American Journal of Cardiology
Volume 101, Issue 9 , Pages 1247-1252, 1 May 2008

Relation of Adult-Onset Asthma to Coronary Heart Disease and Stroke

  • Stephen J. Onufrak, PhD

      Affiliations

    • Agricultural Research Service, US Department of Agriculture, Stoneville, Mississippi
    • Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
    • Corresponding Author InformationCorresponding author: Tel: 662-686-3437; fax: 662-686-3522.
    • ,
  • Jerome L. Abramson, PhD

      Affiliations

    • Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
    • ,
  • Harland D. Austin, DSc

      Affiliations

    • Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
    • ,
  • Fernando Holguin, MD, MPH

      Affiliations

    • Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia
    • ,
  • William M. McClellan, MD, MPH

      Affiliations

    • Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
    • ,
  • L. Viola Vaccarino, MD, PhD

      Affiliations

    • Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
    • Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.

Received 16 November 2007; received in revised form 19 December 2007; accepted 19 December 2007. published online 06 March 2008.

Article Outline

Asthma was associated with atherosclerotic disease in several studies, with evidence that this association may be limited to women. However, most previous studies failed to account for the heterogeneity of asthma subtypes. We previously reported increased carotid intima-medial thickness in women with adult-onset asthma. In this study, the association of adult- and child-onset asthma with incident coronary heart disease (CHD) and stroke were examined. Subjects were classified according to self-report of physician-diagnosed asthma and age of asthma onset. Cox proportional hazards models were used to test the association of adult- and child-onset asthma with incident CHD and stroke, testing for gender interaction. Subanalysis was also performed using only never smokers. Women with adult-onset asthma experienced a 2-fold increase in incident CHD and stroke that was independent of other risk factors, including smoking, body mass index, and physical activity, and persisted when analysis was restricted to never smokers. No significant association was found in women with child-onset asthma or in men. In conclusion, adult-onset asthma may be a significant risk factor for CHD and stroke in women, but not men.

 

Asthma was associated with vascular disease, carotid atherosclerosis, coronary heart disease (CHD), or stroke in at least 9 studies.1, 2, 3, 4, 5, 6, 7, 8, 9 In studies that presented results stratified by gender, there was a suggestion that the association may be stronger for or entirely limited to women.1, 2, 3, 4 However, asthma is not a single disease, but a collection of distinct underlying subtypes with differing causes.10, 11 Child- and adult-onset asthma differ in regard to asthma triggers,11 gender distribution,11 and systemic inflammation.12 We previously reported an association between carotid intima-medial thickness and adult-onset asthma in women in the Atherosclerosis Risk In Communities (ARIC) Study.4 This association was not observed in women with child-onset asthma or men with either adult- or child-onset asthma. In this study, we examined the association of asthma age of onset phenotypes with incidence of CHD and stroke according to gender within the ARIC cohort.

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Methods 

Study population 

The ARIC Study is a prospective study of the cause of atherosclerotic, cardiovascular, and cerebrovascular disease in 4 US communities in North Carolina, Mississippi, Minnesota, and Maryland.13 The study population of 15,792 men and women aged 45 to 64 years included both black and white subjects. Subjects completed a baseline clinic visit in 1987 to 1989 and were followed up for incidence of CHD and stroke events. We used publicly available data with follow-up available through 2001 for 15,732 subjects. We excluded subjects missing data for asthma status (n = 28) or who reported ever having asthma but did not report a physician diagnosis of asthma (n = 131). We also excluded subjects with self-reported history of stroke (n = 320) or prevalent CHD (n = 692), defined as history of myocardial infarction (MI), silent MI, or revascularization surgery at baseline. This left 14,567 subjects for analysis.

