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(Chest. 2006;130:1642-1649.)
© 2006 American College of Chest Physicians

Lung Function and Ischemic Stroke Incidence*

The Atherosclerosis Risk in Communities Study

Atsushi Hozawa, MD, PhD; Joanne L. Billings, MD; Eyal Shahar, MD; Tetsuya Ohira, MD, PhD; Wayne D. Rosamond, PhD and Aaron R. Folsom, MD

* From the Division of Epidemiology and Community Health (Drs. Hozawa, Shahar, Ohira, and Folsom), School of Public Health, and the Department of Medicine (Dr. Billings), University of Minnesota, Minneapolis, MN; and the Department of Epidemiology (Dr. Rosamond), University of North Carolina, Chapel Hill, NC.

Correspondence to: Aaron R. Folsom, MD, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 South Second St, Suite 300, Minneapolis, MN 55454-1015; e-mail: folsom{at}epi.umn.edu

Abstract

Background: Few studies have examined the relation between lung function and ischemic stroke incidence; none have studied African Americans.

Methods: We followed 13,842 middle-aged adults initially free of stroke and coronary heart disease and observed 472 incident ischemic strokes over 13 years. Quartiles of FEV1 as a percentage of predicted value (FEV1PP) and FVC as a percentage of a predicted value (FVCPP) were used as the indicators of lung function.

Results: In the age-, race-, gender-, and education-adjusted models, both lung function measures were significantly inversely related to ischemic stroke incidence (linear trend for FEV1PP, p < 0.01; linear trend for FVCPP, p < 0.01), but adjustment for possible confounders attenuated these relations. For white subjects, a significant inverse relation remained even after full adjustment (relative hazards [RH] across FEV1PP quartiles (lowest to highest) were 1.59, 1.52, 1.26, and 1.00; and for FVCPP quartiles were 1.56, 1.80, 1.09, and 1.00 [trend for both, p < 0.05]). There was no association for African Americans (RH across FEV1PP and FVCPP quartiles were 0.74, 0.89, 0.73, 1.00 [linear trend, p = 0.27] and 0.81, 1.07, 0.61, 1.00 [linear trend, p = 0.75], respectively). An inverse relation between lung function and ischemic stroke was also observed among white subjects who never smoked (FEV1PP) or had no respiratory symptoms (both FEV1PP and FVCPP) but not among their African-American counterparts.

Conclusions: Among white subjects, participants with impaired lung function have a modestly higher risk of ischemic stroke even if they have never smoked nor had respiratory symptoms.

Key Words: cigarette smoking • ischemic stroke • lung function • prospective study • respiratory symptom

Several studies have reported that impaired lung function increases the risk of cardiovascular disease mortality.1 Some studies have provided information on the relation between lung function and stroke mortality,23456789101112 but few have examined the relation with stroke incidence.24671112

Several issues remain unresolved. First, previous studies did not control the effect of some confounders, such as diabetes,234891011 which has been correlated with both lower lung function1213 and higher stroke incidence. Second, only a few studies57812 have reported the relation between lung function and stroke among never smokers. Third, although the Atherosclerosis Risk in Communities (ARIC) study14 previously reported that respiratory symptoms were related to ischemic stroke incidence, it remains unclear whether asymptomatic participants with lower lung function are at risk for ischemic stroke. Fourth, previous studies did not analyze African Americans separately. Thus, to clarify these issues, we examined the relation between lung function and ischemic stroke incidence in the ARIC study.

Materials and Methods

Study Design and Subjects
The ARIC study is a multicenter, prospective cohort study investigating the natural history of atherosclerotic disease in four US communities: Forsyth County, NC; Jackson, MS; Washington County, MD; and the northwest suburbs of Minneapolis, MN.15 The cohort comprised, at baseline from 1987 to 1989, 15,792 men and women aged 45 to 64 years who were selected from lists or by area-probability sampling. Only African Americans were recruited in the Jackson study center. The study protocol was approved by the institutional review boards of the collaborating institutions, and informed consent was obtained from each participant.

Baseline Lung Function Tests
Lung function was measured by the FVC maneuver, which quantifies the volume of air exhaled starting from a position of full inspiration and ending at complete forced expiration. Lung function was measured by trained and certified technicians according to American Thoracic Society guidelines, using a standardized protocol.16 Water-seal spirometers (Collins Survey II; Collins Medical; Braintree, MA) were used and were connected to personal computers. Software (Pulmo-Screen; PDS Healthcare Products; Louisville, CO) was used to assist the technicians with quality control, calculation of pulmonary function variables, and compilation of results for transmission to the ARIC Pulmonary Function Reading Center. Quality control was carefully monitored, as described previously.1316 FEV1 as a percentage of predicted value (FEV1PP) and FVC as a percentage of predicted value (FVCPP) were calculated using equations that included age, sex, height, and race.16 For African Americans, equation-derived predictions were multiplied by 0.88.1617

In some analyses, we used FEV1/FVC ratio to check whether airway obstruction per se was associated with ischemic stroke. The ARIC study also obtained both FEV1PP and FVCPP data at visit 2 (from 1990 to 1992).

