International Journal of Cardiology 176 (2014) 464–469

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The association of asthma and atrial fibrillation — A nationwide population-based nested case–control study Wan-Leong Chan a,b,c,⁎, Kun-Pin Yang b, Tze-Fan Chao b, Chin-Chou Huang b,c,e,f, Po-Hsun Huang b,c,g, Yu-Chun Chen d,h, Tzeng-Ji Chen d,h, Shing-Jong Lin b,c,g, Jaw-Wen Chen b,c,f, Hsin-Bang Leu a,b,c,e,f a

Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan d Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan e Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan f Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan g Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan h Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan b c

a r t i c l e

i n f o

Article history: Received 2 May 2012 Received in revised form 21 July 2014 Accepted 26 July 2014 Available online 1 August 2014 Keywords: Atrial fibrillation Asthma Corticosteroid Population-based nested case–control study

a b s t r a c t Background: Asthma and atrial fibrillation (AF) have been reported to be related to an increased risk of cardiovascular events. However, the relationship between asthma and AF has not been fully elucidated. The purpose of this study was to examine the association between asthma and AF risk. Methods: We conducted a population-based nested case–control study including a total of 7439 newly-diagnosed adult patients with AF and 10,075 age-, gender-, comorbidity-, and cohort entry date-matched subjects without AF from the Taiwan National Health Insurance database. Exposure to asthma as well as medications including bronchodilators and corticosteroid before the index date was evaluated to investigate the association between AF and asthma as well as concurrent medications. Results: AF patients were 1.2 times (adjusted OR 1.2, 95% CI 1.109–1.298) more likely to be associated with a future occurrence of asthma independent of comorbidities and treatment with corticosteroids and bronchodilator. In addition, the risks of new-onset AF were significantly higher among current users of inhaled corticosteroid, oral corticosteroids, and bronchodilators. Newly users (within 6 months) have the highest risk (inhaled corticosteroid: OR, 2.13; 95% CI, 1.226–3.701, P = 0.007; oral corticosteroid: OR, 1.932; 95% CI, 1.66–2.25, P b 0.001; non-steroid bronchodilator: OR, 2.849; 95% CI, 2.48–3.273, P b 0.001). A graded association with AF risk was also observed among subjects treated with corticosteroid (inhaled and systemic administration) and bronchodilators. New users (within 6 months) of these medications had the highest risk of AF (ICS: OR, 2.13; 95% CI, 1.226– 3.701, P = 0.007; oral corticosteroid: OR, 1.932; 95% CI, 1.66–2.25, P b 0.001; non-steroid bronchodilator: OR, 2.849; 95% CI, 2.48–3.273, P b 0.001). A graded association with AF risk was also observed among subjects treated with ICS or bronchodilator. Conclusions: Asthma was associated with an increased risk of developing future AF. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and is associated with marked morbidity, mortality and medical burden [1]. The lifetime risk for the development of AF is approximately 25% in the general population [2]. An association between AF and total mortality (1.5–1.9 fold increase) and stroke (5-fold ⁎ Corresponding author at: Healthcare and Management Center, Division of Cardiology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan. Tel.: +886 2 2871 2121x3424; fax: +886 2 2875 7735. E-mail address: [email protected] (W.-L. Chan).

http://dx.doi.org/10.1016/j.ijcard.2014.07.087 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

increase) has also been reported in the Framingham Heart Study [3,4]. Cardiovascular diseases such as coronary artery disease (CAD), valvular heart disease, hypertension, and congestive heart failure have also been associated with the occurrence of AF; however, the pathophysiology of AF remains incompletely understood. In addition to hemodynamic stress, etiologies such as atrial ischemia, autonomic imbalance, and neurohormonal activation have been identified as possible mechanisms of AF. Additionally, inflammation and oxidative stress have been implicated in the pathogenesis of AF. Aviles et al. demonstrated that elevated C-reactive protein (CRP) level, a systemic marker of inflammation, was predictive of AF incidence [5]. Furthermore, Schnabel et al. demonstrated that subjects with elevated CRP had an additional 25% increased risk

