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Cerebral atherosclerosis in selected chronic disease states
Atherosclerosis. 18 (1973) 321-336 0 Elsevier Scientific Publishing Company, Amsterdam
CEREBRAL STATES
ATHEROSCLEROSIS
A. C. KLASSEN,
R. B. LOEWENSON
IN
AND
321 - Printed in The Netherlands
SELECTED
CHRONIC
DISEASE
J. A. RESCH
Department of Neurology, Universityof’Minnesora (U.S.A.)
Health Sciences Center, Minneapolis, Minn. 55455
(Revised, received November 7th, 1972)
SUMMARY
The severity of atherosclerotic involvement of the intracranial cerebral arteries was assessed at autopsy in 3942 adult subjects. The values obtained in groups of subjects at various ages were correlated with the presence or absence of selected chronic disease states. The presence of clinical or pathological evidence of cerebral vascular disease, atherosclerotic heart disease, diabetes mellitus, and, to a lesser degree, chronic renal disease was associated with a relative increase in the severity of cerebral atherosclerosis. In contrast, cerebral atherosclerosis was apparently less severe in groups of subjects with malignant neoplastic disease and peptic ulcer disease. In males with cirrhosis or alcoholism, atherosclerosis.
there was a possible
Atherosclerotic
Key words:
tendency
toward
heart disease - Cancer - Cerebral
less severe cerebral
atherosclerosis
ebral vascular disease - Chronic disease - Chronic pulmonary Chronic renal disease - Diabetes mellitus - Malignant
- Cer-
disease -
neoplastic disease -
Peptic ulcer disease
_ INTRODUCTION
Atherosclerosis of cerebral arteries is probably the most important etiological factor in the development of ischemic cerebral vascular disease. The development of atheromatous lesions in these vessels is presumably determined by factors identical or closely related to those causing similar changes in other arterial systems. In recent
Supported
by NINDS Grant No. NS-03364.
322 decades,
A. C. KLASSEN,
certain
conditions,
notably
elevated
blood
R. B. LOEWENSON,
pressure,
diabetes
.I. A. RESCH
mellitus,
and
conditions associated with elevated levels of serum cholesterol and other serum lipids have been implicated as etiological factors associated with the increased prevalence and severity of atherosclerotic disease. In contrast, other chronic diseases, especially malignancies, have been thought to be associated with a relatively lower degree of atherosclerosis. This paper will examine the extent and severity of cerebral atherosclerosis in subjects with selected chronic disease states as found in an autopsy population. METHODOLOGY
The intracranial cerebral arteries utilized in this study were obtained during consecutive routine autopsies at the University of Minnesota Hospitals and the Hennepin County General Hospital during the years 1961-1965. The semiquantitative scoring method for assessing the severity of atherosclerotic involvement has been previously described and validated 1,s. In essence, the method assigns a numerical grade of O-4, related to the degree of luminal encroachment by an atherosclerotic lesion, to each of 22 sites in the circle of Willis and its major branches. The sum of the grades for all 22 sites is then utilized as the numerical score for each subject. Cerebral arteries were obtained from 5032 autopsy subjects. For this study, however, only subjects over 19 years of age were considered (n = 3942). Information regarding the presence or absence of specific chronic disease states was obtained by review of the clinical records and autopsy reports of all subjects. For data analysis, cumulative percentage distributions of the vessel scores were computed for each sex and IO-year age group. From these distributions the 25th, 50th (median) and 75th percentiles were determined. These percentile points were plotted at the midpoints of the lo-year age intervals. The curves connecting equal percentile points indicate graphically the extent and severity of cerebral atherosclerosis in each chronic disease state. Subgroups with sample sizes of less than 10 subjects were omitted from the analysis. Percentiles, rather than mean scores and standard deviations, were used to describe the distributions of the vessel scores. The distributions of the scores are markedly skewed in the younger age groups, with high relative frequencies of zero and very low-value scores, and only a few elevated scores. Consequently, the means are larger than the medians in these age groups, and the standard deviations are poor estimates of variability in skewed distributions. The percentile distributions of the vessel scores for the total sample, by age and sex, including the 5th and 95th percentiles, have been presented previouslyrJ. In the present report the sample sizes in the various disease categories, by decade of age and sex, are small in most instances. For this reason the 5th and 95th percentiles are statistically unreliable and are consequently omitted. For each chronic disease state, the vessel scores of subjects with the diagnosis of the disease were compared with scores of the remaining cases. Furthermore, these comparisons were repeated after all cases with a clinical diagnosis of hypertension
CEREBRALATHEROSCLEROSIS IN SELECTEDCHRONIC DISEASESTATES
323
TABLE 1 NUMBERS
OF SUBJECTS
Age (years)
Males
2(r29 3&39 4Wl9 50-59 60-69 70-79 80 and above Total
BY AGE AND SEX
Females
Total __-
174 180 315 525 538 497 186
86 143 281 321 334 256 106
260 323 596 846 872 753 292
2415
1527
3942
TABLE 2 NUMBERS
OF SUBJECTS
BY CHRONIC
Hypertension Cerebral vascular disease Atherosclerotic heart disease Diabetes mellitus Chronic renal disease Malignant neoplastic disease Peptic ulcer disease Alcoholism Hepatic cirrhosis Chronic pulmonary disease
DISEASE
STATES
Male
Female
Total
363 389 1184 127 367 678 274 237 157 547
292 223 522 129 217 628 107 75 84 211
655 612 1706 256 584 1306 381 312 241 758
Male
Female
Total
103 460 563 350 853 86
70 143 569 145 548 52
173 603 1132 495 1401 138
TABLE 3 MAJOR
CAUSES
OF DEATH
Cerebral vascular disease Atherosclerotic heart disease Malignant neoplastic disease Trauma and suicide Other Unknown
were excluded. For the analysis relative to malignant neoplastic disease, cases with atherosclerotic heart disease, cerebral vascular disease and diabetes mellitus were also excluded. The age and sex distributions of the autopsy population are listed in Table 1. The numbers of subjects in whom each of the chronic disease states was diagnosed
324
A. C. KLASSEN,
R. B. LOEWENSON,
J. A. RESCH
are indicated in Table 2. Major causes of death and numbers of subjects in each of these categories are listed in Table 3. RESULTS
In Fig. 1 are plotted the average cerebral arterial scores (medians) as related to the major cause of death categories. In males, highest scores (most severe cerebral atherosclerosis) were present in subjects in whom death was attributed to cerebral vascular disease. Lowest scores (least severe cerebral atherosclerosis) in males were present in subjects dying of malignant neoplastic disease. In females, highest scores were present when death was due to cerebral vascular disease or atherosclerotic heart disease. No apparent differences in scores were noted among female subjects in other major cause of death categories. Cerebral vascular disease
In both males and females, the presence of cerebral vascular disease was associated with considerably higher scores (Fig. 2). Exclusion of hypertensive subjects did Medians
at Given Age
50 - Males
50 - Females
30
40
50
60
70
80
90
Age in Years
Fig. 1. Median cerebral arterial atherosclerosis of death.
scores in subjects grouped according to major causes
325
CEREBRAL ATHEROSCLEROSIS.IN SELECTED CHRONIC DISEASE STATES
50
c
Percentiles
at Given Age
Ma/es
251h Percentdes
30
40
50
,T-
b” 40
30
I ’
20
90
i75’h /“f ,/’ j’
-/
1
32th
/
IO
31
80
P
females
50
o
70
60
1 Agk
in
Years
Fig. 2. Percentile plots at IO-year intervals of cerebral atherosclerosis without (0) cerebral vascular disease (CVD).
