TABLE lg.-Autopsy studies of atheroacletoei.9 (cont.)
(Fhm In prrcnthesn o re number of lndlvldurla In that #moklng e&tcp~t~)'
           [SM = nnoken    NS = nonbmokeml

WC1      1,160 m*ka      IntervIew rlth   The resulti concemlng lnternrl Abrow &e&s and frttlThe authors conclude tbnt:
et IL,     and 290        rclrtlrn.      plaques In the left anterior descending coronmy artery  "No relatlonahlp be-
1868     femrln who             art reported fn uraphic form only, An txsmin%tion of twcln ~thtmsclrmtlc
Chile     died vlolcntly             this data Indlcater that the modernlc and heavy umoken  Mona and the use of
000)     In 1961-1964.              nppcared to ahow consistently hlpher Dcr0enUen of tobacco WM divxmlbls."
        Smoklne Infor-              dlwrsed uenr than the nonsmokcn. But the statement
        mrtlon awlI-              of the authors implies that thcac dlfcrmca were not
        rble only on              rtatlstieally aixniflesnt when rubjreted to in borlyrle
        666 mmln.                 of vsrlwlce.

fbmr    141 mrln 20-     IntervIew rltb   Ilwal Croup (czcludinu dirmwc +rh:rd Lo rmokinp CT The authors conclude tbat: TbL wor( concetpn 0114
et aI,     64 yearn of      next of kin    CHD). Mron percmhps of ~070~~ w!cw inJumuI "Atberoselrmtlc lo-      agea Lb-64.
1969     we ~utoprled     WIthIn 8 WeekJ   rurfecs involved with rairrd JAonr (number of earcr). valvemmf of aotirad    No &tr on atdstld
UQA.    bctrm 196b     of death.                           Whitd          COvJII.lY wierles ll      8lyollkmce Dmrlded.
(J66)     1866 st Chwltl                            ts-34   SK-44   G-K4   K&s4   z`reatmt In bavy
        IkUDltd h               NS I,- . . . . ..I............ 2 (6) 19(14) 20 (6) SO(l1) unokcnmdle~th
        New Orleans.             l-24 cl,nrettn/dw . , , , 9(14) 17(10) 26(16) 29 (7) nonunokm."
                           126 ciewctlcs/day . ...12 (9) Sl(14) 26(26) 89(20)
                                                NWV
                             NS  . . . . . . ..a.......... 4(14)  a 18) 16(11) 17(14)
                          1-24 elrxrettcs/day :.:. s(39) ii ir(a0) 28(22)
                          >26 clmrettes/day  . . ..17(10) 14117) 29(12) 16(111

                                                     .-.
`~IGJW dm-wlre ~~eclAed, dlsparitlcs bctwen the total number of ln-


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, VieI, 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, 19.2, 193, 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, myocardia1 oxygen consumption, arrhythmia formation,
and electrocardiographic or ballistocardiographic 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 experimenti. In humans,
Irving and Yamamota (89) and Von Ahn (202) duplicated the

52


effects of cigarette smoking by the administration of nicotine intra-
VenOUSlY. Similar results in animals were noted by Kien and
Sherrod (112).

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
atria1 myocardium, Bum and Rand (55) 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, 221) (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 cornsi!k 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 (14.2) 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 tb
catecholamine release.

53


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.
(161, 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
bad 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 probabIy
predispose the myocardium to the initiation of arrhythmias.

CORONARY Bmn 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 Bless (160), Travel], et al. (189), and West et al. (208))
working with normal animaIs, and Bargeron, et al. (179, 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 bIock the response to nico-
tine by pretreatment with pentobnium.
The direct action of catecholamines on the coronary arteries
may not, however, be solely responsible for the increase in CRF
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 tracbeostomized dogs, found that without blood pressure and
cardiac output changes CRF did not increase following either the
inhalation of cigarette smoke or the administration of nicotine

54


intravenously, although CBF did increase folIowing such changes.
Recent work by Leb, et al. (126) has utilized Rb8' as a radioactive
marker in order to distinguish capillary flow from overall totai
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, noted 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 normaIs. Regan, et al. (1.54) 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-
r&e 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 p0, values incom-
Nible with proper tissue oxygenation.

