clinical examination, while among 204 responding negatively, two
were found to have angina by clinical criteria. None of the 11
women who were diagnosed as positive by questionnaire was found
to be clinically affected, and of the 136 reporting as negative, three
had symptoms of angina pectoris.

Other major difficulties associated with these studies include the
problems of using prevalence data in the investigation of a disease
(CHD) from which a significant number of those affected die
shortly after the onset of symptoms, the inclusion of ex-smokers
in the smoking population, and the low numbers of heavy cigarette
smokers in the Swedish population.

In general, the problems of using twin registries to study the
etiology of cardiovascular disease with mortality and morbidity
ratios in the neighborhood of 2 to 1 are much more difficult than
in studying the etiology of bronchopulmonary disease in which the
relationships are of the order of magnitude of 4 to 1.

More recently, Friberg, et al. (69) reported on mortality data
from the Swedish Twin Registry. The authors suggested that part
of the increased mortality observed among smokers when com-
pared with nonsmokers was not due to smoking per se but to fac-
tors associated with smoking. The very small numbers of total
deaths presently available (47 deaths among 706 dizygotic pairs
and 13 deaths among 246 monozygotic pairs) do not provide a sta-
tistically stable base for deriving any conclusions at the present
time.

Hauge, et al. (87) have recently reported on the influence of
smoking on the morbidity and mortality observed in the Danish
Twin Register. Among 762 monozygotic and same-sexed dizygotic
twin pairs, angina pectoris was found to be significantly more fre-
quent in those cotwins with a higher consumption of tobacco than
in those with a lower or no consumption. A similar tendency was
observed for myocardial infarctions but was not of statistical
Significance,

Seltzer, who has been a proponent of the constitutional hypothe-
sis, in a recent review of some of the experimental, clinical, and
pathological data relating smoking and CHD, concluded that the
evidence from these areas has not “reasonably substantiated” the
“hypothesis” of the acute effect of cigarette smoking on the coro-
nary circulation, nor has the chronic effect of cigarette smoking on
the cardiovascular system been shown to be a “clear” and con-
sistent one (170). His views are contrary to those of most re-
searchers in this field.

Although the data from the twin studies are inconclusive with
regard to a role for genetic factors in heart disease, it would be
Surprising if genetic factors did not play such a role. It is open to

51
question whether findings from twin studies can be used to distin-
guish between the hypothesis that genetic factors govern the level
of host susceptibility or resistance to the effects of an exogenous
influence such as cigarette smoking and the hypothesis that genetic
factors “cause” both heart disease and smoking.

AUTOPSY STUDIES RELATING SMOKING,
ATHEROSCLEROSIS, AND SUDDEN CHD DEATH

A number of researchers have investigated the cigarette smoking
habits and the cardiovascular pathology of those individuals dying
suddenly from CHD and of large populations of individuals with
and without histories of overt CHD.

Spain and Bradess (175) recently analyzed the smoking habits
of 189 individuals who died suddenly and unexpectedly, apparently
from the first acute clinical episodes of CHD. The authors noted a
close correlation of a history of cigarette smoking with this type
of sudden death and also with shorter survival times following the
acute episode. This association was strongest in those persons
under 50 years of age.

The authors also observed that those surviving very short pe-
riods of time showed a notable lack of intracoronary artery throm-
bi at autopsy and that the frequency of thrombi present increased
with increasing survival time. They suggested that thrombi found
at autopsy may be the result rather than the cause of certain
instances of myocardial infarction, particularly of lesions showing
subendocardial necrosis. This finding is of significance in the study
of the effect of smoking on myocardial metabolism and oxygen
supply and demand rather than on thrombus or platelet plug
formation.

While the autopsy study of Spain and Bradess (175) concerned
sudden death among smokers, other autopsy studies from various
countries have been directed towards the relationship of cigarette
smoking to the presence of atherosclerotic disease in the aorta and
coronary arteries. These are concerned with the long-term effects
which smoking has on the cardiovascular system and are sum-
marized in table 19. The studies of Auerbach, et al. (12), Avtan-
dilov, et al. (12), Sackett, et al. (165), and Strong, et al. (182)
found that aortic and coronary atherosclerosis were more common
and more severe among smokers than among nonsmokers. Auerbach,
et al. (12) noted that this relationship persisted when the cases
were matched for both age and cause of death or when the follow-
ing cases were excluded; men with a history of diabetes; men who
had died of any type of heart disease; and men whose hearts
weighed 400 grams or more. Sackett, et al. (765) found that the

52
es

(Figures in parentheses are number of individuals in that smoking category)!

[SM = smokers

NS = nonsmokers]

 

 

 

Author,
year, Autopsy Data
country, population collection Cigarettes per day Conclusions Comments
reference
Wilens 989 consecutive Routine clinical Severity of aortic sclerosis 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 NS wi. ee sees 9.9(161) 60.2 29.8 degree of sclerosis at Each aorta specimen given
U\S.A. City VA present <20 . 19.1(152) 63.2 17.8 autopsy was commen- an “atherosclerotic age”
(214). hospitals. admissions. 20-30 .... ee eee 26.4 (288) 62.5 11.1 surate with age of patient, by comparison witha
>30 coerce e F25.1(199) 61.3 $13.6 regardless of smoking standard, If ‘‘athero-
habits. In the remaining sclerotic age’ was found
40 percent there is evi- to be 10 years more than
dence that cigarette real age, the aorta was
smoking may be asso- said to show above-
ciated with an above- average sclerosis.
average degree of aortic tp<(0.001 comparing 9.9
sclerosis. with 25.1 and 29.8 with
13.6.
Auerbach, 1,372 autopsies Interview with Degree of coronary artery atherosclerosig (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 sclerosis Slight Moderate Advanced coronary atherosclerosis
(12). Jersey, VA NS vee ee BB (69) 57.3 21.8 15.3 was higher among ciga-
hospital for Current rette smokers than among
whom smoking cigarette nonsmokers and that the
habit data were <20 .....,2.6(139) 30.9 37.3 29.2 percentage increased
available and 20-39 ....0.8(299) 19.7 42.1 37.4 with amount of cigarette
who did not >40 ......0.6(144) 18.1 35.4 45.9 smoking. This relation-
have overt CHD ship persisted even
at death. when cases were matched

for age and cause of
death.

