28
Hypertension—in black and white of cardiovascular of genetic and environmental influences. This may sound like a cliche but it is not. We do not know how many factors there are or how they interact with each other. However, we do know that there are enough of them effectively to obscure subpopulations within the overall blood pressure distribution, as Pickering pointed out many years ago. The difficulties of unravelling these complexities are well illustrated in genetically hypertensive rats, in which inbreeding and a constant environment simplify the picture but underline its magnitude. Hilbert et al2lately showed a weak linkage between a locus on chromosome 10 (which may act as a marker for the angiotensin converting enzyme [ACE] gene) and blood pressure. This linkage became much stronger with the application of an environmental stress in the form of sodium loading. It seems likely that, in the same way, environmental influences may expose genetic factors in human hypertension. Ethnic differences in blood pressure are an illuminating example and have provided a tantalising insight into the nature of
Hypertension, like other forms disease, is a complex mixture
hypertension. Blacks of African origin in the United States have higher blood pressures and a higher prevalence of hypertension at all ages than whites.They also have a higher risk of cardiovascular disease, which is not wholly attributable to the difference in blood pressure.3Nevertheless, in two large epidemiological studies, when other risk factors for cardiovascular disease were taken into account, raised blood pressure in whites carried no worse cardiovascular prognosis. 1,5 A recent report based upon a work-site programme of blood pressure control supports the conclusion that, given access to adequate antihypertensive treatment, blacks fare no worse than whites.61807 blacks and 2962 whites were screened for cardiovascular risk factors and then offered traditional stepped-care
antihypertensive therapy. Although blacks were less likely to be treated for hypertension for similar initial blood pressure levels, their antihypertensive response was as good as that in whites and they had at least as good an outcome as far as cardiovascular disease was concerned. Myocardial infarction rates were significantly lower. Thus, although blood pressure is higher in American blacks, the associated risks are no different from those in whites. This observation does not explain why blood pressure is higher in the first place. Either environmental or genetic factors could be responsible. There is evidence for both. When African blacks move from a rural to an urban environment blood pressure rises within a few weeks.7 The move to a western pattern of blood pressure rise with age is associated with blacks adopting a westernised diet and
with cultural stress.8 United States blacks also suffer from potential social stress in terms of lower social and educational status, and they have less ready access to medical care. The inverse correlation of social class with blood pressure is not sufficient to account for the difference in blood pressure between blacks and whites.3 Nevertheless, the finding that differences in blood pressure between American blacks and whites seem to be diminishing with the passage of time suggests environmental effects.9 Moreover, one British investigation failed to find any difference between blood pressure of Afro-Caribbean blacks and whites in Binningham.1o Is it possible, therefore, that the high prevalence of hypertension in American blacks is largely environmental, even if we cannot completely specify the relevant factors? The answer has important implications both for public health measures and for individual patient management. The closely interwoven relation between environment and heredity adds to the complexities. Thus, the South Carolina Heart Study showed a correlation between the degree of skin colour and blood pressure," but the relation disappeared when data were adjusted for social class.12 The same doubts are relevant to possible genetic markers for hypertension in blacks. There are reported racial differences in transmembrane ionic fluxes;13 plasma renin activity is low in blacks;14 and excretion of a sodium load has been reported to be impaired in blacks. is All of these factors could theoretically influence blood pressure control systems. One group has put forward an imaginative hypothesis to link this phenomenon to hypertension. is These researchers propose that enhanced renal conservation of sodium carries advantages when the climate is hot and salt intake is low. Such conservation becomes less desirable in more temperate conditions with a westernised diet. Under these circumstances sodium retention and hypertension occur, with suppression of renin secretion. The difficulty with such a theory is that there is no convincing evidence that low-renin hypertension is associated with sodium retention.16
The
genetically hypertensive rat illustrates the into which it is possible to fall when attributing pitfalls causality. When hypertensive and control strains are compared there are numerous phenotypicl’ and genotypic18 differences between the two. Some are unrelated to hypertension; some are secondary to hypertension; and perhaps a few are associated with physiological processes that raise blood pressure. Examining linkages with blood pressure in generations of hybrids will help to clarify the last aspect. In man living in an unregulated environment and usually outbred, the problem is infinitely more complex. Whether having a black skin is a marker for environmental or genetic factors that increase blood pressure is still unresolved. For clinical scientists the painful fact is that there are many physiological
29
differences between black and white hypertensives.19
increasing volume of research into ethnic aspects of hypertension has brought some spin-off for clinicians in that they have learnt about differences in response to various classes of antihypertensive agents. Low-renin hypertension would be expected to respond poorly to ACE inhibitors but better to diuretics, since activation of the renin-angiotensin system helps to limit the blood pressure fall induced by sodium depletion. In giving consensus advice, the Joint National Committee on Development, Evaluation and Treatment of High Blood Pressure20 stated that blacks respond better to diuretics and calcium antagonists than to beta blockers or ACE inhibitors. This advice was based on general clinical wisdom rather than critical review of published work. Zing and co-workers2l have now remedied this deficiency by examining all relevant published studies. In general, their results support the Joint National Committee recommendations in showing a The
weaker response to beta blockers and ACE inhibitors in blacks. Unfortunately, only four trials compare responsiveness in the two ethnic groups in an
acceptably stringent way. Although a widely accepted belief is not overturned, therefore, there is clearly scope for much more intensive study.
