TABLE 5.—Age-adjusted means Jor selected coronary heart disease risk
factors and personal characteristics, by smoking category: Western
Collaborative Group Study, males 39-49 years of age

[414 years average observation data]

 

 

 

 

 

Smoking category
Variable Percent
Never Smoked 26 difference
smoked cigarettes or more
per day
Serum cholesterol.._...-_-___.___.____ 217.2 231. 8 +6.7
Beta/alpha ratio.....--.._-_..__. 1.9 2.1 +10.5
Lipalbumin___--.--_- 88 21.1 19, 4 —8. 1
Systolic blood pressure..-___._________ 126. 3 129. 9 +2,9
Diastolic blood pressure_-_____________ 82.0 81.3 —0.9
Ponderal index__._._--___.____..._.._. 12.6 12.7 +0.8
Physical activity on job-.-_____.._____ 1. 95 1.95 0
Amount of exercise.._._____._._______ 2.18 2. 05 —6.0
Income. _____.2 22-28 2.75 2.75 0

 

Source: Rosenman, R. H. (125).

Tare 6.—Percent distribution by behavior type of smokers and non-
smokers: Western Collaborative Group Study, males 39-49 years
of age

[414 years average observation data]

 

Smoking category

 

 

 

 

 

 

 

 

 

 

 

Behavior type Total |

Never Former Current 1-15 | 16-25 2% cig-

smoked smokers pipe or cigarettes | cigarettes | arettes

cigar only per day per day | or more

per day
Total__.- 100. 0 100. 0 100. 0 100. 0 100. 0 100.0; 100.0
Type A_________ | 47.5 41.3 45. 0 48. 3 44.8 | 48.9 56. 7
Type B__._____. 52.5| 587] 53.0 | 51.7| 55.2 | 511] 43.3

 

 

 

Test of difference of distributions: X?= 24.70; df=3; p=.001.
SouRcE: Rosenman, R. H. (128).

Behavioral pattern type A is characterized by an enhanced com-
petitiveness, drive, aggressiveness and hostility, and an excessive sense
of time urgency as contrasted to type B. There was a difference in
the distribution of personality types A and B among smokers and
nonsmokers (table 6).

The foregoing data refer to concurrent observations gathered in
1960-1961 on 3,182 men who were then free of manifestations of
coronary heart disease. A follow-up of this population during the

26
next 414 years disclosed that cigarette smokers experienced substan-
tially higher rates of coronary heart disease than those who had never
smoked. This finding is based on data for men 39-49 years of age,
which have been adjusted for the confounding influences of related
risk factors, such as age, cholesterol, etc. (table 7).

TasBie 7.—Incidence of new coronary heart disease by smoking category:
Western Collaborative Group Study, males 39-49 years of age

[434 years average observation data]

 

 

 

Rate per 10,000 population
Smoking category Number :
of men Adjusted for Not
concomitant adjusted
variables

Never smoked_______.__-2- =e 540 36 29
Former cigarette smokers... 22.22.2222 241 67 92
Pipe and cigar only__.__.____-----.-------_- 406 27 16
1-15 cigarettes____.. 2-22-2222 --- 212 51 | 52
16-25 cigarettes.....___.....------- eee 436 89 | 92
26 cigarettes and over_______.-_-_- ee 425 98 104

 

 

 

Sotrce: Rosenman, R. H. (125).

The coronary heart disease rate for those men smoking 26 or more
cigarettes a day is seen to be about three times greater than for those
who never smoked. The rate for former smokers is still rather high,
even after adjustment for concomitant variables. The largest impact.
of the adjustment procedure is noted among this group, and suggests
that those who quit may have done so because they were already a
relatively high-risk group for reasons other than smoking. The rela-
tively low rate among men smoking only pipes and cigars is noted
in this as in other prospective studies.

The nature of the association of smoking and coronary heart disease
incidence among type A and type B personality groups is not easy
to characterize or interpret. Among the type A group, the pipe and
cigar smokers and the light cigarette smokers had the lowest rates
of incidence of new coronary heart disease, while the highest rates
were found among those smoking 26 or more cigarettes a day. For the
type B group, the lowest rates occurred among those who had never
smoked, and the highest among the light cigarette smokers. The age-
adjusted rates of new incidence of coronary heart disease per 10,000
men 39-49 years of age are shown in table 8.

Additional data to permit concomitant analysis of these variables
and those in table 7 are needed.

27
Tape 8.—ZJncidence of new coronary heart disease by smoking
category and behavior type: Western Collaborative Group Study,
males 39-49 years of age

[4% years average observation data]

 

 

Rate per 10,000 population
Smoking category rs

Behavior Behavior

type A type B
Total___.. 22 eee eee 91 33
Never smoked____. 2222-22-22 ee 53 13
Former smokers.__.__.____-..-.-.------------------ 107 36
Pipe and cigars only....____. 2-2 -- 18 36
Cigarettes:

1-15____ 2 eee ee 18 60
16-25______-____ eee 135 33
26 and over.__.___-_._-_. 2 -_--- ------------- 149 51

 

 

 

Source: Rosenman, R. H. (128).

Lane, et.al. (96) found significant relationships of smoking intensity
and duration with personality factors—im pulsiveness, emotional insta-
bility and belligerence scales.

Thomas (7/43) after reviewing various studies of psychological
variables related to coronary heart disease, concludes that smoking
may have different effects on different personality types and at differ-
ent anxiety levels.

Multiple Risk Factors

The acceptance of a multiple factor causation hypothesis for coro-
nary heart disease emphasizes the need for more sophisticated statis-
tical analyses of appropriate data. Our understanding of the relative
importance of various risk factors from the limited number of such
special analyses has not been altered significantly from that obtained
by more conventional statistical analyses (38).

Clarification of the apparent independence of several of the major
risk factors has resulted.

Truett, et al. (745) emphasize that the major risk factors are noted
to have a different order of importance by age and sex. Cigarette
smoking is particularly important among younger males as noted in
table 9.

Genetic and Constitutional Studies

Baer (5) found that heavy smokers among college males were taller
than light smokers and nonsmokers, Lane, et al. (96) also found sig-
nificant associations between body size measurements, including
ponderal index (though not with height or weight individually), and
amount of smoking in the study of over 675 aviators.

28
TABLE 9.—Linear discriminant function coefficients (in standard
units) for various risk factors in coronary heart disease, by sex and
age: . 12 Year Framingham Study

 

 

 

 

 

 

 

 

2556 0. 21970. 3048 0. 2234.0. 2526

Men | Women
Risk factors |
Combined | 30-39 40-49 50-62 Com- 30-49 50-62
ages i years years years bined years years
| ages
Age... ----- 2288. 0. sons 2394) 0. asad 0. 23700 6259) 0. 7325 0. 2600
Cholesterol. __.___- 0. 4444.0. 9613) 0. 3207; 0. 3790.0. 2844] 0. 7322.0. 1207
Systolic blood | | | |
pressure_________ 0. 3334 0. 3427; 0. 1669) 0. 3809 0. 5556 0. 1947/0. 4776
Relative weight..._| 0. 1890 0. 1941) 0. 3619, 0, 1036'0. 0975! 0. 07510. 1481
Hemoglobin_______ —0. 1050/0. 0313, — 0. 0134, —0. 2206 0. 0392 — 0. 0304 0. 0734
Cigarettes smoked__| 0. 41920. 6523 0.5084 0. 3004 0. 0625 — 0. 07310. 1262
ECG abnormality__| 0. 20780 2689 0. |

i

 

Source: Truett, J. (144.)

Cederlof (78) has emphasized the value of studies of twins for
investigating aspects of coronary heart disease and presents certain
suggested modifications in methodology. The 1967 Report (146) dis-
cussed the studies by Cederlof on Swedish twin pairs (19. 20). His
cata on American twin pairs was recently presented and showed re-
sults similar to those of the Swedish twins (28).

The problems with interpretation of these studies are several. The
small numbers of cases and the combining of data for both sexes in
various subcategories make rates and ratios subject to significant
chance variations. In addition, use of a questionnaire for angina, with
only modest levels of reliability and validity requires a larger study
population before definitive conclusions can be made. The lack of
information on the distribution of risk factors other than smoking
in subsamples of discordant twin pairs and the total group of twin
pairs makes the comparison of ratios for prevalence of symptoms
difficult to evaluate. The inclusion in the “smoking” group of those
who had stopped smoking up to 3 years previous to the study, would
also tend to diminish the differences between smokers and nonsmokers.
Definitions of discordant smoking habits must conform to those differ-
ences identified as significant in the large-scale population studies.

