EXPERIMENTAL
AND
MOLECULAR
PART
PATHOLOGY
31,
163-168 ( 1979)
I-CARDIOVASCULAR
Atherosclerotic
Disease
DISEASES
and
the Vessel
Wall
G. C. MCMILLAN Division
of
Heart
and
Vascular
Diseases; National Bethesda, Maryland
Heart, 20014
Lung,
and
Blood
Institute,
It has been almost a necessity for anyone speaking about arteriosclerosis to emphasize how common it is, how severe the lesions are in the Western World, how variable and plemorphic they may be, and how great a burden of heart attack, stroke and other ischemic vascular disease it brings with it. The public health and clinical importance of arteriosclerosis do not lie directly in the pathological lesions of the arterial wall. They lie in the incidence of heart attacks, strokes and peripheral vascular disease that arteriosclerosis entrains. The association between the extent and severity of arteriosclerosis and ischemic disease is high on the average, but it also manifests a surprising degree of variability. When cases judged to be examples of ischemic heart disease are arrayed in terms of the severity of arteriosclerosis found at autopsy a wide scatter is seen. The findings of the International Atherosclerosis Project presented pertinent data in 1968 that emphasize the general association between the severity of coronary arteriosclerosis and coronary heart disease, but also show the wide deviations in severity that may be found after death (Strong, 1968). There is a distribution curve of the severity of arteriosclerosis that is found in the event of heart attack. The observations indicate that there is an average severity that is the common threshold for heart attack, but that there must be circumstances which either promote or protect against a reaction to this average threshold value. What these other variables may be is largely speculative, but their existence cannot be doubted. In the last few decades, particularly in the 50’s and early 60’s death rates from ischemic disease were very high. It was said that they were of epidemic proportions. Around 1968, however, the rates in the USA began to fall for both men and women. Since 1970, for example, rates for coronary heart disease have fallen about 13% from 228 to 198 per 100,000 (age adjusted to the 1940 population base). There has been a minus 17% change in stroke mortality. The decrease in death rates from heart attack between 1968 and 1975 has been about 18% in each age decade for white men and women between ages 45 and 74, approximately 21% for black men and close to 30% for black women. The decrease in the age decade 35 to 44 has been even greater. The change is not small; its slope is fairly constant; it is expressed in both sexes and strongly across the younger susceptible age periods of the thirties
0014-4800/79/040163-06$02.00/O All
Copyright 0 1979 rights of reproduction
by Academic Press Inc. in any form reserved.
164
G. C. hfcMILLAN
through the sixties. About 100,000 persons are now surviving each year who would have died had the heart disease death rates of 1968 persisted. The number of those who died amnrally from cardiovascular diseaseshas exceeded a million for a number of years. In 1975 it was 979,180. The findings raise the question whether some large but unknown diminution in morbidity may also have occurred. Are we seeing less lethal, better treatment of, or, in fact fewer heart attacks? Unfortunately data to answer these critical questions are not available. Can we link the vessel wall with these remarkable changes? There are no suitable descriptive or statistical data. There are no reports from pathologists, chemists, pathophysiologists, angiographers or clinicians which demonstrate that the severity, extent, distribution, frequency or kind of ateriosclerotic plaque has recently changed, nor are there reports which demonstrate that the local complications of plaques such as intramural hemorrhage, rupture or thrombosis have changed in kind or frequency. But then, historically, it must be admitted that there have been few suggestions that the lesions of the 50’s were of a different kind than those of the turn of the century (Morris and Glasg, 195I), or that individuals in regions of the USA where rates are low, such as the southwest, or from comltries with low rates such as Greece, have plaques of a different kind when compared with persons from regions with high rates of ischemic cardiac deaths. Indeed, even in the face of frank dyslipoproteinemia, with the possible exception of Type III disease, the lesions are not distinguishable as being of special kinds in the few casesthat have been studied (Roberts & al., 1970), although it has been suggested that the root of the aorta shows more severe lesions in homozygous familial hypercholesterolemia than would be expected at this anatomical location in comparison with the distal aorta. Generally only the prevalence or extent of lesions have been found to be less where rates are low (McGill et al., 1968). It would appear at the moment that one camrot link