Other Baseline Measurements
Fasting blood was drawn from the antecubital vein of seated participants into vacuum tubes containing sodium citrate for hemostatic factors, ethylenediaminetetraacetic acid for lipids, and serum separator gel for chemistries. The tubes were centrifuged at 3,000g for 10 min at 4°C. Plasma and serum aliquots were frozen at – 70°C until analysis a few weeks later. High-density lipoprotein (HDL) cholesterol18 was measured after dextran-magnesium precipitation of non-HDL lipoproteins. Fibrinogen and von Willebrand factor (vWF) antigen were measured using published methods.19 Laboratories in each study community performed WBC counts by Coulter counter. Smoking status (current, former, or never) and usual ethanol intake were estimated from interviews.20 Sitting BPs were measured three times using a random-zero sphygmomanometer after 5 min of rest.21 The mean of the last two measurements was used for analysis. Use of antihypertensive medications within the past 2 weeks of the baseline interview was self-reported.20 Prevalent diabetes mellitus was defined as a fasting glucose level ≥ 126 mg/dL, a nonfasting glucose level ≥ 200 mg/dL, a reported history of physician-diagnosed diabetes, or current use of diabetes medication. Body mass index (BMI) was computed as weight (kilograms) divided by height (meters squared). Waist-to-hip ratio (WHR) was computed as the circumference of the waist (umbilical level) in centimeters divided by the maximum circumference of the hips in centimeters. The sports index, derived from the survey of Baecke et al,22 ranged from 1 (low) to 5 (high) for physical activity from sports during leisure time. Preexisting coronary heart disease (CHD) at baseline was defined as self-reported physician diagnosis of myocardial infarction, coronary revascularization, or prevalent myocardial infarction by ARIC study ECG.23 Preexisting stroke was defined as any self-reported physician diagnosis of stroke.

Assessment of respiratory symptoms was based on responses to a standardized questionnaire adopted from the Epidemiology Standardization Project.24 Chronic bronchitis was defined as chronic cough and phlegm production on most days for at least 3 consecutive months of the year for at least 2 years. Wheezing was defined as wheezing for at least 2 years, and dyspnea was reported as shortness of breath and having to stop for breath when walking on level ground compared with people of the same age. Ascertainment of asthma was based on a self-report of ever having had asthma. We defined respiratory symptoms as having at least one of the above symptoms (chronic bronchitis, wheezing, dyspnea, or asthma).

Ascertainment of Incident Events
Stroke incidence was ascertained by contacting participants annually, identifying hospitalizations during the previous year, and by surveying discharge lists from local hospitals and death certificates from state vital statistics offices for potential cerebrovascular events.252627 Potential strokes were found by selecting records with International Classification of Diseases, Ninth Revision, Clinical Modification discharge codes 430–438 or with mention of stroke or neuroimaging in the discharge summary. For these, hospital records were copied and abstracted by a trained nurse. Each eligible case was classified by computer algorithm and by a physician reviewer, according to criteria adapted from the National Survey of Stroke.27 Differences in diagnosis were adjudicated by another reviewer. Details on quality assurance for ascertainment and classification of events are presented elsewhere.23 The criteria for classification were based on combinations of symptom type, duration, and severity, results of neuroimaging and other diagnostic procedures, and autopsy evidence when available.2526 The category "ischemic stroke" includes validated definite or probable hospitalized embolic or thrombotic strokes.

Data Analysis
Of 15,792 ARIC study participants at baseline, we excluded 1,357 subjects who had a history of CHD or stroke or who could not be classified on history of CHD or stroke. We further excluded participants who did not have information on lung function (n = 90) and, due to small numbers, nonwhite and non-African-American subjects (n = 43). Subjects who did not have data on all of the covariates (n = 460) were also excluded. In all, 13,842 participants were included in the analysis.

The association of baseline lung function with other risk factors was assessed using analysis of variance or {chi}2 test, as appropriate. The association between lung function and ischemic stroke incidence was estimated from Cox proportional hazard models. We checked the proportionality assumption and found no significant violation. Relative hazards (RH) for stroke were computed across quartiles of lung function variables using the top quartile (best lung function) as the reference category.