 

1 Unless otherwise specified, disparities between the total number of in-
dividuals and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellaneous, mixed, or ex-smokers.
vs

TABLE 19.—Autopsy studies of atherosclerosis (cont.)
(Figures in parentheses are number of individuals in that smoking category )+

[SM = smokers

NS = nonsmokers]

 

 

 

Author,
year, Autopsy Data
country, population collection Cigarettes per day Conclusions Comments
reference
Avtandilov, 259 male and Not specified, Comparative size of mean area of atherosclerotic lesions 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.
qs). 220 NS. SM NS SM NS right coronary arteries {T-test for significance
30-39 .. $15.5 (30) 1.8 (32) $6.3 2.2 with less severe changes of difference between
40-49 .. 23.6 (34) 11.5 (27) 15.8 4.4 in circumflex artery means is significant
50-59 .. 136.3 (39) 14.8 (39) $27.9 9.9 and aorta. at p<0.05 level.
60-69 .. $31.9 (32) 23.8 (36) $26.5 22.5
70-79... 41.9(18) 31.7 (36) 26.1 35.8
Sackett, 893 total, Patient The results concerning aortic atherosclerosis are given in The authors conclude that
etal. including 433 interview on form of figure presentation of ridit-analysis. among males, “... &
1968, male and 450 admission. large increase in the
ULS.A. female (white) severity of aortic athero-
(165). patients autop- sclerosis occurred in the

sied at Roswell
Park Memorial

Hospital.
Represents all

deaths 1956-1964

exclusive of 81
male pipe and
cigar smokers
and 55 incom-
plete files.

1 Unless otherwise specified, disparities between the total number of in-
dividuals and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellaneous, mixed, or ex-smokera.

groups using either ciga-
rettes only or both ciga-
rettes and alcohol as
compared with the group
using neither cigarettes
nor alcohol... there
was only a small and
statistically insignificant
difference between the
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.
Ss

TABLE 19,-Autopsy studies of atherosclerosis (cont.)
(Figures in parentheses are number of individuals in that smoking category)!

[SM = smokers NS = nonsmokers]

 

 

 

Author,
year, Autopsy Data
country, population collection Cigarettes per day Conclusions Comments
reference
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 be-
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
(200), 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 that these differences were not
able only on statistically 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
etal, 64 years of next of kin CHD). Mean percentage of coronary artery internal ‘Atherosclerotic in- ages 25-64.
1969 age autopsied within 8 weeks surface involved with raised lesions (number of cases). volvement of aorta and No data on statistical
U.S.A. betwen 1963— of death. White coronary arteries is significance provided.
(182). 1966 at Charity 25-84 S5—-44 45-54 55-64 greatest in heavy
Hospital in NS ooo eee eee ee eee 2 (5) 19(14) 20 (6) 80(11) smokers and least in
New Orleans. 1-24 cigarettes/day . 9(14) 17(10) 26(16) 39 (7) nonsmokers.”
>25 cigarettes/day --12 (9) 31(14) 26(25) 3920)
Negro
NS woe eee ee ee ees 414) 8 (8) 16011) 17(14)
1-24 cigarettes/day .... 3(39) 11(31) 14(30) 28(22)
>25 cigarettes/day --17(10) 14017) 29082) 16 (11)

 

1Unless otherwise specified, disparities between the total number of in-
dividuals and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellaneous, mixed, or ex-smokers.
severity of aortic atherosclerosis, as measured both by intensity
and duration, increased with increasing use of cigarettes and that
this dose-relationship persisted when the patients were matched
for the consumption of alcohol. On the other hand, Viel, et al.
(200) concluded from their study of accidental deaths in Chile
that “no relationship. between atherosclerotic lesions and the use
of tobacco was discernible.” Examination of the data (provided in
graph form only) indicates that heavy smokers showed consistently
higher percentages of diseased areas than nonsmokers, but appar-
ently these differences were not statistically significant when sub-
jected to an analysis of variance.

Thus, in addition to the acute effects which smoking exerts on
cardiovascular physiology, cigarette smoking is associated with a
significant increase in atherosclerosis.

EXPERIMENTAL STUDIES CONCERNING THE
RELATIONSHIP OF CORONARY HEART DISEASE
AND SMOKING

Several areas of interest in cardiovascular pathophysiology have
been investigated in the search for the mechanisms by which ciga-
rette smoking contributes to cardiovascular disease, particularly
coronary artery disease. Previous Public Health Service Reviews
(191, 192, 198, 198) have described in detail and commented on
the results of experiments by many teams of researchers.

Central to the discussion which follows is a concept of cardiac
physiology which provides a framework for analysis and under-
standing of the varied research. That concept concerns the dynamic
balance between myocardial oxygen need and supply.

CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE

The inhalation of tobacco smoke or the parenteral administra-
tion of nicotine has been found by many researchers to be asso-
ciated with a number of specific acute cardiovascular responses.
These responses have been observed in human as well as animal
subjects, including increased heart rate, blood pressure, cardiac
output, stroke volume, velocity of contraction, myocardial contrac-
tile force, myocardial oxygen consumption, arrhythmia formation,
and electrocardiographic or ballistocardiographie changes (tables
A20 to A22). The effect of these responses on coronary blood flow
will be discussed in a following section.

That the acute effects observed following the inhalation of ciga-
rette smoke are due primarily to the nicotine present in the smoke
may be seen in the results of a number of experiments. In humans,
Irving and Yamamota (89) and Von Ahn (202) duplicated the

56
effects of cigarette smoking by the administration of nicotine intra-
venously. Similar results in animals were noted by Kien and
Sherrod (712).

The mechanism by which cigarette smoke and hence nicotine in-
duces these changes has been of interest to numerous investigators.
Nicotine has long been known as a stimulator of both sympathetic
and parasympathetic ganglia. Research has centered, therefore, on
the function of catecholamines, mainly epinephrine and norepi-
nephrine, as mediators, of these responses. Using isolated rabbit
atrial myocardium, Burn and Rand (85) noted that the prior ad-
ministration of reserpine to the perfusate blocked the increased
rate and amplitude of contraction seen following the administra-
tion of nicotine. West, et al. (208) showed that the in vivo cardiac
stimulating effect of nicotine was blocked by tetraethylammonium
chloride. Leaders and Long (125), Romero and Talesnik (156),
and, more recently, Ross and Blesa (160) have all demonstrated
this blockade in animals using agents such as pentolinium, hexa-
methonium, guanethidine, and reserpine.

More direct evidence of the catecholamine-releasing effect of
nicotine has been found by Watts (203) and Westfall, et al. (209,
210, 211) (table A22). Among animal subjects, nicotine adminis-
tration and the inhalation of the smoke of standard cigarettes
caused significant increases in peripheral arterial epinephrine lev-
els, while cornsilk cigarette smoke inhalation evoked no such
change. In humans, cigarette smoking was found to be associated
with a significant increase in urinary epinephrine excretion,

The source of these nicotine-released catecholamines, particu-
larly those which mediate the immediate and local cardiac re-
sponses to intracoronary injections of nicotine, is felt to be the
myocardial chromaffin tissue (35, 160). The more widespread
effects are most probably mediated by hormones released from the
adrenal gland.