the vessel wall to the falling death rates. Perhaps it is for lack of an appropriate epidemiological study of the vessel wall, perhaps it is because the appropriate observations are not being recorded with enough precision to display the putative differences, or perhaps the findings are not due to changes in arteriosclerosis at all but to the other unspecified variables that influence the events of heart attack or stroke and, in particular, death from these events. Are similar changes occurring in other countries? The data should be available shortly. It is only a few years since it was reported that several countries in Europe with historically low mortality rates from coronary heart disease were experiencing an acceleration of these rates, some approaching those of the USA (Rose, 1970). If one cannot marshal1 evidence about the vessel wall (and surely this must reflect uncomfortably in any discussion of research on arteriosclerosis), can evidence be marshalled that the change in incidence of death from coronary heart disease is attributable to changes in exposure to risk-factors? It is not possible to do so with any rigor or acceptable quality of proof, but in fact there have been changes in diet (Call and Sanchez, 1967; Data from NHLBI), blood cholesterol ( NCHS, 1977; Data from NHLBI), smoking habits ( Owen, 1976)) and in the awareness and treatment of hypertension (Data from NHLBI) that are
ATHEROSCLEROTIC
DISEASE
AND THE
VESSEL
WALL
165
theoretically in the right direction to be associated with such a decrease in death rate. There has been a marked change in the kind of tobacco smoked and the form in which it is smoked, Compared with the average market cigarette of 15 to 20 years ago, the present filter cigarettes deliver a low tar, low nicotine smoke. Part of this change resides in the tobacco blend itself, and part in the filter. The use of filter cigarettes has increased while that of non-filter types has decreased. At the same time, the per capita use of tobacco has decreased in some sections of the society, particularly among middle-aged white males. Such data are, of course, subject to many qualifications relating to the style of smoking and of attributing the particular smoking habit to the appropriate segment of the population, but there has been an appreciable overall decrease in the delivery of tobacco tar and nicotine to accompany the decreased death rates. Similarly, there are data from the National Health Examination Survey of 1960 to 62 and the National Health and Nutrition Examination Survey of 1971 to 74 to indicate a small decrease in mean serum cholesterol levels in both sexes and all adult ages. Preliminary data from the Lipid Research Clinic population studies indicate that there has been a substantial decline in serum cholesterol levels in the population in comparison with the data accrued earlier by the Framingham Heart Study. The average plasma cholesterol value for middle-aged men is close to 200 mg% in the Clinic group. Food disappearance rates have changed too and trend data for the years from 1940 to 1967 show decreases, for example, in butter and lard as grams of fat per person per day with increases in margarine, other fats and oils, and shortenings. Cooking fats have decreased, whereas cooking and salad oils have increased. The shift has been from fats to oils, and from saturated to unsaturated fatty acids. In terms of grams of fat per person per day, soybean oil has shown a marked increase and dominates the disappearance of vegetable oils used for food, Data presented recently to the Senate Select Committee on Nutrition and Human Needs show over the years a rising consumption of fat but also a consumption in which the content of mono- and polyunsaturated fatty acids is rising. Observations from the Lipid Research Clinic populations indicate a current polyunsaturated to saturated fat ratio in the diet of about 0.5 rather than the 0.1 to 0.2 that was observed in earlier findings. The data indicate a dietary cholesterol intake of under 500 mg daily for men and about 350 mg for women. These are smaller values than had been anticipated. Finally, the data developed by the National High Blood Pressure Education Program suggest that hypertension is now diagnosed more commonly and more patients are under therapeutic control than was true a few years ago. All these associations are intriguing but at present they only permit speculation about their ultimate meaning. The improving mortality rates, dramatic as they are, do not abrogate the need to increase our understanding of the pathogenesis of atherosclerosis. The conventional risk-factors for atherosclerotic disease may be somewhat less burdensome now than they were a decade or more ago and this may possibly explain some part of the changing mortality rates, but it should be recalled that these risk-factors are thought to explain only about a half of the variance in coronary heart disease death. There are individuals who have heart attacks
166
G.
