Association of adult-onset asthma with specific cardiovascular conditions

Respiratory Medicine (2012) 106, 948e953

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Association of adult-onset asthma with specific cardiovascular conditions Hwa Mu Lee a,b,*, Steven T. Truong a, Nathan D. Wong a a

Heart Disease Prevention Program, Division of Cardiology, Department of Medicine, School of Medicine, 112 Sprague Hall, University of California, Irvine, CA 92697-4101, USA b Division of Pulmonary Medicine, Department of Medicine, University of California, Irvine, CA, USA Received 13 October 2011; accepted 25 February 2012 Available online 24 March 2012

KEYWORDS Asthma; Cardiovascular disease; NHANES

Summary Background: While asthma is known to be associated with cardiovascular disease (CVD), the relation to specific manifestations of CVD has not been previously described. Our objective was to explore the relation of child and adult-onset asthma with specific CVD conditions. Methods: We examined data from 16,943 (projected 178 million) U.S. adults aged 18e90 years old with relevant information on asthma and CVD. The study was a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999e2006. We determined the prevalence of CVD risk factors and likelihood of CVD conditions according to gender and asthma status using multiple logistic regression adjusted for age, gender and other CVD risk factors. Results: The proportions of subjects with child and adult-onset asthma were 4.8% (n Z 702) and 3.3% (n Z 534), respectively. Adult-onset asthma was significantly associated with total CVD (OR Z 2.07, CI Z 1.2e3.7), but child-onset asthma was not associated with any CVD conditions. Of the four specific CVD endpoints, adult-onset asthma overall was only associated with coronary heart disease (CHD) (OR Z 2.26, CI Z 1.2e4.2) in the total population. Conclusions: Our data suggests that CHD is the major cardiovascular condition associated with asthma; a prospective study must be done to confirm a causal relationship. ª 2012 Elsevier Ltd. All rights reserved.

Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; CHF, congestive heart failure; MI, myocardial infarction; Hs-CRP, high sensitivity C-reactive protein; HDL, high-density lipoprotein; BP, blood pressure; CI, confidence interval; OR, odds ratio; RR, relative risk; NHANES, National Health and Nutrition Examination Survey; ARIC, Atherosclerosis Risk in Communities. * Corresponding author. Heart Disease Prevention Program, Division of Cardiology, Department of Medicine, School of Medicine, 112 Sprague Hall, University of California, Irvine, CA 92697-4101, USA. Tel.: þ1 949 824 5561; fax: þ1 949 824 5567. E-mail address: [email protected] (H.M. Lee).

Introduction Asthma is a chronic inflammatory process in the airway characterized by bronchospasms and airflow obstruction and affects an estimated 300 million people worldwide. Adults with asthma or asthmatic symptoms have been shown to have higher levels of C-reactive protein (Hs-CRP),4 a known inflammatory marker and risk factor for cardiovascular disease (CVD). Inflammation has been considered

0954-6111/$ - see front matter ª 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2012.02.017

Asthma association with cardiovascular conditions to have a significant role in pathogenesis of atherosclerosis,1e3 but despite many studies examining the association of impaired lung function and CVD5e16 there were relatively few publications to relate asthma to CVD. However, in recent years, several studies support the association of asthma and CVD.17e23 A prospective study of 15,792 adults in 2008 by Onufrak showed a 2-fold increase in the risk of stroke and coronary heart disease (CHD), while a Canadian study determined people with asthma were at increased odds of heart disease when compared to people without asthma.18 In a retrospective study of a large insurance cohort in 2004, Iribarren et al. reported multivariate adjusted HRs of 1.22 in women with asthma19 with CHD as the endpoint. Although all the papers support the association of asthma and CVD, they all relate different specific CVD endpoints to asthma: stroke, CHD and hypertension, sometimes with different results for the same condition. A study by Dogra found no correlation between stroke and asthma, while an Onufrak study found that there was a stroke correlation. Even though asthma has been shown to be associated with CVD, the relation to specific manifestations of CVD, such as myocardial infarction, stroke, heart failure or angina, varies from paper to paper and has not been described in depth. In this paper we examined in a population-representative sample of U.S. adults the relation of child-onset and adult-onset asthma with specific CVD conditions in order to clarify which conditions form the association. We also examined whether levels of inflammation measured by C-reactive protein influenced the relation of asthma with CVD.

