current smokers had a penile cancer risk I .6 times that of never smokers. but the risk
among former smokers was similar to that among current smokers (Table 8).

Primary hepatocellular cancer has been associated with smoking in a number of
recent studies (Trichopoulous et al. 1980: Lam et al. 1981: Yu et al. 1983: Oshima et
al. 1984: Trichopoulos et al. 1987; Hirayama 1989). This association is of potentially
great public health importance because of the high incidence of primary liver cancer
and the epidemic of cigarette smoking worldwide, which is increasingly involving
countries in which liver cancer is the leading cause of cancer mortality. The mechanism
whereby smoking might affect liver cancer risk is unknown.  Although potential
confounding by alcohol consumption is of concern in interpreting this association. the
association of smoking with hepatocellular cancer has remained significant in several
studies after controlling for alcohol intake (Trichopoulos et al. 1980: Yu et al. 1983;
Oshimaet al. 1984; Trichopoulos et al. 1987). One case<ontroI study (Yu et al. 1983)
and two cohort studies (Cederlof et al. 1975: Carstensen. Pershagen. Eklund 1987:
Rogot and Murray 1980) have examined the effects of smoking cessation on liver cancer
risk. In all three studies. current smokers were found to have higher risks than either
never smokers or former smokers. In the case<ontrol study. potential confounding by
different alcohol consumption of current and former smokers was controlled (Yu et al.
1983). Many of the earlier studies (including the prospective studies reviewed in thi\
Chapter) did not exclude the possibility that cancer of the liver may have been primary
in another (smoking-related) organ. The possible role of hepatitis B as a modifier of
the effect of smoking on the risk of liver cancer is not clear (IARC 1986).

Tobacco has been associated with stomach cancer. but whether this association i\
causal remains unclear (IARC 1986: US DHHS 1982. 1989). Fe& studies have
considered the effect of cessation on the risk of stomach cancer. The U.S. Veterans
Study (Kahn 1966; Rogot and Murray 1980) and the Swedish study (Cederlof et al.
1975) indicate a reduction in stomach cancer risk after cessation. although the relative
risks among current smokers were small in these studies (Table 8).

Leukemia has recently been implicated as a smoking-related disease (Austin and Cole
1986: Severson 1987: Kinlen and Rogot 198X). hut this observation has not been
consistent (for review. see Kinlen and Rogot 1988). The U.S. Veterans Study showed
only a slight dose-response relationship formyelogenous leukemias. but there uas little
difference in risk between current and former smokers (Kahn 1966: Ropot and Murray
1980: Kinlen and Roget 1988 ). In the earlier presentation of these data. there was no
difference in risk among ex-\mohers. compared b ith current smokers. at any of four
levels of prior cigarette smoking (Kahn 1966). The most recent analysis of these data
indicated there was little difference in risk among fomrer smokers compared with
current smoker5 for any of the subtype\ of leukemia. One study demonstrated a poorer
prognosis for patients with myelogenous leukemia who were cigarette smohers (Ar-
chimbaud et al. I989 ).

MULTIPLE PRIMARY CANCERS

The occurrence of multiple primary cancers may reflect the effects of the same risk
factor\ in the pathogenesis of the multiple cancers. the effects of agent5 used in treating

176


the initial malignancy. or simply the consequence of chance (Schottenfeld 1982). Thus.
multiple primary cancers have been investigated with the goals of examining envJiron-
mental and host factors increasing cancer risk and of identifying adverse consequences
of cancer treatment. Tobacco use, including cigarette smoking. has been examined as
a risk factor for the development of a second primary cancer. after diagnosi\ of a first
malignancy at cigarette-associated and non-cigarette-associated \ites: the effect of
smoking cessation on the occurrence of second cancers has also been addressed in
several investigations.

Descriptive studie\ have shown that an initial malignancy at a smoking-a5sociatsd
site is followed by an increased risk for cancer at the same or another cigarette-
associated site (Wynder et al. 196% Schottenfeld 1082). In an early study of multiple
primary cancers. Berg. Schottenfeld. and Ritter (lY70) examined the risks of second
primary cancers in persons evaluated at Memorial Hospital for squamous cell cancers
of the respiratory or upper digestive tract or other histologic types of lung cancer.  In
comparison with expected numbers of cases based on incidence rates for New York
State. significant excesses wtere observed for cancer\ of the lip. oral cav,ity or pharynx.
esophagus, larynx, and lung.

Only limited evidence is available on the effects of smoking cessation on the
occurrence of multiple primary cancer\. Moore reported two studies ( 1965. I97 I ) of
second primary cancers in persons with an index malignancy of the mouth, pharynx. or
larynx: both showed reduced risk for a second primary cancer in persons who stopped
smoking after diagnosis of the first cancer. For I to IS years. Silverman, Gorsky. and
Greenspan (1983) observed I17 smokers who had a primary cancer of the head and
neck region. Thirty percent of continuing smokers developed a second oral primary
cancer compared with IS percent of those reducing smoking and I3 percent of those
completely stopping.