Medians
at Given Age
Moles 50
(Y
40
oB ___ .-
___
scores for groups with (0) and
50 - Feinafes
Cerebral Vascular Dtseare --___ C”D present CVD obsen,
} AlICOSTS
CVD presenf CVD absen,
1Hyperlenswes
excluded
I 60
70 Age
80
90
in Years
Fig. 3. Median vessel scores (50th percentiles) for subjects with and without cerebral vascular disease (0) and with hypertensive subjects excluded (0).
326
A. C.
KLASSEN,
R. B. LOEWENSON,
J. A. RESCH
appreciably alter this relationship (Fig. 3). In males the average vessel scores for the nonhypertensive subjects were consistently lower than those for all cases. The reduction in average scores obtained by exclusion of hypertensive subjects was greater for the cerebral vascular disease cases than for the non-cerebral vascular cases. However, the non-hypertensive cerebral vascular disease group still showed a considerable excess of cerebral atherosclerosis over the corresponding non-cerebral vascular disease cases. In females, exclusion of hypertensive subjects lowered the median curve for the cerebral vascular disease cases in the age groups below 80 years, particularly in the age interval 60-69. Excessively high scores were noted in males age 40-49. In this group, 11 of 15 subjects died due to either atherosclerotic heart disease or cerebral vascular disease and 8 subjects were also clinically hypertensive. not
Atherosclerotic
heart disease
The presence of atherosclerotic heart disease was similarly associated with more marked cerebral atherosclerosis in both sexes (Fig. 4). The differences in atherosclerosis scores between cases with and without atherosclerotic heart disease were slightly
50
Moles
Percentiles
at Given Age
t
30
w-50-60
70
00
90
Age in Years
Fig. 4. Percentile plots at lo-year intervals of vessel scores for groups with (0) and without (0) atherosclerotic heart disease (ASHD).
CEREBRAL ATHEROSCLEROSIS IN SELECTED CHRONIC DISEASE STATES
Percentiles 50
-
40
_
g.
327
at Given Age
Males Diabetes
Mellitus
O,,,.
DM pesent
.=
DM absent
lx 30 6 “, $
20
50 e
40
x fn 30 1 z ’
20 IO
30
40
50 Age
60 in
70
a0
90
Years
Fig. 5. Percentile plots of vessel scores at IO-year intervals for groups with (0) diabetes mellitus (DM).
50
and without (e)
females
t .-
---
DM present DM &sent I Hypertensives
z 8
excluded
40
;
30
5 ’
20
IO
50
60 Age
70 in
80
90
Years
Fig. 6. Median vessel scores for subjects with and without diabetes mellitus (0) and with hypertensive subjects excluded (0).
328
A. C. KLASSEN,
Percentiles
30
40
50
60
R. B. LOEWENSON,
J. A. RESCH
at Given Age
70
80
90
Age in Years
Fig. 7. Percentile plots of vessel scores at lo-year intervals for groups with (0) chronic renal disease (CRD).
Medians
at Given
Age
and without (0)
50 - Females
Chronic Renal Disease
Hyperlensives ~
excluded
30
D f
20
IO
IO -
50
60 Age
70
80
90
in Years
Fig. 8. Median vessel scores for subjects with and without chronic renal disease (0) and with hypertensive subjects excluded (0).
CEREBRAL
ATHEROSCLEROSIS
reduced, but not eliminated from both groups. Diabetes mellitus Cerebral atherosclerosis
IN SELECTED
CHRONIC
at any age when
DISEASE STATES
hypertensive
329
subjects
in both sexes was more severe in diabetic
diabetic subjects in all decades (Fig. 5). Exclusion of hypertensive did not affect this association in the males where the differences
were excluded
than in non-
subjects (Fig. 6) in average vessel
scores between diabetics and non-diabetics remained approximately the same as those found for all cases. Among the diabetic females a large reduction in average vessel scores was found in the age groups 50-59 when hypertensive subjects were omitted from the analysis. Chronic renal disease Chronic renal disease of various types was associated with increased cerebral atherosclerosis in both sexes (Fig. 7). The comparison of average vessel scores between non-hypertensive subjects with and without this condition males and in the younger females the increased cerebral
revealed that in the older atherosclerosis in subjects
with chronic renal disease was primarily related to the presence of hypertension (Fig. 8). In the remaining age groups, particularly in the female age 70-79 years, subjects with chronic renal disease still showed even after hypertensive subjects were excluded.
more severe cerebral
atherosclerosis
Malignant neoplastic disease In subjects with malignant neoplastic disease of all types, cerebral atherosclerosis scores were lower than in subjects without malignant neoplastic disease (Fig. 9). Exclusion of hypertensive subjects from this analysis slightly reduced but did not eliminate this apparent association. Subsequent exclusion of subjects with atherosclerotic heart disease, cerebral vascular disease and diabetes mellitus as well as hypertension further reduced this association (Fig. IO). In males, this latter analysis continued to demonstrate a decrease in atherosclerosis scores in subjects with malignant neoplastic disease in the fifth through the eighth decades. In females, a similar association between malignant neoplastic disease and decreased cerebral atherosclerosis was seen except in the seventh decade where median scores were identical in both groups. Analysis of the data by site and type of malignancy in both sexes revealed no apparent differences in the degree of atherosclerotic involvement among subjects in these categories. Peptic ulcer disease In both sexes, the presence of clinical or pathological evidence of peptic ulcer disease tended to be associated with slightly less severe cerebral atherosclerosis in the sixth, seventh, and eighth decades (Fig. 11). Exclusion of hypertensive subjects did not appear to affect this relationship appreciably.
330
A. C. KLASSEN, R. B. LOEWENSON, J. A. RESCH
Percentiles 50
at Given Age
Males
t 40 E :! In 30 1 p 20 I IO t
Age
in Years
Fig. 9. Percentile plots of vessel scores at lo-year intervals for groups with (0) malignant neoplastic disease (MND).
40 wgnont ,,-
---
Newlostic
and without (0)
r-------l - females
Disease
MND present MND absent
011 cases HypertenSion.Cerebroi Vascular Arferimclerolic Heoft Dnseose ood Dmbefes Mellitus
Lkease.