CARDIOVASCULAB EPFECTS OF CARBON MONOXIDE

Carbon monoxide (CO) is a colorless and odorless gas, low
levels of which have significant effects on human and animal physi-
ok%?y which are just now beginning to be understood. According
to WCjynder and Hoffmann (21.5). 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

55


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 approxi-
r&&ely 4 percent CO in cigarette smoke will produce alveolar levels
elf around 0.04 percent which, equilibrated with hemoglobin, result
in carboxyhemogIobin (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 IeveIs of 6.8
percent and that smokers of lesser amounts had intermediate
Ievels. Occupational exposure accounted for the mean nonsmokers'
level being over 1.0 percent, an uriusual 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 inhaiing
emokers 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-
aive review by the United States Public Health Service National
Air Pollution Control Administration (ISA). Apart from its effects
Oti respiratory and circulatory function, CO has been found to
affect certain central nervous system functions adversely. These
effecta 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
lz'reater than its afiinity for oxygen, and thus CO can easily dis-
PlsCe oxygen from hemoglobin. Second, CO shifts the oxyhemo-
globin dissociation curve. By increasing the avidity with which
oxygen ia bound by hemoglobin, CO interferes with 0, 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
b Proximately 40 percent saturation: Here the shift can sub-
tintially dec&e the oxygen tension supplying the tissues.

Third, and of more recent note, is the possible interference by
0 with the homeostatic mechanism by which 2, 3-diphosphogly-
-rate (2, 3-DPG) controls the affinity of hemoglobin for oxygen.
BUM and Jandl (54) have recently reviewed the various experi-

36


merits 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, l&?),
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. (14,15) observed unexpectedly that
exposure of individuals to'C0 sufficient to raise their levels of
COHb to between 5 and 10 percent was associated with a signifi-
cant fall in arterial p0 Greater fall in venous pOi was noted,
but this was considered secondary to increased tissue extraction.
In a recent article, Brady 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 small 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-
fomatic 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 COW. Accord-
ing to the investigators this implied that the same work was being
done at a greater metabolic cost. These same authors, (121,162)
had previously noted similar findings among smokers and observed

57


that cessation of smoking was associated with a significant im-
provemeat 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 pi pa-
tients suffering from CHD (proven arteriographically). The induG
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,
.&id lactate and pyruvate extraction ratios. The induction of simi-
Iar COW 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
p0, 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 couId not extract 0, from
IGO, which was under the influence of CO, coronary sinus oxygen
tension decreased to a point which could inactivate certain oxida-
five 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 periods 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 (225), 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 f&e other factors mentioned above- which tend to decrease the
oxygen supply available and increase the need for oxygen on the
part of the myocardium.

58


EFFECTS OF SMOKING ON THE FORMATION OF

          ATHEXOSCLER~T Ic LESIONS
A number of autopsy studies have demonstrated a significant

association between cigarette smoking ar.d 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 A23). When administered alone, nicotine induces Cedin
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 (7.5) or
definite atheromatous lesions (46, 75, 80, 130, 178). Studies by
Choi (AZ) 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. (II&)
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 T-month period than when exposed only to room air.

ReceCt 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 (II), 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 (ZIZ), who
considers the filtration theory to be an inadequate hypothesis for

59


TABUS !U.-Expdmnta evncedng the athemgmic efect of carbon monde ezpoeure and hyporia

Ucldrcn   X4 cutrated mde  hdat dlct p!U8 X WKent         Tbr uDer~mcntd1 D,V"D cxpored to hYDoxl4 lboaed kaCP?6sed ttW~OD!O UHtlS
et al,    rlblno rabblta.    cboleateml:                  atberomatod# over that ahown by eontml o nim& bfkroacoDk uamtnathxI rc
ID68.                  I. (12) control.              w&d mom Intlmal and sublatin lipid dcposltlon In the o ortu of the cr~mod
Dcnmrrt               II. (12) continub, qry~~~m.        rabbit-s than In those of the noncxwaed. The total amount of ebcltiterol dt-
(117).                   to hypoxia:            Posited In tbs sort&n of the experiment&l Om"D wan tbrn tha t&her thw h
                 10 DWCe"t.$ for 6 weeks.     chow of tbe cootrol sroup.
                  8 DetCWIt Ox for 2 weeks.

