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Atherosclerosis of the aorta and coronary vessels of the heart in cases of various diseases
179
Journal of Atherosclerosis Research Elsevier Publishing C o m p a n y , A m s t e r d a m - P r i n t e d in The N e t h e r l a n d s
A T H E R O S C L E R O S I S OF T H E AORTA AND CORONARY VESSELS OF T H E H E A R T IN CASES OF VARIOUS DISEASES
A. M. V I H E R T , V. S. Z H D A N O V AND E. E. M A T O V A
The A. L. Myasnikov Institute of Cardiology, U.S.S.R. Academy of Medical Sciences, Moscow
(u.s.s.R.)
(Received D e c e m b e r 4th, 1968)
SUMMARY
The authors investigated the occurrence of atherosclerosis in "healthy" people (selected accidental deaths), in people, who died of complications due to atheroselerosis, and in some diseases: i.e., diabetes, hypertensive disease, renal hypertension and malignant tumours. In their observations, they used the visuoplanimetric method of estimation of vascular atheroselerotic changes recommended b y the WHO. In diabetics under the age of 50, extensive atherosclerosis was found in only 16 of the 38 patients. In some of these 16 cases, the duration of diabetes was over 8 years (in 8 cases). The accelerated development of atherosclerotic changes (mostly fibrous plaques) was usually observed in 1 or 2 vessels out of the 5 studied. In some instances, despite a long duration of diabetes in young people, the authors did not note any accelerated development of atherosclerotic changes as compared with the control groups. In people of 50 years of age and over, atherosclerotic changes in diabetics were as pronounced as in those who died of atherosclerosis unattended with diabetes. Hypertension of any etiology (essential, renal) involves a more pronounced atherosclerosis of the aorta than found in healthy people or those who died of complications due to atherosclerosis unattended with hypertension. The average area of atherosclerotic changes in the right coronary artery in patients with essential hypertension is larger than in persons who died of complications due to atherosclerosis but did not suffer from hypertension. The differences in the descending branch of the left coronary artery are less pronounced, although there is a tendency towards more severe lesions of this vessel in patients with essential hypertension, especially in men. In patients 30-39 years of age suffering from symptomatic renal hypertension, atherosclerosis of the aorta is more intensive than in patients with essential hypertension. There is also a tendency towards an increase in the area of atherosclerosis
J. Atheroscler. Res., 1969, 9:179-192
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A. M. VIHERT, V. S. ZHDANOV, E. E. MATOVA
of the coronary arteries in patients suffering from symptomatic hypertension, especially between the ages of 30 and 39. After 40, the intensity of atherosclerosis in these two groups is essentially the same. In cases of new malignant growths, atherosclerotic changes in the aorta and coronary arteries were less prevalent than in cases of other ailments studied (diabetes, essential hypertension, symptomatic hypertension). In their prevalence, however, they differed little from atherosclerotic changes in healthy people.
] NTRODUCTION The detection of qualitative and quantitative differences in the course of atherosclerosis associated with some diseases may be of importance for understanding its pathogenesis. It is, however, rather difficult to describe atherosclerosis in various groups of people, for there have so far been no generally accepted methods of quantitative assessment of atherosclerosis, and no single classification of atherosclerotic changes or objective criteria for the manifestation of the process. That is why it is so difficult to compare available work on the subject. In recent years a quantitative method has been proposed for characterising atherosclerosis; it has been described by HOLMAN et al. 17 and used in PIA (International Atherosclerosis Project). At the suggestion of the World Health Organisation, this znethod is being further elaborated by a group of pathologists21, 49. At present, this method is used for studying questions of the pathology and epidemiology of atherosclerosislb,a4,44,45, 50. MATERIALS AND METHODS The present report contains some data on atherosclerosis iI1 those who died of various diseases: i.e., diabetes (283 cases), essential hypertension (420 cases), symptomatic hypertension (213 cases), or a malignant tumour (1049 cases). The vessels from "healthy" people (1983 cases of accidental death) who exhibited no cysts in the brain and whose hearts were of normal weight and without myocardial lesions, served as controls. In addition comparisons were made with those who had died of various manifestations of atherosclerosis (e.g., an infarction of the myocardium, cerebral haemorrhage), but who had no increased blood pressure and did not suffer from the diseases mentioned above (908 cases (see Table 1). The authors used materials obtained mainly in Moscow, Kharkov, Riga, Tallin, Tartu, Kaunas and Ryasan from 1963 to 1966. Atherosclerosis was studied in the following blood vessels: the descending thoracic aorta, the abdominal aorta, the right coronary artery and the descending and circumflex branches of the left coronary artery. The authors used the following classification of atherosclerotic changes: (1) Lipoid stripes and spots; (2) fibrous plaques; (3) complicated lesions (plaques with haemorrhages, ulcerations, thrombosis); (4) calcified plaques 4~. J. Atheroscler. Res., 1969, 9:179-192
ATHEROSCLEROSIS IN AORTA AND CORONARY VESSELS IN VARIOUS DISEASES
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The blood vessels to be examined were cut lengthwise and fixed spread out. They were then fully stained with Sudan IV solution and placed in transparent plastic bags. A grid was drawn with a pencil on each one of the bags, each division of the grid corresponding to a definite area of the vessel: 50, 25, 12.5, 6.25 and 3.1 ~o. This grid was used to determine visually the total area of the atherosclerotic changes and their various types relative to the total area of the vessel. The results were processed statistically, with the arithmetic mean deduced for the areas of all types of atherosclerotic changes. The values of the differences were found with the aid of the coefficient t. The final results are shown in Figs. 1-4. RESULTS
Diabetes To describe atherosclerosis accompanied b y diabetes, 283 observations were made (180 women and 103 men). Cases in which diabetes was associated with other diseases (hypertension, malignant tumours, tuberculosis, etc.) were excluded from the analysis. The degree of atherosclerotic changes in patients who had been suffering from diabetes mellitus and died of various causes and also in patients who had diabetes mellitus and died of various atherosclerotic complications was determined. The latter patients belonged to the older age groups (50 years and over), for in the younger age groups only one case of death associated with atherosclerosis was recorded. The main causes of death for those under 50 who suffered from diabetes (38 cases) were diabetic coma and various infectious complications, and sometimes a combination of both. Moreover, in 5 cases, diabetic glomerulosclerosis was observed. In those who died under the age of 50, no myocardial infarctions, postinfarction scars
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Fig. 1. E x t e n t of atherosclerotic lesions of the abdominal aorta in males, aged 20 69, grouped according to various diseases, l, Healthy people; 2, malignant tumour; 3, diabetes; 4, atheroscterosis; 5, essential hypertension; 6, symptomatic hypertension. jr. A t h e r o s c l e r .
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Fig. 2. Extent of atherosclerotic lesions of the left anterior descending coronary artery in males, aged 20-69, grouped according to various diseases. For explanation of figures, see legend Fig. 1.
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Fig. 3. Extent of atherosclerotic lesions of the abdominal aorta in females, aged 20-69, grouped according to various diseases. For explanation of figures, see legend Fig. 1.
or d i s t u r b a n c e s of t h e b l o o d circulation in t h e b r a i n were o b s e r v e d e x c e p t for 1 case (a w o m a n of 40) where gangrene of t h e left leg was found. I n older age groups (over 50), t h e m a i n cause of d e a t h of those who h a d d i a b e t e s was c o n n e c t e d w i t h p a t h o l o g y of t h e c a r d i o v a s c u l a r s y s t e m (72.3 % in m e n a n d 6 7 . 1 % in women). C o m p a r i s o n of d e a t h s resulting from atherosclerosis w i t h d i a b e t e s mellitus or w i t h o u t it r e v e a l e d a s o m e w h a t higher incidence of p a t h o l o g i c a l changes in t h e c a r d i o v a s c u l a r s y s t e m in diabetes. Thus, m y o c a r d i a l infarction a n d p o s t i n f a r c t i o n a l cardiosclerosis occurred in 61.7 % of d i a b e t i c male p a t i e n t s a n d in 46.4 % of d i a b e t i c female p a t i e n t s , whereas t h e respective figures in n o n - d i a b e t i c s are 55.7% a n d 41.4 %. Gangrene of t h e lower e x t r e m i t i e s in d i a b e t i c p a t i e n t s was f o u n d in 38.3 % of males a n d 33 % of females, as c o m p a r e d w i t h 7.8 % a n d 4.8 % of n o n - d i a b e t i c m a l e a n d j . Atheroscler. Res., 1969, 9:179-192
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Fig. 4. Extent of atherosclerotic lesions of the left anterior descending coronary artery in females, aged 20-69, grouped according to various diseases. For explanation of figures, see legend Fig. 1. female patients, respectively. Disturbances of cerebral circulation in diabetic patients were found in 30 % of males and 21.4 % of females, compared with 18 % and 27 %, respectively, for non-diabetics. These types of lesion frequently occurred in combination (for instance, fresh myocardial infarction combined with previous apoplexy, or gangrene of lower extremeties combined witll postinfarctional cardiosclerosis). Infectious complications (abscesses, phlegmons, suppurative pyelonephritis, sepsis, etc.) in diabetics 50 years old and older were found in 15.6 % of the men and 7.7 % of the women. Diabetic coma (often attended with infarctions and vascular complications) was observed in 3.6 and 11.4 % of cases, respectively. Diabetic glomerulonecrosis was found in 3.7 and 5.3 % of the cases, respectively. There were 38 cases of diabetics under the age of 50. In most of them the spread of atherosclerotic changes in tile aorta and coronary arteries did not go beyond the limits typical of the corresponding age and sex groups of clinically healthy people. The differences were considered to be significant if the normal deviation was equal to two or more times the standard deviation. In only 16 cases out of the 38 was the extent of these changes in one or more of the examined vessels beyond the control limits, i n 12 cases the area occupied by fibrous plaques was significantly increased; in 4 cases only the areas of lipid spots were increased. In the 12 cases in which there was a considerable increase in the area of fibrous plaques, the duration of diabetes was from 1-3 years in 3 cases, from 8-11 years in 8 cases and unascertained in 1 case. In the remaining 26 observations the duration of the disease was very rarely more than 3 years. However, among our observations in the age group of 1 0 4 9 years, there are individual cases of a very protracted course of diabetes (up to 13 years) in which we could not find any considerable differences as compared with the control groups. In the age groups of 50-59, 60-69 and 70-79 years, the various types of atherosclerotic changes (except lipoidosis in the aorta and coronary arteries of diabetic men and women) took up a much greater area than in the corresponding groups of J. Atheroscler. Res., 1969, 9:179-192
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"healthy" subiects. At the same time, the authors did not find any statistically significant differences in the manifestation of atherosclerosis between the dead patients with diabetes and those who died of atherosclerosis unattended with diabetes. As indicated above, although the majority of diabetic patients aged 50 or more died of various manifestations of atherosclerosis, there were other causes of death (coma, infections). It was of interest, therefore, to make separate estimates of the degree of atherosclerotic changes in these groups. It was found that those diabetic patients who died from diabetic coma or infection exhibited more pronounced changes than normal subjects but less pronounced than those who died of atherosclerosis, whether combined with diabetes or without it. However, no statistically significant differences were found in degree of atherosclerotic changes in patients who died of various manifestations of atherosclerosis, either with diabetes of without it. Yet, with diabetes atherosclerotic changes were more pronounced. The study of the inci,dence of stenosis in 3 main coronary arteries (only constrictions of more than 50 % of the lumen was taken into consideration) demonstrated that in diabetic patients aged between 50 and 79 who died of various atherosclerotic manifestations, stenosis occurred in 4 1 . 1 % of males and 37.9 % of females. In atherosclerosis without diabetes, the respective figures were 42.3 and 39.5 %. Therefore there was no difference in the incidence of coronary stenosis in males and females. In these age groups, the duration of diabetes in the dead patients was often within the limits of 3-6 years.
