Association of Airflow Limitation With Carotid Atherosclerosis in a Japanese Community　― The Hisayama Study ―

Kunihiro Kudo; Jun Hata; Koichiro Matsumoto; Yuki Shundo; Satoru Fukuyama; Hiromasa Inoue; Takanari Kitazono; Yutaka Kiyohara; Toshiharu Ninomiya; Yoichi Nakanishi

doi:10.1253/circj.CJ-16-1305

Abstract

Background: There has been no large-scale observational study examining the association between chronic obstructive pulmonary disease (COPD) or airflow limitation and carotid atherosclerosis in the general population across a wide range of generations in Asia. In the present study we assessed the association between airflow limitation and carotid intima-media thickness (IMT) in a general Japanese population, with consideration of a comprehensive array of cardiovascular risk factors.

Methods and Results: In all, 2,099 community-dwelling Japanese subjects were included in the study. Airflow limitation was defined by spirometry. Maximum and mean IMT values were measured using carotid ultrasonography. Among the subjects, 352 (16.8%) had airflow limitation. The geometric mean values of maximum IMT and mean IMT were significantly higher in subjects with than without airflow limitation (1.27 vs. 1.18 mm, respectively, for maximum IMT; 0.73 mm vs. 0.72 mm, respectively, for mean IMT) and increased with the severity of airflow limitation after adjustment for conventional risk factors, including smoking habits and serum high-sensitivity C-reactive protein. It should be noted that the magnitude of these associations was greater in the middle-aged (40–64 years) than elderly (≥65 years) subgroup.

Conclusions: The findings of the present study suggest that airflow limitation is a significant risk factor for carotid atherosclerosis, especially in midlife, in the general Japanese population.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation in the respiratory system and is associated with a variety of systemic comorbidities. Cardiovascular comorbidity has been attracting particular attention due to its close association with the prognosis of COPD.¹ Cardiovascular comorbidity ranks after respiratory disease as the second leading cause of death in patients with COPD, accounting for 10–40% of total deaths.²

Editorial p 1770

Carotid intima-media thickness (IMT) has been acknowledged as a good indicator of carotid atherosclerosis, and IMT can be estimated feasibly and non-invasively using carotid ultrasonography. Moreover, in large-scale epidemiological studies, increased carotid IMT has been reported to be associated with a greater risk of future cardiovascular events.³^,⁴ Several observational studies have consistently shown that carotid IMT is significantly greater in patients with COPD or airflow limitation than in those without.⁵^–¹⁰ However, in Asia, there have been only 2 case-control studies targeting middle-aged smokers and untreated COPD patients with relatively small sample sizes,⁵^,⁶ and no large-scale observational studies have been performed in Asian general populations to date. In Western countries, 3 of 4 published reports are of large-scale observational studies in general populations.⁷^–⁹ However, the generalizability of the results from these studies is limited because these studies have been performed in specific populations (e.g., individuals with cardiovascular disease,⁷ middle-aged individuals,⁸ and elderly people⁹). No study has investigated the association between airflow limitation and carotid atherosclerosis across a wide range of generations, from middle-aged to elderly. Thus, the aim of the present study was to investigate the association between airflow limitation and carotid IMT more precisely in a general population in Japan.

Methods

Study Population

The Hisayama study is a population-based observational study of cardiovascular disease started in 1961 in the town of Hisayama, a suburb of the Fukuoka metropolitan area on Kyushu Island, Japan. Using data from the national census, since the 1960 s the age and occupational distributions in Hisayama have been almost identical to those in Japan as a whole.¹¹ In 2008, a total of 2,108 residents aged ≥40 years (47.1% of the total population of this age group) participated in a comprehensive health examination, which included spirometry¹² and assessment of cardiovascular risk factors. Carotid ultrasonography was added to the health examination in 2007 and 2008.¹³ After excluding 9 individuals (1 who refused to participate in the epidemiological study, 6 who did not undergo spirometry due to poor maneuver or rejection, and 2 who did not undergo carotid ultrasonography), the remaining 2,099 subjects (890 men, 1,209 women) were enrolled in the present study. This study was approved by the Institutional Review Board for Clinical Research of Kyushu University (Approval no. 19-15, 21-37, and 28-368). Written informed consent was obtained from all subjects.

