Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle age cohort

Abstract

Lung function impairment may be a risk factor for cardiovascular disease (CVD) events.
To determine the relationship between the severity of airflow obstruction based on modified Global Initiative on Obstructive Lung Disease (GOLD) criteria and the prevalence and incidence or recurrence of CVD in a cohort of US adults, aged 45-64 years, from 1987 to 2001.
We analysed data from 14 681 adults using logistic regression to determine the cross sectional association between lung function impairment and prevalent CVD at baseline and Cox regression to examine the prospective association of lung function impairment at baseline with CVD over 15 years of follow-up. Models were adjusted for age, sex, race, smoking, comorbid hypertension and diabetes, cholesterol levels and fibrinogen level.
At baseline, the crude prevalence of CVD was higher among subjects with GOLD 2 (OR 2.9, 95% CI 2.4 to 3.6) and GOLD 3 or 4 chronic obstructive pulmonary disease (COPD) (OR 3.0, 95% CI 2.0 to 4.5), compared with normal subjects. These relative risks were greatly reduced after adjusting for covariates (OR 1.4, 95% CI 1.1 to 1.8 for GOLD 2 and OR 1.3, 95% CI 0.8 to 2.1 for GOLD 3 or 4). Similarly, the association between COPD and risk of incident or recurrent CVD was much stronger in the unadjusted models (hazard ratio (HR) 2.4, 95% CI 2.1 to 2.7 for GOLD 2 and 2.9, 95% CI 2.2 to 3.9 for GOLD 3 or 4) than in the adjusted ones (HR 1.2, 95% CI 1.03 to 1.4 for GOLD 2 and 1.5, 95% CI 1.1 to 2.0 for GOLD 3 or 4).
We observed a crude association between lung function impairment and prevalent and incident or recurrent CVD that was greatly reduced after adjusting for covariates, including age, sex, race, smoking, comorbid hypertension and diabetes, cholesterol levels and fibrinogen level. These data suggest that this association may be, in part, mediated through established CVD risk factors included in our adjusted models.

Full text

Relationship between lung function impairment and
incidence or recurrence of cardiovascular events in a
middle-aged cohort
A K Johnston,
1
D M Mannino,
1
G W Hagan,
2
K J Davis,
3
V A Kiri
2
cSupplementary tables 1–3 are
published online only at http://
thorax.bmj.com/content/vol63/
issue7
1
Division of Pulmonary and
Critical Care Medicine,
University of Kentucky Medical
Center, Lexington, Kentucky,
USA;
2
GlaxoSmithKline R&D,
Greenford, UK;
3
GlaxoSmithKline Research and
Development, Research Triangle
Park, North Carolina, USA
Correspondence to:
Dr D M Mannino, Division of
Pulmonary and Critical Care
Medicine, University of Kentucky
Medical Center, 800 Rose
Street, MN 614, Lexington, KY
40536; dmannino@uky.edu
Received 30 July 2007
Accepted 23 December 2007
Published Online First
1 February 2008
ABSTRACT
Introduction: Lung function impairment may be a risk
factor for cardiovascular disease (CVD) events.
Objective: To determine the relationship between the
severity of airflow obstruction based on modified Global
Initiative on Obstructive Lung Disease (GOLD) criteria and
the prevalence and incidence or recurrence of CVD in a
cohort of US adults, aged 45–64 years, from 1987 to
2001.
Methods: We analysed data from 14 681 adults using
logistic regression to determine the cross sectional
association between lung function impairment and
prevalent CVD at baseline and Cox regression to examine
the prospective association of lung function impairment at
baseline with CVD over 15 years of follow-up. Models
were adjusted for age, sex, race, smoking, comorbid
hypertension and diabetes, cholesterol levels and fibrino-
gen level.
Results: At baseline, the crude prevalence of CVD was
higher among subjects with GOLD 2 (OR 2.9, 95% CI 2.4
to 3.6) and GOLD 3 or 4 chronic obstructive pulmonary
disease (COPD) (OR 3.0, 95% CI 2.0 to 4.5), compared
with normal subjects. These relative risks were greatly
reduced after adjusting for covariates (OR 1.4, 95% CI 1.1
to 1.8 for GOLD 2 and OR 1.3, 95% CI 0.8 to 2.1 for GOLD
3 or 4). Similarly, the association between COPD and risk
of incident or recurrent CVD was much stronger in the
unadjusted models (hazard ratio (HR) 2.4, 95% CI 2.1 to
2.7 for GOLD 2 and 2.9, 95% CI 2.2 to 3.9 for GOLD 3 or
4) than in the adjusted ones (HR 1.2, 95% CI 1.03 to 1.4
for GOLD 2 and 1.5, 95% CI 1.1 to 2.0 for GOLD 3 or 4).
