See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/6336785

Systemic Effects of Smoking

Article  in  Chest · June 2007

DOI: 10.1378/chest.06-2179 · Source: PubMed

CITATIONS READS

627 4,653

5 authors, including:

Dilyara Yanbaeva Mieke A Dentener

30 PUBLICATIONS   909 CITATIONS   
Maastricht University
46 PUBLICATIONS   2,185 CITATIONS   
SEE PROFILE
SEE PROFILE

Eva Charlotte Creutzberg Emiel Wouters

Ferring Pharmaceuticals Maastricht University
34 PUBLICATIONS   3,521 CITATIONS    750 PUBLICATIONS   28,918 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Economic Evaluation Chronic Care Programs View project

The Burden of Obstructive Lung Disease Global Study View project

All content following this page was uploaded by Eva Charlotte Creutzberg on 02 August 2016.

The user has requested enhancement of the downloaded file.

 CHEST Special Feature

Systemic Effects of Smoking*

Dilyara G. Yanbaeva, PhD; Mieke A. Dentener, PhD; Eva C. Creutzberg, PhD;
Geertjan Wesseling, MD, PhD; and Emiel F. M. Wouters, MD, PhD, FCCP

Smoking is one of the major lifestyle factors influencing the health of human beings. Life-long
cigarette smokers have a higher prevalence of common diseases such as atherosclerosis and
COPD with significant systemic impact. The present review evaluates current knowledge
concerning possible pathways through which cigarette smoking can affect human health, with
special focus on extrapulmonary effects. Long-term smoke exposure can result in systemic
oxidants-antioxidants imbalance as reflected by increased products of lipid peroxidation and
depleted levels of antioxidants like vitamins A and C in plasma of smokers. A low-grade systemic
inflammatory response is evident in smokers as confirmed by numerous population-based
studies: elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, as well as
increased counts of WBC have been reported. Furthermore, rheologic, coagulation and endo-
thelial function markers like hematocrit, blood and/or plasma viscosity, fibrin d-dimer, circulating
adhesion molecules (intracellular adhesion molecule-1, selectins), tissue plasminogen activator
antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers.
Although most of smoking-induced changes are reversible after quitting, some inflammatory
mediators like CRP are still significantly raised in ex-smokers up to 10 to 20 years after quitting,
suggesting ongoing low-grade inflammatory response persisting in former smokers. New longi-
tudinal epidemiologic and genetic studies are required to evaluate the role of smoking itself and
possible gene/environment interplay in initiation and development of smoking-induced common
diseases affecting humans. (CHEST 2007; 131:1557–1566)

Key words: endothelial dysfunction; hemostasis; smoking; systemic inflammation; systemic oxidative stress

Abbreviations: APP ⫽ acute-phase protein; CRP ⫽ C-reactive protein; Cys ⫽ cysteine; CySS ⫽ oxidized cysteine;
GSH ⫽ glutathione; ICAM ⫽ intracellular adhesion molecule; IL ⫽ interleukin; LDL ⫽ low-density lipoprotein;
NHANES ⫽ National Health and Nutrition Examination Survey; NO ⫽ nitric oxide; PAI ⫽ plasminogen activator
inhibitor; PGF2 ⫽ prostaglandin F2; PMN ⫽ polymorphonuclear neutrophil; ROS ⫽ reactive oxygen species;
TBARS ⫽ thiobarbituric acid-reactive substances; TEAC ⫽ Trolox-equivalent antioxidant capacity; TNF ⫽ tumor
necrosis factor; t-PA ⫽ tissue plasminogen activator

T obacco smoking is one of the most potent and

prevalent addictive habits, influencing behavior
of human beings for ⬎ 4 centuries. Smoking is now
increasing rapidly throughout the developing world
and is one of the biggest threats to current and future
world health.1 Furthermore, while the prevalence of
tobacco use has declined among men in some high-
income countries, it is still increasing among young
people and women.2 Cigarette smoking is the most
common type of tobacco use. In average, to date
*From the Department of Respiratory Medicine (Drs. Yanbaeva,
Dentener, Wesseling, and Wouters), University Hospital Maas-
tricht/Maastricht University, Maastricht, the Netherlands; and
CIRO Horn (Dr. Creutzberg), Haelen, the Netherlands.
Funding was provided by the European Respiratory Society
(fellowship No. 161).
The authors have no conflicts of interest to disclose.
47.5% of men and 10.3% of women are current
smokers. Tobacco continues to be the second major
cause of death in the world. By 2030, if current
trends continue, smoking will kill ⬎ 9 million people
annually.3
Tobacco smoking affects multiple organ systems
resulting in numerous so-called tobacco-related dis-
eases. The well-known health risks in tobacco smok-
Manuscript received September 1, 2006; revision accepted Oc-
tober 16, 2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Emiel F. M. Wouters, MD, PhD, FCCP,
Department of Respiratory Medicine, University Hospital Maas-
tricht/Maastricht University, PO Box 580, 6202 AZ Maastricht,
the Netherlands; e-mail: e.wouters@lung.azm.nl
DOI: 10.1378/chest.06-2179