In contrast, an effect of cessation was not found in two other studies (Castigliano
1968; Schottenfeld. Gantt. Wynder 1974). Castigliano's 1968 study included 88
subjects with mouth or throat cancer who survived for at least 3 years without evidence
of recurrence. During a minimum followup period of 3 years, the occurrence of a
second primary cancer was not related to smoking status. Schottenfeld. Gantt, and
Wynder (1974) examined multiple primary cancers in 733 patients admitted to
Memorial Sloan-Kettering Cancer Center with a primary epidermoid carcinoma of the
Ordl cavity, pharynx, or larynx. During the .5-year followup period. the smoking status
of those developing and not developing a second primary did not differ significantly.

Interpretation of these studies is limited by the small numbers of subjects and the
limited duration of followup. Furthermore. the interactions of tobacco smoking with
other risk factors of cancers of the head and neck, particularly alcohol consumption,
complicate interpretation of these data.

SUMMARY

This review of the relationship between cigarette smoking cessation and the risk of
nonrespiratory cancers has shown that former smokers tend to have lower risk than
current smokers forcancers of the oral cavity, esophagus, pancreas, bladder, and uterine

177


cervix. This lower risk appears to be neither an artifact of a lower exposure to cigarettes
in former smokers prior to quitting nor a result of confounding by other known risk
factors for these cancers. This observation of a diminution in risk further supports the
hypothesis that cigarette smoking is a causal factor for cancers of many sites other than
the respiratory system. Although smoking is not as strong a risk factor for non-
respiratory cancers as it is for cancers of the lung and larynx, substantial numbers of
cases of many nonrespiratory cancers can be attributed to tobacco use (US DHHS 1989).
The patterns of diminution in risk with increasing duration of abstinence indicate that
smoking cessation provides a substantial reduction in the risk of nonrespiratory cancer.

CONCLUSIONS

I. Smoking cessation halves the risks for cancers of the oral cavity and esophagus.
compared with continued smoking, as soon as 5 years after cessation, with further
reduction over a longer period of abstinence.

2. Smoking cessation reduces the risk of pancreatic cancer, compared with continued
smoking, although this reduction in risk may only be measurable after IO years of
abstinence.

3. Smoking is a cause of bladder cancer; cessation reduces risk by about SO percent
after only a few years. in comparison with continued smoking.

4. The risk of cervical cancer is substantially lower among former smokers in com-
parison with continuing smokers. even in the first few years after cessation. This
finding supports the hypothesis that cigarette smoking is a contributing cause of
  cervical cancer.

5. Neither smoking nor smoking cessation are associated with the risk of cancer of the
  breast.

178


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184


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IX6


     CHAPTER 6
SMOKING CESSATION AND
CARDIOVASCULAR DISEASE

IX7


CONTENTS

Introduction  ....................................................... IY I

P~tthopli~~iol(lfic Framen orb  ......................................... I Y I
Smohing and Development ot.CHD  .................................. I Y I
  .r\thcrosclero\i~ .................................................  I Y I
  Thrombosi\ .................................................... I Y,i
  Sp~lslll ........................................................ IYS
  .L\rrh~~thmia\  ................................................... I Y5
  Reduced Blood Os!sen Deli\,er!  .................................. IO.5
Smohing and Development of Peripheral Arterial Diwase ................. I Yh
Smohing and Development ofC~rebrc~\34cttl;tr Diseae  IY)h
Anticipated Effect\ of Smohin, cr Ce\ation on Ri\h of`Cardio\ acular Disca\e\
  Bawd on Knou ledge of Mech;tniwl\  ............................... 197

Smohing Ceaation and CHD  ......................................... 197
Cross-Sectional Studie\  ............................................ IYY
Studies 01` Smohing Ceh\ation and Ri\h of` MI Among Health! Person\  ...... 700
  Cax-Control Studies ............................................ 200
   Cohort Studie\  ................................................. 70.5
  Intervention Trials  .............................  ................ 22-1
Smohing Cexttion and CHD Ri\h Among Person\ With Diqywed CHD  ... 770
Summary of Smohing Ce\ation and CHD Rish ......................... 23Y

Smohing Cewttion and Aortic Aneur>wl ................................ 211
Studies of Smohing Cessation and Rish of Aortic Aneurysm ............... 211

Smohing Cessation and Peripheral Arterial Occlusive Di\ea\e  ............... 211
Smohing Cessation and Development of Peripheral c\rtery Di\ea\e Z-l.3
Smohinf Cessation and Prognosi\ of Peripheral Artery Disease Z-l.1
Surnmar~ ........................................................ 11-J

Smohing Cehation and Cerebrovascular Disease ..............  ........... 215
Studies of Smohing Cessation and Ri+ of Cerebrovawular Disease ......... 2-W
  Cro\s-Sectional Studic\  .......................................... 7-K
  Case-Control Studieh ...........  ................................ 7-K
  Prospective Cohort Studies  ....................................... 2IY
  Summary of Observational Studies  ........  ........................ 75 I
   Intervention Studie\ ............................................. 251
  Influence of Prior Levels of` Smohing  ............................... 25 I
   Effect of Duration of Abstinence ................................... 32
  Oral Contraceptives and Stnohing Cessation  ......................... 25X
  Effect of Smoking Cessation After Strohe  ....  ...................... 260
Summary ........................................................ 2hO