1. Pickering GW. Nature of hypertension. Lancet 1962; i: 1298-99. 2. Hilbert P, Lindpaintner K, Beckmann JS, et al. Chromosonal mapping of two genetic loci associated with blood pressure regulation in hereditary hypertensive rats. Nature 1991; 353: 521-29. 3. Tyroler HA. Socio-economic status, age, and sex in the prevalence and prognosis of hypertension in blacks and whites. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis and management.
New York: Raven, 1990: 159-74. 4. Neaton JD, Kuller LH, Wentworth D, et al. Multiple Risk Factor Intervention Trial Research Group: total and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration and diastolic blood pressure among black and white males followed for five years. Am Heart J 1984; 108: 759-69. 5. Langford HD, Stamler J, Wassertheil-Smoller S, Prineas RJ. All cause mortality in the Hypertension Detection and Follow-Up Program: findings for the whole cohort and for persons with less severe hypertension with and without other traits related to risk of mortality. Prog Cardiovasc Dis 1986; 29 (suppl 1): 29-54. 6. Ooi WL, Budner NS, Cohen H, Madhaven S, Alderman MH. Impact of race on treatment response and cardiovascular disease amongst hypertensives. Hypertension 1989; 14: 227-34. 7. Poulter N, Khaw KT, Hopwood BEC, et al. Determinants of blood pressure due to urbanisation: a longitudinal study. J Hypertens 1985; 3 (suppl 3): S375-77. 8. Seedat YK. Race, environment and blood pressure: the South African experience. J Hypertens 1983; 1: 7-12. 9. Persky V, Pan WH, Stamler J, Dyer A, Levy P. Time trends in the US racial difference in cardiovascular disease. Am J Epidemiol 1986; 124: 724-37. 10. Cruickshank JK, Stephen HD, Jackson D, et al. Similarity of blood pressure in blacks, whites and Asians in England: the Birmingham factory study. J Hypertens 1985; 3: 365-72. 11. Boyle E. Biological patterns in hypertension by race, sex, body weight and skin color. JAMA 1970; 213: 1637-43. 12. Keidl JE, Tyroler HA, Sandifer SH, Boyle E. Hypertension: effects of social class and racial admixture—the results of a cohort study in the black population of Charleston, South Carolina. Am J Publ Health
1977; 67: 634-39. 13. Aviv A, Gardner J. Racial differences in ion regulation and their possible links to hypertension in blacks. Hypertension 1989; 14: 584-89. 14. Levy SB, Lilley JJ, Frigon RP, Stone RA. Urinary kallikrein and plasma renin activity as determinants of renal blood flow: the influence of race and dietary sodium intake. J Clin Invest 1977; 60: 129-35.
15.
