TABLE 8.—Percent of persons 17 years old and older, who
perceive their health to be “excellent,” by cigarette
smoking status, sex, and age: United States, 1974

 

 

Present Former Never
Sex and age a smoker smoker smoked
Both Sexes
W+ 42.7 415 43.0 42.8
17-44 513 47.7 55.4 53.1
45-64 34.0 32.6 36.7 32.0
65+ 27.1 24.7 26.5 23.2
Male
17+ 416.8 44.1 44.0 52.0
17-44 56.7 52.9 59.9 60.8
45-64 36.9 82.3 38.0 40.9
65+ 255 19.2 25.4 30.0
Female

17+ 39.0 38.7 41.2 38.7
17-44 46.3 42.0 49.2 48.7
45-64 313 33.0 34.1 28.9
65+ 28.3 32.4 29.3 21.7

 

SOURCE: Wilson, R.W. (16).

been analyzed to determine if this increased hospitalization is for
diseases usually associated with smoking.1

While smokers tended to report more hospitalizations than did
persons who had never smoked, there was no tendency for smokers to
report more frequent visits to physicians than those who had never
smoked, although former cigarette smokers reported the largest
proportion with five or more physician visits during the past year
(Table 10).

Respondents in the 1974 Health Interview Survey were also asked
whether they had ever tried to quit smoking, whether a doctor had
advised them to quit, and whether they had been advised to quit
because of specific health conditions. Just under a quarter of all
Persons who had ever smoked reported that they had been advised by a
doctor at one time or another to stop smoking (Table 11). Surprisingly,
at least from a public health point of view, at those ages at which the
effects of smoking often begin to manifest themselves, 45 to 64, less
than one-third of the smokers reported that they had been advised by

their physicians to stop smoking. This would appear to indicate a need
ee

‘There are many types of analyses that could be performed on these data that have not been done because of
differing priorities and lack of resources. For example, one interesting area of investigation that was begun, but not
completed because of the apparent complexities of the issue, is the relationship between cigarette smoking, health
variables, and weight. However, NCHS does make available to researchers public-use data tapes from the various
surveys, so that they can conduct their own analyses (12).

3—15
TABLE 9.—Percent of persons 17 years old and older, with one
or more hospital episodes in the year prior to
interview, by cigarette smoking status, sex, and age:
United States, 1974

 

Present Former Never
Sex and age Total smoker smoker smoked
Both sexes
17+ 13.1 13.5 14.4 7
17-44 123 18.8 1.7 12.0
45-64 12.9 123 16.1 21
65+ 16.5 16.5 19.7 15.8
Male
17+ 10.2 10.5 128 83
11-44 7.0 8.6 8.0 53
45-64 13.1 124 14.5 125
65+ 174 19.0 18.5 149
Female
17+ 15.7 16.9 175 14.7
17-44 17.2 19.5 16.8 15.9
45-64 128 123 16.2 120
65+ 15.8 12.9 2.1 154

 

SOURCE: Wilson, R.W. (16).

not only for increased public education, but also for increased
educational programs among health professionals. About two-thirds of
all present smokers had tried to stop smoking at some time (Table 12).

Since detailed smoking history information was not obtained, it is
difficult with these data to determine the more precise relationships
between illness, physicians’ advice to stop smoking, and actual
attempts to stop. Some of the studies conducted in the past by the
National Clearinghouse for Smoking and Health and reported
elsewhere in this report have attempted to investigate these relation-
ships as well as some of the more attitudinal and psychological aspects
of smoking.

Respondents to the Health Interview Survey were asked if a doctor
had ever told them they had heart trouble. Among persons under 65
years of age, a larger proportion of both present smokers and former
smokers had been told that they had heart trouble compared with
persons who had never smoked (Table 13). For example, 15 percent of
the male former smokers aged 45 to 64 had been told they had heart
trouble compared to 10 percent of those who had never smoked. There
is some difficulty interpreting the data for persons over 65 years old,
where a higher proportion of those who had never smoked report heart

3—16
TABLE 10.—Percent of persons 17 years old and older, with five
or more physician visits in the year prior to
interview, by cigarette smoking status, sex, and age:
United States, 1974

 

Present Former Never
Sex and age a smoker smoker smoked
Both sexes
W+ 24.8 23.7 27.0 26.1
17-44 22.0 23.0 BA 22.3
45-64 25.5 24.3 26.4 27.2
65+ 34.2 27.0 37.1 349
Male
1T+ 17.9 16.9 22.9 173
17-44 18.4 14.1 16.1 B1
45-64 213 20.7 24.1 20.8
65+ 30.2 24.8 33.5 30.4
Female

t+ 30.8 313 34.5 30.0
17-44 29.9 82.9 33.5 27.6
45-64 29.2 28.3 31.1 29.4
65+ 37.0 30.1 468 36.3

 

SOURCE: Wilson, R.W. (16).

trouble, since many of the smokers with heart trouble have already
died.

Of those smokers who have been advised by a doctor to stop, about
28 percent were advised to stop because of respiratory disease. About
23 percent of the smokers 65 and older were advised to stop because of
circulatory problems, but this proportion drops for the younger
smokers. Hardly any smokers reported they were advised to stop
because of cancer. However, these data on cancer are also misleading;
since the survival rate for lung cancer is relatively low, many smokers
would not live long enough to report that the doctor had told them to
stop smoking.

The first cycle of the Health and Nutrition Examination Survey
contained a number of questions that, when combined, formed an
Index of General Psychological Well-Being.2 This measure provides
data on another dimension of the relationship between cigarette
smoking and health. In general, current cigarette smokers were found
LL

* The Index of General Psychological Well-Being is composed of 18 itema with a total of 128 response options. The
response option for each item that indicates the greatest distress is scored zero. Some of the items and their reaponse
options also permit representations of high-level positive well-being. The total index scores range from 0 thru 110,
With low scores indicating distress and high scores indicating positive well-being. Generally positive affect is
represented by scores above 78 and marginal well-being by scores of 73 to 77. The median score for the population
estimates of adults, 25 to 74 years old, was between 83 and 84 (3).

