Association between chronic obstructive pulmonary disease and ventricular arrhythmia: a nationwide population-based cohort study

The ventricular arrhythmia (VA)–chronic obstructive pulmonary disease (COPD) association and related risk factors remain unclear. Using 2001–2012 data from National Health Insurance Research Database, we retrospectively reviewed 71,838 patients diagnosed as having COPD and 71,838 age- and sex-matched controls. After adjustments for comorbidities, medication, urbanization level, and monthly income, patients with COPD had higher incidence rates of VA than did the controls (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 1.45 [1.25–1.68]). More hospitalization or emergency visits because of acute COPD exacerbation (aHRs [95% CIs] for first, second, and third visits: 1.28 [1.08–1.50], 1.75 [1.32–2.32], and 1.88 [1.46–2.41], respectively) and asthma–COPD overlap (aHR [95% CI]: 1.49 [1.25–1.79]) were associated with high VA risk in patients with COPD. In the multivariate analysis, heart failure (aHR [95% CI]: 2.37 [1.79–3.14]), diabetes (aHR [95% CI]:1.64 [1.29–2.08]), age ≥75 (aHR [95% CI]: 2.48 [1.68–3.67]), male (aHR [95% CI]: 1.69[1.34–2.12]), and class III antiarrhythmic drug use (aHR [95% CI]: 2.49 [1.88–3.28]) are the most significant risk factors of new onset of VA in patients with COPD.


INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a severe lung disease and a major cause of mortality and morbidity worldwide 1 . The causes of death in patients with COPD include acute or chronic respiratory failure, infection, coronary artery disease (CAD), heart failure (HF), and cardiac arrhythmia 2,3 . The major risk factors for mortality in patients with COPD are acute myocardial infarction (AMI) and underlying CAD 2 . Because COPD is associated with systemic inflammation, which initiates or aggravates comorbid diseases, cardiovascular disease and arrhythmia risks have been reported to be associated with COPD [4][5][6][7] . In previous studies, supraventricular arrhythmia, particularly atrial fibrillation, was the most common cardiac arrhythmia in patients with COPD 6 . However, in patients with acute COPD exacerbation, the most common arrhythmia was reported to be ventricular premature beats 8 . In addition, COPD and its severity have been reported as independent risk factors for ventricular tachycardia 7,9 . However, because of COPD complexities, such as comorbidities, prescribed medications, and asthma-COPD overlap (ACO) risk, the COPD-ventricular arrhythmia (VA) association remains unclear. In this study, VA risk in patients with COPD was assessed by analyzing nationwide population-based data.

RESULTS
Baseline characteristics of the study population Records of 172,642 patients with COPD were retrieved, of which 71,838 patients met the inclusion criteria (mean age: 57.66 ± 16.61 years, 54% men). The control cohort was matched with the COPD cohort according to sex and age. The total follow-up duration was 491,198.3 and 497,038.3 person-years in the patient and control cohorts, respectively (Fig. 1).
With regard to the prescribed medication, patients with COPD exhibited a greater use of aspirin, statin, and renin-angiotensin-aldosterone system inhibitors (RAASi) than the controls did. In addition, compared with the control cohort, more patients with COPD were prescribed antiarrhythmic drugs (AADs); this difference was the largest for class II AADs (20.81% vs. 27.10%, p < 0.001) and class IV AADs (11.37% vs. 16.26%, p < 0.001).

VA incidence in patients with COPD
The cumulative and relative risks of VA in the patients and controls are presented in Table 2. Compared with the controls, patients with COPD demonstrated higher VA risk during the follow-up period (incidence rates: 57. 5 Table 3 presents the effects of acute COPD exacerbation on the occurrence of VA. VA risk in patients with COPD increased with each hospitalization or emergency visit because of acute COPD exacerbation. For the first, second, and third visits (whether for hospitalization or an emergency visit), the crude HRs (95% CIs) were 1. 35  . Patients with ACO exhibited poorer long-term outcomes than those with COPD did (Fig. 4).    AMI acute myocardial infarction, COPD chronic obstructive pulmonary disease, RAASi renin-angiotensin-aldosterone system inhibitor. *The chi-squared test for categorical variables, and t-test for continuous variable, two-tailed p value.

Effect of COPD inhalation medications
No significantly increased VA risk was observed in patients with COPD who had been prescribed short-acting beta-agonists (SABAs), long-acting beta-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), inhalation corticosteroids (ICSs), or LABA-ICS combination therapy. Patients with COPD who were prescribed SABA-shortacting muscarinic antagonist (SAMA) combination therapy had lower VA risk ( (Table 5).