uetdrcn   x4 ca1lrrtAd male  h~ulat dlst DlUS 2 percent         bhOtWODkdY, the exDerhe"tll WOUD ahowed &diCl"tb feWt StbWoUMbUI
et aL.     albino rrbbltr.    cholcsteml:                changn. Micro~coDlc~ll~, tie uperlmrntal PKIUD ~hoaed ~ignlflcant~ krr rortlo
1060.                  I. (12) conttc1.              Intimrl liDId deposItIon.
Dmmwk               11. (12) CXDOIUM t0 28 DtrCmt
(JJ4).              O2 for 10 weeks.
Webster   x2 femrb lpulrrel  Diet eontalnlng 0.1 percent         The uprr~mtntal proup cxpoml to trrbon moaoxldr rhowad 8 prertrt maan Wr-
e &I..     moakeya.       chol~~ttrol rnd 26 DUCC"t fat:       eentalpe of comnar~ rrtcrlar rlth rtheruclemtlc lcalon~ rnd more lumen occlu-
1970,                  I. (IO) control.
U.S.A.                                   don among the &ccted arteries Them wm ~lmifluntb mom CO-treat4
                 11. (12) eIDdme"trk!Y UpO8d t0     monkeys than control monkcn having 11 per-ant or more o ????*? athem-
(W).                   200400 P.P.~. errbon monoxide   AerotIc rtenorlt among the wTected arterlcr. Aorttlc atbcmrclcroaL wu &PP*~-
                      for 20 hOWa DW week for 7     cntlv not agemwkl by exposure to CO. COHb IevcL at the md of each ewaun
                         montha.               perlad averaged 18-28 percent durlw the flnrl 24 wrnkr of tbhs apsrlment


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 mitochondrid
enzymes whose hydrogen donor is NADH. Substances which slow
or impair the reoxidation of this compound tend to increase mite-
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,
ParticuIarIy in view of the fact that cyanide is also a respiratory
chain inhibitor and thus may also adversely affect arterial wall fat
metabolism.

In the discussion concerning the epidemiologica aspects of CEID,
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 A 25 and A 25a. The tabIe is divided into a section concem-
he 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 responsibIe 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 hated in
table A26. Among rabbits fed increased amounts of cholesterol,

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

TEE EFFECT OF SMOKING ON THROMBOSIS

In the study of CHD, a number of investigators have turned
their attention to thrombosis because myocardial 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-ari
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 tbrombus 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 v&-o but few about the effect of smoking on platelet
behavior in wivo. 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 still
inconclusive as to whether smoking shortens platelet survival.

OTHER AREAS OF IFNEXT~GATION

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-
Finns 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
piougly (192, I%?), and the reader is referred to those discussions.

CEREBROVAXKJLAR DISEASE

The term cerebrovascular disease (CVD) refers to a number of
merent 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
Wed as dying from CVD as the underlying cause (196).
Epidemiological studies indicate that cigarette smoking is asso-

62


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 23,
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 pathophysiological 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 (~zS), 20 habitual smokers X+
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 (15.2) studied the effect of smoking
on the cerebral circulation of 12 moderate/heavy cigarette smokers
88 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 66 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-
h]JT its extracranial portion) is Iikely 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 i_ncrease the risk of dying
from this disease, perhaps by promoting the atherosclerotic proc-
aaa'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.

63


TABW PL-Deaths jrma cerebruva.mdar disease related to making
(Xcutdity ratIoa--actual number of death8 ahown In ~nrmthesca)~
            [SM = lmokcn    NS = non~mdrsnl

PROSPECTIVE STUDIES

Age r1rhtIon

commcntr

1.060   NS . . . . . . ..l.OO  (lE4)                                 t(Pco.01).
   Ckarcttn
     SM  . . . . ..tl.aO  (666)
    Other SM  . .1.26 (HO)
      Ciuarstter only
    <IO  ..,,,,,. 1.24 (41)
    x-20  ..,., ..1.44 (140)
    >20  . . . . . . . 1.46  (83)

Doll and   ADDR~u~~Y Questlonnalrs 10      606 NS  . ..,...,. 1.00
RIU     41,ObO mole   md fqlIow-              All SM ,,.,., 1.06
1064,     Brltlsh     up of death              All
CRlt    phyrlelan~.    certine*te.              clgrrctta 1.12
B?ibLn                                 l-14  . . . . ..l.lO
(lob.                                  16-24 . ...,. 1.W
                                   >26  .,,,,... 1.26

Kmnsl    6,127 males    MedICal       12      1s  NS  . . . .L.OO   161                                     Data o o~lu onlv


