CHAPTER 1

Cardiovascular Diseases


Contents

Page

Introduction_---__-_--------------~---------------------
Coronary Heart Disease
Epidemiological Studies

3

Smoking and Certain Risk Factors- _ _ _ _ _ _ _ _ _ _ _ __ _ _
BloodLipids_-__-____--_--___________-_______---
Electrocardiogram_----.- ____ ---__--_ _-__ - -___---
Experimental Studies

4
11
12

   CigaretteSmoke---------- _____ -__- ___________-_    13
    Nicotine-.. _______ -_-- _____ ---_---- _-_- ---- __--__    15
    CarbonMonoxide_--_---___---------------------    17
   Smoking and Thrombosis-- _ _ _ - _ - - _ _ _ _ _ _ _ _ _ _ _ _ _ _ - -    19
Cerebrovascular Disease------- ______ --_----__-__----- ____    19
PeripheralVascular Disease-..-- ______ ---_---_--_-__--- ____    19
Summary of Recent Cardiovascular Findings------....-------    23
References ______ -----_-__-_- ______ -_-_- _____ --_-----___    24

List of Figures

Figure I.-Age-adjusted incidence rates of CHD by body
weight and cigarette smoking (white males) ____ __ _ _ __ _ _- - -
Figure 2.-Age-adjusted incidence rates of CHD comparing
farmers who smoke cigarettes with nonsmoking farmers- - - -
Figure 3.Atandardized mortality ratios for arteriosclerotic
heart disease for males and females by age at initiation of
rigarette smoking (Prospective study 1966-1970) - - - - - - - - -
l%ure 4.-The effect of cigarette smoke inhalation on the ven-
tricular fibrillation threshold (VFT) of normal dogs and dogs
\rith experimentally produced acute myocardial infarction
`~?lII)-..-__________---____-_-_--__----_--F_----_------
l$ure 5.-Eff ec s
           t of smoking five consecutive cigarettes on
Pkrla nicotine concentration-------_-- -_-_---------- ---
piFXre 6.-Relative risk of developing arteriosclerosis oblit-
(`rans (ASO) for males by amount of cigarettes smoked- - -
l'%Wre 7.-Relative risk of developing arteriosclerosis oblit-
prws (ASO) for females by amount of cigarettes smoked---

6

7

8

14

16

20

21

1


Introduction

In the United States, coronary heart disease (CHD) is the leading
cause of death and is the largest contributor to excess deaths among
cigarette smokers. The following is a brief summary of the major
relationship between smoking and cardiovascular diseases as outlined
in previous reports of the health consequences of smoking (62, 63,
l;& 65,66,67).
Many prospective and retrospective epidemiological studies have
identified cigarette smoking, elevated serum cholesterol, and high
blood pressure as major risk factors for t,he development of coronary
heart disease. Cigarette smoking acts independently of and synergis-
tically with the other CHD risk factors to greatly increase the risk of
developing coronary heart disease, The risk of developing CHD for
pipe and cigar smokers is much less than it is for cigarette smokers,
but more than it is for nonsmokers. In the United States, cigarette
smoking can be considered the major cause of car pulmonale since it is
the most important cause of chronic nonneoplast.ic bronchopulmonary
disease.

dutopsy studies have demonstrated that aortic and coronary athero-
sclerosis are more common and severe, and myocardial arteriole wall
thickness is greate.r, in cigarette smokers t,han in nonsmokers.
Those who stop smoking cigarettes experience a decrea.sed risk of
d&h from coronary heart disease compared to that of continuing
smokers.

Experimental studies in humans and animals suggest that cigarette
sllloking may contribute to the development of CHD through the
:l(`tion of several independent ok complementary mechanisms : The
folmation of significant levels of carboxyhemoglobin, the release of
"@cholamines, inadequate myocardial oxygenation which may result
from a number of mechanisms, and an increase in platelet adhesiveness
\vllich may contribute to acute thrombus formation. There is evidence
th;lt cigarette smoking may accelerate the pathophysiological changes
"f I'reexisting coronary heart, disease and therefore contributes to
*II&n death from CHD.
liecently published epidemiological, autopsy, and experimental in-
"`%ations have added to the understanding of the association be-
t'\-& smoking and cardiovascular diseases.
   495-028 O-73-2

3


Coronary Heart Disease

Epidemio2ogicaZ Studies

SXOKING AND CERTAIN RISK FACTORS

A prospective epidemiological study of the factors associated with
cardiovascular diseases was conclucted among the 4,847 white and 2,434
black men and women of Evans County, Ga. ($8). The investigation
was initiated with a private census and preliminary examinations
beginning in 1960. Followup examinations were conducted after 7
years. Cassel (23) reported that high blood pressure, elevated serum
cholesterol, and cigarette smoking were major risk factors for the
development of coronary heart disease. Increased body weight, an
elevated hematocrit, and ECG abnormalities were additional fact,ors
that were associated with elevated CHD rates. A significant finding of
this study was the very low prevalence and incidence of coronary heart
disease (myocardial infarction and angina pectoris) in black men. The
age-adjusted prevalence rates among black men were only half those of
white men. The study showed that blacks were affected by the various
risk factors for CHD in a similar fashion to whites but at a lower level
of disease. This appeared to be true for any level of any risk factor or
any combination of risk factors. Greater physical activity of blacks as
compared to whites appeared to account for part of the observed dif-
ference in rates.

In this study, subjects were classified on the basis of their smoking
history at enrollment and both current smokers and exsmokers were
considered smokers. Both black and white male smokers had a higher


incidence of CHD than did nonsmokers, but white males had a higher
incidence than blacks whether they were smokers or not. The age-
adjusted incidence rate for white nonsmokers was 52.7 per thousand
compared to 9.8 per thousand for black nonsmokers. White smokers
had an incidence of 101, whereas the rate in black smokers was only
3G. The prevalence of CHD increased with the number of cigarettes
smoked per day in both groups.