www.chestjournal.org CHEST / 131 / 5 / MAY, 2007 1557

ing pertain to diseases of the respiratory tract such as
COPD and cancer, particularly lung cancer and
cancers of the larynx and tongue.4,5
While the adverse effects of cigarette smoke on
lung health are well established, it is becoming more
evident that smoke has an important extrapulmonary
toxicity. Injury in the lung, primary target of inhaled
smoke, can be explained by the direct chemical
exposure to cigarette smoke, but effects causing
chronic diseases in other organ systems are likely to
be the result of indirect consequences of the expo-
sure. However, despite the overwhelming amount of
studies demonstrating the relationship of smoking
with numerous widespread “systemic” diseases such
as atherosclerosis and COPD, the precise mecha-
nisms how smoke potentiates its systemic effects
need to be clarified. In a article by van der Vaart et
al,6 the local and systemic effects of acute smoke
exposure on oxidative stress and inflammatory me-
diators were reviewed. In the present article, we aim
to review systemic effects of long-term smoking
exposure in humans. In particular, traditional mark-
ers of generalized response to smoking such as
systemic oxidative stress and systemic inflammation
are reviewed. In addition, in view of findings sug-
gesting the relationship between some of these
markers and atherosclerosis, aspects of hemostatic
and coagulation systems are discussed in relation to
tobacco smoking.
Systemic Oxidative Stress in Smokers
Cigarette smoke contains approximately 1017 oxi-
dant molecules per puff.7 This oxidative stress can be
Table 1—Markers of Increased Oxidative Stress in Smokers
Markers
Direct measurements of oxidative burden
Release of ROS from circulating phagocytes
Release of superoxide from peripheral blood neutrophils
ROS production by endothelial progenitor cells
Intraplatelet peroxynitrite
Effects of oxidative stress on target molecules
Oxidized and nitrated proteins
Oxidized LDL
Lipid peroxidation products
F2 isoprostanes
Malondialdehyde
TBARS
Antioxidants
Reduced TEAC
Reduced vitamin C
Reduced ␤-carotene
Decreased GSH and oxidized GSH/GSSG couple
Decreased cysteine and oxidized Cys/CySS couple
*GSSG ⫽ oxidized GSH.
1558
registered in several different ways, either by direct
measurements of the oxidative burden (reactive ox-
ygen species [ROS] production by peripheral blood
cells) or by the effects of oxidative stress on target
molecules (lipid peroxidation products and oxidized
proteins), or as the responses to the oxidative stress
(antioxidant capacity of plasma)8 [Table 1].
Only a few studies9 –11 have used ROS production
by blood cells extracted from the circulation of
smokers. Perhaps more important than the presence
of oxidative stress are the effects of this oxidative
stress on a variety of vital target molecules. Numer-
ous markers for oxidative damage have been pro-
posed, including oxidation and nitration of proteins.
For example, nitration of tyrosine residues of pro-
teins leads to the production of 3-nitrotyrosine,
which may be considered as a marker of nitric oxide
(NO)-dependent oxidative damage. Indeed, NO-
mediated and peroxynitrite-mediated formation of
3-nitrotyrosine is elevated in plasma and platelets of
chronic smokers.12,13 Furthermore, Pignatelli and
coworkers14 reported significantly higher levels of
nitrated and oxidized fibrinogen, transferrin, plas-
minogen, and ceruloplasmin in smokers than in
nonsmokers.
Free radicals from cigarette smoke also cause
peroxidation of the polyunsaturated fatty acids of cell
membranes that amplify oxidative stress during
smoking. The F2-isoprostanes, prostaglandin-like
compounds, are products of free radical-catalyzed
lipid peroxidation of arachidonic acid. Several stud-
ies15–17 have reported an increased level of isopros-
tane 8-iso-prostaglandin F2 (PGF2)␣ formation in
smokers. It has been found that urinary 8-epi-
Source
van Antwerpen et al9
Ludwig and Hoidal10
Michaud et al11
Takajo et al13
Petruzzelli et al12; Pignatelli et al14
Yamaguchi et al75
Morrow et al15; Reilly et al16; Helmersson et al17
Rumley et al20; Smith et al21
Orhan et al22; Ochs-Balcom et al23
Petruzelli et al12; Rahman et al24
Wei et al25; Lykkesfeldt et al26; Schectman et al27; Marangon et al28
Wei et al25; Marangon et al28
Moriarty et al31
Moriarty et al31
Special Feature
PGF2␣ excretion was significantly increased in long-
term current and former smokers compared with the
age- and sex-matched nonsmoking control sub-
jects.17 In addition, a dose-response relationship was
observed between the number of cigarettes smoked
and both urinary cotinine and urinary 8-epi-
PGF2␣.16 The biological role of isoprostanes is not
clear yet. It has been shown that F2 isoprostane
levels are significantly increased in atherosclerotic
plaques compared with normal vascular tissue, sug-
gesting that these compounds may play a role in the
pathogenesis of the disease.18 The observation of
elevated levels urinary 8-iso-PGF2␣ in patients with
coronary heart disease strengthens this hypothesis.19
Increased levels of malondialdehyde, which are
degradation product of lipid peroxides, have been
found associated with current smoking status in
population-based studies.20,21 Similarly, higher levels
of thiobarbituric acid reactive substances (TBARS)
have been found in smokers compared to nonsmok-
ers.22 New evidence for the association of systemic
oxidative stress with pulmonary function comes from
population-based study23 conducted in the New York
State (n ⫽ 2,346). Ochs-Balcom and coworkers23
showed an inverse association of TBARS with per-
centage of predicted FEV1 and percentage of pre-
dicted FVC in men but not in women, suggesting
gender differences in the relation of oxidative stress
to pulmonary function.
Exposure to oxidant chemicals in smoke is associ-
ated with depletion of endogenous levels of antioxi-
dants in the systemic compartment. Numerous stud-
ies have reported that smoking results in low
antioxidant concentrations in plasma. The total
plasma Trolox-equivalent antioxidant capacity
(TEAC) was significantly lower in smokers than in
nonsmokers.12,24 However, no relationship was
found between spirometric end points (FEV1 or
FEV1/FVC) and plasma levels of TEAC in healthy
smokers.24 The third National Health and Nutrition
Examination Survey (NHANES) and other stud-
ies17,25 reported that smokers have significantly
lower serum levels of vitamin C, ␣-carotene, ␤-car-
otene, ␤-cryptoxanthin, melatonin, ␣-tocopherol,
and lutein/zeaxanthin. However, diet could also in-
