986
LETTERS to the EDITOR
Double-edged role of endogenous nitric oxide SiR,—We suggest that endogenous nitroc oxide (NO) has both beneficial and deleterious roles. Nitrinergic signal transduction1 involves NO synthase types I-III (synthesising NO from Larginine), and soluble guanylyl cyclase, which is activated by NO and forms the "second messenger" cyclic guanosine-3’,5’monophosphate (cGMP). This pathway was first described in vascular endothelial cells, which release NO and thereby increase vascular smooth-muscle cGMP levels and cause vasodilatation. It can also be induced in vascular smooth-muscle cells during sepsis, where NO formation may be responsible for the severe hypotension in septic shock and in which, as Dr Petros and colleagues (Dec 21/28, p 1557) report, pharmacological inhibition of NO biosynthesis by NG-methyl-L-arginine can be beneficial. However, complete inhibition of NO biosynthesis may not be desirable since, as Dr Hotchkiss and colleagues (Feb 15, p 434) and Dr Cohen and Dr Silva (March 21, p 751) remark, several other essential functions of NO such as organ perfusion and inhibition of platelet aggregation would also be blocked. The nitrinergic signal transduction pathway is also present in epithelial cells, endocrine organs, and the nervous system, NO being involved consequently in the regulation of smooth-muscle stimulus-secretion tone, coupling, and neurotransmission, respectively. As first described in immunologically activated macrophages, higher concentrations of NO can exert cGMP-independent effects that convert this signalling molecule into a cytotoxic and mutagenic2 agent. cGMP levels are raised in neoplasms, proliferating tissues, and associated disease states.3 Here, we would like to draw attention to the physiological and pathophysiological implications of the balance of NO formation in three organs (brain, pancreas, and stomach). The so called NO-hypothesis of the brain suggests that postsynaptic cells contain NO synthase and that NO acts as a retrograde messenger to sharpen axonal arbors in an activitydependent manner. This mechanism may, at least in part, account for long-term potentiation4 and other memory-related functions of the brain. Neural NO would also be suited as a mediator coupling cerebral blood-flow to neural activity. Inhibition of NO synthesis decreases cerebral blood-flow.5 The site of action for these effects may be the basal forebrain, especially the perifascicular thalamic nucleus. We have found that hippocampal pyramidal cells and the perifascicular thalamic nucleus contain NO synthase immunoreactivity (unpublished). In contrast to these beneficial effects, NO also has pathophysiological significance in the brain.5 NO and L-arginine cause (or facilitate) glutamate neurotoxicity and the development of epileptic foci,6 The gastrointestinal tract contains NO synthase, located in so-called nitrinergic or nitroxergic nerves, where it mediates reflex relaxation to accommodate food or fluidand in the epithelium where it exerts gastroprotective effects.8 At neutral pH, NO has a very short half-life and is rapidly degraded to nitrite and nitrate; however, in the acid gastric lumen the half-life will be much increased, resulting in concentrations that could induce tissue damage in the stomach and are highly mutagenic.2 In the pancreas NO is likely to be involved in the regulation of stimulus-secretion coupling. NO synthase is found in the B-cells of islets of Langerhans; upon exposure to L-arginine and D-glucose these form NO, display increased cGMP-levels, and release insulin, and inhibition of NO synthesis prevents D-glucose-induced insulin release.9 Insulin release thus seems to be in part caused by or dependent on nitrinergic signal transduction-but again NO seems
have a dual role. Interleukin-lp, at high concentrations,1O can induce a different isoform of NO synthase, which results in a big increase in NO formation in the islets of Langerhans, and eventually in a B-cell destruction indistinguishable from that in type-I diabetes mellitus. Endogenous NO has a double-edged role in specialised tissues and cells. It is a potent and essential physiological signalling molecule but it is also prone to cause potentially cytotoxic and mutagenic effects: to
Benefit
Organ/tissue Brain Stomach Pancreas Blood vessels
Neurotransmitter, longterm potentiation Cytoprotective, reflex dilatation, motility Insulin release
Vasodilator, antithrombotic
Leucocytes
Immune defence
Harm Neurotoxic
Cytotoxic, mutagenic?