Baseline assessment of asthma status and other covariates 

Based on self-report of physician-diagnosed asthma and age of asthma onset, subjects were classified as having adult-onset asthma if age of onset was ≥21 years or child-onset asthma if onset was at age <21 years. Smoking was measured using self-reported smoking status (former, current, or never). Classification of diabetes was based on ≥1 of fasting plasma glucose >126 mg/dl, nonfasting plasma glucose >200 mg/dl, self-reported diabetes, or use of diabetes medications. Low- and high-density lipoprotein cholesterol were included in models as continuous variables. All laboratory tests were run at centralized chemical, hemostasis, and lipid laboratories, and hematologic tests were run at local laboratories. Hypertension was defined as diastolic blood pressure ≥90 mm Hg, systolic blood pressure >140 mm Hg, or self-report of antihypertensive drug use.14 Physical activity was assessed according to the scale of Baecke et al,15 based on frequency, duration, and intensity of physical activity. Education level was classified according to number of years of school completed (<12, 12 to 16, or >16 years). Asthma medication use (β-adrenergic and oral glucocorticoid medication) was classified according to use during the 2-week period before the baseline clinic visit and ascertained by having subjects bring all prescription and nonprescription medications used during this period to the clinic during their baseline visit. Forced expiratory volume in 1 second (FEV1) and forced expiratory vital capacity were assessed using spirometry according to the ARIC Study protocol.16 This protocol includes strict quality-control procedures to ensure recorded spirometry measurements are technically acceptable and reproducible.16 FEV1 was categorized for use in multivariable analysis according to gender-specific quartiles. Chronic bronchitis and emphysema were classified based on self-report of physician diagnosis.

Ascertainment of incident CHD and stroke events 

For our primary analysis, incident CHD was defined as definite or probable MI or fatal CHD. We also performed subanalyses in which incident CHD events included revascularization procedures and silent MI detected using electrocardiography. Incident strokes included both ischemic and hemorrhagic strokes. Potential CHD and stroke events were identified in cohort members through annual follow-up, survey of area hospital discharge lists, and state vital statistics. When discharge summaries indicated diagnosis codes for cardiovascular disease, diabetes, or stroke or included stroke-related keywords, hospital records were abstracted by trained study personnel. Out-of-hospital deaths were investigated using death certificates, interview with ≥1 next of kin, and a physician questionnaire, coroner report, or autopsy report. MI events were classified based on chest pain, cardiac enzymes, and electrocardiogram results. Fatal CHD classification was based on chest pain symptoms, cause of death from the death certificate, and available hospital information and medical history, including ARIC clinic visits. For stroke events, records were reviewed in detail by a member of the ARIC Study Stroke-Mortality and Morbidity Classification Committee, and the patient was classified according to type of stroke (ischemic or hemorrhagic). The outcome ascertainment process was described in further detail by ARIC investigators.17

Analysis 

Analysis was completed using SAS, version 9 (SAS Institute, Cary, North Carolina). Baseline covariates were compared by asthma history in men and women separately using chi-square test, Fisher's exact test, and pooled or unpooled t test. Missing covariate values, which occurred at <3% for any covariate, were imputed using multiple imputation methods.18 Crude incidence density rates of CHD and stroke were calculated in men and women for those without asthma, those with child-onset asthma, and those with adult-onset asthma. Crude and multivariate hazard ratios (HRs) comparing patients with each asthma subtype with those without asthma were computed using Cox proportional hazards models. Multivariate models were adjusted for age, body mass index, black race, smoking status, diabetes, hypertension, education level, low- and high-density lipoprotein, and leisure physical activity. We tested for interactions between asthma and gender in crude and multivariate models using Wald's chi-square tests. In subanalyses, we used an expanded definition of CHD to include revascularization and silent MI.

We also performed additional analyses to investigate the impact of asthma medications, lung function, and the respiratory co-morbidities chronic bronchitis and emphysema on the association of asthma with cardiovascular outcomes. To further examine the possible confounding effect of smoking and the possible misclassification of chronic obstructive pulmonary disease (COPD) as asthma on our results, we repeated the analysis in the subgroup of patients who never smoked. Finally, we also performed age-adjusted analysis of women free of diabetes, hypertension, emphysema, and chronic bronchitis. In all these additional analyses, we used a combined outcome of incident CHD or stroke to maximize the number of events in the model.

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Results 

The distribution of asthma age of onset in men and women is shown in Figure 1. The prevalence of child-onset asthma was higher in men (3.3%) than women (2.5%), whereas adult-onset asthma was more common in women (3.4%) compared with men (2.0%). Compared with their counterparts without asthma, men and women with adult-onset asthma were older and had a higher prevalence of diabetes and hypertension, more pack-years of smoking, higher fibrinogen, and higher prevalence of β-adrenergic and glucocorticoid steroid asthma medication use at baseline (Table 1). Women with adult-onset asthma also had significantly higher body mass index and lower physical activity and were more often postmenopausal than women without a history of asthma. Compared with patients without asthma, FEV1, percent of expected FEV1, and FEV1/forced expiratory vital capacity were lower in men and women with either asthma subtype, but were lowest in those with adult-onset asthma. Likewise, chronic bronchitis, emphysema, and use of asthma medications were more prevalent in all patients with asthma, but were most prevalent in those with adult-onset asthma (Table 1).