Diagnosis and Severity of Airflow Limitation

Spirometry was performed in accordance with the guidelines of the Japanese Respiratory Society¹⁴ using a CHESTGRAPH HI-105 spirometer (Chest MI Inc., Tokyo, Japan), as described previously.¹² The measurements were made in seated subjects by specially trained laboratory technicians. At least 2 and up to 4 tests were conducted until satisfactory flow-volume curves were obtained. A bronchodilator was not used in the present study. Pulmonary physicians assessed the quality of the flow-volume curves by visual inspection. Predictions of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) were derived from the Japanese criteria.¹⁵ Airflow limitation was defined as an FEV₁/FVC ratio <70%. The severity of the airflow limitation was based on the percentage of predicted FEV₁, in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (mild, percent predicted FEV₁ ≥80%; moderate, percent predicted FEV₁ 50–79%; severe, percent predicted FEV₁ ≤49%).¹⁶

Measurement of Carotid IMT

Carotid ultrasonography was performed using a real-time B-mode ultrasound imaging unit (Toshiba Sonolayer SSA-250A; Toshiba, Tokyo, Japan) with a 7.5-MHz annular array probe, as described previously.¹³ IMT in areas of the left and right common carotid arteries, bulbs, and internal carotid arteries that could be observed was measured manually using the short-axis view. For mean IMT, long-axis images of each common carotid artery were obtained, and the IMT of the right and left common carotid arteries in the region 20 mm proximal to the origin of the bulb at the far wall was measured using a computer-assisted measurement system (Intimascope; Media Cross, Tokyo, Japan).¹⁷ Mean IMT values were calculated by averaging the IMT measurements made in the left and right common carotid arteries. Carotid wall thickening was defined as a maximum IMT >1.5 mm (the 75th percentile value in this population).

Measurement of Other Risk Factors

Each participant completed a self-administered questionnaire about their medical history, including items regarding treatment for hypertension, diabetes mellitus, and dyslipidemia, and items on smoking habits, alcohol intake, and regular exercise. Each questionnaire was checked by trained nurses. Smoking habits were classified as never smoked and ever smoked (which included current and former smokers). Alcohol intake was classified as yea or no. Subjects engaging in sports or other forms of exercise ≥3 times a week during their leisure time were defined as the “regular exercise group”. Blood pressure was measured 3 times using an automated sphygmomanometer in seated subjects after at least 5 min rest. The mean of the 3 blood pressure measurements was used in analyses. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg and/or the current use of antihypertensive agents. Body height and weight were measured in light clothing without shoes, and the body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m²). Underweight, normal weight, and overweight were defined as BMI <18.5, 18.5≤BMI<25.0, and ≥25.0 kg/m², respectively. Serum total and high-density lipoprotein (HDL) cholesterol levels were determined enzymatically. Blood glucose levels were measured by the hexokinase method. Diabetes was defined as fasting glucose levels ≥7.0 mmol/L (126 mg/dL), 2-h post-load or casual glucose levels ≥11.1 mmol/L (200 mg/dL), and/or the current use of insulin or oral glucose-lowering agents. Aliquots of serum specimens were stored at −80℃ until 2009, when they were used for determination of high-sensitivity C-reactive protein (hs-CRP) concentrations, which were measure using the latex-enhanced nephelometric method (Behring Diagnostics, Westwood, MA, USA).

Statistical Analysis

The significance of differences in mean values and frequencies of risk factors between subjects with and without airflow limitation was tested using Student’s t-test and the χ² test, respectively. Adjusted geometric mean values of maximum IMT and mean IMT across airflow limitation status were assessed using analysis of covariance (ANCOVA). The adjusted odds ratio (OR) and 95% confidence intervals (CIs) for the presence of carotid wall thickening were assessed using multivariable logistic regression analysis. The heterogeneity in the association between subgroups was estimated by adding an interaction term to the relevant statistical model. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA). Two-sided P values <0.05 was considered significant.

Results

Baseline Characteristics of the Study Subjects

The mean age of the 2,099 subjects was 64 years, 42.4% were men, and 40.0% were ever smokers. Airflow limitation was identified in 352 (16.8%) subjects.

Baseline characteristics of study subjects with and without airflow limitation are given in Table 1. Mean age and systolic blood pressure, the geometric mean of hs-CRP, and the proportion of men, hypertensives, overweight, and ever smokers were significantly higher in subjects with airflow limitation than in those without. Subjects with airflow limitation had significantly lower mean total cholesterol, BMI, FVC, FEV₁, FEV₁/FVC, and percent predicted FEV₁ than those without.

