Context.— Cigarette smoking is a powerful risk factor for incident heart disease
and stroke, but the relationship of active and passive smoking with the progression
of atherosclerosis has not been described.
Objective.— To examine the impact of active smoking and exposure to environmental
tobacco smoke (ETS) on the progression of atherosclerosis.
Design.— A longitudinal assessment of the relationship between smoking exposure
evaluated at the initial visit and the 3-year change in atherosclerosis.
Setting.— A population-based cohort of middle-aged adults from 4 communities in
the United States.
Participants.— A total of 10914 participants from the Atherosclerosis Risk in Communities
(ARIC) study enrolled between 1987 and 1989.
Main Outcome Measure.— Change in atherosclerosis from baseline to the 3-year follow-up as indexed
by intimal-medial thickness of the carotid artery assessed by ultrasound and
adjusted for demographic characteristics, cardiovascular risk factors, and
lifestyle variables.
Results.— Exposure to cigarette smoke was associated with progression of atherosclerosis.
Relative to never smokers and after adjustment for demographic characteristics,
cardiovascular risk factors, and lifestyle variables, current cigarette smoking
was associated with a 50% increase in the progression of atherosclerosis (mean
progression rate over 3 years, 43.0 µm for current and 28.7 µm
for never smokers, regardless of ETS exposure), and past smoking was associated
with a 25% increase (mean progression rate over 3 years, 35.8 µm for
past smokers and 28.7 µm for never smokers). Relative to those not exposed
to ETS, exposure to ETS was associated with a 20% increase (35.2 µm
for those exposed to ETS vs 29.3 µm for those not exposed). The impact
of smoking on atherosclerosis progression was greater for subjects with diabetes
and hypertension. Although more pack-years of exposure was independently associated
with faster progression (P<.001), after controlling
for the number of pack-years, the progression rates of current and past smokers
did not differ (P=.11).
Conclusions.— Both active smoking and ETS exposure are associated with the progression
of an index of atherosclerosis. Smoking is of particular concern for patients
with diabetes and hypertension. The fact that pack-years of smoking but not
current vs past smoking was associated with progression of atherosclerosis
suggests that some adverse effects of smoking may be cumulative and irreversible.
CIGARETTE SMOKING is widely accepted as a major risk factor for the
development of clinical cardiovascular disease resulting from direct effects
on atherosclerosis and hemostasis.1 Cross-sectional
studies have shown a relationship between active smoking and carotid artery
atherosclerosis in population-based cohorts.2,3
In addition, atherosclerosis has been associated with both current3 and past4 exposure
to environmental tobacco smoke (ETS). Previous longitudinal studies in small
populations have examined the association of smoking with the progression
of atherosclerosis with mixed results. While an association was observed between
duration of smoking and progression of carotid atherosclerosis among 100 Finnish
men,5 no difference in the rate of atherosclerosis
progression was shown between current smokers and those not currently smoking
cigarettes in 3 other studies.6-8
To our knowledge, no report has examined the impact of smoking, including
ETS, in a large longitudinal cohort.
Systematic differences in other atherosclerosis risk factors and behaviors
between smokers and never smokers may confound the relationship between smoking
and atherosclerosis. While passive smoking has been associated with clinical
cardiovascular diseases,9-11
the association between ETS exposure and atherosclerosis has only been shown
in cross-sectional analyses.3,4
This article assesses the relationship of active smoking and exposure to ETS
with a 3-year change in carotid artery intimal-medial thickness (IMT).
The Atherosclerosis Risk in Communities (ARIC) study is a population-based
investigation of approximately 16000 persons aged 45 to 64 years at the baseline
visit conducted between 1987 and 1989. Approximately 4000 participants were
examined at each of the centers in Minneapolis, Minn; Washington County, Maryland;
Jackson, Miss; and Forsyth County, North Carolina. Participants were reexamined
after 3 years, and this report will focus on the atherosclerosis progression
during that time. Further details on the ARIC study design have been published
elsewhere.12
The primary outcome variable in this article is "progression of atherosclerosis"
between 2 visits approximately 3 years apart. There has been growing acceptance
of B-mode real-time ultrasound to serve as a surrogate measure of atherosclerosis,
offering a noninvasive index of atherosclerosis that has proven reliable and
valid.13-20
In this study, ultrasound was used to assess the common carotid IMT in a 1-cm
segment proximal to the dilation of the carotid bulb. Assessments were made
at the baseline visit and at a follow-up visit approximately 3 years later.
