Ischemic heart disease among subjects with and without chronic obstructive pulmonary disease – ECG-findings in a population-based cohort study

The prevalence of chronic obstructive pulmonary disease (COPD) is approximately 10 %, and there is still a significant under-diagnosis with up to 80 % of the cases not yet identified by healthcare [1‐3]. COPD is associated with several comorbidities whereof cardiovascular disease (CVD) is the most common [4] and both of these conditions are among the leading causes of death worldwide [5, 6]. The associations between COPD and CVD are complex; besides sharing common risk factors such as smoking and aging [7, 8], also systemic inflammation is suggested as a possible link between the conditions [9, 10].

Among cardiovascular diseases, ischemic heart disease (IHD) is of particular interest. . According to the WHO, globally IHD was responsible for 7.5 million out of the total 17.4 million CVD deaths in 2012. Hospital-based studies have shown that IHD is common among subjects with COPD [11, 12] and there is an increased risk for death after a myocardial infarction among those with COPD compared to those without [13‐15]. A recently published review clearly shows that IHD worsens the disease progress as well as prognosis among subjects with COPD [5, 6, 16]. However, the under-diagnosis of COPD most probably contributes to an underestimation of the real impact of IHD among subjects with COPD in the general population. Simple diagnostics signs of IHD in COPD, such as ischemic findings on electrocardiogram (ECG), have hardly been evaluated in population-based studies.

The aim of this population-based study was to estimate the prevalence of self-reported ischemic heart disease and ischemic ECG changes among subjects with COPD in comparison with subjects without obstructive lung function impairment, divided into normal lung function and restrictive pattern. Our hypothesis was that the prevalence of IHD would be higher among subjects with COPD compared with subjects with normal lung function and that the prevalence of IHD would increase with COPD disease severity, as assessed by spirometry.

In this cross sectional population based study, self-reported as well as ECG changes of ischemic heart disease (IHD) according to Whitehall were equally prevalent among subjects with COPD and those with normal lung function (NLF). There was a significant association between increasing presence of self-reported IHD as well as probable ECG changes of IHD, according to the Whitehall criteria, in relation to COPD disease severity, both classified according to GOLD stage as well as assessed as FEV₁ percent of predicted. The significant relationship between FEV₁ percent of predicted and self-reported IHD but not probable ECG-findings remained after adjustment for age and sex.

According to a recent review, the prevalence of coronary heart disease (CHD) in different COPD populations varies between 4.7 % and up to 60 % [27]. Since the recruitment of study population, as well as the definitions of CHD and COPD, vary between the studies, it is difficult to compare the results. In a Danish population-based study [28], the prevalence of IHD was 8.6 % in non-COPD and increased in COPD by GOLD stage 1, 2 and 3–4; 12.1 %, 14.9 % and 13.7 % respectively; the corresponding prevalences of Q-wave (major + minor) were 2.7 % in non-COPD, and 3.3 %, 6.2 % and 6.9 % by GOLD stages. Overall, self-reported heart disease and presence of corresponding ECG-findings were markedly more common in our study compared with in the Danish survey. One possible explanation for the observed difference is that although the COPD classification in the Danish study was based on spirometry, they used pre-bronchodilator values, i.e. not following current guidelines recommending post-bronchodilator spirometry for the diagnosis of COPD. Other studies have shown that the use of pre-bronchodilator spirometry misclassify up to 27 % of non-obstructive subjects as obstructive, which might contribute to the lower IHD prevalence [29]. Further, the Danish study was a close to 25-year follow-up of the large-scale Copenhagen City Heart study (with the addition of a smaller random sample of younger adults) and a healthy survivor effect can thus be expected to have affected the results. In a population-based study using the Burden of Obstructive Lung Disease (BOLD) survey, close to 100 cases of COPD were identified based on post-bronchodilator spirometry and they found no increased risk for self-reported cardiovascular disease or hypertension in either of the GOLD-stages [30]. In general, population based data on CHD among subjects with COPD identified by post-bronchodilator spirometry is mainly self-reported, and other clinical findings of CHD, such as ECG-changes, have rarely been evaluated.