Conclusions ..................................................... ..~60

References ...................................................... ..26 I


IIVTRODLCTION

Cigarette smoking is firmly established as an important cause of coronary heart
disease (CHD). arteriosclerotic peripheral vascular disease. and stroke (US DHHS
1983. 1989). Eliminating smohing presents an opportunit) for bringing about a major
reduction in the occurrence of CHD. the leading cause of death in the United States.
Before examining the epidemiologic evidence relating zmohin, ~7 cessation and rish of
CHD and other forms of cardiovascular disease (CVD). the mechanisms by uhich
smohing leads to these diseases are briefly reviewed. The objectives in considering
these mechanisms are to address the plausibility that smoking cessation reduces rish of
CVD. to estimate the expected magnitude in rish reduction. and to assess the rapidit)
with which any risk reduction might occur. Whether these mechanisms are immedi-
ately reversible. irreversible. or slowly reversible i\ of particular rele\,ance to the
rapidity with which smoking cessation will reduce rich. The role of smohins in the
pathogenesis of CHD is discussed at length.  Th e etiologies of peripheral \ ascular
disease and stroke share several common features M ith CHD: thus. discussion focuses
on distinguishing features.

PATHOPHYSIOLOGIC FRAMEWORK

Smoking and Development of CHD

Pathogenesis of CHD. which includes the clinical manifestations of myocardial
infarction (MI). angina pectoris. and sudden death. is extremely complex and mediated
by multiple mechanisms and etiologic factors (Munro and Cotran 198X). At least five
interrelated processes are likely to contribute to the clinical manifestations of MI-
atherosclerosis. thrombosis, coronary artery spasm. cardiac arrhythmia, and reduced
capacity of the blood to deliver oxygen. Smoking appears to influence many steps in
the development of CHD. Although not all of these effects are proven fully. the
evidence for an influence on several mechanisms is convincing. The exact components
of cigarette smoke that are responsible are not known in each instance. but experimental
data have implicated nicotine and carbon monoxide (CO) in several processes. Other
products of cigarette smoking, such as cadmium. nitric oxide. hydrogen cyanide. and
carbon disulfide. have been hypothesized to play a rote. but their quantitative contribu-
tions remain unknown (US DHHS 1983).

Atherosclerosis

Atherosclerosis is the mechanical narrowing of medium-sized arteries by the
proliferation of smooth muscle cells. lipid accumulation. and ultimately. plaque forma-
tion and calcification (Munro and Cotran 1988). These lesions develop over decades
and are not immediately reversible; whether they are substantially reversible at all in
humans is a matter of current interest. Reversibility has been demonstrated in non-
human primates (Clarkson et al. 1984: Malinow and Blaton 1983) and huggested in
studies of humans using repeated arteriography (Blanhenhorn et al. 1987). Smohing is

I91


clear]) associated with the presence of atherosclerosis of the coronary arterie>, small
arteries of the myocardium. the aorta. and other vessels ;I\ demonrtrated in man!
autops) and angiographic studies (US DHHS lYX3). The development of athero-
sclerosis is complex. and several processes are likely to be important.
Endothelial damage is thought to play ;I primary role in the development of
atherosclerosis by exposing the arterial intima to blood lipids and white cells and bj
stimulating platelet adhesion. The endothelial damage can be an actual physical
denudation. but toxic functional damage may have similar consequences. In animal
studies. serum nicotine at levels similar to those of human smokers caused endothelial
damage (Krupshi et al. 19X7: Zimmerman and McGeachie 19X7). Evidence that
smoking has a direct toxic effect on human endothelium is provided by the observation
that smoking 9 tobacco cigarettes approximately doubled the number of nuclear-
damaged endothelial cells in circulating blood (Davis et al. 198.5. 1986): smoking
non-tobacco cigarettes had little effect. In addition. Asmussen and Kjeldsen (1975)
found pronounced degenerative changes of the umbilical artery endothelium at the time
of delivery among mothers who smoked: these changes were not present in the arteries
of nonsmoking mothers.
Smooth muscle cell proliferation is a primary feature of atherosclerotic lesions and
may result from several stimuli: the mo5t clearly demonstrated is platelet-derived
growth factor from adherent platelets. Smoking appears to increase the adherence of
platelets to arterial endothelium: blood draun from persons after smoking 3 cigarettes
results in a more-than-hundredfold adhesion of platelets to rabbit endothelium than does
blood drawn from persons before smoking or from ne\`er smohers (Pittilo et al. 19X1).
Platelets from chronic smohers have a greater tendenc) to aggregate on an artificial
surface than do those from nonsmokers (Rival. Riddle. Stein lY87). In minipig>. both
cigarette smoke and CO increase the adhesion of platelets to arterial endothelium
(Marshall I YX6). The intluence of smohing on platelet activity is discussed further in
the following section.
Lipid infiltration of the arterial intima. largely cholesterol, is another primaq feature
of atherosclerosis and is directly related to higher blood levels of low-densit!
lipoprotein cholesterol (LDL-C) and reduced blood levels of high-density lipoprotein
cholesterol (HDLC'). Smoking reduces the level of HDL-C. A strong inverse associa-
tion betv,eren daily cigarette consumption and HDL-C has been observed in man)
cross-sectional studies in the United States (Freedman et al. 19X7; Gordon and Doyle
19X6: Reichle!, Mueller. Hanis et al. lYX7: Willett et al. IYX3) and in other countries
(Assmann. Schultc. Schrleuer IYXI; Goldhourt et al. I9Xh: Gomo lY86; Jacobsen and
Thelle IYX7: Pellctier and Baher IYX7: Robinson et al. 19X7: Tuomilehto et al. 19X6).
In a longitudinal. community-based study. HDL-C decreased among persons starting
to smoke and increased among those &ho stopped smoking (Fortmann. Haskell.
Williams 19X6). In other prospectike studies. smoking abstinence ha\ been associated
M,ith substantial increases in HDL-C levels in both men and women (Hulley. Cohen.
Widdouson IY77: Hubert et al. 19X7: Rabhin 19X-t). In a stud) among young adults
in Louisiana. those \vho began smohing experienced substantial reductions in HDL-C
compared with those u ho did not start (Freedman et al. I%%). HDL-C increased among
I3 adult women who \uccessfully stopped smohing for 18 days. but decreased to its