Hypertensive disease and symptomatic hypertension The authors have conducted a comparative study of the degree of atherosclerotic changes in the aorta and coronary vessels in male and female patients who died of hypertensive disease or of complications caused by atherosclerosis without hypertension (myocardial infarction, cerebral haemorrhage, etc.) as well as in patients with kidney diseases with symptomatic hypertension, primarily associated with glomerulonephritis or pyelonephritis. The vessels of clinically normal individuals who died accidentally were used as controls. We defined the intensity of atherosclerosis by the sum of fibrous plaques, complicated lesions and calcified lesions, because the relationship between lipoid streaks and atherosclerosis is unresolved. In both males and females aged between 20 and 29, atherosclerosis of the aorta and coronary vessels in the presence of renal hypertension was much more pronounced than in the control group (Figs. 1-4). We had no opportunity to compare atherosclerosis in patients aged 20-29 with and without essential hypertension with other groups because of the small number of deaths occurring in this age group. In the 30-39-year-old group atherosclerotic changes of the aorta and coronary arteries in males with elevated blood pressure of various etiologies were greater not only than those in normal subjects, but also than in those individuals who died of atherosclerotic complications without hypertension. j. Atheroscler. Res., 1969, 9:179-192
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A, M. V l t t E R T , V. S, Z H D A N O u
E, E, M A T O V A
Differences in the degree of atherosclerosis between patients with hypertension and those who died of atherosclerotic complications without hypertension were statistically significant. Comparison of the degree of atherosclerosis in the aorta and coronary artery, especially in its right branch, in male patients aged 30 39 and having symptomatic hypertension showed that atherosclerosis was more intensive in symptomatic hypertension than in essential hypertension. Females aged between 30 and 39 and having symptomatic or essential hypertension showed a marked prevalence to atherosclerosis of the aorta and coronary arteries, as compared to the control group. Because of tl~e sinai1 number of femaIes of this age group who died from atherosclerosis without hypertension, we were unable to compare the degree of the atherosclerosis found with and without symptomatic and essential hypertension. In the 40-49- and 50.59-year-old groups, atherosclerosis of the aorta both in males and females was more intensive in the presence of hypertension, irrespective of its etiology. Over the age of 40, however, differences in the degree of coronary atherosclerosis disappeared, so that the anterior descending branch of the left coronary artery in dead males and females was equally affected both in e3sential or symptomatic hypertension and in atherosclerosis without hypertension As to the differences in the degree of atherosclerosis in hypertension of different etiologies, these were found to be smoothed out after the age of 40, wl~ile in individuals with essentia[ hypertension aged over 50, atherosclerosis of the aorta and coronary arteries tended to predominate. After the age of 60 the tendency to more extensive atherosclerosis was noted in those who had suffered from hypertensive disease than in those who died of atherosclerosis either in the aorta or coronary arteries and without hypertension. The differences in atherosclerosis of the aorta in males and females with symptomatic or essential hypertension were not statistically significant, but coronary atherosclerosis predominated in cases of essential hypertension. Malignant tumours According to our observations among men affected with malignant tumours, the area of atheroselerotic changes in the aorta was somewhat greater than in the control groups except for the age group of 30-39. This was largely due to the prevalence of fibrous plaques. These differences, however, were not statistically significant. Complicated lesions in the abdominal aorta in the age groups 60-69 and 70-79 years were more widespread than m the control groups. Lipoid spots and calcified areas ill those who died of malignant tumours were of the same dimensions as in the male control groups. In the coronary arteries the extent of atherosclerotic changes in the presence of malignant tumours differed very little from the control groups (only in the age group of 70-79). These changes were not very widespread, primarily because of the smaller area of calcium deposits. in women wire died of malignant tumours, the total ~rea of atheroscierotic J, Atheroscler. Res., 1969, 9:179-192
A T H E R O S C L E R O S I S IN A O R T A A N D C O R O N A R Y V E S S E L S IN V A R I O U S D I S E A S E S
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changes in the aorta was close to that in the corresponding control group. The authors observed a tendency towards an increase in the area of fibrous plaques in those who died of tumours. These differences, however, were not statistically significant and were less pronounced than in men. Lipoidosis in the thoracic aorta was more pronounced and in the abdominal aorta less pronounced than in the control groups. Complicated lesions, and calcinocis in particular, were less prevalent in the age groups 60-69 and 70-79 years than in the control groups. In the coronary arteries of the heart in women who died of tumours, atherosclerotic changes were rather less widely distributed, chiefly because of the smaller area taken up by fibrous plaques and deposits of calcium salts. The distinctions were most pronounced between 70 and 79 years of age. The authors separately analysed atherosclerotic changes (a) in cases of cancer of the stomach and the lungs in men; (b) in cases of cancer of the stomach, the genitals and the m a m m a r y gland in women. I t turned out that in men who died of cancer of the lung, atherosclerotic changes were much more widespread than in those who died of cancer of the stomach. In cases of cancer of the lung, we often observed stenosis of the coronary arteries (i.e. cases in which the arterial orifice was constricted by more than 50 %). Between the ages of 50 and 59, for instance, such strictures in all the main branches of the coronary arteries in cases of cancer of the lung were found in 23.1 4- 8.3 % of the observations and between the ages of 60 and 69, in 29.0 48.2 %. In cases of cancer of the stomach the figures were 0 and 16.1 4- 6.6 ~o respectively. The authors did not observe any constantly significant differences in the extent of atherosclerostic changes in women who died of cancer of the stomach and in those who died of cancer of the genitals and the m a m m a r y gland. DISCUSSION
Biometrical research into atherosclerotic changes makes it possible to obtain objective criteria for the manifestation of atherosclerosis of the various blood vessels in people of the same age affected with various diseases. Reports in the literature on the influence of various ailments on the development of atherosclerosis are very contradictory. For instance, the fact that atherosclerosis in often associated with diabetes and disorders of lipoid metabolism in diabetes has enabled most researchers to speak of the growing influence of diabetes on the development of atherosclerosis 1,5,20,23,27,29. This conclusion has been further confirmed b y observations of a higher incidence of coronary lesions, especially of myocardial infarction, in diabetes mellitus4,12, 46. Some authors are of the opinion, however, that diabetes does not accelerate the development of atherosclerosis3,9A1,32, 33,a2,56. They point out that not infrequently there is no relation between the duration and severeness of diabetes and the manifestation of atherosclerosis, and that very often (especially in aged people) diabetes develops in the presence of already pronounced atherosclerosis. Our observations regarding atherosclerosis in the presence of diabetes in young
J. Atheroscler. Res., 1969, 9:179-192
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A.M. VIHERT, V. S. ZHDANOV, E. E. MATOVA