W.-L. Chan et al. / International Journal of Cardiology 176 (2014) 464–469

of developing AF in the future [6], suggesting that inflammatory process may contribute in the pathogenesis of AF formation. Asthma is a disease of chronic airway inflammation with increasing worldwide prevalence [7,8]. The pathogenesis of asthma includes inflammatory cell accumulation and cytokine activation [9]. In addition, oxidative stress and airway remodeling also play an important role in the pathogenesis of asthma [10,11]. Independent of the airway, there is increasing evidence which indicates that asthma is a systemic inflammatory disorder [12]. Furthermore, it has been mentioned that asthma was associated with a 1.40-fold increased hazard of CAD, a 1.20-fold hazard of cerebrovascular disease, a 2.14-fold hazard of heart failure, and a 3.28-fold hazard of all-cause mortality, indicating that asthma significantly is associated with cardiovascular disease [13]. Subjects with asthma have also been demonstrated to present with significant atherosclerosis, independently related to cardiovascular events such as myocardial infarction and stroke [14–16]. Recently, Vijayakumar et al. further use 18F-fluorodeoxyglucose positron emission tomography/ computed tomography (FDG-PET/CT) to demonstrate that asthmatics have increased arterial inflammation than non-asthma controls, indicating that bronchial asthma is associated with increased arterial inflammation status beyond airway inflammation [17]. However, there is a paucity of research investigating the association between asthma and AF. Of interest, a widely administered corticosteroid has recently been demonstrated to increase the occurrence of AF in patients with asthma [18]. In order to evaluate the relationship between asthma and AF, as well as corticosteroid and bronchodilator, we conducted a population-based nested case–control study. 2. Methods 2.1. Database source A population-based nested case–control study design was employed that utilized data from the National Health Insurance Research Database (NHIRD). The National Health Insurance Program in Taiwan has operated since 1995 and enrolls nearly all the inhabitants of Taiwan (21,869,478 beneficiaries of 22,520,776 inhabitants at the end of 2002). Currently, the NHIRD at the National Health Research Institutes (NHRI) in Miaoli (Taiwan) has published several dozen extracted data sets for researcher's reference. The NHRI has released a cohort data set comprised of 1 million randomly sampled subjects alive during 2000. All patient records for these subjects were collected from 1995 onward. It is also one of the largest nationwide population-based databases in the world. The random samples released by the NHRI have been confirmed by the NHRI to be representative of the Taiwanese population. In this cohort data set, original patient identification numbers have been encrypted for privacy. 2.2. Patient identification All selected patients were older than 18 years old with newly diagnosed atrial fibrillation (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9CM] code 427.3X) in both outpatient and inpatient settings from January 1, 2000 to December 31, 2007. Diagnosis of AF was confirmed by results from electrocardiography (EKG) and Holter monitoring. The date of AF diagnosis was recorded as the date of cohort entry. As to control group, those without AF, we identified those who have received either ECG or Holter monitoring without subsequent diagnosis of AF before being enrolled in our study as our controls. Using an incidence density sampling approach, each patient with AF was matched with controls nested within the study cohort by age, sex, cohort entry date, occurrence of hypertension (ICD-9-CM codes 401.xx to 405.xx), diabetes mellitus (250.xx), coronary artery disease (410.xx to 414.xx), congestive heart failure (428.xx), and chronic renal disease (580.xx to 587.xx). Each control subject was assigned the same index date as the corresponding case patient. 2.3. Exposure to asthma and associated medications Exposure to asthma before the index date among all study subjects including atrial fibrillation and matched controls was carefully evaluated. Asthma was identified with ICD code 493.xx as described in our previous study [19]. The use of medications for asthma control prior to index date was evaluated. Subjects who were treated with a corticosteroid for oral, parenteral, or inhaled use within one year before the index date were defined as being “exposed” (inhaled or oral administration); all others were considered “non-exposed”. Exposed persons were further categorized as new users (first prescription within 6 months before index date) and former users (prescription within 7–12 months but not within 6 months before the index date). In addition to corticosteroid use, bronchodilator use was also evaluated.

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2.4. Statistical analysis Microsoft SQL Server 2005 was used for data management and computing. All statistical analyses were performed using the Statistical Package for the Social Sciences software, version 15.0 (SPSS, Chicago, Illinois). All data are expressed as the frequency (percentage), and mean ± SD. The parametric continuous data between the different groups were compared using an unpaired Student's t test. Categorical data between groups were compared using chi-square test and Yates' correction or Fisher's exact test, as appropriate. Conditional logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between asthma, the use of corticosteroids or bronchodilators, and the risk of AF. To adjust for potential confounders, cofactors associated with the occurrence of AF were analyzed, including age, gender, hypertension, diabetes, history of CAD, and chronic renal failure. Statistical significance was inferred at a 2-sided P value of b0.05.