Conclusion: We observed a crude association between
lung function impairment and prevalent and incident or
recurrent CVD that was greatly reduced after adjusting for
covariates, including age, sex, race, smoking, comorbid
hypertension and diabetes, cholesterol levels and fibrino-
gen level. These data suggest that this association may
be, in part, mediated through established CVD risk factors
included in our adjusted models.
Ischaemic heart disease and cerebrovascular disease
are currently the top two leading causes of death
worldwide, responsible for more than one-fifth of all
deaths, and are projected to remain so until 2020.
12
Chronic obstructive pulmonary disease (COPD) is
expected to be the third leading cause of worldwide
mortality by 2020 and the fifth leading cause of
disability adjusted life years lost.
2
This triad of
cardiac disease, stroke and COPD have an enormous
economic, medical and social burden on adults in
the USA.
3–10
Processes that result in restriction on
spirometry, which comprise interstitial lung dis-
eases, diabetes mellitus, congestive heart failure and
other causes of small lung volumes, also impart
significant morbidity and mortality in the US.
67
The role of systemic inflammation and systemic
inflammatory markers such as C reactive protein,
fibrinogen and tumour necrosis factor amay be
important in all of these disease processes.
11–15
Cardiovascular mortality has been shown to be
up to twofold higher in patients with COPD than
in a matched population without COPD.
516
Previous studies have linked lung function impair-
ment with the risk of developing cardiovascular
disease and stroke, even after adjusting for factors
such as body mass index (BMI), physical activity,
hypertension, diabetes and smoking status.
5 17–23
However, lung function impairment in these
studies has been classified by quartiles of forced
expiratory volume in 1 s (FEV
1
) or mean FEV
1
which are not routinely used clinically to assess the
severity of impairment.
18 20 21
In 2001, the Global Initiative for Chronic
Obstructive Lung Disease (GOLD) was formed to
improve investigation and management of this
complex disease and treatment strategies have
been recommended based on GOLD staging.
24
Our goal was to examine the prevalence, incidence
and recurrence of cardiac events and stroke in the
Atherosclerosis Risk in Communities (ARIC)
cohort of adults, aged 45–64 years, and followed
from 1987 to 2001 using a modification of the
GOLD classification of lung function impairment.
METHODS
Study population
The ARIC study was initiated in 1987 as a
longitudinal, population based study of the aetiol-
ogy and clinical sequelae of atherosclerosis. Study
protocols were approved for protection of human
subjects. Participants were selected from the
entire population by probability sampling from
four US communities: Forsyth County, North
Carolina; Minneapolis, Minnesota; Washington
County, Maryland; and Jackson, Mississippi
(where only African Americans were sampled).
Specific details of the ARIC study are published
elsewhere.
25
Our analysis was limited to ARIC
participants aged 45–64 years at baseline, who
provided information on respiratory symptoms
and diagnoses, cardiovascular events or stroke,
and medical history, had lipid profiles available
and who underwent adequate pulmonary func-
tion testing at the baseline examination. Only
those participants for whom follow-up data were
available were analysed (n = 14 681).
Chronic obstructive pulmonary disease
Thorax 2008;63:599–605. doi:10.1136/thx.2007.088112 599

Pulmonary function data
Spirometry was conducted using contemporary American
Thoracic Society guidelines.
26 27
We developed sex and race
specific internal prediction equations for FEV
1
and FVC
following standard methods previously described.
28
We defined
a subject as having a respiratory symptom if they reported
cough, phlegm, dyspnoea or wheeze.
A modification of the GOLD criteria was used to classify
subjects according to their stage of COPD
24 29
: GOLD 3 or 4
(FEV
1
/forced vital capacity (FVC) ,0.70 and FEV1,50%
predicted), GOLD 2 (FEV
1
/FVC ,0.70 and FEV
1
>50 to
,80% predicted), GOLD 1 (FEV
1
/FVC ,0.70 and FEV
1
>80%
predicted), restricted (FEV
1
/FVC >70% and FVC ,80%
predicted), GOLD 0 (presence of respiratory symptoms in the
absence of any lung function abnormality) and no lung disease
(table 1). Bronchodilator response was not evaluated so
classification was based on ‘‘prebronchodilator’’ level. Only
the baseline pulmonary function data were used to stratify
participants, and they remained in these groups for interpreta-
tion of prevalent risk and incident or recurrent events.