A total of 6 sites were examined by ultrasound imaging, and 3 measurements
were taken in each carotid artery at different angles of interrogation. Additional
measurements of carotid IMT were made over the 1-cm segment proximal to the
flow divider (the "bifurcation") and the 1-cm distal to the flow divider in
the internal carotid artery. Measurements at these sites were more frequently
missing and had more variability; hence, we restricted our analysis to the
common carotid artery. The ultrasound images were recorded on videotape and
forwarded to a central reading center for interpretation. The ultrasound readers
were masked from patient characteristics, including smoking status. For each
of the 6 images from the common carotid artery, attempts were made to measure
the IMT over a 1-cm distance at 1-mm increments (a total of up to 11 measurements);
the mean wall thickness for each segment was calculated. A mean common carotid
IMT adjusted for reader differences and reading date was then calculated.
This protocol produces a single index of atherosclerosis with improved precision
provided by the averaging of multiple IMT assessments. This approach is similar
to the approaches used in a wide range of epidemiologic studies13-17
and clinical trials.18-20
Specific details of the ultrasound scanning14
and reading15 protocols are provided elsewhere.
Smoking history was assessed by participant self-report. For these analyses,
participants were first classified as current smokers, past smokers (more
than 100 cigarettes in the past), and never smokers. Exposure to ETS was assessed
using the following question: "During the past year, about how many hours
per week, on average, were you in close contact with people when they were
smoking? For example, in your home, in a car, at work, or other close quarters."
Never smokers and past smokers were classified as exposed to ETS if they reported
being in close contact with smokers for more than 1 hour per week. This categorization
yields 5 strata: current smokers, past smokers exposed to ETS, past smokers
not exposed to ETS, never smokers exposed to ETS, and never smokers not exposed
to ETS. Current smokers were not stratified by exposure to ETS because we
felt that exposure to active smoking would overwhelm any potential effect
of ETS in this group. Pack-years of exposure (number of packs per day multiplied
by years of smoking) was calculated among the current and past smoker groups.
The number of hours of ETS exposure was calculated for secondary analysis
among past and never smokers.
Methods for assessment of cardiovascular risk factors used as covariates
in these analyses have been described elsewhere,12
but we briefly describe them here. Hypertension was defined as either systolic
blood pressure greater than 140 mm Hg, diastolic blood pressure greater than
90 mm Hg, or self-reported use of antihypertensive medications. Low-density
lipoprotein cholesterol concentration was estimated using the Friedewald formula.21 Participants were defined as having diabetes if they
reported having diabetes, if they were taking blood glucose–lowering
medications, or if they had an 8-hour fasting glucose level of at least 11.1
mmol/L (200 mg/dL). Fat intake was assessed by Keys score as calculated from
a modified Willett food frequency questionnaire.22
Reported leisure-time physical activity was assessed by an interviewer-administered
questionnaire.23 Participants were categorized
as current, past, or never alcohol users based on self-report. Body mass index
was calculated as a measure of weight in kilograms divided by the square of
the height in meters.
Analyses in this report were restricted to participants who were black
or white (48 subjects who were neither black nor white were excluded); participants
who had good-quality B-mode ultrasound evaluations of the common carotid artery
both at the baseline and at the 3-year follow-up (the first 1255 subjects
at the beginning of visit 1 were excluded because of less than adequate ultrasound
examinations, 775 with ultrasound data missing from visit 1, 1256 who failed
to return for visit 2, and 395 who were missing ultrasound data from visit
2); participants who were not current users of other tobacco products (304
current pipe, cigar, and cigarello smokers were excluded); and participants
who responded to the smoking history questionnaire at the baseline visit (845
were excluded). After exclusions, 10914 participants remained for these analyses.
Statistical analyses were performed using linear regression analysis.
The primary independent variable was the smoking category, while the outcome
variable was the progression of atherosclerosis as reflected by the difference
in IMT as measured at the baseline and follow-up (3 years later) visits. The
relationship between smoking category and progression of atherosclerosis was
explored using 3 models that were specified a priori. In the first model,
the effects of smoking category on progression of atherosclerosis were estimated
after adjustment for age, race, sex, and baseline IMT (demographic model).
The second model adjusted for these factors and also for hypertension, low-density
lipoprotein cholesterol, prevalent coronary heart disease (CHD), and diabetes
(cardiovascular risk factor model). The final model adjusted for all preceding
factors and also for Keys score, education, leisure-time physical activity,
body mass index, and alcohol intake (lifestyle model). Secondary analyses
were also performed to assess the relationship between pack-years of smoking
and atherosclerosis progression in current and past smokers and the relationship
between the number of hours of ETS exposure and progression of atherosclerosis
in past and never smokers. These models included all the variables described
in the lifestyle model. Two-way interactions between smoking strata and other
risk factors were also assessed.