Luft FC, Grim CE, Higgins JT, Weinberger MH. Differences
in sodium administration in normotensive white and black subjects. J Lab Clin Med 1977; 90: 555-61. 16. Lebel M, Schalekamp MA, Beevers DG, et al. Sodium and the renin-angiotensin system in essential hypertension and mineralocorticoid excess. Lancet 1974; ii: 308-10. 17. Yamori Y. Physiopathology of the vanous strains of spontaneously hypertensive rats. In: Genest J, Kuchel O, Hamet P, Cantin M, eds. Hypertension. New York: McGraw-Hill, 1983: 556-81. 18. Samani NJ, Swales JD, Jeffreys AJ, et al. DNA finger-printing of spontaneously hypertensive and Wistar-Kyoto rats: implications for hypertension research. J Hypertens 1989; 7: 809-16. 19. Gillum RF. Pathophysiology of hypertension in blacks and whites: a review of the basis of racial blood pressure differences. Hypertension 1979; 1: 468-75. 20. Joint National Committee. The 1988 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988; 14: 1023-38. 21. Zing W, Ferguson RK, Vlasses Ph. Calcium antagonists in elderly and black hypertensive patients: therapeutic controversies. Arch Intern Med 1991; 151: 2154-62. response
to
Epidermolysis bullosa simplex:
a
disorder of keratin Keratin is an essential component of the epidermis, but attempts to explain scaly dermatoses in terms of abnormal keratinisation have been unrewarding. Psoriasis and pityriasis rubra pilaris are traditionally called disorders of keratinisation, yet there is little evidence that abnormal keratin plays a part in pathogenesis. Although blisters are not usually classified under that heading, we now have surprising evidence that production of abnormal keratin causes the inherited blistering disease, epidermolysis bullosa
simplex. There are many types of epidermolysis bullosa.1 The commonest type, epidermolysis bullosa simplex (EBS), is characterised by the fact that the traumainduced blistering is due to cytolysis of the epidermal basal cells, as shown by electron microscopy-ie, the split occurs within the cytoplasm. There are several subtypes, even of the simplex form. The WeberCockayne type is a mild form, with blisters localised to the hands and feet, whereas the Kobner type, though likewise mild, is more generalised. The DowlingMeara type is distinguished by its greater severity, and by the presence on electron microscopy of large cytoplasmic clumps of tonofilaments, which are intermediate filaments composed of keratin. Intermediate filaments are proteins that are found in the cytoplasm of virtually all mammalian cells. They all have a similar molecular architecture, with four long helices that are essential for their function. There are several groups of intermediate filaments, of which keratins are the most diverse, there being more than twenty types of keratin in epithelial cells. The keratinous filaments that make up the cytoskeleton of human epidermal cells are formed by the polymerisation of two different keratin moleculestype I (acidic), and type II (basic).2 Neither type can polymerise on its own, but any type I and type II molecules can unite to form a filamentous
dipolymer.
Hypertension—in black and white of cardiovascular of genetic and environmental influences. This may sound like a cliche but it is not. We do not know how many factors there are or how they interact with each other. However, we do know that there are enough of them effectively to obscure subpopulations within the overall blood pressure distribution, as Pickering pointed out many years ago. The difficulties of unravelling these complexities are well illustrated in genetically hypertensive rats, in which inbreeding and a constant environment simplify the picture but underline its magnitude. Hilbert et al2lately showed a weak linkage between a locus on chromosome 10 (which may act as a marker for the angiotensin converting enzyme [ACE] gene) and blood pressure. This linkage became much stronger with the application of an environmental stress in the form of sodium loading. It seems likely that, in the same way, environmental influences may expose genetic factors in human hypertension. Ethnic differences in blood pressure are an illuminating example and have provided a tantalising insight into the nature of
Hypertension, like other forms disease, is a complex mixture
hypertension. Blacks of African origin in the United States have higher blood pressures and a higher prevalence of hypertension at all ages than whites.They also have a higher risk of cardiovascular disease, which is not wholly attributable to the difference in blood pressure.3Nevertheless, in two large epidemiological studies, when other risk factors for cardiovascular disease were taken into account, raised blood pressure in whites carried no worse cardiovascular prognosis. 1,5 A recent report based upon a work-site programme of blood pressure control supports the conclusion that, given access to adequate antihypertensive treatment, blacks fare no worse than whites.61807 blacks and 2962 whites were screened for cardiovascular risk factors and then offered traditional stepped-care