3. Results A total of 7439 cases of new-onset AF and 10,075 controls from January 1, 2000 to December 31, 2007 (Fig. 1) were identified during the follow-up period. The underlying characteristics in patients with newonset AF and controls were similar (Table 1). There was no significant difference in age, gender, hypertension, diabetes, congestive heart failure, and coronary artery disease between these two groups. AF cases were more likely to have asthma and were more likely to be current users of medication for asthma control, including oral, inhaled corticosteroid, and non-steroid bronchodilators. (See Table 2.) After adjusting for age, gender, hypertension, diabetes, congestive heart failure, coronary artery disease, chronic renal disease, and use of inhaled corticosteroids, oral corticosteroids, and bronchodilators, asthma was independently associated with the increased risk of newonset of AF (OR, 1.2; 95% CI, 1.109–1.298, P b 0.001) (Table 2). The association between AF and asthma was independent of comorbidities, as well as corticosteroids and bronchodilators (Fig. 2). The impact of medications, including corticosteroids and bronchodilators, was also analyzed (Fig. 2). The risk of new-onset AF was significantly higher in patients with current medication use compared with non-users. This association was observed among users of inhaled corticosteroids, oral corticosteroids, and bronchodilators. New medication users (within 6 months) demonstrated the highest risk of AF (inhaled corticosteroid: OR, 2.13; 95% CI, 1.226–3.701, P = 0.007; oral corticosteroid: OR, 1.932; 95% CI, 1.66–2.25, P b 0.001; non-steroid bronchodilator: OR, 2.849; 95% CI, 2.48–3.273, P b 0.001) and the graded association with AF risk was observed among subjects taking either corticosteroid or bronchodilators, respectively (Table 2). Subgroup analyses further demonstrated that the association between AF and asthma was independent with other cardiovascular risk factors (Fig. 3). 4. Discussion The primary result of the current study was the association between asthma and the higher risk of developing new-onset of AF, independent of corticosteroid and bronchodilator use. Furthermore, current use of steroids and bronchodilators was associated with an increased risk of AF, especially for new users, which suggests careful management of patients with asthma to avoid the development of AF. 4.1. Asthma and AF risk The current study demonstrated that asthma is associated with a 1.2-fold higher risk of new-onset atrial fibrillation after adjusting for underlying risk factors (co-morbid medical disorders and medication), suggesting that asthma may play an important role in AF initiation. The current findings expand upon the data from previous studies in regard to the relationship between asthma and AF [20,21]. Warnier et al. reported that adult patients with asthma more commonly presented with tachycardia and premature ventricular contractions compared with patients without asthma, despite treatment with β2 mimetics [20]. Ferreira et al. reported a genetic variant in the IL-6 receptor gene

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Fig. 1. Flow chart of study.

(IL6R Asp358Ala). IL-6 is a key determinant of the inflammatory process and is associated with the increased risk of several common diseases including AF and asthma [21]. These results suggest that inflammation may play an important role in these diverse diseases. An association between inflammation and AF has been widely cited. Frustaci et al. described AF in patients with paroxysmal lone AF by right atrial septal biopsy samples [22]. Bruins et al. found the highest concentration of C-reactive protein (CRP) when assessed on the second or third day after cardiac surgery was correlated with an increased risk of AF, further supporting the role of the inflammatory response in the development of AF [23]. Furthermore, increased levels of CRP are associated with a higher recurrence rate after electrical cardioversion and catheter ablation [24,25]. Thus, preventing inflammation may form a basis for the treatment or prevention of AF. Statins, which have anti-inflammation properties, have been reported to significantly decrease levels of CRP and AF occurrence, further supporting the role of inflammation in initiating or maintaining AF [26,27]. Airway inflammation is a cornerstone characteristic of bronchial asthma. The presence of local inflammation in asthma is well studied, as evidenced by increased levels of certain cytokines and inflammatory cells within the airway [9]. The long-term airway remodeling in asthma associated with the inflammatory response and subsequent repair can produce irreversible airway obstruction [28] and airway structural

Table 1 Characteristics of cases and matched controls.

