Zhu et al.

BMC Public Health (2019) 19:103

https://doi.org/10.1186/s12889-019-6419-8

RESEARCH ARTICLE Open Access

Nicotine dependence as an independent

risk factor for atherosclerosis in the
National Lung Screening Trial
Junjia Zhu1, Kevin Nelson1, Jennifer Toth2 and Joshua E. Muscat1*

Abstract
Background: Atherosclerosis and COPD are systemic inflammatory diseases that share common risk factors
including cigarette smoking. A high level of nicotine dependence is emerging as a recently identified risk factor for
pulmonary impairment, chronic obstructive pulmonary disease and tobacco-related cancers. We hypothesized that
nicotine dependence is associated with the risk of atherosclerosis in long-term cigarette smokers.
Methods: A nested case-control study was conducted within the National Lung Cancer Screening Trial- American
College of Radiology Imaging Network. Cases were defined as having a new diagnosis of any type of
atherosclerosis. Controls were matched on a 2:1 basis by age, sex, race, study center, smoking status, years of
smoking, and frequency of smoking. Dependence was measured by the time to first cigarette after awakening
(TTFC).
Results: The study included 166 cases and 286 controls. Compared to participants who smoked within 5 min after
waking, the risk of atherosclerosis for participants who smoked an hour or more after waking was borderline non-
significant (odds ratio = 0.49, 95% confidence intervals [CI] 0.23, 1.00). Findings were similar for men and women.
For aortic atherosclerosis, the corresponding odds ratio was 0.24 (95% CI 0.08, 0.69). Hypertension was associated
with an increased risk and body mass index was associated with a decreased risk of aortic atherosclerosis. The TTFC
was unrelated to coronary atherosclerosis.
Conclusions: Compared to smoking immediately after waking, delaying an hour or more reduces the risk of aortic
atherosclerosis even among long-term heavy smokers. Possible mechanisms that explain this association are
intensity of smoking, inflammation and oxidative stress, and elevated lipid levels.
Keywords: Atherosclerosis, Tobacco smoking, Tobacco use disorder, Risk factors

Background increases the risk of aortic and coronary atherosclerosis,

Cigarette smoking is an established cause of the clinical with higher risks associated with aortic atherosclerosis
consequences of atherosclerosis including peripheral ar- [4]. Smoking also increases the pathogenic potential of
terial disease and coronary artery disease [1]. In a atherosclerosis by increasing the thickness of
meta-analysis of 55 studies, the relative risk of peripheral intimal-medial thickness of the arteries [5, 6]. The asso-
arterial disease (PAD) associated with cigarette smoking ciation is dose-dependent with pack-years of exposure
was 2.71 (95% CI 2.28 to 3.21, p < 0.001) [2]. The risk [5]. A history of smoking and especially heavy smoking
for coronary heart disease is similar [3]. is associated with the presence and size of aortic athero-
Cigarette smoking also causes atherosclerosis. In the sclerotic lesions [7–10] although the findings for coron-
Multi-Ethnic Study of Atherosclerosis, cigarette smoking ary atherosclerosis are not entirely consistent [11].
Recently, a literature has been emerging that nicotine
* Correspondence: [email protected] dependence itself, independent of the amount of smok-
1
Penn State College of Medicine, Department of Public Health Sciences,
Pennsylvania State University, MC CH69, 500 University Drive, P.O. Box 850,
ing, is a strong factor for several major causes of mortal-
Hershey, PA 17033, USA ity from tobacco-related diseases. Using the measure
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Zhu et al. BMC Public Health (2019) 19:103 Page 2 of 6

