ATVB in Focus

Tobacco Related Cardiovascular Diseases in the 21st Century

Series Editor: Muredach P. Reilly

Understanding the Effects of Tobacco Smoke on the

Pathogenesis of Aortic Aneurysm
Paul E. Norman, John A. Curci

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AbstractAneurysmal arterial disease is a vascular degenerative condition that is distinct from atherosclerotic and other
occlusive arterial diseases. There is regionalization of the predisposition to aneurysm formation within the vascular tree,
and the pathological process varies with location. Infrarenal abdominal aortic aneurysm (AAA) is the most common
manifestation of aneurysmal disease, and smoking is the dominant risk factor. Smoking is a much greater risk factor
for AAA than for atherosclerosis. In addition to playing a role in the pathogenesis of AAA, smoking also increases the
rate of expansion and risk of rupture of established AAA. The mechanistic relationship between AAA and smoking
is being established by the use of enhanced animal models that are dependent on smoke or smoke components. The
mechanisms seem to involve durable alterations in vascular smooth muscle cell and inflammatory cell function. This
review examines the clinical, epidemiological, and mechanistic evidence implicating smoking as a cause of aneurysms,
focusing on AAA.(Arterioscler Thromb Vasc Biol. 2013;33:1473-1477.)
Key Words: aneurysm smoking pathogenesis risk factor

neurysmal arterial disease is clinically, histologically,

and mechanistically quite distinct from atherosclerosis
and other occlusive arterial disease. Although atherosclerotic
change may be seen in many aneurysms, the relationship is
not necessarily a causal one. Aneurysms are more common
in some arteries than others, and their pathogenesis varies
by location, with, for example, hypertension dominating in
cerebral arteries, genetic factors dominating in the ascending aorta, and smoking dominating in the abdominal aorta.1
Given the importance of smoking in abdominal aortic aneurysm (AAA), this review focuses on AAA. Although there is
less evidence implicating smoking in other manifestations of
aneurysmal disease, this does not exclude a role for smoking
in the development or progression of other aneurysms.

Swedish men aged 65 years, 87% of men with AAA were current or ex-smokers, and smoking was the dominant risk factor
for AAA (odds ratio, 3.5; 95% CI, 2.45.1).4
Results from a screening study of >3 million individuals
in the United States showed that there was a clear relationship between prevalent AAA and both duration and amount of
smoking (Figure 1).5 There is evidence of a strong linear dose
response effect with duration of smoking.2,5,6 The relationship
with the amount smoked is also linear in current smokers and
to a lesser extent in ex-smokers.5,6 In ex-smokers, the duration
seems to be more important than the level of exposure.5,6
The magnitude of risk with smoking eclipses all other
modifiable risk factors for prevalent AAA. Intriguingly, smoking
seems to be a substantially greater risk factor for AAA than for
occlusive atherosclerotic disease. In a systematic review by
Lederle et al,7 the association between smoking and AAA was
2.5-fold (95% CI, 2.22.8) greater than the association between
smoking and coronary heart disease. The divergent effect of
smoking on these 2 vascular diseases supports the distinct
pathogenesis of aneurysmal and occlusive arterial disease.
The US Preventive Services Task Force considered smoking
a sufficiently dominant risk factor for AAA to recommend
screening men aged 65 to 75 years who have ever smoked, rather
than all men of that age.8 Kent et al5 have demonstrated that the
efficiency of screening can be improved using algorithms based
on risk factors, such as smoking. However, other studies have
not supported selective screening based on risk factors.9,10
Although AAA is less common in women, outcomes seem
to be worse in women with AAA compared with men with