DISCUSSION
The present nationwide population-based study showed that compared with the controls, patients with COPD had a significantly higher VA incidence after adjustments for comorbidities, medications,   Additional drug: use of additional drugs such as Class 1, Class 2, Class 3, and Class 4 antiarrhythmic drugs as well as Aspirin, Stain, and renin-angiotensin-aldosterone system inhibitor. This was included in the model.
C.-C. Chen et al. monthly income, and urbanization level. In addition, VA occurrence in patients with COPD increased with the frequency of hospitalization or emergency department visits. Further, the incidence of VA increases with the complexity of airway diseases. Finally, age, chronic or acute heart disease, stroke, hypertension, and amiodarone prescription were VA predictors in patients with COPD. To the best of our knowledge, the present study involved the largest COPD cohort that has been investigated for VA risk thus far. Studies have demonstrated high VA risk in patients with COPD 7,9 . COPD is also associated with sudden cardiac death 10 . According to 24-h Holter recordings, patients with COPD had a higher prevalence of sustained or nonsustained ventricular tachycardia, and COPD severity was associated with the burden of ventricular tachycardia 7,9 . In the present study, compared with controls, patients with COPD were at higher risk of developing VA in the future, and the risk was not affected by comorbidities or medication. The autonomic system, hypoxemic status, and betaagonist inhalation are factors that cause arrhythmogenicity in patients with COPD [11][12][13] . In addition, a significantly higher T-wave peak-to-end interval also puts patients with COPD into proarrhythmic status 14,15 .
The majority of inhalation medications for COPD used in the present study were not associated with increased fatal VA risk. Bronchodilators could increase supraventricular arrythmia risk, but they did not increase the risk of fatal arrythmias such as ventricular fibrillation, ventricular flutter, or sudden cardiac death 13 . However, we observed that SABA-SAMA combination therapy helped reduce VA risk. This could be attributed to several reasons. First, the combination of SABA-SAMA inhalation medication was administered mainly during the acute exacerbation stage of COPD. Relief of bronchoconstriction and prevention of further  respiratory complications might reduce the risk of occurrence of cardiovascular complications, including VA. Second, SABA-SAMA combination therapy could effectively reduce the hyperdynamic inflation in COPD, which might improve cardiovascular outcomes [16][17][18][19] .
In the present study, VA risk increased with the frequency of emergency department visits or hospitalization. According to Konecny et al. 9 , nonsustained or sustained ventricular tachycardia risk increased with COPD severity. In addition to the determination of pulmonary function through spirometry, increased episodes of acute COPD exacerbation was associated with poorer outcomes 20 . Hirayama et al. 21 demonstrated that the risk of hospitalization or emergency events related to atrial fibrillation increased with the frequency of acute COPD exacerbations. In addition, patients with COPD who had no history of emergency department visits or hospitalizations because of acute exacerbation did not show increased VA incidence. Therefore, maintaining a stable status and avoiding episodes of acute exacerbation are essential for reducing VA risk. Furthermore, the present study reported different outcomes in patients with different complexities of airway diseases. Compared with patients with COPD alone, patients with ACO had higher VA risk, and the effects of the complexity remained slightly high after adjustments for comorbidities and medications. A study demonstrated that patients with ACO were more likely to be young; female; and have multiple comorbidities, high obesity risk, or low socioeconomic status 22 . Despite the conflicting results reported in the literature, the long-term mortality, morbidity, and decline of lung function remained critical concerns in patients with ACO 22 . Yeh et al. 23 demonstrated that compared with patients without ACO, those with ACO had higher cardiac arrhythmia risk, although the types of arrhythmia were not distinguished. To the best of our knowledge, the present study is the first to focus on the effects of ACO on VA occurrence. The results of this study suggest that a more detailed analysis of the relationship between the complexity of lung disease and arrhythmia is required. CHA 2 DS 2 -VASc scores are known to predict ischemic stroke risk in patients with atrial fibrillation. Moreover, a previous study validated the utility of CHA 2 DS 2 -VASc scores for predicting major adverse cardiovascular event risk in patients with COPD 24 . In the present study, patients with lower CHA 2 DS 2 -VASc scores or ORBIT scores had significant high VA risk than non-COPD patients with same score. While both scores increased, the difference of risk of VA occurrence became less even non-significant. This indicated that in patients with less comorbidities, the association between COPD and unstable VA became more significant. In the further multivariate analysis, CHA 2 DS 2 -VASc scores or ORBIT scores had no significant difference for predicting new-onset VA in patients with COPD.
The multivariate analysis indicated that age >65 years; male sex; previous HF; and a history of stroke, AMI, hypertension, and diabetes mellitus predicted VA risk in patients with COPD. These risk factors are also well-known factors associated with atherosclerotic disease. VA is a complication that occurs in patients with CAD 25 . The major therapies for VA include AAD use, implantable cardioverter defibrillators, and catheter ablation 25,26 . Notably, in our study cohort, the use of class III AADs in patients with COPD was associated with high VA risk. The only class III AAD available in Taiwan is amiodarone, which is widely used for treating arrhythmia in patients with COPD, particularly in patients who cannot tolerate beta-blockers or calcium channel blockers. The association between amiodarone and high VA risk could have several possible explanations. First, amiodarone was reported to exhibit pulmonary toxicity, which may occur even at low doses 27 . A study reported that arrhythmia risk may increase with a decline in respiratory function in patients with COPD, even if their left ventricular function is intact 28 . Second, amiodarone is an AAD that can cause prolongation of the QT interval. In patients with COPD, an increase in the severity of disease is associated with a prolonged QT interval 29 . In addition, the QT interval was noted to be associated with mortality, and it is significantly prolonged in the acute stage of COPD 30 . Excess prolongation of QT intervals increases the risk of VAs such as torsades de pointes 31 .
The present study has several limitations. First, this was a retrospective study, and information on several critical factors, such as direct measurements of pulmonary function and COPD stage, could not be obtained. Rather than direct measurements of COPD severity, emergency department visit and hospitalization frequencies were considered, because acute COPD exacerbation is an indication of COPD severity. In addition, the presence of ACO indicated the complexity of the disease. Second, other possible causes of VA, such as acid-base status, electrolyte levels, renal function, and levels of cardiac biomarkers (e.g., troponin, creatinine kinase, and B-type natriuretic peptide) could not be determined. Using propensity matching, most of the diseases associated with abnormalities in the aforementioned laboratory data were adjusted and equalized in both cohorts. In addition, biomarkers have limited clinical applicability and debatable utility as predictors of sudden death 32 . Finally, some medications that have been demonstrated to reduce VA risk, such as angiotensin-neprilysin inhibitors 33 , were not investigated in the present study, because these drugs were not available in Taiwan from 2008 to 2012. We adjusted for all other medications that had been used for the treatment of cardiovascular disease according to the applicable guidelines 34-37 . In conclusion, in the present nationwide population-based cohort study, the presence of COPD, acute COPD exacerbation, and airway disease complexity were positively associated with VA risk. In addition to risk factors that are similar to CAD, male and