TABLE `&I.-Deaths from cerebrovaamlar diseaee related to making (cont.)
      (Mortality ntlw-actual number of dwthr ahown In partnthnel)'
              [SM = mokcn    NS = nonamokersl

PROSPECTIVE STUDIES

Irhn.     U.S. mab    Queatloonalra 6%    2,008 NS  . . . . . . . . 1.00  (614)     PIPU
1060.     Vetm-uIl     and follor-              AU              shl  . .1.06 (82)
U.S.A.    2966.674     up of death             current . . . .1.60(1,894) NS . .1.00(614)
(011.     pmon      MrufiUk              Chtl-tnt             CXQLW
        Y-                         dgetla . 51.62 (682) NS  . .1.00(614)
                                      1-v  . . . . . , . 1.61 (88) 8M ..1.06(186)
                                    lo-20 . . ...1.42 (826)
                                   21-89 . . . ..l.?O (216)
                                    >se  .# ..*.* 1.69 (87)

Elmmond 868.d64 make Quatlonn~lm 6
md      446,876      and follow-
Cuflnkd, fcrmla 40-79 UP of death
196O.     ,eara of we   CertlIlC~tc.
U.S.A.    at entry.
(78).

4.09D

CUW#UC
rcoukw
duortfle 40-u
Never
rmoktd 1.00
l-9  . . . ...2.79
lo-18  . . ...1.14
2049 . . ...2.21
,>40  . . . ...1.64

NeVW
amoked  1.00
l-9 . . . ...1.60
IO-19  . . ...2.60
20-39 . . ...2.90
>tO  . . . ..t6.70

  Maksr
so-se  004

1.00   1.00
1.96   1.to
1.48  tl.44
LOS   1.62'
2.40   1.72
Fcnrclkr

1.00   1.00
1.26   1.26
2.70   2.16
2.67   1.88
t6.62    -

   trlued on only
     69 death.
TO-78

1.00
0.86
0.92
1.22
to.68

1.00
0.83
to.67
1.26


T)~BLE 28.-Deaths from cerebromscular dieease veluted to smoking (cont.)
  (Mortrllty ratios-actual number of dtrtha ehoan In parentheses)l
           SY = Smoken.    NS = Nonsmokers.

PROSPECTIVE STUDIES

Pbf?ra.    8.268 m&b    IraM multi- 16      67 NSand
buglt,   bnoabaremhn pbdc             -30, . . . . . . . ..l.OO  (42)
rtd.     s-e4 Yea"    lC~e+nltlg              x0 . . . . . . . al.16  (26)
1970     of .* In     and follow-
U.&A.    1961.       UD of death
(144).              ceruncrte.

                               RETROSPECTIVE STUDY

>SO,OOO male  Inltlal eolleps                                 Death Rater                       The 69 deaths from

barper    Unlvcnlty    entrsnce                          Corer (fad,   Catrok (ala)                    occlualvc stroke
u.d      ,tudrnt.,     medld cx-              SM  ,,..,.,,...,,...,..,. 46.0     81.8 (p<o.oi)                    contributtd to the
wluluu   folloned up    UnInbtlonI            Clgnrette SM >tO per day . 20.9     11.2(P<O.O1)                   atatlatlcd slg-
1067     to 60 Ye.".    with follow-                                                               nlHcanee.
U.S.A.             UD of death                                                               The 96 deaths from
(146).              cetiincatc.                                                               hemurrhs&
                 ConkoIl-                                                                arrokeabowed
                sumlving                                                                 no statlatlc~l
                 claasmstes                                                            slgnIflcancc"
                an+-makhcd.                                                              8 single group.

  ' Unlm othcr-wkc ~~eclRed, dlap4tl.x between the total number of deaths
md the aum of tbs ladivldual smoking qtwries are due to the cxcluion of
dtbcr ~~~lond, mbeellanmua, mhd, or ex-mmokcn.


TABLE 29.-Deatha from nonsyphilitic aortic aneurysm related to umoking-prospective studiee

(Mortdlty rallar-nctual number af death ahown In parentheses)'
       [SM = Smokera    NS = Noasmokenl

Author,
Ye-.
countl7,
rdermcs

FoUoa-up Number
Ye*"     of
       deaths

Clgarcttes per day

Hammond 187,783 white   Questionnaire      3%     68 NS . . . . . .,. .1.00(26) (cxwcted)
and Horn.  males In 9     and follow-up               SM  . . I..,,. 2.72(68) (P<O.o06)

1968.
U.S.A.

ststes 60-69
year0 of age.