Age, yr Male gender, n (%) Hypertension, n (%) Diabetes mellitus, n (%) CAD, n (%) Congestive heart failure, n (%) Chronic renal failure, n (%) Asthma, n (%) Medication for asthma treatment Inhaled corticosteroid, n (%) Oral systemic use of corticosteroid, n (%) Non-steroid bronchodilator, n (%) CAD indicates coronary artery disease.

Population controls

Atrial fibrillation

P

n = 10,075

n = 7439

71.13 ± 13.72 23,254 (50.07%) 7539 (74.83%) 3297 (32.72%) 5952 (59.08%) 3358 (33.33%) 1927 (19.13%) 2005 (19.90%)

71.52 ± 13.1 3270 (43.96%) 5496 (73.88%) 2510 (33.74%) 4392 (59.04%) 2587 (34.78%) 1566 (21.05%) 1970 (26.48%)

0.056 0.490 0.155 0.158 0.961 0.046 0.002 b.0001

60 (0.60%) 1004 (9.97%)

77 (1.04%) 1360 (18.28%)

0.001 b.0001

1773 (17.60%)

2433 (32.71%)

b.0001

changes characterized by fibrosis [29]. Taken together, airway remodeling involves changes in the extracellular matrix (ECM), collagen, elastin, and smooth muscle [11]. In the atria, the electrical and anatomical remodeling processes have been reported to result in the perpetuation of AF [30,31]. Furthermore, the matrix metalloproteinases (MMPs), the proteolytic enzymes degrading ECM of injured tissue, have also been implicated to contribute to the connections between AF and asthma. Nakano et al. collected biopsies from the right atrium of patients undergoing cardiac procedures and the results demonstrated significantly increased MMP-9 expression in patients with AF compared with those in non-AF controls [31]. Mattos et al. demonstrated that patients with severe asthma had increased levels and activity of MMP-9 in their sputum; the activity of MMP-9 was also increased after allergen stimulation [32]. These results suggest that MMP-9 is positively associated with structural remodeling of the airway and atrium consistent with AF. In addition, increased oxidative stress has been found to be associated with asthma, and is considered to play an important role in the perpetuation of AF [33,34]. Eosinophil and neutrophil infiltration in the airway of patients with asthma produces reactive oxygen species (ROS) and reactive nitrogen species [35,36]. ROS such as superoxide, hydrogen peroxide, and possibly hydroxyl radicals contribute to the inflammation in the asthmatic airway. Kim et al. examined the gene transcriptional profiles in human atrial tissue from patients with permanent AF and demonstrated that the regulation of pro- and anti-oxidation shifted toward pro-oxidation in AF patients. This imbalance resulted in a significant increase in the oxidative stress and subsequent damage and AF [37]. Recently, Neuman et al. showed an independent association between persistent or permanent AF and oxidative stress markers, while this was not the case with respect to the inflammatory markers [38]. Taken together, these results indicate that inflammation and increased oxidative stress may exist independently and collectively contribute to the pathogeneses of AF and asthma. 4.2. Medications for asthma control and AF risk The relationship between medication used for the treatment of asthma and risk of new-onset AF was also examined in the current study. Corticosteroid use has been demonstrated to be associated with an increased risk for AF. Cornelis et al. have demonstrated that patients treated with high dose corticosteroids were at an increased risk of developing AF [18]. Christiansen et al. analyzed a nationwide, population-based database demonstrating that patients currently

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Table 2 Odds ratio (OR) of asthma and related medications and risk of atrial fibrillation (AF). Variables

Asthma Inhaled corticosteroid, n (%) Never user Previous users (≧6 months before) New users (b6 months) Oral corticosteroid Never user Previous users (≧6 months before) New users (b6 months) Non-steroid bronchodilator Never user Current use, n (%) New users, n (%)

OR Model 1

Model 2

1.45 (1.35–1.56)

1.447 (1.34–1.56)

Model 3

1 (reference) 1.65 (1.25–2.18) 3.10 (1.80–5.32)

1 (reference) 1.37 (1.03–1.82) 2.59 (1.49–4.49)

1 (reference) 1.12 (0.84–1.49) 2.13 (1.23–3.70)

1 (reference) 1.11 (1.028–1.198) 2.25 (1.95–2.61)

1 (reference) 1.08 (1.00–1.18) 2.17 (1.87–2.52)

1 (reference) 0.99 (0.92–1.08) 1.93 (1.66–2.25)

1 (reference) 2.41 (2.24–2.60) 2.88 (2.52–3.29)