A population-based COPD-cohort, such as in our study, will include a majority of subjects with GOLD 1 and 2 and only a low number of subjects with GOLD 3–4 [1]. Self-reported IHD as well as ischemic ECG-findings according to the Whitehall criteria clearly increased by GOLD stage and were considerably more common in GOLD 3–4 than among subjects with mild COPD. Even though our study include a large COPD-cohort, almost comparable to that of the National Health and Nutrition Examination Survey (NHANES) I [31], the distribution of GOLD stages contributes to a lack of power to show statistical significance due to the small proportion of severe/very severe COPD in a population based study, as also demonstrated by the quite large confidence intervals in Fig. 1. However, each of the GOLD stages include rather wide ranges of FEV₁ % predicted, and the continuous variable FEV₁ % predicted may be useful when it comes to evaluating events in relation to disease severity. The found positive associations between level of FEV₁ among COPD-subjects and self-reported IHD as well as probable ischemic ECG-changes according to the Whitehall criteria, thus further support a relationship between IHD and COPD disease severity. Interpretation of the results is that higher FEV₁ is protective, consequently, the presence of IHD increase the lower FEV₁ is, i.e. by increasing COPD disease severity. Furthermore, the observed high prevalence of ischemic ECG-changes in more severe COPD disease is comparable with findings from studies using hospitals records including severe stages of COPD [11, 12, 32].

It has also been observed that subjects with COPD have increased arterial stiffness [33], which is considered a marker of early atherosclerosis and a risk factor for development of CVD. In a recent review it was even suggested that measurements of arterial stiffness should be included in routine health care to assess the risk for CVD among subjects with COPD [34]. We have previously shown that central arterial stiffness is higher in GOLD 3–4 than in non-COPD [35] also in a population based study, which is in line with the current findings of IHD being most prevalent in GOLD 3–4. The clinical implication may be that not only non-invasive measurements of arterial stiffness, but also ECG may be of value when evaluating risk for and presence of cardiovascular disease when diagnosing subjects with COPD. The underlying pathological mechanism by concomitant COPD and IHD is, however, not fully understood, but may be related to systemic inflammation and endothelial dysfunction [5, 6, 16], and in addition high on-treatment platelet reactivity has been discussed as reason for the observed worsened prognosis among subject with concomitant COPD and IHD [5, 6, 36].

The original design of the study defined cases and sex and age-matched controls based on spirometry (COPD and non-COPD) in 2002–04. It has been described in other COPD studies that a proportion of the study population will transfer mainly from COPD to non-COPD but also vice versa during follow up [37]. To address this potential bias, data from 2005 is presented as a straight cross-sectional analysis defining COPD and non-COPD by current spirometry, but also by presenting data when the subjects had to fulfill the spirometric criteria of either COPD or non-COPD not only in 2005 but also at baseline, i.e. at recruitment in 2002–04. Among subjects with non-obstructive pulmonary function, also subjects with a restrictive pattern on dynamic spirometry were included. Restrictive pattern has in previous studies been shown to associate with metabolic disorders such as diabetes, as well as a higher prevalence of IHD [38] or risk for cardiovascular disease [30]. Thus we divided non-COPD into NLF and restrictive spirometric pattern and compared subjects with COPD with those having NLF.

A limitation of this study is that the self-reported burden of comorbid conditions, in this study specifically ischemic heart disease, may be affected by recall bias as well as misclassification since interview data were not verified by medical records, even though literature has shown a good agreement between self-reported diabetes, hypertension and myocardial infarction, but not heart failure [39]. Further, a 12-lead ECG only gives a short glimpse of the electrical activity of the heart, and has limited sensitivity and specificity for detecting ischemic myocardial events. Different ischemic ECG changes, for example ST segment changes and those involving the T-waves, have great variations in sensitivity and specificity, are dynamic and may thus vary over time [40, 41]. However, the strength of this epidemiological study is the large sample size, the distribution of disease severity representative for COPD in the general population [31, 42], the use of standardized post-broncho-dilator spirometry for defining COPD in accordance with the GOLD document [24], and double blinded Minnesota coded ECGs. To the best of our knowledge, this is the first population-based study addressing ischemic heart disease among subjects with COPD using validated and generally recommended classifications of ECG-findings and COPD.

In this population-based study, ischemic heart disease was equally common among subjects with COPD and those with normal lung function. Among subjects with COPD, there was a significant association between higher prevalence of self-reported ischemic heart disease and the results also indicate that there is an association between ECG changes of ischemic heart disease and increasing disease severity, as assessed by level of FEV₁. A longitudinal follow-up is important to evaluate the prognostic value as well as progression of the observed ECG-findings among subjects with and without COPD.