time to first cigarette after waking, which is often con- prevent the occurrence of future cardiovascular disease
sidered the best single indicator of nicotine dependence [21, 22]. Chest CT can image the entire heart whereas
[12], a later time to first cigarette (TTFC) was found to CT methods performed specifically for coronary calcium
decrease the risk of smoking-associated outcomes in- have a more limited visual view. However chest CT is
cluding COPD [13], pulmonary impairment [14], lung not conducted for individuals who do not meet the
cancer [15–17] and other cancers [18]. When smokers screening guidelines of chest CT [23]. In our data, 220
delay having their first morning cigarette, their risks are of 14,028 (about 1.57%) NLST –ACRIN participants
reduced compared to smokers who take their first were diagnosed with any type of atherosclerosis.
cigarette within minutes after waking, even after adjust- A matched case-control study was created from NLST
ment for smoking history. The reasons for these associa- files made available for third party use, which represent
tions are not well understood but they have been 90% of total NLST subjects. Fifty-five participants were
consistently shown for both malignant and nonmalig- diagnosed with ICD-9 code 440 [aortic atherosclerosis],
nant conditions. and 40 cases were coded as having both 440 and ICD-9
Consequently, we were interested in determining code 414 [coronary atherosclerosis]). Seventy-one partic-
whether nicotine dependence itself is a possible inde- ipants were coded as having 414 only. Although there is
pendent predictor of atherosclerosis. This may provide limited data, the pathologic process and effect of risk
insights into the etiology of heart disease, but also has factors for coronary atherosclerosis may differ from that
potentially important public health implications in iden- for atherosclerosis in the abdominal location of the aor-
tifying smokers who are at the greatest risk and targeting tic artery, where most aortic aneurisms occur [24]. Con-
prevention programs towards them. sequently, the analysis also included aortic and coronary
atherosclerosis in subgroup analysis. Control subjects
Methods were randomly selected by a 2:1 ratio to cases from par-
The National Lung Screening Trial (NLST) was con- ticipants without atherosclerosis. Controls were matched
ducted to compare the detection rates of lung cancer to cases by age (+/− 5 years), sex, race, study center,
using low-dose helical (spiral) computed tomography smoking status (current/ex-smoker), years of smoking
(CT) vs. standard chest X-ray in a high-risk population (+/− 2 years) and cigarettes per day (+/− 2). A total of
of over 53,454 middle aged to elderly current or former 166 cases and 286 matched controls were included in
heavy smokers. The methods and materials including the dataset. The matching process was performed using
consent procedures have been previously described in R program language version 3.4.4 (R Foundation). Base
detail [19], including questionnaire data on age, sex R software via direct programming was used for match-
demographics and self-reported medical conditions such ing and no specific matching packages were used.
as hypertension and diabetes. The NLST population was
self-referred. As part of the NLST, a separate protocol Statistical analysis
was conducted by the American College of Radiology Conditional logistic regression was conducted to deter-
Imaging Network (ACRIN) to develop and maintain a mine the relationship with TTFC using SAS statistical
biomarker repository to test biomarkers that assist or re- software version 9.4 (SAS Institute, Cary, NC, USA). In-
place imaging for early detection of lung cancer. Serial dicator variables were used to code the associations
blood, sputum, and urine samples were collected from using TTFC≤5 min as the reference category, relative to
10,300 NLST ACRIN participants. The ACRIN partici- the categories of 6–29 min, 30–60, and > 1 h. This refer-
pants also completed an additional questionnaire that ence category was selected since the there were relatively
included an assessment of nicotine dependence, includ- few subjects who smoked > 1 h and the goal was to de-
ing questions on smoking after waking. (A PDF version termine if delayed smoking is a potential preventative
of the questionnaire is available via ACRIN website at behavior. An alternative model substituted the Fager-
https://www.acrin.org/Default.aspx?tabid=282). High strom Score, which can be calculated from the 6-item
resolution computed tomography has been used for Fagerstrom Test for Nicotine Dependence [25] and in-
screening coronary artery calcium, but chest CT per- cludes TTFC as one of its most heavily weighted items.
formed for lung cancer screening has been adapted for Initial models examined the potentially confounding
coronary calcium detection [20] and can reveal a num- effects of other tobacco factors including cigarette brand
ber of other abnormalities for conditions other than lung (e.g. Menthol (yes/no), pipe use (ever/never), and cigar
cancer. Radiographically detected coronary artery calcifi- use (ever/never). None of these factors were predictive
cation in the NLST and CT screening in general using of atherosclerosis risk. The final models were adjusted
chest CT can detect the presence and extent of subclin- for body mass index (continuous), reported past diagno-
ical atherosclerotic plaques which potentially could be ses of diabetes (categorical), hypertension (categorical)
used to develop medical intervention strategies to and myocardial infarction (categorical). Matched odds
Zhu et al. BMC Public Health (2019) 19:103 Page 3 of 6