According to recent research of Saphir and Rapaport, catechol-
amine release may not be the sole mediator of these responses
(166). These investigators reported that intra-arterial injections
of nicotine into the mesenteric circulation of cats were followed
within 1 to 2 seconds by enhanced myocardial performance, in-
creased left ventricular systolic pressure, and increased systemic
resistance. Sectioning of the mesenteric afferent nerves led to a
diminished response. The authors concluded that the cardiovascu-
lar response to nicotine may also be neurogenic in nature. Nadeau
and James (142) injected nicotine directly into the sinus node
artery of dogs and noted an initial bradycardia, due probably to
direct vagal stimulation, followed by tachycardia, due probably to
catecholamine release.

57
That the presence of nicotine may predispose the myocardium,
particularly a hypoxic or previously damaged myocardium, to ar-
rhythmia formation is suggested by the research of Balazs, et al.
(16), Bellet, et al. (21), and Greenspan, et al. (74). Balazs pro-
duced myocardial lesions in dogs either by pretreatment with iso-
proterenol or ligation of the anterior descending coronary artery.
It was found that while normal animals did not develop arrhy-
thmias upon challenge with small doses of intravenous nicotine,
the animals with damaged myocardiums responded with increased
arrhythmia formation shortly after their spontaneous arrhythmias
had ceased. More recently, Bellet, et al. (20) studied the effect of
cigarette smoke inhalation on the ventricular fibrillation threshold
in anesthetized dogs. They observed a statistically significant de-
crease in the threshold following smoke inhalation. Greenspan, et
al. (74), using isolated dog right ventricular myocardium, ob-
served that nicotine perfusion increased the automaticity of the
Purkinje fibers system and decreased the conduction velocity. The
authors consider that these two nicotine-induced effects probably
predispose the myocardium to the initiation of arrhythmias.

CORONARY BLOOD FLOW

Studies in animals and humans (tables A20, A21) have noted
alterations in coronary blood flow (CBF) following the inhalation
of cigarette smoke or the administration of nicotine. Generally,
exposure of the normal subject to these agents results in an in-
crease in flow. Kien and Sherrod (112), Leb, et al. (126), Ross
and Blesa (160), Travell, et al. (189), and West et al. (208),
working with normal animals, and Bargeron, et al. (17), working
with normal humans, have demonstrated this response. As with
the other cardiac responses to the administration of nicotine, it has
been found that the augmentation in CBF is most probably due to
the release of catecholamines. Using instantaneous coronary arte-
rial flow measurement in dogs, Ross and Blesa (160) were able to
reproduce the effects of intracoronary nicotine with the adminis-
tration of epinephrine and were able to block the response to nico-
tine by pretreatment with pentolinium.

The direct action of catecholamines on the coronary arteries
may not, however, be solely responsible for the increase in CBF
seen with cigarette smoking and intravenous nicotine administra-
tion. It appears that the catecholamine-induced increase in myo-
cardial work and therefore in myocardial oxygen requirement is a
prerequisite for the increase in CBF. Kien and Sherrod (112),
using tracheostomized dogs, found that without blood pressure and
cardiac output changes CBF did not increase following either the
inhalation of cigarette smoke or the administration of nicotine

58
intravenously, although CBF did increase following such changes.
Recent work by Leb, et al. (126) has utilized Rb* as a radioactive
marker in order to distinguish capillary flow from overall total
CBF. The authors consider that this capillary flow represents that
portion of CBF which is effectively involved in nutrient and
oxygen exchange. The researchers observed that the increase in
effective coronary flow was almost proportional to the nicotine-
induced increase in myocardial oxygen consumption. However, the
increase in total coronary flow which may be due to increased
myocardial shunting was far in excess. Thus, the increased work
evoked by the effect of nicotine on the myocardium may induce
local hormonal release in the myocardium and coronary vessels
leading to coronary vasodilatation and increased CBF.

This homeostatic response to increased work appears to be fully
effective only in the subjects with normal coronary arteries. Bellet,
et al. (22), working with normal dogs and dogs that had under-
gone either coronary artery ligation or artificially-induced coro-
nary artery narrowing, noled that the increase in CBF following
the intravenous administration of nicotine was significantly less
among the animals with coronary insufficiency. Work with humans
discussed above has revealed a similar increase in CBF with smok-
ing in normals. Regan, et al. (154) studied seven men with EKG-
proven myocardial infarction and observed that cigarette smoke
evoked slight increases in myocardial oxygen consumption in only
three patients and caused no overall rise in CBF. A number of
other investigators have noted that patients with overt CHD do
not respond to the stimulus of cigarette smoke as readily as do
normals (67, 149, 164).

Thus, patients with compromised coronary circulation may not
be capable of increasing their coronary flow in the face of the in-
creased demands of a myocardium stimulated by nicotine or ciga-
rette smoke. In the normal state, the heart responds to increased
oxygen demands by increasing coronary flow because even at rest
oxygen extraction is almost at a maximal level. Any further in-
crease in extraction may produce coronary sinus pO, values incom-
patible with proper tissue oxygenation.

CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE

Carbon monoxide (CO) is a colorless and odorless gas, low
levels of which have significant effects on human and animal physi-
ology which are just now beginning to be understood, According
to Wynder and Hoffmann (215), it is present in cigarette smoke
in concentrations of approximately 2.9 to 5.1 percent. The concen-
tration of CO in smoke is subject to many factors, among them

59
the type of tobacco and the porosity of cigarette paper. The con.
centration of CO in smoke has been found to increase significantly
toward the last puffs of the cigarette.

According to Chevalier, et al. (41 ), a concentration of approx.
mately 4 percent CO in cigarette smoke will produce alveolar levels
of around 0.04 percent which, equilibrated with hemoglobin, result
in carboxyhemoglobin (COHb) concentrations of from 3 to 10 per.
cent. A number of investigators have compared COHb levels in
smokers and nonsmokers. Goldsmith and Landaw (73) reported
the analysis of expired air samples obtained from 3,311 longshore.
men. Using a regression analysis, they calculated the concentra.
tion of COHb and found that nonsmokers showed levels of 1.2 per.
cent while those smoking over 2 packs per day had levels of 6.8
percent and that smokers of lesser amounts had intermediate
levels. Occupational exposure accounted for the mean nonsmokers’
level being over 1.0 percent, an unusual finding in comparison with
other studies. Kjeldsen (113) interviewed and obtained blood
samples from 934 CHD-free smokers and nonsmokers. The mean
COHb level for 196 nonsmokers was 0.4 percent while all inhaling
smokers had a mean level of 7.3 percent. All 416 cigarette smokers,
regardless of inhalation or amount smoked, showed a mean level
of 4.0 percent.