Statistical analysis
The aforementioned baseline patient characteristics are presented in Table  1. Categorical variables were reported as percentages and number of occurrences, and quantitative variables were reported as their mean ± standard deviation. The t-test and chi-square test were used to compare the COPD and control cohorts. To determine VA risk in the COPD and control cohorts, a Cox proportional hazards model was used to calculate the HRs and 95% CIs. HRs were adjusted with respect to the aforementioned confounders. Stratified analysis was conducted with the data segmented by age and sex ( Table 2). The Cox proportional hazards model was used to estimate the risk of various VA types, with respect to the number of acute exacerbations (Table 3) and complexity (Table 4), in the COPD and control cohorts. Finally, multivariate analysis was used to estimate the association of sociodemographic characteristics, comorbidity, and medications with VA risk (Table 5). Using the Kaplan-Meier method, the VA-free survival rates for the COPD and control cohorts were compared. To examine the effects of hospital admission or emergency department visits (because of acute COPD exacerbation) on VA-free survival rate, we categorized the patients into four groups according to their COPD status (0, 1, 2, and ≥3). To examine the effects of the severity of COPD on VA-free survival rate, we categorized the patients into three groups according to their COPD status: without COPD, with COPD alone, and with ACO. All analyses were performed using SAS, and two-tailed p values <0.05 indicated statistical significance.

Reporting summary
Further information on experimental design is available in the Nature Research Reporting Summary linked to this article.

DATA AVAILABILITY
The data supporting the findings of the present research were sourced from NHIRD in Taiwan. Owing to the legal restrictions imposed by the Government of Taiwan related to the Personal Information Protection Act, the database cannot be made publicly available. However, with reasonable request from authors and with permission from Taiwan NHIRD, the relevant data are available.