How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for

Smoking-Attributable Disease: A e!ort of the Surgeon "eneral#

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Centers for Disease Control and Prevention (US); National Center for Chronic
Disease Prevention and Health Promotion (US); Office on Smoking and Health
(US).
tlanta (!)" Centers for Disease Control and Prevention (US); #$%$.
$atho!hysiology
&his section on 'atho'h(siolog( foc)ses 'rimaril( on mechanisms *( which cigarette
smoking ma( increase risk of C+D.
Cigarette Smoke Constituents and Cardiovascular Disease
&hree constit)ents of cigarette smoke have received the greatest attention as 'otential
contri*)tors to C+D" nicotine, car*on mono-ide (CO), and o-idant gases. Some research also
investigated the contri*)tions of 'ol(c(clic aromatic h(drocar*ons (PHs), 'artic)late
matter, and other constit)ents of to*acco smoke to the 'atho'h(siolog( of C+D incl)ding
atherogenesis (.rook et al. #$$/; +erm(len et al. #$$0; .hatnagar #$$1).
Nicotine, which is a*sor*ed ra'idl( from cigarette smoke, was fo)nd in arterial *lood levels
of /$ to %$$ ng2m3 after each cigarette was smoked (Henningfield et al. %445). &he t('ical
dose of nicotine s(stematicall( a*sor*ed from each cigarette is % to # milligrams (mg).
ltho)gh 'lasma nicotine levels 'eaked shar'l( after each cigarette, tro)gh val)es also rose
d)ring the first si- to eight ho)rs of reg)lar smoking d)ring the da( (.enowit6 et al. %47#a).
&his acc)m)lation 'attern was consistent with an elimination half8life for nicotine of two
ho)rs (.enowit6 et al. %47#a). 9n 'ersons who smoke reg)larl(, veno)s 'lasma levels of
nicotine reached a 'latea) in earl( afternoon and remained at that level )ntil *edtime (:ig)re
1./). Significant levels of nicotine were in the smoker;s veno)s *lood even on waking in the
morning. &h)s, these findings indicate that the reg)lar smoker is e-'osed to significant levels
of nicotine #/ ho)rs 'er da(.
Figure 6.4
Plasma nicotine and car*o-(hemoglo*in concentrations thro)gho)t a da( of cigarette
smoking. Source: .enowit6 #$$5. da'ted from .enowit6 et al. %47#* with 'ermission from
<lsevier, = #$$5. Note: >ean (? standard error of meas)rement) *lood (more...)
Nicotine is a s(m'athomimetic dr)g that releases catecholamines *oth locall( from ne)rons
and s(stemicall( from the adrenal gland. 9n st)dies of the 'harmacod(namics of nicotine, the
intensit( of its ma-imal effect was greater with more ra'id deliver( (Porchet et al. %47@).
Pharmacod(namic st)dies also indicated that altho)gh tolerance to the effects of nicotine
develo'ed ra'idl(, tolerance was incom'lete (Porchet et al. %47@). 9n one st)d(, a constant
intraveno)s inf)sion of nicotine increased the heart rate even tho)gh nicotine levels in the
*lood were relativel( low. s the inf)sion contin)ed, the heart rate reached a 'latea) des'ite
a 'rogressive rise in *lood levels of nicotine (.enowit6 et al. %47#a). &he same 'henomenon
was o*served in com'arisons of acceleration of heart rate with level of *lood nicotine d)ring
reg)lar cigarette smoking thro)gho)t the da( (.enowit6 et al. %47/).
9n another st)d(, heart rate meas)red *( am*)lator( monitoring was higher thro)gho)t the
da( when 'ersons were smoking than when the( were not smoking (.enowit6 et al. %47/).
&he e-tent of elevation was inde'endent of the *lood level of nicotine a*sor*ed from the
cigarettes. &he researchers concl)ded that the elevated heart rate reflected 'ersistent
stim)lation of the s(m'athetic nervo)s s(stem, a 'ossi*le contri*)ting factor to C+D.
Nicotine ma( also contri*)te to endothelial d(sf)nction, li'id a*normalities, and ins)lin
resistance (.enowit6 #$$5).