: 30 x 5 0 20 >”
IO
ia, 110 30
40
50
60
70
80
Age in Years
30
40
50
60
70
80
Fig. 10. Median vessel scores for subjects with and without malignant neoplastic disease (O), and for subjects excluding those with hypertension, atherosclerotic heart disease, cerebral vascular disease, and diabetes mellitus (0).
CEREBRAL ATHEROSCLEROSIS IN SELECTED CHRONIC DISEASE STATES
Percentiles
30
40
50
60 Age
331
at Given Age
7C
80
90
in Yews
Fig. 11. Percentile plots of vessel scores at IO-year intervals for groups with (0) peptic ulcer disease (PUD).
and without (0)
Alcoholism and hepatic cirrhosis In male subjects with either a clinical history of excessive alcohol intake or evidence of hepatic cirrhosis, a tendency to lower average scores was noted in older age groups (age 50-70 years) but this association was not marked. Inadequate numbers of female subjects with alcoholism or cirrhosis were available for comparison. Chronic pulmonary disease In subjects of both sexes with chronic pulmonary disease no relationship to the degree of cerebral atherosclerosis could be demonstrated. However, in males age 4049 and 70-79 years, and in females age 70-79 and 80 years or over, subjects with chronic pulmonary disease tended to have higher vessel scores. Exclusion of hypertensive subjects eliminated these apparent differences between subjects with and without chronic pulmonary disease in both sexes in the older age groups, but not in males age 40-49 years. Other chronic diseases For other chronic
diseases, including
rheumatic
heart disease, pulmonary
tuber-
332
A. C. KLASSEN,
culosis, collagen disorders and various endocrinopathies, most decades were too small for analysis.
R. B. LOEWENSON,
the number
.I. A. RESCH
of subjects
in
DISCUSSION
Numerous clinical and pathological studies have clearly demonstrated the role of elevated blood pressure in the development of atherosclerotic cardiac and peripheral vascular disease. A similar relationship between hypertension and cerebral atherosclerosis has been demonstrated in a previous study utilizing the same autopsy population being considered in this report 4. Because of this definite relationship between elevated blood pressure and increased cerebral atherosclerosis, the analyses in this study were undertaken both with and exclusive of subjects with elevated blood pressure. Sexes were considered separately because of previously demonstrated differences in cerebral atherosclerosis in males and female+. The assumption that ischemic cerebral disease is etiologically related largely, if not solely, to atherosclerotic involvement of cerebral arteries is supported by relatively little data in other pathologically verified studiess. In this study, however, both clinical and pathological evidence of cerebral vascular disease was associated with a relative excess in the severity of cerebral atherosclerosis. Although this study does not yield information regarding the relative roles of atherosclerosis of the intracranial and extracranial cerebral vessels in the production of ischemic cerebral lesions, the data do lend support to the possibility of a causal relationship between the presence of intracranial cerebral atherosclerosis and the occurrence of cerebral ischemic disease. This, however, does not exclude the potential roles of other factors in the production of cerebral ischemic lesions such as atherosclerotic heart disease, hypertension or diabetes mellitus. Attempts to evaluate the relationship between cerebral vascular disease and cerebral atherosclerosis in the absence of all other disease states known to be or suspected of being associated with increased atherosclerosis (atherosclerotic heart disease, hypertension, etc.) resulted in groups too small for adequate comparisons to be made. Exclusion of subjects with elevated blood pressure, however, did not appreciably affect this relationship. Groups of subjects dying of atherosclerotic heart disease, or in whom clinical or pathological evidence of atherosclerotic heart disease was present, also showed increased severity of cerebral atherosclerosis. These findings support the assumptions that both cerebral and coronary atherosclerotic disease may share common etiological factors. No quantitative data regarding the degree of coronary atherosclerosis in this autopsy population is available, however. The important role of diabetes mellitus in the development of atherosclerosis and its complications seems clearly establishedc. Most available data on this topic are based on studies of atherosclerosis of the aorta, coronary or peripheral limb arteries or on studies of clinical atherosclerotic heart disease or peripheral vascular disease in diabetic populations. Clinical studies have reported considerable variation in the frequency of diabetes mellitus in patients with cerebral vascular disease7-9, but
CEREBRAL
ATHEROSCLEROSIS
IN SELECTED CHRONIC
DISEASE STATES
333
these differences may well be related to different populations and different diagnostic criteria. In general, diabetes mellitus appears to be more frequent, or detected more often in subjects with cerebral vascular disease than in control populations. Autopsy studies have also suggested a relative increase in the incidence of diabetes in subjects with cerebral infarction9 and an increased incidence of cerebral infarction in diabetic subjects as compared to non-diabetics 6*7. Available studies suggest that death due to cerebral vascular disease occurs in approximately 5 to 7% of diabetic subjectslo-is. However, death rates due to cerebral vascular disease may be similar in diabetic and non-diabetic groups14J5. In agreement with others16 the data in the present study strongly suggest that the presence of diabetes mellitus is associated with a relative increase in the severity of cerebral atherosclerosis. Because of the frequent association of elevated blood pressure with diabetes mellitus raJ7--19, it has been suggested that much or all of the apparent effect of diabetes mellitus on the development of atherosclerotic heart disease is related to coexistent hypertension rather than to the diabetic state1a~20. In the present study, removal of hypertensive subjects did not appreciably alter the apparent tendency for diabetic subjects to have increased cerebral atherosclerosis. It would thus appear that elevated blood pressure plays a relatively minor role with respect to the increased severity of cerebral atherosclerosis in diabetic subjects. In patients with chronic renal disease of multiple etiologies, the concomitant presence of hypertension appeared to play an etiological role in the production of increased cerebral atherosclerosis. Removal of hypertensive subjects tended to reduce differences in cerebral atherosclerosis in most age groups. This would be in essential agreement with the findings of other investigators2i. The relationship between malignant neoplastic disease of various types and the atherosclerotic process has been the subject of much discussion in recent years. Numerous pathological studies suggest that atherosclerotic disease of the aorta and coronary vessels is less severe in patients with malignant neoplastic diseasess-29. In contrast, it has also been suggested that atherosclerosis of the aorta and coronary vessels may actually be increased in certain malignant conditions, notably carcinoma of the lung24JoJs. Moreover, other studies have failed to demonstrate any relationship between atherosclerotic disease and malignant neoplastic disease31-3s. Data related to cerebral atherosclerosis and malignant neoplastic disease are limited but previous studies have not demonstrated differences in cerebral atherosclerosis in relationship to the presence or absence of malignant neoplastic diseaseasJQ5. Indeed, it has been suggested that the apparent decrease in severity of atherosclerosis of the aorta and coronary vessels associated with malignant disorders is due to incorrect data analysis in that subjects with atherosclerotic diseases should be removed from the control group prior to comparison 36. In view of the above, it is of interest that in our series the presence of malignancy or death due to malignant neoplastic disease was associated with less severe cerebral atherosclerosis, even when subjects with hypertension, atherosclerotic heart disease and diabetes mellitus were excluded. Whether or not this demonstrates a definite relationship between malignant disease and a