(3-cell destruction Reperfusion injury, endotoxic shock, anaphylactic shock Endotoxic shock
Modulation of the NO system may well prove to be of therapeutic significance in future but selective modifications and perturbations of NO synthetic pathways will be required. Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611, USA
H. H. H. W. SCHMIDT
William Harvey Research Institute, St Bartholomew’s Hospital, London EC1
TIMOTHY D. WARNER
Abbott Laboratories, Chicago,
F.MURAD
1. Schmidt
HHHW, Murad F. Purification and characterization of a human NO synthase. Biochem Biophys Res Commun 1991; 181: 1372-77 2. Wink DA, Kasprzak KS, Maragos CM, et al. DNA deamination ability and genotoxicity of nitric oxide and its progenitors. Science 1991; 254: 1001-03. 3. Cnss WE, Murad F, Kimura H. Properties of guanylate cyclase from rat cortex and transplantable kidney tumours. J Cyclic Nucleotide Res 1976; 2: 11-19. 4. Bohme GA, Bon C, Stutzmann J-M, et al. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol 1991; 199: 379-81. 5. Beckman JS. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Develop Physiol 1991; 15: 53-59. 6. Dawson VL, Dawson TM, London ED, et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991; 88: 6368-71. 7. Desai KM, Sessa WC, Vane JR. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 1991; 351: 477-79. 8. Whittle BJR, Lopez-Belmonte J, Moncada S. Damage or protection of the gastric mucosa by exogenous nitric oxide. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press). 9. Schmidt HHHW, Warner TD, Ishii K, et al. Insulin-secretion from pancreatic B-cells caused by L-arginine-derived nitrogen oxides. Science 1992; 255: 721-23. 10. Southern C, Delaney C, Schulster D, et al. Nitric oxide-stimulated cGMF production and the dose-dependent effects of IL-1&bgr; on insulin secretion from rat islets of Langerhans. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press).
Coronary heart disease in women SIR,-Dr Isles and colleagues’ (March 21, p 703) fmding of a lower mortality from coronary heart disease (CHD) in women than in men, despite higher serum cholesterol concentrations, illustrates the well known cardiovascular superiority of the female and our ignorance of the physiological basis of this difference. It is, however, astonishing that these researchers’ advice to women was only to stop smoking, treat hypertension, take regular physical exercise, and reduce weight. Despite the abundant evidence (admittedly based on large-scale studies from the USA)
987
that oestrogen therapy is cardioprotective,’ Isles et al grudgingly state that lower CHD rates "might be conferred by female sex hormones". Nevertheless, as they admit, raised cholesterol concentrations play only a minor part in the pathogenesis of CHD in women. They have ignored the fact that whereas oestrogen therapy reduces the risk of CHD by up to 50%,1 especially in women with coronary atheroma,2it lowers low-density lipoprotein cholesterol by only 5-9%.3 Furthermore, in ovariectomised monkeys fed an atherogenic diet oestrogens reduced the degree of coronary atheroma by about 30%, irrespective of cholesterol concentrations.4 Their advice, especially for women with a history of CHD, should therefore have included consideration of oestrogen therapy. Isles et al correctly underscore the inadvisability of extrapolating data from men to women, an aspect we have also emphasised.5,6 Women are haemodynamically younger than men by some 15 years. The question at issue is, what is the physiological basis of this difference? But there is a regrettable lack of data on this subject.6 Our studies show substantial cardiovascular differences between the sexes. Although peripheral (forearm) blood-flow increases with age in both men and women, the main increase in women takes place in the seventh decade, by contrast with an earlier but gradual increase in men; the trend is similar with vascular reactivity, which decreases with age. In premenopausal women, endogenous oestradiol concentrations correlate negatively with peripheral blood flow, an association that has not been reported for serum testosterone in men. On the other hand, exogenous oestradiol increases forearm flow (and cardiac output) in non-flushing women.7 In hypertensive adults, premenopausal women have a higher cardiac output and lower peripheral resistance than men; a difference not seen after the menopause.8 Studies of the precise circulatory differences between the sexes could therefore potentially prove more relevant to the elucidation of female cardiovascular superiority than "waiting for Godot", in the form of more trials of treatment of hypercholesterolaemia in women, as Isles et al advocate. Department of Endocrinology, Royal Free Hospital School of Medicine, London NW3 2QG, UK
1
JEAN GINSBURG STANLEY OKOLO PAUL HARDIMAN
Stampfner MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991, 325: 756-62.