Table 1. Baseline comparison of men and women according to self-reported asthma history
VariableMenWomen
No Asthma (n = 5,931)Child-Onset⁎ Asthma (n = 210)Adult-Onset⁎ Asthma (n = 131)No Asthma (n = 7,809)Child-Onset⁎ Asthma (n = 203)Adult-Onset⁎ Asthma (n = 283)
Age (yrs)54.353.3†55.4†53.752.9†54.3
Black race (%)23.3%19.1%15.3%†29.6%30.1%33.2%
High school graduate (%)77.5%82.3%65.7%†77.2%76.4%69.3%†
Body mass index (kg/m2)27.427.227.327.828.328.9†
Diabetes mellitus (%)10.5%10.6%14.5%10.8%17.2%†17.8%†
Hypertension (%)32.4%29.2%37.4%34.1%33.0%43.6%†
Chronic bronchitis (%)4.0%15.1%†27.9%†9.2%39.6%†43.1%†
Emphysema (%)1.9%4.3%†8.4%†0.9%3.9%†5.3%†
Current smoker (%)27.6%22.4%21.4%24.6%22.8%29.0%
Pack-years21.720.124.310.011.213.8†
Leisure physical activity index2.342.352.352.382.332.29†
FEV1 (L)3.373.11†2.74†2.442.20†2.05†
FEV1 (% predicted)91.4%83.2%†74.6%†97.1%86.5%†83.3%†
FEV1/forced expiratory vital capacity73.568.3†63.5†75.971.1†70.3†
Low-density lipoprotein cholesterol (mg/dl)139135139136133134
High-density lipoprotein cholesterol (mg/dl)454547†585858
Albumin (mg/dl)3.923.963.913.833.78†3.81
Fibrinogen (mg/dl)295294306307315316†
Present hormone replacement therapy (%)———19.2%22.6%15.7%
Postmenopausal or hysterectomy (%)———67.1%58.9%†75.9%†
β-Adrenergic asthma medication use (%)0.6%6.2%†29.0%†0.4%13.3%†22.6%†
Oral glucocorticoid asthma medication use (%)0.5%2.9%†12.2%†1.0%3.5%†9.2%†

⁎Child onset = age <21 years; adult onset = age ≥21 years.

†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.

Women, but not men, with adult-onset asthma experienced a 2-fold increase in rate of CHD compared with their counterparts without asthma (Table 2). This association was attenuated, but remained significant, after adjustment for age, body mass index, black race, smoking status, diabetes, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity (Table 2). Child-onset asthma was not significantly associated with incident CHD in women or men. Tests of interaction between gender and adult-onset asthma were significant (p <0.05) in all CHD models, whereas interaction tests of child-onset asthma with gender were not. Results were similar in subanalyses in which incident CHD also included revascularization procedures and silent MI, with an adjusted HR of 1.86 (95% confidence interval [CI] 1.31 to 2.63) for women with adult-onset asthma and nonsignificant associations observed in all other asthma–gender subgroups.

Table 2. Incident coronary heart disease rates and hazard ratios in men and women according to asthma history
MenWomen
No History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaNo History of AsthmaChild-Onset AsthmaAdult-Onset Asthma
Crude rate⁎ (cases/person-yrs)7.85(565/72,006)8.52(22/2,582)6.22(10/1,607)3.52(348/98,963)3.49(9/2,580)7.34(25/3,407)
Crude HR (95% CI)1.0(reference)1.08(0.71–1.66)0.80(0.43–1.49)1.0(reference)0.99(0.51–1.93)2.10(1.40–3.16)
Multivariate-adjusted† HR (95% CI)1.0(reference)1.25(0.82–1.92)0.71(0.38–1.32)1.0(reference)0.95(0.49–1.83)1.78(1.18–2.67)

⁎Per 1,000 person-years.

†Adjusted for age, body mass index, black race, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity.

