to other influences on vasoconstrictor. Precise estimates as to the benefit of hormone replacement therapy are difficult in view of the various selection factors that have operated in establishment of existing cohort studies but the overall estimate is that it is considerable. It is depressing that so little attention seems to be paid by primary care physicians to the potential protective benefits of hormone replacement
NEW HORIZONS IN CORONARY HEART DISEASE therapy against cardiovascular disease, as well as osteoporosis. Professor D. Barker (Southampton, UK) demonstrated that much of the incidence of coronary heart disease could be related to the small baby syndromein other words, many of the metabolic disturbances known to be present in middle aged patients with coronary heart disease and stroke originate through impaired growth and development during fetal life and infancy. These diseases may be a consequence of ‘programming’ in early life resulting in long-term changes in physiology and metabolism. Thus, there is a strong inverse relationship between body weight at birth and at 1 year with the incidence of CHD in middle and late middle-age and late life. Professor Barker has been able to draw on an unique database for measurement of weight and head circumference at birth and weight at 1 year with a follow-up of people into their late 50s and 60s. He put particular emphasis on the importance of the maturation of the pancreas. Failure of maturation of the pancreas during early life may be irretrievable and is in its turn related to nutritional deprivation in utero. Surely this conference on ‘New Horizons’ justifies its title when evidence is provided to suggest that the function of the pancreas at birth might influence subsequent coronary heart disease! Nutritional deprivation in early life can programme the size and DNA contents of many systems and organs. Little is known about the maternal influences which impair early growth but adult levels of blood pressure, lipids, glucose metabolism, haemostatic factors and even the distribution of body fat may all be determined in part by intra-uterine influences. It is an interesting speculation that one of the explanations of the decrease in coronary heart disease and stroke during the last 30-40 years may be related to improvement of fetal and neonatal nutrition in comparison with the years between the wars and before The First World War. This question of undernutrition and social impoverishment was taken up by Professor M. Marmot (London, UK) who indicated very clearly the steep inverse association which exists between social class and CHD mortality in the United Kingdom, drawing particularly on the Whitehall study of Civil Servants. An inverse association exists between employment grade and prevalence of angina, electrocardiographic evidence of ischaemia and symptoms of chronic bronchitis. There are striking employment grade differences with regard to smoking, diet and exercise. Monotonous work characterized by boredom and inability to control one’s destiny is associated with a high incidence of CHD. This may partly explain the alarming
763
increase in CHD incidence in many Eastern European countries, while there is a concurrent progressive fall in Western European countries. Professor Marmot proposed that one explanation for the low CHD rates in Japan (where CHD is actually decreasing) is the country’s increased prosperity and a more equitable distribution of income and opportunity; he did not believe that reduction in CHD in Japan over the last 20 years could be explained simply by changes in diet and, anyway, the Japanese smoke to excess. The message is obvious. One of the best investments for Government to reduce CHD in the United Kingdom is economic and social class policy directed at improving living and working conditions and improving opportunities in those socially impoverished. This was a stimulating conference, sponsored by the Butter Council, throwing out numerous new ideas, and going beyond the entrenchment of scientific thinking induced by the dominance of the cholesterol hypothesis, important that this may be. Government based research and health education programmes, pharmaceutical houses, basic and clinical scientists have a great deal more to address in this decade. Summing up, Professor M. Oliver (London) stated ‘It is not good enough simply to assume that measurement and control of the ‘orthodox’ risk factors is all that needs to concern us’. At last, new fields of endeavour are emerging and there are distinct possibilities that further research into a number of the themes developed in this conference may provide us with answers about the missing one half or more of the risk factors leading to coronary heart disease and consequently their eventual control. Representative references Diplock AT. Anti-oxidants nutrients and disease prevention: an overview. Am J Clin Nutr 1991;53:189 Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991;88:1785-92. Lelchuk R, Radomski M, Martin JF, Moncada S. Constitutive and inducible nitric oxide synthases in human megakaryoblastic cells. J Pharmacol Exp Therap 1992; (in press). Meade TW, Brozovic M, Mellows S, Miller G et a/. Haemostatic function and ischaemic heart disease: Principal results of the Northwich Park Heart Study. Lancet 1986; ii: 533-7. Smith U. Gudbjornsdottir S, Landin K. Hypertension as a metabolic disorder. J Int Med 1991;229:1-7. Austin MA, King MC, Vranizan KM, Krauss AM. Atherogenic lipoprotein phenotype: A proposed genetic marker for coronary heart disease risk. Circulation 1990;82(2):495-506. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991;265:1861-7. Barker DJP. Fetal and infant origin of adult disease. Br Med J Marmot MG. Davey-Smith G, StanfTeld S, Patel C e t a / .Inequalities in health twenty years on: The Whitehall I1 Study of British Civil Servants. Lancet 1991;337:1387-93.