ratios (OR) and 95% confidence intervals (CI) were deter- significantly lower with OR = 0.24 (95% CI 0.08, 0.69).
mined. Separate models were developed for ICD-9414, There was no association between diabetes and heart at-
and for ICD-9440 (includes participants with co-diagnosis tack with aortic atherosclerosis. The risk associated with
of 414). All statistical tests were two-sided and the signifi- hypertension (OR = 2.34) was statistically significant.
cance level used was 0.05. There was a significant inverse association between BMI
and risk (OR = 0.93). Limiting the analysis to ICD 440
Results only, the associations were very similar. For example, the
The basic demographic characteristics of the participants odds ratio for TTFC > 60 min was 0.30 (95% CI 0.08,
are shown in Table 1. Participants were very similar with 1.06). None of the TTFC categories were associated with
respect to the levels of the matching variables. About coronary atherosclerosis (Table 2). None of the other
40% of participants were women and 99% were white. medical risk factors were associated with coronary ath-
Over 36% held college degrees. erosclerosis, except for diabetes (OR = 2.58).
Table 2 shows the relationship between TTFC and ath-
erosclerosis. Compared to subjects who smoked ≤5 min
after waking, there was no significant relationship be- Discussion
tween categories of TTFC and atherosclerosis risk. The These findings show that a behavioral measure of nico-
risk for the greatest contrast, i.e. > 60 min, was 0.49 (95% tine dependence, the TTFC, is significantly associated
CI 0.24, 1.00). In an alternative model replacing TTFC with the risk of aortic atherosclerosis among long-term
with the Fagerstrom Score, the score variable was not heavy smokers. Subjects who delayed smoking for more
significant (p = 0.32). A significant association was ob- than 60 min had a 0.24 risk compared to subjects who
served for hypertension (OR = 1.78) but not for BMI, smoked within 5 min after waking. Atherosclerosis is an
diabetes and myocardial infarction. In sex-specific ana- asymptomatic progressive disease that may become
lyses, the results were similar for men and women. symptomatic with the development of pain in the chest
The risks were examined separately for subjects with or extremities, or loss of physical function. The cases
aortic atherosclerosis (ICD 440 and 440 + 414). Com- that were newly diagnosed in the NLST are assumed to
pared to subjects who smoked ≤5 min after waking, be asymptomatic. An analysis of ICD codes from the
there was no significant relationship with the TTFC cat- medical evaluation of subjects in this dataset did not
egories 6–29 min and 30–60 min. The risk of having aor- find symptomatic conditions associated with advanced
tic atherosclerosis for those with TTFC > 60 min was atherosclerosis (e.g. angina).
There is evidence that the level of nicotine dependence
Table 1 Baseline characteristics of cases and matched controls, in smokers, as measured by TTFC and the Fagerstrom
NLST-ACRIN participants Test for Nicotine Dependence, is associated with cardio-
Cases N = 166 Controls N = 286 vascular disease and respiratory disorders in the Na-
Mean age 63.0 62.6 tional Health and Wellness Survey [26]. The findings are
Sex (female, %) 39.8 38.5 cross-sectional and represent comorbid conditions ra-
Race (white, %) 98.8 98.6 ther than causal associations. The specific cardiovascular
Years of Education (%) diseases were not described but the findings suggest that
like COPD and cancer, less addicted smokers have lower
<8 1.8 1.1
rates of cardiovascular and respiratory disease. The
9–11 4.8 5.4
current findings from NLST-ACRIN appear to be con-
12 21.8 23.7 sistent in that a later time to first cigarette is associated
13–16 31.5 33.4 with a reduced risk of aortic atherosclerosis, which is an
≥ 16 40.0 36.3 independent predictor of cardiovascular disease events
Smoking status (current %) 51.8 53.0 [27]. The association in this study is apparent even after
careful matching for cigarette smoking history. The as-
Mean cigarettes per day 27.1 26.7
sociation between TTFC and atherosclerosis was found
Mean pack-years of smoking 56.7 55.4
specifically for aortic atherosclerosis and not for coron-
Menthol (%) 16.3 21.3 ary atherosclerosis. This is consistent with other data
TTFC (%) that examined the risks of smoking history and athero-
≤ 5 min 38.0 31.1 sclerosis. In the Multi-Ethnic Study of Atherosclerosis,
6–29 min 36.1 41.0 the strength of risk factors differed between aortic and
coronary atherosclerosis, with higher risks associated
30–60 min 15.1 12.4
with aortic atherosclerosis [4]. For smoking, current
> 60 min 10.8 15.6
smokers in that study had a 3.3 increased risk of aortic
Zhu et al. BMC Public Health (2019) 19:103 Page 4 of 6

