Relation of Adult-Onset Asthma to Coronary Heart Disease and Stroke
2008; Elsevier BV; Volume: 101; Issue: 9 Linguagem: Inglês
10.1016/j.amjcard.2007.12.024
ISSN1879-1913
AutoresStephen Onufrak, Jerome L. Abramson, Harland Austin, Fernando Holguín, William M. McClellan, Viola Vaccarino,
Tópico(s)Chronic Obstructive Pulmonary Disease (COPD) Research
ResumoAsthma 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 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.1Toren K. Lindholm N.B. Do patients with severe asthma run an increased risk from ischaemic heart disease?.Int J Epidemiol. 1996; 25: 617-620Crossref PubMed Scopus (57) Google Scholar, 2Iribarren C. Tolstykh I.V. Eisner M.D. Are patients with asthma at increased risk of coronary heart disease?.Int J Epidemiol. 2004; 33: 743-748Crossref PubMed Scopus (103) Google Scholar, 3Schanen J.G. Iribarren C. Shahar E. Punjabi N.M. Rich S.S. Sorlie P.D. Folsom A.R. Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study.Thorax. 2005; 60: 633-638Crossref PubMed Scopus (123) Google Scholar, 4Onufrak S. Abramson J. Vaccarino V. Adult-onset asthma is associated with increased carotid atherosclerosis among women in the Atherosclerosis Risk in Communities (ARIC) Study.Atherosclerosis. 2007; 195: 129-137Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 5Zureik M. Kony S. Neukirch C. Courbon D. Leynaert B. Vervloet D. Ducimetiere P. Neukirch F. Bronchial hyperresponsiveness to methacholine is associated with increased common carotid intima-media thickness in men.Arterioscler Thromb Vasc Biol. 2004; 24: 1098-1103Crossref PubMed Scopus (14) Google Scholar, 6Liss G.M. Tarlo S.M. Banks D. Yeung K.S. Schweigert M. Preliminary report of mortality among workers compensated for work-related asthma.Am J Ind Med. 1999; 35: 465-471Crossref PubMed Scopus (25) Google Scholar, 7Liss G.M. Tarlo S.M. Macfarlane Y. Yeung K.S. Hospitalization among workers compensated for occupational asthma.Am J Respir Crit Care Med. 2000; 162: 112-118Crossref PubMed Scopus (46) Google Scholar, 8Soriano J.B. Visick G.T. Muellerova H. Payvandi N. Hansell A.L. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care.Chest. 2005; 128: 2099-2107Crossref PubMed Scopus (440) Google Scholar, 9Knoflach M. Kiechl S. Mayr A. Willeit J. Poewe W. Wick G. Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies.Arch Intern Med. 2005; 165: 2521-2526Crossref PubMed Scopus (82) Google Scholar In studies that presented results stratified by gender, there was a suggestion that the association may be stronger for or entirely limited to women.1Toren K. Lindholm N.B. Do patients with severe asthma run an increased risk from ischaemic heart disease?.Int J Epidemiol. 1996; 25: 617-620Crossref PubMed Scopus (57) Google Scholar, 2Iribarren C. Tolstykh I.V. Eisner M.D. Are patients with asthma at increased risk of coronary heart disease?.Int J Epidemiol. 2004; 33: 743-748Crossref PubMed Scopus (103) Google Scholar, 3Schanen J.G. Iribarren C. Shahar E. Punjabi N.M. Rich S.S. Sorlie P.D. Folsom A.R. Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study.Thorax. 2005; 60: 633-638Crossref PubMed Scopus (123) Google Scholar, 4Onufrak S. Abramson J. Vaccarino V. Adult-onset asthma is associated with increased carotid atherosclerosis among women in the Atherosclerosis Risk in Communities (ARIC) Study.Atherosclerosis. 2007; 195: 129-137Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar However, asthma is not a single disease, but a collection of distinct underlying subtypes with differing causes.10Bel E.H. Clinical phenotypes of asthma.Curr Opin Pulm Med. 2004; 10: 44-50Crossref PubMed Scopus (209) Google Scholar, 11Wenzel S.E. Asthma: defining of the persistent adult phenotypes.Lancet. 2006; 368: 804-813Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar Child- and adult-onset asthma differ in regard to asthma triggers,11Wenzel S.E. Asthma: defining of the persistent adult phenotypes.Lancet. 2006; 368: 804-813Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar gender distribution,11Wenzel S.E. Asthma: defining of the persistent adult phenotypes.Lancet. 2006; 368: 804-813Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar and systemic inflammation.12Olafsdottir I.S. Gislason T. Thjodleifsson B. Olafsson I. Gislason D. Jogi R. Janson C. C Reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study.Thorax. 2005; 60: 451-454Crossref PubMed Scopus (116) Google Scholar We previously reported an association between carotid intima-medial thickness and adult-onset asthma in women in the Atherosclerosis Risk In Communities (ARIC) Study.4Onufrak S. Abramson J. Vaccarino V. Adult-onset asthma is associated with increased carotid atherosclerosis among women in the Atherosclerosis Risk in Communities (ARIC) Study.Atherosclerosis. 2007; 195: 129-137Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar 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. 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.13The ARIC InvestigatorsThe Atherosclerosis Risk in Communities (ARIC) Study: design and objectives.Am J Epidemiol. 1989; 129: 687-702Crossref PubMed Scopus (2848) Google Scholar 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. 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 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.14Jones D.W. Hall J.E. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and evidence from new hypertension trials.Hypertension. 