fluence levels of antioxidants, and independent ef-
fects of smoking have only been shown on plasma
levels of vitamin C and ␤-carotene.25–27 In addition,
an inverse relationship between cigarette consump-
tion and plasma levels of vitamin C and ␤-carotene
corrected for habitual dietary intake has been
found.27,28 Such decreases in plasma antioxidants can
disturb the normal oxidative-antioxidative balance in
smokers. Remarkably, numerous studies29,30 have
shown that antioxidant supplements provide at best
only a limited protection.
www.chestjournal.org
Glutathione (GSH) is a major antioxidant used to
eliminate peroxides to nontoxic hydroxyl fatty acids
and/or water and to maintain vitamins C and E in
their reduced and functional forms. Cigarette smoke
contains ROS that oxidize GSH to disulfide form
(oxidized glutathione), resulting in decreased plasma
GSH levels.31 Similar processes are responsible for
an even more extensive oxidation of the cysteine
(Cys)/oxidized cysteine (CySS) redox couple and
reduced Cys levels showing that smoking has addi-
tional effects on sulfur amino acid metabolism. Tak-
ing into account that cysteine is the critical molecule
for normal GSH synthesis, this observation suggests
that evaluation of the Cys/CySS redox couple may be
a new sensitive marker of oxidative stress in smokers.
In summary, the oxidative burden in the systemic
compartment of smokers is mainly characterized by
elevated levels of peroxides (isoprostanes and
TBARS) and decreased levels of traditional plasma
antioxidants (vitamins A and C), whereas GSH-
related antioxidants are affected to a lesser extent.
Systemic Inflammation in Smokers
Activation and release of inflammatory cells into
the circulation, and an increase in circulating inflam-
matory mediators such as acute phase proteins and
proinflammatory cytokines, characterize the sys-
temic inflammation.
Circulating Inflammatory Cells
The systemic inflammatory response is character-
ized by the stimulation of the hematopoietic system,
specifically the bone marrow resulting in the release
of leukocytes and platelets into the circulation. Nu-
merous studies32–34 have shown that long-term ciga-
rette smoking increases total WBC counts, mainly
due to an increase in polymorphonuclear neutrophil
(PMN) counts in the circulation of smokers. A large
population-based study35 of 6,902 men and 8,405
women performed in Great Britain revealed that
current smoking had a stronger effect on mean total
WBC than cumulative exposure as measured by
pack-years. However, other authors36 reported a
dose-response relationship with pack-years smoked
and WBC. This inflammatory response in smokers is
characterized not only by an increase in the number
of circulating cells but also by phenotypic changes.
Indeed, neutrophilia related to chronic smoking was
associated with an increase in numbers of circulating
band cells, a hallmark of early bone marrow release
of PMNs, and an increase in L-selectin expression, a
cell adhesion molecule, constitutively highly ex-
pressed on maturating PMNs.32 L-selectin could
initiate the adherence of PMNs to endothelium and
CHEST / 131 / 5 / MAY, 2007 1559
has been shown to be important for the recruitment
of PMNs to inflamed tissue.37 In addition, PMNs
from smokers have higher levels of myeloperoxidase,
an enzyme produced at the early stages of PMN
proliferation.32,38 Overall, these findings suggest that
smoking causes bone marrow stimulation and the
release of younger cells from bone marrow. van
Eeden and colleagues39 speculated that circulating
cytokines like interleukin (IL)-1␤ and IL-6 may be
responsible for bone marrow stimulation induced by
lung inflammation. Indeed, the same authors39 have
shown that IL-6 cytokine also potently stimulates the
bone marrow to release leukocytes and platelets.
Reports40 have underlined the role of T-lympho-
cytes as a potentially important factor in the systemic
inflammatory process associated with smoking-in-
duced diseases like COPD. Some studies41– 43 have
reported increased total numbers of circulating T-
lymphocytes in humans exposed to cigarette smoke.
Studies investigating the influence of smoking on
different lymphocyte subsets have produced con-
flicting data. In heavy smokers, a decrease in CD4⫹
cells (helper T-cells) and increase in CD8⫹ cells
(suppressor T-cells) with subsequent decrease in
CD4⫹/CD8⫹ ratio have been reported.41 In con-
trast, Tollerud and colleagues44 found that cigarette
smoke was associated with an increase in leukocyte
count with a selective increase in CD4⫹ cells,
resulting in significant increase in the CD4⫹/CD8⫹
ratio in healthy white subjects. Other studies45,46
support these findings. Further analysis has shown
that smokers have higher absolute numbers of pe-
ripheral blood memory T-cells and naive T-cells as
compared with nonsmokers.43,46 Analysis of T-cell
subpopulations in heavy and light-to-moderate
smokers revealed that numbers of memory T-cells
were significantly correlated with daily cigarette
consumption.42 Overall, the results of these studies
suggest that smoking may exert a selective influence
on subsets of T-cells. Therefore, taking into account
the role of lymphocytes in a number of inflammatory
conditions associated with smoking, additional stud-
ies would be relevant to better understand the
response of circulating lymphocytes to cigarette
smoke.
Inflammatory Mediators in Peripheral Blood of
Smokers
Activated inflammatory cells produce a great vari-
ety of inflammatory mediators in response to ciga-
rette smoke, first of all, acute-phase proteins (APPs)
and cytokines. Conditions that commonly lead to
substantial changes in the plasma concentrations of
APPs and cytokines include infection, trauma, sur-
gery, burns, tissue infarction, various immunologi-
1560
cally mediated inflammatory conditions, and cancer.
In recent years, these inflammatory mediators have
been studied as potential markers of subtle and
persistent systemic alterations. Many studies have
reported changes in levels of inflammatory mediators
not only in the lungs but also in the circulation of
healthy smokers. Several studies47– 49 have reported
strong associations between cigarette smoking and
different APPs such as C-reactive protein (CRP) and
fibrinogen (Table 2).
For example, the large-scale, population-based
NHANES III study revealed a strong independent
dose-response relationship between cigarette smok-
ing and elevated levels of CRP and fibrinogen.50 This
analysis was based on ⬎ 4,187 current smokers,
4,791 former smokers, and 8,375 never-smokers with