Table 2 Time to first cigarette and other risk factors for atherosclerosis in long-term heavy smokers
Effect Odds ratios and their 95% CIs
All matched samples Aortic Atherosclerosisa Coronary atherosclerosis only
N = 166 cases, 286 controls N = 95 cases, 164 controls N = 71 cases, 122 controls
TTFC
≤ 5 min Reference Reference Reference
6–29 min 0.72 (0.44–1.16) 0.54 (0.27–1.10) 0.9 (0.45–1.82)
30–60 min 0.94 (0.49–1.82) 1.08 (0.46–2.52) 0.9 (0.29–2.74)
> 60 min 0.49 (0.24–1.00) 0.24 (0.08–0.69) 1.27 (0.43–3.74)
BMI 0.95 (0.91–1.00) 0.93 (0.86–0.99) 0.98 (0.91–1.05)
Diabetes 1.45 (0.79–2.64) 0.58 (0.20–1.68) 2.58 (1.16–5.76)
Hypertension 1.78 (1.15–2.74) 2.34 (1.25–4.38) 1.36 (0.72–2.59)
Heart Attack 1.22 (0.70–2.13) 1.58 (0.71–3.52) 0.98 (0.42–2.29)
a
All estimates were adjusted for the other covariates in the model. Includes 40 cases with co-diagnosis of coronary atherosclerosis

atherosclerosis compared to never smokers, and a 1.51 LDL/HDL ratio [35]. An earlier TTFC was also associ-
increased risk for coronary atherosclerosis. ated with having high cholesterol levels (> 200 mg/dL).
The strong statistical associations between early TTFC The mechanism for this association is unknown. In ex-
and lung and other cancers have more recently been ex- perimental animals, oral nicotine increases LDL and de-
tended to COPD and, at least in this study, aortic ath- creases the HDL/total cholesterol ratio through
erosclerosis. The mechanisms underlying these impaired clearance of LDL from the plasma [36, 37]. A
associations are unknown, but are noteworthy in that a forth possible explanation as an alternative to TTFC as a
simple measure of behavior has a strong association with marker of smoking intensity is that a cigarette smoked
a number of distinct pathologies. The TTFC appears to immediately after waking is more toxic than when
be a predictor of both malignant and nonmalignant smoked later in the day, raising the intriguing hypothesis
smoking-associated disease. One possible explanation that delaying the first cigarette smoked for an hour or
for these findings is that the TTFC may reflect the inten- more may substantially decrease the risk of aortic ath-
sity and dose of smoking, and is strongly correlated with erosclerosis. Our data indicate a significant decrease in
biomarkers of tobacco smoke constituents [28, 29]. The risk when delaying for an hour or more. Delaying for
mechanisms of cigarette smoke-induced cardiovascular less than one hour had no beneficial effect. Delaying the
disease are not well understood but likely involve in- first cigarette could be a potential preventative strategy.
flammation [30]. Smoking cessation and lighter vs. heav- Cigarette smoke exposure leads to an adaptive response
ier smoking is associated with lower markers of characterized by increased synthesis of the major intra-
inflammation such as glutathione and myeloperoxidase cellular antioxidant, glutathione (GSH). Evidence sug-
[31, 32]. Nicotine dependence itself, independent of gests diurnal variation in GSH production in mammals
smoking amount, may have pro-inflammatory effects. [38]. Human studies are needed to determine if GSH re-
Higher levels of nicotine dependence are found in per- sponse to smoking varies by time after waking.
sons with psychiatric comorbidities including major de- In other findings from this study, the association of a
pressive and mood disorders [33]. Depression is decreased risk of aortic atherosclerosis with increasing
associated with an increase in oxidative stress and dam- body mass index confirm a recent autopsy series that
age to neurological processes. Depressed smokers have higher BMI was associated with less severe aortic ath-
significantly higher levels of oxidative and inflammatory erosclerosis [39]. BMI was unrelated to coronary athero-
biomarkers than non-depressed smokers [34]. Under this sclerosis in the current study. There are mixed findings
hypothesis, an alternative explanation for smoking inten- from forensic data on obesity and lower incidence/sever-
sity as the cause for an earlier TTFC increasing (aortic) ity of coronary atherosclerosis [40, 41].
atherosclerosis risk would be increased oxidative stress Strengths of the study included the very large data set
associated with stress or depression that characterizes that allowed for multiple and highly refined matching
higher levels of nicotine dependence. An early time to criteria that allowed us to isolate the independent effect
first cigarette has also been related to lipid levels. In an of TTFC. Controls were matched to cases on not just a
analysis of four consecutive waves of the National Health range of smoking history variables but to a very tight
and Nutrition Survey (NHANES), an earlier TTFC was range for number of cigarettes per day. This process
significantly associated with lower HDL levels, a lower minimizes any residual confounding due to smoking
Zhu et al. BMC Public Health (2019) 19:103 Page 5 of 6