The fact that discordance for smoking does occur among monozy-
gotic twins certainly indicates that the smoking habit cannot be deter-
mined by genetic factors alone. Twin studies with further sophistica-
tion of design, larger number of cases, better definitions of clisease,
and more significant identification of discordant exposures have the
potential of contributing substantially to our understanding of the
interactive factors in coronary heart disease.

29
Tn an article reviewing some of the epidemiological evidence in the
3% years subsequent to the 1964 report, Seltzer (729) concluded that
there was no substantial evidence to indicate a further association of
cigarette smoking with coronary heart disease beyond that stated in
the 1964 report.

Seltzer alluded to what he called “inconsistencies” in the recent
literature relating to duration, amount, age, inhalation and mode of
tobacco smoking with coronary heart disease.

The addition of many more person years of experience, from the
new and continuing studies. provides data since the 1964 Report that
“unr be analyzed age-specifically. When this is done most of these “in-
consistencies” disappear.

Seltzer’s conclusion is contrary to that of most epideniiologists who
are familiar with the current research. Furthermore, he has not con-
sidered the important relevance of the experimental, pathological, and
clinical data that have been reported since 1964 concerning cigarette
smoking and cardiovascular diseases.

INFLUENCE OF SMOKING AND NicoTINE ox Bioop Lapips

Epidemiological Studies

The results of epidemiological studies on the relationship of smok-
ing to serum lipid levels have not been consistent. Several studies
reported no significant difference in serum cholesterol (36, 40, 61,
150) and triglyceride levels (40, 61) between smokers and nonsmok-
ers. In their study of twins, Blomstrand, et al. (7Z) state that pro-
longed smoking had an insignificant effect on all serum lipid levels
in their monozygotic twins and only elevated phospholipids in their
dizygotic group. However, they quote a personal communication
from Carlson, et al. who found elevated trigylceride levels in smokers
ina prospective study of 6,000 persons.

In a very comprehensive study of 657 former naval aviation cadets
over a period of 23 years, Harlan, et al. (5G) investigated the relation-
ship of various constitutional and environmental factors to serum
lipid and lipoprotein levels. They found that serum Sf 0-12 (beta)
lipoproteins and cholesterol levels were related to cigarette smoking
and that the duration of smoking also had a significant correlation.
The authors felt that the relationship of smoking to these lipids was
presumably direct, because cigarette smoking did not. correlate with
other factors related to lipids.

Experimental Studies—Animal
Studies in dogs of the immediate effects of tobacco smoke inhalation

and nicotine administration showed an increase in serum triglycerides
but not cholesterol, in addition to a rise in free fatty acids (76). There

30
were no differences in cigarette, cigar or pipe smoke effects when the
depth of inhalation was kept constant. Chronic administration of
nicotine in dogs resulted in a 50 percent rise in serum cholesterol levels
but did not affect triglycerides (82). Kershbaum, et al. (83) have also
shown that pronethalol (a beta-receptor blocker) inhibits the serum-
free fatty acid and triglyceride rise induced by nicotine in dogs.

In studies of the lipid and atherogenic effects of chronic nicotine
administration in cholesterol-fed rabbits, one report found no effect
in serum lipid levels but a significantly higher incidence of aortic
fibrosis (57). Other investigators found that nicotine iereased the
amount of cholesterol in the blood and the intensity of lesions in the
aorta (28). In cholesterol-fed rabbits administered vitamin D, Hass,
et al. (59) found that nicotine induced severe calcific athero-arterio-
sclerosis and occlusive thromboarteritis, especially conspicuous in
cardiac, smooth and skeletal muscle.

Astrup (2) has shown that in rabbits on a high cholesterol diet,
chronic carbon monoxide exposure had a marked atherogenic effect.

Gudbjarnason (52) has shown that chronic nicotine administration
in dogs leads to a diminution in the rate of cholesterol turnover.

Studies in Humans

It has previously been reported (78) that cigarette smoking mobil-
izes free fatty acids, resulting in increased plasma concentrations.
It was also found that this effect of smoking was the result of increased
sympathetic and adrenal activity initiated by the absorbed nicotine
(84), the latter having no direct lipolytic action in adipose tissue (85).
This response to smoking has now been confirmed by other investi-
gators (47,90, 110).

Studies in man, on the immediate effect of cigarette smoking, have
shown no effect on serum concentrations of lipoproteins and lipopro-
tein lipids (cholesterol, phospholipids, triglycerides) (78, 92, 115).
In a recent study, however, an increase in serum beta-lipoproteins
was observed 10 minutes after smoking (72).

In a study of the comparative effects of cigarette, cigar and pipe
smoking on free fatty acid mobilization and catecholamine excretion,
cigarette smoking was found to have a much greater effect (87). Less
nicotine absorption in cigar and pipe smoking, due to the absence
of inhaling, was considered to be the explanation for the milder bio-
chemical effects with these two forms of smoking (80). Kershbaum,
et al. also compared the effects of various types of cigarettes on these
parameters (79). They found no difference in free fatty acid and
catecholamine response or nicotine absorption with several brands of
filter and non-filter cigarettes. Cigarettes containing shredded lettuce
leaf had no effect.

31
In other lipid studies it was observed that smoking might increase
the tendency of human blood serum to crystallize cholesterol (87).

Kershbaum has also shown that cigarette smoking increases the
blood steroid levels in humans (86).

Stupres on Turompvs ForMatTIon

The 1967 Report reviewed the effects of smoking on 7n vitro throm-
bus formation, varying platelet characteristics and other serum factors
associated with blood coagulation. It is not in the scope of this report
to go into a detailed analysis of blood coagulation and/or thrombosis.
However, the role of smoking and blood lipids on thrombogenesis will
be briefly discussed, as they relate to thrombosis and cardiovascular
disease.

Catecholamines

The role of catecholamines (especially epinephrine) in thrombo-
genesis must be stressed (777). The nieotine-induced catecholamine
release, which plays a major role in cardiovascular dynamics might
also be the mediating factor in the relation between cigarette smoking
and thrombosis. Ardlie (7) has shown that catecholamines enhance
ATP or ADP induced platelet aggregation. ADP and noradrenaline
in low concentration (up to 0.05 pg./ml.) were found to increase
platelet mobility (55). The reverse was true in higher concentration.
Rowsell (728) has shown increases in both thrombus formation in
an extracorporeal system and clotting time in silicon-coated tubes with
moderate doses of epinephrine. Large doses gave values closer to the
control state, Besterman (8) has shown a diurnal variation in “plate-
let” stickiness which might be associated with diurnal variations in
catecholamine release. Glynn (48) found no difference in platelet
ageregation between smokers and nonsmokers.

Shimamoto (/33) proposes that epinephrine has a primary effect
on the arterial wall causing the release of a thromboplastin-like sub-
stance which then leads to increased platelet aggregation. An autopsy
study in humans by Auerbach (3) showed increased fibrous thickening
in the walls of arterioles and small arteries of 5 organs, in smokers
as compared to nonsmokers, This effect might be secondary to platelet
changes which then caused damage to the arterial wall. As discussed
earlier in the study by Hass (59), in which rabbits on a high choles-
terol and vitamin D diet were given nicotine, at the site of the oc-
currence of thrombus there was usually an inflammation of the arterial
wall.

Blood Lipids

Conner, et al. (26) and Warner, et al. (752) have described various
experiments in dogs and rabbits, in which infusion of long-chain
saturated free fatty acids caused extensive thrombosis and death. Zn

32
wtro coagulation and platelet aggregation were also increased. Long-
chain unsaturated free fatty acids, however, did not have these effects
although microscopic platelet aggregation was observed (66). /n vitro
studies have shown that linoleic and linolenic acids might have a pro-
tective effect against platelet aggregation induced by long-chain satu-
rated fatty acids (73, 101).

The rise in plasma-free fatty acids which follows cigarette smoking
was associated with increased platelet adhesiveness (7/0). The long-
chain fatty acid-induced platelet aggregation was suggested to be due
to ADP release from platelets (58). Harrison (57) suggests that 7m
vitro platelet adhesiveness tests are influenced by ADP release from
damaged red cells and that the platelet change might really be a
reflection of red cell abnormalities.

Bray (74) found that coronary heart disease patients have an ex-
aggerated platelet adhesiveness in response to ADP or ATP.

Several studies have shown disturbances in lipid and carbohydrate
metabolism in coronary heart disease patients (24, 95, 136).