3—17
TABLE 11.—Percent of persons 17 years old and older who have
ever smoked and who were ever advised by a
physician to stop smoking, by smoking status, sex,
and age: United States 1974

Smoking status All ages

 

and sex 17+ V4 8+
Total ever smoked
Both sexes B9 19.6 29.2 30.1
Male B.5 178 29.2 32.4
Female 244 218 292 25.3
Former smoker
Both sexes 213 14.2 26.3 28.2
Maile 22.7 13.5 28.0 29.6
Female 18.9 15.0 22.6 24.2
Present smoker
Both sexes 25.2 21.5 31.1 32.6
Male 24.0 19.4 30.2 37.0
Female 26.6 239 32.1 262

 

SOURCE: Wilson, R.W. (16).

TABLE 12.—Percent of present cigarette smokers 17 years old
and older who have tried to stop smoking, by sex
and age: United States, 1974

All ages

 

Sex 17 17-44 45-64 65+
Both sexes 64.7 66.0 62.8 61.1
Male 66.0 66.7 65.1 63.3
Female 63.3 65.3 60.2 57.9

 

SOURCE: Wilson, R.W. (16).

to have a slightly lower level of well-being than were nonsmokers.
Heavy smokers (more than 1 1/2 packs a day) under 65 years of age
report the lowest levels of general well-being and report mean levels of
general well-being at marginal levels or lower.

Conclusions

The available evidence in the relationship between cigarette smoking
and illness and disability has increased markedly since the first

3—18
TABLE 13.—Percent of persons 17 years old and older who have
been told by a doctor that they had heart trouble,
by cigarette smoking status, sex, and age: United

 

 

States, 1974
Present Former Never
Sex and age Total smoker smoker smoked
Both sexes
17+ 9.0 78 12.9 94
17-44 4.2 48 47 41
45-64 111 11.6 14.9 9.9
65+ 22.9 17.9 25 23.3
Male
T+ 89 8.2 1.8 84
17-44 3.8 45 47 3.6
45-64 12.0 18.0 15.2 10.0
65+ 245 18.6 23.5 26.5
Female

+ 9.0 14 114 9.9
17-4 46 5.1 49 44
45-64 10.3 10.0 143 99
65+ 218 16.8 5 22.4

 

SOURCE: Wilson, R.W. (26).

Surgeon General’s report was issued, largely as a result of data
collected from national probability surveys conducted by NCHS. These
data range from the standard health indicators, such as measures of
chronic and acute illness and measures of disability days, to less
commonly used indicators of lifestyles. The results of analysis
Performed on these data vary from the more frequently reported
findings on disability to data from the Index of General Psychological
Well-Being, first reported in this chapter.

The findings tend to be consistent with the large amount of evidence
on the relationship between cigarette smoking and mortality, ie.,
People who smoke cigarettes report more illness and disability than
People who have never smoked cigarettes. While many studies show a
reduction in the risk of mortality among former cigarette smokers,
data on disability and illness often show continued high risk for former
smokers, indicating both a lack of refinement in the current data to
distinguish between types of former smokers as well as the fact that
once certain diseases occur they do not go away.

; The most important aspect of these data collected by NCHS lies not
In the substantive analysis prepared by the NCHS staff, but in the

3—19
analytic potential of the data to other researchers in the smoking area
through the use of NCHS’s public-use data tape program.
Morbidity: References

(1)

(2)
(3)

(4)

(5)

(6)

{8)

(9)

(10)

(12)

(12)

AHMED, P.I., GLEESON, G.A. Changes in Cigarette Smoking Habits Between
1955 and 1966. U.S. Department of Health, Education, and Welfare, Public
Health Service, Health Services and Mental Health Administration, National
Center for Health Statistics, Series 10, No. 59, PHS Publication No. 1000, April
1970, 33 pp.

BELLOC, N.B. Relationship of health practices and mortality. Preventive
Medicine 2: 67-81, 1978.

FAZIO, A.F. A Concurrent Validational Study of the NCHS General Well-Being
Schedule. U.S. Department of Health, Education, and Welfare, Public Health
Service, Health Resources Administration, National Center for Health
Statistics, Series 2, No. 73, DHEW Publication No. (HRA) 78-1347, September
1977, 53 pp.

HAENSZEL, W., SHIMKIM, M.B., MILLER, H.P. Tobacco Smoking Patterns
in the United States. Public Health Monograph No. 45. U.S. Department of
Health, Education, and Welfare, Public Health Service, PHS Publication No.
463, 1956, 111 pp.

HAMMOND, E.C. Smoking in relation to death rates of one million men and
women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of
Cancer and Other Chronic Diseases. National Cancer Institute Monograph No.
19. U.S. Department of Health, Education, and Welfare, Public Health
Service, National Cancer Institute, January 1966, pp. 127-204.

HAMMOND, E.C., HORN, D. Smoking and death rates - Report on 44 months of
follow-up of 187,783 men. Journal of the American Medical Association
166(10): 1159-1172, 1958.

MADOW, W.G. Net Differences in Interview Data on Chronic Conditions and
Information Derived From Medical Records. U.S. Department of Health,
Education, and Welfare, Public Health Service, Health Services and Mental
Health Administration, National Center for Health Statistics, Series 2, No. 57,
DHEW Publication No. (HSM) 73-1331, June 1973, 58 pp.

MILLER, H.W. Plan and Operation of the Health and Nutrition Examination
Survey: United States, 1971-1973. U.S. Department of Health, Education, and
Welfare, Public Health Service, Health Resources Administration, National
Center for Health Statistics, Series 1, Nos. 10a, 10b, DHEW Publication No.
(HSM) 73-1310, February 1973, 123 pp.