Methods The 1999e2006 U.S. National Health and Nutrition Survey (termed NHANES IV) is a cross-sectional study providing information on more than 16,000 adults with asthma, CVD and other relevant cardiovascular information.24 The data from NHANES were self-reported (physician diagnosis, age when first diagnosed, current asthma status) for asthma, CVD risk factors, and demographic information. We examined data taken from adults ages 18 and above (n Z 16,943 weighted to U.S. population, 51.7% female). 18 persons with missing asthma data were excluded from the study. The asthma variable was also created from self-reported data because NHANES IV (1999e2006) specifically does not provide spirometric data or any form of quantitative lung function testing. People designated as adult-onset asthma had to be 18 or older and have been diagnosed with asthma at the age of 18 or greater. Anyone who had been diagnosed with asthma below the age of 18 was labeled child-onset asthma, and all others were set as no asthma. The four endpoints used for the analysis were stroke, congestive heart failure (CHF), coronary heart disease (CHD), and total CVD. Total CVD was defined by a doctor telling the subject that they had one of the following conditions 1) myocardial infarction, 2) stroke, 3) angina, 4) congestive heart failure (CHF), or 5) CHD. CHD was defined as having either having angina, a myocardial infarction, or the direct label of CHD. C-reactive protein (Hs-CRP) levels were categorized as either above (high) or below or equal

949 to (low) 3 mg/L.25 Diabetes was defined as having either a glucose level of 126 mg/dl26 or higher with a fasting time greater than 12 h, being told that by a doctor that the subject has diabetes, or if the subject is taking insulin or diabetic pills. Smoking was defined as currently smoking or not. Body mass index (BMI) was categorized into three groups: BMI < 25, BMI greater than 25 and less than 30, and BMI  30. A Chi-squared test of proportions was used to find the proportions of asthma, CVD, diabetes and other risk factors within the subject population. The population itself was divided and categorized by gender across asthma status. Variables such as age, systolic blood pressure and cholesterol were continuous variables, and their means and standard deviations were determined. Multiple logistic regression was used to calculate the odds of CVD and specific CVD conditions according to asthma status, adjusted for other CVD risk factors (age, systolic blood pressure, HDL cholesterol, BMI, Hs-CRP, smoking, and diabetes mellitus). The logistic regressions were done using those without asthma as the reference. Another logistic regression was done to test for an interaction between asthma status and Hs-CRP. Multiple logistic regressions were also done with each of the specific CVD conditions as the endpoint.

Results Females made up 52% (n Z 8761) of the total subject sample (n Z 16,943), and had twice the prevalence of males affected with adult-onset asthma (4.5% vs. 2.1%). The proportions of child and adult-onset asthma were 4.8% (n Z 702) and 3.3% (n Z 534) respectively. People with child-onset asthma tended to be the youngest (37.7  16.0 years) and have a higher proportion of smoking (26.3%). Table 1 shows the proportions or means of CVD risk factors across the total population. The table also shows the prevalence of the four CVD conditions for all asthma groups: stroke, CHF, CHD, and CVD. Table 2 displays the prevalence of the four conditions across asthma status. Within the overall population, the prevalence of all CVD conditions was highest in people with adult-onset asthma and lowest in persons with child-onset asthma, with the exception of CHF. People with adult-onset asthma tended to be older (53.1  18.4 years), more likely to be overweight (44%) and diabetic (9.8%)and had higher HDLcholesterol (56.0  16.3 mg/dL) levels than the other groups. Men and women with adult-onset asthma had a similar prevalence of obesity (43.8% vs. 44.4%) and women with asthma had a substantially higher Hs-CRP level (6.0 vs. 4.6 mg/L). The ratio of women with adult-onset asthma to men was 2:1, while the proportions of other conditions such as total CVD and CHD were equal across gender in people with adult-onset asthma. Table 2 shows the odds ratios for specific CVD conditions in various populations split by asthma status and gender. The columns show the odds ratios for each of the CVD endpoints in an asthmatic group, further divided among males, females, and overall. Adult-onset asthma was found to have a significant association with total CVD (OR Z 2.1, CI Z 1.2e3.7). Only one specific cardiovascular condition