Kurien (95) postulates that the increases in free fatty acid levels
immediately after either an acute myocardial infarction or cerebro-
vascular accident result from tissue anoxia with a secondary cate-
cholamine release, which then leads to the increases in free fatty
acids. Malhrotra (703) studied two population groups in India. There
was no difference in the cholesterol, triglyceride, and free or esterified
fatty acid levels between the two groups. However, the incidence of
coronary heart disease was much higher in the population whose diet
and fat absorption predispose to an abundance of long-chain fatty
acids.

A majority of coronary heart disease patients have an abnormal
glucose tolerance test. In most of these patients there is a greater
decrease in free fatty acids in response to glucose and a slower return
to normal values (24, 136).

Soloff and Schwartz (136) have determined two subgroups of these
patients: one “A”, in which the free fatty acid response to glucose
resembled a normal curve except for an exaggerated rise after 5 hours:
another “B”, in which the free fatty acid response to glucose re-
sembled that. of diabetics, there being a slower decrease and a sub-
normal return of free fatty acid levels after 5 hours, The significant
effect, however, is that type “B” patients had a relative hyporesponse
of stearic acid (long-chain saturated) decline with a relatively de-
creased rise in linoleic acid (long-chain unsaturated) after 5 hours.

These findings may be related to the effect of saturated and un-
saturated fatty acids on blood coagulation and suggest further re-
search to delineate the specific fatty acids elicited after smoking and in
coronary heart disease patients.

33
Carpiovascutar Response to SMOKING AND/oR NICOTINE

This section should be read in conjunction with the findings re-
viewed in the 1967 report.

Eeperimental Studies

Nadeau, et al. (112) cannulated the sinus node artery in an-
esthetized dogs and noted chronotropic changes in response to doses
of nicotine ranging from 1.0 to 100 »g./ml. Intranodal atropine
abolished bradycardia and intranodal propranolol or hexamethonium
abolished tachycardia. Nicotine inhibited the effects of cervical vagus
nerve stimulation without modifying the response to intranodally
injected acetylcholine. Nicotine did not inhibit the effect of stellate
ganglion stimulation. These results illustrate the varying effects of
nicotine under experimental conditions on the complicated neural and
humoral mechanisms affecting heart rate and rhythm.

Sleight (735) and Bergel, et. al. (7) have demonstrated cardiovas-
cular depressor reflexes in dogs elicited by nicotine stimulation of
the surface of the left ventricle. Studies have been undertaken in
dogs to determine the effect of beta sympathetic receptor blockade by
propranolol on the cardiac actions of nicotine. Westfall (758),
Edmundowicz (32), Papacostas, et al. (176), Shanks (737) and Puri
(120) have noted that propranolol can prevent the usual positive
inotropic effects of nicotine or norepinephrine stimulation on the
myocardium as well as the indirect beta dilator effects on peripheral
vessels, This results proportionately in a greater increase in left
ventricular afterload accompanied by a reciprocal decline of the
velocity of myocardial fiber shortening (120). It was also noted that
resulting unopposed alpha receptor activiation by nicotine could lead
to increased total peripheral resistance with impaired storke volume
and cardiac output. This is further evidence that catecholamines, the
release of which is induced by smoking. intermediate the cardiovas-
cular response to nicotine.

The effect of nicotine in single and repeated administrations was
studied on the terminal vascular bed of the heart by Corsini, et al.
(27). Results indicated that in dogs with intact coronary circulations.
the single intravenous infusion of nicotine (150 yg./kg. body weight /
minute) increased both the left ventricular capillary blood flow as
well as the terminal vascular capacity: the chronic intramusenlar
administration (0.5 mg. ke. body weight given 3 times ‘day for 2
months). however, had no such effect. In contrast, in dogs with con-
striction of the coronary arteries, nicotine administration in either
(single or repetitive doses) form resulted ina fall of capillary blood
flow but an increase in the terminal vaseular capacity. Capillary blood
flow as measured in these studies represents a nutrient inflow to the
myocardium. Nicotine administration resulted in an increase in both

34
the velocity of myocardial shortening as well as the force of con-
traction, and these effects of nicotine are identical to those of norepine-
phrine. In addition, there was also an increase in the rate of left
ventricular pressure rise (dp/dt) and a decline in left ventricular end-
diastolic pressure (121).

Coleman, et al. (25) studied isolated cat papillary muscles to deter-
mine the mechanism of the norepinephrine-induced stimulation of
myocardial oxygen consumption. They found that norepinephrine
does not increase the myocardial tissue oxygen demand unless con-
tractility is increased, other factors being held constant. Norepine-
phrine is known to increase myocardial contractility.

Further studies (49 742) on anesthetized open-chest dogs to deter-
mine the relative influences of changes in either the contractile state
or in tension development on myocardial tissue oxygen consumption,
indicate that both are significant factors. Basal oxygen requirements,
activation energy, and the cost of contractile element shortening
against a load appear to influence myocardial tissue oxygen consump-
tion to a lesser degree.

Chidsey, et al. (22, 22) studied the relationship of norepinephrine
to heart failure and the functional state of the human myocardium.
They reemphasize the role of norepinephrine in altering myocardial
fiber Jength and contractile status as demonstrated in human left
ventricular papillary muscles removed from patients at the time of
mitral valve replacement.

Ayres (4) has noted products of anaerobic cardiac metabolism in
dogs made ischemic by exposure to carbon monoxide. These will be
presented in a subsequent section of this chapter. Weissler, et al. (756),
in experiments with isolated perfused rat hearts, have reported on the
importance of glucose as a substrate for anaerobic metabolism of the
heart subjected to anoxia for 30 minutes. When glucose was added to
the anaerobic perfusate, the electrical and mechanical performance
of the heart improved markedly, as did the recovery of the heart dur-
ing the subsequent period of reoxygenation. Lactate production was
fivefold greater in the glucose-supported anoxic heart than in the
anoxic heart without glucose. In similar fashion, morphologic changes
of the mitochondria and longitudinal tubules of the anoxie heart
noted by electron microscopy, were averted by the inclusion of glucose
m the perfusion fluid. This experiment suggests that glucose might
help temporarily to prevent myocardial infarction, caused by relative
myocardial anoxia, by providing a substrate for anaerobie cardiac
metabolisin.

The isolated perfused rat heart was also studied by Braclhfeld, et al.
(72) to determine the effects of nicotine on lysosomal, mitochondrial,
and supernatant enzyme systems of the myocardium. They suggested
that nicotine toxicity may be expressed in terms of damage to the

35
lysosomal membrane and the cell wall. Shibata, et al. (732) studied
the action of nicotine on the transmembrane potential and contractility
of isolated rat atria. They suggest that while nicotine may influence
membrane electrodynamics, there may also be a direct action on the
contractile mechanism of the cardiac muscle cell by changing the
duration of the action potential, which implies alterations in potassium
fluxes.

Nicotine-induced changes, in dogs, in action potentials and conduc-
tion depression, with enhancement of Purkinje fibre “automaticity,”
may lead to the development of ventricular fibrillation (450). Post
myocardial infarction dogs were much more sensitive to the adminis-
tration of nicotine, as measured by electrocardiographic changes, than
were normal dogs, especially in the acute stage of myocardial infarc-
tion (6). Webb, et al. (154) state that changes in fibrillation thresholds
after cigarette smoking noted in dogs, by analogy, “may have relevance
to the higher incidence of coronary deaths without increased incidence
of angina in cigarette smokers.”

Studies in Humans

The 1967 report noted that sudden death from previously undetected
coronary heart disease appeared to occur frequently among cigarette
smokers. Kuller (94) showed in a study of sudden death in Baltimore
that arteriosclerotic heart disease was a major cause (61.4 percent)
of death. No smoking histories were recorded. Luke, et al. (99)
reviewed 275 consecutive autopsied cases of sudden unexpected death
from natural causes, in individuals age 20 to 45 years, and noted that
asymptomatic coronary artery disease comprised 28 percent of the
causes of sudden death. Again, no smoking data were taken. Data
pooled from 10 studies available to Burch, et al. (77), indicated that
‘ardiovascular disease accounted for 51 percent of 8,151 adult sudden
deaths.

Present. clinical evidence indicates that ventricular asystole or
fibrillation may be the mechanism of sudden cardiovascular death in
most. cases. It is known that hypoxia, hypercapnia, ischemia, elec-
trolyte disturbances, and increased catecholamine activity all can
predispose to ventricular fibrillation. From available physiological
evidence noted elsewhere in this and the bronchopulmonary chapter,
and also in the 1967 Report, it would appear that smoking can direetly
or indirectly contribute to the development of these predisposing con-
ditions. It is well accepted clinically that ventricular, nodal, or atrial
premature contractions can be increased or induced by cigarette smok-
ing, as well as by other factors, and can be reduced by the cessation of
cigarette smoking in both normal and ischemic hearts. These pre-
mature contractions are frequently precursors of their respective
tachyeardias. Also, a person with an acute or impending myocardial
infarction subjected to the sympathoadrenal effect of smoking could

36
more readily develop a fatal arrhythmia (75). The relationship of
smoking to cardiac arrhythmias must be studied further to determine
more exactly both the physiology and the mechanisms involved in
sudden deaths from cardiovascular disease.