Table 1. Baseline Characteristics of the Study Subjects

	No airflow limitation (n=1,747)	Airflow limitation (n=352)	P value
Age (years)	63±11	70±10	<0.001
% Men	39.0	59.1	<0.001
SBP (mmHg)	130±18	134±18	<0.001
DBP (mmHg)	80±11	80±10	0.94
Hypertension (%)	48.8	58.0	0.002
Diabetes (%)	13.3	16.8	0.09
Total cholesterol (mmol/L)	5.25±0.91	5.04±0.85	<0.001
HDL cholesterol (mmol/L)	1.73±0.47	1.68±0.44	0.12
Lipid-lowering medication (%)	19.7	21.9	0.35
BMI (kg/m²)	23.1±3.5	22.6±3.2	0.006
% Underweight	7.4	8.8	0.36
% Normal weight	66.8	72.7	0.03
% Overweight	25.8	18.5	0.004
% Smokers	36.4	57.9	<0.001
% Former smoker	22.8	33.7	<0.001
% Current smoker	13.6	24.2	<0.001
Current alcohol intake (%)	47.2	50.9	0.21
Regular exercise (%)	13.5	11.7	0.36
hs-CRP (mg/L)	0.41 [0.18–0.77]	0.47 [0.24–1.02]	<0.001
FVC (L)	2.83±0.75	2.64±0.72	<0.001
FEV₁ (L)	2.21±0.60	1.68±0.53	<0.001
Percent predicted FEV₁	94.6±13.5	74.1±18.3	<0.001
FEV₁/FVC (%)	77.9±4.8	63.1±6.8	<0.001

Data are presented as the mean±SD, frequencies, or median values [interquartile range]. Underweight, normal weight, and overweight were defined as body mass index (BMI) <18.5, 18.5≤BMI<25.0, and ≥25.0 kg/m², respectively. FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein.

We also examined baseline characteristics among middle-aged (40–64 years) and elderly (≥65 years) subgroups (Table S1). The geometric mean of hs-CRP was significantly higher in subjects with airflow limitation than in those without in the middle-aged subgroup, but not in the elderly subgroup. Conversely, mean total cholesterol and BMI, especially the prevalence of overweight (BMI ≥25 kg/m²), were significantly lower in subjects with airflow limitation than in those without in the elderly subgroup, but not in the middle-aged subgroup.

Association Between Airflow Limitation and Carotid IMT

The geometric mean of maximum IMT and mean IMT in all subjects were 1.20 and 0.72 mm, respectively, and carotid wall thickening (maximum IMT >1.5 mm) was detected in 499 subjects.

Table 2 compares maximum IMT and mean IMT between subjects with and without airflow limitation. The age- and sex-adjusted geometric mean of maximum IMT was significantly higher in subjects with airflow limitation than in those without (1.27 vs. 1.18 mm, respectively; P=0.001; Table 2, Model 1). This association remained significant even after additional adjustment for cardiovascular risk factors, such as hypertension, diabetes, total cholesterol, HDL cholesterol, the use of lipid-lowering medications, BMI, smoking status, alcohol intake, and regular exercise (P=0.002; Table 2, Model 2), as well as after further adjustment for hs-CRP, an indicator of chronic systemic inflammation (P=0.002; Table 2, Model 3). Similar associations were observed between airflow limitation and mean IMT, although the associations failed to reach the level of statistical significance in the age- and sex-adjusted analyses. No evidence of heterogeneity in the association of airflow limitation with maximum or mean IMT was observed between men and women (all P_{heterogeneity}>0.40).

Table 2. Adjusted Geometric Mean Values of Maximum and Mean IMT in Subjects With and Without Airflow Limitation