C. McMILLAN
in the absence of conventional risk-factors and other individuals who carry a burden of risk without the expected advent of coronary heart disease. The variation in severity of coronary atherosclerosis found at autopsy in individuals with coronary heart disease was noted earlier. Clearly there are other as yet unidentified pathogenetic factors operating to increase susceptibility on the one hand and protection on the other, and knowledge of them is needed if atherosclerosis and heart attack are to be understood in about half of the affected population. Is it possible to link risk-factors to the vessel wall? Yes, to a limited but essential degree this is possible for both man and animals. Hypertension in man is accompanied by extensive and severe atherogenesis, and regional hypertension by regional arteriosclerosis. Individuals with elevated serum cholesterol levels or with dyslipoproteinemia suffer an advancement of atherogenesis. Animal experiments in which hypercholesterolemia is the atherogenic correlate are legion (although even among single species or strains of animals there is a wide variation in atherogenic response). Smoking history in man has been correlated positively with severity of aortic and coronary artery atherosclerosis. Beyond these essential primary facts, can conventional risk-factors be linked to the plaque in the vessel wall? The answers are curious and worth pondering. At one level of penetration into the issue there is a considerable amount of sophisticated fundamental research devoted to exploring hypotheses in which elements of risk-factors are the major independent variables and aspects of atherogenesis or some surrogate response are the dependent variables. It is the hypothesis, and indeed to an important degree the fact, in this kind of research that risk-factors and the vessel wall plaque can be linked. At another level of the issue however, the linkage has not been demonstrated at present. It is not possible to identify the degree and kind of risk-factors present (or indeed, absent) by looking at hunlan arteries grossly or microscopically at autopsy or in surgical specimens. To discriminate plaques in a blind procedure into those arising in relation to the presence or absence of hypertension is not really possible at present. There are no ordinary characteristics of plaques which allow the observer to say that this patient smoked, and this one did not. In relation to serum cholesterol levels or dyslipoproteinemia, it is possible to recognize plaques as advancing or more quiescent, and to be lipid-rich or lipid-poor, but not to relate them to the status of the lipid metabolism of the patient with any certainty. The observer cannot tell by looking at a plaque whether it was derived from a diabetic patient or not. What does it mean if one cannot identify plaques according to their etiology except, perhaps in particular animal experimental models? One may speculate that the observations on pleomorphic plaques are not being made with enough sensitivity and specificity and that the data are being displayed too crudely. Or, one may speculate that the postulated differences do not exist in chronic lesions but rather that there is a strongly expressed pathogenetic final common pathway for plaques regardless of the nature of the stimulus. This may imply, that notwithstanding the involvement of several different types of cells and their differentiation, the reactions of the artery are so limited or so narrowly
ATHEROSCLEROTIC
DISEASE
AND
THE
VESSEL
WALL
167
programmed that their responses to continuing stimuli as remarkably varied as inhaled tobacco smoke, elevated blood pressure, diabetes or increased circulating beta lipoproteins, are indistinguishable in their chronic form. The idea that the etiological basis for lesions may not be determinable from an examination of some stage in their pathogenesis is not a novel one in pathology. There are many processes, for example inflammation and repair, in which the final common pathways of pathogenetic expression are not much modulated by the etiological stimuli which initiated them. There are only a few major theories of atherogenesis although there are many variations on them. One is derived from the teaching of Virchow and has fostered the family of theories involving permeation of lipids from the lumen into the intima and the failure of vascular homeostasis to keep the vessel free of lipid accumulation. A second has been that of Rokitansky which implicates the accretion of blood products on the surface of the arterial intima. It was reformulated by Duguid with an emphasis on vascular injury. It has recently been expanded in concept by the observation that blood platelets carry a mitogen which will