smoking status based on cotinine levels and was
adjusted for different confounders. These findings
are in accordance with results of two other stud-
ies47,51 of APPs in smokers. Data from several pro-
spective studies support the hypothesis that CRP,
and fibrinogen levels in particular, are primarily
related to lifetime exposure of smoking (pack-years)
and not to years since quitting smoking. In the
MONICA Augsberg Study49 and the Speedwell
Study,52 CRP was still significantly raised 10 years
after smoking cessation. Data from the British Re-
gional Heart Study33 indicate that smoking cessation
results in a rapid reduction in hemostatic and inflam-
matory markers, but CRP levels remained signifi-
cantly raised after 10 to 19 years and did not revert
to that of never-smokers until after 20 years; for
CRP, the reduction was dependent on the number of
cigarettes smoked. A dose-effect relationship be-
tween the number of cigarette smoked per day and
plasma fibrinogen concentrations have also been
reported.53,54 Interestingly, the NHANES III study
(of 7,685 participants) confirmed that cigarette
smoking contributes significantly to low-grade sys-
temic inflammation and, furthermore, shows that
reduced lung function by itself is also associated with
increased odds of elevated CRP, fibrinogen, and
blood leukocytes; but having both risk factors sug-
gests an additive effect contributing to higher levels
of systemic inflammation in susceptible individuals.55
Furthermore, a large-scale population-based study56
confirmed that low FVC was associated with higher
plasma levels of fibrinogen, ␣1-antitrypsin, haptoglo-
bin, ceruloplasmin, and ␣1-acid glycoprotein, and
with increased incidences of myocardial infarction
and cardiovascular death. However, the nature of the
observed associations between decreased lung func-
tion and APPs induction is still unclear.
The role of other APPs is less extensively investi-
gated. It has been reported that concentrations of
␣1-acid glycoprotein, ceruloplasmin, and ␣2-macro-
Special Feature
www.chestjournal.org
Table 2—Baseline Information on Complex Studies of Smoking Effect on Levels of Inflammatory, Endothelial Dysfunction and Hemostatic Markers*
Source Study Design
Wannamethee et al33 British Regional Heart Study;
population based; cross-
sectional
Helmersson et al17 Uppsala longitudinal study of
adult men; population based;
cross-sectional
Lind et al58 Malmö Preventive Project;
population based, cross-
sectional
Frohlich et al49 MONICA Augsburg Survey;
population based; cross-
sectional
Bazzano et al50 NHANES III; population based;
cross-sectional
Bermudez et al51 Women’s Health Study;
population based; cross-
sectional
Lowe et al52 Speedwell Study; community
based; cross-sectional
Yarnell et al34 Caerphilly Study; community-
based; cross-sectional
CHEST / 131 / 5 / MAY, 2007
Woodward et al67 Third MONICA Survey in North 753 men and 821 women (IL-6
Glasgow; community based;
cross-sectional
Eliasson et al83 Northern Sweden MONICA
Study; community based; cross-
sectional
*1 ⫽ increased levels; % ⫽ no differences found; 2 ⫽ decreased levels; N/D ⫽ not determined; SAA ⫽ serum amyloid A; hsCRP ⫽ high-sensitivity CRP.
1561
Study Groups
2,920 men aged 60 to 79 yr with
no history of myocardial
infarction, angina, stroke, or
diabetes; 837 never-smokers;
1,503 ex-smokers; 391 current
smokers
642 men at 77 yr; no history of
diabetes; 55 current smokers;
391 ex-smokers; 196 never-
smokers
6,075 men aged 28 to 61 yr with
no history of myocardial
infarction, cancer, stroke; 1,489
never-smokers; 1,685 former
smokers; 2,901 current smokers
2,305 men and 2,211 women aged
25–74 yr
4,187 current smokers, 4,791
former smokers, and 8,375
never-smokers ⱖ 18 yr old of
both genders
340 apparently healthy women;
28% current smokers; 28% ex-
smokers; 43% never-smokers
1,690 men aged 49 to 67 yr; 527
current smokers; 734
ex-smokers; 265 never-smokers
2,188 men aged 49–55 yr; 726
current smokers; 819
ex-smokers; 388 never-smokers
measured as in 196 men and
221 women) aged 25–74 yr;
47% current smokers; 26% ex-
smokers; 27% never-smokers
604 men and 662 women 25 to
64 yr old; 317 current smokers;
238 ex-smokers; 581 never-
smokers
Smoking Status Determination
Self-reported and validated using hsCRP1; WBC1; albumin2
carboxyhemoglobin
measurements
Self-reported
Self-reported and validated by
blood carboxyhemoglobin
Self-reported
Self-reported and confirmed by
serum cotinine levels
Self-reported
Self-reported
Self-reported
Self-reported and confirmed by
cotinine level
Self-reported and confirmed by
nicotine and cotinine levels
Markers of Hemostasis and
Inflammatory Markers Endothelial Dysfunction
Fibrinogen1; blood viscosity1;
plasma viscosity1;
hematocrit1; fibrin-d-dimer1;
tPA antigen1
IL-61; PGF2␣1; CRP %; SAA N/D
%
␣ 1-acid glycoprotein1; Fibrinogen 1
␣1-antitrypsin1; haptoglobin1;
ceruloplasmin1
WBC1; hsCRP1 (men only); Fibrinogen1 (men only); plasma
albumin % viscosity1 (men only)
CRP1; homocysteine1 Fibrinogen1
hsCRP1; IL-61 Soluble ICAM-11; E-selectin1
hsCRP1 Fibrin d-dimer1
WBC1 Fibrinogen1; plasma viscosity1;
tPA antigen1; PAI-I activity1;
fibrin d-dimer1
WBC1; IL-61 Fibrinogen1; hematocrit1;
blood viscosity1 (only in
women); red cell
aggregations1 (only in
women)
N/D Fibrinogen1; tPA activity %;
PAI-I activity %
globulin are increased in the plasma of smokers as
compared to nonsmokers by 39%, 28%, and 12%,
respectively.57 Furthermore, the large prospective
Malmö Preventive Project study58 with 18-year fol-
low-up revealed that all measured APP levels (␣1-
acid glycoprotein, ␣1-antitrypsin, haptoglobin, fibrin-
ogen, and ceruloplasmin) increased significantly with
increasing cigarette consumption in healthy adult
men, independent of other known cardiovascular
risk factors.
While these blood changes in smokers may simply
be markers of smoking-induced tissue damage, it is
also possible that high APP levels may have a direct
effect on the promotion of cardiovascular diseases.
Increased levels of CRP and fibrinogen have been
associated with risk for subsequent cardiovascular
events in several large prospective studies.59,60 An-
other study61 showed that CRP might be not only a
biomarker of different cardiovascular diseases but
may have direct effects on the pathogenesis of
atherosclerosis and endothelial dysfunction. For ex-
ample, CRP stimulates IL-6 and endothelin-1 pro-
duction and upregulates adhesion molecules, pro-
moting a cascade of events that can lead to clot
formation and even promotes atherosclerosis in apo-