334
A. C. KLASSEN,
R. B. LOEWENSON,
J. A. RESCH
lessened tendency to atherosclerotic involvement of cerebral vessels still remains unclear. In comparing cerebral atherosclerosis in subjects dying of malignant neoplastic disease and those dying due to accidental trauma, males with malignant neoplastic disease still tended to demonstrate less severe cerebral atherosclerosis, but this association was not evident in females (Fig. 1). A possible association between the presence of peptic ulcer disease and diminished cerebral atherosclerosis as demonstrated in this study has not, to our knowledge, been noted previously. A study utilizing standardized death rates from peptic ulcer and from vascular lesions of the central nervous system has actually suggested a strongly positive relationship between the two diseasess7. Pathological studies of aortic and coronary atherosclerosis have not, however, demonstrated any relationship to the presence of duodenal or gastric ulcer 3s. Of additional interest is a recent report of a strong inverse relationship between peptic ulcer and blood pressuress. A number of pathological studies have suggested that atherosclerosis may be less marked in subjects with hepatic cirrhosiss4940-4s or in alcoholic subjects, with or without cirrhosis44. Other pathological studies have been unable to demonstrate such an associations4>4s. The slight tendency towards lower cerebral atherosclerosis scores noted in older males with cirrhosis or alcoholism in the present study is suggestive of such an association but does not permit any definite conclusions in this regard. CONCLUSIONS
In the autopsy population under consideration in this study, cerebral atherosclerosis appeared to be more severe in patients with clinical or pathological evidence of cerebral vascular disease, atherosclerotic heart disease and diabetes mellitus. The association in these conditions was apparently not solely due to the concomitant presence of elevated blood pressure. Where death was due to cerebral vascular disease or atherosclerotic heart disease, the degree of cerebral atherosclerosis was more pronounced in comparison to other causes of death. In the presence of chronic renal disease, cerebral atherosclerosis was also found to be increased, but a large proportion of this increase was probably related to the frequent occurrence of hypertension in this group. Cerebral atherosclerosis was apparently less severe in groups suffering from malignant neoplastic disease. This relationship appeared to be independent of the site or type of neoplastic disease, or of the presence or absence of hypertension, atherosclerotic heart disease, cerebral vascular disease and diabetes mellitus. In the presence of peptic ulcer disease and in males with hepatic cirrhosis or alcoholism, cerebral atherosclerosis tended to be relatively less severe. The severity of cerebral atherosclerosis was apparently unrelated to the presence of chronic pulmonary disease. It is to be emphasized that these associations in no way identify the role of any of the above mentioned conditions as definite etiological factors in the pathogenesis of cerebral atherosclerosis.
CEREBRAL ATHEROSCLEROSIS IN SELECTED CHRONIC DISEASE STATES
335
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Circulation, 39 (1969) 701. 5 Moossu, J., Cerebral infarction and intracranial
arterial thrombosis, Arch. Neural., 14 (1966) 119. 6 BERNS, A. W., GOLDENBERG, S., AND BLUMENTHAL, H. T., Diabetes as an etiologic factor in atherosclerosis. In: H. T. BLUMENTHAL(Ed.), Cowdry’s Arteriosclerosis, 2nd edition, Thomas, Springfield, Ill., 1967, p. 474. 7 ALEX, M., BARON, E. K., GOLDENBERG, S., ANDBLUMENTHAL,H. T., An autopsy study of cerebrovascular accident in diabetes mellitus, Circulation, 25 (1962) 663. 8 CONANT, R. G., PERKINS, J. A., AND AINLEY, A. B., Stroke morbidity, mortality and rehabilitative potential, J. Chronic Dis., 18 (1965) 387. 9 NAJENSON, T., MENDELSON, L., SELIBIANSKY, H., DON, R., AND SANDBANK, U., Diabetes and cerebrovascular accidents, Israel J. Med. Sci., 6 (1970) 598. 10 JORDAN, W. R., AND WAT~ERS, P., Spontaneous cerebral vascular accidents in diabetes, Amer.
J. Med. Sci., 186 (1933) 488. 11 POLLACK, H., DOLGER, H., AND ELL~NBERG, M., Analysis of diabetes morbidity and mortality in a general hospital, Amer. J. Med. Sci., 202 (1941) 246. 12 MILLARD, E. B., AND ROOT, H. F., Degenerative vascular lesions and diabetes mellitus, Amer. J. Digest. Dis., 15 (1948) 41. 13 WHITE, P., Natural course and prognosis of juvenile diabetes, Diabetes, 5 (1956) 455. 14 BELL, E. T., A postmortem study of vascular disease in diabetics, Arch. Puthof., 53 (1952) 444. 15 GOLDENBERG.,S., ALEX, M. AND BLUMENTHAL,H. T., Sequelae of arteriosclerosis of the aorta and coronary arteries. A statistical study of diabetes mellitus, Diabetes, 7 (1958) 98. 16 SOLBERG, A., AND MCGARRY, P. A., Cerebral atherosclerosis in persons with selected diseases, Lab. Invest., 18 (1968) 613. and hypertension in diabetes, Ann. Znterna! 17 ROOT, H. F., AND SHANKEY, T. P., Arteriosclerosis
Med., 9 (1936) 873. 18 LIEBOW, I. M., HELLERSTEIN, H. K., AND MILLER, M., Arteriosclerotic heart disease in diabetes mellitus, Amer. J. Med., 18 (1955) 438. 19 PELL, S., AND D'ALONZO, C. A., Some aspects of hypertension in diabetes mellitus, J. Amer. Med. Assoc., 202 (1967) 10. 20 ROBERTSON, W. B., AND STRONG, J. P., Atherosclerosis in persons with hypertension and diabetes mellitus, Lab. Invest., 18 (1968) 538. 21 WILKINS, R. H., ROBERTS, J. C.. AND MOSES, C., Autopsy studies in atherosclerosis, Part 3 (Distri-
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bution and severity of atherosclerosis in the presence of obesity, hypertension, nephrosclerosis, and rheumatic heart disease), Circulation, 20 (1959) 527. WANSCHER, O., CLEMMESEN,J., AND NIELSEN, A., Negative correlation between atherosclerosis and carcinoma, Brit. J. Cancer, 5 (1951) 172. LOBER, P. H., Pathogenesis of coronary sclerosis, Arch. Puthol., 55 (1953) 172. CREED, D. L., BAIRD, W. F., AND FISHER, E. R., The severity of aortic arteriosclerosis in certain diseases. A necropsy study, Amer. J. Med. Sci., 230 (1955) 385. JUHL, S., Cancer and atherosclerosis, Acta Pathol. Microbial. Stand., 37 (1955) 167. JUHL, S., Cancer and atherosclerosis, Part 2 (Applicability of postmortem statistics in the study of the negative correlation), Acta Puthol. Microbial. Scund., 41 (1957) 99. SPAIN, D. M., GREENBLATT, I. J., SNAPPER, I,,AND COHN, T., The degree of coronary and aortic atherosclerosis in necropsied cases of multiple myeloma, Amer. J. Med. Sci., 231 (1956) 165. MITCHELL, J. R. A., SCHWARTZ, C. J., AND ZINGER, A., Relationship between aortic plaques and age, sex, and blood pressure, Brit. Med. J., i (1964) 205. EAKINS, D., Atherosclerosis and malignant disease, Erit. J. Cuncer, 19 (1965) 9. PARRISH, H. M., GOLDNER, J. C., AND SILBERG, S. L., Coronary atherosclerosis and cancer in women, Arch. Internal Med., 117 (1966) 639.