2. Sullivan JM, Zwaag RV, Hughes JP, et al. Estrogen replacement and coronary artery disease effect on survival in postmenopausal women Arch Intern Med 1990; 150:
2557-62. 3 Samisoe G Cardiovascular disease and lipid metabolism: the influence of HRT. Long-term HRT. perceptions and realities. Carnforth: Parthenon Publishing, 1991. 4 Koudy Williams J, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation 1990; 81: 1680-87. 5 Ginsburg J, ed. The circulation in the female from the cradle to the grave. Camforth: Parthenon Publishing, 1989. 6 Ginsburg J. The menopause, hormone replacement therapy and the cardiovascular system. In: Burger H, Boulet M, eds. A portrait of the menopause: expert reports on medical and therapeutic strategies for the 1990s. Carnforth: Parthenon Publishing, 1991. 7. Ginsburg J, Hardiman P Cardiovascular effects of transdermal oestradiol in postmenopausal women. Ann NY Acad Sci 1990; 592: 424-25. 8 Messerli FH, Garavaglia GE, Schmieder RE, et al. Disparate cardiovascular findings in men and women with essential hypertension. Ann Intern Med 1987; 107: 158-61.
omental adipose tissues, which have a high turnover of free fatty acids and are drained by the portal vein, have been implicated in unfavourable risk patterns for CHD. Advice for women with respect to weight loss to lower their risk for cardiovascular disease may therefore be mainly dependent on their fat distribution. Department of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen,
JACOB C. SEIDELL
Netherlands
1. Seidell
JC, Cigolini M, Charzewska J, et al. Fat distribution and gender differences in lipids m men and women from four European communities. Atherosclerosis 1991; 87: 203-10. 2. Freedman DS, Jacobsen SJ, Barboriak JJ, et al. Body fat distribution and male/female differences in lipids and lipoproteins. Circulation 1990; 81: 1498-03. 3. Ostlund RE, Staten M, Kohrt WM, Schultz J, Malley M. The ratio of waist-to-hip circumference, plasma insulin level, and glucose tolerance as independent predictors of HDL2 cholesterol in older adults. N Engl J Med 1990; 332: 229-33. 4. Larsson B, Bengtsson C, Björntorp P, et al. Is abdominal fat distribution a main explanation for the male/female difference in the risk of myocardial infarction? Int J Obesity 1990; 14 (suppl 2): 80. 5. Seidell JC, Oosterlee A, Thijssen MAO, et al. Assessment of intra-abdominal and subcutaneous fat: relation between anthropometry and computed tomography. Am J Clin Nutr 1987; 45: 7-13. 6. Bjomtorp P. "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10: 493-97 serum
Coronary heart disease and dietary factors W R, 1’rofessor Ulbricht and Proiessor Southgate (Oct 19,
985) propose two indices, one of atherogenicity and one of thrombogenicity, to assess the effect of dietary fat on coronary heart disease (CHD). We have calculated these indices from 7-day weighed food intake records for 665 men aged 45-59 years in the Caerphilly Prospective Heart Disease Study.’Fatty-acid intakes were calculated with the aid of food composition tables3 together with data from manufacturers on the composition of spreading fats and cooking fats and oils. The mean (SD) atherogenicity index was 0-92 (0-20) and thrombogenicity index 1-27 (0-23). The two indices were positively associated with each other (r=0’87). Although there were differences in the numerators, intakes of the saturated fatty acids 14:0, 16:0, and 18:0 were strongly positively associated with each other (r 0-80 to 0-96). This is because their major food sources are p
=