The combined effect of body weight and cigarette smoking on t.he
incidence of CHD was also examined (~3;). The "Quetelet index" 1
\yas used to determine relative weight. The risk of developing CHD
did not change with increases in relative we.ight among nonsmokers,
but smokers experienced a substantial risk of developing CHD with
increases in weight (fig. 1).
The relabionship of smoking to occupat,ion and CHD was examined
I 1-i). Farmers who performed sustained physical activity had lower
Mes of CHD than nonfarmers. Figure 2 shows that, while smoking
inc*reased the risk of CHD in bot.h farmers and nonfarmers, farmers
ha.d lower rates than nonfarmers whether or not they smoked.

          weight
' W?telet index= -
     height ,x1oo'


Figure 1 .-Age-adjusted incidence rates of CHD by ' body weight and 1 cigarette
     smoking (white males).

160 ,                                                  1

Nonsmoker

140

' Smoker

    120 -

    110 -

    100 -

     90 -

' Rate  80  -
m'ales lP&  70  -

     60.

     50-

     40.

     30 -

     20 -

     10 -

      0
' Distribution
by weight

80

Lower third
(lean)

Number            90    183     99    161     127    119

Cases              5    15     3    14     16     9

1 Smokers excluding ex-smokers.
`67 months follow-up period.
I Based on Quetelet index.

SOURCE: Heyden, S., et al. (26).

6


Figure 2.-Age-adjusted incidence rates of CHD comparing farmers who smoke
    cigarettes with nonsmoking farmers.

Farmers

   100
Rate
per
1,000
males
   50

0

Cases . . . . (8)   (9)
        Nonsmokers

Nonfarmers El
  158.2

(11) (39)
Smokers and
Ex-smokers

SOURCE Cassei. J. C., et al. (18.

Hirayama (27) reported 5-year followup data on smoking in &a-
tion to death rates from a large prospective epidemiological study of
%,118 men and women in Japan. This investigation was the first of
its kind to be conducted in an Asian population. During the followup
Period, 11,858 deaths occurred during 1,269,382 person years of obser-
Wion. Male and female cigarette smokers experienced higher mor-
tnlitv rates from arteriosclerotic heart disease than did nonsmokers.
.\nlong cigarette smokers, the mortality ratios for arteriosclerotic heart
~hise were 1.56 (P<O.oOl) for men and 1.44 (P<O.O5) for women.
I)~s+response relationships were found for both men and women as
tlh\`asured by the number of cigarettes smoked per day and age at initia-
t ion of smoking (fig. 3).


figure 3.-Standardized mortality ratios for arteriosclerotic heart disease for
     males and females by age at initiation of cigarette smoking (Prospec-
      tive study 1966-1970).

     1.50

Mortality
ratio

     1.00

0.50

     0.00
       Age at start   Non-
       of smoking smoker

SOURCE Hirayama, 1. (27).

34      20-24    <20

Gordon, et al. (%`Z! 57)) in a further analysis of the Framingham
data, considered both by univariate and multivariate analysis the rela-
tion of certain key characteristics to the development of coronary heart
disease. The characteristics were : High blood pressure, elevated serum
cholesterol, cigaret,te smoking, left ventricular hypertrophy diagnosed
by electrocardiogram, and glucose int.olerance. Cigarette smoking
emerged as one of the important risk factors for the development of
coronary heart disease. There was a strong association between ciga-
rette smoking and CHD other t,han angina pectoris, particularly
among young male and female smokers. The relative role of cigarette
smoking as a risk factor was emphasized by multivariate analysis.
Cigarette smoking was not. as strongly related to CHD in women as it
was in men. This ma\- have been in part due TV the fact that there are
fewer heavy smokers among women? and women tend to inhale smoke
less than men.

Kapan. et al. (31) reported preliminary findings from the Honolulu
Heart Study. The effect of migration on dietary pat.terns and the inci-
dence of cardiovascular diseases in a cohort of men of Japanese ances-
try born between 1900 and 1919, who were residents of Oahu in 1965,
was examined in this prospective study. During the 2 years of fol-
lowup, 101 men developed CHD in t.he population of 8,006 men ini-


tially examined. A significant relat,ionship to CHD was found for the
following risk factors: Cigarette smoking, elevated systolic and dia-
stolic blood pressure, increased serum cholesterol, triglycerides or uric
acid, and various measures of obesity.

using data from the International Cooperative Study on Cmdio-
vascular Epidemiology, Keys, et al. (34) calculate the probabilities
for men aged 40 to 59 to develop coronary heart disease in 5 years.
The authors noted "* * * that the relative CHD risk of different
men within a given population is well predicted from the results of
the multivariate analysis of the experience of men in other far-distant
populations differing in socioeconomic circumstances, language, and
ethnic background." Although the CHD incidence rate of European
men was about half that of the Americans, the fact still remained
that investigation of the four variables (cigarette smoking, age,
systolic blood pressure, and cholesterol) was sufficient to identify
men whose likelihood of dying of CHD or having a definite myo-
cardial infarction within 5 years was greatly above the average.
Punsar (61) reported IO-year follo:vup data on the cohort of men
in Finland who were part of t,he seven-country study of coronary heart
&sea+ confirming that c.igarette smoking was a major risk factor for
CHD. The authors reported a 1.`7-fold increase in CHD mortality
among cigarette smokers. They estimated that 1,700 excess CHD
deaths occur each year among cigarette smoking men in Finland.
Kozarevic, et al. (38) reported the results of the initial prevalence
survey and the e-year incidence data from the Yugoslavian study
of cardiovascular disease. A total of 11,121 men between the
Wes of 35 and 62 were examined in the towns of Tuzla and Remetinec.
(`iiteria for the diagnosis of CHD were based on objective electro-
"ardiographic findings of myocardial infarction, left bundle branch
IJock, or sudden death. A very low prevalence of myocardial infarc-
tion was initially found, and only 36 new cases of CHD developed
`)~r t.lle 2-year period. The subjects who developed CHD smoked
I`iLmrMes at about the same level as the total study population. The
~`llrl~ml average incidence rate of acute coronary heart disease was
:Iimut 1.6 per 1,000 among both the smokers and nonsmokers. The CHD
irli+&e rates found in this Yugoslavian study are appreciably below
"lo found in the United States.
(`olnstock (16) examined the association between water hardness,
V"ri~lls other environmental factors including cigarette smoking, and
"bill from CHD. A total of 189 deaths from CHD occurred in the
I"Wlntion of Washington County, Md.. in the 3-year period follow-
"`ca C(`INIS in 1963 For each case, two c*ontrols were randomly selected
fr'c'ltl the census list's and matched for race, sex, and year of birt,h. The
r""ltiv~ risk of CHD for all smokers was 1.5 compared to nonsmokers
' 1'<(~.1,5). Th' ' 1s relative risk among cigarette smokers WRS dose-