MOSS, A.J., SCOTT, G. Characteristics of Persons with Hypertension: United
States, 1974. U.S. Department of Health, Education, and Welfare, Public
Health Service, National Center for Health Statistics, Series 10, No. 121,
DHEW Publication No. (PHS) 79-1549, 1979. (In press)

NATIONAL CENTER FOR HEALTH STATISTICS. Cigarette smoking:
United States, 1970. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration,
National Center for Health Statistics. Monthly Vital Statistics Report
21(3)Supplement), June 2, 1972, 8 pp.

NATIONAL CENTER FOR HEALTH STATISTICS. Health, United States,
1976-1977. U.S. Department of Health, Education, and Welfare, Public Health
Service, Health Resources Administration, National Center for Health
Statistics, National Center for Health Services Research, DHEW Publication
No. (HRA) 77-1282, 1977, 441 pp.

NATIONAL CENTER FOR HEALTH STATISTICS. Standardized Micro-Data
Tape Transcripts. U.S. Department of Health, Education, and Welfare, Public
Health Service, National Center for Health Statistics, DHEW Publication No.
(PHS) 78-1218, June 1978, 36 pp.

3—21
(13) NATIONAL CLEARINGHOUSE FOR SMOKING AND HEALTH. Smoking
and Illness. U.S. Department of Health, Education, and Welfare, Public
Health Service, Bureau of Disease Prevention and Environmenta)] Control,
National Center for Chronic Disease Control, National Clearinghouse for
Smoking and Health, PHS Publication No. 1662, July 1967, 6 pp.

(14) WILSON R.W. Cigarette Smoking and Health Characteristics. United States,
July 1964-June 1965. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Center for Health Statistics, Series 10, No. 34,
PHS Publication No. 1000, May 1967, 64 pp.

(15) WILSON R.W. Cigarette smoking, disability days and respiratory condition.
Journal of Occupational Medicine 15(3): 236-240, March 1973.

(16) WILSON R.W. Testimony presented at Regional Forum sponsored by the
National Commission for Smoking and Public Policy. Philadelphia, June 16,
1977, 27 pp.
4. CARDIOVASCULAR DISEASES.

 

National Heart, Lung, and Blood Institute
CONTENTS

 

 

 

 

 

Atherosclerosis ............ccsceeceeereeeeeernees Vee eeneeeeeeeeeeeeaeneaes 7
The Nature of Atherosclerosis in Man.................066- 7
The Effect of Smoking on Atherogenesis................ 10
Experiments in Animals................ eee eee eeneee 16
Research Needs............0ccccsccceeeeneeecneeenee ee eeeens teens 18
Conclusions ..........-.sccceccceeenesenceseaeneueeeees de edeneeenenas 19

Myocardial Infarction...............ccceceeeteeeeeen ens Dereeeeiveeeeee 19
The Nature of Myocardial Infarction ke deeeecececeneneees 19
Summary of Epidemiological Data ....................0.. .. 20
The Effect of Smoking on Myocardial

Infarction in Man...............ccccecenceeeececeeeeeeeeee snes BO
The Effect of Smoking on Myocardial

Infarction in Animals...............ccceceeeeeeereeeeeeeeees 40
Research Needs.............ccceccccececececcseeeseecsenescenenes 40
Conclusions...............ccececcececcececeeceeeececeeeeceeneeneeees 41

Sudden Cardiac Death ...........ccc.ccccccesseccessesceceueeceeaees 41
The Nature of Sudden Cardiac Death in Man.......... 41
Sudden Cardiac Death in Animals..................0.000085 43
Summary of Epidemiological Data ................:6.0:00 43
The Effect of Smoking on Sudden Cardiac

Death in Man..............:ccccececeeescceececeeneeeeeseeeenes 44
The Effect of Smoking on Sudden Cardiac

‘Death in Animals .................cccccseseeecenseceneeaeeeees 45
Research Needs...........c.cccccceeceeececeeceeeseeneeeceaseeeaes 45
Conclusions.............ccceccccceecseceeceeceeceeeeseneseeeeeeenees 45

Angina Pectoris .............csccceseeeseeeeesceseseseersunsssseeeeeeess 46
The Nature of Angina Pectoris in Humans............. 46
Summary of Epidemiological Data ..............:.::000000 46
The Effect of Smoking on Angina Pectoris............. 48
Research Needs...........ccccccccseccecsscuescresteneeeesueeeees 48
Conclusions...........csseccceeeeccessscesnseceensseececsueneeseaees 49

Cerebrovascular Disease...........00..:cecscseseceesseeesseeesseees 49
The Nature of Cerebrovascular Disease in Man........ 49
Summary of Epidemiological Data ..............::::::00 50

The Effect of Smoking on Cerebrovascular Disease ..50

4—3
Research Needs.............cccccccscccceuceccesceeceeaeerecaceces 52

 

 

 

 

 

 

Conclusions .............ccceccsceccscesescuseseususcaestecsceenecess 52
Peripheral Vascular Disease ...............cccccsccceeceesseuscesees 52
The Nature of Peripheral Vascular Disease in Man ..52
Summary of Epidemiological Data ............0..0.0..0.0e. 53
The Effect of Smoking on Peripheral
Vascular Disease ..............cccecseecuecceececeseseucnseeess 53
Research Needs.............ccccccccceccecescecscenceseusenseesucs 54
Conclusions.......... 02... .ccecseceececececeeeeeecenseusecnseecee 54
Aortic Aneurysm of Atherosclerotic Type..............c.cc0008 55
The Nature of Atherosclerotic Aortic Aneurysm....... 55
Summary of Epidemiological Data ..............0c.0c00008- 55
The Effect of Smoking on Aortic Aneurysm............ 56
Research Needs...............ccceceesceesceceeescssecuceasseuenes 56
Conclusions.............2:ccceceececescncnsceseensseeeucuseaveneaees 56
High Blood Pressure................cccecesceeccececcenseesscescescs 56
The Nature of Hypertension .................cccccesceeeeees 56
Summary of Epidemiological Data ................c.ccc008- 57
The Effect of Smoking on Blood Pressure .............. 58
Research Needs............ccccccecsescnesecerececesentecscceenes 58
COnclusions...........ccccscceeessesecceceecaecnseeeceuseusenseueees 58
Other Conditions .............cccccccceceeecnescaececscesentescneneaas 58
Venous Thrombosis ...............ccccccsccececeeesseeeseccusees 59
Thromboangiitis Obliterans (Buerger’s Disease)......... 60
Oral Contraceptives, Smoking, Myocardial Infarction,
and Subarachnoid Hemorrhage Among Women...... 60
The Effect of Smoking on Blood Lipids.................. 61
Other Constitutents of Smoke ................0..ccccceeeeeee 62
Discussion and Conclusions.................ccccecscsesevccasesucenes 63
References ..........ccccececee cence ececeseeneaenecerecsenccsereneucecaees 67