similar. The main difference in the denominators is the greater emphasis on n-3 polyunsaturated fatty acids (PUFA) in the thrombogenicity index. However, intakes of these fatty acids are low in the British diet and therefore constitute a minor component of the index. The table shows that the contribution of the various fatty acids to the two indices was strikingly similar. The relation of 14:0 was somewhat stronger with the atherogenicity index than with the thrombogenicity index and n-3 PUFA were more strongly inversely related to the thrombogenicity index than to the atherogenicity index. However, the table also shows that there were very strong associations between both these indices and total saturated fatty acids (as a percentage of total fat and as a percentage RELATIONS BETWEEN FATTY-ACID INTAKES AND INDICES OF ATHEROGENICITY AND THROMBOGENICITY (PEARSON CORRELATION COEFFICIENTS)
SIR,-Dr Isles and colleagues conclude that smoking habits, blood pressure, serum cholesterol, body mass index, and social class
explain the differences in coronary mortality between men and women. They do briefly mention that indices of central obesity could have greater predictive power than body mass index for coronary heart disease (CHD). These indicators of fat distribution may also be especially relevant in the sex difference in CHD. We1 and others23 have shown that gender differences in HDL-cholesterol and serum triglyceride concentrations disappear after adjustment for differences in indices of fat distribution between men and women. In fact, a preliminary prospective study’ shows that the difference in incidence of CHD between men and women could be attributed to variations in fat distribution. At a specific weight and height men have more fat stored in their abdominal cavity5 than women. In particular, the mesenteric and
cannot
All correlation coefficients greater than 0 10
are
statistically significant
LETTERS to the EDITOR
Double-edged role of endogenous nitric oxide SiR,—We suggest that endogenous nitroc oxide (NO) has both beneficial and deleterious roles. Nitrinergic signal transduction1 involves NO synthase types I-III (synthesising NO from Larginine), and soluble guanylyl cyclase, which is activated by NO and forms the "second messenger" cyclic guanosine-3’,5’monophosphate (cGMP). This pathway was first described in vascular endothelial cells, which release NO and thereby increase vascular smooth-muscle cGMP levels and cause vasodilatation. It can also be induced in vascular smooth-muscle cells during sepsis, where NO formation may be responsible for the severe hypotension in septic shock and in which, as Dr Petros and colleagues (Dec 21/28, p 1557) report, pharmacological inhibition of NO biosynthesis by NG-methyl-L-arginine can be beneficial. However, complete inhibition of NO biosynthesis may not be desirable since, as Dr Hotchkiss and colleagues (Feb 15, p 434) and Dr Cohen and Dr Silva (March 21, p 751) remark, several other essential functions of NO such as organ perfusion and inhibition of platelet aggregation would also be blocked. The nitrinergic signal transduction pathway is also present in epithelial cells, endocrine organs, and the nervous system, NO being involved consequently in the regulation of smooth-muscle stimulus-secretion tone, coupling, and neurotransmission, respectively. As first described in immunologically activated macrophages, higher concentrations of NO can exert cGMP-independent effects that convert this signalling molecule into a cytotoxic and mutagenic2 agent. cGMP levels are raised in neoplasms, proliferating tissues, and associated disease states.3 Here, we would like to draw attention to the physiological and pathophysiological implications of the balance of NO formation in three organs (brain, pancreas, and stomach). The so called NO-hypothesis of the brain suggests that postsynaptic cells contain NO synthase and that NO acts as a retrograde messenger to sharpen axonal arbors in an activitydependent manner. This mechanism may, at least in part, account for long-term potentiation4 and other memory-related functions of the brain. Neural NO would also be suited as a mediator coupling cerebral blood-flow to neural activity. Inhibition of NO synthesis decreases cerebral blood-flow.5 The site of action for these effects may be the basal forebrain, especially the perifascicular thalamic