Background
Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular morbidity and mortality [
1‐
3]. Previous population-based studies suggested that patients with COPD have a two to three fold increased risk of sudden cardiac death (SCD) [
4]. However, the mechanisms underlying the association between COPD and SCD are currently unclear and predictors of malignant cardiac arrhythmias and SCD in COPD have not been defined.
Alteration of cardiac repolarization is an important mechanism for the development of malignant arrhythmias and the occurrence of SCD [
5‐
7]. Measures derived from the surface electrocardiography (ECG) represent the dispersion of repolarization and the electrical inhomogeneity of the ventricles during repolarization [
7,
8]. The findings of previous studies in patients with heart failure [
9], patients with long QT syndrome [
10] and elderly persons [
11] indicated an association between alteration of measures of cardiac repolarization, such as QT interval and QT dispersion with the development of malignant arrhythmia and SCD.
Evidence from longitudinal studies suggests that a low forced expiratory volume in 1 s (FEV
1) is associated with an increased risk for ischemic heart and cerebral disease and SCD, even after correcting for conventional cardiovascular risk factors [
12,
13]. It has also been suggested that COPD patients may have a higher frequency of cardiac arrhythmias and the severity of airflow obstruction seems to be associated with the occurrence of arrhythmia [
14,
15].
Preliminary evidence from a small case-control study suggests that increased maximal QT interval is associated with the development of ventricular arrhythmia in patients with COPD [
16]. However, the prevalence of and the mechanisms contributing to altered cardiac repolarization in patients with COPD are currently unknown.
Therefore, the aim of this study was to evaluate the prevalence of and possible factors contributing to altered cardiac repolarization in a group of COPD patients.
Discussion
This study investigated the prevalence of altered cardiac repolarization in a heterogeneous group of COPD patients and evaluated possible underlying risk factors. The main findings of this study are that approximately one third of a typical COPD population has altered cardiac repolarization and increased dispersion of repolarization, which may be related to hypoxia. Altered cardiac repolarization may expose these patients to an increased risk for malignant ventricular arrhythmias and SCD.
Several pathologies have been reported to increase the risk of SCD including CAD, cardiomyopathies, congenital heart disease and electrophysiological abnormalities including long QT syndrome [
27].
A prolonged QT interval and increased QT dispersion are markers of an increased risk for malignant cardiac arrhythmia and SCD [
9,
26]. The QT interval represents the electrocardiographic correlate of ventricular de- and repolarization including the vulnerable period for reentry tachycardia. As such, QTc prolongation to >450 ms has been identified as a risk factor for malignant ventricular arrhythmias and SCD [
26,
28]. QT dispersion reflects spatial differences in myocardial recovery time. Previous studies have shown that an increase in QT dispersion >60ms is associated with the development of malignant ventricular arrhythmias [
16] and SCD [
9].
In large population-based studies including elderly subjects, the prevalence of an altered QTc interval has been estimated to be approximately 8% [
11]. In contrast, the COPD patients in the current study showed a fourfold higher prevalence of an altered QTc interval compared to the general population. In a case-control study, investigating the risk of SCD in patients with coronary heart disease with and without prolonged QTc interval, the prevalence of prolonged QTc interval was 39% in the group with subsequent SCD [
29]. This prevalence of altered QTc in SCD patients is comparable with the findings of the current study in COPD patients.
In a retrospective study including 162 chronic heart disease patients, the prevalence of increased QT dispersion >60 ms was 24% [
30], which is similar to our observations in COPD patients (24%). These findings suggest a comparable prevalence of increased QT dispersion in patients with chronic heart disease and COPD patients.
There are some previous studies examining possible factors leading to an alteration in cardiac repolarization in COPD patients, however, the COPD patients in these studies [
16,
31‐
33] were free from comorbidities. Zulli et al. [
31] found a significant univariate association between QT dispersion with FEV
1% pred
. and FVC% pred. respectively in COPD patients. However, in the multivariate analysis correcting for covariates, this association did not remain statistically significant. Yildiz et al. [
16] compared 30 COPD patients with and without increased QT dispersion regarding possible factors influencing QT dispersion and found no independently associated factors. Similarly, in our study, only pack years of smoking and use of statins was statistically significantly associated with QT dispersion in the univariate analysis. However, after correcting for age, BMI, SaO
2 and use of medication, none of the possible influencing risk factors were independently associated with QT dispersion.
None of the previously described studies [
16,
31] examined possible factors leading to an altered QTc interval in COPD patients. In the current study, age, pack years of smoking, Pocock risk score, respiratory variables, use of combined inhaled long-acting β-adrenergic and steroid and consumption of statins were significantly associated with a QTc >450ms in univariate analysis. Only SaO
2 remained statistically significantly associated with QTc >450 ms after correction for covariates in the multivariate analysis. Thus, hypoxia may be a risk factor for a prolonged QTc interval. There is some evidence that hypoxia may prolong repolarization duration. In a study by Roche et al. [
34], healthy subjects were exposed to normobaric hypoxic conditions and it was found that hypoxia significantly prolonged the QTc interval. In 12 COPD patients, Tirlapur et al. [
35] observed that patients who had a low mean basal SaO
2 (<80%) showed electrocardiographic changes such as a prolonged QTc interval. These findings are somewhat in contrast to the study by Sarubbi et al. [
33], where QTc was measured in 15 hypoxemic/hypercapnic COPD patients before and after oxygen therapy and was not significantly reduced after 24 h of oxygen therapy. Thus it is still a matter of debate whether hypoxia affects cardiac repolarization and the underlying mechanism through which hypoxia may possibly influence cardiac repolarization remains currently unknown.
There is some evidence that autonomic neuropathy may results in prolonged cardiac repolarization in COPD patients. In a case-control study by Stewart et al. [
32], 17 COPD patients with autonomic neuropathy were compared to 17 COPD patients without autonomic neuropathy. QTc was significantly longer in COPD patients with autonomic neuropathy. However, autonomic neuropathy was not measured in our study and thus we cannot directly compare the results of the study by Stewart et al. with our findings.
The current study has some limitations. We performed standard resting 12-lead ECG and not continuous 24-h ECG. Therefore it is not possible to evaluate the prevalence of alteration in cardiac repolarization both during a longer daytime period and during sleep. Furthermore, the cross-sectional study design does not allow to establish a causal relationship between altered cardiac repolarization in COPD patients and malignant ventricular arrhythmias and SCD, respectively. If prolonged cardiac repolarization promotes sudden cardiac death in COPD patients is currently unknown. Further controlled and longitudinal studies are needed to evaluate if prolonged cardiac repolarization promotes malignant ventricular arrhythmia and SCD in COPD patients.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
NAS and MK had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NAS, CFC, GC, VAR and ARJVG contributed to the acquisition of data, data analysis and interpretation, drafting of the manuscript, revision for intellectual content and approved the final version. MK contributed to the conception and design, acquisition of data, data analysis and interpretation, drafting of the manuscript, revision for intellectual content and approved the final version. All authors read and approved the final manuscript.