LIST OF TABLES

Table 1.—Autopsy studies of atheroclerosis.................... 11

 

4—4
 

Table 2.—Coronary heart disease mortality ratios
related to smoking—prospective studies.................0.005 22

 

Table 3.—Coronary heart disease morbidity as related to
SMOKING «0.02... ee cece nec eecceenseeeeeseeeseeeeneeaeseeeereses 27

 

Table 4.—The effect of the cessation of cigarette
smoking on the incidence of CHD....................0c00 000s 34

 

Table 5.—Annual probability of death from coronary heart
disease, in current and discontinued smokers, by age,
maximum amount smoked, and age started smoking....35

 

Table 6.—Coronary heart disease morbidity as related to
smoking—angina pectoris—prospective studies............. 47

 

Table 7.—Age-standardized death rates and mortality
ratios for cerebral vascular lesions for men and
women, by type of smoking (lifetime history) and age
at start of study........ cece eececeeseseerecersaeeecessrens 51

4—5
Atherosclerosis

Most studies of the pathology of atherosclerosis have been based on
autopsies of coroner’s or hospital populations in which only a limited
fraction of decedents have been examined. They have been valuable
for an understanding of the pathogenesis and complications of
atherosclerosis. Such studies cannot be taken to represent the
prevalence of atherosclerosis in the general population. Studies which
attempt to minimize selection bias at autopsy by examining the great
majority of decedents in a defined population are rare (66, 114).

The most extensive and comprehensive autopsy study that has been
conducted is the International Atherosclerosis Project, which collected
data from 15 cities in 14 countries and recorded more than 21,000
autopsies according to a standardized protocol and method of
evaluation (85). The study found a remarkably frequent occurrence of
atherosclerotic lesions in the United States; detailed international or
geographic differences in the severity of atherosclerosis; raised the
issue of whether childhood atherosclerosis evolves into adult forms of
atherosclerosis; and documented that, on the average, there are more
frequent and extensive coronary plaques in cases with coronary heart
disease than in comparison cases regardless of age, sex, geographic
location, or race. Approximately the same prevalence and extent of
advanced atherosclerosis were seen in coronary heart disease cases
regardless of age, sex, and, with few exceptions, of geographic
location. While individuals may show considerable variability in the
severity of atherosclerosis, the conclusion is that coronary atherosclero-
sis is of primary importance in the development of coronary heart
disease in a population (133). Another extensive study in five towns in

Europe has been reported by the World Health Organization (WHO)
(66).

The Nature of Atherosclerosis in Man

Information about atherosclerosis in man derives from pathological
studies and from associations observed in clinical or epidemiological
studies.

The lesion or plaque is a cellular proliferation in the arterial intima.
It contains chiefly smooth muscle cells, but also fibrocytes and cells
typical of chronic inflammation. Lipid is commonly present along with
cellular products such as collagen, elastic tissue, glycosaminoglycans,
and cellular debris from necrosis. Elements of thrombus are common
both in and on the plaque. Focal calcification is frequent. Thus, a
highly variable and complex range of lesions can be considered under
the term atherosclerosis.

The concept of the development of lesions is a synthetic one derived
from the observation of many lesions rather than from the actual
observation of a single lesion over time. At present, there is

4—7
controversy over whether the fatty streaks seen in childhood are the
precursors of the more fibrous, raised, and complex adult lesions, or
whether some or many adult lesions arise independently of fatty
streaks (which also occur in adult life) (89). The usual prevalence of
atherosclerotic lesions in adult life is such that the aorta and carotid
arteries are affected about a decade before the coronary arteries and
cerebral arteries, and the latter are affected a decade in advance of the
arteries of the leg. However, such relationships are not constant;
individual variations are common and, indeed, specific clinical syn-
dromes of localized atherosclerosis are recognized.

Atherosclerotic plaques distort and narrow the calibre of the
affected arteries. This reduces the flow of blood through them and
creates the condition called ischemia. When ischemia becomes severe,
the organs and tissues deprived of blood no longer function properly
and clinical disease occurs in the form of coronary heart disease, stroke,
or peripheral vascular disease. The occurrence of severe ischemia may
arise because of the enlargement of plaques, or it may be precipitated
by the development of thrombosis (clot) on plaques, or by other
complications that can affect them. The various diseases resulting
from ischemia are considered subsequently in this chapter.

Conditions that predispose to the onset of disease in the future,
increasing the risk of its occurrence, are spoken of as “risk factors”,
The concept of risk factors arose from clinical experience with
cardiovascular disease, particularly coronary heart disease, rather than
with atherosclerosis itself. Prospective population studies such as those
considered in the Pooling Project (107) further developed the
predictive value of selected factors such as cigarette smoking and
levels of blood pressure and cholesterol.