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31 VIHERT, A. M., ZHDANOV,V. S., AND MATOVA, E. E., Atherosclerosis of the aorta and coronary vessels of the heart in cases of various diseases, J. Atheroscler. Res., 9 (1969) 179. 32 RESTREPO, C., MONTENEGRO,M. R., AND SOLBERG, L. A., Atherosclerosis in persons with selected diseases, Lab. Invest., 18 (1968) 552. 33 PARRISH, H. M., Epidemiology of ischemic heart disease among white males, Part 1 (Relationship between coronary atherosclerosis and cancer at various sites), J. Chronic Dis., 14 (1961) 331. 34 ROBERTSON, W. B., Some factors influencing the development of atherosclerosis: A survey in Jamaica, J. Atheroscler. Res., 2 (1962) 78. 35 GIERTSEN, J. C., Atherosclerosis in an autopsy series, Part 8 (Relation of malignant disease to Acfa Puthol. Microbial. Stand., 66 (1966) 341. atherosclerosis), 36 GROSSE, H., Arteriosklerose und Krebs, 2. Krebsforsch, 62 (1958) 519. 37 STOCKS, P., Indications of a possible association between peptic ulcer and vascular lesions of the central nervous system, Brit. J. Prevent. Social Med., 22 (1968) 206. 38 DUNGAL, N., AND B~NEDIKTSSON,T., Gastric cancer and atherosclerosis, Lancet, i (1958) 931. 39 MEDALIE, J. H., N~UFELD, H. N., GOLDBOURT, U., KAHN, H. A., RISS, E., ANDORON, D., Association between blood-pressure and peptic-ulcer incidence, Lancer, ii (1970) 1225. 40 HALL, E. M., OLSEN, A. Y., AND DAVIS, F. E., Portal cirrhosis. Clinical and pathological review of 782 cases from 16,600 necropsies, Amer. J. Puthol., 29 (1953) 993. 41 GRANT, W. C., WASSERMAN,F., RODENSKY, P. L., AND THOMSON,R. V., The incidence of myocardial infarction in portal cirrhosis, Ann. Internal Med., 51 (1959) 774. 42 HOWELL, W. L., AND MANION, W. C., The low incidence of myocardial infarction in patients with portal cirrhosis of the liver: A review of 639 cases of cirrhosis of the liver from 17,731 autopsies, Amer. Heart .Z.. 60 (1960) 341. 43 HIRST, A. E., HADLEY, G. G., AND GORE, I., The effect of chronic alcoholism and cirrhosis of the liver on atherosclerosis, Amer. J. Med. Sci., 249 (1965) 143. 44 WILENS, S. L., The relationship of chronic alcoholism to atherosclerosis, J. Amer. Med. Assoc.,
135 (1947) 1136. 45 VIEL, B., DONOSO, S., SALCEDO, D., AND ALESSANDRI, R., Alcoholism and socioeconomic hepatic damage, and arteriosclerosis, Arch. Internal Med., 117 (1966) 84.
status,
CEREBRAL STATES
ATHEROSCLEROSIS
A. C. KLASSEN,
R. B. LOEWENSON
IN
AND
321 - Printed in The Netherlands
SELECTED
CHRONIC
DISEASE
J. A. RESCH
Department of Neurology, Universityof’Minnesora (U.S.A.)
Health Sciences Center, Minneapolis, Minn. 55455
(Revised, received November 7th, 1972)
SUMMARY
The severity of atherosclerotic involvement of the intracranial cerebral arteries was assessed at autopsy in 3942 adult subjects. The values obtained in groups of subjects at various ages were correlated with the presence or absence of selected chronic disease states. The presence of clinical or pathological evidence of cerebral vascular disease, atherosclerotic heart disease, diabetes mellitus, and, to a lesser degree, chronic renal disease was associated with a relative increase in the severity of cerebral atherosclerosis. In contrast, cerebral atherosclerosis was apparently less severe in groups of subjects with malignant neoplastic disease and peptic ulcer disease. In males with cirrhosis or alcoholism, atherosclerosis.
there was a possible
Atherosclerotic
Key words:
tendency
toward
heart disease - Cancer - Cerebral
less severe cerebral
atherosclerosis
ebral vascular disease - Chronic disease - Chronic pulmonary Chronic renal disease - Diabetes mellitus - Malignant
- Cer-
disease -
neoplastic disease -
Peptic ulcer disease
_ INTRODUCTION
Atherosclerosis of cerebral arteries is probably the most important etiological factor in the development of ischemic cerebral vascular disease. The development of atheromatous lesions in these vessels is presumably determined by factors identical or closely related to those causing similar changes in other arterial systems. In recent
Supported
by NINDS Grant No. NS-03364.