lipoprotein E-deficient mice.62 However, the exact
role of CRP in development of cardiovascular dis-
eases is still under discussion.63 Some causative
speculations are also discussed concerning the role of
fibrinogen in atherogenesis. Probably, fibrinogen
may promote cardiovascular diseases through effects
on blood viscosity, platelet aggregation, and fibrin
formation.64 In conclusion, these data clearly indi-
cate that CRP and fibrinogen levels are markedly
increased in smokers, possibly contributing to the
proinflammatory and proatherogenic effects of
chronic smoking exposure.
Raised levels of plasma APPs may partly reflect
elevations of inflammatory cytokines such as IL-6
and tumor necrosis factor (TNF)-␣, which are major
inductors of APP and, therefore, regulators of sys-
temic inflammatory response. Similarly to APPs,
increased levels of proinflammatory cytokines like
TNF-␣ and IL-6 have been shown to be a risk factor
and predictor for myocardial infarction, coronary
heart disease, and stroke.65,66
Several studies17,51 have shown increased levels of
TNF-␣ and IL-6 in smokers. The population-based
MONICA III North Glasgow study67 revealed that
mean IL-6 levels were substantially raised in current
smokers (by approximately 46% compared to never-
smokers), while ex-smokers had similar levels of IL-6
to never-smokers. Furthermore, a significant corre-
lation was found between IL-6 and fibrinogen, and
IL-6 and WBC counts, reflecting the major role of
IL-6 as inducer of fibrinogen. The Women’s Health
1562
Study51 from the United States showed a trend
toward increasing IL-6 levels across never, former,
and current smoking women. Further, Wirtz and
colleagues68 reported a trend for higher baseline
TNF-␣ levels among healthy smokers. However, a
study conducted by Gander and coworkers69 failed
to show significant effects of smoking on TNF-␣
plasma levels.
Taken as a whole, these data suggest that there are
limited data yet on circulating concentrations of IL-6
and TNF-␣ in healthy smokers. Taking into account
the possible predictive effects of major cytokines for
cardiovascular diseases, it would be worth to address
large-scale population-based studies to investigate
potential relationship of cytokine plasma levels with
traditional cardiovascular risk factors including
smoking.
Smoking and Markers of Endothelial
Dysfunction, Coagulation, and Hemostasis
The biological mechanism linking smoking and
atherogenesis, the process leading to cardiovascular
diseases, is complex and not fully understood. Be-
sides inflammation, proposed potential mechanisms
by which smoking increases the risk of cardiovascular
pathology include several other pathways: vascular
endothelial dysfunction, systemic hemostatic and
coagulation disturbances, and lipid abnormalities.
Many of these indexes including fibrinogen (marker
of coagulation), fibrin d-dimer (a marker of cross-
linked fibrin turnover), and tissue plasminogen acti-
vator antigen (t-PA, marker of endothelial dysfunc-
tion) have been identified as independent predictors
of subsequent cardiovascular events in prospective
studies70,71 conducted in healthy subjects. In addi-
tion, platelet hyperaggregation and activation,
plasma viscosity, and plasminogen activator inhibitor
(PAI) type I (marker of impaired fibrinolysis) levels
have also been associated with cardiovascular mor-
bidity and mortality in prospective studies.72,73 The
effect of smoking on these variables has also been
investigated in several cross-sectional studies, as will
be discussed below (Table 2).
Vascular Endothelial Dysfunction
Endothelial dysfunction is mainly caused by di-
minished production or availability of NO.61 It has
been demonstrated that the serum concentration of
nitrate and nitrite, metabolic end-products of NO, is
significantly decreased in smokers relative to that in
nonsmokers.74 In cigarette smokers, low-density li-
poprotein (LDL) is more prone to oxidation due to
higher level of ROS and reactive nitrogen species.75
Oxidatively modified LDL limits the bioactivity of
Special Feature
endothelium-derived NO; and, in turn, the loss of
NO bioactivity is associated with increased inflam-
matory cell entry into the arterial wall.76 Oxidatively
modified LDL is taken up by macrophage scavenger
receptors, promoting cholesterol ester accumulation
and foam cell formation.
Most recently, upregulation of the CD40/CD40L
dyad and increased platelet/monocyte aggregation
have been proposed as potential contributors to the
atherothrombotic consequences of smoking.77
CD40-CD40 ligand couples, members of TNF fam-
ily, are coexpressed by all of the major cellular
players in atherosclerosis. In particular, smokers
appeared to have elevated plasma levels of soluble
CD40 and increased surface expression of CD40 on
monocytes together with increased CD40 ligand on
platelets. Furthermore, plasma cotinine concentra-
tions correlated with CD40 and CD40 ligand expres-
sion, and with rate of platelet-monocyte aggrega-
tions. A recent study suggests that oxidatively
modified LDL may play the role of initial trigger for
CD40/CD40L expression in human endothelial and
smooth-muscle cells.78
Dysfunctional endothelial cells lose their critical
physiologic property of nonadherence to circulating
immune effector cells (monocytes, macrophages,
T-lymphocytes, platelets). Some adhesion molecules
are known to be elevated in plasma of smokers.
Several groups reported significantly higher levels of
soluble intracellular adhesion molecule (ICAM)-1
and P-selectin and E-selectin in current smokers
than in nonsmokers among healthy women.51,79 A
dose-dependent relationship was observed between
plasma ICAM-1 concentration and daily cigarette
consumption, plasma cotinine level, and exhaled
carbon monoxide level.80 Generally, impaired endo-
thelial function caused by cigarette smoking may
lead to increased susceptibility of vasculature to
atheroma formation and can be considered as an
early feature of atherogenesis in humans.81
Hemostatic and Coagulation Markers
There is increasing evidence that blood levels of
rheologic variables are associated with subsequent
cardiovascular events.70 These indexes include
whole-blood viscosity and its main determinants:
hematocrit and plasma viscosity, principally com-
posed by plasma fibrinogen and lipoproteins.67 Sev-
eral studies33,67 revealed that current smokers have
increased blood viscosity, associated with increased
hematocrit or/and plasma viscosity resulting in a
procoagulant condition. Increased plasma viscosity
may be caused by higher levels of fibrinogen re-