Risk factor associations for atherosclerosis as distinct from coronary
heart disease are limited in their documentation. The International
Atherosclerosis Project (85), dealing with autopsy data, concluded that
the severity of atherosclerosis is closely associated with the proportion
of total calories derived from saturated fat in the diet of the
population, with the serum cholesterol levels measured in the
population, and with hypertension. The association with smoking was
not examined. The WHO (66) study documented the association of a
number of disease states and conditions with the extent and severity of
atherosclerosis. A recent report has described the associations between
several variables measured during life and the extent of atherosclero-
sis of the aorta and coronary arteries seen at autopsy in Japanese-
Americans participating in a prospective cardiovascular risk factor
study (112). Statistically independent associations were found by
multivariate analysis between aortic atherosclerosis and age at death,
cigarettes smoked per day, serum cholesterol concentration, and blood
pressure level. Coronary atherosclerosis was related to relative body

4—8
weight, cigarettes smoked per day, and serum cholesterol concentra-
tion.

Models of experimental atherosclerosis in species as different as
birds, rodents, dogs, swine, and nonhuman primates have been
developed. The majority of these models have been induced by feeding
saturated fat or cholesterol leading to fat-rich plaques that resemble
the fatty streaks of childhood or the very fat-laden plaques occasional-
ly seen in adult life. Other experimental techniques of inducing lesions
are: the use of physical injury to arteries leading to acute proliferative
plaque development with little or no pid accumulation; the induction
of intimal thrombi with their tissue organization yielding fibro-fatty
plaques; immunologic vascular injury with lipid or cholesterol feeding;
and, recently (in chickens), viral infection. Among different species of
nonhuman primates, the same dietary regimen will produce character-
istically a somewhat different distribution of plaques in the arterial
tree. Different experimental diets will produce lesions that are
characteristically more fatty or more fibrous. Spontaneous fibrous or
fibro-fatty plaques occur in many species including birds, rabbits,
swine, and nonhuman primates. The enhancement of spontaneous
atherogenesis in chickens by polycyclic hydrocarbons has been reported
(1). A strong genetic control exists in pigeons both for the expression
of experimental atherosclerosis and for its localization predominantly
either in the aorta or in the coronary arteries. Thus, there is a wide
variety of experimental and spontaneous animal models available with
which to study atherogenesis.

A huge body of literature deals with the pathogenesis of human and
experimental atherosclerosis. Several recent reviews provide a detailed
and critical consideration of current concepts (3,21,22,84,89,
117,119,126,155,156). The various interrelationships of different patho-
genetic processes such as cellular proliferation, lipid accumulation, and
thrombotic phenomena are not fully understood. Nevertheless, it is
possible to synthesize available data into a frequently explored major
working hypothesis of the initial stages of atherogenesis based on
extensive experimental data (see particularly 117,155,156) that support
the pathogenetic concept that the arterial endothelium functions
normally to separate the intima and media from the blood. The
hypothesis holds that local injury results in failure of this barrier
function or in loss of endothelial cells and exposure of the subendothe-
lium to whole plasma and to blood platelets. Platelets and plasma
Contain growth factors capable of inducing smooth muscle cells in the
intima and adjacent media to multiply. This loss of barrier function
also allows macromolecules such as fibrinogen and very low density
(VLDL), intermediate, low density (LDL), and high density (HDL)
'poproteins freer access to the vessel wall. More lipid is internalized by
intimal smooth muscle cells and macrophages than their lysosomal

IZestive systems can catabolize, and they become overloaded with fat

4—9
and cholesterol. The amount of sterol externalized metabolically by
such cells may exceed the local capacity of HDL to accept and
transport it away. Cellular necrosis occurs and both intracellular and
structural lipids spill into the extracellular compartment of the intima
where they contribute to the lipid burden. The sequence in this
hypothesis is endothelial injury, impaired barrier function, and
subendothelial exposure to plasma and to platelets, followed by cellular
metabolic overload, failed homeostasis, cellular proliferation, and
necrosis. In addition, the stigmata of mild chronic inflammation occur
promptly, and appearances suggestive of a migration of smooth muscle
cells to the lesion are seen. Local cellular production of glycosaminogly-
cans, collagens, and elastin follows. Progression of the lesions can be
through a continuation or cyclical repetitions of the same processes or
by thrombosis. Thrombosis, necrosis, calcification, hemorrhage, and
ulceration may further complicate the lesion. A large number of agents
are suspected to be capable of injuring endothelium and altering its
barrier function. It should be noted that the foregoing views are
derived from animal experimentation but appear to be congruent with
the nature of atherosclerosis in humans.

A novel theory of atherogenesis has been proposed recently that does
not necessarily contradict the concepts stated above, but which
designates a prior abnormality of the smooth muscle cells that
proliferate to form plaques. It has been found that the cells that
constitute individual fibrous atherosclerotic plaques in adults are
homogenous for an isoenzyme marker. That is, each plaque must either
be monoclonal or initially polyclonal with the development of a
monotypic character as it has developed (21, 22, 104, 105, 185). If the
correct interpretation is that plaques are monoclonal, it is necessary to
consider whether this represents a mutation or transformation of
vascular cells leading to a local proliferation analogous to benign
smooth muscle cell neoplasia. In this view, environmental agents
capable of inducing somatic cell mutation, including mutagens derived
from tobacco, could be fundamental to the pathogenesis of atheroscle-
rotic plaques, and might cause the primary cellular changes facilitating
other conventional risk factors or agents to produce lesions in man. At
the present time, data to settle the validity of these interpretations are
not available.

The Effect of Smoking on Atherogenesis

Autopsy studies in which smoking behavior has been recorded are not
common. Table 19 (pp. 49-51) of the 1976 reference edition of the
report, The Health Consequences of Smoking (138), lists several
investigations into this aspect of smoking. This table is reproduced
below as Table 1.