nucleus. We have found that hippocampal pyramidal cells and the perifascicular thalamic nucleus contain NO synthase immunoreactivity (unpublished). In contrast to these beneficial effects, NO also has pathophysiological significance in the brain.5 NO and L-arginine cause (or facilitate) glutamate neurotoxicity and the development of epileptic foci,6 The gastrointestinal tract contains NO synthase, located in so-called nitrinergic or nitroxergic nerves, where it mediates reflex relaxation to accommodate food or fluidand in the epithelium where it exerts gastroprotective effects.8 At neutral pH, NO has a very short half-life and is rapidly degraded to nitrite and nitrate; however, in the acid gastric lumen the half-life will be much increased, resulting in concentrations that could induce tissue damage in the stomach and are highly mutagenic.2 In the pancreas NO is likely to be involved in the regulation of stimulus-secretion coupling. NO synthase is found in the B-cells of islets of Langerhans; upon exposure to L-arginine and D-glucose these form NO, display increased cGMP-levels, and release insulin, and inhibition of NO synthesis prevents D-glucose-induced insulin release.9 Insulin release thus seems to be in part caused by or dependent on nitrinergic signal transduction-but again NO seems
have a dual role. Interleukin-lp, at high concentrations,1O can induce a different isoform of NO synthase, which results in a big increase in NO formation in the islets of Langerhans, and eventually in a B-cell destruction indistinguishable from that in type-I diabetes mellitus. Endogenous NO has a double-edged role in specialised tissues and cells. It is a potent and essential physiological signalling molecule but it is also prone to cause potentially cytotoxic and mutagenic effects: to
Benefit
Organ/tissue Brain Stomach Pancreas Blood vessels
Neurotransmitter, longterm potentiation Cytoprotective, reflex dilatation, motility Insulin release
Vasodilator, antithrombotic
Leucocytes
Immune defence
Harm Neurotoxic
Cytotoxic, mutagenic?
(3-cell destruction Reperfusion injury, endotoxic shock, anaphylactic shock Endotoxic shock
Modulation of the NO system may well prove to be of therapeutic significance in future but selective modifications and perturbations of NO synthetic pathways will be required. Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611, USA
H. H. H. W. SCHMIDT
William Harvey Research Institute, St Bartholomew’s Hospital, London EC1
TIMOTHY D. WARNER
Abbott Laboratories, Chicago,
F.MURAD
1. Schmidt
HHHW, Murad F. Purification and characterization of a human NO synthase. Biochem Biophys Res Commun 1991; 181: 1372-77 2. Wink DA, Kasprzak KS, Maragos CM, et al. DNA deamination ability and genotoxicity of nitric oxide and its progenitors. Science 1991; 254: 1001-03. 3. Cnss WE, Murad F, Kimura H. Properties of guanylate cyclase from rat cortex and transplantable kidney tumours. J Cyclic Nucleotide Res 1976; 2: 11-19. 4. Bohme GA, Bon C, Stutzmann J-M, et al. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol 1991; 199: 379-81. 5. Beckman JS. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Develop Physiol 1991; 15: 53-59. 6. Dawson VL, Dawson TM, London ED, et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991; 88: 6368-71. 7. Desai KM, Sessa WC, Vane JR. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 1991; 351: 477-79. 8. Whittle BJR, Lopez-Belmonte J, Moncada S. Damage or protection of the gastric mucosa by exogenous nitric oxide. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press). 9. Schmidt HHHW, Warner TD, Ishii K, et al. Insulin-secretion from pancreatic B-cells caused by L-arginine-derived nitrogen oxides. Science 1992; 255: 721-23. 10. Southern C, Delaney C, Schulster D, et al. Nitric oxide-stimulated cGMF production and the dose-dependent effects of IL-1&bgr; on insulin secretion from rat islets of Langerhans. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press).