	No. of subjects	Model 1		Model 2		Model 3
	No. of subjects	Geometric mean (95% CI)	P value	Geometric mean (95% CI)	P value	Geometric mean (95% CI)	P value
Maximum IMT (mm)
All
No airflow limitation	1,746	1.18 (1.16–1.20)		1.18 (1.16–1.20)		1.18 (1.16–1.20)
Airflow limitation	352	1.27 (1.22–1.32)	0.001	1.27 (1.22–1.31)	0.002	1.27 (1.22–1.32)	0.002
Men
No airflow limitation	681	1.32 (1.28–1.36)		1.33 (1.29–1.37)		1.33 (1.29–1.37)
Airflow limitation	208	1.43 (1.35–1.51)	0.02	1.41 (1.34–1.49)	0.04	1.41 (1.34–1.49)	0.05
Women
No airflow limitation	1,065	1.09 (1.07–1.11)		1.09 (1.07–1.11)		1.09 (1.07–1.11)
Airflow limitation	144	1.15 (1.09–1.22)	0.06	1.16 (1.10–1.22)	0.04	1.16 (1.10–1.22)	0.04
P_{heterogeneity} (between the sexes)		0.46		0.47		0.45
Mean IMT (mm)
All
No airflow limitation	1,747	0.72 (0.71–0.72)		0.72 (0.71–0.72)		0.72 (0.71–0.72)
Airflow limitation	352	0.73 (0.72–0.74)	0.06	0.73 (0.72–0.74)	0.02	0.73 (0.72–0.74)	0.02
Men
No airflow limitation	682	0.74 (0.73–0.75)		0.74 (0.73–0.75)		0.74 (0.73–0.75)
Airflow limitation	208	0.75 (0.74–0.77)	0.12	0.75 (0.74–0.77)	0.09	0.75 (0.74–0.77)	0.07
Women
No airflow limitation	1,065	0.70 (0.69–0.71)		0.70 (0.69–0.71)		0.70 (0.69–0.71)
Airflow limitation	144	0.71 (0.69–0.73)	0.24	0.71 (0.70–0.73)	0.14	0.71 (0.70–0.73)	0.14
P_{heterogeneity} (between the sexes)		0.93		0.84		0.82

Model 1: Adjusted for age and sex (sex was not adjusted for in the sex-specific analysis). Model 2: Adjusted for covariates in Model 1 plus hypertension, diabetes, total cholesterol, LDL cholesterol, use of lipid-lowering medications, BMI, smoking status (current/former or never smoked), alcohol intake, and regular exercise. Model 3: Adjusted for covariates in Model 2 plus high-sensitivity C-reactive protein. CI, confidence interval; IMT, intima-media thickness. Other abbreviations as in Table 1.

Table 3 lists adjusted ORs for carotid wall thickening. The age- and sex-adjusted OR for carotid wall thickening was significantly greater in subjects with than without airflow limitation (OR 1.45; 95% CI 1.10–1.89; P=0.008; Table 3, Model 1). This association remained significant after adjustment for the aforementioned cardiovascular risk factors (OR 1.43; 95% CI 1.08–1.89; P=0.01; Table 3, Model 2) and hs-CRP (OR 1.44; 95% CI 1.09–1.90; P=0.01; Table 3, Model 3). There was no evidence of heterogeneity in the ORs between the sexes (all P_{heterogeneity}>0.70).

Table 3. Adjusted ORs for Carotid Wall Thickening in Subjects With and Without Airflow Limitation

	No. cases/subjects	Model 1		Model 2		Model 3
	No. cases/subjects	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
All
No airflow limitation	355/1,746	1.00 (Ref.)		1.00 (Ref.)		1.00 (Ref.)
Airflow limitation	144/352	1.45 (1.10–1.89)	0.008	1.43 (1.08–1.89)	0.01	1.44 (1.09–1.90)	0.01
Men
No airflow limitation	210/681	1.00 (Ref.)		1.00 (Ref.)		1.00 (Ref.)
Airflow limitation	106/208	1.49 (1.06–2.09)	0.02	1.38 (0.97–1.98)	0.07	1.37 (0.96–1.95)	0.09
Women
No airflow limitation	145/1,065	1.00 (Ref.)		1.00 (Ref.)		1.00 (Ref.)
Airflow limitation	38/144	1.44 (0.93–2.24)	0.10	1.45 (0.93–2.28)	0.11	1.46 (0.93–2.30)	0.10
P_{heterogeneity} (between the sexes)		0.76		0.74		0.76

Model 1: Adjusted for age and sex (sex was not adjusted for in the sex-specific analysis). Model 2: Adjusted for covariates in Model 1 plus hypertension, diabetes, total cholesterol, HDL cholesterol, use of lipid-lowering medications, BMI, smoking status (current/former or never smoked), alcohol intake, and regular exercise. Model 3: Adjusted for covariates in Model 2 plus hs-CRP. OR, odds ratio. Other abbreviations as in Tables 1,2.

Association Between Airflow Limitation Severity and Carotid IMT

Figure 1 shows the association between the severity of airflow limitation and carotid IMT. The multivariable-adjusted geometric mean maximal IMT and mean IMT, as well as the multivariable-adjusted ORs for carotid wall thickening increased significantly with the severity of airflow limitation (all P_trend<0.05).

Figure 1.

Multivariable-adjusted geometric means of (A) maximum intima-media thickness (IMT) and (B) mean IMT, and (C) odds ratios for carotid wall thickening according to the severity of airflow limitation. *P<0.05 compared with subjects without (−) airflow limitation. Values are adjusted for age, sex, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, the use of lipid-lowering medications, body mass index, smoking status (current/former or never smoked), alcohol intake, regular exercise, and high-sensitivity C-reactive protein.