Of the 10914 participants, 2956 (27%) were current smokers, 1849 (17%)
were past smokers exposed to ETS, 1344 (12%) were past smokers not exposed
to ETS, 2449 (22%) were never smokers exposed to ETS, and 2316 (21%) were
never smokers not exposed to ETS (Table
1). No differences were observed in the mean age across the smoking
groups. Past smokers were much more likely to be white and male, while women
were more likely to be never smokers. The need for covariate adjustment is
supported by the dramatic differences in the prevalence of cardiovascular
risk factors and lifestyle variables. Because of these differences in risk
factors across smoking categories, the comparison of unadjusted atherosclerosis
progression rates across the smoking strata (which shows increased progression
rates with increased cigarette smoke exposure) should be made cautiously.
The actual mean time between the 2 ARIC visits was 1062 days, with an SD of
74 days, so the 3-year visit interval was well performed for most participants
(and deviations are unlikely to influence results).
Table 2 shows mean IMT progression
(and SEs) after adjustment for demographic characteristics (model 1), cardiovascular
risk factors (model 2), and lifestyle variables (model 3). After adjustment
for demographic factors, a consistent relationship between smoking exposure
and progression of atherosclerosis is apparent. In the demographic model,
the progression rate was lowest (27.0 µm per 3 years) for never smokers
not exposed to ETS and increased in never smokers exposed to ETS (33.2 µm
per 3 years), in past smokers not exposed to ETS (32.5 µm per 3 years),
and in past smokers exposed to ETS (39.6 µm per 3 years). The highest
progression rate was observed in current smokers (41.0 µm per 3 years).
Exposure to ETS was estimated to increase the progression rate by 6.7 µm
per 3 years (the average difference between those exposed and not exposed
to ETS among never and past smokers), a difference that proved significant
(P=.003). Past smokers were estimated to progress
an average of 5.9 µm per 3 years more rapidly than never smokers, and
current smokers were estimated to progress an average of 4.9 µm per
3 years more rapidly than past smokers (P=.01 and P =.05, respectively). Further adjustment for cardiovascular
risk factors and lifestyle variables proved (1) to make the ordered response
between smoking and progression of IMT more consistent, (2) to marginally
decrease the estimated ETS effect on progression of IMT from 6.7 µm
per 3 years to 5.9 µm per 3 years, (3) to increase marginally the estimated
difference in progression of IMT between past and never smokers from 5.9 µm
per 3 years to 7.0 µm per 3 years, and (4) to increase the estimated
difference in progression between current and past smokers from 4.9 µm
per 3 years to 7.3 µm per 3 years. This further adjustment for cardiovascular
risk factors and lifestyle variables made the relationship between increased
progression of atherosclerosis and smoking exposure clear and consistent,
and the significance of the effects between groups (ie, the ETS effect, etc)
persisted after adjustment (Figure 1).
The progression rate for current smokers was estimated to be 43.0 µm,
and the average progression rate of the 2 groups of never smokers was 28.7
µm ([31.6 µm+25.9 µm]/2), implying that a 50% increase in
the progression of atherosclerosis is attributable to current smoking ([43.0
µm−28.7 µm]/28.7 µm).
Interactions between smoking exposure and all covariates were also evaluated
(after adjustment for all other factors included in the final model including
lifestyle variables). A clear interaction was observed between smoking category
and diabetes (P=.004), hypertension (P=.04), and prevalent CHD (P=.04); otherwise,
differences between smoking strata were consistent across strata defined by
other risk factors (P>.05). The observed interaction
with diabetes reflects larger differences at each step of smoking exposure
in participants with diabetes as compared with their counterparts without
diabetes (Table 3). For participants
with hypertension, a marginally significant interaction was largely a product
of a substantially faster rate of progression for current smokers with hypertension
(58.0 µm per 3 years) than participants in other smoking categories
(34.7 µm per 3 years to 42.8 µm per 3 years). A similar increase
was not observed for current smokers without hypertension, where progression
rates were similar to those observed for past smokers (36.8 µm per 3
years compared with 36.9 µm per 3 years for past smokers exposed to
ETS and 30.8 µm for past smokers not exposed to ETS). This suggests
that the impact of smoking exposure is larger among participants with diabetes
than for participants without diabetes, and the impact of current smoking
may be particularly large for participants with hypertension. While the interaction
for prevalent CHD was marginally significant (P=.04),
the relatively small proportion of participants with prevalent CHD who never
smoked (<3% of the population that never smoked) resulted in unstable estimates
for participants with prevalent disease, making the significant interaction
more likely a chance happening.