Coronary heart disease in women SIR,-Dr Isles and colleagues’ (March 21, p 703) fmding of a lower mortality from coronary heart disease (CHD) in women than in men, despite higher serum cholesterol concentrations, illustrates the well known cardiovascular superiority of the female and our ignorance of the physiological basis of this difference. It is, however, astonishing that these researchers’ advice to women was only to stop smoking, treat hypertension, take regular physical exercise, and reduce weight. Despite the abundant evidence (admittedly based on large-scale studies from the USA)
987
that oestrogen therapy is cardioprotective,’ Isles et al grudgingly state that lower CHD rates "might be conferred by female sex hormones". Nevertheless, as they admit, raised cholesterol concentrations play only a minor part in the pathogenesis of CHD in women. They have ignored the fact that whereas oestrogen therapy reduces the risk of CHD by up to 50%,1 especially in women with coronary atheroma,2it lowers low-density lipoprotein cholesterol by only 5-9%.3 Furthermore, in ovariectomised monkeys fed an atherogenic diet oestrogens reduced the degree of coronary atheroma by about 30%, irrespective of cholesterol concentrations.4 Their advice, especially for women with a history of CHD, should therefore have included consideration of oestrogen therapy. Isles et al correctly underscore the inadvisability of extrapolating data from men to women, an aspect we have also emphasised.5,6 Women are haemodynamically younger than men by some 15 years. The question at issue is, what is the physiological basis of this difference? But there is a regrettable lack of data on this subject.6 Our studies show substantial cardiovascular differences between the sexes. Although peripheral (forearm) blood-flow increases with age in both men and women, the main increase in women takes place in the seventh decade, by contrast with an earlier but gradual increase in men; the trend is similar with vascular reactivity, which decreases with age. In premenopausal women, endogenous oestradiol concentrations correlate negatively with peripheral blood flow, an association that has not been reported for serum testosterone in men. On the other hand, exogenous oestradiol increases forearm flow (and cardiac output) in non-flushing women.7 In hypertensive adults, premenopausal women have a higher cardiac output and lower peripheral resistance than men; a difference not seen after the menopause.8 Studies of the precise circulatory differences between the sexes could therefore potentially prove more relevant to the elucidation of female cardiovascular superiority than "waiting for Godot", in the form of more trials of treatment of hypercholesterolaemia in women, as Isles et al advocate. Department of Endocrinology, Royal Free Hospital School of Medicine, London NW3 2QG, UK
1
JEAN GINSBURG STANLEY OKOLO PAUL HARDIMAN
Stampfner MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991, 325: 756-62.
2. Sullivan JM, Zwaag RV, Hughes JP, et al. Estrogen replacement and coronary artery disease effect on survival in postmenopausal women Arch Intern Med 1990; 150:
2557-62. 3 Samisoe G Cardiovascular disease and lipid metabolism: the influence of HRT. Long-term HRT. perceptions and realities. Carnforth: Parthenon Publishing, 1991. 4 Koudy Williams J, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation 1990; 81: 1680-87. 5 Ginsburg J, ed. The circulation in the female from the cradle to the grave. Camforth: Parthenon Publishing, 1989. 6 Ginsburg J. The menopause, hormone replacement therapy and the cardiovascular system. In: Burger H, Boulet M, eds. A portrait of the menopause: expert reports on medical and therapeutic strategies for the 1990s. Carnforth: Parthenon Publishing, 1991. 7. Ginsburg J, Hardiman P Cardiovascular effects of transdermal oestradiol in postmenopausal women. Ann NY Acad Sci 1990; 592: 424-25. 8 Messerli FH, Garavaglia GE, Schmieder RE, et al. Disparate cardiovascular findings in men and women with essential hypertension. Ann Intern Med 1987; 107: 158-61.