Similar to results for CHD, adult-onset asthma was associated with incident stroke in women, but not men, with a significant gender interaction (p <0.05; Table 3). The association of adult-onset asthma with stroke in women remained significant after adjustment for demographic variables and established CHD risk factors (Table 3). The small numbers of stroke events precluded multivariate analysis in men. Child-onset asthma was not significantly associated with incident stroke in men or women, and the interaction of child-onset asthma and gender was nonsignificant (Table 3).

Table 3. Incident stroke rates and hazard ratios in men and women according to asthma history
MenWomen
No History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaNo History of AsthmaChild-Onset AsthmaAdult-Onset Asthma
Crude rate⁎ (cases/person-yrs)3.50(257/73,489)2.27(6/2,639)1.22(2/1,634)2.39(238/99,443)3.51(9/2,565)5.57(19/3,411)
Crude HR (95% CI)1.0(reference)0.65(0.29–1.45)0.35(0.09–1.41)1.0(reference)1.47(0.76–2.87)2.36(1.48–3.76)
Multivariate-adjusted† HR (95% CI)1.0(reference)——1.0(reference)1.25(0.64–2.44)2.08(1.30–3.32)

⁎Per 1,000 person-years.

†Adjusted for age, body mass index, black race, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity.

Because of the similarity of results for CHD and stroke outcomes, we performed additional analyses using a combined end point of incident cardiovascular disease, including CHD or stroke (Figure 2). In the fully adjusted model including covariates for asthma medications, FEV1, chronic bronchitis, and emphysema, adult-onset asthma was significantly associated with this combined outcome in women (HR 1.68, 95% CI 1.21 to 2.35). Results remained robust in analyses restricted to never smokers, which again confirmed a significant association of adult-onset asthma in women, but not in men or in women or men with child-onset asthma (Table 4). Finally, in age-adjusted analysis in women free of diabetes, hypertension, emphysema, and chronic bronchitis, adult-onset asthma was strongly associated with incidence of CHD or stroke (HR 3.93, 95% CI 2.01 to 7.02), whereas child-onset asthma was not significantly associated (HR 1.80, 95% CI 0.67 to 4.87).

  • View full-size image.
  • Figure 2. 

    HRs for incident CHD or stroke according to age of asthma onset and gender. Adjusted model 1 includes age, body mass index, black race, smoking status, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity; Adjusted model 2 includes model 1 covariates plus FEV1, chronic bronchitis, emphysema, and use of glucocorticoid or β-adrenergic medicines.

Table 4. Never smokers only: combined coronary heart disease or stroke event rates and hazard ratios in men and women according to asthma history
MenWomen
No History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaNo History of AsthmaChild-Onset AsthmaAdult-Onset Asthma
Crude rate⁎ (cases/person-yrs)8.31(181/21,757)5.49(5/910)10.69(5/468)4.75(251/52,868)5.40(7/1,296)10.59(18/1,699)
Crude HR (95% CI)1.0(reference)0.65(0.27–1.68)1.31(0.54–3.18)1.0(reference)1.14(0.51–2.43)2.24(1.39–3.62)
Multivariate-adjusted† HR (95% CI)1.0(reference)0.74(0.30–1.80)1.04(0.43–2.53)1.0(reference)1.10(0.52–2.33)2.05(1.28–3.31)

⁎Per 1,000 person-years.

†Adjusted for age, body mass index, black race, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity.

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Discussion 

In this large community-based follow-up study, women with adult-onset asthma experienced a nearly 2-fold increase in rate of CHD and stroke independent of other risk factors, including smoking, body mass index, and physical activity, that persisted when analysis was restricted to never smokers. This result was consistent with our previous finding that women, but not men, with adult-onset asthma had increased carotid intima-medial thickness compared with their counterparts without asthma4 and with other reports suggesting a role of asthma in atherosclerotic disease in women, but not men.1, 2, 3