Ascertainment of baseline cardiovascular status and incident or
recurrent events
Cardiovascular disease (CVD) events included cardiac disease
and stroke. CVD was considered present at baseline if the
subject self-reported a myocardial infarction, coronary artery
bypass graft, angioplasty, had been hospitalised for a myocardial
infarction, had evidence on the ECG of a myocardial infarction
or had a self-reported stroke at the baseline examination
(table 1).
25
Incident cardiac events were defined as a definite
or probable hospitalised myocardial infarction, coronary heart
disease death or myocardial infarction that was detected at
follow-up by ECG changes (major Q wave or a minor Q wave
with ischaemic ST-T changes or a myocardial infarction by
computerised NOVACODE criteria,
30
confirmed by side-to-side
ECG comparison) who did not meet this criterion at base-
line.
31 32
CVD recurrence was defined as a definite or probable
hospitalised myocardial infarction, coronary heart disease death
or myocardial infarction that was detected at follow-up by ECG
changes (major Q wave or a minor Q wave with ischaemic ST-T
changes or a myocardial infarction by computerised NOVACODE
criteria, confirmed by side-to-side ECG comparison) in those
participants identified as having baseline cardiovascular disease.
Stroke was defined according to published criteria related to the
occurrence and duration of neurological signs and symptoms, the
results of neuroimaging and diagnostic procedures, and treat-
ments provided.
10 33
The analysis was restricted to definite or
probable ischaemic stroke only.
Variable definitions
Participants were classified as ‘‘former smokers’’ or ‘‘current
smokers’’ based on positive responses to ‘‘Have you ever smoked
cigarettes?’’ and ‘‘Do you now smoke cigarettes?’’, respectively.
Pipe or cigar smokers were considered as ‘‘smokers’’ (ie, subjects
who denied current cigarette smoking but reported current or
former pipe or cigar smoking were considered current or former
smokers, respectively). Never smokers were defined as persons
who had not smoked more than 400 cigarettes in their lifetime
and had never smoked pipes or cigars. Diabetes mellitus was
defined as a baseline glucose level >126 mg/dl or use of a
medication for diabetes or high blood sugar. Subjects were
classified as having hypertension if they either reported a
physician diagnosis of hypertension, were on treatment for
hypertension or had evidence of hypertension at the examina-
tion (either a diastolic blood pressure >90 mm Hg or a systolic
blood pressure >140 mm Hg, based on three measurements).
BMI was calculated as weight divided by height squared (kg/m
2
),
measured at the baseline examination. Education level was
categorised as less than high school, completion of high school
or more than high school. High density lipoprotein cholesterol
(HDL-C), low density lipoprotein cholesterol (LDL-C) and
fibrinogen levels were measured in serum samples.
34
Analysis
All analyses were conducted with SAS V.9.1 (SAS Institute,
Cary, North Carolina, USA), SUDAAN V.9.0 (RTI, Research
Triangle Park, North Carolina, USA) and SPSS V.10 (SPSS,
Chicago, Illinois, USA).
Our primary outcome of interest was incidence or recurrence
of cardiac events or stroke that occurred during the study
period. Secondary outcomes were the relationship between
prevalent CVD and lung function impairment at the baseline
examination and the relationship between lung function
impairment and CVD in the study population stratified by
gender, age, race and smoking status. For CVD events, censoring
occurred on the first CVD related hospitalisation or event, death
or the date the person was last known to be alive. We developed
Cox proportional hazards models using the procedure
SURVIVAL in SUDAAN. Plots of the log–log survival curves
for each covariate were produced to ensure that the propor-
tional hazards assumptions were satisfied. Age, sex, race,
smoking status, pack-years of smoking, BMI, education level,
HDL-C, LDL-C, fibrinogen, diabetes mellitus and hypertension
at baseline were included in the adjusted models. Analyses were
also performed on subsets of subjects stratified by sex, race,
smoking status and age category, and interactions were evaluated
between these variables and our modified GOLD categories.