previous levels among those vvho returned to smohing (Stamford et al. IYXh). Thus.
data indicate that smoking reduces the level of HDL-C. a potent protective factor against
CHD.

In a number of studies. smokers ha\,e been found to hav,e higher levels of triglycerides
(Freedman et al. 19X6: Jacobsen and Thelle 19X7; Gomo 19X6: Willett et al. lYX3):
however. the independent relation of triglyceride level with rish of CHD is not clear.
Smoking appears to have little. if any. relation with LDL-C level. Howsever. smokers
have approximately twice the level of serum malondialdehydt of nonsmohers (Nadiger.
Mathew. Sadasivudu lYX7): malondialdehyde can alter LDL-C and may promote its
incorporation into arterial wall macrophages (Steinberg et al. IYXY). In a metabolic
study among young men. smokers had a decreased cholesterol net transport from cell
membranes into plasma. which could partially explain the accumulation of cholesterol
in arterial walls (de Parscau and Fielding 19X6).

Thrombosis

Coronary artery thrombosis, resulting from platelet-fibrin thrombi, is a key element
in most cases of MI. Thrombi are visualized in a high percentage of coronary arteries
studied angiographically within hours of the onset of infarction (DeWood et al. I YXO).
and agents that lyse thrombi are effective treatments for MI (Stampfer et al. 19x7;
Loscalzo and Braunwald IYXX). The efficacy of aspirin. an antiplatelet agent. in
preventing MI further supports the role of thrombus formation (Steering Committee of
the Physicians' Health Study Research Group lYX9). The finding that smoking is
associated with history of MI even after controlling for atherosclerosis (Hartz et al.
19X I ) emphasizes the importance of mechanisms in addition to those that promote
atherosclerosis.

Platelets play a central role in thrombus formation in addition to releasing growth
factors that stimulate the proliferation of smooth muscle cells in arterial intima (Pack-
ham and Mustard 19X6). Platelets can form microthrombi that become incorporated
into the arterial wall, thus contributing to plaque formation and participating in
generation of larger platelet-fibrin thrombi that may acutely occlude a coronary artery.
Smoking cigarettes acutely increases spontaneous platelet aggregation in humans
(Davis et al. 1985) and in dogs with coronary artery stenosis (Folts and Bonebrake
19X2). Madsen and Dyerberg ( 19X4) observed that smoking 2 high-nicotine cigarettes
substantially reduced bleeding time among healthy young men, although ex vivo tests
of platelet aggregability vvere only minimally inhibited. In this study. smoking low
nicotine cigarettes and inhalation of CO had little effect on bleeding time. Shortened
platelet survival, an indirect indicator of activation. was observed in smokers and
reverted to normal after 4 weeks of smoking abstinence (Fuster et al. 19X I ).

Studies of smoking and platelet aggregation ex vivo in response to the typical stimuli
used in the laboratory. such as adenosine diphosphate (ADP) or thrombin. are incon-
sistent. Increased aggregation has been seen with platelets from chronic smokers
(Belch et al. 1984) and in blood drawn IO minutes after smoking I cigarette (Renaud
et al. 19x5; Renaud et al. 1984); in the latter study. aggregation was associated with
blood nicotine levels but not with carboxyhemoglobin (COHb) levels. However. in