2004; 43: 1-3Crossref PubMed Scopus (165) Google Scholar Physical activity was assessed according to the scale of Baecke et al,15Baecke J.A. Burema J. Frijters J.E. A short questionnaire for the measurement of habitual physical activity in epidemiological studies.Am J Clin Nutr. 1982; 36: 936-942PubMed Google Scholar based on frequency, duration, and intensity of physical activity. Education level was classified according to number of years of school completed ( 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.16The ARIC InvestigatorsARIC Protocol 4 Pulmonary Function Assessment, Version 7. National Heart Lung and Blood Institute, National Institutes of Health, Chapel Hill, NC1987Google Scholar This protocol includes strict quality-control procedures to ensure recorded spirometry measurements are technically acceptable and reproducible.16The ARIC InvestigatorsARIC Protocol 4 Pulmonary Function Assessment, Version 7. National Heart Lung and Blood Institute, National Institutes of Health, Chapel Hill, NC1987Google Scholar 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. 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.17The ARIC InvestigatorsAtherosclerosis Risk in Communities (ARIC) Study Surveillance Component Procedures Protocol 3, Version 4. Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC1987Google Scholar 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.18Barnard J. Meng X.L. Applications of multiple imputation in medical studies: from AIDS to NHANES.Stat Methods Med Res. 1999; 8: 17-36Crossref PubMed Scopus (230) Google Scholar 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. 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 1Baseline comparison of men and women according to self-reported asthma historyVariableMenWomenNo Asthma (n = 5,931)Child-Onset⁎Child onset = age <21 years; adult onset = age ≥21 years. Asthma (n = 210)Adult-Onset⁎Child onset = age <21 years; adult onset = age ≥21 years. Asthma (n = 131)No Asthma (n = 7,809)Child-Onset⁎Child onset = age <21 years; adult onset = age ≥21 years. Asthma (n = 203)Adult-Onset⁎Child onset = age <21 years; adult onset = age ≥21 years. Asthma (n = 283)Age (yrs)54.353.3†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.55.4†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.53.752.9†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.54.3Black race (%)23.3%19.1%15.3%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.29.6%30.1%33.2%High school graduate (%)77.5%82.3%65.7%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.77.2%76.4%69.3%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Body mass index (kg/m2)27.427.227.327.828.328.9†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Diabetes mellitus (%)10.5%10.6%14.5%10.8%17.2%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.17.8%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Hypertension (%)32.4%29.2%37.4%34.1%33.0%43.6%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Chronic bronchitis (%)4.0%15.1%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.27.9%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.9.2%39.6%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.43.1%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Emphysema (%)1.9%4.3%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.8.4%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.0.9%3.9%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.5.3%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Current smoker (%)27.6%22.4%21.4%24.6%22.8%29.0%Pack-years21.720.124.310.011.213.8†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Leisure physical activity index2.342.352.352.382.332.29†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.FEV1 (L)3.373.11†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.2.74†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.2.442.20†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.2.05†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.FEV1 (% predicted)91.4%83.2%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.74.6%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.97.1%86.5%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.83.3%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.FEV1/forced expiratory vital capacity73.568.3†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.63.5†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.75.971.1†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.70.3†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Low-density lipoprotein cholesterol (mg/dl)139135139136133134High-density lipoprotein cholesterol (mg/dl)454547†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.585858Albumin (mg/dl)3.923.963.913.833.78†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.3.81Fibrinogen (mg/dl)295294306307315316†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Present hormone replacement therapy (%)———19.2%22.6%15.7%Postmenopausal or hysterectomy (%)———67.1%58.9%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.75.9%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.β-Adrenergic asthma medication use (%)0.6%6.2%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.29.0%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.0.4%13.3%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.22.6%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.Oral glucocorticoid asthma medication use (%)0.5%2.9%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.12.2%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.1.0%3.5%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender.9.2%†p <0.05 comparing subjects within asthma subtype with subjects reporting no history of asthma within each gender. 