antihypertensive therapy. Although blacks were less likely to be treated for hypertension for similar initial blood pressure levels, their antihypertensive response was as good as that in whites and they had at least as good an outcome as far as cardiovascular disease was concerned. Myocardial infarction rates were significantly lower. Thus, although blood pressure is higher in American blacks, the associated risks are no different from those in whites. This observation does not explain why blood pressure is higher in the first place. Either environmental or genetic factors could be responsible. There is evidence for both. When African blacks move from a rural to an urban environment blood pressure rises within a few weeks.7 The move to a western pattern of blood pressure rise with age is associated with blacks adopting a westernised diet and
with cultural stress.8 United States blacks also suffer from potential social stress in terms of lower social and educational status, and they have less ready access to medical care. The inverse correlation of social class with blood pressure is not sufficient to account for the difference in blood pressure between blacks and whites.3 Nevertheless, the finding that differences in blood pressure between American blacks and whites seem to be diminishing with the passage of time suggests environmental effects.9 Moreover, one British investigation failed to find any difference between blood pressure of Afro-Caribbean blacks and whites in Binningham.1o Is it possible, therefore, that the high prevalence of hypertension in American blacks is largely environmental, even if we cannot completely specify the relevant factors? The answer has important implications both for public health measures and for individual patient management. The closely interwoven relation between environment and heredity adds to the complexities. Thus, the South Carolina Heart Study showed a correlation between the degree of skin colour and blood pressure," but the relation disappeared when data were adjusted for social class.12 The same doubts are relevant to possible genetic markers for hypertension in blacks. There are reported racial differences in transmembrane ionic fluxes;13 plasma renin activity is low in blacks;14 and excretion of a sodium load has been reported to be impaired in blacks. is All of these factors could theoretically influence blood pressure control systems. One group has put forward an imaginative hypothesis to link this phenomenon to hypertension. is These researchers propose that enhanced renal conservation of sodium carries advantages when the climate is hot and salt intake is low. Such conservation becomes less desirable in more temperate conditions with a westernised diet. Under these circumstances sodium retention and hypertension occur, with suppression of renin secretion. The difficulty with such a theory is that there is no convincing evidence that low-renin hypertension is associated with sodium retention.16
The
genetically hypertensive rat illustrates the into which it is possible to fall when attributing pitfalls causality. When hypertensive and control strains are compared there are numerous phenotypicl’ and genotypic18 differences between the two. Some are unrelated to hypertension; some are secondary to hypertension; and perhaps a few are associated with physiological processes that raise blood pressure. Examining linkages with blood pressure in generations of hybrids will help to clarify the last aspect. In man living in an unregulated environment and usually outbred, the problem is infinitely more complex. Whether having a black skin is a marker for environmental or genetic factors that increase blood pressure is still unresolved. For clinical scientists the painful fact is that there are many physiological
29
differences between black and white hypertensives.19
increasing volume of research into ethnic aspects of hypertension has brought some spin-off for clinicians in that they have learnt about differences in response to various classes of antihypertensive agents. Low-renin hypertension would be expected to respond poorly to ACE inhibitors but better to diuretics, since activation of the renin-angiotensin system helps to limit the blood pressure fall induced by sodium depletion. In giving consensus advice, the Joint National Committee on Development, Evaluation and Treatment of High Blood Pressure20 stated that blacks respond better to diuretics and calcium antagonists than to beta blockers or ACE inhibitors. This advice was based on general clinical wisdom rather than critical review of published work. Zing and co-workers2l have now remedied this deficiency by examining all relevant published studies. In general, their results support the Joint National Committee recommendations in showing a The
weaker response to beta blockers and ACE inhibitors in blacks. Unfortunately, only four trials compare responsiveness in the two ethnic groups in an
acceptably stringent way. Although a widely accepted belief is not overturned, therefore, there is clearly scope for much more intensive study.
1. Pickering GW. Nature of hypertension. Lancet 1962; i: 1298-99. 2. Hilbert P, Lindpaintner K, Beckmann JS, et al. Chromosonal mapping of two genetic loci associated with blood pressure regulation in hereditary hypertensive rats. Nature 1991; 353: 521-29. 3. Tyroler HA. Socio-economic status, age, and sex in the prevalence and prognosis of hypertension in blacks and whites. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis and management.