stimulate arterial smooth muscle cells to proliferate. The Virchowian concept received a strong impetus from the development of experimental dietary cholesterol atherosclerosis by Ignatowsky and Saltykow. The Rokitansky-Duguid concept has been handicapped by a lack of convenient animal models. Both major theories can be cast in the context of a still more basic concept of injury to the vessel wall and the attempted repair processes. The past few years have seen the presentation of a new theory as fundamental as the others. The Benditts have presented evidence that individual plaques are genetically homogeneous with respect to an isoenzymic cell marker (Benditt and Benditt, 1973). Whether this represents the monoclonality of transformed cells or the monotypism of selective cell growth in plaques is a matter for further research (Thomas et al., 1976). However, it is clear that we now have an alternative theory of fundamental type to consider. The theory would establish a prior condition to the application of other theories such as the lipid or thrombopathic hypotheses, but it is not incompatible with them. It is also one that can be modulated subsequently by injury and repair. It will be of great importance to determine whether plaques are monoclonal or monotypic, but in either case there is an additional pathogenetic implication of the data. If plaques are monoclonal a.5 initio the range of reactions manifested by the cells of plaques to their local environment should be homogeneous or within a limited and common range of responses. Similarly, if plaques acquire selective monotypism the cells within an individual plaque should gradually adopt a more uniform and restricted range of responses to pathogenetic stimuli. There is thus a paradox in the available data. On the one hand mature atherosclerotic plaques are morphologically highly variable or pleomorphic. On the other hand they cannot be shown to be etiologically-specific in pathogenetic development and they are homogeneous in terms of a cell marker. Assuming that the paradox is real and not merely a product of faulty data, its resolution will require the recognition of those phenomena which are qualitatively essential to plaque development and those factors which are quantitative modulations or complications of the basic process, The integration of both qualitative
16S
G.
C. McMILLAN
and quantitative data will be a complex undertaking, we are to understand the progression of plaques.
but a necessary
step if
REFERENCES E. P., and RE~YDITT, J. M. (1973). Proc. Nat. Acud. Sci. USA 70, 1753-1756. D. L. and SANCHEZ, A. M. (1967). Trends in fat disappearance in the United States 1909-1965. J. Nurt. 93, Suppl. 1, l-48. Data from the Lipid Research Clinics, Sational Heart, Lung and Blood Institute, USA. Data from the National High Blood Pressure Education Program. National Heart, Lung, and Blood Institute, USA. MCGILL, H. et al. (1968). The Geographic PathoIogy of Atherosclerosis. Lnb. Inoestigatiorl 18, Number 5, 463-653. MORRIS, J., and GLASG, M. A. ( 1951). R ecent History of Coronary Disease. Lancet 1, 69-73. National Center for Health Statistics (USA) (1977). A Comparison of Levels of Serum Cholesterol of Adults 18-74 Years of Age in the United States in 1960-62 and 1971-74. Adaance Data, No. 5, February, 22, 1-7. OWEA-, T. B. (1976). Tar and Nicotine from U.S. Cigarettes: Trends over the Past Twenty Years, Proc. 3rd World Conference on Smoking and Health (Wynder, Hoffman and Gori, eds.), Vol. 1, 73-80. DHEW Publication No. (NIH) 76-1221. ROBERTS, W. C., LEVY, R. I., and FREDRICKSOS, D. S. (1970). Hyperlipoproteinemia. A Review of the Five Types with a First Report of Necropsy Findings in Type 3. Arch. Path. 90, 46-56. ROSE, G. ( 1970). Current Developments in Europe in Atherosclerosis, Proceedings of the Second International Symposium (R. J. Jones, ed.). Springer-Verlag, 310-314. STRONG, J. P. (1968). Atherosclerosis in Persons with Coronary Heart Disease. Lab. Incestig&on 18, 527-537. THOMAS, W. A., JANAKIDEVI, K., REIKER, J. M., and LEE, K. T. (1976). Glucose-6-Phosphate Dehydrogenase (G-6-PD) Monotypism in Atherosclerotic Lesions of Heterozygotes Related to Lesion Thickness. Circulation 54: No. 4. October 11-137, Abstract No. 0540. BENDITT,
CALL,
AND
MOLECULAR
PART
PATHOLOGY
31,
163-168 ( 1979)
I-CARDIOVASCULAR
Atherosclerotic
Disease
DISEASES
and
the Vessel
Wall
G. C. MCMILLAN Division
of
Heart
and
Vascular
Diseases; National Bethesda, Maryland
Heart, 20014
Lung,
and
Blood
Institute,