322 decades,
A. C. KLASSEN,
certain
conditions,
notably
elevated
blood
R. B. LOEWENSON,
pressure,
diabetes
.I. A. RESCH
mellitus,
and
conditions associated with elevated levels of serum cholesterol and other serum lipids have been implicated as etiological factors associated with the increased prevalence and severity of atherosclerotic disease. In contrast, other chronic diseases, especially malignancies, have been thought to be associated with a relatively lower degree of atherosclerosis. This paper will examine the extent and severity of cerebral atherosclerosis in subjects with selected chronic disease states as found in an autopsy population. METHODOLOGY
The intracranial cerebral arteries utilized in this study were obtained during consecutive routine autopsies at the University of Minnesota Hospitals and the Hennepin County General Hospital during the years 1961-1965. The semiquantitative scoring method for assessing the severity of atherosclerotic involvement has been previously described and validated 1,s. In essence, the method assigns a numerical grade of O-4, related to the degree of luminal encroachment by an atherosclerotic lesion, to each of 22 sites in the circle of Willis and its major branches. The sum of the grades for all 22 sites is then utilized as the numerical score for each subject. Cerebral arteries were obtained from 5032 autopsy subjects. For this study, however, only subjects over 19 years of age were considered (n = 3942). Information regarding the presence or absence of specific chronic disease states was obtained by review of the clinical records and autopsy reports of all subjects. For data analysis, cumulative percentage distributions of the vessel scores were computed for each sex and IO-year age group. From these distributions the 25th, 50th (median) and 75th percentiles were determined. These percentile points were plotted at the midpoints of the lo-year age intervals. The curves connecting equal percentile points indicate graphically the extent and severity of cerebral atherosclerosis in each chronic disease state. Subgroups with sample sizes of less than 10 subjects were omitted from the analysis. Percentiles, rather than mean scores and standard deviations, were used to describe the distributions of the vessel scores. The distributions of the scores are markedly skewed in the younger age groups, with high relative frequencies of zero and very low-value scores, and only a few elevated scores. Consequently, the means are larger than the medians in these age groups, and the standard deviations are poor estimates of variability in skewed distributions. The percentile distributions of the vessel scores for the total sample, by age and sex, including the 5th and 95th percentiles, have been presented previouslyrJ. In the present report the sample sizes in the various disease categories, by decade of age and sex, are small in most instances. For this reason the 5th and 95th percentiles are statistically unreliable and are consequently omitted. For each chronic disease state, the vessel scores of subjects with the diagnosis of the disease were compared with scores of the remaining cases. Furthermore, these comparisons were repeated after all cases with a clinical diagnosis of hypertension
CEREBRALATHEROSCLEROSIS IN SELECTEDCHRONIC DISEASESTATES
323
TABLE 1 NUMBERS
OF SUBJECTS
Age (years)
Males
2(r29 3&39 4Wl9 50-59 60-69 70-79 80 and above Total
BY AGE AND SEX
Females
Total __-
174 180 315 525 538 497 186
86 143 281 321 334 256 106
260 323 596 846 872 753 292
2415
1527
3942
TABLE 2 NUMBERS
OF SUBJECTS
BY CHRONIC
Hypertension Cerebral vascular disease Atherosclerotic heart disease Diabetes mellitus Chronic renal disease Malignant neoplastic disease Peptic ulcer disease Alcoholism Hepatic cirrhosis Chronic pulmonary disease
DISEASE
STATES
Male
Female
Total
363 389 1184 127 367 678 274 237 157 547
292 223 522 129 217 628 107 75 84 211
655 612 1706 256 584 1306 381 312 241 758
Male
Female
Total
103 460 563 350 853 86
70 143 569 145 548 52
173 603 1132 495 1401 138
TABLE 3 MAJOR
CAUSES
OF DEATH
Cerebral vascular disease Atherosclerotic heart disease Malignant neoplastic disease Trauma and suicide Other Unknown
were excluded. For the analysis relative to malignant neoplastic disease, cases with atherosclerotic heart disease, cerebral vascular disease and diabetes mellitus were also excluded. The age and sex distributions of the autopsy population are listed in Table 1. The numbers of subjects in whom each of the chronic disease states was diagnosed
324
A. C. KLASSEN,
R. B. LOEWENSON,
J. A. RESCH
are indicated in Table 2. Major causes of death and numbers of subjects in each of these categories are listed in Table 3. RESULTS
In Fig. 1 are plotted the average cerebral arterial scores (medians) as related to the major cause of death categories. In males, highest scores (most severe cerebral atherosclerosis) were present in subjects in whom death was attributed to cerebral vascular disease. Lowest scores (least severe cerebral atherosclerosis) in males were present in subjects dying of malignant neoplastic disease. In females, highest scores were present when death was due to cerebral vascular disease or atherosclerotic heart disease. No apparent differences in scores were noted among female subjects in other major cause of death categories. Cerebral vascular disease
In both males and females, the presence of cerebral vascular disease was associated with considerably higher scores (Fig. 2). Exclusion of hypertensive subjects did Medians
at Given Age
50 - Males
50 - Females
30
40
50
60
70
80
90
Age in Years
Fig. 1. Median cerebral arterial atherosclerosis of death.
scores in subjects grouped according to major causes
325
CEREBRAL ATHEROSCLEROSIS.IN SELECTED CHRONIC DISEASE STATES
50
c
Percentiles
at Given Age
Ma/es
251h Percentdes
30
40
50
,T-
b” 40
30
I ’
20
90
i75’h /“f ,/’ j’
-/
1
32th
/
IO
31
80
P
females
50
o
70
60
1 Agk
in
Years
Fig. 2. Percentile plots at IO-year intervals of cerebral atherosclerosis without (0) cerebral vascular disease (CVD).
Medians
at Given Age
Moles 50
(Y
40
oB ___ .-
___
scores for groups with (0) and
50 - Feinafes
Cerebral Vascular Dtseare --___ C”D present CVD obsen,
} AlICOSTS
CVD presenf CVD absen,
1Hyperlenswes
excluded
I 60
70 Age
80
90
in Years
Fig. 3. Median vessel scores (50th percentiles) for subjects with and without cerebral vascular disease (0) and with hypertensive subjects excluded (0).
326
A. C.
KLASSEN,
R. B. LOEWENSON,
J. A. RESCH
appreciably alter this relationship (Fig. 3). In males the average vessel scores for the nonhypertensive subjects were consistently lower than those for all cases. The reduction in average scores obtained by exclusion of hypertensive subjects was greater for the cerebral vascular disease cases than for the non-cerebral vascular cases. However, the non-hypertensive cerebral vascular disease group still showed a considerable excess of cerebral atherosclerosis over the corresponding non-cerebral vascular disease cases. In females, exclusion of hypertensive subjects lowered the median curve for the cerebral vascular disease cases in the age groups below 80 years, particularly in the age interval 60-69. Excessively high scores were noted in males age 40-49. In this group, 11 of 15 subjects died due to either atherosclerotic heart disease or cerebral vascular disease and 8 subjects were also clinically hypertensive. not
Atherosclerotic
heart disease
The presence of atherosclerotic heart disease was similarly associated with more marked cerebral atherosclerosis in both sexes (Fig. 4). The differences in atherosclerosis scores between cases with and without atherosclerotic heart disease were slightly
50
Moles
Percentiles
at Given Age
t
30
w-50-60
70
00
90
Age in Years
Fig. 4. Percentile plots at lo-year intervals of vessel scores for groups with (0) and without (0) atherosclerotic heart disease (ASHD).
CEREBRAL ATHEROSCLEROSIS IN SELECTED CHRONIC DISEASE STATES
Percentiles 50
-
40
_
g.
327
at Given Age
Males Diabetes
Mellitus
O,,,.
DM pesent
.=
DM absent
lx 30 6 “, $
20
50 e
40
x fn 30 1 z ’
20 IO
30
40
50 Age
60 in
70
a0
90
Years
Fig. 5. Percentile plots of vessel scores at IO-year intervals for groups with (0) diabetes mellitus (DM).