9


related ; persons smoking more than two packs a day had the highest
risk of CHD. No significant association was found between CHD and
water hardness.

Casciu, et al. (I$?), reported the prevalence of cardiovascular disease
among 4,668 miners on Sardinia. Smoking and drinking habits, blood
pressure, and heart rates were recorded. Smokers had higher rates
of CHD than nonsmokers, and a dose-response was noted with the
number of c.igarettes smoked per day. The prevalence of myocardial in-
farction was 0.9 percent for nonsmokers, 1.62 percent for smokers
of 10 or less cigarettes, 2.34 percent for smokers of 11 to 20 cigarettes,
9.9 percent for smokers of 20 or more cigarettes a day, and 1.42 percent
for cigar or pipe smokers. When cigarette smokers were grouped by
alcohol consumption, no significant difference was found in the prev-
alence of myocardial infarction between drinkers and nondrinkers

Kornitzer, et al. (36, 36, 37) examined the prevalence of CHD in
566 male bank employees aged 40 to 59 in Brussels. They determined
an individual's smoking history, blood lipids, ECG, peak flow rates,
relative weight, skinfold thickness, and blood pressure. The preva-
lence of possible CHD as determined by ECG and CHD history was
7.1 percent in nonsmokers, 11.6 percent in cigarette smokers who in-
haled, 6.9 percent in cigarette smokers who did not inhale, 10.6 percent
in smokers of pipes and cigars, and 15.5 percent in the ex-smokers.
Among the various risk factors examined, the strongest association
was found for elevations in the serum cholesterol and the other blood
lipids examined. Weaker associations were found for increased rela-
tive weight, high blood pressure, and tobacco use.

Agnese, et al. (2) examined 265 patients in Italy aged 20 to 65 years
who had myocardial ischemia. Patients were matched with an eq,ual
number of controls by age. A number of risk factors for CHD were
measured in both groups. Cigarette smoking and elevated serum
cholesterol were identified as major risk factors for CHD, particularly
for individuals under the age of 50.

Boudik (20) found the prevalence of myocardial infarction to be
significantly (P<O.OOl) higher in cigarette smokers than in non-
smokers in a population of 8.292 Czechoslovakian men between the ages
of 52 and 67.

Starch, et al. (GO). Estandia Cano, et al. (17)) and Jakuszewska
(30)) in studies in Germany, Mexico, and Poland of CHD in individ-
uals under the age of 10, reported that cigarette smoking was the
dominant factor in the development of CHI) in these patients.
Golovchiner (;?I) found cigarette smoking to be a significant factor
in the development of myocardial infarction-in a study of 530 patients
with CHD in Leningrad hospitals.

10


Three studies without control groups from New Zealand (69),
Sq)al (47), and India (58) reviewed the prevalence of various risk
factors, including cigarette smoking in populations with documented
(`IID.

BLOOD LIPIDS

In lnost of the follo\ving studies where the effect of cigarette smok-
111~ 011 blood lipids was examined, there was no control for dietary
facstors that may independently affect serum lipid levels. Schwartz,
rt al. (56) examined serum lipids in relation to smoking habits and
h~latire weight in 7,972 male employees of the Parisian civil Service
in the city of Paris. Cigarette smoking was associated with a slight
bet significant (P <O.OOl) increase in serum cholesterol. The authors
f~~llnd a positive correlation between increased relative weight and
WIII~ cholesterol levels, and a negative correlation between rela-
tive weight and smoking habits. These factors would operate in such a
ray as to reduce the apparent effect of cigarette smoking on the
cholesterol levels. After controlling for relative weight, however, the
irlrestigaton found a significant (P <O.OOl) positive relat.ionship be-
tiveen smoking and serum cholesterol.
111 a study of various factors in relation to the mean serum choles-
r(`rol. Pincherle (@) examined the following parameters : blood pres-
Rw. height, weight, and skinfold thickness, X-ray findings of the
rhrst and abdomen, the electrocardiogram, and smoking history ;
l".`H)u British business executives between the ages of 25 and 65 were
p~rnuined. d significant association was found between elevated serum
"licllesterol, obesity, elevated systolic blood pressure, inadequate exer-
"I*`. radiographic evidence of arterial calcification of the iliac arteries,
~lll (Wain other factors. The increase observed in mean serum choles-
`~1 Gth increasing number of cigarettes smoked was not stabistically
Wlti f&~t.
lhsi~ (53) studied the distribution of serum lipids in 324 Nor-
Wi:hl military recruits Cigarette smokers had a small but insignifi-
"`irlt increase in serum &glycerides. No elevation was found for serum
r}~olt5terol. Th e subjects were young, and most smokers had only
"`k'bktYl for a fern years.

llllrlley and Enslein (11) investigated changes in clinical laboratory
t-ts as r&t ec 1 t o aging and smoking in a S-year study of 502 healthy
"~1~' veterans It \vas found that five variables were needed to predict
aK"sr~`bd changes in those over 50. These were: fasting blood glu-

11


case, e-hour post-glucose blood sugar, total serum protein, hemoglobin,
and cholesterol esters. No significant differences in the laboratory data
between smoking and nonsmoking subgroups were found.