It has been almost a necessity for anyone speaking about arteriosclerosis to emphasize how common it is, how severe the lesions are in the Western World, how variable and plemorphic they may be, and how great a burden of heart attack, stroke and other ischemic vascular disease it brings with it. The public health and clinical importance of arteriosclerosis do not lie directly in the pathological lesions of the arterial wall. They lie in the incidence of heart attacks, strokes and peripheral vascular disease that arteriosclerosis entrains. The association between the extent and severity of arteriosclerosis and ischemic disease is high on the average, but it also manifests a surprising degree of variability. When cases judged to be examples of ischemic heart disease are arrayed in terms of the severity of arteriosclerosis found at autopsy a wide scatter is seen. The findings of the International Atherosclerosis Project presented pertinent data in 1968 that emphasize the general association between the severity of coronary arteriosclerosis and coronary heart disease, but also show the wide deviations in severity that may be found after death (Strong, 1968). There is a distribution curve of the severity of arteriosclerosis that is found in the event of heart attack. The observations indicate that there is an average severity that is the common threshold for heart attack, but that there must be circumstances which either promote or protect against a reaction to this average threshold value. What these other variables may be is largely speculative, but their existence cannot be doubted. In the last few decades, particularly in the 50’s and early 60’s death rates from ischemic disease were very high. It was said that they were of epidemic proportions. Around 1968, however, the rates in the USA began to fall for both men and women. Since 1970, for example, rates for coronary heart disease have fallen about 13% from 228 to 198 per 100,000 (age adjusted to the 1940 population base). There has been a minus 17% change in stroke mortality. The decrease in death rates from heart attack between 1968 and 1975 has been about 18% in each age decade for white men and women between ages 45 and 74, approximately 21% for black men and close to 30% for black women. The decrease in the age decade 35 to 44 has been even greater. The change is not small; its slope is fairly constant; it is expressed in both sexes and strongly across the younger susceptible age periods of the thirties
0014-4800/79/040163-06$02.00/O All
Copyright 0 1979 rights of reproduction
by Academic Press Inc. in any form reserved.
164
G. C. hfcMILLAN
through the sixties. About 100,000 persons are now surviving each year who would have died had the heart disease death rates of 1968 persisted. The number of those who died amnrally from cardiovascular diseaseshas exceeded a million for a number of years. In 1975 it was 979,180. The findings raise the question whether some large but unknown diminution in morbidity may also have occurred. Are we seeing less lethal, better treatment of, or, in fact fewer heart attacks? Unfortunately data to answer these critical questions are not available. Can we link the vessel wall with these remarkable changes? There are no suitable descriptive or statistical data. There are no reports from pathologists, chemists, pathophysiologists, angiographers or clinicians which demonstrate that the severity, extent, distribution, frequency or kind of ateriosclerotic plaque has recently changed, nor are there reports which demonstrate that the local complications of plaques such as intramural hemorrhage, rupture or thrombosis have changed in kind or frequency. But then, historically, it must be admitted that there have been few suggestions that the lesions of the 50’s were of a different kind than those of the turn of the century (Morris and Glasg, 195I), or that individuals in regions of the USA where rates are low, such as the southwest, or from comltries with low rates such as Greece, have plaques of a different kind when compared with persons from regions with high rates of ischemic cardiac deaths. Indeed, even in the face of frank dyslipoproteinemia, with the possible exception of Type III disease, the lesions are not distinguishable as being of special kinds in the few casesthat have been studied (Roberts & al., 1970), although it has been suggested that the root of the aorta shows more severe lesions in homozygous familial hypercholesterolemia than would be expected at this anatomical location in comparison with the distal aorta. Generally only the prevalence or extent of lesions have been found to be less where rates are low (McGill et al., 1968). It would appear at the moment that one camrot link the vessel wall to the falling death rates. Perhaps it is for lack of an appropriate epidemiological study of the vessel wall, perhaps it is because the appropriate observations are not being recorded with enough precision to display the putative