people show that t o d a y diabetes does not always lead to accelerated atherosclerotic changes. For instance, among people between the ages of 10 and 49 we made 38 detailed observations, and in only 16 cases were atherosclerotic changes more widespread (usually in only one or two vessels) than in the group of "healthy" people. The area of fibrous plaques was larger than in the control group in only 12 cases (in the other 4 cases, only the distribution of lipoid spots was different). I t should be mentioned that the duration of diabetes in these 12 cases was greater t h a n in all the other diabetic patients of this age group. This points to the definite rote which the duration of diabetes plays in the development of atherosclerosis. However, among our observations made in the age group of 10-19 years, there were individual cases of diabetes lasting up to 13 years, which were attended, with an insignificant amount of atherosclerosis. Of course, the development of atherosclerotic changes depends not only on the duration of diabetes, but also on its severity, as well as on the effectiveness of treatment and individual predisposition to atherosclerosis. In diabetics above the age of 50, atherosclerotic changes were present to the same extent as in people who had died of various manifestations of atherosclerosis unattended with diabetes. This explains why over two-thirds of the people with diabetes die of atherosclerotic complications. W h a t is the relationship between atherosclerosis and diabetes in aged people ? Our data indicate that very often these two ailments go together. I t seems to us t h a t atherosclerotic changes predispose the body to diabetes (this is attested to b y the higher frequency of diabetes among people over the age of 50). I t is, however, difficult to say that diabetes, in its turn, does not have an accelerating effect on the development of atherosclerosis. Some other authors have also pointed to atherosclerosis as the predisposing factor in the development of diabetes. REINER et al. 62 reported that severe atherosclerosis in mesenteric arteries was associated with an exceptionally high frequency of diabetes. BUTKI~S59 found that atherosclerosis of the arteria lienalis was accompavied b y considerable pathological changes in the islands of the pancreas. These changes depended on the degree of atherosclerosis in the artery. The author also pointed out t h a t the atherosclerotic changes in the arteria lienalis have appeared after 40 years of age, and later on they progressed very quickly. BUTKUSs9 comes to the conclusion t h a t in old age diabetes might be connected with the changes in the vessel. The effect of hypertensive diseases on atherosclerosis has been studied b y RAU aT, DAVIS AND KLAINER 6, SIGLER 40, MIASNIKOV 28, DIMOND 7, EVANS 10, MASTER 25, MITCHELL et al. 31, MITCHELL AND SCHWARTZ30, SCHWARTZ et al. 39, PATERSON e~ al. 36, and ROBERTSON3s among others. I t is generally recognized that hypertensive disease is usually combined with severe atherosclerosis. This belief is based chiefly on clinical data on the incidence of atherosclerotic complications in hypertensive disease, rather than on morphological findings which would seem to give a more objective picture of the degree of atherosclerotic changes ill the vessels. Biochemical data, too14, do not alwaysreflect the severity of ather osclerosis. J. Atheroscler. Res., 1969, 9:179-192
ATHEROSCLEROSIS IN AORTA AND CORONARY VESSELS IN VARIOUS DISEASES
f89
Experimental data on the effect of hypertension on the development of atherosclerosis16,~,~6,53, ss cannot be unconditionally applied to human pathology. The influence on atherosclerosis of hypertensions of various etiologies is still not quite clear, particularly that of renal hypertension, although it is of great importance for understanding the of relationship between atherosclerosis and hypertension. Our results have demonstrated that elevated blood pressure contributes to a more intensive development of atherosclerotic vascular changes. This becomes especially clear in comparison with normal individuals. In hypertensive individuals atherosclerotic changes in the aorta and coronary vessels were invariably more severe than in normal persons, these differences being statistically significant. Atherosclerotic changes were also found to be greater in symptomatic and essential hypertensive cases than in patients who died of various atherosclerotic complications but had not suffered from hypertension. These changes were especially marked and frequent in the aorta, and less regularly, in the coronary vessels. Comparison of the degree of atherosclerosis in people with hypertensive diseases and symptomatic hypertension has demonstrated that in a younger age group (30-39), atherosclerosis of both the aorta and coronary vessels was more pronounced in symptomatic hypertension. After the age of 40, the intensity of atherosclerosis in these two groups showed no significant difference. This fact seems to be of interest, since the cause of death in renal hypertension accompanied b y an intensive coronary sclerosis was not coronary insufficiency, but uremia, while in essential hypertension, most of the patients died of coronary insufficiency and myocardial infarction. Therefore, clinical manifestations of atherosclerosis, particularly that of the coronary vessels, do not always match the severity of the morphological changes in the vascular wall. Thus, the accelerating effect of hypertension on the development of atherosclerotic vascular changes in man is observed in hypertensions of various etiologies. An important factor in the occurrence of atherosclerotic changes is the degree and duration of hypertension. In our opinion, this accounts for a greater degree of atherosclerosis in younger individuals having symptomatic hypertension. Cancer and atherosclerosis are now the main causes of death. Therefore the combination of these two diseases is usual, particularly in aged people. I t has been established, however, that in the presence of cancer, severe forms of atherosclerosis are rarely observedl,18,19. Some authors studying the relationship between atherosclerosis and cancer have noted a definite antagonism between predisposition to cancer and predisposition to atherosclerosis8,47, sl. Other authors indicate that in the presence of new malignant growths, atherosclerotic changes m a y be subject to reversion 24. According to our data, atherosclerosis accompanied b y malignant tumours differs little in its manifestation from the changes observed in the control groups of clinically healthy people. There was some tendency towards an increase in the area of fibrous plaques in the aorta and towards a decrease in the area taken up b y j . Atheroscler. Res., 1969, 9:179-192
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A . M . VIHERT, V. S. ZHDANOV, E. E. MATOVA
complicated lesions a n d deposits of calcium salts in those who died of m a l i g n a n t tumours. Similar d a t a were o b t a i n e d b y PARRISH35, who compared cancer patients, not with p a t i e n t s d y i n g of various causes, b u t only with accidental deaths. PARRISH'S d a t a were p a r t i a l l y confirmed b y GIERTSEN 13, who detected certain differences between cancer p a t i e n t s a n d all p a t i e n t s who died of other diseases. However, if one excluded the i n d i v i d u a l s with h y p e r t e n s i o n a n d atherosclerotic lesions of the heart, the differences b e t w e e n the group with m a l i g n a n t t u m o u r s a n d the control group were n o t so striking, a n d there were no differences in the cerebral arteries. These d a t a indicate t h a t in m a l i g n a n t t u m o u r s , atherosclerotic changes in the vessels are similar in e x t e n t to those observed in the n o r m a l subject. These findings do n o t s u p p o r t the claim t h a t m a l i g n a n t t u m o u r s retard the d e v e l o p m e n t of atherosclerosis. The expression of atherosclerotic changes in males was definitely related to the location of the cancer. Subjects with lung cancer h a d more atherosclerosis t h a n subiects with cancer of the stomach a n d t h a n " h e a l t h y " people. This has also been p o i n t e d out b y other investigatorsSS, 6~ The reasons for the occurrence of more severe atherosclerosis in l u n g cancer still are n o t quite clear. P r o b a b l y one of the reasons is s m o k i n g (among the subjects with l u n g cancer, the n u m b e r of people smoking a great deal a n d for a long time is more t h a n a m o n g the other subjects). Some authors have p o i n t e d out a connection between s m o k i n g a n d the d e v e l o p m e n t of atherosclerosis61, G3. A significant dependence of the expression of atherosclerotic changes on the site of the cancer was n o t observed in females.
REFERENCES
1 ANITSCHKOW, N., Pathologische Anatomie und allgemeine Pathologie der Arteriosklerose,
C. R. 2~me Conf. int. Path. gdogr., Utrecht, 1934. AVTANDILOV, G. G., Dynamics of Pathological Changes and the Pathogenesis of Atherosclerosis
of the Aorta and Coronary Arteries of Man's Heart, Annotation of a thesis for a Doctor's degree, Moscow, 1965 (in Russian). 3 BOAS, E. P., Arteriosclerosis and diabetes, J. M t Sinai Hosp., 1952, 19: 411. 4 CLAWSON, B. J. AND E. T. BELL, Incidence of fatal coronary disease in nondiabetic and diabetic persons, Arch. Path., 1949, 48: 105. 5 CZERKAWSKI, J. W . , Diabetes and vascular degeneration. In: D. A. HALL (Ed.), International Review of Connective Tissue Research, Academic Press, New York, London, 1963, p. 307. 6 DAVIS, O. AND M. J. KLAINER, Studies in hypertensive heart disease, Part 1 (The incidence of coronary atherosclerosis in cases of essential hypertension), Amer. Heart. J., 1940, 19: 185. 7 DIMOND, G. E., Hypertension, body weight and coronary heart disease, Arch. intern. Med. (Chic.), 1963, 112: 550. 8 DORMANNS, E. AND E. EMMINGER, Vergeleichende Untersuchungen fiber Ausbreitung und St~rke der Atherosklerose an 100O Leichen yon fiber 20 Jahre alten Personen mit besonderer Berficksichtigung yon Krebs, Tuberkulose und Lues, Virchows Arch. path. A nat., 1936,293: 545. 9 DOWNIE, E. AND F. J. R. MARTIN, Vascular disease in juvenile diabetic patients of long duration, Diabetes, 1959, 8: 383. 10 EVANS, P. H . , Relation of longstanding blood-pressure levels to atherosclerosis, Lancet, 1965, i: 516. 11 FABER, M. AND F. LUND, The human aorta, Part 4 (The aorta in diabetes mellitus), Arch. Path., 1951, 52: 239. 12 FELDMAN, M. AND M. FELDMAN, JR., The association of coronary occlusion and infarction in diabetes mellitus, Amer. J. reed. Sci., 1954, 228: 53. 1~ GIERTSEN, J. C., Atherosclerosis in an autopsy series, Part 8 (Relation of malignant disease to atherosclerosis), Acta path. microbiol, scand., 1966, 66: 341. f . Atheroscler. Res., 19e9, 9:179-192