50
and without (e)
females
t .-
---
DM present DM &sent I Hypertensives
z 8
excluded
40
;
30
5 ’
20
IO
50
60 Age
70 in
80
90
Years
Fig. 6. Median vessel scores for subjects with and without diabetes mellitus (0) and with hypertensive subjects excluded (0).
328
A. C. KLASSEN,
Percentiles
30
40
50
60
R. B. LOEWENSON,
J. A. RESCH
at Given Age
70
80
90
Age in Years
Fig. 7. Percentile plots of vessel scores at lo-year intervals for groups with (0) chronic renal disease (CRD).
Medians
at Given
Age
and without (0)
50 - Females
Chronic Renal Disease
Hyperlensives ~
excluded
30
D f
20
IO
IO -
50
60 Age
70
80
90
in Years
Fig. 8. Median vessel scores for subjects with and without chronic renal disease (0) and with hypertensive subjects excluded (0).
CEREBRAL
ATHEROSCLEROSIS
reduced, but not eliminated from both groups. Diabetes mellitus Cerebral atherosclerosis
IN SELECTED
CHRONIC
at any age when
DISEASE STATES
hypertensive
329
subjects
in both sexes was more severe in diabetic
diabetic subjects in all decades (Fig. 5). Exclusion of hypertensive did not affect this association in the males where the differences
were excluded
than in non-
subjects (Fig. 6) in average vessel
scores between diabetics and non-diabetics remained approximately the same as those found for all cases. Among the diabetic females a large reduction in average vessel scores was found in the age groups 50-59 when hypertensive subjects were omitted from the analysis. Chronic renal disease Chronic renal disease of various types was associated with increased cerebral atherosclerosis in both sexes (Fig. 7). The comparison of average vessel scores between non-hypertensive subjects with and without this condition males and in the younger females the increased cerebral
revealed that in the older atherosclerosis in subjects
with chronic renal disease was primarily related to the presence of hypertension (Fig. 8). In the remaining age groups, particularly in the female age 70-79 years, subjects with chronic renal disease still showed even after hypertensive subjects were excluded.
more severe cerebral
atherosclerosis
Malignant neoplastic disease In subjects with malignant neoplastic disease of all types, cerebral atherosclerosis scores were lower than in subjects without malignant neoplastic disease (Fig. 9). Exclusion of hypertensive subjects from this analysis slightly reduced but did not eliminate this apparent association. Subsequent exclusion of subjects with atherosclerotic heart disease, cerebral vascular disease and diabetes mellitus as well as hypertension further reduced this association (Fig. IO). In males, this latter analysis continued to demonstrate a decrease in atherosclerosis scores in subjects with malignant neoplastic disease in the fifth through the eighth decades. In females, a similar association between malignant neoplastic disease and decreased cerebral atherosclerosis was seen except in the seventh decade where median scores were identical in both groups. Analysis of the data by site and type of malignancy in both sexes revealed no apparent differences in the degree of atherosclerotic involvement among subjects in these categories. Peptic ulcer disease In both sexes, the presence of clinical or pathological evidence of peptic ulcer disease tended to be associated with slightly less severe cerebral atherosclerosis in the sixth, seventh, and eighth decades (Fig. 11). Exclusion of hypertensive subjects did not appear to affect this relationship appreciably.
330
A. C. KLASSEN, R. B. LOEWENSON, J. A. RESCH
Percentiles 50
at Given Age
Males
t 40 E :! In 30 1 p 20 I IO t
Age
in Years
Fig. 9. Percentile plots of vessel scores at lo-year intervals for groups with (0) malignant neoplastic disease (MND).
40 wgnont ,,-
---
Newlostic
and without (0)
r-------l - females
Disease
MND present MND absent
011 cases HypertenSion.Cerebroi Vascular Arferimclerolic Heoft Dnseose ood Dmbefes Mellitus
Lkease.
: 30 x 5 0 20 >”
IO
ia, 110 30
40
50
60
70
80
Age in Years
30
40
50
60
70
80
Fig. 10. Median vessel scores for subjects with and without malignant neoplastic disease (O), and for subjects excluding those with hypertension, atherosclerotic heart disease, cerebral vascular disease, and diabetes mellitus (0).
CEREBRAL ATHEROSCLEROSIS IN SELECTED CHRONIC DISEASE STATES
Percentiles
30
40
50
60 Age
331
at Given Age
7C
80
90
in Yews
Fig. 11. Percentile plots of vessel scores at IO-year intervals for groups with (0) peptic ulcer disease (PUD).
and without (0)
Alcoholism and hepatic cirrhosis In male subjects with either a clinical history of excessive alcohol intake or evidence of hepatic cirrhosis, a tendency to lower average scores was noted in older age groups (age 50-70 years) but this association was not marked. Inadequate numbers of female subjects with alcoholism or cirrhosis were available for comparison. Chronic pulmonary disease In subjects of both sexes with chronic pulmonary disease no relationship to the degree of cerebral atherosclerosis could be demonstrated. However, in males age 4049 and 70-79 years, and in females age 70-79 and 80 years or over, subjects with chronic pulmonary disease tended to have higher vessel scores. Exclusion of hypertensive subjects eliminated these apparent differences between subjects with and without chronic pulmonary disease in both sexes in the older age groups, but not in males age 40-49 years. Other chronic diseases For other chronic
diseases, including
rheumatic
heart disease, pulmonary
tuber-
332
A. C. KLASSEN,
culosis, collagen disorders and various endocrinopathies, most decades were too small for analysis.