Kerrigan, et al. (74) studied cardiac output in both smokers and
nonsmokers who had no evidence of coronary heart disease and found
rises in cardiac output in response to exercise and to cigarette smok-
ing separately and then in combination. They note that the total
increase in cardiac output appears to be the sum of the exercise and
the smoking effects. Smoking may create an additional myocardial
tissue oxygen demand above and beyond the demand attributable to
exercise.

Moses, et al. (105) reported that pretreatment of healthy normals
with glucose blocks the increased cardiac output response to cigarette
smoking by inhibiting the increases in stroke volume but not heart:
rate.

Frankl, et al. (42) noted that after 5 normal male chronic smokers
were given propranolol, cigarette smoking caused a significant in-
crease in systemic blood pressure and a significant decrease in cardiac
output. Thus cigarette smoking after propranolol administration may
be especially hazardous. Yamamoto noted similar results (160).

Sen Gupta, et al. (730) studied 11 ischemic cardiac patients and
14 healthy controls for abnormal ECG changes after smoking one
cigarette and noted specific or nonspecific changes in almost all of
the cardiac patients as compared to few changes in the healthy smok-
ers and no abnormalities in the healthy nonsmokers. Pentecost, et al.
(717) studied the acute effects of cigarette smoking in patients with
angina or post-myocardial infarction as compared with normal con-
trols. Normal men and those with angina in the absence of infarction
behaved similarly with an increase in pulse rate, mean pressure, stroke
volume, and cardiac output. The majority of the patients among the
post-myocardial infarction group showed a marked fall in stroke
volume and cardiac output while smoking. In another study (43) to
evaluate the interrelationship of smoking and exercise effects on
cardiac output, a fall in cardiac output that occurred in some post-
infarction coronary patients as a result of smoking alone was noted.
Also noted were decreases in cardiac output after smoking and exer-
cising as compared to post-exercise cardiac output in the same patients
before they smoked.

Starr (139) suggests that the ballistocardiographic (BCG) find-
ings in cardiac disease and after cigarette smoking may provide
valuable information about the rate of acceleration of myocardial
contractile velocity that cannot be determined by studying cardiac
output or stroke volume alone. A diseased heart has a slower accelera-
tive rate of contraction. BCG abnormalities have frequently been

37
related to cigarette smoking in subjects with or without heart disease,
including angina pectoris. The BCG findings of Jackson, et al. (68)
indicate that cigarette smoking itself may have acute and chronic
harmful effects on myocardial function, since duration of smoking
was also correlated with certain abnormalities.

Gazes, et al. (47), Braunwald, et al. (73), and Klensch, et al. (97)
have found higher plasma norepinephrine levels in coronary patients
at rest and after smoking as compared to normals. Kershbaum, et
al. (77) have reported that the rise in free fatty acids after cigarette
smoking is also greater in patients with coronary heart disease, prob-
ably due to an enhanced norepinephrine response,

Burch, et al. (7@) also stress the importance of the action of norep-
inephrine on the venous vascular system. “Greater than 70% of the
blood volume is contained within the systemic venous system and a
10% reduction in venous capacity would result in the sudden shifting
of 350 ml. of blood (assuming a blood volume of 5 L.) centrally into
the pulmonary veins and atria. In the presence of a diseased left ven-
tricle, such a sudden increase in central blood volume may result in
acute left ventricular failure’ (/7). (Additional cardiopulmonary
considerations are noted in the bronchopulmonary disease chapter of
this Report).

Human Myocardial Tissue Function in Relation to Anoxia and to
Carbon Monoxide

Likoff, et al. (98) suggest that an oxvgen-diffusion impairment or
Inappropriate oxygen utilization at the myocardial microcirculatory
or cellular level could be responsible for the anginal symptoms and
ECG sigus of apparent myocardial ischemia in the presence of ade-
quate arterial saturation and patent coronary arteries by coronary
arteriography. Ayres (4) and Eliot (33) suggest that these mecha-
nisms may be related to the carbon monoxide effect and abnormal hemo-
globin function.

Tn addition to a review of the coronary circulation as related to
myocardial ischemia and angina pectoris, Elliott, et al. (35) studied
zonal myocardial ischemia (60) by ECG, coronary angiography and
regional lactate metabolism in 50 patients with proven coronary heart
disease. They found that the ECG findings could be normal even when
severe coronary disease was present with myocardial production of
lactate. The regional lactate pattern was very helpful in determining
the location of myocardial ischemia and significant coronary artery
lesions.

In studies of coronary patients exposed to relatively low levels of
carbon monoxide, Ayres (4) has reported that nyocardial lactate and
pyruvate extraction decreased or shifted to actual production, sug-
gesting the presence of anaerobic metabolism. These data support his

38
previous findings noted in the 1967 report that carboxyhemoglobin can
interfere with oxygen delivery to the myocardium to the degree that
relative myocardial anoxia can occur. The shift to anaerobic cardiac
metabolism, which is relatively ineffective as a source of energy, In-
dicates the presence of myocardial anoxia, and should be regarded as
a warning sign. In these same experiments Ayres has noted that the
myocardial oxygen extraction is decreased in response to carbon
monoxide inhalation, and thus has further demonstrated the relation-
ships of carbon monoxide with relative myocardial anoxia and anaero-
bic myocardial metabolism. The shift to the left of the hemoglobin-
oxygen dissociation curve, describing the decreased ability of
hemoglobin to release oxygen at the tissue level, is directly related to
increased carboxyhemoglobin levels.

The animal experiments of Weissler (156), noted in the previous
section, suggest that glucose might possibly help to temporarily pre-
vent myocardial infarction from relative myorardial anoxia, by pro-
viding a substrate for anaerobic metabolism. Since myocardial
ischemia may be caused not only by complete coronary arterial ob-
struction, but also by increased myocardial tissue oxygen demand
above and beyond available oxygen supply, it would be important to
know whether cigarette smokers have more products of anaerobic
myocardial metabolism than do nonsmokers.

Eliot (34) has noted apparent hemoglobin abnormalities in patients
with signs of myocardial ischemia or acute necrosis, and in smokers
as compared to controls. However, he suggests that there are other
hemoglobin abnormalities also present besides the well documented
carboxyhemoglobin abnormalities associated with the carbon monoxide
effect of cigarettes. Some reverted to normal hemoglobin status after
stopping smoking.

Anomalous hemoglobin-oxygen dissociation was noted in “heavy”
cigarette smokers (more than one pack per day) without. known coro-
nary heart disease. In experiments where the amount of cigarette smok-
ing was controlled, there appeared to be a threshold effect : more than 12
cigarettes per day caused this anomalous dissociation to occur (58).
Birnsting] (9) reports finding an increased hemoglobin affinity for
oxygen in smokers, which does not appear to be explained solely by
the increased carboxyhemoglobin levels in smokers.

Research to further study the interrelationships of carbon monoxide
to the myoglobin of heart muscle should be performed because it is
possible that carbon monoxide may replace oxymyoglobin with car-
boxymyoglobin and disturb the oxygen-dissociation phenomena of
myoglobin (88, 1.26, 159). The limitations of blood supply and the high
energy output of heart muscle as compared to skeletal muscle may
make the myoglobin impairments by carbon monoxide of possible
etiologic importance in cigarette smoking and heart disease.

315-131 O-—68——4 39
Hydrogen cyanide appears to be rapidly converted to thiocyanates
by the body, but the absorption by the lung of cyanide from cigarette
smoke might possibly result in higher serum cyanide levels in the coro-
nary arteries than in the systemic circulation. As noted in the 1964
Report, the cyanide ion is capable of stopping cellular respiration
abruptly through inactivation of cytochrome oxidase. In sublethal
exposures, the cyanide ion is gradually released from its combination
with the ferric ion of cytochrome oxidase, converted to thiocyanate ion
and excreted in the urine. Thiocyanate blood levels in smokers are three
times higher than in nonsmokers and relative differences in urinary
excretion are even more pronounced. Cytochrome oxidase is very im-
portant in cellular respiration of all body cells. In view of the ex-
tremely high myocardial cellular needs for aerobic metabolism, it is
possible that the cyanide ion inactivation of cytochrome oxidase also
can occur in myocardial cells and be of critical importance, especially
in light of other risk factors such as impaired coronary blood
flow, the carbon monoxide effect, and the known increases in myo-
cardial tissue oxygen demand caused by the smoking/nicotine-induced
catecholamine release. Further research is needed to determine whether
or not cyanide ions in concentrations equivalent to those found in
cigarette smokers, have a harmful effect. on the myocardium, in terms
of both acute and chronic exposures.