other studie\. ex viva platelet aggregation was not related to cigarette smoking (Pittilo
et al. 19x3; Dotevall et al. 19X7: de Loyeril et al. IYXS: Madsen and Dyerberg 19X3).
In one large study. aggregation in response to ADP stimulation was actually somewhat
greater in nonsmoker\ (Meade et al. 19X5). Studies of the effect of smoking on platelet
production of thromboxane. which mediates the aggregatorv effect. have also been
inconsistent. In some studie\. smohing was found to acutely increase thromboxane
blood levels. which reflect the capacity to produce thromboxane in response to stimula-
tion. and urinary metabolitea. which reflect the normal steady-state production
(Toivanen. Ylikorhala. Viinihka 19X6: Marasini et al. 19X6: Fischer et al. 1986).
However. serum thromboxane B? level\ were found to be similar among chronic
smokers compared with nonsmokers in another study (DotevaIl et al. 19X7). The
serious limitation\ of cx vivo aggregability measurements in the evaluation of in vivo
platelet activity have been noted (Fitqerald. Oates. Nowak 19Xx). These researchers
meawred urinary excretion of a thromboxane metabolite and found elevated levels in
chronic smohers that were reduced to the level ofnon~mokers after aspirin administra-
tion. suggesting ;I platelet origin of the excess excretion (Nowak et al. 1987).
The luch of a consistent relation between making and ex viva te\ts of platelet
aggregability despite the demowtration that platelets of smoker\ adhere more readily
to endothelium has led to the suggestion that wioking inhibits the production in arterial
walls ofprostacyclin. an inhibitor of platelet aggregation (Mad\en and Dyerberp 1984).
Reinders and coworkers ( 19X6) demnnwated that the production of prostacyclin b)
cultured human endothelial cells is impaired by incubation with cigarette \mokc
condensate. Pittilo and colleague3 ( 1982) also found that smoking reduce\ endothelial
cell synthesis of pro\tacyclin in rats. Thu\. in \.i\o making-related effects on platelet
function may be mediated in part b>, an interaction with endothelium.
Fibrinogen levels have been found to be elevated among smoker\ in numerow
cross-sectional studies (Meade et al. 19X6: Kennel. D'Agostino. Belanger 19X7: Wil-
helm\en et at. 19x3: DotevaIl et al. 19X7: Belch et al. IYX3: Ballei\en et al. IYX5).
Fibrinogen levels. in turn. are \trongl!. related to ri\h ofCHD and stroke (Meade et at.
lYX6: Kannel. D'Ago\tino. Bel;inycr 19X7: Wilhelmwn et al. t9X4). Smohing ce\w
tion rewlted in ;I decrease in fibrinogen levels after 1 w,eeh\ among Y female moher\
(Harenberg et aI. t YX5) and after X LI eeh\ among I1 mule maker\ (Ernst and Matrai
1987). In the latter stud\. the level\ after X v,eeh\ \+eere similar to those among nc\`er
maker\. When fibrinogen M;I\ remeasured after 5 bears. \ alues had decreased to the
level\ofnever smoker\ among men u ho had stopped wiohin, L ~7 ,tnd had incren\ed amonp
thaw M,ho started or rrsumcd wiohing (Made. Imcson. Stirling 19X7). In multivariate
analk\e\ ofdata from the Fram~ngham Stud! (Kanncl. D'.Qo\tino. Belrmger 19X7) and
Northu ich Parh Stud! (Me& et al. 19X6) that both included cigarette smoking as uell
;I\ fibrinogen le\ttl\, fibrinogen retained a clear independent a\socistion \\ ith ri\h ot
CHD. whereas the effect of smohing \~a\ sub~tantiatt! reduced after the inclusion of
fibrinogen in the model. Thi\ anatysi\ wggest\ that elevated fibrinogen le\,els ma>
mediate a quantitativeI! important part of the effect ot` smoking on CHD rish.
Other clotting abnormrrlitie\. such as increuwd plasma viscosity and reduced red cclt
deformabilit>. that tend to promote thrombw formation ha\,e alw been obwrwd in
smohers (Belch et al. IYX-!). In addition. Iewls of plawiinogen. which promote\ I\\i\


of thrombi. are lower in smokers (Wilhelmsen et a). 1983: Belch et al. 1984). but the
levels increase after smoking cessation (Harenberg et al. 1985).

Spasm

Coronary artery spasm can cause acute ischemia manifested as angina pectoris and
may promote thrombus formation at the site of repeated arterial constriction (Felts and
Bonebrake 19X2). Both chronic and acute cigarette smoking have a demonstrable
vasoconstrictor effect on the coronary vasculature (Klein 1 YX3). Compared V. ith never
smokers. current smokers have an approximately twentyfold risk ofvasospastic angina
pectoris (Scholl et al. 1986). Coronary artery spasm has also been identified bl
angiography after smoking a single cigarette (Maouad et al. 1983). Smohing-induced
vasoconstriction has been demonstrated in patients with atherosclerotic coronary artq
disease (Martin et al. 19X3) that is mediated by an cx-adrenergic increase in coronary
artery tone (Winniford et al. 19X6). In addition. smokin, L 0 3cutely increases platelet and
plasma vasopressin (Nussey et al. 19X6) as well as the carrier protein of vasopressin
and oxytocin (de Lorgeril et al. 1985). In addition to causing acute arterial spasm.
cigarette smoking appears to be associated with a reduction in long-term coronary arter)
diameter independent of atherosclerotic plaque (Fried. Moore. Pearson 19X6). although
the mechanism for this relationship is unclear.