RESULTS
Our analysis included 14 681 of the initial 15 732 ARIC cohort
participants. Excluded subjects did not differ significantly with
regard to age, sex or smoking status (p.0.05 for all) from
Table 1 Definitions of prevalent, incident and recurrent cardiovascular
disease and lung function impairment using a modification of the Global
Initiative for Lung Disease (GOLD) criteria for chronic obstructive
pulmonary disease
Cardiovascular disease at baseline
Self-reported myocardial infarction
Coronary artery bypass graft
Angioplasty
Self-reported hospitalised for a myocardial infarction
Myocardial infarction on ECG
Self-reported prior stroke
Cardiovascular disease—incident or recurrent
New changes on ECG consistent with myocardial infarction
Definite or probable hospitalisation for myocardial infarction (validated)
Definite or probable ischemic stroke
Coronary heart disease death
Modified GOLD stages of lung disease
GOLD 3 or 4—FEV
1
/FVC ,0.70 and FEV
1
,50% predicted
GOLD 2—FEV
1
/FVC,0.70 and FEV
1
>50 to ,80% predicted
GOLD 1—FEV
1
/FVC ,0.70 and FEV
1
>80%
GOLD 0—presence of respiratory symptoms with no lung function abnormality
Restricted—FEV
1
/FVC >0.70 and FVC ,80% predicted, and no lung disease
Normal—Not in any of the above categories
FEV
1
, forced expiratory volume in 1 s; FVC, forced vital capacity.
Chronic obstructive pulmonary disease
600 Thorax 2008;63:599–605. doi:10.1136/thx.2007.088112

included subjects, but were more likely to be of black race
(p,0.01). The demographic distribution of the analysis cohort is
included in table 2. Baseline 5 year age groups were evenly
distributed from 45 to 64 years. The cohort was 55.2% female
and 74.2% white. Diabetes was present in 11.2%, hypertension
in 34.0%, overweight (BMI 25–29) in 39.4% and obesity (BMI
>30) in 27.1%. Mean HDL-C level was 52.0 (SE 0.1) mg/dl,
mean LDL-C was 137.7 (0.3) mg/dl and mean fibrinogen level
was 303.3 (SE 0.5) mg/dl.
The baseline prevalence of CVD was 6.0% and higher among
those with advanced age, male sex, presence of diabetes and
hypertension, higher BMI and lower education level (table 2).
The prevalence was also increased among current or former
smokers and related to the number of pack-years. In the
Table 2 Demographic distribution of study participants, proportion with prevalent cardiovascular disease
(CVD) at baseline, and results from univariate and multivariable logistic regression models
No (%)
With prevalent
CVD at baseline
(%)*
Univariate risk of
CVD at baseline
(OR (95% CI))
Multivariate risk of
CVD at baseline
(OR (95% CI)){
Age (y)
45–49 3913 (26.7) 105 (2.7) 1.0 1.0
50–54 3806 (25.9) 172 (4.5) 1.7 (1.3, 2.2) 1.4 (1.1, 1.8)
55–59 3591 (24.5) 264 (7.4) 2.9 (2.3, 3.6) 1.9 (1.5, 2.4)
60–64 3026 (22.9) 345 (10.2) 4.1 (3.3, 5.2) 2.3 (1.8, 3.0)
Sex
Female 8104 (55.2) 253 (3.1) 1.0 1.0
Male 6577 (44.8) 633 (9.6) 3.3 (2.9, 3.8) 2.3 (1.9, 2.7).
Race
White 10 887 (74.2) 659 (6.1) 1.0 1.0
Black 3794 (25.8) 227 (6.0) 1.0 (0.9, 1.2) 1.0 (0.8, 1.2)
Smoking status
Current smoker 4170 (28.4) 291 (7.0) 2.3 (1.9, 2.7) 0.9 (0.6, 1.4)
Former smoker 4751 (32.4) 410 (8.6) 2.9 (2.4, 3.4) 1.4 (0.9, 2.2)
Never smoker 5760 (39.2) 185 (3.2) 1.0 1.0
Pack-years
60 or more 711 (4.8) 126 (17.7) 6.1 (4.8, 7.7) 2.5 (1.6, 4.2 )