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14 GIERTSEN, J. C., Atherosclerosis in an a u t o p s y series, P a r t 10 (Relation of nutritional state to atheroselerosis), P a r t 11 (General s u m m a r y and conclusion), Acta path. microbiol, scan&, 1966, 67: 305. 15 GORE, I., T. NAKASHIMA, T. IMAI AND P. D. WHITE, Coronary atherosclerosis and myocardial infarction in K y u s h u , J a p a n , and Boston, Massachusetts, Amer. J. Cardiol., 1962, 10: 400. 16 HEPTINSTALL, R. H., H. BARKLEY AND K. A. PORTER, The relative roles of blood cholesterol level and blood pressure level in the production of experimental aortic a t h e r o m a in rabbits, Angiology, 1958, 9: 84. 17 HOLMAN, R. L., H. C. McGILL, JR., J. P. STRONG AND J. C. GEER, Technics for s t u d y i n g atherosclerotic lesions, Lab. Invest., 1958, 7: 42. 18 JUHL, S., Cancer and atheroselerosis: Negative correlation, Acta path. microbiol, scan&, 1955, 37: 167. 19 JIJHL, S., Cancer a n d atherosclerosis, P a r t 2 (Applicability of p o s t m o r t e m statistics in the s t u d y of the negative correlation), Acta path. microbiol, scan&, 1957, 41: 99. 20 JOSLIN, E. P., H. F. ROOT, P. WHITE AND A. MARBLE, Treatment of Diabetes Mellitus, Lea and Febiger, Philadelphia, t959, p. 407. 2i KAGAN, A. AND K. UEMURA, Grading atherosclerosis in aorta and coronary arteries obtained at autopsy. W H O trials of macroscopic methods, Bull. Wld Hlth Org., 1962, 27: 667. 22 KASATKINA, L. V., N. M. POZDUNINA AND V. V. SUCHKOV, Some indices of mucopolysaecharide metabolism in experimental cerebro-ischemic hypertension, Cardiology, 1968, 4:40 (in Russian). 23 KRAMER, D. W. AND P. I{. PERILSTEIN, Arteriosclerosis-atherosclerosis in relation to diabetes. In: S. S. SAMUELS (Ed.), Diagnosis and Treatment of Vascular Disorders, Williams and Wilkins, 24 KREMNEV, T. N., Atherosclerosis in e x h a u s t i n g diseases. In: G. E. OSTROVERCHOV AND H. N. LEVITHAN (Eds.), Problems of the Clinical Fund and Pathology of the Cardiovascular System, Regional Publishers, Kursk, 1951, p. 30 (in Russian). 25 MASTER, A. M., Hypertension and coronary occlusion, Circulation, 1953, 8: 170. 26 MCGILL, JR., H. C., M. H. FRANK AND J. C. GEER, Aortic lesions in hypertensive monkeys, Arch. Path., 1961, 71: 96. 27 MIASNIKOV, A. L., Atherosclerosis, Medical Publishers, Moscow, 1960, p. 76 (in Russian). 28 MIASNIKOV, A. L., Hypertensive Disease and Atherosclerosis, Medicine, Moscow, 1965, p. 343 (in Russian). 29 MIASNIKOV, L. A. AND 1. S. I~LIMASH]~V, Atherosclerosis and diabetes mellitus, Soviet Med. 1965, 2 : 1 0 (in Russian). a0 MITCHELL, J. R. A. AND C. J. SCHWARTZ, Arterial Disease, Davis, Philadelphia, 1965, p. 411. 31 MITCHELL, J. R. A., C. J. SCHWARTZ AND A. ZINGER, Relationship between aortic plaques and age, sex, and blood pressure, Brit. reed. J., 1964, i: 205. 32 MOSCHKOWITZ, E. Z., The relation of hyperplastic arteriosclerosis to diabetes mellitus, Ann. intern. Med., 1951, 34: 1137. 33 MOSCHKOWlTZ,E. Z . , Diabetes mellitus and atherosclerosis, Clin. Med., 1958, 36:76 (in Russian). 34 MURTHY, M. S. N., ]3. N. DUTTA AND xf. RAMALINGASWAMI, Coronary atherosclerosis in North India, J. Path. Bact., 1963, 85: 93. 35 PARRISH, H. M., Epidemiology of ischemic heart disease a m o n g white males, P a r t 1 (Relationship between coronary atheroselerosis and cancer of various sites), J. chron. Dis., 1961, 14:311. 36 PATERSON, J. C., J. MILLS AND C. H. LOCKWOOD, The role of hypertension in the progression of atherosclerosis, Canad. reed. Ass. J., 1960, 82: 65. 37 RAU, H., Zur B e d e u t u n g der chronischen BlutdruckerhGhung fiir die E n t s t e h u n g der Arteriosklerose, Klin. Wchschr., 1956, 1: 167. 38 ROBERTSON, W. ]~., Some factors influencing the development of atherosclerosis. A survey in Jamaica, W e s t Indies, J. Atheroscler. Res., 1962, 2: 79. 39 SCHWARTZ, C. J., N. S. STENHOUSE, A. I~. TAYLOR AND T. A. WHITE, Coronary disease severity at necropsy, Brit. Heart J., 1965, 27: 731. 40 SIGLER, L. H., The role of hypertension in the etiology and prognosis of coronary occlusion, Ann. intern. Med., 1955, 42: 369. 41 SPAIN, D. M., D. J. NATHAN AND M. GELLIS, Weight, body type and the prevalence of coronary atherosclerotic h e a r t disease in males, Amer. J. reed. Sci., 1963, 245: 63. 42 STAMLER, J., Interrelationships between the two diseases, hypertension and atherosclerosis, Amer. J. Cardiol., 1962, 9: 743. 43 STERNBY, N. H., Atherosclerosis in a defined population. Acta. path. microbiol, scan&, Suppl. 194: 7. 45 STERNBY, N., R. VANI~CEK, A, VIHERT, A. KAGAN and K. UEMURA, Correlation of t y p e and extent of atherosclerosis in aorta and coronary arteries obtained at autopsy, Bull. Wld Hlth Org., 1965, 33: 741. 45 STRONG, J. P. AND H. C. McGILL JR., T h e n a t u r a l history of aortic atberosclerosis: Relations h i p to race, sex, and coronary lesions in New Orleans, Exp. molec. Path., 1963, Suppl. 1: 15.
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46 THOMAS, W. A., KYU TAIK LEE AND E. R. RABIN, F a t a l a c u t e m y o c a r d i a l infarction in d i a b e t e s p a t i e n t s , Arch. intern. Med. (Chic.), 1956, 98: 489. 47 TICHY, J., H. GVABOVE-TICHE AND V. MALY, R a k o v i n a ve v z t a h u k c h o r o b a m s p o r u s e n o u v # m ~ n o u cholesterolu, Gas. Lek. ~es., 1953, 92: 1005. 4s TOBIAN, L., H y p e r t e n s i o n a n d atherosclerosis, Minn. Med., 1955, 38: 784. 49 UEMURA, •., ~%~.STERNBY, R. VANI~CEK, A. VIHERT AND A. KAGAN, G r a d i n g atherosclerosis in a o r t a a n d c o r o n a r y arteries o b t a i n e d a t a u t o p s y . A p p l i c a t i o n of a t e s t e d m e t h o d , Bull. Wld Hlth Org., 1964, 31: 297. 50 VIHERT, A. M., V. S. ZHDANOV, E. ]~. MATOVA AND V. V. ALPATOV, A c o m p a r a t i v e c h a r a c t e r istics of atherosclerotic affections in s t a i n e d a n d n o n s t a i n e d vessels, Path. Arch., 1966, 8 : 3 1 (in R u s s i a n ) . 51 WANSCHER, O., J. CLEMI~SSEN AND H. NIELSEN, N e g a t i v e correlation b e t w e e n atherosclerosis a n d c a r c i n o m a , Brit. J. Cancer, 1951, 5: 172. 52 "WILDER, R. M., Clinical Diabetes MeUitus and Hyperinsulism, S a u n d e r s , P h i l a d e l p h i a , 1940, p. 327. 53 "WILENSS, L., T h e e x p e r i m e n t a l p r o d u c t i o n of lipid deposition in excised arteries, Science, 1951, 114: 389. 54 "~VILKINS, R. H . , J. C. ROBERTS JR. AND C. MOSES, A u t o p s y s t u d i e s in atherosclerosis, P a r t 3 ( D i s t r i b u t i o n a n d s e v e r i t y of atherosclerosis in t h e presence of obesity, h y p e r t e n s i o n , n e p h r o sclerosis a n d r h e u m a t i c h e a r t disease), Circualtion, 1959, 20: 527. 55 WlSSLER, R. W., M. L. EILERT, M. A. SCHROEDER AND L. COHEN, P r o d u c t i o n of l i p o m a t o u s a n d a t h e r o m a t o u s arterial lesions in t h e a l b i n o - r a t , Arch. Path., 1954, 57: 333. 56 YONASH, V. AND L. KOZAK, V a s c u l a r c h a n g e s in d i a b e t e s p a t i e n t s , Czech. reed. Rev., 1963 9: 173. 57 YOUNG, "VV., J. W. GOFMAN, R. TANDY, N. MALAMUD AND E. S. O. WATERS, T h e q u a n t i t a t i o n of atherosclerosis, P a r t 2 ( Q u a n t i t a t i v e a s p e c t s of t h e r e l a t i o n s h i p of blood p r e s s u r e a n d a t h e r o sclerosis), Amer. J. Cardiol., 1960, 6: 294. 58 BURKHARDT, L., 13ber B e z i e h u n g e n z w i s c h e n B r o n c h u s C a r c i n o m u n d Atherosclerose, Med. Klin., 1959, 5 4 : 1 6 1 3 (No. 36). 59 BUTEUS, R., Functional Morphology of Islands of Pancreas in Atherosclerosis, Thesis, U n i v e r sity of K a u n a s , 1967. 60 CREED, D. L., W. F. ]~AIRD AND E. R. FISSCHER, T h e s e v e r i t y of aortic atherosclerosis in certain diseases: a n e c r o p s y s t u d y , Amer. J. reed. Sci., 1955, 385: 230. 61 IiERSHBAUM, A. AND S. BELLET, Cigarette s m o k i n g a n d blood lipids, J. Amer. reed. Ass., 1964, 187: 32. 62 REINER, L., F. A. JIMENEZ AND F. L. RODRIGUES, Atherosclerosis in t h e m e s e n t e r i c circulation, Amer. Heart J., 1963, 200: 66. s3 SEBRELL, W . H. JR., An over-all look a t atherosclerosis, J. Amer. Diet Ass., 1962, 40: 403.
j . Atheroscler. Res., 1969, 9 : 1 7 9 - 1 9 2
Journal of Atherosclerosis Research Elsevier Publishing C o m p a n y , A m s t e r d a m - P r i n t e d in The N e t h e r l a n d s
A T H E R O S C L E R O S I S OF T H E AORTA AND CORONARY VESSELS OF T H E H E A R T IN CASES OF VARIOUS DISEASES
A. M. V I H E R T , V. S. Z H D A N O V AND E. E. M A T O V A
The A. L. Myasnikov Institute of Cardiology, U.S.S.R. Academy of Medical Sciences, Moscow
(u.s.s.R.)