Arrhythmias

In some instances, arrhythmias can precipitate Ml by reducing cardiac output or
increasing myocardial demand. More importantly. arrhythmias are a major complica-
tion of infarction. Thus. reducing the threshold for serious arrhythmias tends to increase
the case-fatality rate of MI. Cigarette smoking was found to lower the threshold for
ventricular fibrillation in a study of animals (Downey et al. 1977) and was found to be
associated with a 2 I -percent increased prevalence of ventricular premature beats on
two-minute electrocardiographic rhythm strips obtained from IO. I I9 men (Hennekens
et al. 19X0). Smoking-related ventriculararrhythmias may contribute to the occurrence
of cudden death and to increased case-fatality ratios during the courre of MI.

Reduced Blood Oxygen Delivery

Cigarette smoking acutely increases myocardial oxygen demand b\, raising
peripheral resistance, blood pressure, and heart rate (Martin et al. 1983: Klein 1984).
Concurrently, the capacity of the blood to deliver oxygen is reduced by increased
COHb, greater viscosity (Galea and Davidson 19X.S). and higher coronaq vascular
resistance. Imbalance between oxygen requirement and delivery as a result of these
factors is not likely to be a cause of MI but may contribute to infarction in the presence
of significant atherosclerotic narrowing of vessels. Consistent with these mechanisms.
low levels of COHb exacerbate myocardial ischemia during graded exercise (Allred et
al. 19X9). and smoking is associated with more frequent and longer ischemic episodes
detected by ambulatory electrocardiographic monitoring among patients M ith chronic


stable CHD (Barr\ et al. 19X9). Blood and plasma 1 iscwities among former smokers
are lower than thaw among current smoker\ and Gmilar to thaw amon never smoker\
(Ernst and Matrai 19X7 ). In the wit stud>,. both blood and pluma viscosity decreased
after wioking ce\\ation and were similar to levels of never makers after X weeks.
Reduced oxygen delivery to the myocardium ma) play a role in lowering the threshold
for ventricular arrhythmias.

In addition to influencing the development ofCHD. smoking ha\ been hypotheGzed
to have direct toxic effect\ on the myocardium. Hartz and coworkers ( I9X-I) found ;i
nearly threefold increavzd prevalence of diffuse ventricular hypoLine\is among heavy
smoker5 compared with never makers within 3 population of patients undergoing
diagnostic coronary ungiography and ventriculogrsphy.

Smoking and Development of Peripheral Arterial Disease

The extremely strong aswcistion between smoking and peripheral artery disease is
likely to be mediated largely through the mechanisms that promote atherosclerosis
(Criqui et al. 1989). The peripheral \awcon\trictive effect\ of smoking. mediated bj
nicotine-stimulated release of catecholamines (US DHHS 19X3). are likely to play a
further important role (Lusty et al. 19X I ).

Smoking and Development of Cerebrovascular Disease

Cerebrovawulur diwae reprewnt\ a heterogeneous group of pathologic processes
that include infarction due to jteno\is and thrombo\i\ (referred to here a\ ischemic
stroke). embolism from the heart. and hemorrhage from medium-hized vessels in the
wbarachnoid space (wbarachnoid hemorrhage) and from microaneutyms of smaII
penetrating vessel\ (intracerebral hemorrhage).  The association of \mokinp with
ischemic strobe i\ likely to be mediated largely through the mechanisms that promote
atherosclerwis and thrombus formation. Associations between smoking and extent of
cerebral artery athcrowlero\i\ ha\ e been obher\ ed at Irutop\) among persons u ho haw
died of cauw\ unrelated to CVD (Reed et al. I9XX) and among volunteer\ in 3
crowaectlonal stud> evaluated b! ;I nonin\as~\.t` method (Rogers et al. 19X.3). Smoking
was a1w ;I strong predictor of the extent and w~erity of cerebral ve\\el atherowlcro\i\
in an Italian multicenter \tud> of rever\ible cerebral ischemic attack> fPas\ero et A.
19X7) and in an in\c\tiyation of 2X pair\ of Finnish tn in\ (Haapanen et al. 19x9).

The mechanistic ba\i\ i\ unhnoun for the strong relation hettieen smoking and
\ubarachnoid hemorrhage (US DHHS 19X9: Shinton and Beever\ 19X9). which is
thought to result mo\t commonl! from the rupture of a baccuI;Lr aneurysm. .Although
hypertension i\ a\sociatcd uith thij occurrence. chronic \mohing is unrelated to
w\tained elwation in blood prehwre.  A ueah and clinically unimportant inverse
relation with hypertension ha\ been \een in several studie\ ISchoenenbeqer 19X2; US
DHHS 1983). although the association betw,ecn cigarette smoking and risk of hyper-
tension was obser\,ed in 3 large pro\pecti\e ime5tigation (Witteman et al. 1990).