Clinical and Epidemiological Studies of

Smoking and AAA
Smoking Increases Prevalence and Incidence
All epidemiological studies of AAA have identified the importance of smoking as a risk factor. Smoking is a very strong risk
factor for the presence of an AAA in both men and women, with
odds ratios ranging from 3 to 12.2,3 In the large (n=114567)
Aneurysm Detection and Management (ADAM) screening
study, a history of ever smoking was associated with an odds
ratio of 2.97 (95% CI, 2.653.32) for 3- to 3.9-cm AAAs and
5.07 (95% CI, 4.136.21) for 4-cm AAAs.2 Smoking was
considered to be responsible for 75% of the excess prevalence of AAAs 4 cm. In a recent report of screening 22187

Received on: September 17, 2012; final version accepted on: November 20, 2012.
From the School of Surgery, University of Western Australia, Fremantle, Australia (P.E.N.); and Department of Surgery, Section of Vascular Surgery,
Washington University School of Medicine, Saint Louis, MO (J.A.C.).
Correspondence to Paul Norman, School of Surgery, University of Western Australia, Fremantle Hospital, PO Box 480, Fremantle, WA 6959, Australia.
E-mail paul.norman@uwa.edu.au
2013 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org

1473

DOI: 10.1161/ATVBAHA.112.300158

1474 Arterioscler Thromb Vasc Biol July 2013

1.333.06) for current smoking versus ex/never smoker, an
effect that was independent of aneurysmal diameter.15

Influence of Smoking on Intervention and Prognosis

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Smoking is relevant when patients require intervention for AAA.

For patients undergoing surgical intervention for AAA, current
smoking is likely to increase the risk of perioperative death and
late mortality. In the UK Small Aneurysm Trial, continued smoking 1 year after randomization was associated with significantly
increased mortality (hazard ratio, 3.23; 95% CI, 1.736.03).17
Although smokers are less likely to develop an endoleak after
endovascular repair (presumably as a result of prothrombotic
effects), they are at increased risk of stent migration.18
The recently documented decline in incidence of AAA
interventions and deaths and the lower than expected prevalence in screening studies have been attributed to falling
rates of smoking.4,19,20 Smoking cessation is associated with a
decline in risk of an AAA of 30% for each decade after quitting (Figure 1).2,5,6 Nevertheless, the legacy of increased risk
of AAA from smoking lasts many decades.14

Mechanistic Studies of Smoking

and Aneurysm Formation
Figure 1. Age-adjusted effects of: smoking duration (A), quantity
(B), and time since quitting (C) on the risk of abdominal aortic
aneurysm (AAA). Reference groups are nonsmokers for all smoking variables. The vertical error bars show 95% CIs. Adapted with
permission from Kent et al.5

AAA.11 There is some evidence that smoking may be a greater

risk factor for AAA in women than in men. In the Rotterdam
Study, 56% of women with AAA were current smokers compared with 38% of men.12 In the ADAM study, the odds ratio
for ever smoking was 3.80 (95% CI, 1.579.20) in women
compared with 3.34 (95% CI, 3.043.67) in men.13 It is
unclear how important these differences are.
Smoking is also the dominant factor for incident AAA. In
a prospective analysis of the Troms study, there was a dose
response effect with both smoking duration and quantity.14
Even individuals who had stopped smoking 10 to 19 years
earlier had nearly a 3-fold risk of an incident AAA compared
with nonsmokers. This suggests that smoking has a durable
influence on AAA formation an effect also seen in recent
experimental studies (see below).

Smoking Increases Expansion

Rate and Rupture Risk
Smoking is an important cause of progression of AAA.
Continued smoking in individuals with an AAA is associated
with both increased rates of expansion and the risk of rupture.
In a recent meta-analysis using data from 15475 patients with
small (35.5 cm) AAAs, current smoking was associated with
an increased rate of expansion of 0.35 (95% CI, 0.230.48)
mm/year.15 In the UK Small Aneurysm Trial, current smoking
doubled the risk of rupture, although this was not statistically
significant, with a hazard ratio of 2.11 (95% CI, 0.95 4.67).16
However, this doubling of risk was confirmed as significant
in a recent meta-analysis with a hazard ratio of 2.02 (95% CI,