Vlaicu, et al. (70) examined the interaction of cigarette smoking
with blood pressure and serum lipids in 100 patients with angina pec-
toris who were between the ages of 40 and 59. Half the patients were
smokers using more than 25 cigarettes a day. The smokers had lower
serum lipids and lower blood pressure than the 50 nonsmoking pa-
tients with angina pectoris.

Miturzynska-Stryjeeka, et al. (@`) found that cigarette smoking
immediately following a fatty meal did not significantly alter the
serum free fatty acid, esterified fatty acid, cholesterol, or plasma tur-
bidity levels over control values.

Ciampolini, et al. (16) examined the effects of cigarette smoking
on blood lipid values in 10 healthy volunteers between the ages of 20
and 40. Cigarette smoking resulted in a prompt rise in free fatty acids
and a delayed rise in serum triglycerides.
The relationship between cigarette smoking and changes in various
serum lipid levels has not been clearly determined. Studies in this area
continue to present conflicting results.

ELECTROCARDIOGRAM

Wysokinski (76') examined the effect of smoking on certain param-
eters of cardiovascular function in 100 healthy nonsmokers and 106
healthy smokers who were military recruits 19 to 2.5 years of age in
Poland. Significant prolongation of the QRS interval (P<O.OOl) , flat-
tening of the T wave, and ST segment depression following exercise
were seen more frequently in the smokers than in the nonsmokers.

Van Buchem, et al. (69) examined the occurrence and significance
of extrasystoles and conduction disorders in 760 healthy Dutch men
between the ages of 40 and 67 who were followed for 7 years. The pres-
ence of extrasystoles was not correlated with cigarette smoking or ele-
vated serum cholesterol and was not associated with the development
of CHD over the Y-year period.

Kattus, et al. (33) tested 314 healthy males 23 to 82 years of age for
ischemic ST segment depression on the ECG during or after submaxi-
mal exercise. The abnormal ST segment depression identified in 30
subjects was correlated significantly with elevated serum cholesterol,
abnormal rest)ing ECG, and a history of cardiac symptoms but not
wit.h smoking, high blood pressure, physical inactivity, or family his-
tory of coronary disease.

12


Van Buchem, et al. (68) found no significant association between
+arette smoking and ischemic ST segment depression on ECG in 120
apparently healthy men who demonstrated this abnormality among a
population of `760 men 50 to 70 years of age.

Experimental Xtudi.438

CIGARETTE SJ~OKE

Studies in Man

Summers, et al. (61) examined the effect of cigarette smoking on
csrtliac lactate metabolism in 15 patients with severe angina pectoris
nho had at least 75 percent obstruction in each of two or three major
c'oronary vessels. All patients had been long-term cigarette smokers.
Cigarette smoking produced increases in heart rate, systolic aortic
pressure, the systolic ejection period per minute, and the tension-time
index per minute, but lactate production was not induced by smoking
in any patient who did not also have lactate production in the control
state. In three patients with lactate abnormalities prior to smoking,
inhalation of cigarette smoke sustained and slightly aggravated this
Wtdition.

Studies in Animals

The effect of Inhalation of cigarette smoke on ventricular fibrillation
threshold (VF'I') in normal dogs and dogs v&h experimentally pro-
lll~d acute myocardial infarction was studied by Bellet,, et al. (6) . .
llongrel dogs weighing 25 to 30 kilograms were anesthetized with
>O(liurn pentobarbital, and respiration was maintained using a Harvard
V~`l~tilator attached to an endotracheal tube. In one group the electrical
iInl)ulses used to precipitate ventricular fibrillation were delivered
tllrough the chest wall, and in another group the impulses were deliv-
`~4 directly to the heart through electrodes implanted in the myo-
Qrcliurn. The experimental group of dogs were exposed to the smoke
`)f three cigarettes over a IO-minute period. Each cigarette contained
:`lWosimately 2 mg. of nicotine. With acute myocardial infarction, the
"VT was significantly (P<O.OOl) decreased, but in both the normal
"11ti lllvocardial infarction groups cigarette smoking resulted in a de-
i'rt';lse'in VFT that averaged 30 to 40 percent of the control value
! !iK. 4). These findings are of interest in view of the increased inci-
`lPI1~(> of sudden death observed among coronarv patients who are
`l";lVY cigarette smokers (65).                  Y

13


Figure 4.The effect of cigarette smoke inhalation on the ventricular fibrillation
     threshold (VFT) of normal dogs and dogs with experimentally pro.
     duced acute myocardial infarction (Ahll).

0.8 r

0.6 t   t
       o ?
      o ??

=.
`* %. smoking (normal)
     . . . . . . . - . . . . . . . *I-.-

                0    15   30   45   60   75   90
                 Time in minutes following
                   cigarette smoking
SOURCE: Bellet, S.. et al. (6).

The effects of passively inhaled cigarette smoke on several measure
of cardiovascular function in treadmill-exercised dogs were examined
by Reece and Ball (52). The experimental dogs were trained on the
treadmill for approximately 1 year before exposure to cigarette smoke
began. Each dog was passively exposed to the smoke of 36 cigarettas
over a 3-hour period 5 days a lveek in a 2.2 m.3 chamber ventilated at
the rate of seven exchanges per hour. The dogs were exposed to this
cigarette smoke and were continued on their exercise program for an
additional year. Exposure to cigarette smoke was associated with
cadiac enlargement, ST segment depression, and an increase in post-
exercise serum lactate concentrations.