ported in plasma of smokers, as have been discussed
before in this review.
www.chestjournal.org
Furthermore, elevated levels of markers of fibri-
nolysis have been reported in healthy smokers. t-PA,
the main fibrinolytic activator, converting plasmino-
gen to plasmin is synthesized by endothelial cells. In
vivo studies82 have demonstrated major impairment
of t-PA release from the vascular endothelium of
smokers. The primary inhibitor of fibrinolysis is
PAI-I, which inhibits plasminogen activation by
binding with t-PA to form the PAI/t-PA complexes.
Current smoking is associated with a significant
increase in t-PA antigen, which represents mainly
the circulating PAI/t-PA complexes and indicates
impaired fibrinolytic activity in smokers.33,34 Sup-
porting previous findings,34,83 plasma PAI-1 antigen
and/or activity is significantly higher in smokers than
in nonsmokers and is correlated with pack-years
smoked.
Plasmin promotes the degradation of fibrin within
the thrombus, disintegrating clots, and hence main-
tains vascular patency. Fibrin d-dimer is a degrada-
tion product of cross-linked fibrin that is related to
cardiovascular diseases risk.52 As been reported,
smoking is positively associated with fibrin
d-dimer.33,84 The increased d-dimer in smokers
probably reflects increased coagulation activation
because this antigen is present in several degradation
products from the cleavage of cross-linked fibrin by
plasmin.85 Taking into account possible adverse ef-
fects of abnormal fibrinolysis and excess coagulation
on vascular health, further studies are essential to
evaluate the impairment of the fibrinolytic system in
smokers.
Overall, data presented in this review suggest that
smoking is one of the major lifestyle factors influenc-
ing levels of a number of novel inflammatory, coag-
ulation, and hemostatic markers associated with
common widespread diseases in population-based
prospective studies. Systemic oxidative stress fol-
lowed by low-grade inflammation and endothelial
dysfunction caused by chronic smoking exposure
could be one of “real-working” mechanisms that
explain increased prevalence of common diseases of
modern civilization like coronary heart disease, pe-
ripheral vascular disease, and COPD in smokers.
However, this hypothesis has to be taken cautiously
because not all smokers acquire one or more of these
diseases. It clearly suggests the existence of other
mechanisms influencing common disease develop-
ment, and, beyond doubt, genetic susceptibility is
one of them.86 Different approaches like case-con-
trol and whole-genome association studies, linkage
analysis of extended pedigrees, and affected sibling
pairs are used to dissect genetic component of
complex traits. For genetically complex disease like
cardiovascular diseases, common disease-common
variant hypothesis has been put forward, which
CHEST / 131 / 5 / MAY, 2007 1563
assumes that common disease susceptibility or resis-
tance variants are expected to be few at each genetic
locus, relatively common in the human population
and enriched in the coding and regulatory sequence
of genes.87 Despite the small effects of such genes
individually, the magnitude of their attributable risk
may be large because they are quite frequent in the
population, making them of public health signifi-
cance. However, there is a possibility that many rare
variants, each with small contribution, underlie the
susceptibility to common human disease.88 Never-
theless, it seems that complete model of complex
disease initiation and progression is based on coop-
eration where these multiple genes are likely to
operate through interactions with many environmen-
tal factors where smoking is only one but a very
important variable.
Conclusion
The possible biological mechanisms responsible
for the observed association of smoking with various
diseases and global mortality are numerous and, in
spite of a many attempts to find causative relation-
ships, are still unclear. It is a great scientific task to
unravel exact pathways through which smoking af-
fects human health. Although the effects of smoking
on inflammatory markers may persist for many years,
a majority of the adverse health effects of smoking
are reversible. Therefore, quitting smoking avoids
much of the excess health-care risk associated with
smoking and allows increasing life expectancy.
References
1 Edwards R. The problem of tobacco smoking. BMJ 2004;
328:217–219
2 Tobacco control: country profiles. Atlanta, GA: American
Cancer Society, 2000
3 World health report 2002: Reducing risks, promoting healthy
life. Geneva, Switzerland: World Health Organization, 2002
4 Crofton J, Bjartveit K. Smoking as a risk factor for chronic
airways disease. Chest 1989; 96(3 suppl):307S–312S
5 Boyle P. Cancer, cigarette smoking and premature death in
Europe: a review including the Recommendations of Euro-
pean Cancer Experts Consensus Meeting, Helsinki, October
1996. Lung Cancer 1997; 17:1– 60
6 van der Vaart H, Postma DS, Timens W, et al. Acute effects
of cigarette smoke on inflammation and oxidative stress: a
review. Thorax 2004; 59:713–721
7 Pryor W, Stone K. Oxidants in cigarette smoke radicals, hydro-
gen peroxides, peroxynitrate, and peroxynitrite. Ann N Y Acad
Sci 1993; 28:12–27
8 MacNee W. Pulmonary and systemic oxidant/antioxidant
imbalance in chronic obstructive pulmonary disease. Proc Am
Thorac Soc 2005; 2:50 – 60
9 van Antwerpen VL, Theron AJ, Richards GA, et al. Vitamin
E, pulmonary functions, and phagocyte-mediated oxidative
stress in smokers and nonsmokers. Free Radic Biol Med
1995; 18:935–941
1564
10 Ludwig PW, Hoidal JR. Alterations in leukocyte oxidative
metabolism in cigarette smokers. Am Rev Respir Dis 1982;
126:977–980
11 Michaud SE, Dussault S, Haddad P, et al, Circulating
endothelial progenitor cells from healthy smokers exhibit
impaired functional activities. Atherosclerosis 2006; 187:423–
432
12 Petruzzelli S, Puntoni R, Mimotti P, et al. Plasma 3-nitroty-
rosine in cigarette smokers. Am J Respir Crit Care Med 1997;
156:1902–1907
13 Takajo Y, Ikeda H, Takajo Y, et al. Augmented oxidative stress
of platelets in chronic smokers: mechanisms of impaired
platelet-derived nitric oxide bioactivity and augmented plate-
let aggregability. J Am Coll Cardiol 2001; 38:1320 –1327
14 Pignatelli B, Li CQ, Boffetta P, et al. Nitrated and oxidized
plasma proteins in smokers and lung cancer patients. Cancer
Res 2001; 61:778 –784
15 Morrow JD, Frei B, Longmire AW, et al. Increase in
circulating products of lipid peroxidation (F2-isoprostanes) in