(Received D e c e m b e r 4th, 1968)
SUMMARY
The authors investigated the occurrence of atherosclerosis in "healthy" people (selected accidental deaths), in people, who died of complications due to atheroselerosis, and in some diseases: i.e., diabetes, hypertensive disease, renal hypertension and malignant tumours. In their observations, they used the visuoplanimetric method of estimation of vascular atheroselerotic changes recommended b y the WHO. In diabetics under the age of 50, extensive atherosclerosis was found in only 16 of the 38 patients. In some of these 16 cases, the duration of diabetes was over 8 years (in 8 cases). The accelerated development of atherosclerotic changes (mostly fibrous plaques) was usually observed in 1 or 2 vessels out of the 5 studied. In some instances, despite a long duration of diabetes in young people, the authors did not note any accelerated development of atherosclerotic changes as compared with the control groups. In people of 50 years of age and over, atherosclerotic changes in diabetics were as pronounced as in those who died of atherosclerosis unattended with diabetes. Hypertension of any etiology (essential, renal) involves a more pronounced atherosclerosis of the aorta than found in healthy people or those who died of complications due to atherosclerosis unattended with hypertension. The average area of atherosclerotic changes in the right coronary artery in patients with essential hypertension is larger than in persons who died of complications due to atherosclerosis but did not suffer from hypertension. The differences in the descending branch of the left coronary artery are less pronounced, although there is a tendency towards more severe lesions of this vessel in patients with essential hypertension, especially in men. In patients 30-39 years of age suffering from symptomatic renal hypertension, atherosclerosis of the aorta is more intensive than in patients with essential hypertension. There is also a tendency towards an increase in the area of atherosclerosis
J. Atheroscler. Res., 1969, 9:179-192
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A. M. VIHERT, V. S. ZHDANOV, E. E. MATOVA
of the coronary arteries in patients suffering from symptomatic hypertension, especially between the ages of 30 and 39. After 40, the intensity of atherosclerosis in these two groups is essentially the same. In cases of new malignant growths, atherosclerotic changes in the aorta and coronary arteries were less prevalent than in cases of other ailments studied (diabetes, essential hypertension, symptomatic hypertension). In their prevalence, however, they differed little from atherosclerotic changes in healthy people.
] NTRODUCTION The detection of qualitative and quantitative differences in the course of atherosclerosis associated with some diseases may be of importance for understanding its pathogenesis. It is, however, rather difficult to describe atherosclerosis in various groups of people, for there have so far been no generally accepted methods of quantitative assessment of atherosclerosis, and no single classification of atherosclerotic changes or objective criteria for the manifestation of the process. That is why it is so difficult to compare available work on the subject. In recent years a quantitative method has been proposed for characterising atherosclerosis; it has been described by HOLMAN et al. 17 and used in PIA (International Atherosclerosis Project). At the suggestion of the World Health Organisation, this znethod is being further elaborated by a group of pathologists21, 49. At present, this method is used for studying questions of the pathology and epidemiology of atherosclerosislb,a4,44,45, 50. MATERIALS AND METHODS The present report contains some data on atherosclerosis iI1 those who died of various diseases: i.e., diabetes (283 cases), essential hypertension (420 cases), symptomatic hypertension (213 cases), or a malignant tumour (1049 cases). The vessels from "healthy" people (1983 cases of accidental death) who exhibited no cysts in the brain and whose hearts were of normal weight and without myocardial lesions, served as controls. In addition comparisons were made with those who had died of various manifestations of atherosclerosis (e.g., an infarction of the myocardium, cerebral haemorrhage), but who had no increased blood pressure and did not suffer from the diseases mentioned above (908 cases (see Table 1). The authors used materials obtained mainly in Moscow, Kharkov, Riga, Tallin, Tartu, Kaunas and Ryasan from 1963 to 1966. Atherosclerosis was studied in the following blood vessels: the descending thoracic aorta, the abdominal aorta, the right coronary artery and the descending and circumflex branches of the left coronary artery. The authors used the following classification of atherosclerotic changes: (1) Lipoid stripes and spots; (2) fibrous plaques; (3) complicated lesions (plaques with haemorrhages, ulcerations, thrombosis); (4) calcified plaques 4~. J. Atheroscler. Res., 1969, 9:179-192
ATHEROSCLEROSIS IN AORTA AND CORONARY VESSELS IN VARIOUS DISEASES
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J. Atheroscler. Res., 1969, 9 : 1 7 9 - 1 9 2
182
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The blood vessels to be examined were cut lengthwise and fixed spread out. They were then fully stained with Sudan IV solution and placed in transparent plastic bags. A grid was drawn with a pencil on each one of the bags, each division of the grid corresponding to a definite area of the vessel: 50, 25, 12.5, 6.25 and 3.1 ~o. This grid was used to determine visually the total area of the atherosclerotic changes and their various types relative to the total area of the vessel. The results were processed statistically, with the arithmetic mean deduced for the areas of all types of atherosclerotic changes. The values of the differences were found with the aid of the coefficient t. The final results are shown in Figs. 1-4. RESULTS
Diabetes To describe atherosclerosis accompanied b y diabetes, 283 observations were made (180 women and 103 men). Cases in which diabetes was associated with other diseases (hypertension, malignant tumours, tuberculosis, etc.) were excluded from the analysis. The degree of atherosclerotic changes in patients who had been suffering from diabetes mellitus and died of various causes and also in patients who had diabetes mellitus and died of various atherosclerotic complications was determined. The latter patients belonged to the older age groups (50 years and over), for in the younger age groups only one case of death associated with atherosclerosis was recorded. The main causes of death for those under 50 who suffered from diabetes (38 cases) were diabetic coma and various infectious complications, and sometimes a combination of both. Moreover, in 5 cases, diabetic glomerulosclerosis was observed. In those who died under the age of 50, no myocardial infarctions, postinfarction scars
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Fig. 1. E x t e n t of atherosclerotic lesions of the abdominal aorta in males, aged 20 69, grouped according to various diseases, l, Healthy people; 2, malignant tumour; 3, diabetes; 4, atheroscterosis; 5, essential hypertension; 6, symptomatic hypertension. jr. A t h e r o s c l e r .
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1969, 9:179-192
ATHEROSCLEROSIS IN AORTA AND CORONARY VESSELS IN VARIOUS DISEASES
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Fig. 2. Extent of atherosclerotic lesions of the left anterior descending coronary artery in males, aged 20-69, grouped according to various diseases. For explanation of figures, see legend Fig. 1.
70 60
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Fig. 3. Extent of atherosclerotic lesions of the abdominal aorta in females, aged 20-69, grouped according to various diseases. For explanation of figures, see legend Fig. 1.
or d i s t u r b a n c e s of t h e b l o o d circulation in t h e b r a i n were o b s e r v e d e x c e p t for 1 case (a w o m a n of 40) where gangrene of t h e left leg was found. I n older age groups (over 50), t h e m a i n cause of d e a t h of those who h a d d i a b e t e s was c o n n e c t e d w i t h p a t h o l o g y of t h e c a r d i o v a s c u l a r s y s t e m (72.3 % in m e n a n d 6 7 . 1 % in women). C o m p a r i s o n of d e a t h s resulting from atherosclerosis w i t h d i a b e t e s mellitus or w i t h o u t it r e v e a l e d a s o m e w h a t higher incidence of p a t h o l o g i c a l changes in t h e c a r d i o v a s c u l a r s y s t e m in diabetes. Thus, m y o c a r d i a l infarction a n d p o s t i n f a r c t i o n a l cardiosclerosis occurred in 61.7 % of d i a b e t i c male p a t i e n t s a n d in 46.4 % of d i a b e t i c female p a t i e n t s , whereas t h e respective figures in n o n - d i a b e t i c s are 55.7% a n d 41.4 %. Gangrene of t h e lower e x t r e m i t i e s in d i a b e t i c p a t i e n t s was f o u n d in 38.3 % of males a n d 33 % of females, as c o m p a r e d w i t h 7.8 % a n d 4.8 % of n o n - d i a b e t i c m a l e a n d j . Atheroscler. Res., 1969, 9:179-192
184
A.M. VIHERT, V. S. ZHDANOV,E. E. MATOVA
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Fig. 4. Extent of atherosclerotic lesions of the left anterior descending coronary artery in females, aged 20-69, grouped according to various diseases. For explanation of figures, see legend Fig. 1. female patients, respectively. Disturbances of cerebral circulation in diabetic patients were found in 30 % of males and 21.4 % of females, compared with 18 % and 27 %, respectively, for non-diabetics. These types of lesion frequently occurred in combination (for instance, fresh myocardial infarction combined with previous apoplexy, or gangrene of lower extremeties combined witll postinfarctional cardiosclerosis). Infectious complications (abscesses, phlegmons, suppurative pyelonephritis, sepsis, etc.) in diabetics 50 years old and older were found in 15.6 % of the men and 7.7 % of the women. Diabetic coma (often attended with infarctions and vascular complications) was observed in 3.6 and 11.4 % of cases, respectively. Diabetic glomerulonecrosis was found in 3.7 and 5.3 % of the cases, respectively. There were 38 cases of diabetics under the age of 50. In most of them the spread of atherosclerotic changes in tile aorta and coronary arteries did not go beyond the limits typical of the corresponding age and sex groups of clinically healthy people. The differences were considered to be significant if the normal deviation was equal to two or more times the standard deviation. In only 16 cases out of the 38 was the extent of these changes in one or more of the examined vessels beyond the control limits, i n 12 cases the area occupied by fibrous plaques was significantly increased; in 4 cases only the areas of lipid spots were increased. In the 12 cases in which there was a considerable increase in the area of fibrous plaques, the duration of diabetes was from 1-3 years in 3 cases, from 8-11 years in 8 cases and unascertained in 1 case. In the remaining 26 observations the duration of the disease was very rarely more than 3 years. However, among our observations in the age group of 1 0 4 9 years, there are individual cases of a very protracted course of diabetes (up to 13 years) in which we could not find any considerable differences as compared with the control groups. In the age groups of 50-59, 60-69 and 70-79 years, the various types of atherosclerotic changes (except lipoidosis in the aorta and coronary arteries of diabetic men and women) took up a much greater area than in the corresponding groups of J. Atheroscler. Res., 1969, 9:179-192
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185
"healthy" subiects. At the same time, the authors did not find any statistically significant differences in the manifestation of atherosclerosis between the dead patients with diabetes and those who died of atherosclerosis unattended with diabetes. As indicated above, although the majority of diabetic patients aged 50 or more died of various manifestations of atherosclerosis, there were other causes of death (coma, infections). It was of interest, therefore, to make separate estimates of the degree of atherosclerotic changes in these groups. It was found that those diabetic patients who died from diabetic coma or infection exhibited more pronounced changes than normal subjects but less pronounced than those who died of atherosclerosis, whether combined with diabetes or without it. However, no statistically significant differences were found in degree of atherosclerotic changes in patients who died of various manifestations of atherosclerosis, either with diabetes of without it. Yet, with diabetes atherosclerotic changes were more pronounced. The study of the inci,dence of stenosis in 3 main coronary arteries (only constrictions of more than 50 % of the lumen was taken into consideration) demonstrated that in diabetic patients aged between 50 and 79 who died of various atherosclerotic manifestations, stenosis occurred in 4 1 . 1 % of males and 37.9 % of females. In atherosclerosis without diabetes, the respective figures were 42.3 and 39.5 %. Therefore there was no difference in the incidence of coronary stenosis in males and females. In these age groups, the duration of diabetes in the dead patients was often within the limits of 3-6 years.