14


Studies in Man

Isaac and Rand (98) have recently described a method for the assay
If plasma nicotine. An alkali flame ionization detector was used with a
!a.+liquid chromatograph. The test is sensitive to 1 ng./ml. of nicotine
In a 2.5 ml. sample ; 30 minutes elapsed between end of one cigarette
md start of next. Blood samples were taken before smoking and at 5,
10, and 30 minutes after the last puff of each cigarette. Plasma nicotine
lrvels increased rapidly during cigarette smoking (fig. 5). The post-
making decay curve consisted of two components: an initial rapid
I)hase which may be due to the uptake of nicotine from the blood by
various tissues, and a slower phase which may represent metabolism
:md excretion of nicotine. Some accumulation of plasma. nicotine 00
rarred during a day of smoking, but the background level never ap-
proached the peaks attained during and immediately following active
L8igarette smoking. The rate of elimination was rapid enough to prevent
:Iny appreciable accumulation of nicotine from 1 day to the next. The
dWelopment of sensitive tests of plasma nicotine levels will allow a
greater understanding of various dynamics of smoking. Inhalation
Patterns can be objectively measured, and the role of nicotine in
habituation to cigarettes can be evaluated.

15


Figure 5.-Effects of smoking five consecutive cigarettes on plasma rhOtin@
       concentration.

60

50

Plasma
nicotine   40
(w/ml.)

30

20

10

         0
Smoking period  .  .  .  .

0

1

2        3

Time (hours)

4       5

SOURCE: Isaac, P. F., Rand, M. J. (28).

Studies in Animals

The effect. of nicotine on regional blood flow in the canine heart w&s
exan1ine.d by Mathes and Rival (42). The effects of nicotine were
examined in normal hearts and after partial coronary artery occlusion.
I-rider normal circumstances, as well as after infusion of nicotine in
normal hearts, the subendocardial portion of the myocardium had II
!I..`-percent greater capillary flow than the subepicardial fraction.
Partial ligation of the coronary arteries resulted in a 22.Cpercent
reduction in left ventricular blood flow ; however, the subendocardial
portion remained X.6 percent higher than in the epicardium. After

16


coicnary artery ligation, an infusion of nicot.ine resulted in a signifi-
cast (P<O.OOl) reduction in the capillary flow of the inner portion of
the myocardium relative to the outer part.

Bhagat, et al. (7) examined the effect of cigarette smoking on the
cardiovascular system of dogs, various pharmacological agents; e.g.,
tyramine hydrochloride, propranolol, and chlorisondamine. were used
tn modify the evoked response to tobacco smoke in order to clarify the
nlrchanisms producing the observed effects. The authors concluded that
the more important actions of nicotine include a stimulation of sympa-
thet.ic ganglia and t.he adrenal medulla and the release of catec.hola-
rnines from sympathetic nerve endings and chromaffin tissue.
Bing, Hellberg, and associates (8. ., 95) st~atlied t.he microcirculation
of the left atrium of anesthetized cats by direct visualization using
hiih-speed c.inematopraphg. Nicotine injCctions produced a slight but
insignificant increase in red cell velocity in the capillary circulation
during both systole and diastole.
The effects of nicot.ine on t.he biosyilthesis of various lipid fractions
in the aorta of dogs \\eere studied by Kupke (.@) . After nicotine admin-
istration, significant reduction occurred in the formation of free ("C) -
strrols, while elevated levels of unesterified fatt.y acids were formed in
the media and intima of these in vitro specimens. The author sugested
that nicotine may impair oxidative enzyme systems possibly by damag-
ing the mitochondrial structures, thereby leading to lipid accumulation
ill the aorta.
SchieveIbein and Eberhardt (.54) reviewed the cardiovascular
actions of nicotine and smoking.

CARBOX MONOXIDE

Studies in Man

Sumerous articles have recently been published on the various effects
of carbon monoxide on man and animals and are of particular interest
l*cause of the relatively high levels of carbon monoxide found in the
rllain and sidestream smoke of cigarettes. Only those articles are dis-
"l~%d here which contain data on t.he cardiovascular effects of carbon
`Ii()t\oxide.
.\ronow and Rokaw (,I) examined the effects of smoking-induced
"arl~xyhemoglobin levels on angina pectoris in 10 patients with CHD.
`l'htl time to the onset of angina after smoking a nonnicotine cigarette
`V:IS measured- Each patient had smoked more than a pack of ciga-
r"ttrs a dav f;r at least 1~ yeat*s and had a classical history of ~xel'-
tir)lMl tlyq~lle:~. Snl()kiJip nonnicotine cigarettes failed to twdt in an
"l(Ution of the blood prrsslll.e, or the heart, rate : however, t,here was a

17


significant (P <O.Ol) increase in COHb levels to about 8 percent. Tb
resulted in a significant decrease in exercise performance compared b
the nonsmoking state (P<O.Ol) . This confirms that carbon monoxide
can compromise oxygen delivery independently of the effect of nicotine,

Maximal oxygen consumption under conditions of carbon monoxide
intoxication were studied in human volunteers by several authors (4,
71, 72). COHb levels of 15 or 20 percent resulted in a proportionah
reduction in maximal 0, consumption. The volunteers responded to the
decrease in oxygen-carrying capacity of the blood with a tachycardia
and relative hyperventilation during moderate exercise. Carbon man.
oxide produces a limitation of an individual's maximal oxygen con.
sumption by decreasing the availability of oxygen supplied under con.
ditions of increased oxygen demand.

Heistad and Wheeler (24) reported that the hypoxia induced bI
carbon monoxide inhalation caused an inhibition of reflex vasocon.
strictor responses despite the presence of normal arterial oxygq
tension.

Studies in Animals

The effects of carbon monoxide on coronary hemodynamics and left
-ventricular function in six unanest,hetized dogs were studied by Adarm
et al. (I). The animals reacted to a B-percent carboxyhemoglobin level
with a 14-percent increase in coronary blood flow. Twenty percent
COHb resulted in a 57-percent increase in coronary flow and slight
increases in heart rate and stroke volume.