These investigations compare, within their particular group of study
cases, smokers with nonsmokers and different levels of smoking,

4—10
TABLE 1.—Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in that smoking
category)! [SM = smokers NS = nonsmokers]

 

Author, Autopsy Data
year, population collection Cigarettes per day Conclusions Comments
country
Wilens 989 consecutive Routine clinical Severity of aortic scierosis The authors conclude that Smoking data unavailable
and Plair, male autopsies records of Above average Average Below average in 60 percent of cases, the for 120 cases.
1962, at New York previous and 9.161) 60.2 298 degree of sclerosis at Each aorta specimen given
USA. City VA present 19.1(152) 8.2 178 autopsy was commen- an “atherosclerotic age”
hospitals. admissions. 26.4(288) 62.5 Ml surate with age of patient, by comparison with a
+25.1(199) 613 13.6 regardless of smoking standard. If “athero-

 

habits. In the remaining
40 percent there is evi-
dence that cigarette
smoking may be asso-
ciated with an above-
average degree of aortic
sclerosis.

sclerotic age” was found
to be 10 years more than
real age, the aorta was
said to show above-
average sclerosis.

tp<0.001 comparing 9.9
with 25.1 and 298 with
13.6.

 
Daa

|
iS

TABLE 1.—Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in that smoking
category)! [SM = smokers NS = nonsmokers]—Continued

 

 

Author, Autopsy Data
year, population collection Cigarettes per day Conclusions Comments
country

Auerbach, 1,372 autopsies Interview with Degree of coronary artery atherosclerosis (overall age- The authors conclude that
et al, of male next of kin. adjusted results) the percentage of men
1965, patients in No athero- with an advanced degree of
U.S.A. Orange, New selerosis Slight Moderate Advanced coronary atherosclerosis

Jersey, VA NS... 5.6(69) 573 218 15.3 was higher among ciga-
hospital for Current rette smokers than among
whom smoking cigarette nonsmokers and that the
habit data were | 2.6139) 30.9 373 29.2 percentage increased
available and 2039 |. 0.8(299) 19.7 42.1 374 with amount of cigarette
who did not | 0.6(144) 18.1 35.4 459 smoking. This relation-
have overt CHD ship persisted even
at death. when cases were matched
for age and cause of
death.

Avtandilov, 259 male and Not specified, Comparative size of mean area of atherosclerotic legions The author concludes that Causes of death 96-athero-
1965, 141 female but there were: in inner coat of coronary arteries. the worst changes were sclerotic, 102-accidental,
Russia autopsies. 180 SM and Right coronary artery Left coronary artery found in the left and 202-various diseases.

220 NS. 5M NS SM NS right coronary arteries +T-test for significance
+15.5(30) 1.3(32) 163 22 with less severe changes of difference between
$23.6(34) 11.427) $15.8 44 in circumflex artery means is significant
+36.3(39) 14.839) 279 99 and aorta. at p<0.05 level.
131.432) -23.8(36) $26.5 225

 

41.918) 31.7(36) 26.1 35.8
&T

TABLE 1.—Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in that smoking
category)! [SM = smokers NS = nonsmokers]—Continued

 

Author, Autopsy Data
year, population collection Cigarettes per day Conclusions Comments
country
Sackett, 893 total, Patient The results concerning aortic atherosclerosis are given in The authors conclude that
et al., including 433 interview on form of figure presentation of ridit-analysis. among males, ".. . a
1968, male and 450 admission. large increase in the
U.S.A. female (white) severity of aortic athero-
patients autop- sclerosis occurred in the
sied at Roswelt groups using either ciga-
Park Memorial rettes only or both ciga-
Hospital. reties and alcohol as
Represents ali compared with the group
deaths 1956-1964 using neither cigarettes

exclusive of 81 nor alcohol . . . there

male pipe and was only a small and
cigar smokers statistically insignificant
and 55 incom- difference between the
plete files. group using cigarettes

alone and the group using
both cigarettes and alcohol,
...” The severity of
aortic atherosclerosis
increased with increasing
use of cigarettes, when
measured both by in-
tensity and by duration

of smoking.

 
, TABLE

1.—Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in that smoking
category)! [SM = smokers NS = nonsmokers]—Continued

 

 

 

 

 

 

 

—_
Cy
Author, Autopsy Data
year, population callection Cigarettes per day Conclusions Comments
country
Viel 1,150 males Interview with The results concerning internal fibrous streaks and fatty The authors conclude that:
et al., and 290 relatives. plaques in the left anterior descending coronary artery “No relationship he-
1968 females who are reported in graphic form only. An examination of tween atherosclerotic
Chile died violently this data indicates that the moderate and heavy smokers lesions and the use of
in 1961-1964. appeared to show consistently higher percentages of tobacco was discernible.”
Smoking infor- diseased areas than the nonsmokers. But the statement
mation avail- of the authors implies thal these differences were not
able only on slatistically significant when subjected to an analysis
566 males, of variance.
Strong 747 males 20 Interview with Basal Group (excluding diseases related to smoking or The authors conclude that: This report concerns only
et al. 64 years of next of kin CHD). Mean percentage of coronary artery internal “Atherosclerotic in- ages 25-4.
1969 age autopsied within & weeks surface involved with raised lesions (number of cases). volvement of aorta and No data on statistical
USA, between 1963 of death. White coronary arteries is significance provided.
1966 at Charity 2-34 3544 4554 55-64 greatest in heavy
Hospital in NS occ cccc cc cceeeeteeceeeeer ter ees 45) 1914) 206) = 8(11) smokers and least in
New Orleans. 1 24 cigarettes. day 14) 17(10) 2616) 3&7) nonsmokers.”
‘25 cigarettes: day 149) 31(14) 2625) 320)
Negro
NG oot 414) 3(8)—1{11)—17(14)
1 24 cigarettes day ...... beset eeees (39) 11381) 1430) —-28(22)
S25 cigarettes day o..00.000000.. 1110) 1417) 29(12) 161)
1Unteas otherwise specified, disparities between the total number of individuals and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-
smokers.

SOURCE: U.S. Public Health Service (1.9%).
particularly cigarettes. The trend in such data is that a history of
cigarette smoking is associated in a dose-related manner with the
severity or extent of aortic or coronary atherosclerosis. In some
studies, the differences in atherosclerosis between smokers and
nonsmokers are statistically significant. In others, the trend is
congruent but not statistically significant. These autopsy studies
documenting smoking behavior have generally not permitted analysis
for risk factors other than smoking that might affect the severity of
atherosclerosis, and have not permitted multivariate analysis common
in the large prospective population studies dealing with the morbidity
and mortality of heart attack.