In a secondary analysis, the impact of pack-years of smoking on progression
rates was estimated for current and past smokers (with and without exposure
to ETS). All analyses were performed in the lifestyle model, which contained
adjustments for demographic characteristics, cardiovascular risk factors,
and lifestyle variables. There was no interaction between pack-years of exposure
and smoking status (P=.33), suggesting increases
in pack-years of exposure had a similar impact on the progression rates for
current smokers, past smokers exposed to ETS, and past smokers not exposed
to ETS. However, in models with both pack-years and smoking status category
included, pack-years of exposure was highly significant (P<.001), while smoking status category was not (P=.11). This would suggest that the primary explanation of differences
between these smoking groups was the increasing exposure to smoking as measured
by pack-years. Note that in Table 1,
the mean pack-years for past smokers not exposed to ETS was 19, as compared
with 24 for past smokers exposed to ETS and 31 for current smokers.
In addition to assessing the impact of the presence or absence of exposure
to ETS, the ARIC investigators also asked those exposed to ETS to estimate
the number of hours per week that they were in the immediate presence of smokers.
These data were analyzed in the 2 ETS groups (never smokers exposed to ETS
and past smokers exposed to ETS) to assess if those participants exposed to
more hours of ETS per week had a faster progression rate than those exposed
to fewer hours of ETS. In an analysis conducted using the lifestyle model,
there was no evidence of a dose-response relationship between increasing weekly
hours of ETS exposure and increased progression rates (P=.38) among those exposed to ETS.
These longitudinal ARIC data show a consistent relationship between
increasing exposure to cigarette smoke and greater progression of carotid
atherosclerosis. Large differences were observed in the progression rates
between past smokers and never smokers (7.0 µm per 3 years or 24% [7.0/([31.6+25.9]/2)]
greater) and in the progression rates of current and past smokers (7.3 µm
per 3 years or 20% [7.3/([38.8+32.8]/2)] greater). The increase in atherosclerosis
progression attributable to this modifiable risk factor is among the most
substantial of any of the cardiovascular risk factors assessed by the ARIC
study.24 After adjustment for demographic characteristics,
cardiovascular risk factors, and lifestyle variables, exposure to ETS was
also estimated to increase progression by 5.9 µm over a 3-year period.
The difference in progression rates between those participants least exposed
to cigarette smoke (never smokers not exposed to ETS) and those most exposed
(current smokers) was 17.1 µm per 3 years. Since exposure to ETS was
estimated to increase progression of atherosclerosis by 5.9 µm per 3
years, the impact of exposure to ETS was 34% (5.9/17.1) as great as the impact
of active smoking on the progression of atherosclerosis.
Some groups argue that the exposure to passive smoke measured in "cigarette
equivalents" rarely exceeds a single cigarette a day.25
However, as reported by Glantz and Parmley,9
the content of ETS is potentially more toxic than "mainstream" smoke, and
the cardiovascular system of an individual exposed to passive smoke may be
more sensitive than that of an active smoker because of the lack of a fully
developed protective response. Thus, the increased progression of atherosclerosis
associated with ETS exposure should be considered in light of the estimated
30000 to 60000 annual deaths in the United States attributable to ETS.9-11
Differences in the profile of cardiovascular risk factor burden could
potentially confound differences in atherosclerosis progression between active
and passive smokers and between those exposed and those not exposed to ETS.26 However, adjustment for a wide range of other cardiovascular
risk factors and lifestyle variables had only modest impact on the estimated
effect of exposure to ETS, reducing it by only 12%, from an estimated 3-year
progression rate of 6.7 µm to 5.9 µm. Thus, it is unlikely that
further control for other risk factors would explain the ETS effect.