Hypertensive disease and symptomatic hypertension The authors have conducted a comparative study of the degree of atherosclerotic changes in the aorta and coronary vessels in male and female patients who died of hypertensive disease or of complications caused by atherosclerosis without hypertension (myocardial infarction, cerebral haemorrhage, etc.) as well as in patients with kidney diseases with symptomatic hypertension, primarily associated with glomerulonephritis or pyelonephritis. The vessels of clinically normal individuals who died accidentally were used as controls. We defined the intensity of atherosclerosis by the sum of fibrous plaques, complicated lesions and calcified lesions, because the relationship between lipoid streaks and atherosclerosis is unresolved. In both males and females aged between 20 and 29, atherosclerosis of the aorta and coronary vessels in the presence of renal hypertension was much more pronounced than in the control group (Figs. 1-4). We had no opportunity to compare atherosclerosis in patients aged 20-29 with and without essential hypertension with other groups because of the small number of deaths occurring in this age group. In the 30-39-year-old group atherosclerotic changes of the aorta and coronary arteries in males with elevated blood pressure of various etiologies were greater not only than those in normal subjects, but also than in those individuals who died of atherosclerotic complications without hypertension. j. Atheroscler. Res., 1969, 9:179-192
186
A, M. V l t t E R T , V. S, Z H D A N O u
E, E, M A T O V A
Differences in the degree of atherosclerosis between patients with hypertension and those who died of atherosclerotic complications without hypertension were statistically significant. Comparison of the degree of atherosclerosis in the aorta and coronary artery, especially in its right branch, in male patients aged 30 39 and having symptomatic hypertension showed that atherosclerosis was more intensive in symptomatic hypertension than in essential hypertension. Females aged between 30 and 39 and having symptomatic or essential hypertension showed a marked prevalence to atherosclerosis of the aorta and coronary arteries, as compared to the control group. Because of tl~e sinai1 number of femaIes of this age group who died from atherosclerosis without hypertension, we were unable to compare the degree of the atherosclerosis found with and without symptomatic and essential hypertension. In the 40-49- and 50.59-year-old groups, atherosclerosis of the aorta both in males and females was more intensive in the presence of hypertension, irrespective of its etiology. Over the age of 40, however, differences in the degree of coronary atherosclerosis disappeared, so that the anterior descending branch of the left coronary artery in dead males and females was equally affected both in e3sential or symptomatic hypertension and in atherosclerosis without hypertension As to the differences in the degree of atherosclerosis in hypertension of different etiologies, these were found to be smoothed out after the age of 40, wl~ile in individuals with essentia[ hypertension aged over 50, atherosclerosis of the aorta and coronary arteries tended to predominate. After the age of 60 the tendency to more extensive atherosclerosis was noted in those who had suffered from hypertensive disease than in those who died of atherosclerosis either in the aorta or coronary arteries and without hypertension. The differences in atherosclerosis of the aorta in males and females with symptomatic or essential hypertension were not statistically significant, but coronary atherosclerosis predominated in cases of essential hypertension. Malignant tumours According to our observations among men affected with malignant tumours, the area of atheroselerotic changes in the aorta was somewhat greater than in the control groups except for the age group of 30-39. This was largely due to the prevalence of fibrous plaques. These differences, however, were not statistically significant. Complicated lesions in the abdominal aorta in the age groups 60-69 and 70-79 years were more widespread than m the control groups. Lipoid spots and calcified areas ill those who died of malignant tumours were of the same dimensions as in the male control groups. In the coronary arteries the extent of atherosclerotic changes in the presence of malignant tumours differed very little from the control groups (only in the age group of 70-79). These changes were not very widespread, primarily because of the smaller area of calcium deposits. in women wire died of malignant tumours, the total ~rea of atheroscierotic J, Atheroscler. Res., 1969, 9:179-192
A T H E R O S C L E R O S I S IN A O R T A A N D C O R O N A R Y V E S S E L S IN V A R I O U S D I S E A S E S
187
changes in the aorta was close to that in the corresponding control group. The authors observed a tendency towards an increase in the area of fibrous plaques in those who died of tumours. These differences, however, were not statistically significant and were less pronounced than in men. Lipoidosis in the thoracic aorta was more pronounced and in the abdominal aorta less pronounced than in the control groups. Complicated lesions, and calcinocis in particular, were less prevalent in the age groups 60-69 and 70-79 years than in the control groups. In the coronary arteries of the heart in women who died of tumours, atherosclerotic changes were rather less widely distributed, chiefly because of the smaller area taken up by fibrous plaques and deposits of calcium salts. The distinctions were most pronounced between 70 and 79 years of age. The authors separately analysed atherosclerotic changes (a) in cases of cancer of the stomach and the lungs in men; (b) in cases of cancer of the stomach, the genitals and the m a m m a r y gland in women. I t turned out that in men who died of cancer of the lung, atherosclerotic changes were much more widespread than in those who died of cancer of the stomach. In cases of cancer of the lung, we often observed stenosis of the coronary arteries (i.e. cases in which the arterial orifice was constricted by more than 50 %). Between the ages of 50 and 59, for instance, such strictures in all the main branches of the coronary arteries in cases of cancer of the lung were found in 23.1 4- 8.3 % of the observations and between the ages of 60 and 69, in 29.0 48.2 %. In cases of cancer of the stomach the figures were 0 and 16.1 4- 6.6 ~o respectively. The authors did not observe any constantly significant differences in the extent of atherosclerostic changes in women who died of cancer of the stomach and in those who died of cancer of the genitals and the m a m m a r y gland. DISCUSSION
Biometrical research into atherosclerotic changes makes it possible to obtain objective criteria for the manifestation of atherosclerosis of the various blood vessels in people of the same age affected with various diseases. Reports in the literature on the influence of various ailments on the development of atherosclerosis are very contradictory. For instance, the fact that atherosclerosis in often associated with diabetes and disorders of lipoid metabolism in diabetes has enabled most researchers to speak of the growing influence of diabetes on the development of atherosclerosis 1,5,20,23,27,29. This conclusion has been further confirmed b y observations of a higher incidence of coronary lesions, especially of myocardial infarction, in diabetes mellitus4,12, 46. Some authors are of the opinion, however, that diabetes does not accelerate the development of atherosclerosis3,9A1,32, 33,a2,56. They point out that not infrequently there is no relation between the duration and severeness of diabetes and the manifestation of atherosclerosis, and that very often (especially in aged people) diabetes develops in the presence of already pronounced atherosclerosis. Our observations regarding atherosclerosis in the presence of diabetes in young