Glucose Metabolism and Possible Cardiovascular E Ffrects

Epstein (37) has reviewed the relationships of hyperglycemia to
coronary heart disease. Although he states that there appeared to be
no relationship of cigarette smoking to the hyperglycemia that was
associated with the prevalence of coronary heart disease in the
Tecumseh population, Higgins (63) reports that the Tecumseh ciga-
rette smokers, both male and female, had approximately a 10 mg. per-
cent elevation in blood glucose as compared to nonsmokers, although
the percentage elevations above the median levels were not statistically
significant. Since Epstein (39) reported that cigarette smokers in the
Tecumseh study population had a higher incidence of coronary heart
disease, it would be interesting to see what the interrelationship of the
incidence of coronary heart disease is to the cigarette smokers who
have elevated blood glucose levels.

Cohen, et al. (24) have reported abnormal glucose tolerance in
some postinfarction patients, suggesting the possibility that this group
has difficulty utilizing glucose. It is known that smoking induces
release of catecholamines which can create an increased demand for
glucose by the body. Wahlberg (152) had noted that in patients with
atherosclerotic disease but without clinical diabetes mellitus, the glu-
cose tolerance was pathologic in 46 percent as compared with 10 per-
cent of controls, and normal in 33 percent as compared with 71 percent

40
controls. From this he infers that subclinical diabetes mellitus may
predispose to vascular disease in the same way as clinical diabetes
mellitus.

Kingsbury, et al. (89) studied a small group of male patients with
peripheral] arteriosclerotic disease to determine the serum glucose, non-
esterified fatty acids, and immunoreactive insulin responses to sub-
cutaneous adrenaline and to smoking. Under basal conditions, the fatty
acid response was normal. While adrenaline consistently caused a rise
in serum glucose. cigarette smoking either had no effect or lowered
the fasting concentration. In 5 patients smoking caused an elevation
in the immunoreactive insulin which could not be explained by blood
sugar changes. The implication is that these patients were hypersecre-
tors of insulin. Unfortunately, detailed smoking histories are not
available for these individuals. Szanto (141), in a very small study
of habitual smokers, noted a “hyperinsulinism” response during oral
glucose tolerance testing after smoking two cigarettes. This response
was markedly reduced when the test was repeated after a 14-day absti-
nence from smoking. The view that hyperinsulinemia is associated
with atherogenesis has been suggested (714, 118, 149, 157) and dis-
cussed by Mahler (102). If smoking directly or indirectly causes a
hyperinsulin response in some individuals, then this may possibly be
one mechanism by which cigarette smoking may enhance atherogenesis.

Kershbaum, et al. (86) have noted higher plasma 11-hydroxy cor-
ticosteriod levels in smokers. Whether the “hyperinsulinism” reported
to be present in smokers is related to increased adrenal corticosteriods
remains to be determined. Hyperinsulinism could be a response to the
frequent catecholamine-induced hyperglycemia caused by cigarette
smoking in individuals without significant clinical or subclinical
coronary heart disease; but conceivably the hyperinsulinism response
might be more pathological in coronary patients. Also, the potassium
and other ion changes caused by glucose shifts in response to shifts in
insulin levels may predispose to cardiac arrhythmias and sudden death.

Additional Considerations Regarding Coronary Blood Flow
Coronary blood flow, besides being influenced by the size of the
inner lumen of the coronary vessel wall and its ability to dilate for
the purpose of increasing flow of oxygenated blood when needed by
heart muscle, is also dependent upon the viscosity of the blood (/6).
The concepts of fluid mechanics, such as laminar or turbulent flow, are
well known. For any given aperture and pumping pressure, fluid flow
will depend somewhat upon the physical characteristics of the fluid
itself. It has been demonstrated in both cigarette smokers (700) and
in patients with myocardial infarction that hemoconcentration occurs
(15, 137), sometimes to a relatively small degree in terms of absolute
changes in hematocrit, but the changes in viscosity are much greater

41
than might have been predicted from consideration of hematocrit
changes alone. At this point, other factors related to fluid mechanics
also enter in, such as the quality and amount of lipids in the blood.
Burch, et al. (75) have demonstrated that increased fatty acids in-
crease the force necessary to “shear” the blood, thus contributing to a
reduction in the capacity of the blood to flow in laminar fashion
through a given aperture. When coronary arteries are impaired by
partial obstruction of the inner lumen or by decreased distensibility,
there may be a critical interaction with blood viscosity causing marked
turbulence of flow and thus reducing further the potential for increas-
ing coronary blood flow.

SUMMARY. CONCEPT AND CONCLUSION

Additional evidence has been presented which tends to confirm and
extend the positive findings previously reported in the 1964 and 1967
reports.

1. Epidemiological studies show that “heavy” cigarette smoking is
strongly associated with an increased risk of dying from coronary
heart disease.

2. New data confirm and help to clarify the relationship between
cigarette smoking and other “risk factors” in the development of
coronary heart disease suggesting that both independent and inter-
acting effects are involved.

3. Evidence indicates that cigarette smoking may accelerate the
pathophysiological changes of pre-existent coronary heart clisease and
contribute to sudden cardiovascular death. This relationship helps to
explain why stronger epidemiological correlations between cigarette
smoking and coronary heart disease tend to be found in incidence
studies rather than in prevalence studies where the population is
under-represented for those people who have had fatal outcomes from
coronary heart disease.

4, Present evidence continues to support the position that giving up
cigarette smoking is beneficial to cardiovascular health.

5. Some progress is being made in the study of the interrelationships
of selected psychological factors, smoking behavior, and the develop-
ment of coronary heart disease.

Recent data provide a basis for the formulation of a theoretical
concept by means of which it is possible to correlate the interaction of
several known coronary heart disease risk factors with the physio-
logical mechanisms by which cigarette smoking may affect the
myocardium.

The epidemiological studies continue to indicate that “heavy”
cigarette smoking is strongly associated with a fatal outcome from
coronary heart disease. This fact may be accounted for by a mechanism

42
whereby, in the presence of impaired coronary circulation due to coro-
nary heart disease, cigarette smoking may “trigger” myocardial oxy-
gen deficits of critical degree. One or more of the following mechanisms
may be involved in this process:

1. The increase of myocardial wall tension and velocity of contrac-
tion, largely mediated through norepinephrine released in response
to cigarette smoking, thereby increasing the myocardial demand for
oxygen and other nutrients.

9. The relative reduction of nutrient capillary blood flow in the
region of the myocardium distal to and dependent upon blood flow
through a partially occluded coronary artery.

3. The impairment of oxygen dissociation from hemoglobin due to
the formation of carboxyhemoglobin from carbon monoxide, thereby
diminishing the availability of oxygen to the myocardium.

4. The reduction of the supply of oxygen available to the myo-
cardium as a consequence of hypoxemia due to severely impaired pul-
monary function from chronic obstructive bronchitis.

5. The impairment of coronary blood flow as a result of the in-
creased blood viscosity associated with hyperlipemia or hemoconcen-
tration.

6. The increase in platelet adhesiveness which might contribute to
thrombus formation or coronary occlusion.

7. The predisposition to acute cardiac arrhythmias as a consequence
of harmful neurogenic reflexes or catecholamine release.

8. The possible, although presently speculative, contributions to
impairment of myocardial cellular respiration by cyanide ion.

Thus, the interaction of the factors which decrease oxygen supply
to the myocardium and those which increase the myocardial demand
for oxygen may play a major role in precipitating the fatal outcome
in some individuals with coronary heart disease. On the other hand,
it is possible that the same factors, in less severe clinical circumstances,
could precipitate temporary coronary insufficiency or contribute to
nonfatal myocardial infarctions or cardiac arrhythmias.

The pathophysiological factors associated with cigarette smoking
may further interact with other known epidemiological risk factors
associated with coronary heart disease such as high serum cholesterol
and high blood pressure. Although not a “risk factor’, unusually high
physical stress may also create physiological demands for additional
oxygen supply to the myocardium.