(77, 78).

Kdm.

U.S. m&e     QuestIonnalre

8%    491 NS  .,,,,,,,..,...,.. s1.00 (68) NS ..1.00(68) NS ..1.00(68)

1386.
U.S.A.
IUS).

                       .-
veteranl      and f0bV.U~         Current cIgarettea . ,. .6.24(2343 SM ,.1.1a csi SM . .2.06(24j
2.266,674      of death                 l-9 cigarettes/day . .2.12 (13)
Derlon yean.    ecrtincatc.                lo-20  .,,,.,,....,, ,..6.63(124)
                                21-39  ..a,,,.. (.a ..,.. 6.96 (76)
                                >39  . . . . . . . . . . . . . . . . . 7.26 (17)

Hammond 368.634 males    Queationn~irc      6      337 NS  . . . . . . . . . . . . 1.00                            Data r~uly onlv

and      446.816 femrles   and follow-up               1-9  . . . . . . . . . ..2.62                             toms1ec SO-69
GarRnkcl.  40-79 ye,* Of   of death                  10-19 .:.....,..8.86                             yt.m of Lge.
1369,     age at entry.    certificate.                20-3s  . . . . . a.... 4.64
V.S;A*                                    >40
(76).                               , . . . . .._.I . ..8.00

Web ind  68,163 Callfomla Queatlannalre      S-8     61 NS  . . . ..,.,...* 1.00
DlInIl,    tide workera   and fOl!OW-Up               All  . . . ,. . . . . . . . .2.64
1970.     E-64 ye.n ot   al death                  Cl0  I.. ..a,. a .,.2.44
U.S.A.    age at entry.    crrtificste.                 520  ,... * . . . . . . . 2.88
(IDS).                                ZSO . . . . . . . . . ...2.64

' Unlnr ofJwrwlse 1~4fled, dl#parltlh between the total number of
dsrthl and the sum of the Indlvldual cskgorlw .re due to the urclulon

Sk! Include
cr-amoken.
NS include plge
and clg~r
amoken.

m    of elthcr oeculonrl, mlscell~neou~, mlxed, or rxamokcn.


PERIPHERAL ARTERIOSCLEROSIS

Peripheral arteriosclerosis represents the effects on the vascu-
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 factcr 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. (9.2) reviewed the records of and contacted 478
maIe patients with arteriosclerosis obIiterans (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
impIicated 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 arterial disease, is a significant cofactor in its develop-
ment in almost ali cases. The author also noted obesity, high blood
Pressure, and elevated serum choIestero1 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 h.ad been hospitalized for injuries. The in-
vestigators reported that certain risk fa_ctors, including hyper-
cholesterolemia, hypertension, and cigarette smoking, were signifi-

68


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. (215) compared 277 male patients with arteriaI
occlusion of the limbs as demonstrated by aortography or oscilIog-
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
Striimblad (181) on blockade of this response with automatic SYS-
tern blockers indicates that the reactivity of these vessels is se&
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) in 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 froqperipheral arterioscle:
r&is. McKusick, et al. (128) consider it to be a distinct entity

69


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 physica 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 acceIerate tfle
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

70


velocity, and heart rate, and thereby increases the lvork of the
heart and the myocardial demand for os'gen and other
nutrients.

b. -among individuals \vith coronar> atherosclerosis, cigarette
smoking appears to create an imbalance betlveen the increased
needs of the mvocardium and an insufficient increase in coro-
nary blood flow and oxygenation.

c Carboxyhemoglobin, formed from the inhaled carbon mon-
oxide, diminishes the a\.`ailability 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 hyposemia, 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.

CEREBROVASCULXR DISEASE

1. Data from numerous prospective studies indicate that ciga-
rerte smoking is associated with increased mortalit>- from cerebro-
vzscnlar disease.

`3. Experimental evidence concerning the relationship of smok-
ing and cerebrovascular disease is at present insufficient to allow
for conc!usions concerning pathogenesis. However, some of the
pathophgsiological considerations discussed concerning CHD may
also pertain to the relationship of smoking and 0-D, particularly
cerebral infarction.

NON-SYPHILITIC XORTIC 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 vascuiar disease. Cigarette smoking also appears to
be a factor in the aggravation of peripheral vascular disease.
2. Cigarette smoking hB's been observed to alter peripheral
b!ood f?ow and peripheral vascular resistance.

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71


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