Carbon monoxide has many varied and Significant effects on
human physiology. An overall review of these effects may be found
in a discussion by Lilienthal (127) or more recently in an exten-
sive review by the United States Public Health Service National
Air Pollution Control Administration (7 94). Apart from its effects
on respiratory and circulatory function, CO has been found to
affect certain central nervous system functions adversely. These
effects are probably due to interference by CO with the proper
oxygenation and oxidative metabolism of the tissue in question.

CO interferes with oxygen transport in a variety of ways. First,
the affinity of hemoglobin for CO is approximately 200 times
greater than its affinity for oxygen, and thus CO can easily dis-
place oxygen from hemoglobin. Second, CO shifts the oxyhemo-
globin dissociation curve. By increasing the avidity with which
oxygen is bound by hemoglobin, CO interferes with O, release at
the tissue level. This is of greatest importance at the tissue level
where the oxygen content of the capillary blood has been reduced
to approximately 40 percent saturation. Here the shift can sub-
stantially decrease the oxygen tension supplying the tissues.

Third, and of more recent note, is the possible interference by
CO with the homeostatic mechanism by which 2, 3-diphosphogly-
cerate (2, 3-DPG) controls the affinity of hemoglobin for oxygen.
Bunn and Jandl (34) have recently reviewed the various experi-

60
ments concerning this glycolytic intermediate. The question of
whether the low levels of CO present in the blood of smokers can
affect this homeostasis is presently under investigation (29, 143),
and firm conclusions cannot be drawn at this time.

Apart from its effect on hemoglobin affinity, CO appears to
induce arterial hypoxemia, and this may act as an additional cause
of tissue hypoxia. Ayres, et al. (74, 15) observed unexpectedly that
exposure of individuals to CO sufficient to raise their levels of
COHb to between 5 and 10 percent was associated with a signifi-
cant fall in arterial pO.. Greater fall in venous pO. was noted,
but this was considered secondary to increased tissue extraction.
In a recent article, Brody and Coburn (30) suggested that this
COHb-induced arterial hypoxemia was due to the interaction of a
number of factors. These authors noted that in the presence of
veno-arterial shunts or of an imbalance in the ventilation-perfu-
sion ratio, the shift in the oxyhemoglobin dissociation curve in-
creased the alveolar-arterial O. gradient and resulted in arterial
hypoxemia. The presence of shunts as smal] as 2 percent of cardiac
output as well as of approximately 10 percent COHb was found
to cause an increase in the gradient. Such ventilation-perfusion
(V/Q) abnormalities have recently been noted even in asymp-
tomatic smokers (see Chapter on Chronic Obstructive Broncho-
pulmonary Disease). The increased levels of COHb found in the
blood of smokers may interact with these V/Q abnormalities to
further decrease available oxygen.

In normal individuals, coronary flow can increase to meet the
increased oxygen demands of a stressed myocardium (as that
under nicotine stimulation), while in individuals with severe CHD
coronary flow cannot respond as readily. In such cases, myocardial
oxygen extraction must be increased above the almost maximal
extraction found at rest. Any interference with arterial oxygen
levels or hemoglobin affinity could very well decrease available
oxygen supplies below the level required for proper tissue func-
tion. That this occurs is suggested by the experiments discussed
below.

Chevalier, et al. (41) exposed 10 young nonsmokers to CO con-
centrations sufficient to induce COHb levels of approximately 4
percent, Taking measurements from blood specimens obtained at
cardiac catheterization under resting and exercise conditions, the
authors noted that the ratio of oxygen debt to oxygen uptake in-
creased significantly under conditions of increased COHb. Accord-
ing to the investigators this implied that the same work was being
done at a greater metabolic cost. These same authors (121, 122)
had previously noted similar findings among smokers and observed

61
that cessation of smoking was associated with a significant im.
provement in oxygen debt accumulation.

More recent work by Ayres, et al. (15) has focused on the dif.
ference in response to CO exposure between 7 normals and 4 pa-
tients suffering from CHD (proven arteriographically) . The induc.
tion of a COHb concentration of approximately 9 percent in the
normals was followed by an increase in coronary blood flow, a
decrease in hemoglobin-oxygen percent extraction and no change
in myocardial oxygen consumption, coronary sinus oxygen tension,
and lactate and pyruvate extraction ratios. The induction of simi-
lar COHb levels in the CHD patients was followed by no change
in coronary blood flow, a decrease in the hemoglobin-oxygen ex-
traction ratio, and no change in myocardial oxygen consumption,
However, these patients did manifest a decrease in coronary sinus
pO, as well as a decrease in lactate and pyruvate extraction. The
latter measures indicate that the myocardium was functioning
under hypoxic conditions. Because the coronary flow could not in-
crease and because the myocardium could not extract O. from
HbO, which was under the influence of CO, coronary sinus oxygen
tension decreased to a point which could inactivate certain oxida-
tive enzyme processes. Thus, the myocardial function of persons
with CHD may be unable to compensate for the stresses induced
by smoking.

Although COHb levels resulting from the CO present in the
atmosphere during pericds of high air pollution are much lower
than those due to the inhalation of cigarette smoke, these concen-
trations of COHb might contribute to the manifestations of CHD.
Cohen, et al. (44) studied the case fatality rates for patients ad-
mitted to 35 Los Angeles area hospitals with myocardial infarction
in relation to atmospheric CO pollution. The authors observed an
increased MI case fatality rate in areas of increased pollution, and
then only during periods of relatively increased CO pollution.

An area of interest which has been discussed in previous reports
concerns the presence of hydrogen cyanide in tobacco smoke.
According to Wynder and Hoffmann (215), the amount present
ranges from 11 to 32 micrograms HCN per puff. It is known that
a significant amount of this material is detoxified to thiocyanate
and excreted as such in the urine or saliva. However, cyanide is a
potent inhibitor of oxidative metabolism. Such inhibition of myo-
cardial oxidative metabolism may be of importance when combined
with the other factors mentioned above which tend to decrease the
oxygen supply available and increase the need for oxygen on the
part of the myocardium.

62
EFFECTS OF SMOKING ON THE FORMATION OF
ATHEROSCLEROTIC LESIONS

A number of autopsy studies have demonstrated a significant
association between cigarette smoking and the presence of aortic
and coronary artery atherosclerosis, even in men without a his-
tory of clinical CHD. The possible pathophysiologic mechanisms
for the atherogenic influence of cigarette smoking are discussed
in this section.