Subgroup Analyses

We further examined the association between airflow limitation and carotid IMT in 2 age groups, namely middle-aged (40–64 years) and elderly (≥65 years) subjects (Figure 2). In the middle-aged subgroup, there were significant differences in the geometric mean of maximal and mean IMT between subjects with airflow limitation and those without. In this group, the OR for carotid wall thickening in subjects with airflow limitation was also significantly elevated. Although similar trends were seen in the elderly subgroup, the associations were modest and failed to reach the level of statistical significance. Significant or marginally significant heterogeneities in these associations were observed between the middle-aged and elderly subgroups (all P_{heterogeneity}<0.10). In the subgroup analyses for hypertension, diabetes, and smoking habits, there were no obvious heterogeneities in the associations between airflow limitation and carotid IMT (all P_{heterogeneity}>0.10; Table 4).

Figure 2.

Association of airflow limitation with (A) maximum intima-media thickness (IMT), (B) mean IMT, or (C) carotid wall thickening in middle-aged (40–64 years) and elderly (≥65 years) subgroups. *P<0.05, ^#P<0.10 compared with those without (−) airflow limitation. Values are adjusted for sex, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering medication use, body mass index, smoking status (current/former or never smoked), alcohol intake, regular exercise, and high-sensitivity C-reactive protein.

Table 4. Association of Airflow Limitation With Maximum IMT, Mean IMT, and Carotid Wall Thickening According to Risk Factors Subgroups

	No. of subjects	Maximum IMT (mm)		Mean IMT (mm)		Carotid wall thickening
	No. of subjects	Geometric mean (95% CI)	P value	Geometric mean (95% CI)	P value	OR (95% CI)	P value
No hypertension
No airflow limitation	891	1.06 (1.04–1.09)		0.67 (0.67–0.68)		1.00 (Ref.)
Airflow limitation	148	1.12 (1.06–1.18)	0.08	0.69 (0.67–0.70)	0.06	1.54 (0.97–2.45)	0.07
Hypertension
No airflow limitation	851	1.32 (1.28–1.35)		0.76 (0.75–0.77)		1.00 (Ref.)
Airflow limitation	203	1.43 (1.35–1.51)	0.01	0.78 (0.76–0.79)	0.14	1.43 (1.01–2.04)	0.046
P_{heterogeneity}		0.18		0.39		0.77
No diabetes
No airflow limitation	1,510	1.16 (1.14–1.18)		0.71 (0.70–0.71)		1.00 (Ref.)
Airflow limitation	293	1.24 (1.19–1.29)	0.004	0.72 (0.71–0.73)	0.08	1.47 (1.08–1.99)	0.01
Diabetes
No airflow limitation	232	1.33 (1.27–1.40)		0.77 (0.75–0.78)		1.00 (Ref.)
Airflow limitation	58	1.43 (1.30–1.57)	0.22	0.80 (0.76–0.83)	0.11	1.28 (0.64–2.56)	0.48
P_{heterogeneity}		0.97		0.42		0.80
Never smoked
No airflow limitation	1,109	1.11 (1.09–1.13)		0.70 (0.70–0.71)		1.00 (Ref.)
Airflow limitation	148	1.17 (1.11–1.23)	0.06	0.71 (0.70–0.73)	0.29	1.38 (0.89–2.14)	0.15
Current or former smoker
No airflow limitation	633	1.31 (1.27–1.35)		0.73 (0.72–0.74)		1.00 (Ref.)
Airflow limitation	203	1.39 (1.32–1.47)	0.07	0.75 (0.74–0.77)	0.04	1.41 (0.98–2.03)	0.07
P_{heterogeneity}		0.30		0.40		0.85

Adjusted for age, sex, hypertension, diabetes, total cholesterol, HDL cholesterol, use of lipid-lowering medications, BMI, smoking status (current/former or never smoked), alcohol intake, regular exercise, and hs-CRP. The subgroup variable was excluded from each model. Other abbreviations as in Tables 1–3.

Discussion

In the present population-based cross-sectional study, subjects with airflow limitation had significantly greater carotid IMT than those without airflow limitation. This association remained significant even after adjustment for potential confounding factors, such as smoking status and other cardiovascular risk factors, as well as after further adjustment for hs-CRP. There was no evidence of heterogeneities among the subgroups defined by sex, hypertension, diabetes, and smoking status. Carotid IMT increased with the severity of airflow limitation. Notably, the magnitude of the association between airflow limitation and carotid wall thickening was greater in the middle-aged than in the elderly.