.Anticipated Effects of Smoking Cessation on Risk of Cardiovascular Diseases
         Based on Know ledge of Mechanisms

The possible effects ofsmohing cessation on the rish of CHD are illustrated in Figure
1. The incidence of CHD increases sharpI!, with age mm~, `7 both smohers and net CI
smokers: similar patterns are seen V. ith other smohing-related cardio\,ascular diseases.
At each age. the rates are higher for smohers. and the increase with age is more rapid
among smokers (US DHHS 19X3: ACS. unpublished tabulations). probabl\ because ot
the ongoing. cumulati\,e damage caused bj smoking. Thus. the absolute excess
incidence or mortalit>. (attributable rish) of CHD due to smohing. represented b> the
vertical difference bet&eeen the lines for- smokers and never smokers in Figure I.
increases u ith age. However. the relative rish. represented b!, the ratio of incidence or
mortality rates, tends to decrease with age.

Theoretically possible outcomes ofsmokinfcessation are depicted by lines A. B. and
C (Figure I ). Line A represents an immediate and complete reversal of the effect ot
smoking. so that the quitter ahnost instantly assumes the rate of the never smoher. Line
B represents the worst-case scenario: although the stimulus for progressive damage is
removed. no reversibility exists so that the former smoker assumes a constant absolute
excess risk above that of the never smoker. In this case. it is apparent that quitting
would still provide a substantial benefit compared with not quitting and that the relatiic
risk for a former smoker compared with a never smoker w,ould decline over time. An
intermediate effect of smoking cessation is depicted by line C: the effects of smohinp
are slow~ly reversed. and the rate for the quitter gradually approaches that of the never
smoker.

The effects of smoking on CHD are probably mediated by multiple mechanisms.
several of which are well established. Some of the effects of smoking appear to be
reversible within days or weeks, including the increase in platelet activation. clotting
factors. COHb, coronary artery spasm. and increased susceptibility to ventricular
arrhythmias. Other effects may be irreversible or only slowly reversible. such as the
development of atherosclerosis as a result of smooth muscle proliferation and lipid
deposition in the arterial intima resulting from lower HDL-C levels. Thus. persons who
stop smoking are likely to experience a component of rapid decline in risk compared
with those who continue to cmoke and another component that more slowly approaches
the risk of never smokers. Because the effects of smoking are multiple and complex.
the rapidity and magnitude of risk reduction achieved by smoking cessation can best
be estimated by empirical data based on epidemiologic studies in humans. Available
data are examined in detail in the remaining sections of this Chapter.

SMOKING CESSATION AND CHD

Epidemiologic evidence on smoking and CHD has been reviewed in detail in previous
reportsofthe U.S. Surgeon General (US PHS 1964: US DHEW 1971. 1979; US DHHS
1983, 1989). After an exhaustive review of the data, the 1983 Report of the Surgeon
General concluded that "cigarette smoking is a major cause of CHD in the United States
for both men and women" and "should be considered the most important of the knon n


CHD Mortality
(par 100,000 porron - yrrrd

700

800

600




400




300




200





100




0

1       I

40     46

I       I

60    66
Age

L       L

60     06

FIGURE I.-Hypothetical effects of smoking cessation on risk of CHD if
     mechanisms are predominantly rapidly reversible (A),
     irreversible (I!), or slowly re\ ersible (C ). (CHD mortalit! rates
      shown in solid lines are for men in ACS CPS-II, 198246.3

modifiable riA t`actors t'or CHD" I C'S DHHS 1983. p.6). O\erull. the Report noted that
smoher\ ha\e about a 70-percent e\c`c`\\ death rate t`rom CHD. and hea\ ier vwLer\
have an even greater eaces\ risk.

IYX


Since IYX3. additional e\,idence has accumulated to further support these con-
clusions. Some of these data were presented or summarized in the I YXY Report of the
Surgeon General (US DHHS IYXY). For IYX5. cigarette smoking was estimated to be
responsible for 71 percent of all CHD deaths in the United States among men aged 65
years or older and for 15 percent of CHD deaths among younger men. Tv.elve percent
of the CHD deaths among women aged 65 or older and -1 I percent of those in bounger
&omen were attributed to cigarette smoking. In 19X5. I I5.0()0 deaths from CHD were
attributed to cigarette smoking.

A large amount of data supports the vie\+ that active cigarette smohing substantialI!
increase5 risk of CHD. Data also indicate that former smokers have a lower risk ot
CHD than do current smokers. Despite methodolofic and geographic differences. the
studies are remarkably consistent in demonstrating a reduced risk of CHD among
former smokers. Much of this literature has been reviewed in earlier reports of the
Surgeon General (US DHEW lY7Y: US DHHS lYX.3) as dell as h> Kuller and
colleagues ( 1987).

This Section reviews the epidemiologic e\,idence of the effects of cigarette smohing
cessation on CHD rish. specifically MI and CHD death. The relevant studies ma\' be
divided into those that examine the effect among apparently healthy individuals
(primary prevention) and the effect among individuals already diagnosed uith CHD
for risk of recurrence or CHD death (secondary prevention). Cross-sectional studies of
the extent of coronary atherosclerosis also provide relevant information.