smokers: smoking as a cause of oxidative damage. N Engl
J Med 1995; 332:1198 –1203
16 Reilly M, Delanty S, Lawson JA, et al. Modulation of oxidant
stress in vivo in chronic cigarette smokers. Circulation 1996;
94:19 –25
17 Helmersson J, Larsson A, Vessby B, et al. Active smoking and
a history of smoking are associated with enhanced prostaglan-
din F(2␣), interleukin-6 and F2-isoprostane formation in
elderly men. Atherosclerosis 2005; 181:201–207
18 Gniwotta C, Morrow JD, Roberts LJ II, et al. Prostaglandin
F2-like compounds, F2-isoprostanes, are present in increased
amounts in human atherosclerotic lesions. Arterioscler
Thromb Vasc Biol 1997; 17:3236 –3241
19 Schwedhelm E, Bartling A, Lenzen H, et al. Urinary 8-iso-
prostaglandin F2␣ as a risk marker in patients with coronary
heart disease: a matched case-control study. Circulation 2004;
109:843– 848
20 Rumley AG, Woodward M, Rumley A, et al. Plasma lipid
peroxides: relationships to cardiovascular risk factors and
prevalent cardiovascular disease. QJM 2004; 97:809 – 616
21 Smith FB, Lowe GD, Fowkes FG, et al. Smoking, haemo-
static factors and lipid peroxides in a population case control
study of peripheral arterial disease. Atherosclerosis 1993;
102:155–162
22 Orhan H, Evelo CT, Sahin G. Erythrocyte antioxidant de-
fense response against cigarette smoking in humans: the
glutathione S-transferase vulnerability. J Biochem Mol Toxi-
col 2005; 19:226 –233
23 Ochs-Balcom HM, Grant BJ, Muit P, et al. Oxidative stress
and pulmonary function in the general population. Am J
Epidemiol 2005; 162:1137–1145
24 Rahman I, Swarska E, Henry M, et al. Is there any relation-
ship between plasma antioxidant capacity and lung function in
smokers and in patients with chronic obstructive pulmonary
disease? Thorax 2000; 55:189 –193
25 Wei W, Kim Y, Boudreau N. Association of smoking with
serum and dietary levels of antioxidants in adults: NHANES
III, 1988 –1994. Am J Public Health, 2001; 91:258 –264
26 Lykkesfeldt J, Christen S, Wallock LM, et al. Ascorbate is
depleted by smoking and repleted by moderate supplemen-
tation: a study in male smokers and nonsmokers with matched
dietary antioxidant intakes. Am J Clin Nutr 2000; 71:530 –536
27 Schectman G, Byrd JC, Gruchow HW. The influence of
smoking on vitamin C status in adults. Am J Public Health
1989; 79:158 –162
28 Marangon K, Herbeth B, Lecomte E, et al. Diet, antioxidant
status, and smoking habits in French men. Am J Clin Nutr
1998; 67:231–239
Special Feature
29 Fuller CJ, May MA, Martin KJ. The effect of vitamin E and
vitamin C supplementation on LDL oxidizability and neutro-
phil respiratory burst in young smokers. J Am Coll Nutr 2000;
19:361–369
30 Pellegrini MP, Newby DE, Johnston NR, et al. Vitamin C has
no effect on endothelium-dependent vasomotion and acute
endogenous fibrinolysis in healthy smokers. J Cardiovasc
Pharmacol 2004; 44:117–124
31 Moriarty SE, Shah JH, Lynn M, et al. Oxidation of glutathi-
one and cysteine in human plasma associated with smoking.
Free Radic Biol Med 2003; 35:1582–1588
32 van Eeden SF, Hogg JC. The response of human bone
marrow to chronic cigarette smoking. Eur Respir J 2000;
15:915–921
33 Wannamethee SG, Lowe GD, Shaper AG, et al. Associations
between cigarette smoking, pipe/cigar smoking, and smoking
cessation, and haemostatic and inflammatory markers for
cardiovascular disease. Eur Heart J 2005; 26:1765–1773
34 Yarnell JW, Sweetnam PM, Runley A, et al. Lifestyle and
hemostatic risk factors for ischemic heart disease: the Caer-
philly Study. Arterioscler Thromb Vasc Biol 2000; 20:271–279
35 Smith MR, Kinmonth KL, Luben RN, et al. Smoking status
and differential white cell count in men and women in the
EPIC-Norfolk population. Atherosclerosis 2003; 169:331–337
36 Yarnell JW, Sweetnam PM, Rogers S, et al. Some long term
effects of smoking on the haemostatic system: a report from
the Caerphilly and Speedwell Collaborative Surveys. J Clin
Pathol 1987; 40:909 –913
37 Tedder TF, Steeber DA, Chen A, et al. The selectins: vascular
adhesion molecules. FASEB J 1995; 9:866 – 873
38 Dash S, Sen S, Behera D. High neutrophil myeloperoxidase
activity in smokers [letter]. Blood 1991; 77:1619
39 van Eeden SF, Yeung A, Quinlam K, et al. Systemic response
to ambient particulate matter: relevance to chronic obstruc-
tive pulmonary disease. Proc Am Thorac Soc 2005; 2:61– 67
40 Kim WD, Kim WS, Koh Y, et al. Abnormal peripheral blood
T-lymphocyte subsets in a subgroup of patients with COPD.
Chest 2002; 122:437– 444
41 Miller LG, Goldstein G, Murphy M, et al. Reversible alter-
ations in immunoregulatory T cells in smoking: analysis by
monoclonal antibodies and flow cytometry. Chest 1982; 82:
526 –529
42 Tanigawa T, Araki S, Nakata A, et al. Increase in memory
(CD4⫹CD29⫹ and CD4⫹CD45RO⫹) T and naive
(CD4⫹CD45RA⫹) T-cell subpopulations in smokers. Arch
Environ Health 1998; 53:378 –383
43 Hughes DA, Haslam PL, Townsend PJ, et al. Numerical and
functional alterations in circulatory lymphocytes in cigarette
smokers. Clin Exp Immunol 1985; 61:459 – 466
44 Tollerud DJ, Clark JW, Brown LM, et al. The effects of
cigarette smoking on T cell subsets: a population-based
survey of healthy Caucasians. Am Rev Respir Dis 1989;
139:1446 –1451
45 Mili F, Flanders WJ, Boring JR, et al. The associations of
race, cigarette smoking, and smoking cessation to measures of
the immune system in middle-aged men. Clin Immunol
Immunopathol 1991; 59:187–200
46 Schaberg T, Theilacker C, Nitschke OT, et al. Lymphocyte
subsets in peripheral blood and smoking habits. Lung 1997;
175:387–394
47 Rohde LE, Hennekens CH, Ridker PM. Survey of C-reactive
protein and cardiovascular risk factors in apparently healthy
men. Am J Cardiol 1999; 84:1018 –1022
48 Mendall MA, Strachan DP, Butland BK, et al. C-reactive
protein: relation to total mortality, cardiovascular mortality
and cardiovascular risk factors in men. Eur Heart J 2000;
21:1584 –1590
www.chestjournal.org
49 Frohlich M, Sund M, Frolich M, et al. Independent associa-
tion of various smoking characteristics with markers of sys-
temic inflammation in men: results from a representative
sample of the general population (MONICA Augsburg Sur-
vey 1994/95). Eur Heart J 2003; 24:1365–1372
50 Bazzano LA, He J, Muntner P, et al. Relationship between
cigarette smoking and novel risk factors for cardiovascular
disease in the United States. Ann Intern Med 2003; 138:891–
897
51 Bermudez EA, Rafai N, Buring JE, et al. Relation between
markers of systemic vascular inflammation and smoking in
women. Am J Cardiol 2002; 89:1117–1119
52 Lowe GD, Yarnell JW, Rumley A, et al. C-reactive protein,