A number of investigators have studied the effect of nicotine
administration, either subcutaneously or intravenously, upon athe-
rosclerotic changes in the aorta and coronary arteries of animals
(table A283). When administered alone, nicotine induces certain
necrotic changes in the arterial wall. However, in combination
with the administration of increased amounts of cholesterol] in the
diet, nicotine aggravates either subendothelial fibrosis (75) or
definite atheromatous lesions (46, 75, 80, 130, 178). Studies by
Choi (42) and by Wenzel, et al. (207) did not demonstrate this
synergism between cholesterol and nicotine.

The other major cigarette smoke component under discussion
in this chapter, carbon monoxide, has also been recently implicated
in atherogenesis. Table 24 presents the studies which have related
exposure to CO in combination with increased dietary cholesterol
to both macroscopic and microscopic aortic and coronary athero-
matosis. Astrup, et al. (10) exposed cholesterol-fed rabbits to CO
continually over a period of up to 10 weeks. The experimental
group showed increased aortic atheromatosis over that shown by
the control group, also cholesterol-fed. Kjeldsen, et al. (114)
observed that exposure of rabbits to increased oxygen concentra-
tions significantly reduced the amount of cholesterol-induced
atheromatosis in rabbits. Most recently, Webster, et al. (204) have
extended this research to primates. These investigators found that
cholesterol-fed squirrel monkeys developed significantly more
coronary artery atherosclerosis when exposed intermittently to CO
over a 7-month period than when exposed only to room air.

Recent discussion has centered on the mechanisms whereby CO
can induce these changes (9, 212). Astrup (9), referring to pre-
vious experiments in humans which had shown increased vascular
permeability for albumin upon chronic exposure to CO (11), con-
siders it likely that this increase in permeability allows for in-
creased filtration of lipoproteins into arterial walls. This, he con-
siders, is a primary cause of intimal and medial lipid accumulation
and, therefore, of atherosclerosis.

Another point of view has been stressed by Whereat (212), who
considers the filtration theory to be an inadequate hypothesis for

63
v9

TABLE 24,—Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia

 

 

 

 

 

Author,

year, Number and
country, type of animal Procedure Results
reference

Astrup 24 female Regular diet plus 2 percent The experimental group exposed to carbon monoxide showed increased macro- and
etal., albino rabbits. cholesterol: mieroscopic aortic atheromatosis over that shown by control animals. Micro-
1967 I. (12) control. scopic examination revealed intimal lipoid deposition limited in penetration by
Denmark TI. (12) continual exposure to the internal elastic membrane. Coronary vessels were found to show similar
(70). carbon monoxide: changes. Carboxyhemoglobin. (COHb) levels averaged 15-19 percent during the

0.017 percent for 8 weeks. first 8 weeks and 33 percent during the final 2 weeks.
0.035 percent for 2 weeks.

Kjeldsen 24 castrated male Regular diet plus 2 percent The experimental group exposed to hypoxia showed increased macroscopic aortic
etal, albino rabbits, cholesterol: atheromatosis over that shown by control animals. Microscopic examination re-
1968, T, (12) control. vealed more intimal and subintimal lipid deposition in the aortas of the exposed
Denmark H, (12) continual exposure. rabbits than in those of the nonexposed. The total amount of cholestero! de-
(117). to hypoxia: posited in the aortas of the experimental group was three times higher than in

10 percent-0, for 6 weeks. those of the control group.
9 percent 0, for 2 weeks,

Kjeldsen 24 castrated male Regular diet plus 2 percent Macroscopically, the experimental group showed significantly fewer atheromatous
etal. albino rabbits. cholesterol: changes. Microscopically, the experimental group showed significantly less aortic
1969, I. (12) control. intimal lipid deposition.

Denmark II, (12) exposure to 28 percent
(114). 0 for 10 weeks,

Webster 22 female squirrel Diet containing 0.5 percent The experimental group exposed to carbon monoxide showed a greater mean per-
et al., monkeys. cholesterol and 25 percent fat: centage of coronary arteries with atherosclerotic lesions and more lumen occlu-
1970, I. (10) eontrol. sion among the affected arteries. There were significantly more CO-treated
U.S.A. Il. (12) experimentally exposed to monkeys than control monkeys having 35 percent or more apparent athero-
(204). 200-300 p.p.m. carbon monoxide sclerotic stenosis among the affected arteries. Aortic atherosclerosis was appar-

for 20 hours per week for 7
months.

ently not aggravated by exposure to CO. COHb levels at the end of each exposure
period averaged 16-26 percent during the final 24 weeks of the experiment.

 
mural lipid accumulation. The author notes that when the oxida-
tion of the pyridine nucleotide, nicotinamideadenine dinucleotide
(NAD), is impaired, the reduced form of this nucleotide (NADH)
provides an essential factor for fatty acid synthesis. Fatty acid
synthesis in the aorta and heart is carried out by mitochondrial
enzymes whose hydrogen donor is NADH. Substances which slow
or impair the reoxidation of this compound tend to increase mito-
chondrial fatty acid synthesis (and decrease fatty acid utilization)
in the arterial wall. Carbon monoxide prevents this oxidation proc-
ess both directly and indirectly. Indirectly, it decreases the oxygen
available for diffusion into the tissue. Directly, carbon monoxide
can stall the process of NADH oxidation by combining with cyto-
chrome oxidase. Further research is required into this problem,
particularly in view of the fact that cyanide is also a respiratory
chain inhibitor and thus may also adversely affect arterial wall fat
metabolism.

THE EFFECT OF SMOKING ON SERUM LIPID LEVELS

In the discussion concerning the epidemiological aspects of CHD,
it was noted that increased serum cholesterol was a significant
risk factor for the development of overt CHD. Serum triglycerides
have also been related to CHD incidence. Of concern also is the
immediate effect which cigarette smoking has upon blood lipid
levels.

The studies concerning this immediate effect are presented in
tables A25 and A25a. The table is divided into a section concern-
ing studies on humans (table A25) and one concerning studies
utilizing animals or in vitro systems (table A 25a). Although no
consistent response was noted for serum cholesterol, serum free
fatty acids were found consistently to rise following smoking. As
with other cardiovascular reactions to nicotine and smoking, it
appears that the fatty acid response is also mediated by catechol-
amine release. This relationship has been observed in a number
of experiments by Kershbaum, et al. (105, 106, 108, 109, 110) and
Klensch (118). That nicotine is primarily responsible for this rise
May be seen by reference to the study by Kershbaum, et al. (105)
in which lettuce-leaf cigarettes of minimal nicotine content had a
negligible effect upon serum free fatty acids in comparison with
that of regular cigarettes.

; While attention has been centered upon nicotine as the agent
Inducing the immediate increase in serum lipids, recent studies
have been concerned with the effect of chronic exposure to carbon
monoxide on serum lipid metabolism. These studies are listed in
table A26. Among rabbits fed increased amounts of cholesterol,

65
the authors observed significant increases in cholesterol and tri.
glyceride concentrations in those exposed to CO versus thoge
maintained in a normal atmosphere.