CO is a maAor constit)ent of cigarette smoke. 9n reg)lar smokers, car*o-(hemoglo*in levels
average a*o)t 0 'ercent, com'ared with %$ 'ercent or higher in heav( smokers (.enowit6 et
al. %47#*). &hese val)es com'are with levels of $.0 to # 'ercent in nonsmokers, de'ending on
e-'os)re to a)tomo*ile e-ha)st. 3ike nicotine levels, elevated car*o-(hemoglo*in levels
'ersist for #/ ho)rs a da( in smokers (:ig)re 1./).
CO e-'os)re can aggravate ischemia and worsen s(m'toms in 'ersons with vasc)lar disease,
altho)gh it is not clear that CO contri*)tes directl( to atherosclerosis (.enowit6 #$$5). CO
*inds avidl( to hemoglo*in, red)cing the amo)nt of hemoglo*in availa*le to carr( o-(gen
and im'eding release of o-(gen *( hemoglo*in. 9n some st)dies, inhalation of CO at levels
com'ara*le to those in cigarette smokers red)ced e-ercise tolerance in 'atients with angina
'ectoris, intermittent cla)dication, or COPD (Calverle( et al. %47%; llred et al. %474).
nother st)d( re'orted that CO e-'os)re in 'ersons with o*str)ctive coronar( disease
res)lted in a greater degree of e-ercise8ind)ced ventric)lar d(sf)nction and an increase in the
n)m*er and com'le-it( of ventric)lar arrh(thmias d)ring e-ercise (She's et al. %44$).
9nhaling CO red)ced the threshold for ventric)lar fi*rillation in animals (De.ias et al. %4@1).
3ong8term CO e-'os)re in smokers res)lted in greater red *lood cell mass and red)ced the
o-(gen8 carr(ing ca'acit( of red *lood cells, res)lting in relative h('o-emia (.enowit6
#$$5). 9n res'onse to h('o-emia, red *lood cell masses increased to maintain the amo)nt of
o-(gen needed *( organs in the *od(. &he increase in red *lood cell mass increased *lood
viscosit( and ma( contri*)te to h('ercoag)lation in smokers.
Cigarette smoke delivers a high level of o-idi6ing chemicals to smokers, incl)ding o-ides of
nitrogen and man( free radicals from *oth the gas and tar 'hases of cigarette smoke (Ch)rch
and Pr(or %470). <-'os)re to o-idant chemicals in smoke was associated with de'letion of
endogeno)s levels of antio-idants, manifested as lower *lood levels of vitamin C in smokers
than in nonsmokers (3(kkesfeldt et al. #$$$). Cigarette smoking also was re'orted to increase
levels of li'id 'ero-idation 'rod)cts in the 'lasma and )rine of smokers (>orrow et al.
%440). St)d( res)lts also indicated that o-idant stress contri*)tes to several 'otential
mechanisms of C+D, incl)ding inflammation, endothelial d(sf)nction, li'id a*normalities
s)ch as o-idation of low8densit( li'o'rotein (3D3), and 'latelet activation (.)rke and
:it6!erald #$$5).
crolein, a reactive aldeh(de 'rod)ced *( endogeno)s li'id 'ero-idation, is 'resent at high
levels in cigarette smoke. crolein *inds covalentl( to form 'rotein add)cts, and acrolein8
ind)ced modification of 'roteins has *een im'licated in atherogenesis. crolein modifies
a'oli'o'rotein 89 (PO 89), the maAor 'rotein in HD3 (Shao et al. #$$0). HD3 'rotects
against atherosclerosis. crolein8'rotein add)cts co8locali6e with PO 89 in macro'hages in
the intima of h)man atheromato)s *lood vessels (S6adkowski and >(ers #$$7).
crolein also o-idi6ed thioredo-ins % and # in endothelial cells. &hioredo-ins are 'rominent
antio-idant 'roteins that reg)late the o-idation8red)ction *alance critical for normal cell
f)nction. &hese res)lts s)ggest that o-idation of thioredo-ins can res)lt in d(sf)nction and
death of endothelial cells, contri*)ting to atherosclerosis. 9n addition, acrolein ind)ces
'rod)ction of the en6(me c(cloo-(genase8# (COB8#) in h)man endothelial cells in vitro
(Park et al. #$$@). &his finding is relevant *eca)se COB8# is e-'ressed in atherosclerotic
lesions and ma( 'artici'ate in atherogenesis. crolein ma( contri*)te to throm*ogenicit( in
smokers *( inhi*iting antithrom*in activit( (!)gli)cci #$$@). :inall(, acrolein ind)ces
h('ercontraction in isolated h)man arteries and co)ld contri*)te to smoking8ind)ced
coronar( vasos'asm (Conklin et al. #$$1).