differences, or perhaps the findings are not due to changes in arteriosclerosis at all but to the other unspecified variables that influence the events of heart attack or stroke and, in particular, death from these events. Are similar changes occurring in other countries? The data should be available shortly. It is only a few years since it was reported that several countries in Europe with historically low mortality rates from coronary heart disease were experiencing an acceleration of these rates, some approaching those of the USA (Rose, 1970). If one cannot marshal1 evidence about the vessel wall (and surely this must reflect uncomfortably in any discussion of research on arteriosclerosis), can evidence be marshalled that the change in incidence of death from coronary heart disease is attributable to changes in exposure to risk-factors? It is not possible to do so with any rigor or acceptable quality of proof, but in fact there have been changes in diet (Call and Sanchez, 1967; Data from NHLBI), blood cholesterol ( NCHS, 1977; Data from NHLBI), smoking habits ( Owen, 1976)) and in the awareness and treatment of hypertension (Data from NHLBI) that are
ATHEROSCLEROTIC
DISEASE
AND THE
VESSEL
WALL
165
theoretically in the right direction to be associated with such a decrease in death rate. There has been a marked change in the kind of tobacco smoked and the form in which it is smoked, Compared with the average market cigarette of 15 to 20 years ago, the present filter cigarettes deliver a low tar, low nicotine smoke. Part of this change resides in the tobacco blend itself, and part in the filter. The use of filter cigarettes has increased while that of non-filter types has decreased. At the same time, the per capita use of tobacco has decreased in some sections of the society, particularly among middle-aged white males. Such data are, of course, subject to many qualifications relating to the style of smoking and of attributing the particular smoking habit to the appropriate segment of the population, but there has been an appreciable overall decrease in the delivery of tobacco tar and nicotine to accompany the decreased death rates. Similarly, there are data from the National Health Examination Survey of 1960 to 62 and the National Health and Nutrition Examination Survey of 1971 to 74 to indicate a small decrease in mean serum cholesterol levels in both sexes and all adult ages. Preliminary data from the Lipid Research Clinic population studies indicate that there has been a substantial decline in serum cholesterol levels in the population in comparison with the data accrued earlier by the Framingham Heart Study. The average plasma cholesterol value for middle-aged men is close to 200 mg% in the Clinic group. Food disappearance rates have changed too and trend data for the years from 1940 to 1967 show decreases, for example, in butter and lard as grams of fat per person per day with increases in margarine, other fats and oils, and shortenings. Cooking fats have decreased, whereas cooking and salad oils have increased. The shift has been from fats to oils, and from saturated to unsaturated fatty acids. In terms of grams of fat per person per day, soybean oil has shown a marked increase and dominates the disappearance of vegetable oils used for food, Data presented recently to the Senate Select Committee on Nutrition and Human Needs show over the years a rising consumption of fat but also a consumption in which the content of mono- and polyunsaturated fatty acids is rising. Observations from the Lipid Research Clinic populations indicate a current polyunsaturated to saturated fat ratio in the diet of about 0.5 rather than the 0.1 to 0.2 that was observed in earlier findings. The data indicate a dietary cholesterol intake of under 500 mg daily for men and about 350 mg for women. These are smaller values than had been anticipated. Finally, the data developed by the National High Blood Pressure Education Program suggest that hypertension is now diagnosed more commonly and more patients are under therapeutic control than was true a few years ago. All these associations are intriguing but at present they only permit speculation about their ultimate meaning. The improving mortality rates, dramatic as they are, do not abrogate the need to increase our understanding of the pathogenesis of atherosclerosis. The conventional risk-factors for atherosclerotic disease may be somewhat less burdensome now than they were a decade or more ago and this may possibly explain some part of the changing mortality rates, but it should be recalled that these risk-factors are thought to explain only about a half of the variance in coronary heart disease death. There are individuals who have heart attacks
166
G.