Birnstingl, e,t al. (9) exposed young adult rabbits to 400 p.p.m. CO
for periods that varied from 6 to 14 hours. The mean COHb level after
a series of 22 exposures was 17 percent. A qualitative increase in plate-,
let stickiness, as measured by the bead-column method, developed dur.
ing the N-hour period following CO exposure. The aut,hors observed
that this (`* * * provides a possible mechanism for intimal deposition
and a further link in the association b&Teen habitual smoking and
peripheral vascular disease." Astrup (5) found the cholesterol level in
the aorta of rabbits exposed to a low level of carbon monoxide for 10
weeks to be, on the average, 2.5 times higher than in the control rabbits
Both the experimental and control groups were maintained on a high-
cholesterol diet.

Gibbons and Mitropoulos (20) reported that CO inhibited cho.
lesterol biosynthesis with accumulation of lanosterol and 24;25-dihy
drolanosterol in an in vitro system of rat liver homogenates exposed
to a go-percent. CO atmosphere. It was felt that CO may have ia.
fluenced an early st,ep in the oxidntive elimination of the l-la-methyl
group of lanosterol.

18


SMOKING AND THROMBOSIS

Previous reports of the Surgeon General on smoking and health
(6.5',63,64 65,66) have reviewed the effects of smoking on thrombosis.
Recent reviews and studies have not, thus far yielded a unifying con-
cept of the effect of smoking on thrombosis (,$,18,19,32, ~$5).

Cerebrovascular Disease

Paffenbarger and Wing (46) examined several precursors of non-
fatal stroke in 102 patients with this disease in a population of 10,327
men who had attended Harvard University between the years of
1916 and 1940 and also returned a self-administered questionnaire in
1966. Examination of university medical records of these former
students revealed four characteristics present in youth that predis-
l'osed those individuals who were more likely to experience a nonfatal
stroke in later life. These factors were: cigarette smoking, elevated
Mood pressure, increased weight for height, and short body stature.
Ihe age and interval-adjusted incidence rates per 1,000 were 10.1 for
uonsmokers, 15.3 for smokers of one to nine cigarettes, and 17.9 for
smokers of 10 or more cigarettes a day. The relative morbidity ratios
for the four factors cited above increased from 1.1 for patients with
()nly one risk factor to 1.7 for those with any two risk factors, and to
X3 for patients with any tl1re.e. or four risk factors.
hfiyazaki (44) studied blood flow in the internal carotid artery
rlsiug ultra sound techniques. Internal carotid blood flow was ex-
:ihed under a variety of experimental conditions. Inhalation of
$arette smoke in three individuals aged 27, 67, and 69 resulted in an
illcreased blood flow due to decre.ased vascular resistance. This effect
`itsted for 10 to 20 minutes following smoking.

Peripheral Vascular Disease

The association betxveen cigarette smoking and arteriosclerosis
f)t)literans (ASO) was invest,igated by JTeiss (7,Y). Patients were con-
>i'l~cl to have AS0 if both the dorsalis pedis and posterior tibia1
!"I~w were absent in one lower extremity and the examining physician
`Il:l(l~ :I diagnosis of XSO. Patients we.re asked the age of init,iation
`If sMiing; the daily number of cigarettes smoked: the amounts
.`liC)k~~d at ages 30. 50, and 70; the age at which they stopped smoking;
  455--028 O-73-~

19


and, for males, whether they smoked cigars or a pipe, A total of 214
male cases, 206 male controls, 390 female cases, and 913 female controls
were studied. The control group was composed of patients with
peripheral vascular problems other than aSO but who had dorsalis
pedis pulses present on initial examination. In each age and sex group,
cigarette smoking was more prevalent among cases than controls. In
both sexes, risks were high for smokers of less than one pack a day,
and increased with the amount smoked (figs. 6 and 7). It was esti.
mated that 70 percent of nondiabetic AS0 in the United States is
related to the use of cigarettes. Diabetes mellitus is a major risk factor
for the development of AS0 ; however, cigarette smoking appeared to
act independently of diabetes.

Figure 6 .-Relative risk of developing arteriosclerosis obliterans (ASO) for males
     by amount of cigarettes smoked.

15.0

10.0

Cases

18         21         33         69

Controls          53         15        26         37

Amount
smoked

Non-
smoker

1 pack
day

SOURCE: Weiss, N. S. (73).

20


Figure 7 .-Relative risk of developing arteriosclerosis obliterans (ASO) for
     females by amount of cigarettes smoked.

1            Fernal&               15.6

cases
Controls
Amount
smoked

79          50          60          41
429          83          69         33
NOW                    1 pack
smoker                 day

SOURCE: Weiss, N. S. (731.

Preuss, et al. (-50) examined the relationship between several factors
including cigarette smoking, blood pressure, weight, and history of
diabetes and the development of occlusive disease of the peripheral
arteries in a population of 300 patients in Germany. Group I consisted
of 150 patients with a mean age of 59 years who had intermittent
claudication. Most of these patients were ambulatory. The 150 patients
in group II had a mean age of 60 years and had far advanced periph-
eral arteriosclerosis with ischemic pain at rest or evidence of gangrene.
There was no control group of patients free of vascular disease. There
Wre few nonsmokers in either group of patients, but. the group with

21


the more severe disease had a higher average daily consumption of
cigarettes t'han did group I.

The influence of cigarette smoking on late occlusion of aortofemoral
bypass grafts was examined by Wray, et al. (75). A series of 100
patients who had aortic reconstruction for aneurysmal or aurtoiliac
occlusive disease between 1965 and 1968 were studied. Of the patients
who had bypass grafts for occlusive disease, 30 patients smoked ciga-
rettes and 16 did not. Late occlusions from thrombosis occurred in nine
patients, each of whom was smoking more than a pack of cigarettes a
day at, the time the thrombosis occurred (P<O.5). The authors re~oxn-
mend cessation of cigarette smoking to all patients undergoing vascu-
lar reconstruction.

Schmauss and Arlt (55): Wilbert (7.4), and Kradjian, et al. (39)
reported a greater than 93 percent prevalence of cigarette smoking in
three separate se+s of patients wit.h severe peripheral vascular
disease.