40–59 1262 (8.6) 157 (12.4) 4.0 (3.2, 5.0) 2.1 (1.3, 3.3)
20–39 2843 (19.4) 226 (8.0) 2.5 (2.0, 3.0) 1.5 (0.99, 2.4)
1–19 3434 (23.4) 145 (4.2) 1.3 (1.01, 1.6) 0.9 (0.6, 1.5)
Unknown 240 (1.6) 21 (8.8) 2.7 (1.7, 4.3) 1.7 (0.9, 3.3)
0 6191 (42.2) 211 (3.4) 1.0 1.0
Diabetes mellitus
Yes 1642 (11.2) 215 (13.1) 2.8 (2.4, 3.3) 1.8 (1.5, 2.2)
No 13 039 (88.8) 671 (5.2) 1.0 1.0
Hypertension
Yes 4992 (34.0) 485 (9.7) 2.5 (2.2, 2.9) 1.9 (1.7, 2.3)
No 9689 (66.0) 401 (4.1) 1.0 1.0
Body mass index
,20 477 (3.3) 24 (5.0) 1.1 (0.7, 1.7) 1.5 (0.96, 2.5)
20–24 4446 (30.3) 209 (4.7) 1.0 1.0
25–29 5778 (39.4) 366 (6.3) 1.4 (1.2, 1.6) 0.9 (0.7, 1.03)
30 and higher 3980 (27.1) 287 (7.2) 1.6 (1.3, 1.9) 0.8 (0.7, 1.01)
Education (y)
,12 3423 (23.3) 321 (9.4) 2.1 (1.8, 2.5) 1.5 (1.2, 1.8)
12 4764 (32.5) 260 (5.5) 1.2 (0.99, 1.4) 1.2 (0.96, 1.4)
.12 6494 (44.2) 305 (4.7) 1.0 1.0
HDL-C (mg/dl){52.0 (0.1) 0.67 (0.63, 0.71) 0.81 (0.76, 0.87)
LDL-C (mg/dl){137.7 (0.3) 1.07 (1.05, 1.08) 1.05 (1.03, 1.06)
Fibrinogen (mg/dl){303.2 (0.5) 1.05 (1.04, 1.05) 1.02 (1.01, 1.03)
GOLD status*
GOLD 3 or 4 262 (1.8) 29 (11.1) 3.0 (2.0, 4.5) 1.3 (0.8, 2.1)
GOLD 2 1388 (9.5) 150 (10.8) 2.9 (2.4, 3.6) 1.4 (1.1, 1.8)
GOLD 1 1612 (11.0) 99 (6.1) 1.6 (1.2, 2.0) 1.0 (0.8, 1.3)
GOLD 0 2039 (13.9) 132 (6.5) 1.7 (1.4, 2.0) 1.4 (1.1, 1.8)
Restricted 1187 (8.1) 148 (12.5) 3.4 (2.8, 4.2) 2.3 (1.9, 2.9)
Normal 8193 (55.8) 328 (4.0) 1.0 1.0
Total 14 681 886 (6.0)
From the Atherosclerosis Risk in Communities Study 1987–1989 and follow-up to 2001.
*Baseline CVD criteria and modified Global Initiative on Obstructive Lung Disease (GOLD) criteria, as defined in table 1.
{Adjusted for age, sex, race, smoking status, pack-years of cigarettes, diabetes mellitus, body mass index, education level,
hypertension, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fibrinogen and GOLD status.
{Third column displays mean value (SE). Risks are displayed per 10 mg/dl increase.
Chronic obstructive pulmonary disease
Thorax 2008;63:599–605. doi:10.1136/thx.2007.088112 601

unadjusted model, the prevalence of CVD was significantly higher
in those with GOLD 2 (odds ratio (OR) 2.9, 95% confidence
interval (CI) 2.4 to 3.6) and GOLD 3 or 4 COPD (OR 3.0, 95% CI
2.0 to 4.5), compared with normal subjects. Adjustment for
covariates decreased the relative risk for prevalent disease
compared with the unadjusted model (OR 1.4, 95% CI 1.1 to
1.8 for GOLD 2 and OR 1.3, 95% CI 0.8 to 2.1 for GOLD 3 or 4).
The highest overall multivariate association between baseline
CVD and lung function impairment was observed for those
classified as restricted (OR 2.3, 95% CI 1.9 to 2.9).
The association between lung function impairment and risk
of incident and recurrent CVD events over 15 years are shown
in table 3. Subjects with baseline CVD were more likely to have
a CVD event (41.8 events vs 8.1 events per 1000 person years)
and to die (34.9 deaths vs 8.8 deaths per 1000 person years) than
those without baseline CVD. Subjects with GOLD 2 (hazard
ratio (HR) 2.4, 95% CI 2.1 to 2.7) and GOLD 3 or 4 COPD (HR
2.9, 95% CI 2.2 to 3.9) had the highest univariate risk of CVD
events. This finding was decreased in the adjusted models (HR
1.2, 95% CI 1.03 to 1.4 for GOLD 2 and 1.5, 95% CI 1.1 to 2.0 for
GOLD 3 or 4 COPD).