H.M. Lee et al. 8057 (91.4) 49.2**  9.8 124**  23.2 61.1  17.3 206  42.8 5.63  8.90 32.0 20.2 7.7 2.2 2.6 2.2 1.7 4.5 7.1 341 (4.11) 36.5  16.4 117  19.3 59.4  14.7 201  51.3 5.95  8.67 35.3 20.1 2.7 0.7 3.0 1.4 1.9 1.7 5.0 7650 (92.5) 50.7**  9.0 127**  18.4 48.9  14.0 199**  43.2 3.94  9.09 28.3 27.6 7.8 4.2 2.0 2.7 2.1 6.9 8.6 361 (5.46) 38.9  15.6 124  14.6 51.0  15.3 191  43.7 3.41  5.52 30.1 31.1 5.8 3.8 1.2 1.9 2.4 4.4 5.5 171 (2.09) 55.1  17.9 128  19.5 50.7  16.4 194  48.2 4.61  11.2 43.8* 11.7** 12.8 5.1 3.8 3.3 5.3 9.9* 13.6*

Discussion

**p < 0.01, *p < 0.05 when compared across asthma status.

15,707 (91.9) 49.9**  9.4 125**  21.0 55.1  16.9 203**  43.1 4.80  9.03 30.2 23.8 7.8 3.2 2.3 2.5 1.9 5.6 7.9 702 (4.77) 37.7  16.0 121  17.3 55.0  15.6 196  47.7 4.64  7.32 32.4 26.3 4.5 2.5 2.0 1.7 2.1 3.2 5.3 534 (3.31) 53.1  18.4 127  21.3 56.0  16.3 202  44.2 5.56  8.84 44.2** 19.0* 9.8** 5.0 4.7 4.5** 3.4 10** 13.8**

Child onset

was significantly associated with adult-onset asthma:CHD (OR Z 2.3, CI Z 1.2e4.2). Child-onset asthma showed no association with any of the CVD conditions. When males with adult-onset asthma were isolated, all the resulting odds ratios were insignificant. In gender stratified analyses, only females with adult-onset asthma showed an increase in the odds for total CVD (OR Z 2.4, CI Z 1.2e4.7) and CHD (OR Z 2.9, CI Z 1.4e6.3). A logistic regression of CRP and asthma status showed that both males and females with adult-onset asthma and females with child-onset asthma had higher Hs-CRP levels when compared to those with no asthma (5.6 and 6.0 vs. 4.8 mg/L). A separate multiple logistic regression adjusting for all risk factors showed Hs-CRP was significantly associated with total CVD (OR Z 1.5, CI Z 1.1e2.0) and CHF (OR Z 1.8, CI Z 1.1e2.8). However, an analysis using an interaction term of asthma status and Hs-CRP testing with an endpoint of CVD did not show any significant relation between asthma status and Hs-CRP levels. A further logistic regression was done examining asthma status with CVD when differed by gender-BMI groups. We found only females with adult-onset asthma and a BMI greater than 25 and less than 30 had a greater likelihood of CVD (OR: 6.5, CI Z 2.2e19.0) compared to people with no asthma.

363 (4.49) 52.2  18.5 126  22.1 59.0  15.5 206  41.8 6.00  7.51 44.4** 22.1 8.4** 5.0** 5.1 5.0* 2.6 10.0** 13.8**

Child onset Adult onset No asthma

Men (n Z 8182)

Adult onset

Child onset

n (Weighted) Age (years) Systolic BP (mmHg) HDL Cholesterol (mg/dL) Total Cholesterol (mg/dL) C-Reactive Protein (mg/L) BMI  30 (%) Smoking (%) Diabetes (%) Myocardial Infarction (%) Stroke (%) Angina (%) Congestive Heart Failure (%) Coronary Heart Disease (%) Total CVD (%)

Table 1

Population demographics (n Z 16,943).