New York: Raven, 1990: 159-74. 4. Neaton JD, Kuller LH, Wentworth D, et al. Multiple Risk Factor Intervention Trial Research Group: total and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration and diastolic blood pressure among black and white males followed for five years. Am Heart J 1984; 108: 759-69. 5. Langford HD, Stamler J, Wassertheil-Smoller S, Prineas RJ. All cause mortality in the Hypertension Detection and Follow-Up Program: findings for the whole cohort and for persons with less severe hypertension with and without other traits related to risk of mortality. Prog Cardiovasc Dis 1986; 29 (suppl 1): 29-54. 6. Ooi WL, Budner NS, Cohen H, Madhaven S, Alderman MH. Impact of race on treatment response and cardiovascular disease amongst hypertensives. Hypertension 1989; 14: 227-34. 7. Poulter N, Khaw KT, Hopwood BEC, et al. Determinants of blood pressure due to urbanisation: a longitudinal study. J Hypertens 1985; 3 (suppl 3): S375-77. 8. Seedat YK. Race, environment and blood pressure: the South African experience. J Hypertens 1983; 1: 7-12. 9. Persky V, Pan WH, Stamler J, Dyer A, Levy P. Time trends in the US racial difference in cardiovascular disease. Am J Epidemiol 1986; 124: 724-37. 10. Cruickshank JK, Stephen HD, Jackson D, et al. Similarity of blood pressure in blacks, whites and Asians in England: the Birmingham factory study. J Hypertens 1985; 3: 365-72. 11. Boyle E. Biological patterns in hypertension by race, sex, body weight and skin color. JAMA 1970; 213: 1637-43. 12. Keidl JE, Tyroler HA, Sandifer SH, Boyle E. Hypertension: effects of social class and racial admixture—the results of a cohort study in the black population of Charleston, South Carolina. Am J Publ Health
1977; 67: 634-39. 13. Aviv A, Gardner J. Racial differences in ion regulation and their possible links to hypertension in blacks. Hypertension 1989; 14: 584-89. 14. Levy SB, Lilley JJ, Frigon RP, Stone RA. Urinary kallikrein and plasma renin activity as determinants of renal blood flow: the influence of race and dietary sodium intake. J Clin Invest 1977; 60: 129-35.
15.
Luft FC, Grim CE, Higgins JT, Weinberger MH. Differences
in sodium administration in normotensive white and black subjects. J Lab Clin Med 1977; 90: 555-61. 16. Lebel M, Schalekamp MA, Beevers DG, et al. Sodium and the renin-angiotensin system in essential hypertension and mineralocorticoid excess. Lancet 1974; ii: 308-10. 17. Yamori Y. Physiopathology of the vanous strains of spontaneously hypertensive rats. In: Genest J, Kuchel O, Hamet P, Cantin M, eds. Hypertension. New York: McGraw-Hill, 1983: 556-81. 18. Samani NJ, Swales JD, Jeffreys AJ, et al. DNA finger-printing of spontaneously hypertensive and Wistar-Kyoto rats: implications for hypertension research. J Hypertens 1989; 7: 809-16. 19. Gillum RF. Pathophysiology of hypertension in blacks and whites: a review of the basis of racial blood pressure differences. Hypertension 1979; 1: 468-75. 20. Joint National Committee. The 1988 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988; 14: 1023-38. 21. Zing W, Ferguson RK, Vlasses Ph. Calcium antagonists in elderly and black hypertensive patients: therapeutic controversies. Arch Intern Med 1991; 151: 2154-62. response
to
Epidermolysis bullosa simplex:
a
disorder of keratin Keratin is an essential component of the epidermis, but attempts to explain scaly dermatoses in terms of abnormal keratinisation have been unrewarding. Psoriasis and pityriasis rubra pilaris are traditionally called disorders of keratinisation, yet there is little evidence that abnormal keratin plays a part in pathogenesis. Although blisters are not usually classified under that heading, we now have surprising evidence that production of abnormal keratin causes the inherited blistering disease, epidermolysis bullosa
simplex. There are many types of epidermolysis bullosa.1 The commonest type, epidermolysis bullosa simplex (EBS), is characterised by the fact that the traumainduced blistering is due to cytolysis of the epidermal basal cells, as shown by electron microscopy-ie, the split occurs within the cytoplasm. There are several subtypes, even of the simplex form. The WeberCockayne type is a mild form, with blisters localised to the hands and feet, whereas the Kobner type, though likewise mild, is more generalised. The DowlingMeara type is distinguished by its greater severity, and by the presence on electron microscopy of large cytoplasmic clumps of tonofilaments, which are intermediate filaments composed of keratin. Intermediate filaments are proteins that are found in the cytoplasm of virtually all mammalian cells. They all have a similar molecular architecture, with four long helices that are essential for their function. There are several groups of intermediate filaments, of which keratins are the most diverse, there being more than twenty types of keratin in epithelial cells. The keratinous filaments that make up the cytoskeleton of human epidermal cells are formed by the polymerisation of two different keratin moleculestype I (acidic), and type II (basic).2 Neither type can polymerise on its own, but any type I and type II molecules can unite to form a filamentous
dipolymer.