A recent report (132) has provided additional information by
analyzing its data in two categories according to the presence or
absence of diseases associated with smoking on the one hand
(emphysema, lung cancer) and coronary heart disease on the other
{myocardial infarction, hypertension, diabetes, stroke). Atherosclerotic
involvement of both the coronary arteries and aorta was greatest in
heavy smokers and least in nonsmokers in the total sample of 1,320
men, and in each of the two categories of disease noted above. This
study of men aged 25 to 64 years represents the examination at
autopsy of residents of the Greater New Orleans area who died in
Orleans parish from any cause. Smoking history information, general-
ly, was obtained retrospectively from a respondent with a close
knowledge of the decedent (88). The WHO study of five towns
reported on the association between smoking and atherosclerosis only
from Yalta (79). The study has less relevance than the New Orleans
study for the United States population. It reported a positive
association between raised plaques in the aorta and smoking. It failed
to find a clear association between coronary artery narrowing or
infarction of the heart and smoking. Calcification of plaques in the
ea and coronary arteries was related to coexisting alechol consump-
ion.

While data from most autopsy series are inadequate for multivariate
analysis, several prospective population studies now have sufficient
standard risk factor data together with autopsy findings to present
Preliminary analyses (131). A prospective study of cardiovascular risk
factors among 8,000 Japanese-Americans living on the island of Oahu
has recently published more extensive systematic pathological findings
on the vessels in 187 autopsies from the cohort in association with prior
risk factor observations. Cigarettes smoked per day were positively
and independently associated with the extent of atherosclerosis
affecting both the aorta and coronary arteries. The aortic regression
‘eefficient was statistically significant at the 0.05 level and the
“ronary coefficient at the 0.01 level (112).

recent study of autopsies from a Veterans’ Administration
°spital (15) reported that advanced coronary artery atherosclerosis

4—15
was 4.4 times as high in those smoking two packs or more per day as in
those who never smoked. This study also examined the coronary
arteries microscopically and found that fibrous thickening of the
coronary arteries and intramyocardial small arteries was more
frequent in smokers. The most marked difference between smokers
and nonsmokers was found in the arterioles of the myocardium.
Advanced hyaline thickening of arterioles was found in 90.7 percent of
those smoking two or more packs per day, in 48.4 percent of those
smoking less than one pack per day, and in none of those who never
smoked regularly. The study reported on a selected series of 1,056
autopsies from which coronary arterial disease deaths, diabetes, and
those with hearts weighing more than 500 g were excluded. A recent
report (98) reaffirms the occurrence of intramyocardial small-artery
sclerosis in smokers. A decrease in arteriolar muscle wall thickness in
the myocardium, especially in smokers, was found that was attributed
to a lower blood perfusion pressure distal to the small artery lesions
noted above.

Overall, there does not appear to be substantial reason to doubt that
male cigarette smokers examined at autopsy manifest more coronary
and aortic atherosclerosis than nonsmokers. The effect is dose-related.
Hyaline thickening of arterioles in the heart apparently is strongly
associated with smoking. Specific morphological features of plaques
that would be characteristic of smoking have not been delineated.

Experiments in Animals

Table A23 (pp. 116-118) of the 1976 report, The Health Consequences of
Smoking (138), lists seven experiments in which nicotine had inconsis-
tent effects on both spontaneous and diet-induced atherosclerotic
lesions in rabbits. In an additional paper, Schievelbein (120) has
reported no induction of spontaneous arteriosclerotic lesions by
nicotine in rabbits, although the aortic content of free fatty acids and
of calcium was reported increased in this long-term experiment.
Fisher, et al. (42) reported no increase in atherogenic effect with smal]
doses of nicotine in animals that were also hypertensive and fed
cholesterol.

These experiments have involved the injection or oral administration
of nicotine rather than inhalation and generally have employed
unusually large doses of nicotine. Equivalent experiments in species
such as swine or nonhuman primates that might be preferable to
rabbits have apparently not been performed, nor have experiments
that simultaneously involve whole smoke or carbon monoxide (CO)
administration. The overall impression from available data is that
nicotine does not affect atherogenesis in animals. Specific experimen-
tal data, however, are unavailable to permit a conclusion about a
possible effect on experimental atherogenesis of nicotine inhaled in
smoke in doses experienced chronically by smokers.

4—16
A small number of experiments involving the effect of CO on
atherogenesis have been reported. Initial reports found an enhance-
ment of atherogenesis in the aorta of cholesterol-fed rabbits (13, 14)
and in the coronary arteries, but not the aorta, of squirrel monkeys
(148). However, subsequent experiments (130) on cholesterol-fed
rabbits from the same laboratory, which had earlier concluded that
there was a positive effect of CO on atherogenesis, have led to the
conclusion that there is no direct enhancement of cholesterol accumula-
tion in the aorta. These more recent short-term experiments controlled
dietary hypercholesterolemia by pair feeding and also studied the
uptake of radioactive tracer cholesterol from the blood by the aorta.
No macroscopically visible atherosclerotic lesions were seen in any
animals, although the aortic free cholesterol of the animals fed
cholesterol was increased in comparison with the animals receiving no
cholesterol. The free cholesterol content of the aortic arch was
increased significantly in the animals exposed to CO, but there were no
significant differences for the thoracic aorta or for the combined
segments. The aortic uptake of labeled cholesterol from the blood was
not affected by CO exposure in either hypercholesterolemic or normal
animals. The authors suggest that their earlier result may have been
due to a relative excess of hypercholesterolemia in CO-exposed animals
that had not been pair fed to maintain equal levels of plasma
cholesterol. Possible effects of CO diminishing VLDL secretion and
chylomicron catabolism have been discussed by Topping (136). Other
recent studies by Davies and colleagues (32) failed to find that
exposure of cholesterol-fed rabbits to CO for 4 hours per day yielding
carboxyhemoglobin (COHb) levels of 20 percent produced any differ-
ences in the aortic content of lipids including cholesterol. The
morphological extent of coronary atherosclerosis was greater in the
animals exposed to CO. Malinow and associates (80) failed to find an
enhancing effect of CO in sodium chloride and cholesterol-fed
cynomolgus monkeys. In experiments (2) with White Carneau pigeons
(which develop fibro-fatty spontaneous as well as dietary atherosclero-
sis), no enhancement of spontaneous aortic atherogenesis was found
after exposure to CO. Enhancement of coronary atherogenesis was
seen in cholesterol-fed birds exposed to CO and killed after one year of
€xposure, but not in those sacrificed after about a year and a half.
Exposure also enhanced hypercholesteremia. It has been reported that
Spontaneous arteriosclerotic disease in rabbits is aggravated by
exposure to CO (147).