No asthma Overall

Adult onset

Women (n Z 8761)

No asthma

950

Our study suggests that only individuals with adult-onset asthma had an increased likelihood for CHD and total CVD when compared to those with no asthma, and that CHD is the major manifestation of CVD related to adult-onset asthma. Women with adult-onset asthma appeared more likely to have CVD than men with adult-onset asthma. The findings for total CVD were consistent with previous studies,17e23 but when comparing the specific CVD endpoints of each paper, there is less consistency in these results. The study by Onufrak found that women with adult-onset asthma had an increased risk of both CHD and stroke, while the Atherosclerosis Risk in Communities (ARIC) study showed that compared to individuals without asthma, those with asthma did not have a higher relative risk (RR) of CHD. On the other hand, the same study found those individuals with asthma did have an increased RR of stroke.20 This was the first study to focus on the association of specific CVD conditions with adult-onset asthma and warrants a deeper investigation as to why CHD is the CVD manifestation most associated with asthma. Because of the chronic inflammatory nature of asthma, inflammatory markers were included in previous studies, but only the two ARIC studies17,20 included fibrinogen as an inflammatory marker, and no studies included Hs-CRP as an inflammatory marker. Since inflammation is also a major factor in CHD, it was important to consider Hs-CRP as a potential link between the CHD and asthma. Hs-CRP was not shown to have any interaction with asthma status, but nonetheless both asthma and Hs-CRP were independently associated with CHD and CVD, which supports previous studies. Since asthma patients are usually treated with corticosteroids to treat their airway inflammation, it would be appropriate to analyze the effects of steroids as the potential connection between asthma and CHD. Since patients with both child-onset and adult-onset asthma use

Asthma association with cardiovascular conditions Table 2

951

Risk factor adjusted odds for specific conditions of CVD by asthma status (n Z 16,943).

OR (95% CI)

Adult onset Overall

Stroke Congestive Heart Failure Coronary Heart Disease Total CVD

Child onset Male

Female

Overall

2.09(0.94e4.67) 1.66(0.49e5.60) 2.06(0.75e5.67) 1.46(0.58e3.66) 1.69(0.42e6.89) 1.29(0.36e4.63)

Male

1.00(0.28e3.60) 1.29(0.25e6.65) 0.88(0.27e2.88) 0.42(0.11e1.58)

Female 0.52(0.07e4.19) 1.72(0.42e7.03)

2.26(1.23e4.17) 1.18(0.42e3.31) 2.94**(1.37e6.33) 0.55(0.24e1.26) 0.39 (0.16e0.99) 0.75(0.19e2.97) 2.07(1.17e3.66) 1.31(0.52e3.28) 2.37*(1.18e4.74)

0.64(0.30e1.33) 0.57(0.22e1.49)

0.63(0.20e4.74)

Reference group is no asthma; estimates adjusted for age, systolic blood pressure, HDL cholesterol, BMI, Hs-CRP, smoking, and diabetes mellitus.

these medicines, steroids would not fully explain why childonset asthma was never found to be significantly associated with CVD. The fact that people with adult-onset asthma were much older than those with child-onset asthma may have contributed to the analysis results due to the fact that age is correlated with CVD risk. A possible explanation for the lack of an association between CVD and child-onset asthma is that child-onset asthma stems from an allergic basis in contrast to adult-onset asthma which has been related to environmental irritants and gender. These factors may contribute to an increase in CVD as a consequence of irritants and hormones. Adult-onset asthma differs from child-onset asthma because it comes from more intrinsic causes in the body, such as hormones and stiffening of chest walls. These factors inside the body can lead to an increase in CVD risk. We observed that adult-onset asthma was more prevalent in women than in men by a 2:1 ratio. Also the odds of both CHD and total CVD were nearly double for women compared to men. It is unclear as to why relationships of asthma and CVD in women are stronger than that observed in men. Onufrak et al. suggests that estrogen enhances proinflammatory cytokines activated from monocytes, macrophages and vascular cells and also regulates the production of leukotrienes from mast cells, all of which are known to stimulate asthma. The incidence rate of asthma in women correlates with shifts in estrogen levels, with incidence increasing after puberty and peaking during the onset of menopause. Authors speculate that women who develop asthma during these hormonal cycle events may be particularly susceptible to estrogen-modulated alterations in inflammatory cytokine and leukotriene regulation.17 To further elucidate possible reasons for the gender difference relating asthma to CVD, we decided to split the patients by three criteria: gender (male and female), asthma status (adult, child-onset and neither) and BMI (<25, 25e<30 and 30). This new variable was used in a subgroup analysis to test for the effects of asthma across BMI-gender groups on CVD morbidity in addition to the asthma analysis. The result showed that males with asthma from all BMI groups were not significantly associated with CVD, but females with adult-onset asthma and a BMI between 25 and 30 (the intermediate group) had a significant association with CVD. This differs from expected results, where the morbidly obese group with 30þ BMI was expected to have the strongest relation to CVD. It is possible that the subject populations had COPD patients