C. McMILLAN
in the absence of conventional risk-factors and other individuals who carry a burden of risk without the expected advent of coronary heart disease. The variation in severity of coronary atherosclerosis found at autopsy in individuals with coronary heart disease was noted earlier. Clearly there are other as yet unidentified pathogenetic factors operating to increase susceptibility on the one hand and protection on the other, and knowledge of them is needed if atherosclerosis and heart attack are to be understood in about half of the affected population. Is it possible to link risk-factors to the vessel wall? Yes, to a limited but essential degree this is possible for both man and animals. Hypertension in man is accompanied by extensive and severe atherogenesis, and regional hypertension by regional arteriosclerosis. Individuals with elevated serum cholesterol levels or with dyslipoproteinemia suffer an advancement of atherogenesis. Animal experiments in which hypercholesterolemia is the atherogenic correlate are legion (although even among single species or strains of animals there is a wide variation in atherogenic response). Smoking history in man has been correlated positively with severity of aortic and coronary artery atherosclerosis. Beyond these essential primary facts, can conventional risk-factors be linked to the plaque in the vessel wall? The answers are curious and worth pondering. At one level of penetration into the issue there is a considerable amount of sophisticated fundamental research devoted to exploring hypotheses in which elements of risk-factors are the major independent variables and aspects of atherogenesis or some surrogate response are the dependent variables. It is the hypothesis, and indeed to an important degree the fact, in this kind of research that risk-factors and the vessel wall plaque can be linked. At another level of the issue however, the linkage has not been demonstrated at present. It is not possible to identify the degree and kind of risk-factors present (or indeed, absent) by looking at hunlan arteries grossly or microscopically at autopsy or in surgical specimens. To discriminate plaques in a blind procedure into those arising in relation to the presence or absence of hypertension is not really possible at present. There are no ordinary characteristics of plaques which allow the observer to say that this patient smoked, and this one did not. In relation to serum cholesterol levels or dyslipoproteinemia, it is possible to recognize plaques as advancing or more quiescent, and to be lipid-rich or lipid-poor, but not to relate them to the status of the lipid metabolism of the patient with any certainty. The observer cannot tell by looking at a plaque whether it was derived from a diabetic patient or not. What does it mean if one cannot identify plaques according to their etiology except, perhaps in particular animal experimental models? One may speculate that the observations on pleomorphic plaques are not being made with enough sensitivity and specificity and that the data are being displayed too crudely. Or, one may speculate that the postulated differences do not exist in chronic lesions but rather that there is a strongly expressed pathogenetic final common pathway for plaques regardless of the nature of the stimulus. This may imply, that notwithstanding the involvement of several different types of cells and their differentiation, the reactions of the artery are so limited or so narrowly
ATHEROSCLEROTIC
DISEASE
AND
THE
VESSEL
WALL
167
programmed that their responses to continuing stimuli as remarkably varied as inhaled tobacco smoke, elevated blood pressure, diabetes or increased circulating beta lipoproteins, are indistinguishable in their chronic form. The idea that the etiological basis for lesions may not be determinable from an examination of some stage in their pathogenesis is not a novel one in pathology. There are many processes, for example inflammation and repair, in which the final common pathways of pathogenetic expression are not much modulated by the etiological stimuli which initiated them. There are only a few major theories of atherogenesis although there are many variations on them. One is derived from the teaching of Virchow and has fostered the family of theories involving permeation of lipids from the lumen into the intima and the failure of vascular homeostasis to keep the vessel free of lipid accumulation. A second has been that of Rokitansky which implicates the