It has been reported that, in rabbits, hypoxia increases cholesterol
atherogenesis and hyperoxia diminishes it (72, 74). Hyperoxia has also

n reported to enhance the regression of plaques in rabbits (139).
Hypoxia and CO have been reported to cause subendothelial edema in
rabbits (13,73) and smoke inhalation (46) to lead acutely to desquama-
“ion of aortic endothelial cells and adhesion of platelets in rabbits.

4-17
Auerbach and associates have reported on the effect of the chronic
inhalation of whole smoke through a tracheostomy apparatus in beagle
dogs. A hyaline thickening of myocardial arterioles was found in them,
the degree of change being related to the duration and amount smoked
(16).

At the present time, animal experiments on atherogenesis and CO
have provided conflicting data and must be regarded as unsatisfactory.
Experiments have variously employed continuous and intermittent
exposure, have estimated lesions biochemically and morphologically,
and have used diverse short- or long-term dietary loads so that
comparisons of results are difficult. Animal experiments remain to be
done in which CO or nicotine are varied in a setting of whole smoke
administered by inhalation without aversive stress and in a suitable
atherogenic context.

Research Needs

While current autopsy data on humans leave no reasonable doubt that
smoking promotes atherosclerosis of the aorta and coronary arteries in
men, equivalent data do not exist for women or for other major
arterial beds. Within practical limits of study, it would be informative
for pathogenetic concepts to have better information on multiple-risk
factors, including oral contraceptives in conjunction with smoking and
with smoking cigarettes of different potential hazard, in autopsy
studies. In particular, it would be of great interest to know the
influence of smoking on the development of the common fatty streaks
and occasional fibrous plaques found at autopsy in adolescents and
young adults.

The mechanisms by which smoking enhances atherogenesis require
elucidation. Such information might assist in the fabrication of a
cigarette less hazardous in terms of atherogenesis and its conse-
quences. Conceptual frameworks and biological systems exist within
which to study the mechanisms by which smoking enhances atherogen-
esis. They include effects on the arterial endothelium, which may alter
its permeability to macromolecules; effects on endothelial-platelet
interactions which influence thrombogenesis or affect the proliferation
of intimal cells; effects on the metabolism of the vessel wall; and
systemic and local effects on lipoprotein or sterol metabolism. With
respect to the monoclonal hypothesis, research to identify mutagens or
promoting agents at the level of the vessel wall is feasible.

A necessary step in such research will be the use of animal models
and biological systems that have a high level of analogy with man and
that are credible both in terms of experimental atherogenesis and in
their exposure to cigarette smoke.

4—18
Conclusions

Cigarette smoking has been shown to enhance the prevalence and
extent of atherosclerosis of the aorta and coronary arteries in men.
Experiments on the effects of nicotine or carbon monoxide on
experimental atherogenesis in animals have produced conflicting
results and are inconclusive. Chronic inhalation of whole smoke is
associated with the development of hyaline thickening of myocardial
arterioles in dogs. In man, cigarette smoking is associated with fibrotic
and hyaline changes in small arteries and arterioles in the myocardium.

Myocardial Infarction
The Nature of Myocardial Infarction

Heart attack as generally understood can comprise nonfatal or fatal
myocardial infarction, cardiac arrest or asystole, and cardiac standstill
or ventricular fibrillation. Asystole and fibrillation result in sudden
cardiac death. These conditions are generally the result of cardiac
ischemia which, in turn, is generally attributable to coronary athero-
sclerosis, although other conditions may uncommonly precipitate heart
attack.

Myocardial infarction is that condition in which a volume of heart
muscle fibers in a discrete part of the heart dies because of inadequate
circulation. It is generally larger than 5mm in diameter and may be
several centimeters in major diameter. It may vary from a small
subendocardial portion of the heart to the full thickness of the
myocardial wall. It may, particularly when subendocardial in location,
impinge on the conducting system of the heart and be conducive to
disturbances in conduction. The infarction may affect primarily the
pumping capacity of the muscle and lead to acute or chronic circulatory
failure. The most common location of infarction involves the left
ventricle, but involvement of the right ventricle and atria is common.
If the myocardial infarction does not prove to be fatal, it may be
subject to local extension during the acute episode of illness. Healing is
by scar formation. The patient is at high risk of a second attack.

The association between atherosclerosis of the coronary arteries and
myocardial infarction is close. Most cases examined at autopsy show an
volvement of about 70 percent or more of the surface of the major
vessels, and more than 50 percent stenosis of the lumen with or
without recent thrombosis. However, a small minority of cases show
less extensive lesions and narrowing, and it has been speculated that
these infarctions may have arisen because of vascular spasm, or

use of transient vascular occlusion by thrombi that have dissolved
after obstructing the coronary circulation.
_Ischemia of a local mass of heart muscle initiates a complex chain of
biochemical, functional, and structural events at the level of the heart
muscle cell that continues to be a subject for intensive research. A

4—19