We did not find any significant interaction between the
GOLD category and smoking status, age category, race or sex
(p.0.10 for each) for our primary outcome of time to CVD
event. When the cohort was stratified by smoking status, the
rate of CVD events and deaths was higher among current
smokers (14.6 CVD events and 16.7 deaths per 1000 person
years) than among former (10.0 CVD events and 9.8 deaths per
1000 person years) or never smokers (6.2 CVD events and 6.1
deaths per 1000 person years) (table 4). In the stratified
analyses, the relation between lung function impairment, in
the adjusted models, was weakest among the current smokers,
but there was a large degree of overlap between all three
smoking categories (table 4). The tables examining the relation-
ship between CVD events and lung function impairment
stratified by gender, age and race are available as an online
supplement (supplementary tables 1–3). Men had twice the rate
of CVD events than women (13.9 vs. 6.5 per 1000 person years),
older subjects (age 55–64 years) had twice the rate of events
than younger subjects (13.4 vs 6.5 per 1000 person years) and
black patients had a slightly higher rate of events than white
subjects (12.1 vs 8.9 per 1000 person years).
Figure 1 depicts the Kaplan–Meier curve of the relation
between lung function impairment and incident or recurrent
CVD, while fig 2 shows the fully adjusted Cox proportional
hazards model curves.
DISCUSSION
In this analysis of a large, prospective, population based cohort,
lung function impairment was associated with an increased risk
Table 3 Incident or recurrent cardiovascular events to 15 years of follow-up among subjects free of
cardiovascular disease or stroke at baseline, those with cardiovascular disease or stroke at baseline and all
subjects, stratified by GOLD stage*
n
Incident or recurrent
cardiovascular
events per 1000
person years*
Deaths per
1000
person
years
Univariate risk of a
cardiovascular event
from Cox
proportional
hazards model
(hazard ratio
(95% CI))
Multivariate risk of
cardiovascular
event from Cox
proportional
hazards model
(hazard ratio
(95% CI)){
No cardiovascular disease at baseline
GOLD 3 or 4 233 16.8 46.4 2.2 (1.6, 4.0) 2.0 (1.03, 3.9)
GOLD 2 1238 13.5 18.0 1.7 (1.3, 2.3) 1.3 (0.96, 1.9)
GOLD 1 1513 8.4 9.7 1.4 (0.9, 2.0) 1.3 (0.9, 1.8)
GOLD 0 1907 9.0 8.7 1.3 (0.96, 1.9) 1.2 (0.9, 1.7)
Restricted 1039 12.3 13.1 1.6 (1.2, 2.2) 1.4 (1.02, 1.9)
Normal 7865 6.4 5.9 1.0 1.0
Total 13 795 8.1 8.8
Cardiovascular disease at baseline
GOLD 3 or 4 29 66.7 98.9 2.8 (2.0, 3.8) 1.3 (0.9, 1.9)
GOLD 2 150 54.4 39.1 2.1 (1.8, 2.5) 1.2 (0.98, 1.4)
GOLD 1 99 43.0 38.4 1.3 (1.1, 1.6) 1.0 (0.9, 1.2)
GOLD 0 132 41.9 37.2 1.4 (1.2, 1.7) 1.1 (0.9, 1.3)
Restricted 148 50.9 39.2 2.0 (1.6, 2.3) 1.2 (0.98, 1.4)
Normal 328 31.4 25.7 1.0 1.0
Total 886 41.8 34.9
All subjects
GOLD 3 or 4 262 20.4 50.8 2.9 (2.2, 3.9) 1.5 (1.1, 2.0)
GOLD 2 1388 16.9 20.1 2.4 (2.1, 2.7) 1.2 (1.03, 1.4)
GOLD 1 1612 10.1 11.2 1.4 (1.2, 1.7) 1.1 (0.9, 1.3)
GOLD 0 2039 10.7 10.2 1.5 (1.3, 1.7) 1.1 (0.98, 1.3)
Restricted 1187 16.1 16.0 2.3 (2.0, 2.6) 1.2 (1.1, 1.5)
Normal 8193 7.2 6.6 1.0 1.0
Total 14 681 9.7 10.2
*Modified Global Initiative on Obstructive Lung Disease (GOLD criteria and incident or recurrent cardiovascular disease (CVD)
criteria are defined as in table 1).
{Adjusted for age, sex, race, smoking status, pack-years of cigarettes, diabetes mellitus, body mass index, education level,
hypertension, high density lipoprotein of cholesterol, low density lipoprotein of cholesterol, fibrinogen, GOLD status and, among all
subjects, prevalent CVD.