The finding that those who discontinue cigarette smoking have a
lower risk of dying from coronary heart disease than those who con-
tinue to smoke might be accounted for by the potential reversibility
of many of the pathophysiological effects of smoking on the cardio-
vascular system. It is reasonable to expect partial reversibility of
factors that interfere with oxygen supply, such as the carbon monoxide

43
effect, and the increased platelet adhesiveness, hyperlipemia, and hemo-
concentration noted in cigarette smokers. Moreover, the increased
myocardial] oxygen requirements associated with the cigarette smoking-
induced catecholamine response and neurogenic reflexes could be
expected to be eliminated upon cessation of cigarette smoking. In some
patients, the cardiopulmonary benefits of stopping smoking may
reduce pulmonary hypertension.

An increased ability to predict future cardiovascular events in
individual persons will depend upon more precise definition and
measurement of the pathophysiologic factors associated with ciga-
rette smoking and their correlation with information about the epi-
demiological risk factors.

Because of the increasing convergence of epidemiological and
physiological findings relating cigarette smoking to coronary heart
disease, it is concluded that cigarette smoking can contribute to the
development of cardiovascular disease and particularly to death
from coronary heart disease.

SMOKING AND CEREBROVASCULAR DISEASES

Many of the pathophysiological considerations noted in the above
section may also pertain to the relationship of smoking and cerebro-
vascular disease.

A mortality study in Japan by Hirayama (65) reports findings
different from those cited in the 1967 Report (146), in which smokers
under age 75 had a mortality ratio of 1.40, or more, for stroke.

Hirayama found that deaths due to vascular lesions of the central
nervous system, after age 40, were one-third less frequent among
smokers than among nonsmokers. Several factors may account for
these different findings. One is that the etiologic spectrum for stroke
in Japan includes more hemorrhagic strokes than in the United States.
Another is that the Japanese study included all stroke deaths over age
40, whereas the studies in the United States found the positive associa-
tion between smoking and stroke mortality occurred under age 75 (54).

In a study reported by Kuhn (43), 20 habitual smokers refrained
from smoking for one-half day and baseline retrograde brachiocere-
bral angiograms were taken: then they smoked one cigarette, inhaled
deeply, and had repeat angiograms, Only those over 60 years of age
failed to have significant acceleration of flow in cerebral precapillary
yessels and markedly increased vessel counts as in carbon dioxide
inhalation experiments.

As in coronary heart disease, it may be that smoking has differett
effects depending upon the degree of underlying arteriosclerotic disease
present. Among patients with stroke, many have arteriosclerotic heart
disease and a significant number die of myocardial infarcts (704).

44
The rate of oxygen uptake in the brain is very high, being approxi-
mately 5 cc. oxygen/100 g. brain/min. (704). As discussed in the
cardiovascular section, if carbon monoxide causes a shift to the left in
the oxygen hemoglobin dissociation curve, it would make less oxygen
available to the brain tissue. Those people with an arteriosclerotic.
cerebrovasculature who cannot increase their cerebral blood flow in
response to smoking may therefore more easily develop a state of rela-
tive cerebral hypoxia; a situation which could be a factor in the
etiology of stroke.

CITED REFERENCES

(1) ARDLIE, N. G., Giew, G., Scuwartz, C. J. Influence of catecholamines
on nucleotide-induced platelet aggregation. Nature (London) 212
(5060) : 415-417. October 22. 1966.

(2) Astrvp, P.. KuELpses, K., WANSTRUP, J. Enhancing influence of carbon
monoxide on the development of atheromatosis in cholesterol-fed rab-
bits, Journal of Atherosclerosis Research 7: 343-304. 1967.

(3) AVERBACH, O., HamMonp, E. C., GaRFINKEL, L. Thickening of walls of
arterioles and small arteries in relation to age and smoking habits.
New Englaud Journal of Medicine 278i 18): 980 984, May 2. 1968.

(4) Ayres, S. M. Personal communication. March 1968.

(5) Barr, D. J. Height, weight, and ponderal index of college male smokers
and nonsmokers. Journal of Psychology 64: 101-105. September 1966.

(6) BELLET, S., KERSHBAUM, A., MEADE, R. IL, Jn., Scowartz. L. The effect of
tobacco smoke and nicotine on the normal heart aud in the presence
of myocardial damage produced by coronary ligation. American Journal
of the Medical Sciences 201(1) : 40-51, January 1941.

(7) Bercer, D. H., Maxtn, G. S. Central and peripheral cardiovascular
changes following chemical stimulation of the surface of the dog’s heart,
Cardiovascular Research 1(1) : 80-90, 1967.

(8) BESTERMAN, E., Myat, G., Travapr, V. Diurnal variations of platelet
stickiness compared with effects produced by adrenaline. British Medi-
eal Journal 1; 597-600, March 11, 1967.

(9) Brenstincl, M., Cote, P., HAwKINs, L. Variations in oxyhaemoglobin
dissociation with age, smoking and Buerger’s Disease, British Journal
of Surgery 54(7) : 615-619, July 1967.

(10) BiacxevrN, H., Keys, aA., KaRVONEN, M., VaN BucHeM, F. 8. P.. TAYLor,
H. L. Relation of “positive” postexercise electrocardiographic re-
sponses to other characteristics of risk. Circulation 36(4) (Supplenrent
Il) : 70, October 1967.

(11) BromstTranp, R., LUNDMAN, T. Serum Hpids. smoking and heredity. Acta
Medica Scandinavica (Supplement 455) : 51-60, 1966.

(12) BRACHFELD, N.. KUEHN, P., KawapbeE, M.. Onan. E. Nicotine medicated
release of myocardial cell and lysosomal enzymes, Annals of Internal
Medicine 66(5) : 1084, May 1967.

(13) Bracnwa.p, F.. Curpsry, (. A. HARRISON, bD. C., Gareney, T. F.. KAWLER,
R. L. Studies on the function of the adrenergic nerve endings in the
heart. Circulation 28(5) : 958-969, November 1963.

(14) Bray, C.. McDonatp, L. A new platelet defect in patients with ischaemic
heart disease. British Heart Journal 28(3) : 429, May 1066.

(15) Burcu, G. E., DePasQuace, N. P. The hematocrit in patients with myo-
cardial infarction. Journal of the American Medical Association 180(1):
63-70, April 7, 1962.

45
(16)
(17)
(18)

(19)

(20)

(22)

(23)

(30)

(31)

(33)

46

Burca, G, E., DePasquatre, N. P. Hematocrit, viscosity and coronary
blood flow, Diseases of the Chest 48(3) : 225-232, September 1965.

Brrcw, G. E., DePasavarr, N. P. Sudden, unexpected, natural death.
American Jonrnal of the Medical Sciences 249: 86-97, January 1965.
CEDERLOF, R. The value of twin studies in epidemiology. World Medical
Journal 14(6) : 168-171, Novenrber-December 1967.

CEpDERLOF, R., Frinera, L.. Jonsson, E., Kats, L. Morbidity among nrono-
zygotic twins. Archives of Environmental Health 19(2): 346-450, Feb-
ruary 1965.

CEDERLOF, R., FRinerG, L.. Jonsson, E., Kats, L. Respiratory symptoms
and “angina pectoris” in twins with reference to smoking habits.
Archives of Environmental Health 13(6) : 726-737, December 1966.

Ciipsey, (. A., BRAUNWALD, E,, Morrow, A. G, Catecholamine exeretion
and cardiac stores of norepinephrine in congestive heart failure.
American Journal of Medicine 39(8): 442-451, September 1965.

CuipsEy, C. A., SONNENBLICK, E. H., Morrow, A. G., Braunwatp, E.
Norepinephrine stores and contractile force of papillary muscle from
the failing human heart. Circulation 33(1) : 43-51, January 1966.

CLARK, V. A., CHAPMAN, J. M., Coutson, A. H. Effects of various factors
on systolic and diastolic blood pressure in the Los Angeles Heart Study,
Journal of Chronic Diseases 20: 571-581, 1967.

Couen, A. M., Srarrir, E. Carbohydrate metabolism in myocardial in-
farction. Behavior of blood glucose and free fatty acids after glucose
loading. Diabetes 14(2): 84-86, February 1965.

CoLteman, H. N., Sonnenpiick. E. H., Brauxwatp, E. Mechanism of the
norepinephrine-induced stimulation of myocardial oxygen consumption
as studied in the isolated cat papillary muscle. Circulation (Supple-
ment II) 36(4) : 89, October 1967.

Connor, W. E., Hoax, J. C., Warner, E. D. Fatty acids and thrombus
formation. In: Sasahara, A. A.. editor, Pulmonary Embolic Disease.
London, 1965. Pp. 50-58.

Corsint, G. C., Purr, P. S. Brine, R. J. Effect of nicotine on capillary
flow and vascular bed of the heart in presence and absence of experi-
mental coronary artery insufficiency. Federation Proceedings 27(2) : 632,
Mareh-April 1968.