omental adipose tissues, which have a high turnover of free fatty acids and are drained by the portal vein, have been implicated in unfavourable risk patterns for CHD. Advice for women with respect to weight loss to lower their risk for cardiovascular disease may therefore be mainly dependent on their fat distribution. Department of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen,
JACOB C. SEIDELL
Netherlands
1. Seidell
JC, Cigolini M, Charzewska J, et al. Fat distribution and gender differences in lipids m men and women from four European communities. Atherosclerosis 1991; 87: 203-10. 2. Freedman DS, Jacobsen SJ, Barboriak JJ, et al. Body fat distribution and male/female differences in lipids and lipoproteins. Circulation 1990; 81: 1498-03. 3. Ostlund RE, Staten M, Kohrt WM, Schultz J, Malley M. The ratio of waist-to-hip circumference, plasma insulin level, and glucose tolerance as independent predictors of HDL2 cholesterol in older adults. N Engl J Med 1990; 332: 229-33. 4. Larsson B, Bengtsson C, Björntorp P, et al. Is abdominal fat distribution a main explanation for the male/female difference in the risk of myocardial infarction? Int J Obesity 1990; 14 (suppl 2): 80. 5. Seidell JC, Oosterlee A, Thijssen MAO, et al. Assessment of intra-abdominal and subcutaneous fat: relation between anthropometry and computed tomography. Am J Clin Nutr 1987; 45: 7-13. 6. Bjomtorp P. "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10: 493-97 serum
Coronary heart disease and dietary factors W R, 1’rofessor Ulbricht and Proiessor Southgate (Oct 19,
985) propose two indices, one of atherogenicity and one of thrombogenicity, to assess the effect of dietary fat on coronary heart disease (CHD). We have calculated these indices from 7-day weighed food intake records for 665 men aged 45-59 years in the Caerphilly Prospective Heart Disease Study.’Fatty-acid intakes were calculated with the aid of food composition tables3 together with data from manufacturers on the composition of spreading fats and cooking fats and oils. The mean (SD) atherogenicity index was 0-92 (0-20) and thrombogenicity index 1-27 (0-23). The two indices were positively associated with each other (r=0’87). Although there were differences in the numerators, intakes of the saturated fatty acids 14:0, 16:0, and 18:0 were strongly positively associated with each other (r 0-80 to 0-96). This is because their major food sources are p
=
similar. The main difference in the denominators is the greater emphasis on n-3 polyunsaturated fatty acids (PUFA) in the thrombogenicity index. However, intakes of these fatty acids are low in the British diet and therefore constitute a minor component of the index. The table shows that the contribution of the various fatty acids to the two indices was strikingly similar. The relation of 14:0 was somewhat stronger with the atherogenicity index than with the thrombogenicity index and n-3 PUFA were more strongly inversely related to the thrombogenicity index than to the atherogenicity index. However, the table also shows that there were very strong associations between both these indices and total saturated fatty acids (as a percentage of total fat and as a percentage RELATIONS BETWEEN FATTY-ACID INTAKES AND INDICES OF ATHEROGENICITY AND THROMBOGENICITY (PEARSON CORRELATION COEFFICIENTS)
SIR,-Dr Isles and colleagues conclude that smoking habits, blood pressure, serum cholesterol, body mass index, and social class
explain the differences in coronary mortality between men and women. They do briefly mention that indices of central obesity could have greater predictive power than body mass index for coronary heart disease (CHD). These indicators of fat distribution may also be especially relevant in the sex difference in CHD. We1 and others23 have shown that gender differences in HDL-cholesterol and serum triglyceride concentrations disappear after adjustment for differences in indices of fat distribution between men and women. In fact, a preliminary prospective study’ shows that the difference in incidence of CHD between men and women could be attributed to variations in fat distribution. At a specific weight and height men have more fat stored in their abdominal cavity5 than women. In particular, the mesenteric and
cannot
All correlation coefficients greater than 0 10
are
statistically significant