This was the first study to test the association of asthma age-of-onset subtypes with cardiovascular outcomes. It is recognized that “asthma” is not a uniform disease, but rather a constellation of distinct conditions.10, 11, 19 Adult-onset asthma differs from child-onset asthma in several aspects, including its distribution in men and women11 and its immunologic and inflammatory pathophysiologic characteristics.10, 19 Nevertheless, previous studies of patients with asthma and atherosclerotic outcomes generally ignored asthma subtypes. Three previous studies presented gender-specific results for the association between asthma and CHD. Toren and Lindholm1 reported age-adjusted standardized mortality ratios for ischemic heart disease of 1.4 (95% CI 0.8 to 2.0) in men with asthma and 2.5 (95% CI 1.7 to 3.3) in women with asthma. In a retrospective cohort study of a large insurance cohort, Iribarren et al2 reported multivariate adjusted HRs of 1.22 (95% CI 1.14 to 1.31) in women with asthma and 0.99 (95% CI 0.93 to 1.05) in men with asthma. Similarly, an earlier report from the ARIC Study found increased risk of stroke in women with asthma, but not men, compared with subjects without asthma, although no association was found with CHD outcomes in either women or men.3 None of these previous reports distinguished among asthma subtypes. Thus, the lack of association of asthma with CHD reported in the previous ARIC Study probably reflected mixing of the heterogeneous effects of adult- and child-onset asthma subtypes.3 By separating asthma subtypes, we uncovered an important risk associated with adult-onset asthma in women.

The precise mechanisms underlying the association between adult-onset asthma and atherosclerotic vascular disease in women are unclear. Asthma may predispose to atherosclerosis through specific pathophysiologic pathways, perhaps linked to the chronic inflammatory response of this disorder. Alternatively, the association between asthma and atherosclerosis may be caused by an inherent joint susceptibility to both diseases through shared inflammatory pathways. For example, cysteinyl leukotrienes, potent inflammatory mediators, were implicated in the pathogenesis of both asthma20 and atherosclerosis.21 Why is the association between asthma and cardiovascular disease observed in only women with adult-onset asthma? Estrogen, which increases at puberty, modulates the release of proinflammatory cytokines from activated monocytes, macrophages,22 and vascular cells23, 24 and also regulates the production of leukotrienes from mast cells.25 The incidence rate of asthma in women is temporally associated with shifts in estrogen levels, with incidence increasing after puberty26 and peaking during the onset of menopause27 (Figure 1). Thus, we may speculate that women who develop asthma during these hormonal life events may be particularly susceptible to estrogen-modulated alterations in inflammatory cytokine and leukotriene regulation.

Our study has several strengths. Foremost, the ARIC cohort is large, multiracial, and prospective and includes rich and high-quality subject data. We were able to control for potentially important confounding variables, such as smoking, physical activity, and asthma medication use, and we further addressed confounding by smoking and other factors by performing subanalyses restricted to never-smoking subjects and subjects free of diabetes, hypertension, emphysema, and chronic bronchitis. The major weakness of our study was that asthma status was based on self-report of physician diagnosis. Although there was evidence to suggest that self-reported asthma yielded high specificity,28 there were also reports to suggest that misdiagnosis of COPD as asthma occurred frequently, and more so in women.29 Because approximately 85% of patients with COPD had a history of smoking, the persistence of the association of adult-onset asthma with CHD in never-smoking women suggested that the observed association was not likely to be caused by misdiagnosed COPD. Nonetheless, there is the need for further research in which asthma classification is objectively determined through established clinical guidelines. Furthermore, we did not have information for immunoglobulin E levels, asthma triggers, or presence of allergies to differentiate asthma according to allergic status. Other limitations included small numbers of events, particularly stroke, in men with adult-onset asthma and lack of data for such inflammatory markers as C-reactive protein. Finally, because our study was observational, we cannot exclude the influence of unmeasured confounding factors or residual confounding because asthma was associated with many known cardiovascular risk factors.

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Acknowledgment 

The authors thank the ARIC researchers for their outstanding work and contributions to the study of cardiovascular disease and Sean Coady, MA, for help in data acquisition. The ARIC Study was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the ARIC Study Investigators. This report was prepared using a limited-access data set obtained by the NHLBI and does not necessarily reflect the opinions or views of the ARIC Study group or the NHLBI. Primary work for this study was performed while Dr. Onufrak was a doctoral student at Emory University, Atlanta, Georgia.

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 This work was supported by Grant No. K24 HL077506 from the National Institutes of Health, Bethesda, Maryland. Dr. Onufrak was supported by a predoctoral fellowship from the American Heart Association, Dallas, Texas (Award Number: 0615219B).

PII: S0002-9149(08)00048-9

doi:10.1016/j.amjcard.2007.12.024

American Journal of Cardiology
Volume 101, Issue 9 , Pages 1247-1252, 1 May 2008

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