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Carbon Monoxide, Smoking, and Cardiovascular Disease
transmittent or scanning electron microscopy.9 The
edema is thought to be caused by an increased
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FOR MANY years nicotine has been considered
responsible for the association between tobacco
smoking and the development of atherosclerotic
cardiovascular disease, due to its pronounced pharmacological effects on the cardiovascular system,
which have been the subject of several epidemiological studies. In animal experiments, however,
nicotine has no atherogenic effect when administered in amounts relatively much higher than the
nicotine uptake by a smoker, but may cause
necrosis and calcifications of the medial arterial
layers,' 2 which suggests probable importance in
the development of the Monckeberg type of
arteriosclerosis in man.
Intimal-subintimal injuries of arterial walls indistinguishable from atherosclerosis are, however,
produced in experimental animals by another
compound in tobacco smoke: carbon monoxide.
Rabbits exposed to carbon monoxide for 13 weeks,
leading to carboxyhemoglobin concentrations of 1011%, develop focal intimal-subintimal changes in a
significantly higher degree than nonexposed control
animals. These are characterized first of all by a
pronounced subintimal edema with various degenerative and reparative processes, increased formation of mucopolysaccharides and collagen, formation of fibrotic plaques, etc.3 When feeding carbon
monoxide exposed rabbits (16-18% carboxyhemoglobin) cholesterol for 8-10 weeks, the aortic
content of cholesterol increases from 2.5 to 5 times.4
This effect of carbon monoxide has been confirmed
by other laboratories.5 Experiments in primates
have shown an increase in the number and size of
lipid containing lesions in the intramural coronary
arteries with carbon monoxide exposure and cholesterol feeding, but did not show an increase in aortic
cholesterol.6 Exposure to hypoxia (16% oxygen in
the breathing air) for 8-10 weeks has a similar
effect on the arterial walls as exposure to carbon
monoxide,7 while hyperoxia (26-28% oxygen) has an
opposite effect.8
The primary effect of carbon monoxide on the
cardiovascular system is an increased endothelial
permeability, leading to subendothelial edema,
which is easily demonstrable by ordinary light
microscopy and which looks very dramatic through
inflow of plasma components through a widening of
the gaps between the endothelial cells. It is
generally agreed that the occurrence of subendothelial edema indicates early atherosclerotic changes.
The edema leads to increased formation of
mucopolysaccharides, which may facilitate the
precipitation of penetrated lipoproteins and eventually result in accumulation of lipids in fatty
streaks or plaques.
Severe ultrastructural changes are also found in
the myocardium after 16-18% carboxyhemoglobin is
maintained for 2 weeks, the most impressive
findings being local areas of partial or total necrosis
of the myofibrils and degenerative changes of the
mitochondria (unpublished observations). Other
observations include extra- and intracellular edema,
capillary wall edema, increase in the number of
ribosomes, and reparative fibrotic changes. The
morphological changes are similar to those found in
hypoxia.
Both the arterial and myocardial changes can
occur after only 4-5 hours exposure to carbon
monoxide (16-18% carboxyhemoglobin).
Since the production of atherosclerosis and
myocardial damage by carbon monoxide exposure
of experimental animals is achieved by carboxyhemoglobin concentrations comparable to those found
in heavy smokers, the experimental results strongly
indicate that carbon monoxide in tobacco smoke is
a toxic compound of major importance. This was
deduced from our earlier findings of high carboxyhemoglobin levels in young smokers with myocardial infarction, Buerger's disease and peripheral
arterial insufficiency.10 An association between
carboxyhemoglobin levels in smokers and the
occurrence of atherosclerosis has been demonstrated,"1 and it could be calculated that smokers with
carboxyhemoglobin levels of 5% or higher had a 21
times higher incidence of atherosclerotic disease
than smokers with values of 3% or lower.12
Nicotine is probably of minor importance in
comparison to carbon monoxide for the association
between smoking and atherosclerosis, but it may
have a synergistic effect on the carbon monoxide
enhanced accumulation of lipids in arterial walls,
and it may also be of importance in the occurrence
of arrhythmias in smokers with myocardial dam-
From the Department of Clinical Chemistry, Rigshospitalet, Copenhagen, Denmark.
Circulation, Volume XLVJII, December 1973
1167
EDITORIALS
1168
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age.'3 The vasoconstrictory effects of nicotine may
further impair oxygen supply to tissues of smokers
with high carboxyhemoglobin concentrations, particularly where obliterations occur due to plaques or
to carbon monoxide induced subendothelial edema.
The edema will also impair diffusion of oxygen and
nutrients through the vascular walls, probably
having especial significance in the myocardium, and
it is very likely that carbon monoxide induced
myocardiopathy is related to increased incidence of
sudden death in smokers as compared with
nonsmokers.
If the hypothesis that carbon monoxide is of
major importance for the development of atherosclerotic disease in smokers is correct-and the
experimental and clinical data are in favor of thatit might he of interest to evaluate the risk of the
individual smoker to develop atherosclerosis and
heart disease, and the role of smoking in epidemiological studies, by measuring carboxyhemoglobin
concentrations after smoking. The smoking of
nicotine weak cigarettes should not influence the
smoker's risk of getting cardiovascular disease, as
long as the carbon monoxide content in the smoke is
not decreased, which probably is impossible. If
nicotine is the addictive compound in the tobacco
smoke, cigarettes with low content of nicotine may
even be more dangerous than usual cigarettes due
to their supposed higher degree of inhalation.
Further, the atherogenic effects of carbon monoxide exposure are of interest also for atherosclerosis
research. The biochemical mechanisms involved in
the effects of carbon monoxide and of hypoxia and
hyperoxia on endothelial permeability and on lipid
metabolism in arterial walls should be identified,
since this might lead to a deeper insight in the
mechanism of the atherogenetic process.
POUL AsTRuP
References
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WANSTRUP J, KJELDSEN K, ASTRUP P: Acceleration of
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AsTRUP P, KJELDSEN K, WANSTRUP J: Enhancing
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Circulation, Volume XLVIII, December 1973
Carbon Monoxide, Smoking, and Cardiovascular Disease
POUL ASTRUP
Circulation. 1973;48:1167-1168
doi: 10.1161/01.CIR.48.6.1167
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