Several epidemiological studies have investigated the association of COPD or airflow limitation with carotid IMT.⁵^–¹⁰ Consistently, these studies found that carotid IMT was greater in subjects with COPD or airflow limitation than in those without. Three of these investigations were population-based studies in Western countries.⁷^–⁹ The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study⁷ and the Atherosclerosis Risk in Communities (ARIC) Study⁸ in the US reported that lower levels of FEV₁ or FEV₁/FVC were associated with a greater carotid IMT. The Rotterdam Study in the Netherlands⁹ showed that subjects with COPD had an increased risk of the presence of carotid wall thickening compared with control subjects with normal lung function, and that the severity of airflow limitation was positively associated with carotid wall thickening. However, the MESA Lung Study excluded individuals with clinical cardiovascular disease, the ARIC Study selected subjects aged 45–64 years, and the Rotterdam Study selected elderly people aged >55 years (mean age 78 years). Similarly, a hospital-based cross-sectional study of patients with vascular surgery in the Netherlands¹⁰ reported that the prevalence of carotid wall thickening increased with the severity of COPD, independent of age and smoking status. In Asian countries, only a few population-based case-control studies with a relatively small sample size have investigated this issue.⁵^,⁶ A case-control study in Japan⁵ reported that the mean IMT was significantly greater in smokers with than without airflow limitation, whereas a case-control study from the Korean Health and Genome Study⁶ reported that subjects with untreated COPD had a significantly higher maximum carotid IMT than those without COPD. Collectively, these findings highlight the clinical importance of airflow limitation or COPD as a risk factor for carotid atherosclerosis. Thus, it was of considerable significance to demonstrate that airflow limitation is significantly associated with greater carotid IMT across a wide range of generations, from middle-aged to elderly, in the present study.

Several hypotheses have been put forward to explain the mechanisms underlying the association between airflow limitation and carotid IMT thickening. Airflow limitation and atherosclerosis are considered to have some of the same risk factors, such as smoking.¹⁸^,¹⁹ However, the results of the present study demonstrate that the association between airflow limitation and carotid IMT thickening is essentially unchanged, even after adjustment for smoking status. In addition, the effect of systemic chronic inflammation should be considered. Subjects with COPD are known to have not only local inflammation in the lung, but also systemic inflammation.²⁰^,²¹ Chronic inflammation is also an underlying factor in various stages of atherosclerosis.²²^–²⁴ In the present study, subjects with airflow limitation had greater carotid IMT than those without airflow limitation even after adjustment for hs-CRP. However, this does not preclude the involvement of chronic inflammation in the association between airflow limitation and the thickening of the carotid IMT, because chronic inflammation would be a complex process reflected by a variety of surrogate markers other than hs-CRP. In addition, there may be other underlying mechanisms, such as oxidative stress.²⁵ Clinical and experimental studies have shown that the production of reactive oxygen species (ROS) is increased in COPD patients by inhalation of toxic substances,²⁶^–²⁸ and that the antioxidative system in these patients is impaired,²⁹ leading to a state of high oxidative stress. After such an increase in ROS production, the spillover of ROS from the lung could lead to systemically increased levels of oxidative stress. Oxidative stress induces atherosclerosis directly by injuring vascular endothelial cells and promotes plaque formation indirectly through oxidized low-density lipoprotein.³⁰

In the present study, the association between airflow limitation and carotid IMT was stronger in the middle-aged than elderly subjects. Given that atherosclerosis is the dominant cause of cardiovascular disease, the strong association between airflow limitation and carotid atherosclerosis in middle-aged subjects is an important finding. Although a similar association was observed in the elderly group, it failed to reach the level of statistical significance. The precise reason for this difference is unclear, but increased systemic inflammation may mediate the association between airflow limitation and atherosclerosis primarily in middle-aged subjects because the level of this systemic inflammation was greater in subjects with airflow limitation than in those without in the case of middle-aged subjects, but not elderly subjects (Table S1). In addition, in the elderly subgroup, mean total cholesterol and BMI and the prevalence of overweight were lower in subjects with airflow limitation than in those without. It has been reported that subjects with airflow limitation have impaired energy balance due to decreased dietary intake and increased energy expenditure.³¹^,³² The reduced burden of metabolic disorders may offset the risk of atherosclerosis for airflow limitation in the elderly. Another explanation is that because aging itself is a strong risk factor for atherosclerosis, carotid atherosclerosis is likely to be present even in subjects without airflow limitation, resulting in a weakened influence of airflow limitation on carotid atherosclerosis in the elderly. Moreover, the possibility of survivor bias, which usually occurs in cross-sectional studies, cannot be ruled out. In our population, the median (interquartile range) percent predicted FEV₁ was significantly higher in elderly subjects with airflow limitation than in middle-aged subjects with airflow limitation (76.8% [64.8–87.9%] vs. 72.7% [62.6–82.6%], respectively; P=0.045), indicating that the severity of airflow limitation was milder in the elderly than middle-aged subjects, probably because those subjects with severe airflow limitation would be likely to die from cardiovascular disease or lung cancer earlier than those without airflow limitation or those with mild airflow limitation, resulting in a “survivor effect”.²^,³³ Further longitudinal studies are needed to clarify this issue.