Czocima-Lysanowicz, %. Gorski. M., Kepra, M. Wplyw nikotrny i
kofeiny na rozwoj miazdzycy u krolikow. Annales Universitatis Mariae

Curie-Sklodowska:; Section D: Medicina 14(20) ; 181-206. 1959.

Dirkex, HW. The etiology of myocardial infarction—with special refer-
ence to cigarette smoking among yeung coronary patients and those
with xecond heart attacks. In: Wynder, E. J.., Hoffmann, D., editors.
Toward a Less Harmful Cigarette. Bethesda, U.S. Public Health Serv-
ice, National Caneer Institute Monograph 28, June 1968. (In press)

D6RKEN, H. Die Rauchgewohnheiten bei Jungeren Frauen mit Herzin-
farkt. Miinchener Medizinische Wochensehrift 109(41) : 2129-2134,
January 1967.

DoOrKEN, H. Die Rauchgewohnheiten bei Jungeren Herzinfarkt-Patienten.
Miénchener Medizinische Wochenschrift 109(4) : 187-192, January 27,
1967.

EpMUNDOWICZ, AL CL. Crpottoxr. PL B.. Penson, K. EL Cardiovascular
responses to cigarette smoke and nicotine in dogs following beta-
adrenergic blockade with propranolol. (Abstract) Federation Proceed-
ings 24: 718, March—April 1965.

Exror. R. S.. Beart, G. 8. Personal communication, April 1946s,

-_
(34)

(35)

(36)

(37)
(38)

(39)

(40)

(46)

(47)

(48)

(49)

(50)

(51)

Exrot, R. 8., MizvKaMI, H. Oxygen affinity of hemoglobin in persons with
acute myocardial infarction and in smokers. Circulation 34: 331-336,
August 1966.

EuiorT, W. C., Gortin, R. The coronary circulation, myocardial ischemia,
and angina pectoris. Modern Concepts of Cardiovasctar Disease
35(10) : 111-116, October 1966.

Epidemiological studies related to coronary heart disease: Characteristics
of men aged 40-59 in seven countries. F. Smoking habits. Acta Medica
Scandinavica (Supplement 460) : 804-315, 1967.

Epstein, F. H. Hyperglycemia. A risk factor in coronary heart disease.
Circulation 36: 609-619, October 1967.

Epsterx. F. H. Predicting coronary heart disease. Journal of the Ameri-
can Medical Association 201(11): 795-800, September 11, 1967.

Epsterx, F. H. Some uses of prospective observations in the Tecumseh
Community Health Study. Proceedings of the Royal Society of Medi-
cine 60(1) : +8, January 1967.

Fipanza, F., Imprmso, B., Dr Benepetta, C. Indagine epidemiologica
delle cardiopatie ischemiche nei reclusi del penitenziario di 8. Stefano
di Ventotene. Giornale dell’-Arteriosclerosi 4: 255-267, 1966.

FRANKEL, W. S., FrreDMAN, R.. Sotorr, L. A, Cardiac output, blood pressure
and free fatty acid responses to smoking in the nonbasal state. American
Journal of the Medical Sciences 252(1): 39-1. July 1906.

FRANKL, W. S.. Sororr, L. A. The hemodynamic effects of propranolol
hydrochloride after smoking. American Journal of the Medical Sciences
254 (5) : 623-628, November 1967.

FRANKL, W. S., Wrxters. W. L.. Sotorr, L. A. The effects of smoking
on the cardiac output at rest and during exercise in patients with healed
myocardial infarction. Circulation 31(1): 42-44, January 1965.

FRIEDEMANN, M., Stem, H., EMMRICH, J., ReEINpELL, H. Der Herzinfarkt
in Atiologiscer und katamnestischer Sicht. Deutsches Archiv fur
Klinische Medizin 211 : 261-296, 1965.

FrrepmMan, E. H., HELLERSTEIN, H. K. Occupational stress, law school
hirearchy, and coronary artery disease in Cleveland attorneys. Psychoso-
matic Medicine 30(1) : 72-86, January-February 1968.

FriepMan, G. D. Cigarette smoking and geographic variation in coronary
heart disease mortality in the United States. Journal of Chronic Diseases
20 : 769-779, 1967.

Gazes, P. C., RicHarpson, J. A., Woops, E. F. Plasma catecholamine
concentrations in myocardial infarction and angina pectoris. Circulation
19(5) : 657-661, May 1959.

GuLywnn, M. F., Mustarp, J. F., BUCHANAN, M. R., Murpny, E. A. Cigarette
smoking and platelet aggregation. Canadian Medical Association Journal
95: 549-553, September 10, 1966.

GranamM, T. P., Jz, Covett, J. W., SONNENBLICK. E. H., Ross, J., JR.,
Bravnwa.p, BE. Control of myocardial oxygen consumption: Relative
influence of contractile state and tension development. Journal of
Clinical Investigation 47 : 375-385, 1968.

GREENSPAN, K., KNOEBEL, S. B., FiscH, C. Effects of nicotine upon human
and canine cardiac action potential and contractile state. (Abstract)
The Project for Research on Tobacco and Health 1964-1968. American
Medical Association Education and Research Foundation. June 1968.
Pp. 24-25.

GroscocEat, Y., ANGUERA, G., LeLLoucn, J., Jacotor, B., Beaumont, J. L.,
Paros, E., Manier, BE. L’intoxication chronique par la nicotine chez

47
le lapin nourri au cholesterol. Effets sur la paroi aortique et sur la
lipidemie. Journal of Atherosclerosis Research 5(8) : 291-301, 1965.

(52) GupBsarnason, S. Effect of nicotine administration on cholesterol metabo-
lism of liver, serum, heart and brain. Journal of Pharmacology and
Experimental Therapeutics 161(1) : 47-54, May 1968.

(53) GuTenKatvr, J. J., Bratt, G. T., Evior, R. 8. Effect of cigarette smoking
on the hemoglobin-oxygen dissociation curve, Circulation (Supplement
II) 36(4) : 129, October 1967.

(54) Wammonp, E. C. Smoking in relation to the death rates of 1 million men
and women. In: Haenszel, W., editor. Epidemiological Approaches to
the Study of Cancer and Other Diseases. Bethesda, U.S. Public Health
Service, National Cancer Institute Monograph No. 19, January 1966.
Pp. 127-204.

(55) Hampton, J. R., MitcHett, J. R. A. Effect of aggregating agents on the
electrophoretic mobility of human platelets. British Medical Journal
1: 1074-1077, 1966.

(56) Haruin, W. R., OBERMAN, A., MITCHELL, R. E., GrayBIEL, A, Constitutional
and environmental factors related to seruni lipid and lipoprotein
levels. Annals of Internal Medicine 66(3): 540-555, March 1967.

(57) Harrison, M. J. G., MitcHett, J. R. A. The influence of red blood cells
on platelet adhesiveness. Lancet 2: 1163-1164, November 26, 1966.

(58) Hastam, R. J. Role of adenosine diphosphate in the aggregation of human
blood-platelets by thrombin and by fatty acids. Nature (London) 202:
765, 1964.

(59) Hass, G. M., LANDERHOLM, W., HemMmens, A. Production of calcific
athero-arteriosclerosis and thromboarteritis with nicotine, vitamin D.
and dietary cholesterol. American Journal of Pathology 49 (4) : 739-771,
October 1966.

(60) Herman, M. V., Exiiorr, W. C., Gorin, R. An electrocardiographic, ana-
tomic, and metabolic study of zonal myocardial ischemia in coronary
heart disease. Circulation (5) : 834-846, May 1967.

(61) Heyven-Srucky, S. ScHIBLer-REICcH, 8. Cardiologische Risikofaktoren
bei Schweizer Mannern. Schweizerische Medizinische Wochenscrift 97
(1) : 20-25, January 7, 1967.

(62) Heypen-Stucky, S. Epidemiologie des Herzinfarktes 1965. Schweizerische
Medizinische Wochenschrift 95(45) : 1535-1540, November 6, 1965.

(63) Hieerns. M, W., Kse.sperc, M. Characteristics of smokers and nonsmok-
ers in Tecumseh, Michigan. II. The distribution of selected physical
Measurement and physiologic variables and the prevalence of certain
diseases in smokers and nonsmokers. American Journal of Epidemi-
ology 86(1) : 60-77, January 1967.

(64) Hinkie, L. E.. Jr. Witney, L. H., Len man. E. W., Dunn, J., BEN-
JAMIN, B., Kine, R., PLlakuy, A., FLEHINGER, B. Personal Communica-
tion, 1968.