1 (reference) 2.38 (2.18–2.58) 2.93 (2.55–3.36)

1 (reference) 2.27 (2.08–2.48) 2.85 (2.48–3.27)

1.2 (1.109–1.298)

Model 1: crude OR. Model 2: adjusted with age, gender, history of diabetes, hypertension, congestive heart failure, coronary artery disease, chronic renal failure. Model 3: adjusted with age, gender, history of diabetes, hypertension, congestive heart failure, coronary artery disease, chronic renal failure and medications.

treated with corticosteroids, not former users of corticosteroids, were associated with an increased risk of new-onset AF [39]. Collectively, current corticosteroid users, especially those patients treated with high doses of corticosteroids were associated with an increased risk of developing AF. The current study confirms previous observations and has further investigated the impact of inhaled corticosteroids, as well nonsteroid bronchodilators, on the risk of AF. Inhaled corticosteroids are considered to have minor systemic effects, but could also provide local anti-inflammatory benefits and airway protection in patients with asthma [40]. In the current study, inhaled corticosteroids were still associated with an increased risk of AF, and patients currently treated with inhaled corticosteroids, especially new users, had higher risk than non-users for AF. The association between AF and the use of inhaled corticosteroids is unclear. Hureta et al. found no association between inhaled corticosteroids and cardiac arrhythmias (relative risk = 1.0; 95% confidence interval = 0.8–1.3), but an increased risk was found among users of oral steroids with greater risk at the beginning of therapy (RR: 2.6; 95% CI: 2.0–3.5) [41]. However, Oteri et al. reported that newly developed AF was induced by inhaled fluticasone propionate [42]. There were no studies that have specifically addressed the

potential relationship with corticosteroid and our current result provided important information. The current study also demonstrated that non-corticosteroid bronchodilator treatment (current user or former user) was associated with an increased risk of developing AF. Bronchodilators which may stimulate and increase cardiac sympathetic activity can affect the electrophysiological mechanisms of AF initiation and/or maintenance [43]. Further larger, prospective studies are still needed to confirm this association. 4.3. Study limitations First, the diagnoses used were from national health insurance claims whose primary purpose was for administrative billing. Diagnostic criteria did not undergo additional verification. In an effort to avoid inaccurate diagnoses, only patients who were diagnosed with AF (ICD9-CM code 427.31) by using an EKG or Holter monitor were selected. Second, variable forms of AF were not subdivided, such as paroxysmal, persistent, and permanent AF due to the limitations of the claims database. In subjects with paroxysmal AF, up to 90% of episodes are asymptomatic, and paroxysmal AF may not be identified if patients are not

Fig. 2. Odds ratio (OR) of asthma and related medications and risk of atrial fibrillation (AF).

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Fig. 3. Odds ratio (OR) for asthma and risk of atrial fibrillation in subgroup analysis; by conditional logistic regression models adjusted with age, gender, medications and co-morbidity.

aware of paroxysmal AF attack. Furthermore, available evidence demonstrated that there is no difference between those with paroxysmal AF and permanent AF in terms of complications such as stroke [44–46]. In addition, they do not have separate ICD-9 codes that could be used for subdividing AF by type; therefore, we did not address different types of AF separately. Furthermore, Because of the limitation of database design, we did not get the information whether asthma is well controlled or not among our study population. Finally, individual information such as alcohol consumption, dietary factors [47], body mass index [47], and smoking [48] all of which may contribute to AF, was not available through the database. 5. Conclusion In this nationwide population study, asthma was independently associated with a higher risk of developing new-onset AF after consideration of cardiovascular risk factors and current pharmacologic treatment for asthma. Furthermore, current use of corticosteroids, either oral or inhaled, and bronchodilator therapy was also independently associated with a higher risk of AF. The risk was especially higher among current users, especially new users. Nevertheless, the effect of asthma on the development of AF needs to be confirmed by further large, prospective and randomized trials. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Wolf PA, Mitchell JB, Baker CS, Kannel WB, D'Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229–34. [2] Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation Aug. 31 2004;110(9):1042–6. [3] Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–52. [4] Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8. [5] Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation Dec. 16 2003;108(24):3006–10. [6] Schnabel RB, Larson MG, Yamamoto JF, et al. Relations of biomarkers of distinct pathophysiological pathways and atrial fibrillation incidence in the community. Circulation 2010;121(2):200–7.

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