R. B. LOEWENSON,
the number
.I. A. RESCH
of subjects
in
DISCUSSION
Numerous clinical and pathological studies have clearly demonstrated the role of elevated blood pressure in the development of atherosclerotic cardiac and peripheral vascular disease. A similar relationship between hypertension and cerebral atherosclerosis has been demonstrated in a previous study utilizing the same autopsy population being considered in this report 4. Because of this definite relationship between elevated blood pressure and increased cerebral atherosclerosis, the analyses in this study were undertaken both with and exclusive of subjects with elevated blood pressure. Sexes were considered separately because of previously demonstrated differences in cerebral atherosclerosis in males and female+. The assumption that ischemic cerebral disease is etiologically related largely, if not solely, to atherosclerotic involvement of cerebral arteries is supported by relatively little data in other pathologically verified studiess. In this study, however, both clinical and pathological evidence of cerebral vascular disease was associated with a relative excess in the severity of cerebral atherosclerosis. Although this study does not yield information regarding the relative roles of atherosclerosis of the intracranial and extracranial cerebral vessels in the production of ischemic cerebral lesions, the data do lend support to the possibility of a causal relationship between the presence of intracranial cerebral atherosclerosis and the occurrence of cerebral ischemic disease. This, however, does not exclude the potential roles of other factors in the production of cerebral ischemic lesions such as atherosclerotic heart disease, hypertension or diabetes mellitus. Attempts to evaluate the relationship between cerebral vascular disease and cerebral atherosclerosis in the absence of all other disease states known to be or suspected of being associated with increased atherosclerosis (atherosclerotic heart disease, hypertension, etc.) resulted in groups too small for adequate comparisons to be made. Exclusion of subjects with elevated blood pressure, however, did not appreciably affect this relationship. Groups of subjects dying of atherosclerotic heart disease, or in whom clinical or pathological evidence of atherosclerotic heart disease was present, also showed increased severity of cerebral atherosclerosis. These findings support the assumptions that both cerebral and coronary atherosclerotic disease may share common etiological factors. No quantitative data regarding the degree of coronary atherosclerosis in this autopsy population is available, however. The important role of diabetes mellitus in the development of atherosclerosis and its complications seems clearly establishedc. Most available data on this topic are based on studies of atherosclerosis of the aorta, coronary or peripheral limb arteries or on studies of clinical atherosclerotic heart disease or peripheral vascular disease in diabetic populations. Clinical studies have reported considerable variation in the frequency of diabetes mellitus in patients with cerebral vascular disease7-9, but
CEREBRAL
ATHEROSCLEROSIS
IN SELECTED CHRONIC
DISEASE STATES
333
these differences may well be related to different populations and different diagnostic criteria. In general, diabetes mellitus appears to be more frequent, or detected more often in subjects with cerebral vascular disease than in control populations. Autopsy studies have also suggested a relative increase in the incidence of diabetes in subjects with cerebral infarction9 and an increased incidence of cerebral infarction in diabetic subjects as compared to non-diabetics 6*7. Available studies suggest that death due to cerebral vascular disease occurs in approximately 5 to 7% of diabetic subjectslo-is. However, death rates due to cerebral vascular disease may be similar in diabetic and non-diabetic groups14J5. In agreement with others16 the data in the present study strongly suggest that the presence of diabetes mellitus is associated with a relative increase in the severity of cerebral atherosclerosis. Because of the frequent association of elevated blood pressure with diabetes mellitus raJ7--19, it has been suggested that much or all of the apparent effect of diabetes mellitus on the development of atherosclerotic heart disease is related to coexistent hypertension rather than to the diabetic state1a~20. In the present study, removal of hypertensive subjects did not appreciably alter the apparent tendency for diabetic subjects to have increased cerebral atherosclerosis. It would thus appear that elevated blood pressure plays a relatively minor role with respect to the increased severity of cerebral atherosclerosis in diabetic subjects. In patients with chronic renal disease of multiple etiologies, the concomitant presence of hypertension appeared to play an etiological role in the production of increased cerebral atherosclerosis. Removal of hypertensive subjects tended to reduce differences in cerebral atherosclerosis in most age groups. This would be in essential agreement with the findings of other investigators2i. The relationship between malignant neoplastic disease of various types and the atherosclerotic process has been the subject of much discussion in recent years. Numerous pathological studies suggest that atherosclerotic disease of the aorta and coronary vessels is less severe in patients with malignant neoplastic diseasess-29. In contrast, it has also been suggested that atherosclerosis of the aorta and coronary vessels may actually be increased in certain malignant conditions, notably carcinoma of the lung24JoJs. Moreover, other studies have failed to demonstrate any relationship between atherosclerotic disease and malignant neoplastic disease31-3s. Data related to cerebral atherosclerosis and malignant neoplastic disease are limited but previous studies have not demonstrated differences in cerebral atherosclerosis in relationship to the presence or absence of malignant neoplastic diseaseasJQ5. Indeed, it has been suggested that the apparent decrease in severity of atherosclerosis of the aorta and coronary vessels associated with malignant disorders is due to incorrect data analysis in that subjects with atherosclerotic diseases should be removed from the control group prior to comparison 36. In view of the above, it is of interest that in our series the presence of malignancy or death due to malignant neoplastic disease was associated with less severe cerebral atherosclerosis, even when subjects with hypertension, atherosclerotic heart disease and diabetes mellitus were excluded. Whether or not this demonstrates a definite relationship between malignant disease and a
334
A. C. KLASSEN,
R. B. LOEWENSON,
J. A. RESCH
lessened tendency to atherosclerotic involvement of cerebral vessels still remains unclear. In comparing cerebral atherosclerosis in subjects dying of malignant neoplastic disease and those dying due to accidental trauma, males with malignant neoplastic disease still tended to demonstrate less severe cerebral atherosclerosis, but this association was not evident in females (Fig. 1). A possible association between the presence of peptic ulcer disease and diminished cerebral atherosclerosis as demonstrated in this study has not, to our knowledge, been noted previously. A study utilizing standardized death rates from peptic ulcer and from vascular lesions of the central nervous system has actually suggested a strongly positive relationship between the two diseasess7. Pathological studies of aortic and coronary atherosclerosis have not, however, demonstrated any relationship to the presence of duodenal or gastric ulcer 3s. Of additional interest is a recent report of a strong inverse relationship between peptic ulcer and blood pressuress. A number of pathological studies have suggested that atherosclerosis may be less marked in subjects with hepatic cirrhosiss4940-4s or in alcoholic subjects, with or without cirrhosis44. Other pathological studies have been unable to demonstrate such an associations4>4s. The slight tendency towards lower cerebral atherosclerosis scores noted in older males with cirrhosis or alcoholism in the present study is suggestive of such an association but does not permit any definite conclusions in this regard. CONCLUSIONS
In the autopsy population under consideration in this study, cerebral atherosclerosis appeared to be more severe in patients with clinical or pathological evidence of cerebral vascular disease, atherosclerotic heart disease and diabetes mellitus. The association in these conditions was apparently not solely due to the concomitant presence of elevated blood pressure. Where death was due to cerebral vascular disease or atherosclerotic heart disease, the degree of cerebral atherosclerosis was more pronounced in comparison to other causes of death. In the presence of chronic renal disease, cerebral atherosclerosis was also found to be increased, but a large proportion of this increase was probably related to the frequent occurrence of hypertension in this group. Cerebral atherosclerosis was apparently less severe in groups suffering from malignant neoplastic disease. This relationship appeared to be independent of the site or type of neoplastic disease, or of the presence or absence of hypertension, atherosclerotic heart disease, cerebral vascular disease and diabetes mellitus. In the presence of peptic ulcer disease and in males with hepatic cirrhosis or alcoholism, cerebral atherosclerosis tended to be relatively less severe. The severity of cerebral atherosclerosis was apparently unrelated to the presence of chronic pulmonary disease. It is to be emphasized that these associations in no way identify the role of any of the above mentioned conditions as definite etiological factors in the pathogenesis of cerebral atherosclerosis.
CEREBRAL ATHEROSCLEROSIS IN SELECTED CHRONIC DISEASE STATES
335
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status,