(65) Hirayama, T. Smoking in relation to the death rates of 265,118 men and
women in Japan. Tokyo, National Cancer Center Research Institute,
September 1967. 14 pp.

(66) Hoax, J. ©, Warner, E, D., Connor, W. E. Platelets, fatty acids and
thrombosis. Circulation Research 20(1) : 11-17, January 1967.

(67) Hyams, L., Seer, M., ArcHER, M. Myocardial infarction in the Japanese.
A retrospective study. American Journal of Cardiology 20(4) ; 549-
554, October 1967.

(68) Jackson, D. H., OnermMan, A., MITCHELL, R. E., GRAYBIEL, A. Factors
contributing to the ballistocardiographic waveform in healthy middle-

48
(69)

(70)
(71)
(72)
(73)
(74)
(15)

(76)

(77)
(78)
(79)
(80)
(81)

(82)
(83)

(84)

aged men. American Journal of Cardiology 20(4): 531-540, October
1967.

KANNEL, W. B., CASTELLI, W. P., MCNAMARA, Pp. M. Cigararette smoking |
and risk of coronary heart disease. Epidemiologic clues to pathogenesis :
The Framingham Study. In: Wynder. E. L., Hoffmann, D., editors.
Toward A Less Harmful Cigarette. Bethesda. U.S. Public Health Serv-
ice, National Cancer Institute Monograph 28 June 1968. (In press)

KANNEL, W. B., CASTELLI, W. P.. McNamara, P. M. The coronary pro-
file: 12-year follow-up in the Framingham study. Journal of Occupa-
tional Medicine 9(12) : 611-619. December 1967.

KawneL, W. B.. Dawser, T. R.. McNamara, P. M. Detection of the coro-
nary-prone adult: The Framingham Study. Journal of the Iowa Medi-
cal Society 56(1) : 26-34, January 1966.

Krpra, M., PoLeszak, J.. PITERA, A. Woplyw tytoniu na poziom tluszezow-
cow krwi. Polski Tygodnik Lekarski 20(3) 2 1452-1574, September 27,
1965.

Krrr. J. W., Mac Atay. 1.. PIReie, R.. Bronxte-STEwarT, B. Plate-
let-aggregation by phospholipids and free fatty acids. Lancet 1: 1296-
1299, June, 19, 1965.

Kerrican. R., Jay, A. C., Doyre, J. T. The circulatory response to ciga-
rette smoking at rest and after exercise. American Journal of the Medi-
cal Sciences 255: 113-119, February 1968. -

Kersupatn, A. Personal communication. March 1968.

Kersuparm, A., BeLtvet, S. Cigarette, cigar, and pipe smoking: Some
differences in biochemical effects. Geriatrics 23: 126-134, March 1968.

KERSHBAUM, A.. BELLETT, 8.. CAPLAN, R. F., FEINBERG, L. J. Effect of
cigarette smoking on free fatty acids in patients with healed myocardial
infarctions. American Journal of Cardiology 10(2) : 204-208, August
1962.

KersHpaumM, A., BELLET, S., DICKSTEIN, E. R., Fernperc, L. J. Effect of
cigarette smoking and nicotine on serum free fatty acids, Based on a
study in the human subject and the experimental animal. Circulation
Research 9(5) : 631-635, May 1961.

Kersupatm, A., Beviet, S., HikapayAsHI, M., Fernperc, L. J. Regular
filter-tip, and modified cigarettes. Nicotine excretion, free fatty acid
mobilization, and catecholamine excretion. Journal of the American
Medical Association 201 (7) : 545-546, August 14, 1967.

KeErsHpaumM, A., BELLET, 8., HIRABAYASHI, M., Frinsere, L. J., ErLserc, R.
Effect of cigarette, cigar and pipe smoking on nicotine excretion. The
influence of inhaling. Archives of. Internal Medicine 120(3): 311-814,
September 1967.

KersupauM, A., BELLETT, 8., JIMENEZ, J.. Ferveerc, L. J. Differences in
effects of cigar and cigarette smoking on free fatty acid mobilization
and catecholamine excretion. Journal of the American Medical Associa-
tion 195(18) : 1095-1098, March 28, 1966.

KeErsHBatM, A., BELLET, 8., KHORSANDIAN, R. Elevation of serum choles-
terol after administration of nicotine. American Heart Journal 69(2) :
206-210, February 1965.

KersuBauM, A., JIMENEZ, J.. BELLET, S., ZANUTTINI, D. Modification of
nicotine-induced hyperlipidemia by antiadrenergic agents. Journal of
Atherosclerosis Research 6: 524-530, 1966.

KERsHBauM, A., KHoRSANDIAN, R., Carian, R. F., Betiet, S., FEINBERG,
L. J. The role of catecholamines in the free fatty acid response to ciga-
rette smoking. Circulation 28(1) : 52-57, July 1963.

 

49
(85)

(86)

4)
~2

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(109)

50

KERSHBAUM, A., Osapa, H., ScriaBINe, A., BeLiet, S., PAPPAsOHN, D. J.
Infivence of nicotine on the mobilization of free fatty acids from rat
adipose tissue in vitro and in the isolated perfused dog limb. Circulation
36 (Supplement II) : 20, October 1967.

KersuspatM, A., Pappasoun, D. J., BELLET, S., HIRABAYASHI, M., SHAFITHA,
H. Effect of smoking and nicotine on adrenocortical secretion. Journal
of the American Medical Association 203(4) : 275-278, January 1968.

KersupauM, A., Pappasomun, J.. Osapa, H. Beet, S. The influence of
tobacco smoking on the crystallization of cholesterol. (Abstract)
Clinical Research 15(2) : 322, April 1967.

Keyes, M. MizuKami, H. Lumry, R. Equilibrium measurement in the
reactions of heme-proteins with gaseous ligands. Analytical Biochemis-
try 18: 126-142, 1967.

Kinesaury, K. J., Jarrett, R. J. Effects of adrenaline and of smoking
in patients with peripheral atherosclerotic vascular disease. Lancet
2(7505) : 22-23, July 1, 1967.

KLeNscH, H. Blut-Kathecholamine und -Fettsauren beim Stress durch
Rauchen und durch korperliche Arbeit. Zeitschrift fur Kreislauffor-
schung 55(10) : 1085-1044, October 1966.

KLENscH, H., SpecKMANN, K., MaETzeL, F. W., Meyer, J. D. Der Plasma-
Noradrenalinspiegel bei Koronarkranken in Ruhe und im Nikotin-
Stress. Zeitschrift fur Kreislaufforschung 56(12) : 1164-1169, December
1967.

KoNTTINEN, A., RaJASALMI, M. Effect of heavy cigarette smoking on post-
prandial triglycerides, free fatty acids, and cholesterol. British Medical
Journal 1(5334) : 850-852, March 30, 1968.

Kvun, R. A. Mode of action of tobacco smoke inhalation upon the cerebral
circulation. Annals of the New York Academy of Sciences 142 (Article
1): 67-71, March 15, 1967.

Kv ter, L., LIJENFELD, A. Epidemiological study of sudden and unexpected
deaths due to arteriosclerotic heart disease. Circulation 34: 1056-1068,
December 1966.

Kvrien, Y. A., Oliver, M. F. Serum-free-acids after acute myocardial in-
farction and cerebral vascular occlusion. Lancet 2: 122-127, July 16,
1966.

Lane, N. E., OnERMaN, A. The thousand aviator study: Smoking history
correlates of selected physiological, biochemical, and anthropometric
measures, U.S. Naval Aerospace Medical Institute. NAMI-961. Under
the Joint sponsorship of the U.S. Public Health Service, and the National
Aeronautics and Space Administration, NASA Order R-136, April 27,
1966. 12 pp.

LEREN, P. The effect of plasma cholesterol lowering diet in male survivors
of myocardial infarction, A controlled clinical trial. Octa Medica Scan-
dinavica (Supplement 466) : 1-92, 1966.

Likorr, W., Seca, B. L., Kasparian, H. Paradox of normal selective coro-
nary arteriograms in patients considered to have unmistakable coronary
heart disease. New England Journal of Medicine 276 (19) : 1063-1066,
May 11, 1967.

Luke, J. L., HeLtpern, M. Sudden unexpected death from natural causes
in young adults. A review of 275 consecutive autopsied cases. Archives
of Pathology 85(1) : 10-17, January 1968.

McDonoven, J. R., Hames, G. G., Garrison, G. E.. Stubs, S. G.. LicheTM an,
M. A., HEFELFINGER, D. C. The relationship of hematocrit to cardiovas-