Progression of atherosclerosis among past smokers was higher than among
never smokers—despite past smokers' nonsmoking status over the period
during which progression was measured. In support of this striking observation,
our secondary analysis found no difference between past and current smokers
after controlling for the number of pack-years of exposure. Atherosclerosis
progression appears to be largely related to the pack-years of cigarette exposure
and not to present smoking status. These 2 observations suggest that the effect
of smoking on atherosclerosis progression may be cumulative, proportional
to lifetime pack-years of exposure, and perhaps irreversible. If this is true,
the primary benefit from quitting smoking on the progression of atherosclerosis
would be to prevent further accumulation of exposure. This hypothesis is not
consistent with data from previous cross-sectional reports of clinical populations
that have suggested the rate of progression slows in people who quit relative
to those who continue to smoke.27 Given that
cigarette smoking may increase the risk of cardiovascular heart disease by
promoting atherosclerosis progression and other triggering factors (eg, by
changes in hemostasis), our observations are not inconsistent with clinical
data suggesting that the risk of coronary events in many smokers returns to
that of never smokers 3 to 5 years after quitting.28
Alternatively, it is possible that past smokers have stopped their habit because
of smoking-related respiratory and cardiovascular symptoms. If this is the
case, then past smokers would have a higher average atherosclerosis burden
and may be more likely to continue to progress at a higher rate, one that
is indistinguishable from current smokers. However, this explanation seems
unlikely since covariate adjustment for cardiovascular risk factors, including
prevalent cardiovascular disease, actually increased the difference in the
progression rates between past and current smoking groups.
A greater impact of smoking on IMT progression was observed in participants
with diabetes compared with those without diabetes. That smoking may accelerate
the atherosclerotic process in participants with diabetes is plausible, given
that participants with diabetes are more likely to have widespread vascular
damage as a consequence of their disease.29
In a 10-year follow-up report of the National Health and Nutrition Examination
Survey I cohort, the relative risk (RR) for CHD mortality among 492 patients
with diabetes was 2.5 for current smokers compared with never smokers; the
RR for smoking was 1.7 among nearly 12000 subjects without diabetes.30 Among men screened for the Multiple Risk Factor Intervention
Trial, the 12-year cardiovascular disease death rate increased more steeply
across increasing levels of cigarettes per day for men with diabetes than
for men without diabetes.31 Both Gay et al32 and Suarez and Barrett-Connor33
have reported an important interaction between smoking and diabetes status
in relation to multiple measures of morbidity and mortality. These authors
suggest that the vascular damage resulting from both diabetes and smoking
may be a possible mechanism compounding this effect. The finding of a greater
impact of smoking on progression of IMT in participants with diabetes as compared
with participants without diabetes is consistent with these reports of morbidity
and mortality. Participants with hypertension are also likely to have similarly
widespread disease, and current smoking may similarly provide an impetus for
more rapid progression. It is not clear why an increasing progression rate
was not observed for participants with hypertension who smoked in the past.
Several potential limitations should be considered in assessing this
report. First, in secondary analyses we found no relationship between the
number of hours of ETS exposure and the progression of atherosclerosis. We
believe that while it is relatively easy for a participant to determine whether
they are exposed to ETS or not, quantifying the number of hours per week is
a difficult task.34 In addition, we asked the
participant to report the average weekly exposure and did not collect data
on specific sources (eg, home, work, etc). It is possible that the ability
to quantify the amount of exposure differs between the sources, again introducing
differential measurement error on the amount (but not presence) of exposure
to ETS. For both these reasons, our failure to demonstrate a dose-response
relationship between ETS exposure and progression of atherosclerosis may be
the result of a measurement error in the quantification of ETS. Second, after
control for pack-years of exposure, there was no significant difference between
past smokers exposed to ETS and past smokers not exposed to ETS. We cannot
be sure whether the difference in progression of atherosclerosis between these
2 past-smoking groups should be attributed to increased pack-years or to exposure
to ETS. However, the similarity of the ETS effect in past and never smokers
supports the existence of the ETS effect. Finally, it is possible that measurement
error, particularly in the assessment of IMT, could introduce bias or noise
in the estimates of progression rates. However, this index of atherosclerosis
has proven to be a powerful predictor of incident coronary events in this
same population, with the prevalence among women increasing from 0.6 per 1000
person-years for participants with IMT of less than 600 µm as compared
with 11.7 per 1000 person-years for participants with IMT of greater than
1000 µm. Prevalence increased in men from 3.0 per 1000 to 12.9 per 1000
for the same contrast of IMT.35
In conclusion, these data represent the first report, to our knowledge,
from a large population-based study of the impact of active smoking and exposure
to ETS on the progression of atherosclerosis. Active smoking was found to
play a major role in the progression of atherosclerosis, as did the duration
of smoking measured by pack-years of exposure. The impact of exposure to ETS
on atherosclerosis progression was not only detected but was also surprisingly
large, increasing the progression rate by 11% above those not so exposed.
Smoking especially increased atherosclerosis progression rates among participants
with diabetes and hypertension. Finally, these data suggest that the effects
of smoking on the progression rate of atherosclerosis may be both cumulative
and irreversible.
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