The most striking feature of AAA histology is the loss of normal medial arterial structure and, in particular, the near complete absence of a normal lamellar elastin matrix, a feature
that it has in common with chronic obstructive pulmonary
disease.21 In the aorta, these matrix changes are attributed to 3
general features that are believed to be interrelated: (1) elaboration of high levels of proteases, (2) chronic inflammatory
infiltration, and (3) loss/dysfunction of parenchymal cells central to matrix deposition and repair.
Although considerable research with human tissue and
animal models over the past 2 decades has begun to inform our
understanding of the initiation and progression of AAA, we are
yet to develop and verify an effective biological therapeutic
that will interrupt development of an AAA or halt the growth
of a small AAA. However, given the importance of smoking
as a risk factor, there has until recently been very little work
on the effects of smoke exposure in these models. Because
of the complex make-up of tobacco smoke (TS) and the
variety of intermediaries that may be involved, the effects on
the vasculature could be mediated through alterations of the
inflammatory response, of resident vascular smooth muscle cell
(VSMC) function, or of the vessel matrix itself. Several different
experimental approaches have been proposed to determine the
mechanisms of AAA formation related to smoking (Table).

Human Studies
There are many challenges to evaluating the mechanistic
effects of smoking on AAA formation in humans. When
looking at the associations of various circulating markers in
patients with AAA, Lindholt et al22 came to the conclusion that
smoking may activate tissue plasminogen activator. Because
tissue plasminogen activator is a potent activator of elastolytic
matrix metalloproteinase, this could link smoking to aortic
elastolysis. In support of this, others have shown endothelial
response to serum from smokers to result in increased tissue

Norman and Curci Smoking and Aneurysm Formation 1475

Table.

Mechanistic Studies of Smoking Components and AAA

Smoke Component

Study Design

Potential Mechanism

Source

Whole smoke

Circulating inflammatory markers in humans with AAA

Increased tPA in smokers which could activate proteases

22

Whole smoke

Genome-wide association study in humans

Association of smoke and AAA on 3p12.3 and epigenetic

modifications

2325

Water-soluble smoke extract

Human VSMC

Suppression of prolyl-4-hydroxylase

Water-soluble smoke extract

Human neutrophils, endothelial cells, and VSMC

Increased MMP production

Nicotine

VSMC and inflammatory cells

Multiple

29

Nicotine

Mouse (ApoE-deficient) model of AAA

AMP-activated protein kinase 2

30

Nicotine

Mouse (ApoE-deficient and elastase perfusion) model

of AAA

miR-21 (also associated with stabilization of aortic dilation)

31

Whole smoke

Mouse (ApoE-deficient) model of AAA

Increased MMP gene expression

32

Whole smoke

Mouse (modified elastase perfusion) model of AAA

Altered T-cell response

33

26
27,28

AAA indicates abdominal aortic aneurysm; tPA, tissue plasminogen activator; VSMC, vascular smooth muscle cells; and MMP, matrix metalloproteinase.
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plasminogen activator without increased plasminogen activator inhibitor-1 or tissue factor pathway inhibitor-1.34
Genetic variants associated with AAA have also shown potential
interactions with smoking. One genome-wide association study
found a variant on 3p12.3, which demonstrated that the genetic risk
was significantly greater in those with a history of smoking.23 Other
studies, however, have not shown a clear relationship among smoking, genetic variants, and AAA.24 It is also possible that smoking
contributes to the pathogenesis of AAA via epigenetic interactions,
although conclusive evidence about this is still lacking.25