The strengths of the present study are its comprehensive adjustment for cardiovascular risk factors, including smoking status and hs-CRP, and its large sample size from a general population. However, several limitations should also be considered. First, the diagnosis of airflow limitation was based on spirometry, but a bronchodilator was not used. Thus, subjects with airflow limitation could not be conclusively determined to have COPD, leaving room for the involvement of other obstructive diseases, such as bronchial asthma. Second, the cross-sectional design of the study could not fully address the causal relationships. In the future, it will be important to investigate the development of atherosclerotic disease longitudinally in this cohort.

Conclusions

The present study demonstrated that airflow limitation was a risk factor for the presence of carotid atherosclerosis, independent of smoking status, other well-known cardiovascular risk factors, and hs-CRP, in a general Japanese population. Because the association between airflow limitation and atherosclerosis was pronounced in the middle-aged subjects, the results of the present study suggest that subjects with airflow limitation, especially in midlife, should be considered a high-risk population for atherosclerotic diseases.

Acknowledgments

The authors thank the members of the Hisayama Pulmonary Physiology Study Group (a complete list of the members of this group has been published elsewhere¹²). The authors also thank the staff of the Division of Health and Welfare of Hisayama for their cooperation.

Sources of Funding

This study was supported, in part, by Grants-in-Aid for Scientific Research (A) (25253048), (B) (25293192) and (C) (25460758, 26350895, 26460748, 15K09267, 15K08738, and 15K09835) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by Health and Labour Sciences Research Grants of the Ministry of Health, Labour and Welfare of Japan (H27-Shokuhin-Sitei-017, H25-Junkankitou [Seishuu]-Sitei-022, H25-Junkankitou [Seisaku]-Ippan-009, and H26-Junkankitou [Seisaku]-Ippan-001); and by the Japan Agency for Medical Research and Development (AMED) (15dk0207003 h0003, 15ek0210001 h0003, 15ek0210004 h0002, 15dk0207009 h0002, and 15 gm0610007 h0203 (CREST)).

Conflict of Interest

The authors report no conflicts of interest.

Supplementary Files

Supplementary File 1

Table S1. Baseline characteristics of study subjects in the middle-aged and elderly subgroups