Chronic obstructive pulmonary disease
602 Thorax 2008;63:599–605. doi:10.1136/thx.2007.088112

of having or developing CVD in adults; the highest risks were
observed among those with GOLD 2 (moderate) and GOLD 3 or
4 (severe/very severe) COPD. After adjusting for multiple
covariates, including age, sex, race, smoking status, diabetes,
hypertension, cholesterol levels and fibrinogen levels, the
relation between lung function impairment and CVD was
reduced, suggesting that some of this relation may be mediated
through these other factors.
Previous research suggests that systemic inflammation pre-
sent in COPD leads to the increased CVD risk, and that
treatment aimed at decreasing inflammation in those with
COPD may decrease the development of cardiovascular disease
or reduce event recurrence. Vascular inflammation may also
Table 4 Incident or recurrent cardiovascular events* and death to 15 years of follow-up among never,
former and current smokers stratified by GOLD stage*
n
Incident or
recurrent
cardiovascular
events per 1000
person years*
Deaths per
1000 person
years
Univariate risk of a
cardiovascular event
from Cox proportional
hazards model (hazard
ratio (95% CI))
Multivariate risk of
cardiovascular event
from Cox proportional
hazards model (hazard
ratio (95% CI)){
Never smokers
GOLD* 3 or 4 19 13.2 17.0 2.6 (0.9, 7.8) 1.9 (0.7, 5.6)
GOLD 2 185 9.4 9.5 1.8 (1.2, 2.9) 1.5 (0.96, 2.3)
GOLD 1 431 4.0 6.1 0.8 (0.5, 1.2) 0.8 (0.5, 1.3)
GOLD 0 761 8.0 6.9 1.5 (1.2, 2.0) 1.2 (0.9, 1.6)
Restricted 469 12.2 12.8 2.4 (1.8, 3.1) 1.5 (1.1, 1.9)
Normal 3895 5.3 4.9 1.0 1.0
Total 5760 6.2 6.1
Former smokers
GOLD 3 or 4 88 24.5 49.7 3.3 ( 2.1, 5.2) 2.3 (1.5, 3.6)
GOLD 2 422 16.3 17.4 2.1 (1.7, 2.8) 1.3 (1.02, 1.8)
GOLD 1 564 10.2 9.2 1.3 (1.03, 1.7) 1.1 (0.9, 1.5)
GOLD 0 510 10.2 9.6 1.3 (1.01, 1.8) 1.2 (0.9, 1.5)
Restricted 315 20.8 19.4 2.7 (2.1, 3.6) 1.4 (1.1, 1.9)
Normal 2852 7.7 7.0 1.0 1.0
Total 4751 10.0 9.8
Current smokers
GOLD 3 or 4 155 19.3 56.5 1.7 (1.1, 2.5) 1.1 (0.7, 1.6)
GOLD 2 781 19.2 24.3 1.7 (1.3, 2.0) 1.1 (0.9, 1.4)
GOLD 1 617 14.6 17.0 1.3 (0.99, 1.6) 1.1 (0.8, 1.4)
GOLD 0 768 13.9 14.2 1.2 (0.9, 1.5) 1.0 (0.8, 1.3)
Restricted 403 17.3 17.0 1.5 (1.1, 1.9) 0.9 (0.7, 1.2)
Normal 1446 11.7 10.7 1.0 1.0
Total 4170 14.6 16.7
*Modified Global Initiative on Obstructive Lung Disease (GOLD criteria and incident or recurrent cardiovascular disease (CVD)
criteria are defined as in table 1).
{Adjusted for age, race, smoking status, diabetes mellitus, body mass index, education level, hypertension, high density lipoprotein
of cholesterol, low density lipoprotein of cholesterol, fibrinogen, GOLD status and prevalent CVD.
Figure 1 Kaplan–Meier curves of incident or recurrent cardiovascular
events among all subjects by GOLD stage. From the Atherosclerosis Risk in
Communities Study 1987–1989 and follow-up to 2001. Modified Global
Initiative on Obstructive Lung Disease (GOLD); criteria and incident or
recurrent cardiovascular disease criteria are defined as in table 1.
Figure 2 Multivariate risk of incident and recurrent cardiovascular events
by GOLD stage. From the Atherosclerosis Risk in Communities Study
1987–1989 and follow-up to 2001. Modified Global Initiative on Obstructive
Lung Disease (GOLD); criteria and incident or recurrent cardiovascular
disease criteria are defined as in table 1. Adjusted for age, race, smoking
status, diabetes mellitus, body mass index, education level, hypertension,
high density lipoprotein of cholesterol, low density lipoprotein of
cholesterol, fibrinogen, GOLD status and prevalent cardiovascular disease.