Isacsson (%9) performed venous occlusion plethysmography in 684
men aged 55 in Malmii, Sweden. In addition to a detailed smoking
history, a number of other factors were studied, including blood pres-
sure, pulse, height, weight, ECG, heart volume, and blood lipids. The
plethysmograms were taken on bot.h legs simultaneously with the
patient in the recumbent position. Measurements were taken at rest and
during reactive hyperemia produced by obstructing arterial inflow to
the legs for 3 minutes with a blood pressure cuff applied to the thigh,
Smokers had a significantly lower mean flow capacity (MFC) than did
nonsmokers. The MFC in the legs was reduced in direct proportion to
the amount of tobacco consumed per day regardless of the mode
of smoking. The MFC was significantly lower with inhalation
(P<O.OOl) and wit.h increasing amount smoked (P<O.OOl).

Matsubara and Sano (42) studied the effect of cigarette smoking on
human precapillary sphincters of the leg using a pressure plethysmo-
graph applied to the calf. Precapillary sphincter tone was e&mated
using the capillary filtration coefficient, which is the product of "funC-
tionai capillary service area"and the filtration constant of the capillary
wall. Four healthy male subjects were tested. All were regular smokeIs
of cigarettes who had not smoked for the previous 24 hours. `TVhen
cigarette smoke was inhaled deeply `at 30-second intervals over a 12- to
15-minute period. there was a 19-percent decrease in the capillary
filtrat.ion coefficient. indicating closure of precapillary sphincters.
Cigarette smoking also resulted in a 31-percent decrease in calf blood
flow3 indicating some degree of constriction of the arterioles in the leg.
The pressure volume curves of the venous system were not affected by
cigarette smoking.

Heistad and Wheeler (24) examined the effect of carbon monoxide
on vascular resistance and reflex vasoconstriction in the forearms of 12

22


healthy men 19 to 23 years old. After control measurements were taken,
the subjects were exposed to enough carbon monoxide to produce car-
boxyhemoglobin levels of 18 to 20 or 25 percent. Carbon monoxide did
not cause a change in alveolar PO, or PCO,. The arterial oxygen satu-
ration was less than 75 percent, but t,his decrease did not result in
altered resting arterial pressure nor was there much evidence of
sympathetic stimulation. Carbon monoxide hypoxia did result in a
significant decrease in vascular resistance in t.he resting forearm
(P<O.O5). Carbon monoxide exposure aalso resulted in a significant
depression of the vasoconstrictor responses of the forearm following
the application of negat.ive pressure to the lower body (P <O.OOl) and
of ice on the forehead. It appears that the hypoxia induced by carbon
monoxide causes an inhibition of reflex of vasconstrictor responses
despite the presence of normal arterial oxygen tension.

Summary of Recent Cardiovascular Findings

In addition to the summary presented in the introduction to this
chapter based on previous reports of the health consequences of smok-
illg, the following statements are made to emphasize the recent develop-
ments in the field :

1. Recently conducted epidemiological st,udies from several coun-
tries continue to confirm that cigarette smoking is one of the major
risk factors contributing to the development of coronary heart
disease.

2. Epidemiological evidence suggests that black men in the rural
South respond to the same risk factors for coronary heart disease,
including cigarette smoking, as white men do but apparently at
lower disease rates, which appears to be in part due to differences
in physical activity.

3. Data from several epidemiological and experimental studies sug-
gest that cigarette smoking is a major risk factor in the develop-
ment of peripheral vascular disease. This may in part be due to the
decreased blood flow in arterioles and capillaries associated with
cigarette smoking. Smoking may complicate the surgical inter-
vention in this disease by contributing to late occlusion of the
treated vessel.

4. A laboratory test has been developed which accurately measures
flicotine levels in blood. This test will be useful in understanding
nicotine metabolism and can be used as an objective measure of
%Yarette smoke inhalation.

23


Cardiovascular References

  (1) ADAMB, J. D., Earcesox, H. II., SIVNE, H. L. The effects of carbon monoxide
     on coronary hemodynamics and left ventricular function in the conscious
-<
`!`d     dog. In: Proceedings of the 1st Annual Conference on Environmental
     Toxicology, September 9-11, 1970. Aerospace Medical Research Labora-
      tory, Wright-Patterson Air Force Base, Ohio, AMRLTR-70-102, Decem-
      ber 1970, pp. 107-110.

(3) AGNES& G., CANEPA, `R., LA ROCCA, M. Eta e valore di alcuni indici per la

P       discrlminazione fra soggetti normali ed ischemici. (Age and value of
      several indices for discrimination in normal and ischemic subjects.)
       Giornale dl Iglene e Medicina Preventiva ll(3) : 140-151, July-S&em-
        ber 1970.

(3) ABONOW, W. S., RQKAW, S. N. Carrboxyhemoglobin caused by smoking non-
   nicotine cigarettes Effects in angina pectorls. Circulation 44 (5) : 7S2-
___ _ 788LN~v~G-wr 1971.

c4) AIITHES, F. r>An epidemiologic survey of hospital&d cases of venous
     thrombosis and pulmonary embolism in young women. Mllbank Memorial
   Fund Quarterly 5O( 1, Part 2) : 233-243, January 1972.
(5) ASTRUP, P. Riiknlng mh koronarsjilkdom (11) : Karbeskadigende virknlng
    af CO og hypoxi. (Smoking and coronary disease (11) : Vascular damag-
    ing effect of CO and hypoxia.) Ukartidningen 67(3) : 44-49, Jan. 14,197O.
(6) BELLET, S., DEGUZMAN, N. T., KOSTIS, J. B., ROMAN, L., FLEIECHMANN, D.
     The effect of inhalation of cigarette smoke on ventricular flbrlllation
    threshold in normal dogs and dogs with acute myocardial infarction.
    American Heart Journal 83 ( 1) : 67-76 January 1972.
(7) BHAQAT, B. RUEHL, A., RAO, P., RANA, `M. W., HUOHES, M. J. Effect of
     cigarette smoke on the cardiovascular system in dogs. Proceedings of the
     Society for Experimental Biology and Medicine 137(3) : 989972, July
     1971.