history. We further controlled for major risk factors for Acknowledgements

atherosclerosis including body weight, diabetes, hyper- Not applicable.

tension and heart attack. However information on exer- Funding

cise and diet was not collected and it was not possible to This work was supported by the National Cancer Institute at the National
control for these potential confounders. Information was Institutes of Health (R03 CA201951). The content is solely the responsibility of
the authors and does not necessarily represent the official views of the
collected on alcohol use but was missing for many of National Institutes of Health.
the participants. The data on atherosclerosis medical risk The funding organizations had no role in the design and conduct of the
factors such as hypertension and diabetes was based on study; collection, management, analysis, and interpretation of the data;
preparation, review, or approval of the manuscript; or decision to submit the
self-report and not a medical diagnosis. However valid- manuscript for publication.
ation studies in United States populations have shown
reasonable agreement between self-reports and medical Availability of data and materials
diagnosis for hypertension, MI, and stroke (κ = 0.71– The data for this study are kept at the Penn State College of Medicine. The
datasets generated and analyzed during the study are not publicly available
0.80) [42], although agreement for hypertension has also due to the terms of agreement consent with the National Lung Cancer
been reported to be fair (k = 0.25) in other surveys [43]. Screening Trial.
Numerous studies have found a very high degree of ac-
Authors’ contributions
curacy of self-reported diabetes [44–46]. Atherosclerosis JZ and JM designed the study, oversaw the statistical analysis and drafted
itself may be misdiagnosed and the ICD code for athero- the manuscript. KN conducted statistical analyses of the data and JT
sclerosis, might represent a different underlying path- interpreted clinical data and assisted with the draft of the manuscript. All
authors read and approved the final manuscript.
ology. Although rare, scleroderma and Buerger’s Disease
cause hardening of the arteries. Ethics approval and consent to participate
Another possible limitation of the current study is that The study was approved by the Institutional Review Board of the
Pennsylvania State University College of Medicine. In the National Lung
the NLST participants were highly educated. About 40% Screening Trial, written informed consent was obtained from all individual
were college graduates, whereas smoking rates in the U.S. participants. The current study was conducted on a de-identified data set.
are very low in adults with a college degree. In addition,
since the ACRIN cohort sub study was conducted in a sub- Consent for publication
Not Applicable.
set of the study centers, the ACRIN participants may not
be representative of all NLSS participants. Previous analysis Competing interests
of the ACRIN cohort subset vs. the entire NLSS showed no The authors declare that they have no competing interests.
meaningful differences by age, sex, smoking history and
other demographic variables [47]. Almost all participants Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
were white, limiting our ability to generalize the findings to
published maps and institutional affiliations.
other racial and ethnic groups. In addition, lung cancer
screening guidelines are limited to smokers ages 55–79. Author details
1
Penn State College of Medicine, Department of Public Health Sciences,
We cannot make inferences about the relationship between
Pennsylvania State University, MC CH69, 500 University Drive, P.O. Box 850,
TTFC and atherosclerosis in younger and older ages. Hershey, PA 17033, USA. 2Penn State Milton S. Hershey Medical Center,
Department of Pulmonary Medicine, 500 University Drive, PO Box 850,
Hershey, PA 17033, USA.

Conclusions Received: 4 September 2018 Accepted: 9 January 2019

Atherosclerosis is a progressive disease that is asymp-
tomatic for decades. It is commonly diagnosed by angi-
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