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people show that t o d a y diabetes does not always lead to accelerated atherosclerotic changes. For instance, among people between the ages of 10 and 49 we made 38 detailed observations, and in only 16 cases were atherosclerotic changes more widespread (usually in only one or two vessels) than in the group of "healthy" people. The area of fibrous plaques was larger than in the control group in only 12 cases (in the other 4 cases, only the distribution of lipoid spots was different). I t should be mentioned that the duration of diabetes in these 12 cases was greater t h a n in all the other diabetic patients of this age group. This points to the definite rote which the duration of diabetes plays in the development of atherosclerosis. However, among our observations made in the age group of 10-19 years, there were individual cases of diabetes lasting up to 13 years, which were attended, with an insignificant amount of atherosclerosis. Of course, the development of atherosclerotic changes depends not only on the duration of diabetes, but also on its severity, as well as on the effectiveness of treatment and individual predisposition to atherosclerosis. In diabetics above the age of 50, atherosclerotic changes were present to the same extent as in people who had died of various manifestations of atherosclerosis unattended with diabetes. This explains why over two-thirds of the people with diabetes die of atherosclerotic complications. W h a t is the relationship between atherosclerosis and diabetes in aged people ? Our data indicate that very often these two ailments go together. I t seems to us t h a t atherosclerotic changes predispose the body to diabetes (this is attested to b y the higher frequency of diabetes among people over the age of 50). I t is, however, difficult to say that diabetes, in its turn, does not have an accelerating effect on the development of atherosclerosis. Some other authors have also pointed to atherosclerosis as the predisposing factor in the development of diabetes. REINER et al. 62 reported that severe atherosclerosis in mesenteric arteries was associated with an exceptionally high frequency of diabetes. BUTKI~S59 found that atherosclerosis of the arteria lienalis was accompavied b y considerable pathological changes in the islands of the pancreas. These changes depended on the degree of atherosclerosis in the artery. The author also pointed out t h a t the atherosclerotic changes in the arteria lienalis have appeared after 40 years of age, and later on they progressed very quickly. BUTKUSs9 comes to the conclusion t h a t in old age diabetes might be connected with the changes in the vessel. The effect of hypertensive diseases on atherosclerosis has been studied b y RAU aT, DAVIS AND KLAINER 6, SIGLER 40, MIASNIKOV 28, DIMOND 7, EVANS 10, MASTER 25, MITCHELL et al. 31, MITCHELL AND SCHWARTZ30, SCHWARTZ et al. 39, PATERSON e~ al. 36, and ROBERTSON3s among others. I t is generally recognized that hypertensive disease is usually combined with severe atherosclerosis. This belief is based chiefly on clinical data on the incidence of atherosclerotic complications in hypertensive disease, rather than on morphological findings which would seem to give a more objective picture of the degree of atherosclerotic changes ill the vessels. Biochemical data, too14, do not alwaysreflect the severity of ather osclerosis. J. Atheroscler. Res., 1969, 9:179-192
ATHEROSCLEROSIS IN AORTA AND CORONARY VESSELS IN VARIOUS DISEASES
f89
Experimental data on the effect of hypertension on the development of atherosclerosis16,~,~6,53, ss cannot be unconditionally applied to human pathology. The influence on atherosclerosis of hypertensions of various etiologies is still not quite clear, particularly that of renal hypertension, although it is of great importance for understanding the of relationship between atherosclerosis and hypertension. Our results have demonstrated that elevated blood pressure contributes to a more intensive development of atherosclerotic vascular changes. This becomes especially clear in comparison with normal individuals. In hypertensive individuals atherosclerotic changes in the aorta and coronary vessels were invariably more severe than in normal persons, these differences being statistically significant. Atherosclerotic changes were also found to be greater in symptomatic and essential hypertensive cases than in patients who died of various atherosclerotic complications but had not suffered from hypertension. These changes were especially marked and frequent in the aorta, and less regularly, in the coronary vessels. Comparison of the degree of atherosclerosis in people with hypertensive diseases and symptomatic hypertension has demonstrated that in a younger age group (30-39), atherosclerosis of both the aorta and coronary vessels was more pronounced in symptomatic hypertension. After the age of 40, the intensity of atherosclerosis in these two groups showed no significant difference. This fact seems to be of interest, since the cause of death in renal hypertension accompanied b y an intensive coronary sclerosis was not coronary insufficiency, but uremia, while in essential hypertension, most of the patients died of coronary insufficiency and myocardial infarction. Therefore, clinical manifestations of atherosclerosis, particularly that of the coronary vessels, do not always match the severity of the morphological changes in the vascular wall. Thus, the accelerating effect of hypertension on the development of atherosclerotic vascular changes in man is observed in hypertensions of various etiologies. An important factor in the occurrence of atherosclerotic changes is the degree and duration of hypertension. In our opinion, this accounts for a greater degree of atherosclerosis in younger individuals having symptomatic hypertension. Cancer and atherosclerosis are now the main causes of death. Therefore the combination of these two diseases is usual, particularly in aged people. I t has been established, however, that in the presence of cancer, severe forms of atherosclerosis are rarely observedl,18,19. Some authors studying the relationship between atherosclerosis and cancer have noted a definite antagonism between predisposition to cancer and predisposition to atherosclerosis8,47, sl. Other authors indicate that in the presence of new malignant growths, atherosclerotic changes m a y be subject to reversion 24. According to our data, atherosclerosis accompanied b y malignant tumours differs little in its manifestation from the changes observed in the control groups of clinically healthy people. There was some tendency towards an increase in the area of fibrous plaques in the aorta and towards a decrease in the area taken up b y j . Atheroscler. Res., 1969, 9:179-192
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complicated lesions a n d deposits of calcium salts in those who died of m a l i g n a n t tumours. Similar d a t a were o b t a i n e d b y PARRISH35, who compared cancer patients, not with p a t i e n t s d y i n g of various causes, b u t only with accidental deaths. PARRISH'S d a t a were p a r t i a l l y confirmed b y GIERTSEN 13, who detected certain differences between cancer p a t i e n t s a n d all p a t i e n t s who died of other diseases. However, if one excluded the i n d i v i d u a l s with h y p e r t e n s i o n a n d atherosclerotic lesions of the heart, the differences b e t w e e n the group with m a l i g n a n t t u m o u r s a n d the control group were n o t so striking, a n d there were no differences in the cerebral arteries. These d a t a indicate t h a t in m a l i g n a n t t u m o u r s , atherosclerotic changes in the vessels are similar in e x t e n t to those observed in the n o r m a l subject. These findings do n o t s u p p o r t the claim t h a t m a l i g n a n t t u m o u r s retard the d e v e l o p m e n t of atherosclerosis. The expression of atherosclerotic changes in males was definitely related to the location of the cancer. Subjects with lung cancer h a d more atherosclerosis t h a n subiects with cancer of the stomach a n d t h a n " h e a l t h y " people. This has also been p o i n t e d out b y other investigatorsSS, 6~ The reasons for the occurrence of more severe atherosclerosis in l u n g cancer still are n o t quite clear. P r o b a b l y one of the reasons is s m o k i n g (among the subjects with l u n g cancer, the n u m b e r of people smoking a great deal a n d for a long time is more t h a n a m o n g the other subjects). Some authors have p o i n t e d out a connection between s m o k i n g a n d the d e v e l o p m e n t of atherosclerosis61, G3. A significant dependence of the expression of atherosclerotic changes on the site of the cancer was n o t observed in females.
REFERENCES
1 ANITSCHKOW, N., Pathologische Anatomie und allgemeine Pathologie der Arteriosklerose,
C. R. 2~me Conf. int. Path. gdogr., Utrecht, 1934. AVTANDILOV, G. G., Dynamics of Pathological Changes and the Pathogenesis of Atherosclerosis
of the Aorta and Coronary Arteries of Man's Heart, Annotation of a thesis for a Doctor's degree, Moscow, 1965 (in Russian). 3 BOAS, E. P., Arteriosclerosis and diabetes, J. M t Sinai Hosp., 1952, 19: 411. 4 CLAWSON, B. J. AND E. T. BELL, Incidence of fatal coronary disease in nondiabetic and diabetic persons, Arch. Path., 1949, 48: 105. 5 CZERKAWSKI, J. W . , Diabetes and vascular degeneration. In: D. A. HALL (Ed.), International Review of Connective Tissue Research, Academic Press, New York, London, 1963, p. 307. 6 DAVIS, O. AND M. J. KLAINER, Studies in hypertensive heart disease, Part 1 (The incidence of coronary atherosclerosis in cases of essential hypertension), Amer. Heart. J., 1940, 19: 185. 7 DIMOND, G. E., Hypertension, body weight and coronary heart disease, Arch. intern. Med. (Chic.), 1963, 112: 550. 8 DORMANNS, E. AND E. EMMINGER, Vergeleichende Untersuchungen fiber Ausbreitung und St~rke der Atherosklerose an 100O Leichen yon fiber 20 Jahre alten Personen mit besonderer Berficksichtigung yon Krebs, Tuberkulose und Lues, Virchows Arch. path. A nat., 1936,293: 545. 9 DOWNIE, E. AND F. J. R. MARTIN, Vascular disease in juvenile diabetic patients of long duration, Diabetes, 1959, 8: 383. 10 EVANS, P. H . , Relation of longstanding blood-pressure levels to atherosclerosis, Lancet, 1965, i: 516. 11 FABER, M. AND F. LUND, The human aorta, Part 4 (The aorta in diabetes mellitus), Arch. Path., 1951, 52: 239. 12 FELDMAN, M. AND M. FELDMAN, JR., The association of coronary occlusion and infarction in diabetes mellitus, Amer. J. reed. Sci., 1954, 228: 53. 1~ GIERTSEN, J. C., Atherosclerosis in an autopsy series, Part 8 (Relation of malignant disease to atherosclerosis), Acta path. microbiol, scand., 1966, 66: 341. f . Atheroscler. Res., 19e9, 9:179-192