Cross-Sectional Studies

In a detailed study of coronary atherosclerosis. Auerbach and couorhers (lY76)
examined I .O% autopsied hearts from patients at the East Orange Veterans Administra-
tion Hospital and found that smokers had more severe disease than never smohers. with
past smokers having intermediate levels. Those who died from CHD or diabetes or
those who had hearts weighing more than 500 g were excluded. After aci,iustment for
age. current cigarette smokers had a prevalence of advanced CHD that ranged from
11.7 to 33.4 percent. depending on the number of cigarettes smohed per day. The
prevalence among never smokers was 5.3 percent compared with I I .O percent among
former smokers. The prevalence odds ratio of advanced versus no disease or minimal
disease was 2.4. when former smokers were compared with never smokers. In contrast.
among current smokers of I to 2 packs per day. the ratio was 6.7. A similar pattern was
observed for different pathologic manifestations of CHD.  The effect of duration ot
abstinence among former smokers was not analyzed.

Ramsdale and coworkers ( 1985) used arteriography to assess the extent of coronar)
atherosclerosis before surgery for valve replacement among 3X7 patients. All patients
provided a smoking history, including age at initiation of smoking and cessation of
smoking and average number of cigarettes cmoked per weeh. Among never smohers.
X7 percent had no stenosis greater than SO percent: only 60 percent of past smohers and
60 percent of current smokers were without this degree of stenosis. Of never smohers.
only 2.6 percent had three or more arteries affected compared with 10.6 percent of
former smokers and 13.2 percent of current smohers. Both current and past smoher-\


had more were coronary artery diseaw. The median xx~re among ne\er smokers and
current smokers was 0.2 and 7.X. respectively.  For pa\t smokers. the data were
prehented by duration since quitting. There was no evidence for a trend of decreased
effect by increasing time since cesation. The median score for those quitting within
the previou\ 5 year\ wa\ 5.0; for 5 to 10 year\. 5.0: and for IO year\ or more. 7.5.
Coronary atherosclerosi\ was positi\,ely correlated with lifetime number of cigarette\
smoked among both current or past smokers. In this study. past smokers had a slightly
worse coronary ri<k profile than other groups. No information v.a\ provided about past
or concurrent illness that may hwe motivated the former mokerh toquit. Nonetheles\.
this study supports the view that cigarette \mohing is a risk factor for atheroxlerohi\
and that a substantial duration of abstinence may be necesw! to appreciably reduce
its extent.

Weintraub and coworhers (1985) evaluated smoking history in I.339 coronq
arteriography patient\. Of thehe patients. YX1 had Ggnificant coronav diseae (7.5
percent or more obstruction).  Amount of current \mohing was not a si~niticant
predictor of serious obstruction after total pack-years were considered. On average. the
rish for such obstruction increased by about I percent per pack-year.

Cross-sectional studies ofarteriogrsphic finding\ can be difficult to interpret hecau\e
patient5 undergoins angiographs are clearl>~ not repre~entati\e of the general popula-
tion. Nonethelchs. the\e studies wpport the view that hmohing cause\ an increase in
atherosclerosi\ and that very recent quitting has little impact on coronar!~ \teno\i\.

Fried. Moore. and Pearson ( IYXh) studied the effects of \mohing h> a\he\Gng the
coronary diameter in 3 I men \\ho had normal coronar\' arteringrams. Men M ith an!
detectable \tenoGs in the main coronary arterie\ or more than 75 percent in an! coronq
branch were excluded to assess the effect\ of mohing on the caliber of coronary arterie\
in the absence of atherosclerosi\. These researcher\ found that after udjuhtment for
alcohol intahe (which i\ ;l\\ociated M ith u ider arteries ). current and former \moher\
had 10 to SO percent nxro~~er urterie\ than did neker smoher\. The pa$t \moher\ had
someuhat narrower arterie\ than current smokers although thi\ uas not stati\ticall!.
Ggniticant. Of the I I cx+mohcr\. 6 had quit in the previous year. This \tudg sugge\th
the po\\ihility of another per\i\ting effect of mohing. apart from promoting
atheroxlero\i\. not rapidI! raerwd b) cc\\stlon.

Studies of Smoking Cessation and Risk of MI Among Healthy Persons

Case-Control Studies

Table I wmmarizes data from ca\e+wntrol \tudie\ (Wlllett et al. 198 I : Rosenberg.
Kaufman. Helmrich. Miller et al. 1985: LaVecchia et al. IYX7: Rosenberg. Palmer.
Shapiro 1990). of men and Momen from the LInited State\ and abroad. Prospective
\tudie\ of CHD are generally considered lea prone to bias than ca\exontrol htudie\.
although casexontrol \tudie\ are probuhly 1~54 susceptible to mi\cla~sificntion rewlt-
in? from resumption of smohing mnong former smoker\. For example. an individual
diagnosed u ith a recent MI can probably recall his or her \mohing \tatu\ .just before
the infarction with cowiderable accuracy (Chapter 7). Thu\. c:l\exontroI \tudiek ma>