Cigarette smoke contains a n)m*er of metals, incl)ding al)min)m, cadmi)m, co''er, lead,
merc)r(, nickel, and 6inc. >etals in cigarette smoke catal(6e the o-idation of cell)lar
'roteins (.ernhard et al. #$$0). &his reaction ma( lead to str)ct)ral damage, endothelial
d(sf)nction, and detachment of endothelial cells from the walls of *lood vessels. >i-t)res of
metals and o-idants ma( *e 'artic)larl( damaging to endothelial cells. Cadmi)m levels are
higher in ser)m of smokers, and cadmi)m acc)m)lates in the aortic walls of smokers (*)8
Ha((eh et al. #$$%). <'idemiologic evidence indicates an association *etween ser)m levels
of cadmi)m and lead and C+D, incl)ding h('ertension and >9 (*)8Ha((eh et al. #$$%).
PHs fo)nd in the tar fraction of cigarette smoke re'ortedl( accelerated atherosclerosis in
e-'erimental animals. Ceekl( inAections of *en6oDaE'(rene and @,%#8
dimeth(l*en6DaEanthracene, at doses *elow those that 'rod)ce t)mors, increased
develo'ment of atherosclerotic 'laF)e in the aortas of cockerels (Penn and Sn(der %477).
Similarl(, inhaled *)tadiene, a com'onent of the va'or 'hase of cigarette smoke, increased
the amo)nt of atherosclerotic 'laF)e in the same animal model (Penn and Sn(der %441). &he
researchers s'ec)lated that one mechanism of atherogenesis is a m)tation, followed *(
h('er'roliferation of smooth m)scle or other cells that ma( contri*)te to growth of
atherosclerotic 'laF)e.
St)dies of the cardiovasc)lar effects of smokeless to*acco ma( *e informative for
)nderstanding the 'atho'h(siolog( of smoking8ind)ced C+D. Oral and nasal smokeless
to*acco 'rod)cts have *een )sed for cent)ries aro)nd the world (9nternational genc( for
Gesearch on Cancer D9GCE #$$@). &raditional smokeless to*acco 'rod)cts var( widel(
among co)ntries; however, similar to Sweden, forms of oral sn)ff are the most common t('es
of 'rod)cts )sed in the United States (S)*stance *)se and >ental Health Services
dministration #$$4). &hese 'rod)cts contain a large arra( of chemicals, incl)ding nicotine,
nitrosamines, nitrosamine acids, PHs, aldeh(des, and metals (9GC #$$@). recent
s(stematic review re'orted that st)dies from *oth the United States and Sweden showed an
increased risk of death from >9 and stroke related to the freF)enc( and d)ration of )se of
smokeless to*acco 'rod)cts (.offetta and Straif #$$4). &his review relied heavil( (70H74
'ercent of the weight) on res)lts of a large U.S. cohort st)d( cond)cted in two waves
*etween %404H%4@% and %47#H%477 and ma( not re'resent risk associated with 'rod)cts
c)rrentl( marketed in the United States and <)ro'e. s in cigarettes, nicotine is the 'rinci'al
alkaloid in smokeless to*acco 'rod)cts, and the concentrations of nicotine (mg2gram DgE
to*acco) are similar *etween cigarettes and the t('es of oral sn)ff sold in the United States
(DAordAevic and Doran #$$4). n anal(sis com'aring the effects of )sing oral sn)ff with
those of smoking cigarettes 'rovided insights into the role of nicotine vers)s the effects of
other to-ins from to*acco smoke on C+D and cardiovasc)lar risk factors (.enowit6 et al.
%477, %474). 9n addition clinical trials of nicotine 'atches in 'atients with known C+D have
not shown that transdermal nicotine increased cardiovasc)lar risk (Corking !ro)' for the
St)d( of &ransdermal Nicotine in Patients with Coronar( rter( Disease %44/; Iose'h et al.