(8) Br~o, R. J., WAYLARD, H., RICKART, A., HELLBERO, K. Studies on the coronary
   microclreulation by direct visualization. Giomale Italian0 di Oardiologla
   1: 401-408, September-October 1971.

(9) BIRNSTINGL, M. A, BILIXSON, K., ,CHAKRABA~TI, B. K. The effect of short-
   term exposure to carbon monoxide on platelet stickiness. British Journal
   of Surgery 5S(ll) : F37-839, November 1971.
(IO) BOFDIK. F. Srdecni infarkt a koureni. (Myocardial infarction and smok-

*L t  , -
/'   --.ing@asopis Lekaru Ceskych llO(26) : 614-820, July 25,1971.
  (II) BVJBN~ S. W., ENSLFZN, K. Investigation of changes in clinical laboratory
L== tests related to aging and smoking. Aging and Human Development
       3( 1) : 95-101, February 1972.

(12) CASCTV, G., MAIUUCCINI, L., ZEDDA, S., CARTA, G. FUL(IILEWJ, G. Sulla
   frequenza delle cardiorasculopatie tra gli operai dell' industrla estrattiva

della sardegna. Sota II: Incidenza in rapport0 all'abitudine al fumo e
all'alcool. (On the incidence of cardiovascular disease among the workers
of the mining industry of Sardinia. Second communication : Incidence in
relation to habitual smoking and consumption of alcohol.) Rassegna

   - *edi? Sarda 71( Supplement 1) : lQl-200,1968.
m>J. C. Summary of major flndings of the Evans County cardlo
     vascular studies. Archives of Internal Medicine 128(6) : 887-339, De
      cember 1971.

24


(14) OASSU, J. C., HEYDEN, S., Baarxr., A. G., KAPLAN, B. H., Txaom!x%, H. A.,
   COBNONI, J. C., HAMES, C. G. Occupation and physical activity and coro-
   nary heart disease. archives of Internal Medicine 123(6) : !%?&%X$ De-
    cember 1971.

(15) CIAMPOLINI, E., DBINBOLI, R., RAVAIOLI, P. Azione de1 fumo di sigarette su
   aleuni parametrl de1 ricambio lipidico. (Action of cigarette smoking on
   several parameters of lipid metabolism.) Atti dell'Accademia dei
   Fisiocritici in Siena ; Sesione Medico-Fisica 17 : 47m, 1968.
    _ ----

(fG~-c'o~s~ocx,~. W. Fatal arteriosclerotic heart disease, water hardness at
   homeyand socioeconomic characteristics. American Journal of Epidemi-
   ology 94(l) : l-10, July 1971.

(17) E~TANDIA CANO, A., ESQUIVEL A~Iu, J., Jim CAMACHO, II., Fzazz
   SANTANDER, S., LEON MONTANEZ, E. Infarto juvenil de1 miocardio. (Myo-
   cardial infarction in the younger age groups.) Archives de1 Instituto de
   ardiologia de Mexico 41(Z) : 137-150, March-April 1971.
(18) FACCHINI, G., SEMEMRO, S., DI BIAS& G., TABARBONI, F., SPA~NOLQ D.,
   BUTORE, A., BONA~ITA,  E. Modificazioni nel soggetto anziano della
   reattivita al fumo di sigaretta : Ricerche sull'equilibrlo emocoagulativo e
   fibrinolitico e au1 circolo perlferico. (Modifications of the reactivity to
   cigarette smoke in old subjects: Research on the hemocoagulative and
   fibrlnolytic equilibrium and on the peripheral circulation.) Giornale di
  Gemlql lS( 10) : 77f+784,1972.
(19) EMNLEIB, M. Venous thrombosis in relation to cigarette smoking, physical
----%%%yTand seasonal factors. Milbank Memorial Fund Quarterly 5S(l,
   Part 2) : 123-141, January 1972.

(20) GIBBONS, G. F., MITROPOUI,OS, K. A. lnhibition of cholesterol biosynthesis
   by carbon monoxide : Accumulation of lanosterol and 24,25-dihydrolano-
   sterol. Biochemical Journal 127(l) : 3X-317, March 1972.
(21) GOLOVCHINEB, I. Y. Nekotoryye sotsial'nyye faktory zabolerayemosti infark-
   tom miodarda. (Some social factors in the incidence of myocardial in-
   farct.) Zdravookhranenie Rossiiskoi Federatsii 15(S) : 12-14, 1971.
(88) GORDON, T., Soamp; P., KANNEL, W. B. Section 27. Coronary heart disease,
   atherothrombotic brain infarction, intermittent claudication-a multi-
   variate analysis of some factors related to their incidence: The Fram-

and Cerebro-

   333-386, December 1971.
Ir4) HEISTAD, D. D ., WHEELER, R. C. Effect of carbon monoxide on reflex vase
   constriction in man. Journal of Applied Physiology 32( 1) : 7-11, January
   1972.

";) B~LLBERQ, K., WAYLAND. H., RICKART, A. I,., BINC, R. J. Studies on the
    coronary microcirculation by direct visualization. American Journal of
-:y 29 : 593697, May 1972.
`~2 Rxvnm, CASSEL, J. C., BARTEI., A., TYROLER, H. A., HAMES, C. G., COR-
    SoNI, J. C. Body weight. and cirgarettc smoking as risk factors. Archives
, -,,- edicine 128(6) : 915919, December 1971.
~,&$~-~YAMA, T. Smoking in relation to the death rates of 265,118 men and
    women in Japan. A report of five years of followup. Presented at the
   American Cancer Society's Fourteenth Science Writers' Seminar, Clear-
    water Beach, Florida, March 27,1972,15 pp.

25