Chronic obstructive pulmonary disease
Thorax 2008;63:599–605. doi:10.1136/thx.2007.088112 603

contribute to impaired airway vascular smooth muscle relaxa-
tion in COPD. Treatment with agents that affect systemic
inflammation or vascular disease such as corticosteroids, statins,
angiotensin converting enzyme inhibitors or angiotensin
receptor blockers have been shown to alter the prognosis of
patients with COPD,
35–39
and one retrospective meta-analysis
has suggested a reduction in all-cause mortality in patients with
COPD treated with inhaled corticosteroids.
40
Our finding that
the risk of CVD was greatly reduced in the models that adjusted
for HDL-C, LDL-C, fibrinogen and comorbid disease suggests
that part of the CVD risk seen in COPD is mediated by these
other factors that may be responsive to intervention.
Although low grade chronic systemic inflammation likely
contributes to the association between lung function impair-
ment and CVD, factors such as the role of the lungs in the
capture and elimination of external toxic agents may also be
important.
20
Previous research has shown a relationship between lung
function impairment based on quartile of FEV
1
per cent predicted
or diagnosed COPD and incident cardiac disease or ischaemic
stroke, with an increased risk primarily noted within population
subsets, such as whites patients,
18
women
20 41
and younger
populations.
23
These analyses, however, were not able to make a
distinction between those with mild, moderate or severe impair-
ment in lung function or separate out those with restrictive
impairment. Our study, however, used the clinically relevant
GOLD staging to classify COPD, which does make this distinction.
An interesting finding in our study was the association
between restriction on spirometry and CVD risk. As shown in
table 2, restriction was a stronger risk factor for CVD than
either GOLD 2 or GOLD 3 or 4 COPD, the risk for incident or
recurrent CVD in those with restriction was similar to that seen
in GOLD 2 COPD. Neither the degree nor causes of restricted
lung disease were examined in this analysis, but future studies
may be undertaken to further investigate the relationship
between CVD and restriction on spirometry.
Strengths of this study include the large cohort of patients,
length of follow-up and well defined outcome events. Even
though this was a very large sample, certain subgroups had
small numbers. For example, the number of subjects with
prevalent CVD was 150 for GOLD 2 and 29 for GOLD 3 or 4.
Also, subjects were classified based on initial pulmonary
function tests which may not have represented a true baseline,
and the restriction category was categorised based on a
decreased FVC with a normal FEV
1
/FVC ratio rather than the
gold standard, total lung capacity measurements. The effect of
lung function impairment on CVD outcomes was decreased in
the fully adjusted models, suggesting that additional confoun-
ders that were not included in the analysis might explain these
findings. Conversely, it is also possible that our models ‘‘over
adjusted’’. For example, if the effect of lung function impair-
ment on CVD is mediated through inflammation or comorbid
disease, then adjusting for these factors might mask the true
association between lung function impairment and CVD.
CONCLUSION
We observed an association between lung function impairment
and risk of prevalent, and incident or recurrent, CVD in a large
population based cohort. This association was reduced in
models that adjusted for age, sex, race, smoking status, diabetes
mellitus, hypertension, cholesterol levels and fibrinogen levels,
suggesting that these effects may be mediated in part through
these other factors. The implications of these findings are that
clinicians should consider spirometry in their patients with
CVD or follow markers of systemic inflammation, such as C
reactive protein, in COPD patients to help assess or manage
their CVD risk. Future studies may be directed towards better
identifying reasons for the linkage between lung function
impairment and CVD risk and determining if interventions can
improve outcomes.
Acknowledgements: The authors thank the staff and participants in the
Atherosclerosis Risk in Communities Study for their important contributions. The ARIC
Study is conducted and supported by the National Heart Lung and Blood Institute
(NHLBI) in collaboration with the ARIC Investigators. This manuscript was not prepared
in collaboration with investigators of the ARIC and does not necessarily reflect the
opinions or views of the ARIC or the NHLBI.
Funding: Funded by a research grant from GlaxoSmithKline.
Competing interests: GW, KD, and VK are employees of GlaxoSmithKline (GSK). DM
has received research funding from GSK, Pfizer and Novartis and is a consultant to
GSK, Pfizer, AstraZeneca, Boehringer-Ingleheim, Dey and Sepracor. AJ hasno
competing interests.
Ethics approval: Ethics approval was obtained.
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