%441). 9n the st)d( of 5,$4/ middle8aged smokers with chronic o*str)ctive l)ng disease, the
U.S. 3)ng Health St)d( fo)nd no evidence of increased cardiovasc)lar risk in s)*Aects who
F)it smoking *( )sing nicotine g)m vers)s those who F)it witho)t )se of nicotine g)m
(>)rra( et al. %441). &hese st)dies and related evidence s)ggest that chemicals other than
nicotine ma( contri*)te to the elevated risk of death from >9 and stroke. 9n the
9N&<GH<G& st)d(, the OG of ac)te >9 was #.#5 among those who )sed onl( smokeless
to*acco com'ared with those who )sed no to*acco. &he OG was com'ara*le to that of
c)rrent cigarette smokers (OG J #.40) com'ared with those who )sed no to*acco (&eo et al.
#$$1). 9n addition, the risk of ac)te >9 among smokers who also )sed smokeless to*acco was
the highest risk related to to*acco )se (OG J /.$4), s)ggesting that some of the to-icants
involved in the elevated cardiovasc)lar risk co)ld *e contained in *oth to*acco smoke and
smokeless 'rod)cts. Smokeless to*acco 'rod)cts have *een fo)nd to have significant
amo)nts of n)mero)s other to-icants and carcinogens, 'artic)larl( to*acco8s'ecific
nitrosamines as well as volatile aldeh(des and PHs (Ste'anov et al. #$$7). dditional
research on these and other to-icants in smokeless to*acco, s)ch as heav( metals like
cadmi)m, is needed to )nderstand the o*served cardiovasc)lar risks among )sers of
smokeless to*acco 'rod)cts.
%echanisms
Cigarette smoking 'rod)ces ac)te m(ocardial ischemia *( adversel( affecting the *alance of
demand for m(ocardial o-(gen and n)trients with m(ocardial *lood s)''l( (:ig)re 1.0). &he
increase in demand for o-(gen in the m(ocardi)m is a conseF)ence of nicotine stim)lation of
the s(m'athetic nervo)s s(stem and the heart. Cigarette smoking ac)tel( increases levels of
'lasma nore'ine'hrine and e'ine'hrine and enhanced #/8ho)r )rinar( e-cretion of these
catecholamines (review *( .enowit6 and !o)rla( %44@). Geg)lar smoking increases the heart
rate *oth in the short term ()' to #$ *eats 'er min)te) and thro)gho)t the da( (average
increase, @ *eats 'er min)te), as meas)red d)ring am*)lator( monitoring. Nicotine also
increases heart rate, *lood 'ress)re, and m(ocardial contractilit(. &hese hemod(namic
changes res)lt in increases in m(ocardial work that in t)rn reF)ire increased m(ocardial
*lood flow.
Figure 6.5
Overview of mechanisms *( which cigarette smoking ca)ses an ac)te cardiovasc)lar event.
Source: .enowit6 #$$5. Ge'rinted with 'ermission from <lsevier, = #$$5.
9n health( 'ersons, cigarette smoking increases coronar( *lood flow in res'onse to increases
in m(ocardial work. 9n smokers, the res'onse in coronar( *lood flow to increased m(ocardial
demand was im'aired (i.e., red)ced coronar( vasodilator( reserve) (C6ernin and Caldherr
#$$5). Cigarette smoking 'la(ed a direct role *( constricting coronar( arteries thro)gh
nicotine8mediated action on K8adrenergic rece'tors and *( ind)ction of endothelial
d(sf)nction *( nicotine and o-idi6ing chemicals (Nicod et al. %47/; P)ranik and CelermaAer
#$$5). 9n addition, o-idant chemicals contri*)te to 'latelet activation and throm*ogenesis
(.)rke and :it6!erald #$$5).
<-'os)re to CO ma( also contri*)te to the adverse hemod(namic effects of cigarette
smoking. .( 'rod)cing f)nctional anemia, CO increases the need for coronar( *lood flow,
es'eciall( d)ring 'h(sical e-ertion. n in8adeF)ate vasodilator( flow reserve 'rod)ced *(
cigarette smoking, in the face of need for increased coronar( *lood flow mediated *( car*on
dio-ide, co)ld contri*)te to m(ocardial ischemia with e-ercise in smokers.
9n addition to the mechanisms descri*ed in :ig)re 1.0, cigarette smoking has effects on
inflammation, ins)lin sensitivit(, and li'id a*normalities that most likel( contri*)te to
smoking8ind)ced C+D.
Daftar ')staka
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