In model 1, we adjusted for age, gender, race (African American, white), and education (less than high school graduate, high school graduate, greater than high school graduate). In model 2, we further adjusted for most major risk factors for ischemic stroke, ie, cigarette smoking (current 1 to 14 cigarettes per day, current 15 to 29/d, current ≥ 30/d, former, and never), BMI, WHR, HDL cholesterol, ethanol intake, sports index, vWF, systolic BP, antihypertensive medication, and diabetes.28 Since WBC count and fibrinogen might be on the causal pathway, we additionally included these variables in a separate model (model 3). All of these analyses were also stratified on race and other variables of interest; p values for tests of trends in hazard ratios were calculated using a linear test across median values of lung function variable quartiles. Differences with a two-tailed p value < 0.05 were considered statistically significant. All statistical analyses were performed using SAS software (Version 8.2; SAS Institute; Cary, NC).

Results

Mean age (± SD) of ARIC study participants at baseline was 54.0 ± 5.7 years. Mean values of FEV1PP and FVCPP were 94.1 ± 17.0% and 101.3 ± 15.1%, respectively. Inverse associations between FEV1PP and most risk factors for ischemic stroke were observed (Table 1 ). Similar patterns were observed when we used FVCPP quartiles instead of FEV1PP quartiles (data not shown). These patterns existed in race-specific analyses (Table 1). As expected, the prevalence of never smoking was higher in successively higher lung function quartiles. This trend was more evident in whites than in African Americans.


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  		Table 1. Baseline Characteristics of Adults Aged 45 to 64 Years by Quartiles of FEV1PP, ARIC Study, 1987–1989*

 
The mean duration of follow-up was 13.5 years (maximum, 16.1 years), during which 472 incident ischemic strokes occurred. The incidence rate of ischemic stroke was highest for the lowest quartile of lung function variables (3.86 per 1,000 person-years for FEV1PP, and 3.95 per 1,000 person-years for FVCPP), and it was lowest for the highest quartile of lung function (1.60 per 1,000 person-years for FEV1PP, and 1.46 per 1,000 person-years for FVCPP). The age-, gender-, race-, and education-adjusted RH for ischemic stroke incidence across FEV1PP quartiles were 1.88, 1.59, 1.17, and 1.00; and for FVCPP quartiles were 2.01, 1.94, 1.02, and 1.00 (Table 2 ). However, the relationship was not significant after adjustment for confounding factors (Table 2). No relation of FEV1/FVC ratio with ischemic stroke incidence was observed (Table 2).


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  		Table 2. Incident Ischemic Stroke in Relation to Lung Function Variables, ARIC Study, 1987–2002*

 
Since the p values from tests of interactions between race and lung function for ischemic stroke were 0.03 for FEV1PP and 0.07 for FVCPP in model 3, we analyzed whites and African American separately. Significant inverse relations existed in whites but not in African Americans (Table 2). Further adjustment for WBC and fibrinogen slightly attenuated the relation between lung function and ischemic stroke in whites (model 3). These relations were unchanged even we used race-specific quartiles for analysis (data not shown).

Supplemental Analysis
As shown in Tables 3, 4 , we conducted a subgroup analysis, stratifying on gender and smoking status. No gender difference in the association between lung function and stroke was observed for either whites or African Americans (range of p values for interaction, 0.23 to 0.87). Significant inverse associations between lung function and ischemic stroke were observed among white former smokers. There tended to be inverse relations between lung function and ischemic stroke incidence among never-smoking whites. However for current smokers, no consistent findings were observed. A significant relation between lung function and ischemic stroke was also observed in whites without respiratory symptoms at baseline. For African Americans, no subgroup showed a strong relation between impaired lung functions and ischemic stroke. We also examined the associations within strata of BMI (< 25, 25 to 30, and > 30) and found no important difference in the pattern among BMI groups (data not shown). The only exception was FEV1PP for whites, in which the association with ischemic stroke was somewhat more apparent for participants with BMI < 25 (data not shown, p value for interaction = 0.03). However, no significant interaction between FEV1PP and BMI (continuous) for ischemic stroke was observed even in whites.


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  		Table 3. Ischemic Stroke in Relation to FEV1PP*

 

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  		Table 4. Ischemic Stroke in Relation to FVCPP*

 
Visit 2 Data
To improve precision, we repeated analyses using both visit 1 and visit 2 lung function data. In this analysis, we further excluded participants with missing lung function data at visit 2 (n = 1,458) and those who had CHD or a stroke event prior to visit 2 (n = 120), leaving 12,264 participants (9,437 whites and 2,827 African Americans). The correlation between visit 1 and visit 2 FEV1PP was 0.94 for whites and 0.88 for African Americans. Similarly, the correlations between visit 1 and visit 2 FVCPP were 0.90 for whites and 0.80 for African Americans. Using the average of visit 1 and visit 2 lung function also showed a significant inverse relation in model 3 between lung function and ischemic stroke among whites and no relation between lung function and ischemic stroke among African Americans.