accretion of blood products on the surface of the arterial intima. It was reformulated by Duguid with an emphasis on vascular injury. It has recently been expanded in concept by the observation that blood platelets carry a mitogen which will stimulate arterial smooth muscle cells to proliferate. The Virchowian concept received a strong impetus from the development of experimental dietary cholesterol atherosclerosis by Ignatowsky and Saltykow. The Rokitansky-Duguid concept has been handicapped by a lack of convenient animal models. Both major theories can be cast in the context of a still more basic concept of injury to the vessel wall and the attempted repair processes. The past few years have seen the presentation of a new theory as fundamental as the others. The Benditts have presented evidence that individual plaques are genetically homogeneous with respect to an isoenzymic cell marker (Benditt and Benditt, 1973). Whether this represents the monoclonality of transformed cells or the monotypism of selective cell growth in plaques is a matter for further research (Thomas et al., 1976). However, it is clear that we now have an alternative theory of fundamental type to consider. The theory would establish a prior condition to the application of other theories such as the lipid or thrombopathic hypotheses, but it is not incompatible with them. It is also one that can be modulated subsequently by injury and repair. It will be of great importance to determine whether plaques are monoclonal or monotypic, but in either case there is an additional pathogenetic implication of the data. If plaques are monoclonal a.5 initio the range of reactions manifested by the cells of plaques to their local environment should be homogeneous or within a limited and common range of responses. Similarly, if plaques acquire selective monotypism the cells within an individual plaque should gradually adopt a more uniform and restricted range of responses to pathogenetic stimuli. There is thus a paradox in the available data. On the one hand mature atherosclerotic plaques are morphologically highly variable or pleomorphic. On the other hand they cannot be shown to be etiologically-specific in pathogenetic development and they are homogeneous in terms of a cell marker. Assuming that the paradox is real and not merely a product of faulty data, its resolution will require the recognition of those phenomena which are qualitatively essential to plaque development and those factors which are quantitative modulations or complications of the basic process, The integration of both qualitative
16S
G.
C. McMILLAN
and quantitative data will be a complex undertaking, we are to understand the progression of plaques.
but a necessary
step if
REFERENCES E. P., and RE~YDITT, J. M. (1973). Proc. Nat. Acud. Sci. USA 70, 1753-1756. D. L. and SANCHEZ, A. M. (1967). Trends in fat disappearance in the United States 1909-1965. J. Nurt. 93, Suppl. 1, l-48. Data from the Lipid Research Clinics, Sational Heart, Lung and Blood Institute, USA. Data from the National High Blood Pressure Education Program. National Heart, Lung, and Blood Institute, USA. MCGILL, H. et al. (1968). The Geographic PathoIogy of Atherosclerosis. Lnb. Inoestigatiorl 18, Number 5, 463-653. MORRIS, J., and GLASG, M. A. ( 1951). R ecent History of Coronary Disease. Lancet 1, 69-73. National Center for Health Statistics (USA) (1977). A Comparison of Levels of Serum Cholesterol of Adults 18-74 Years of Age in the United States in 1960-62 and 1971-74. Adaance Data, No. 5, February, 22, 1-7. OWEA-, T. B. (1976). Tar and Nicotine from U.S. Cigarettes: Trends over the Past Twenty Years, Proc. 3rd World Conference on Smoking and Health (Wynder, Hoffman and Gori, eds.), Vol. 1, 73-80. DHEW Publication No. (NIH) 76-1221. ROBERTS, W. C., LEVY, R. I., and FREDRICKSOS, D. S. (1970). Hyperlipoproteinemia. A Review of the Five Types with a First Report of Necropsy Findings in Type 3. Arch. Path. 90, 46-56. ROSE, G. ( 1970). Current Developments in Europe in Atherosclerosis, Proceedings of the Second International Symposium (R. J. Jones, ed.). Springer-Verlag, 310-314. STRONG, J. P. (1968). Atherosclerosis in Persons with Coronary Heart Disease. Lab. Incestig&on 18, 527-537. THOMAS, W. A., JANAKIDEVI, K., REIKER, J. M., and LEE, K. T. (1976). Glucose-6-Phosphate Dehydrogenase (G-6-PD) Monotypism in Atherosclerotic Lesions of Heterozygotes Related to Lesion Thickness. Circulation 54: No. 4. October 11-137, Abstract No. 0540. BENDITT,
CALL,