because the long-term airway remodeling from the inflammatory response and subsequent repair in asthmatics can produce irreversible airway obstruction and contribute a decline in lung function over time.20,27,28 With this reduced lung function, CVD risk could have been associated with asthma5e16; however, there is no good reason to believe that women with asthma have more association with CVD when reduced lung function is present. Future studies could elaborate on the exact mechanisms of association between men with asthma vs. women with asthma to CVD. These studies could focus on hormonal levels and other biomarkers, as well as the effects of sleep disorders. The methodology of our study was similar to that of Iribarren et al.,19 where the subject population was limited to those aged 18 and greater in order to focus on adultonset asthma. The data collection methods were also similar to the ARIC study because the asthma was selfreported and doctor diagnosed. The main difference between this study and previous projects was the varying methods of data collection. Some previous clinical studies have used physician-reported data from specific hospitals. This study used data from NHANES 1999e2006, where some of the questions used in formulating variables were selfreported without physician confirmation, which may not be valid. Another difference in data collection was the fact that the data from this study was cross-sectional, while the data used from other studies mostly consisted of longitudinal data, which is better for predicting the long-term effects of a disease. In order to discern whether asthma as whole, not just adult-onset asthma, was associated with CVD, a child-onset asthma variable was created to cover all subjects with asthma diagnosed before age 18. An important strength of our study was the use of the large NHANES population that enabled us to generalize our results to free-living adults in the U.S. The survey also included specific cardiovascular conditions and important confounding factors, and the detailed information on asthma subtype within gender allowed for the investigation of increased CVD odds in females. There were also limitations in the study, the most important being the fact that the data from NHANES was cross sectional. Since crosssectional data are derived from taking a sample at a single point in time, we could not confirm a definite causal relation between asthma and CVD. The dataset was not able to describe the temporal relation between asthma and CVD, such as identifying which condition the patient was diagnosed with first. Prospective studies need to be

952 examined to verify temporality and causality. Most of the data was patient self-reported and the asthma variable used in the research did not assess asthma based on spirometry tests because NHANES IV does not provide such data. This is considered a limitation because of concerns of the validity of self-reported asthma data, and the lack of quantitative spirometric data precluded our ability to exclude the possibility that COPD, a potential confounder, may have been present. Another limitation was that the small number of events, particularly, stroke, caused power issues that need to be considered in interpretation. The lack of asthma medication information including dosages was also a limitation, as use of steroids may have also confounded results. The data supports the conclusion that coronary heart disease is the principal cardiovascular manifestation forming the association of asthma with cardiovascular disease; however, not established is whether controlling asthma would actually reduce CHD incidence and further prospective studies should consider investigating this.

H.M. Lee et al.

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Author Disclosure 12.

Dr. Lee, Dr. Wong, and Mr. Truong have no conflicts of interest to disclose.

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Acknowledgments 14.

Dr. Lee: Contributed to the background, clinical implications and data analysis of the study, and was principally involved in the writing of the introduction and discussion of the manuscript. Reviewed and approved the final version of the manuscript for publication. Dr. Lee is the guarantor of the paper. Mr. Truong: Contributed to the data collection, analysis, interpretation and the writing of the manuscript. Conducted the specified analyses and wrote the introduction, methods, and results of the manuscript. Reviewed and approved the final version of the manuscript for publication. Dr. Wong: Contributed to the design and conduct of the study, the analysis and interpretation of the data, and the writing of the manuscript. Reviewed and approved the final version of the manuscript for publication.

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