Discussion

In this prospective, observational study, we found that participants with lower lung function variables, ie, FEV1PP and FVCPP, had higher ischemic stroke incidence. These inverse relations were statistically significant and independent among whites but not among African Americans. Furthermore, among whites, inverse associations were observed when we limited analyses to participants who had no respiratory symptoms or who never smoked (significant for FEV1PP but not FVCPP).

Although it is unclear whether these relations between lung function and ischemic stroke are causal, several explanations may be proposed. First, residual confounding by smoking is a possibility. However, we found an inverse association between lung and ischemic stroke even among never-smoking whites. Therefore, the relation of lung function with ischemic stroke appeared to be independent of smoking, at least in whites. Second, it is possible that inflammation explains the relation of lung function with ischemic stroke. Participants with impaired lung function have increased inflammatory markers, and these predict future atherosclerosis and cardiovascular events.2930 In the ARIC study, for example, WBC counts are associated positively with incident ischemic stroke.31 Thus, adjustment of WBC count and fibrinogen might be overadjustment. However, adjustment for inflammation markers—fibrinogen and WBC count—did not fully explain our findings. Third, a few previous studies reported that respiratory symptoms were associated with increased stroke incidence,14 perhaps due to the following mechanisms: (1) an acute asthma attack or cough may increase BP during the attack, raising the risk of ischemic stroke; (2) hypoxic episodes due to respiratory symptom may be long and severe enough to damage cerebral tissue14; or (3) short but frequent hypoxemic episodes due to respiratory symptoms could increase atherosclerosis risk, as observed in sleep apnea disorders.32 However, we found an inverse relation between lung function and ischemic stroke even among participants without respiratory symptoms. We also checked whether airway obstruction per se predicted ischemic stroke using the FEV1/FVC ratio. However, we did not find any significant relations. Thus, airway obstruction per se might not be associated with ischemic stroke. Further studies might be needed to clarify the issue.

Several other prospective studies also reported that lower lung function is a stroke risk factor, but to our knowledge only one study10 used ischemic stroke as its end point. Similar to ARIC study results, Agnarsson et al10 found an inverse relation between lung function (FEV1) and ischemic stroke. However, they did not separately analyze the relation among never-smokers. Several other prospective studies56789101112 reported a significant inverse relation between lung function and stroke but did not fully adjust for possible confounders. Our results extend previous findings and corroborate that lower lung function is related to higher incidence of ischemic stroke among whites independent of possible confounding factors.

We did not find any significant relation among African Americans. There are at least two possible explanations for this. First, it may be a chance finding related to the smaller sample size for African Americans. Indeed, a formal test of whether findings differed between African Americans and whites was not statistically significant. Further studies that include larger numbers of African American and longer follow-up might be needed to verify whether there is an ethnic difference. Second, it is possible that lung function measures were less reliable in African Americans than whites, which would contribute to regression dilution bias and attenuate the true relation of lung function and ischemic stroke. Indeed, the visit 1/visit 2 correlations of lung function data were lower in African Americans; however, the correlations were still very high. Further, the null finding for African Americans was unchanged when we used the average of visit 1 and visit 2 lung function values to improve precision. Thus, we believe that lower lung function "reliability" did not explain the absence of an association between lung function and stroke in African Americans.

Strengths of this study included a large, population-based cohort, which permitted stratification of data by several factors including race. A standardized protocol was used to measure lung function, with strict quality control procedures. Our study also had limitations. Lung function measurement is effort dependent. Even though technicians were thoroughly trained and certified, lung function is measured with some error. However, the correlations between lung function values obtained at visit 1 and visit 2 were fairly high, especially among whites.

In conclusion, we found a significant inverse relationship between lung function and ischemic stroke among whites but not among African Americans. In addition, among whites, inverse associations were observed when we limited analyses to participants who had no respiratory symptoms or who never smoked (significant for FEV1PP but not FVCPP).

Footnotes

Abbreviations: ARIC = Atherosclerosis Risk in Communities; BMI = body mass index; CHD = coronary heart disease; HDL = high-density lipoprotein; FEV1PP = FEV1 as a percentage of predicted value; FVCPP = FVC as a percentage of predicted value; RH = relative hazards; vWF = von Willebrand factor; WHR = waist-to-hip ratio

Dr. Hozawa was supported by a grant from the Banyu Fellowship Program sponsored by Banyu Life Science Foundation International. The ARIC study is supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022.

This work was performed at the University of Minnesota, Minneapolis, MN.

None of the authors have any conflicts of interests with regard to this publication.

Received for publication May 16, 2006. Accepted for publication August 8, 2006.

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