Studies of Smoke Components

Because the matrix changes in the aorta bear some resemblance to those in the lung, some studies have begun with
a presumption that the mechanisms are likely to be similar.
Applying techniques that were successfully used to define
similar pathological processes induced by TS in the lung,3541
these studies have attempted to develop a mechanistic understanding of TS on vascular biology. Typically, these studies
have relied primarily on gross extracts or purified specific
components of TS applied in vivo or to tissues or cells.
Using a water-soluble cigarette smoke extract (CSE) applied
to VSMC in culture, the expression of a key component of
prolyl-4-hydroxylase is suppressed and thereby reduces collagen production.26 This could promote AAA development
by reducing the ability of the aorta to repair medial structural
damage. Others have shown that CSE can induce metalloprotease production and release in vascular cells and inflammatory cells,27,28 thereby promoting matrix damage.
In other studies, however, there is evidence of effects of CSE
that would be contrary to what is known about AAA pathology.
In VSMC, CSE seems to promote proliferation and survival.42
This would be consistent with the enhancement of intimal
hyperplasia caused by smoking, but the VSMC in AAA are
typically sparse and senescent and reproduce poorly in vitro.43
Furthermore, the immunomodulatory effects of TS and CSE
in the acute situation vary, but it is well described that chronic
exposure effectively induces T-cell anergy,44,45 which seems
contradictory to the chronic inflammation prominent in AAA.
The cellular effects of nicotine have been well studied and
include effects that may both promote and inhibit AAA development, as has been reviewed elsewhere.29 Two recent studies
using the apolipoprotein Edeficient mouse model of AAA

have shown that nicotine can significantly increase aneurysm

formation either with31 or without angiotensin II infusion.30 A
similar AAA augmentation has also been shown with nicotine
infusion in the elastase perfusion model.31
Activation of the AMP-activated protein kinase 2
(AMPK-2) in VSMC may be responsible for the nicotine-enhanced AAA formation,30 consistent with increased
AMPK-2 in both smokers and patients with AAA. In a second
study, microRNA-21 (miR-21) was found to be enhanced late in
aneurysm development in both apolipoprotein Edeficient and
elastase perfusion models and was associated with stabilization
of further dilation.31 Although nicotine exposure increased miR21 in the aneurysms and cell culture, AAA in the model was
abrogated with administration of exogenous premiR-21. The
authors did not resolve the apparent contradiction with respect
to the effects of nicotine on AAA formation and miR-21.
The relationship between these 2 distinct mechanisms of
AAA development related to nicotine exposure remains to be
elucidated, although there are some data to suggest that they
may be regulated similarly in response to cellular stress. Both
miR-21 and AMPK are recognized to be increased in response
to hypoxia.46 There is evidence that miR-21 and AMPK can
both be elevated in the context of a stress on glioma cells.47
Further studies of the downstream effects of miR-21 and
AMPK, particularly in the context of whole-animal smoke
exposure, will probably be necessary to better clarify the role
of these molecules in nicotine-enhanced AAA.

Models Incorporating In Vivo Smoke Exposure

Although smoke component studies do offer important clues to
the effects of TS on AAA development, they are often severely
limited by 3 assumptions: First, that the toxin or limited toxin
mixture applied to the cells in culture (or selected for in vivo
exposure) would elicit the same effect as the in vivo response
when an individual inhales cigarette smoke. Second, that the
components evaluated will elicit the same response when used
in a more complex mixture. Third, that TS or TS component
exposure may activate known pathways of disease. None of
these assumptions has been rigorously investigated or validated.
Models that examine the in vivo effects of smoking on
AAA development have a critical role to play with regard
to exploring the biological response of the aorta to inhaled
smoke and in validating the mechanistic pathways defined by