THE EFFECT OF SMOKING ON THROMBOSIS

In the study of CHD, a number of investigators have turned
their attention to thrombosis because myocardia] infarction and
sudden coronary death frequently result from thrombotic events,
A thrombus may be of either gross or microscopic dimensions, and
a minute thrombus at a strategic site may precipitate a fatal ar.
rhythmia. However, thrombotic and prethrombotic states are dif.
ficult to detect except when gross, and the emphasis has been pri-
marily on factors which can be studied conveniently. Coagulation
is now thought to have a secondary role in the consolidation of an
arterial thrombus and little if any in initiating the process. The
prime mechanism in thrombogenesis appears to be the reaction of
the platelet. Several papers have been written about platelet re.
activity in vitro but few about the effect of smoking on platelet
behavior in vivo. The assay of fibrinolysis, which may also be im-
portant, has received scanty treatment. The relevant studies are
listed in table A27. Many of these are discussed in the 1968 sup-
plement (192) and by Murphy (140). Corroborative data are stil]
inconclusive as to whether smoking shortens platelet survival.

OTHER AREAS OF INVESTIGATION

Certain other aspects of cardiovascular pathophysiology may be
of importance in the relationship of smoking to CHD. Glucose me-
tabolism and insulin response, when altered, may alter myocardial
response. This topic has been covered in detail in the 1968 Supple-
ment to the Health Consequences of Smoking (192). Also, varia-
tions in blood hemoglobin and hematocrit may adversely affect
coronary blood flow. A number of studies showing a possible rela-
tionship of smoking to hemoconcentration have been reviewed pre-
viously (791, 192), and the reader is referred to those discussions.

CEREBROVASCULAR DISEASE

The term cerebrovascular disease (CVD) refers to a number of
different types of vascular lesions affecting the central nervous
system: subarachnoid hemorrhage, cerebral] hemorrhage, cerebral
embolism, and thrombosis (ICD Codes 330 to 334), In 1967 in the
United States, a total of 93,071 males and 109,113 females were
listed as dying from CVD as the underlying cause (196).

Epidemiological studies indicate that cigarette smoking is asso-

66
ciated with increased mortality from cerebrovascular disease,
whether CVD is listed as the underlying or as a contributory cause
of death. Table 28 presents the results of the seven major epidemi-
ological studies. The smoking of pipes and cigars does not appear
to increase significantly the risk of dying from CVD. The impor-
tance of high blood pressure and diabetes as risk factors for mor-
tality from CVD has recently been noted by Hammond and Gar-
finkel (76). The data from their study, as presented in table 28,
also indicate that the mortality ratio for cigarette smokers is
greater for persons under 75 years of age than for older
individuals.

Many of the pathophysiologica] considerations discussed in the
sections concerning CHD may also pertain to the relationship of
smoking and CVD, particularly cerebral infarction.

In a study reported by Kuhn (123), 20 habitual smokers re-
frained from smoking for one-half day, and base line retrograde
brachiocerebral angiograms were taken; they then smoked one
cigarette, inhaling deeply, and had repeat angiograms. Those over
60 years of age failed to have significant acceleration of flow as
demonstrated in carbon dioxide inhalation experiments.

More recently, Miyazaki (132) studied the effect of smoking
on the cerebral circulation of 12 moderate/heavy cigarette smokers
as measured indirectly using an ultrasonic Doppler technique to
record internal carotid artery flow. Measurements were made be-
fore and after ordinary smoking and showed an increase in cere-
bral blood flow and a decrease in cerebral vascular resistance in
all subjects. No significant difference in response was observed
between the 4 younger and 8 older (over 60 years of age) subjects.
More research is needed to clarify the role of cigarette smoking
in the acute pathogenesis of CVD manifestations. However, the
chronic effect of smoking upon the cerebral circulation (particu-
larly its extracranial portion) is likely to be similar to the effect
of smoking upon the aortic and coronary atherosclerosis.

NON-SYPHILITIC AORTIC ANEURYSM

Aortic aneurysm is an uncommon but not rare cause of death.
In 1967 in the United States, a total of 8,448 men and 3,173 women
were listed as dying from aortic aneurysm as the underlying cause
(196). Cigarette smoking appears to increase the risk of dying
from this disease, perhaps by promoting the atherosclerotic proc-
ess which underlies this type of aneurysm. As illustrated in table
29, the mortality ratios for cigarette smokers are high relative to
other cardiovascular diseases in which smoking increases the risk,
and the risk increases in proportion to the amount smoked.

67
89

TABLE 28.—Deaths from cerebrovascular disease related to smoking

(Mortality ratios—actual number of deaths shown in parentheses)!
(SM = smokers NS = nonsmokers]

 

PROSPECTIVE STUDIES

 

 

 

 

 

Number of
Author, Follow- deaths due Pipes
year, Number and Data up to CVD as Cigarettes per day and Age variation Comments
country, type of collection years underlying cigars
reference population cause
Hammond 187,783 white Questionnaire 3% 1,050 NS .....,..1.00 (164) t(p<0.01).
and Horn, males in9 and follow- Cigarettes
1958, states 50-69 up of death SM_......£1.30 (556)
U.S.A. years of age. certificate. Other SM ..1.25 (330)
(77, 78). Cigarettes only
<0 ...0.., 1.24 (41)
10-20 ......1.44 (140)
20 ........1.46 (83)
Doll and Approximately Questionnaire 10 605 NS .........1.00
Hil, 41,000 male and follow- ANISM ......1.05
1964, British up of death All
Great physicians. certificate. cigarette 1.12
Britain 1-14 ......1.10
(50). 15-24 eee 1.09
25 14... 126
Kannel 5,127 males Medical 12 130 NS .........4.00 © (5) Data apply only
etal., and females examination Heavy SM to males 30-59
1965 30-59 years and follow- (20)... .3.23 (8) years of age
U.S.A. of age, up. at entry.
(96), Data apply only

to cerebral
infarction.

 

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion of
either occasional, miscellaneous, mixed, or ex-smokers.
69

TABLE 28.—Deaths from cerebrovascular disease related to smoking (cont.)
(Mortality ratios—actual number of deaths shown in parentheses)?