ATHEROSCLEROSIS IN AORTA AND CORONARY VESSELS IN VARIOUS DISEASES
191
14 GIERTSEN, J. C., Atherosclerosis in an a u t o p s y series, P a r t 10 (Relation of nutritional state to atheroselerosis), P a r t 11 (General s u m m a r y and conclusion), Acta path. microbiol, scan&, 1966, 67: 305. 15 GORE, I., T. NAKASHIMA, T. IMAI AND P. D. WHITE, Coronary atherosclerosis and myocardial infarction in K y u s h u , J a p a n , and Boston, Massachusetts, Amer. J. Cardiol., 1962, 10: 400. 16 HEPTINSTALL, R. H., H. BARKLEY AND K. A. PORTER, The relative roles of blood cholesterol level and blood pressure level in the production of experimental aortic a t h e r o m a in rabbits, Angiology, 1958, 9: 84. 17 HOLMAN, R. L., H. C. McGILL, JR., J. P. STRONG AND J. C. GEER, Technics for s t u d y i n g atherosclerotic lesions, Lab. Invest., 1958, 7: 42. 18 JUHL, S., Cancer and atheroselerosis: Negative correlation, Acta path. microbiol, scan&, 1955, 37: 167. 19 JIJHL, S., Cancer a n d atherosclerosis, P a r t 2 (Applicability of p o s t m o r t e m statistics in the s t u d y of the negative correlation), Acta path. microbiol, scan&, 1957, 41: 99. 20 JOSLIN, E. P., H. F. ROOT, P. WHITE AND A. MARBLE, Treatment of Diabetes Mellitus, Lea and Febiger, Philadelphia, t959, p. 407. 2i KAGAN, A. AND K. UEMURA, Grading atherosclerosis in aorta and coronary arteries obtained at autopsy. W H O trials of macroscopic methods, Bull. Wld Hlth Org., 1962, 27: 667. 22 KASATKINA, L. V., N. M. POZDUNINA AND V. V. SUCHKOV, Some indices of mucopolysaecharide metabolism in experimental cerebro-ischemic hypertension, Cardiology, 1968, 4:40 (in Russian). 23 KRAMER, D. W. AND P. I{. PERILSTEIN, Arteriosclerosis-atherosclerosis in relation to diabetes. In: S. S. SAMUELS (Ed.), Diagnosis and Treatment of Vascular Disorders, Williams and Wilkins, 24 KREMNEV, T. N., Atherosclerosis in e x h a u s t i n g diseases. In: G. E. OSTROVERCHOV AND H. N. LEVITHAN (Eds.), Problems of the Clinical Fund and Pathology of the Cardiovascular System, Regional Publishers, Kursk, 1951, p. 30 (in Russian). 25 MASTER, A. M., Hypertension and coronary occlusion, Circulation, 1953, 8: 170. 26 MCGILL, JR., H. C., M. H. FRANK AND J. C. GEER, Aortic lesions in hypertensive monkeys, Arch. Path., 1961, 71: 96. 27 MIASNIKOV, A. L., Atherosclerosis, Medical Publishers, Moscow, 1960, p. 76 (in Russian). 28 MIASNIKOV, A. L., Hypertensive Disease and Atherosclerosis, Medicine, Moscow, 1965, p. 343 (in Russian). 29 MIASNIKOV, L. A. AND 1. S. I~LIMASH]~V, Atherosclerosis and diabetes mellitus, Soviet Med. 1965, 2 : 1 0 (in Russian). a0 MITCHELL, J. R. A. AND C. J. SCHWARTZ, Arterial Disease, Davis, Philadelphia, 1965, p. 411. 31 MITCHELL, J. R. A., C. J. SCHWARTZ AND A. ZINGER, Relationship between aortic plaques and age, sex, and blood pressure, Brit. reed. J., 1964, i: 205. 32 MOSCHKOWITZ, E. Z., The relation of hyperplastic arteriosclerosis to diabetes mellitus, Ann. intern. Med., 1951, 34: 1137. 33 MOSCHKOWlTZ,E. Z . , Diabetes mellitus and atherosclerosis, Clin. Med., 1958, 36:76 (in Russian). 34 MURTHY, M. S. N., ]3. N. DUTTA AND xf. RAMALINGASWAMI, Coronary atherosclerosis in North India, J. Path. Bact., 1963, 85: 93. 35 PARRISH, H. M., Epidemiology of ischemic heart disease a m o n g white males, P a r t 1 (Relationship between coronary atheroselerosis and cancer of various sites), J. chron. Dis., 1961, 14:311. 36 PATERSON, J. C., J. MILLS AND C. H. LOCKWOOD, The role of hypertension in the progression of atherosclerosis, Canad. reed. Ass. J., 1960, 82: 65. 37 RAU, H., Zur B e d e u t u n g der chronischen BlutdruckerhGhung fiir die E n t s t e h u n g der Arteriosklerose, Klin. Wchschr., 1956, 1: 167. 38 ROBERTSON, W. ]~., Some factors influencing the development of atherosclerosis. A survey in Jamaica, W e s t Indies, J. Atheroscler. Res., 1962, 2: 79. 39 SCHWARTZ, C. J., N. S. STENHOUSE, A. I~. TAYLOR AND T. A. WHITE, Coronary disease severity at necropsy, Brit. Heart J., 1965, 27: 731. 40 SIGLER, L. H., The role of hypertension in the etiology and prognosis of coronary occlusion, Ann. intern. Med., 1955, 42: 369. 41 SPAIN, D. M., D. J. NATHAN AND M. GELLIS, Weight, body type and the prevalence of coronary atherosclerotic h e a r t disease in males, Amer. J. reed. Sci., 1963, 245: 63. 42 STAMLER, J., Interrelationships between the two diseases, hypertension and atherosclerosis, Amer. J. Cardiol., 1962, 9: 743. 43 STERNBY, N. H., Atherosclerosis in a defined population. Acta. path. microbiol, scan&, Suppl. 194: 7. 45 STERNBY, N., R. VANI~CEK, A, VIHERT, A. KAGAN and K. UEMURA, Correlation of t y p e and extent of atherosclerosis in aorta and coronary arteries obtained at autopsy, Bull. Wld Hlth Org., 1965, 33: 741. 45 STRONG, J. P. AND H. C. McGILL JR., T h e n a t u r a l history of aortic atberosclerosis: Relations h i p to race, sex, and coronary lesions in New Orleans, Exp. molec. Path., 1963, Suppl. 1: 15.
j . Atheroscler. Res., 1969, 9 : 1 7 9 - 1 9 2
192
A . M . VIHERT, V. S. ZHDANOV, E. E. MATOVA
46 THOMAS, W. A., KYU TAIK LEE AND E. R. RABIN, F a t a l a c u t e m y o c a r d i a l infarction in d i a b e t e s p a t i e n t s , Arch. intern. Med. (Chic.), 1956, 98: 489. 47 TICHY, J., H. GVABOVE-TICHE AND V. MALY, R a k o v i n a ve v z t a h u k c h o r o b a m s p o r u s e n o u v # m ~ n o u cholesterolu, Gas. Lek. ~es., 1953, 92: 1005. 4s TOBIAN, L., H y p e r t e n s i o n a n d atherosclerosis, Minn. Med., 1955, 38: 784. 49 UEMURA, •., ~%~.STERNBY, R. VANI~CEK, A. VIHERT AND A. KAGAN, G r a d i n g atherosclerosis in a o r t a a n d c o r o n a r y arteries o b t a i n e d a t a u t o p s y . A p p l i c a t i o n of a t e s t e d m e t h o d , Bull. Wld Hlth Org., 1964, 31: 297. 50 VIHERT, A. M., V. S. ZHDANOV, E. ]~. MATOVA AND V. V. ALPATOV, A c o m p a r a t i v e c h a r a c t e r istics of atherosclerotic affections in s t a i n e d a n d n o n s t a i n e d vessels, Path. Arch., 1966, 8 : 3 1 (in R u s s i a n ) . 51 WANSCHER, O., J. CLEMI~SSEN AND H. NIELSEN, N e g a t i v e correlation b e t w e e n atherosclerosis a n d c a r c i n o m a , Brit. J. Cancer, 1951, 5: 172. 52 "WILDER, R. M., Clinical Diabetes MeUitus and Hyperinsulism, S a u n d e r s , P h i l a d e l p h i a , 1940, p. 327. 53 "WILENSS, L., T h e e x p e r i m e n t a l p r o d u c t i o n of lipid deposition in excised arteries, Science, 1951, 114: 389. 54 "~VILKINS, R. H . , J. C. ROBERTS JR. AND C. MOSES, A u t o p s y s t u d i e s in atherosclerosis, P a r t 3 ( D i s t r i b u t i o n a n d s e v e r i t y of atherosclerosis in t h e presence of obesity, h y p e r t e n s i o n , n e p h r o sclerosis a n d r h e u m a t i c h e a r t disease), Circualtion, 1959, 20: 527. 55 WlSSLER, R. W., M. L. EILERT, M. A. SCHROEDER AND L. COHEN, P r o d u c t i o n of l i p o m a t o u s a n d a t h e r o m a t o u s arterial lesions in t h e a l b i n o - r a t , Arch. Path., 1954, 57: 333. 56 YONASH, V. AND L. KOZAK, V a s c u l a r c h a n g e s in d i a b e t e s p a t i e n t s , Czech. reed. Rev., 1963 9: 173. 57 YOUNG, "VV., J. W. GOFMAN, R. TANDY, N. MALAMUD AND E. S. O. WATERS, T h e q u a n t i t a t i o n of atherosclerosis, P a r t 2 ( Q u a n t i t a t i v e a s p e c t s of t h e r e l a t i o n s h i p of blood p r e s s u r e a n d a t h e r o sclerosis), Amer. J. Cardiol., 1960, 6: 294. 58 BURKHARDT, L., 13ber B e z i e h u n g e n z w i s c h e n B r o n c h u s C a r c i n o m u n d Atherosclerose, Med. Klin., 1959, 5 4 : 1 6 1 3 (No. 36). 59 BUTEUS, R., Functional Morphology of Islands of Pancreas in Atherosclerosis, Thesis, U n i v e r sity of K a u n a s , 1967. 60 CREED, D. L., W. F. ]~AIRD AND E. R. FISSCHER, T h e s e v e r i t y of aortic atherosclerosis in certain diseases: a n e c r o p s y s t u d y , Amer. J. reed. Sci., 1955, 385: 230. 61 IiERSHBAUM, A. AND S. BELLET, Cigarette s m o k i n g a n d blood lipids, J. Amer. reed. Ass., 1964, 187: 32. 62 REINER, L., F. A. JIMENEZ AND F. L. RODRIGUES, Atherosclerosis in t h e m e s e n t e r i c circulation, Amer. Heart J., 1963, 200: 66. s3 SEBRELL, W . H. JR., An over-all look a t atherosclerosis, J. Amer. Diet Ass., 1962, 40: 403.
j . Atheroscler. Res., 1969, 9 : 1 7 9 - 1 9 2