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-16-1305

References

1. Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis. Lancet Respir Med 2015; 3: 631–639.
2. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: Role of comorbidities. Eur Respir J 2006; 28: 1245–1257.
3. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: A systematic review and meta-analysis. Circulation 2007; 115: 459–467.
4. van den Oord SC, Sijbrands EJ, ten Kate GL, van Klaveren D, van Domburg RT, van der Steen AF, et al. Carotid intima-media thickness for cardiovascular risk assessment: Systematic review and meta-analysis. Atherosclerois 2013; 228: 1–11.
5. Iwamoto H, Yokoyama A, Kitahara Y, Ishikawa N, Haruta Y, Yamane K, et al. Airflow limitation in smokers is associated with subclinical atherosclerosis. Am J Respir Crit Care Med 2009; 179: 35–40.
6. Kim SJ, Yoon DW, Lee EJ, Hur GY, Jung KH, Lee SY, et al. Carotid atherosclerosis in patients with untreated chronic obstructive pulmonary disease. Int J Tuberc Lung Dis 2011; 15: 1265–1270.
7. Barr RG, Ahmed FS, Carr JJ, Hoffman EA, Jiang R, Kawut SM, et al. Subclinical atherosclerosis, airflow obstruction and emphysema: The MESA Lung Study. Eur Respir J 2012; 39: 846–854.
8. Schroeder EB, Welch VL, Evans GW, Heiss G. Impaired lung function and subclinical atherosclerosis: The ARIC Study. Atherosclerosis 2005; 180: 367–373.
9. Lahousse L, van den Bouwhuijsen QJ, Loth DW, Joos GF, Hofman A, Witteman JC, et al. Chronic obstructive pulmonary disease and lipid core carotid artery plaques in the elderly: The Rotterdam Study. Am J Respir Crit Care Med 2013; 187: 58–64.
10. van Gestel YR, Flu WJ, van Kuijk JP, Hoeks SE, Bax JJ, Sin DD, et al. Association of COPD with carotid wall intima-media thickness in vascular surgery patients. Respir Med 2010; 104: 712–716.
11. Hata J, Ninomiya T, Hirakawa Y, Nagata M, Mukai N, Gotoh S, et al. Secular trends in cardiovascular disease and its risk factors in Japanese: Half-century data from the Hisayama Study (1961–2009). Circulation 2013; 128: 1198–1205.
12. Matsumoto K, Seki N, Fukuyama S, Moriwaki A, Kano K, Matsunaga Y, et al. Prevalence of asthma with airflow limitation, COPD, and COPD with variable airflow limitation in older subjects in a general Japanese population: The Hisayama Study. Respir Investig 2015; 53: 22–29.
13. Fukuhara M, Arima H, Ninomiya T, Hata J, Hirakawa Y, Doi Y, et al. White-coat and masked hypertension are associated with carotid atherosclerosis in a general population: The Hisayama Study. Stroke 2013; 44: 1512–1517.
14. The Committee of Pulmonary Physiology in Japanese Respiratory Society. Guidelines for pulmonary function tests: Spirometry, flow-volume curve, diffusion capacity of the lung. Nihon Kokyuki Gakkai Zassi 2004; 4(Suppl): 1–56 (in Japanese).
15. The Committee of Pulmonary Physiology in Japanese Respiratory Society. Reference values for spirogram and arterial blood gas analysis in Japanese. Nihon Kokyuki Gakkai Zasshi 2001; 3(Suppl): 1–17 (in Japanese).
16. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007; 176: 532–555.
17. Yanase T, Nasu S, Mukuta Y, Shimizu Y, Nishihara T, Okabe T, et al. Evaluation of a new carotid intima-media thickness measurement by B-mode ultrasonography using an innovative measurement software, Intimascope. Am J Hypertens 2006; 19: 1206–1212.
18. Postma DS, Bush A, van den Berge M. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet 2015; 385: 899–909.
19. Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: An update. J Am Coll Cardiol 2004; 43: 1731–1737.
20. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: A systematic review and a meta-analysis. Thorax 2004; 59: 574–580.
21. Agustí A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: A novel phenotype. PLoS One 2012; 7: e37483.
22. Ross R. Atherosclerosis: An inflammatory disease. N Engl J Med 1999; 340: 115–126.
23. Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868–874.
24. Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease. Nature 2008; 451: 953–957.
25. Macnee W, Maclay J, McAllister D. Cardiovascular injury and repair in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008; 5: 824–833.
26. Praticò D, Basili S, Vieri M, Cordova C, Violi F, Fitzgerald GA. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am J Respir Crit Care Med 1998; 158: 1709–1714.
27. Rahman I. Oxidative stress in pathogenesis of chronic obstructive pulmonary disease: Cellular and molecular mechanisms. Cell Biochem Biophys 2005; 43: 167–188.
28. Sundar IK, Yao H, Rahman I. Oxidative stress and chromatin remodeling in chronic obstructive pulmonary disease and smoking-related diseases. Antioxid Redox Signal 2013; 18: 1956–1971.
29. Suzuki M, Betsuyaku T, Ito Y, Nagai K, Nasuhara Y, Kaga K, et al. Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2008; 39: 673–682.
30. Bonomini F, Tengattini S, Fabiano A, Bianchi R, Rezzani R. Atherosclerosis and oxidative stress. Histol Histopathol 2008; 23: 381–390.
31. Vermeeren MA, Schols AM, Wouters EF. Effects of an acute exacerbation on nutritional and metabolic profile of patients with COPD. Eur Respir J 1997; 10: 2264–2269.
32. Schols AM, Fredrix EW, Soeters PB, Westerterp KR, Wouters EF. Resting energy expenditure in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 1991; 54: 983–987.
33. Müllerova H, Agusti A, Erqou S, Mapel DW. Cardiovascular comorbidity in COPD: Systematic literature review. Chest 2013; 144: 1163–1178.

Corresponding author

Register with J-STAGE for free!