[SM = smokers

NS = nonsmokers]

 

 

 

 

PROSPECTIVE STUDIES
Number of .
Author, deaths due Pipes
year, Number and Data Follow- underlying Cigarettes per day and Age variation Comments
country, type of collection up years to CVD as cigars
reference population cause

Kahn, U.S. male Questionnaire 814 2,008 NS ..1.00 (614) Pipes

1966, veterans and follow- All SM ..1.06 (82)
UVS.A. 2,265,674 up of death current ....1.30(1,894) NS ..1.00(614)
(93). person certificate. Current Cigars

years. cigarettes ..1.52 (692) NS ..1.00(614)
1-9 --1.51 (98) SM ..1.08(135)
10-20 «1.42 (325)
21-39 1.70 (215)
>39 ~1.59 (37)

Hammond 358,534 males Questionnaire 6 4,099 Current tBased on only
and 445,875 and follow- regular Males 5-9 deaths.
Garfinkel, females 40-79 up of death cigarette 40-49 50-59 60-69 70-79
1969, years of age certificate. Never
U.S.A. at entry. smoked 1.00 1.00 1.00 1.00
(76). 1-9 «2.79 1.95 1.30 0.95

10-19 .114 1.48 $1.44 0.92
20-39 .....2.21 2.03 1.62" 1.22
>40 1.2... 1.64 2.40 1,72 $0.68
Females
Never
smoked = 1.00 1.00 1.00 1.00
1-9 . 1.50 1.26 1.26 0.83
10-19 . 2.60 2.70 2.15 $0.57
20-39 » 2.90 2.67 1,83 1.28
>40 .....15.70 £8.52 _ —

 

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion of

either occasional, miscellaneous, mixed, or ex-smokers.
oz

TABLE 28.—Deatlhs from cerebrovascular disease related to smoking (cont.)
(Mortality ratios—actual number of deaths shown in parentheses)!
SM = Smokers. NS = Nonsmokers.

 

PROSPECTIVE STUDIES

 

 

 

 

Paffen- 3,263 male Initial multi- 16 67 NS and
barger, longshoremen phasic <20 .........1.00 (42)
et al. 35-64 years screening >20 .........1.15 9 (25)
1970 of age in and follow-
U.S.A. 1951. up of death
(144). certificate.
RETROSPECTIVE STUDY
Paffen- >50,000 male _—i Initial college Death Rates The 63 deaths from
barger University entrance Cases (158) Controls (615) occlusive stroke
and students medical ex- SM wo. ee eee ee ee ee es 45.0 31.3 (p<0.01) contributed to the
Williams followed up aminations Cigarette SM >10 per day . 20.9 11.2 (p<0.01) statistical sig-
1967 to 50 years. with follow- nificance,
U.S.A. up of death The 95 deaths from
(145). certificate. hemorrhagic
Controls— stroke showed
surviving no statistica}
classmates significance as

age-matched.

a single group.

 

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion of
either occasional, miscellaneous, mixed, or ex-smokers.
Z

TABLE 29.—-Deaths from nonsyphilitic aortic aneurysm related to smoking—prospective studies

(Mortality ratios—actual number of deaths shown in parentheses)?
{SM = Smokers NS = Nonsmokers]

 

 

 

 

 

 

Author,
year, Number and Data Follow-up Number
country, type of collection years of Cigarettes per day Pipés Cigars Comments
reference population deaths

Hammond 187,783 white Questionnaire 3, 68 NS ...+..1,00(25) (expected)

and Horn, males in9 and follow-up SM 1, 2.72 (68) (p<0.005)
1958, states 50-69 of death
U.S.A. years of age. certificate.
(77,78).

Kahn, U.S. male Questionnaire By 491 NS ....cee cece ee ee ee 100 (58) NS ..1.00(58) NS . .1.00(58)
1966, veterans and follow-up Current cigarettes ..5.24(284) SM ..1.138 (8) SM ..2.06(24)
U.S.A. 2,265,674 of death 1-9 cigarettes/day ...2.12 (13)

(98). person years. certificate. 10-20 wi. cece cece eee 5.53 (124)
21-89 2... eee eee 595 (76)
89 eee eee ee ee eee T26 (17)

Hammond 358,534 males Questionnaire 6 337 NS... eee eee 100 Data apply only
and 445,875 females and follow-up 1-9 wo. eee eee 2.62 to males 50-69
Garfinkel, 40~79 years of of death 10-19 .......-- 3.85 years of age.
1969, age at entry. certificate. 20-39 ..........4,54
U.S.A. >40 2.0.2.2... 8.00
(76).

Weir and 68,153 California Questionnaire 5-8 51 NS ...........-1.00 SM include
Dunn, male workers and follow-up All ...........-+2.64 ex-smokers,
1970, 35-64 years of of death #10 oe eee 2.44 NS include pipe
U.S.A. age at entry. certificate. #20 ............2.88 and cigar
(205). 2280 2. eee 2654 smokers.

 

1 Unless otherwise specified, disparities between the total number of
deaths and the sum of the individual categories are due to the exclusion
of either occasional, miscellaneous, mixed, or ex-smokers.
PERIPHERAL ARTERIOSCLEROSIS

Peripheral arteriosclerosis represents the effects on the vaseu-
lature of the extremities of the pathophysiologic processes which
Produce coronary and aortic atherosclerosis. A number of studies
have been concerned with smoking as a risk factor in the develop.
ment of this disease. Kannel, et al. (95) observed, in the Framing.
ham study, that diabetes mellitus and elevated serum cholesterol,
as well as cigarette smoking, were also risk factors in the develop.
ment of peripheral vascular disease.

Juergens, et al. (92) reviewed the records of and contacted 478
male patients with arteriosclerosis obliterans (a severe form of
peripheral arteriosclerosis), who had been patients at the Mayo
Clinic between 1939 and 1948. The diagnosis of this condition was
based upon certain clinical criteria: the presence of intermittent
claudication, the marked diminution or absence of lower extremity
arterial pulsations, and objective trophic manifestations of per-
ipheral limb ischemia. Smoking information was available on 401
patients. These patients were compared with a control group of
350 Mayo Clinic patients of similar age who showed no clinical
evidence of vascular disease. It was found, for males under the
age of 60, that 2.5 percent of the cases and 25 percent of the con-
trols were nonsmokers. However, no difference was noted between
the percentages of heavy smokers in each group. The authors also
implicated high blood pressure and elevated serum cholesterol as
risk factors in the occurrence of this disease.

Begg (19) noted similar findings in a study of 294 male patients
with intermittent claudication who were patients at the Western
Infirmary in Glasgow, Scotland. In comparing the smoking his-
tories of 100 patients with this complaint with those of 116 healthy
male controls, the author found that 1 percent of the patients and
21 percent of the controls had never smoked. A total] of 42 percent
of the patients smoked more than 20 cigarettes per day while only
24 percent of the controls had a similar history of heavy smoking.
The author concluded that smoking, while not a prime cause of
peripheral arteria] disease, is a significant cofactor in its develop-
ment in almost all cases. The author also noted obesity, high blood
pressure, and elevated serum cholesterol as risk factors,

Schwartz, et al. (168) compared the prevalence of risk factors
in four groups of subjects: 141 cases with arteriosclerotic disease
of the lower limbs, 551 cases with coronary arteriosclerosis, 58
cases with both conditions, and finally an indefinite number of
control individuals who had been hospitalized for injuries. The in-
vestigators reported that certain risk factors, including hyper-
cholesterolemia, hypertension, and cigarette smoking, were signifi-

72
cant in both coronary and lower limb arteriosclerosis. The authors
noted that the inhalation of cigarette smoke appeared to be an
important risk factor for coronary arteriosclerosis up to age 55
while in arteriosclerosis of the lower extremities, inhalation ap-
peared to increase the risk even in the older age groups.