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. Open table in a new tab 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 2Incident coronary heart disease rates and hazard ratios in men and women according to asthma historyMenWomenNo History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaNo History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaCrude rate⁎Per 1,000 person-years. (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†Adjusted for age, body mass index, black race, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity. 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. Open table in a new tab 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 3Incident stroke rates and hazard ratios in men and women according to asthma historyMenWomenNo History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaNo History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaCrude rate⁎Per 1,000 person-years. (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†Adjusted for age, body mass index, black race, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity. 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. Open table in a new tab 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).Table 4Never smokers only: combined coronary heart disease or stroke event rates and hazard ratios in men and women according to asthma historyMenWomenNo History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaNo History of AsthmaChild-Onset AsthmaAdult-Onset AsthmaCrude rate⁎Per 1,000 person-years. (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†Adjusted for age, body mass index, black race, diabetes mellitus, hypertension, education level, low- and high-density lipoprotein cholesterol, and physical activity. 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. Open table in a new tab 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 asthma4Onufrak S. Abramson J. Vaccarino V. Adult-onset asthma is associated with increased carotid atherosclerosis among women in the Atherosclerosis Risk in Communities (ARIC) Study.Atherosclerosis. 2007; 195: 129-137Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar and with other reports suggesting a role of asthma in atherosclerotic disease in women, but not men.1Toren K. Lindholm N.B. Do patients with severe asthma run an increased risk from ischaemic heart disease?.Int J Epidemiol. 1996; 25: 617-620Crossref PubMed Scopus (57) Google Scholar, 2Iribarren C. Tolstykh I.V. Eisner M.D. Are patients with asthma at increased risk of coronary heart disease?.Int J Epidemiol. 2004; 33: 743-748Crossref PubMed Scopus (103) Google Scholar, 3Schanen J.G. Iribarren C. Shahar E. Punjabi N.M. Rich S.S. Sorlie P.D. Folsom A.R. Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study.Thorax. 2005; 60: 633-638Crossref PubMed Scopus (123) Google Scholar 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.10Bel E.H. Clinical phenotypes of asthma.Curr Opin Pulm Med. 2004; 10: 44-50Crossref PubMed Scopus (209) Google Scholar, 11Wenzel S.E. Asthma: defining of the persistent adult phenotypes.Lancet. 2006; 368: 804-813Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar, 19Miranda C. Busacker A. Balzar S. Trudeau J. Wenzel S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.J Allergy Clin Immunol. 2004; 113: 101-108Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar Adult-onset asthma differs from child-onset asthma in several aspects, including its distribution in men and women11Wenzel S.E. Asthma: defining of the persistent adult phenotypes.Lancet. 2006; 368: 804-813Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar and its immunologic and inflammatory pathophysiologic characteristics.10Bel E.H. Clinical phenotypes of asthma.Curr Opin Pulm Med. 2004; 10: 44-50Crossref PubMed Scopus (209) Google Scholar, 19Miranda C. Busacker A. Balzar S. Trudeau J. Wenzel S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.J Allergy Clin Immunol. 2004; 113: 101-108Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar 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 Lindholm1Toren K. Lindholm N.B. Do patients with severe asthma run an increased risk from ischaemic heart disease?.Int J Epidemiol. 1996; 25: 617-620Crossref PubMed Scopus (57) Google Scholar 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 al2Iribarren C. Tolstykh I.V. Eisner M.D. Are patients with asthma at increased risk of coronary heart disease?.Int J Epidemiol. 2004; 33: 743-748Crossref PubMed Scopus (103) Google Scholar 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.3Schanen J.G. Iribarren C. Shahar E. Punjabi N.M. Rich S.S. Sorlie P.D. Folsom A.R. Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study.Thorax. 2005; 60: 633-638Crossref PubMed Scopus (123) Google Scholar None of these previous reports distinguished among asthma subtypes. 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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,28Toren K. Brisman J. Jarvholm B. Asthma and asthma-like symptoms in adults assessed by questionnaires A literature review.Chest. 1993; 104: 600-608Crossref PubMed Scopus (519) Google Scholar there were also reports to suggest that misdiagnosis of COPD as asthma occurred frequently, and more so in women.29Chapman K.R. Tashkin D.P. Pye D.J. Gender bias in the diagnosis of COPD.Chest. 2001; 119: 1691-1695Crossref PubMed Scopus (280) Google Scholar 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. 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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