fibrin d-dimer, and incident ischemic heart disease in the
Speedwell study: are inflammation and fibrin turnover linked
in pathogenesis? Arterioscler Thromb Vasc Biol 2001; 21:
603– 610
53 Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, ciga-
rette smoking, and risk of cardiovascular disease: insights
from the Framingham Study. Am Heart J 1987; 113:1006 –
1010
54 Heinrich J, Balleisen L, Schulte H, et al. Fibrinogen and
factor VII in the prediction of coronary risk: results from the
PROCAM study in healthy men. Arterioscler Thromb 1994;
14:54 –59
55 Gan WQ, Man SF, Sin DD. The interactions between
cigarette smoking and reduced lung function on systemic
inflammation. Chest 2005; 127:558 –564
56 Engstrom G, Lind P, Hedblad B, et al. Lung function and
cardiovascular risk: relationship with inflammation-sensitive
plasma proteins. Circulation 2002; 106:2555–2560
57 Tappia PS, Troughton KL, Langley-Evans SC, et al. Cigarette
smoking influences cytokine production and antioxidant de-
fences. Clin Sci (Lond) 1995; 88:485– 489
58 Lind P, Engstrom G, Stavenow L, et al. Risk of myocardial
infarction and stroke in smokers is related to plasma levels of
inflammation-sensitive proteins. Arterioscler Thromb Vasc
Biol 2004; 24:577–582
59 Danesh J, Whincup P, Walker M, et al. Low grade inflam-
mation and coronary heart disease: prospective study and
updated meta-analyses. BMJ 2000; 321:199 –204
60 Ridker PM, Haughie P. Prospective study of C-reactive
protein and the risk of future cardiovascular events among
apparently healthy women. Circulation 1998; 98:731–733
61 Szmitko PE, Wang CH, Weisel RD, et al. New markers of
inflammation and endothelial cell activation: part I. Circula-
tion 2003; 108:1917–1923
62 Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the
progression of atherosclerosis in apolipoprotein E-deficient
mice. Circulation 2004; 109:647– 655
63 Jialal I, Devaraj S, Venugopal SK. C-reactive protein: risk
marker or mediator in atherothrombosis? Hypertension 2004;
44:6 –11
64 Kamath S, Lip GY. Fibrinogen: biochemistry, epidemiology
and determinants. QJM 2003; 96:711–729
65 Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration
of interleukin-6 and the risk of future myocardial infarction
among apparently healthy men. Circulation 2000; 101:1767–
1772
66 Cesari M, Penninx BW, Newman AB, et al. Inflammatory
markers and onset of cardiovascular events: results from the
Health ABC study. Circulation 2003; 108:2317–2322
67 Woodward M, Rumley A, Tunstall-Pedoe H, et al. Associa-
tions of blood rheology and interleukin-6 with cardiovascular
risk factors and prevalent cardiovascular disease. Br J Haema-
tol 1999; 104:246 –257
68 Wirtz PH, von Kanel R, Kunz-Ebrecht S, et al. Enhanced
CHEST / 131 / 5 / MAY, 2007 1565
 glucocorticoid sensitivity of cytokine release from circulating
leukocytes stimulated with lipopolysaccharide in healthy male
smokers. Brain Behav Immun 2004; 18:536 –543
69 Gander ML, Fischer JE, Maly FE, et al. Effect of the G-308A
polymorphism of the tumor necrosis factor (TNF)-␣ gene
promoter site on plasma levels of TNF-␣ and C-reactive
protein in smokers: a cross-sectional study. BMC Cardiovasc
Disord 2004; 4:17
70 Lowe GD, Lee AJ, Rumley A, et al. Blood viscosity and risk
of cardiovascular events: the Edinburgh Artery Study. Br J
Haematol 1997; 96:168 –173
71 Koenig W, Sund M, Lowel H, et al. Association between
plasma viscosity and all-cause mortality: results from the
MONICA-Augsburg Cohort Study 1984 –92. Br J Haematol
2000; 109:453– 458
72 Lowe GD, Danesh J, Lewington S, et al. Tissue plasminogen
activator antigen and coronary heart disease: prospective
study and meta-analysis. Eur Heart J 2004; 25:252–259
73 Thogersen AM, Jansson JH, Boman K, et al. High plasmin-
ogen activator inhibitor and tissue plasminogen activator
levels in plasma precede a first acute myocardial infarction in
both men and women: evidence for the fibrinolytic system as
an independent primary risk factor. Circulation 1998; 98:
2241–2247
74 Node K, Kitakazi M, Yoshikawa H, et al. Reversible reduction
in plasma concentration of nitric oxide induced by cigarette
smoking in young adults. Am J Cardiol 1997; 79:1538 –1541
75 Yamaguchi Y, Haginaka J, Morimoto S, et al. Facilitated
nitration and oxidation of LDL in cigarette smokers. Eur
J Clin Invest 2005; 35:186 –193
76 Stocker R, Keaney JF Jr. Role of oxidative modifications in
atherosclerosis. Physiol Rev 2004; 84:1381–1478
77 Harding SA, Sarma J, Josephs DH, et al. Upregulation of the
CD40/CD40 ligand dyad and platelet-monocyte aggregation
in cigarette smokers. Circulation 2004; 109:1926 –1929
78 Schonbeck U, Gerdes M, Varo N, et al. Oxidized low-density
lipoprotein augments and 3-hydroxy-3-methylglutaryl coen-
1566
View publication stats
zyme A reductase inhibitors limit CD40 and CD40L expres-
sion in human vascular cells. Circulation 2002; 106:2888 –
2893
79 Bergmann S, Seikmeier R, Mix C, et al. Even moderate
cigarette smoking influences the pattern of circulating mono-
cytes and the concentration of sICAM-1. Respir Physiol 1998;
114:269 –275
80 Scott DA, Stapleton JA, Wilson JF, et al. Dramatic decline in
circulating intercellular adhesion molecule-1 concentration
on quitting tobacco smoking. Blood Cells Mol Dis 2000;
26:255–258
81 Behrendt D, Ganz P. Endothelial function: from vascular
biology to clinical applications. Am J Cardiol 2002; 90:40L–
48L
82 Newby DE, Wright RA, Labinjoh C, et al. Endothelial
dysfunction, impaired endogenous fibrinolysis, and cigarette
smoking: a mechanism for arterial thrombosis and myocardial
infarction. Circulation 1999; 99:1411–1415
83 Eliasson M, Asplund K, Evrin PE, et al. Relationship of
cigarette smoking and snuff dipping to plasma fibrinogen,
fibrinolytic variables and serum insulin: the Northern Sweden
MONICA Study. Atherosclerosis 1995; 113:41–53
84 Yarnell JW, Sweetnam PM, Rumley A, et al. Lifestyle factors
and coagulation activation markers: the Caerphilly Study.
Blood Coagul Fibrinol 2001; 12:721–728
85 Lowe GD, Rumley A. Use of fibrinogen and fibrin d-dimer in
prediction of arterial thrombotic events. Thromb Haemost
1999; 82:667– 672
86 Cambien F, Tiret L. Atherosclerosis: from genetic polymor-
phisms to system genetics. Cardiovasc Toxicol 2005; 5:143–
152
87 Collins FS, Guyer MS, Charkravarti A. Variations on a theme:
cataloging human DNA sequence variation. Science 1997;
278:1580 –1581
88 Pritchard JK, Cox NJ. The allelic architecture of human
disease genes: common disease-common variant, or not?
Hum Mol Genet 2002; 11:2417–2423
Special Feature