Widmer, et al. (213) compared 277 male patients with arterial
occlusion of the limbs as demonstrated by aortography or oscillog-
raphy with 2,082 men demonstrated by oscillography to be free of
arterial disease. The authors found that cigarette smoking, parti-
cularly heavy smoking, was significantly more frequent among the
cases with arterial occlusion than among the controls. Increased
beta-lipoproteins and systolic hypertension were also found to be
more common among the cases.

EXPERIMENTAL EVIDENCE

A number of experimenters have investigated the acute effects
of smoking or nicotine upon the peripheral circulatory system.
These investigators, as listed in table A30, have measured effects
in terms of alterations in skin temperature and blood flow as meas-
ured by plethysmography, radioactive iodinated albumin clear-
ance, or radiosodium clearance from the skin. The majority of
these studies have shown significant decreases in peripheral blood
flow and skin temperature upon smoking, particularly in persons
without manifest peripheral vascular disease, The study of Freund
and Ward (68) demonstrates the difference in peripheral vascular
reactivity found between normals and patients with arterioscle-
rotic changes in the vessels of their extremities. The work of
Strémblad (181) on blockade of this response with automatic SYS-
tem blockers indicates that the reactivity of these vessels is sec-
ondary to the local release of catecholamines. Most probably, the
degenerative changes associated with this disease create a stiffen-
ing of the vessel wall and prevent rapid alteration, particularly
dilatation, in response to the catecholamines liberated by smoking
or nicotine.

THROMBOANGIITIS OBLITERANS

Thromboangiitis obliterans (Buerger’s Disease) (TAO) is an
uncommon obstructive vasculitis primarily involving the arteries
and veins of the extremities. Severely affected patients may even
lose their limbs secondary to ischemic changes. Much discussion
has centered upon the question as to whether this disease is a clin-
ical and pathological entity separate from peripheral arterioscle-
rosis. McKusick, et al. (128) consider it to be a distinct entity

73
while Eisen (57) concludes that TAO is the acute inflammatory
phase of severe arteriosclerosis,

Clinically, it has been shown that smoking aggravates this dis.
ease and cessation of smoking frequently aids in complete or par.
tial remission, Razdan, et al. (153) and Brown, et al. (32) found
very few nonsmokers in groups of patients diagnosed as having
typical TAO. A recent study from Israel (16) involved a case.
control comparison of 46 patients with TAO and 32 matched con.
trols. Although the controls were found to smoke less per day than
the patients, this difference was not found to be statistically sig.
nificant. However, 100 percent of the smoking patients and only
72 percent of the smoking controls were inhalers, a difference sig-
nificant at the 0.02 level.

CARDIOVASCULAR DISEASES
SUMMARY AND CONCLUSIONS

CORONARY HEART DISEASE

1. Data from numerous prospective and retrospective studies
confirm the judgment that cigarette smoking is a significant risk
factor contributing to the development of coronary heart disease
including fatal CHD and its most severe expression, sudden and
unexpected death. The risk of CHD incurred by smokers of pipes
and cigars is appreciably less than that by cigarette smokers.

2. Analysis of other factors associated with CHD (high serum
cholesterol, high blood pressure, and physical inactivity) shows
that cigarette smoking operates independently of these other fac-
tors and can act jointly with certain of them to increase the risk
of CHD appreciably.

3. There is evidence that cigarette smoking may accelerate the
pathophysiological changes of pre-existing coronary heart disease
and therefore contributes to sudden death from CHD.

4. Autopsy studies suggest that cigarette smoking is associated
with a significant increase in atherosclerosis of the aorta and coro-
nary arteries.

5. The cessation of smoking is associated with a decreased risk
of death from CHD,

6. Experimental studies in animals and humans suggest that
cigarette smoking may contribute to the development of CHD and/
or its manifestations by one or more of the following mechanisms:

a. Cigarette smoking, by contributing to the release of catechol-
amines, causes increased myocardial wall tension, contraction

74
velocity, and heart rate, and thereby increases the work of the
heart and the myocardial demand for oxygen and other
nutrients.

b. Among individuals with coronary atherosclerosis, cigarette
smoking appears to create an imbalance between the increased
needs of the myocardium and an insufficient increase in coro-
nary blood flow and oxygenation,

c. Carboxyhemoglobin, formed from the inhaled carbon mon-
oxide, diminishes the availability of oxygen to the myocardium
and may also contribute to the development of atherosclerosis.

d. The impairment of pulmonary function caused by cigarette
smoking may contribute to arterial hypoxemia, thus reducing
the amount of oxygen available to the myocardium.

e. Cigarette smoking may cause an increase in platelet adhesive-
ness which might contribute to acute thrombus formation.

CEREBROVASCULAR DISEASE

1. Data from numerous prospective studies indicate that ciga-
rette smoking is associated with increased mortality from cerebro-
vascular disease.

2. Experimental evidence concerning the relationship of smok-
ing and cerebrovascular disease is at present insufficient to allow
for conclusions concerning pathogenesis. However, some of the
pathophysiological considerations discussed concerning CHD may
also pertain to the relationship of smoking and CVD, particularly
cerebral infarction.

NOoN-SYPHILITIC AORTIC ANEURYSM

Cigarette smoking has been observed to increase the risk of
dying from nonsyphilitic aortic aneurysm.

PERIPHERAL VASCULAR DISEASE

1. Data from a number of retrospective studies have indicated
that cigarette smoking is a likely risk factor in the development
of peripheral vascular disease. Cigarette smoking also appears to
be a factor in the aggravation of peripheral vascular disease.

2. Cigarette smoking has been observed to alter peripheral
blood flow and peripheral vascular resistance.

CARDIOVASCULAR REFERENCES

(1) ACHESON, R. M., Jessop, W. J. E. Tobacco smoking and serum lipids in
old men. British Medical Journal 2: 1108-1111, October 28, 1961.

(2) Apter, I., HENSEL, QO. Intravenous injections of nicotine and their ef-
fects upon the aorta of rabbits. Journal of Medical Research 15:
229-239, 1906,

75