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smoke component evaluations. Unfortunately, although exposure to smoke in the mouse has been used for years to model
pulmonary disease, no aneurysm phenotype emerged. Several
investigators have demonstrated smoke-enhanced AAA formation with the elastase perfusion model or the angiotensin
IItreated apolipoprotein E knockout model.32,48,49
In the elastase perfusion model, like the human disease where
the increased risk of aneurysm formation persists decades after
cessation of smoke exposure,14 the effects of relatively short
exposure to smoke (6 weeks) result in persistently increased AAA
development at least 8 weeks after smoke cessation. Somewhat
surprisingly, the effects of smoke on aneurysm development are
not inhibited with protease inhibitors or through genetic knockout of elastolytic enzymes.33 The ultrastructure of the aorta is not
altered by smoke exposure alone, but smoke exposure increases
the T-cell infiltrate in the aorta in response to elastase injury.
Even more remarkable was the finding that adoptive transfer
of leukocytes from smoke-exposed animals to smoke-free animals confers the enhanced aneurysm phenotype on the recipient.33 These results suggest that durable alterations in leukocyte
function, particularly the effects on T cells, may contribute to the
enhancement of aneurysm formation by smoking (Figure 2).

Consolidating Current Experimental

Results of Smoking on AAA
The impact of the inhalation of a complex cocktail of potential
toxins in cigarette smoke on the vasculature presents a significant challenge to scientific interrogation. It must be recognized
that the in vivo inhalation of TS results in episodic exposure of
combustion products with a variety of bioactivities (eg, oxygen
radicals) and affinities with the circulation (eg, lipophilic versus
hydrophilic) in the process of delivery to the tissue of interest
the aorta. Cells and enzymes in circulation may also interact
with the absorbed smoke in ways that are not well understood.
Prominent components of tobacco smoke, such as nicotine,
are relatively easy to study in isolation, with some elegant results
in cell culture and animals models that can confirm our bias
regarding the role of smoking on arterial disease. These studies of individual smoke components must be interpreted with
caution, however. The apparent contradictory results of smoke
component experiments seen in some of these studies may well
be because of unique responses to the simplified exposure chosen (Figure 2). The novel aneurysm models based on inhaled
cigarette smoke exposure provide a critical means of validating
the potential mechanisms related to smoke components.

Figure 2. Both nicotine infusion and experimental smoke exposure can lead to enhanced aneurysm development in murine
models. Nicotine seems to directly enhance abdominal aortic
aneurysm (AAA) development via AMP-activated protein kinase
2 (AMPK-2) activation in aortic smooth muscle cells. Nicotine
also increases local production of the microRNA-21 (miR-21),
which may stabilize the aneurysm through improved matrix repair
processes. Inhalation of tobacco smoke enhances AAA development through altered leukocyte function, which seems to be predominantly T-celldependent. It is unclear whether AMPK-2 is
activated by nicotine when inhaled during tobacco smoking.

Sources of Funding
This work was supported by the National Health and Medical
Research Council of Australia grants 458505 and1006266 (to P.E.
Norman), the National Heart, Lung, and Blood Institute K08 HL84004
(to J.A. Curci), Flight Attendants Medical Research Institute (to J.A.
Curci), the American Heart Association 0765432Z (to J.A. Curci),
the American College of Surgeons/Society for Vascular Surgery
Foundation (to J.A. Curci), the Department of Veterans Affairs (J.A.
Curci), and the Peripheral Vascular Surgery Society (J.A. Curci).

Conclusion
There is little doubt that smoking is an important cause of AAA
development and progression. It is, however, not the only cause
of AAA, with 10% to 15% of cases seen in individuals who have
never smoked.4 This highlights the fact that our understanding
of the pathogenesis of AAA is still incomplete. The resistance
of smoke-enhanced AAA models to inhibition of elastolytic
proteases is an important new clue. An understanding of the
unique mechanisms related to smoking is needed to shed light on
new strategies to prevent or retard the growth of AAA. Although
there is no direct evidence that smoking cessation prevents AAA
or decreases the need for AAA intervention, health economic
modeling suggests that it would be a cost-effective strategy and
it remains a priority for all patients with AAA.50

Disclosures
None.

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Understanding the Effects of Tobacco Smoke on the Pathogenesis of Aortic Aneurysm

Paul E. Norman and John A. Curci
Arterioscler Thromb Vasc Biol. 2013;33:1473-1477; originally published online May 16, 2013;
doi: 10.1161/ATVBAHA.112.300158
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