Discussion
In this large prospective study of the general population we observed that risks of coronary heart disease and heart failure were increased in COPD, even in mild-to-moderate disease. We also observed a similar increased risk in individuals with ACO with observed associations largely explained by severity of lung function impairment. Asthma also associated with risks of coronary heart disease and heart failure, with increased risk of coronary heart disease only in individuals who reported presence of allergy. We suggest that cardiovascular risk factors should be assessed systematically in obstructive airway disease with the potential to facilitate targeted treatments.
The burden of cardiovascular comorbidity in obstructive airway disease is increasingly acknowledged, and there is a need of identifying which patients are at increased risk31 to facilitate optimal treatment and prevention. To our knowledge, this is the first large prospective population-based study showing that individuals with ACO have an increased risk of coronary heart disease and heart failure, and that this risk is of similar magnitude, or perhaps even slightly higher, than the risk observed in individuals with COPD. Recently, we have observed a poor survival in individuals with ACO in another Copenhagen cohort, The Copenhagen City Heart Study,29 and therefore the present study suggests that cardiovascular comorbidity is not a major part of the explanation for the poorer prognosis observed in ACO compared with COPD. The prevalence of ACO among those with airflow limitation in the present study was approximately 19%, which is in line with the prevalence reported in other cohorts.16 17 29 32 33 Our definition of ACO is based on objectively verified airflow limitation and self-reported asthma and our main findings of a higher risk of cardiovascular events in ACO are in line with findings of van Boven et al, although these investigators used a register-based diagnosis in their main analyses.16
Ageing in itself is a common risk factor to both obstructive airway disease and cardiovascular disease. However, in a recent study of ACO using the Copenhagen City Heart Study, we reported that age of asthma onset significantly influenced lung function decline and survival.29 Our present findings suggest that the age of asthma onset in ACO does not seem to play a major role with regard to future risk of cardiovascular comorbidity, which is somewhat surprising as previous research has indicated that early onset asthma and late-onset asthma could represent different pathological processes. However, in line with such a hypothesis, our main asthma analysis suggested that an increased risk of coronary heart disease might only be present in individuals with late-onset asthma. Similar results were observed in the Wisconsin Sleep Cohort9 and among women in the Atherosclerosis Risk in Communities Study.10 Importantly, in our sensitivity analysis using 20 years as the cut point, both early onset and late-onset asthma associated with risk of coronary heart disease. Thus, the lack of association with early onset asthma in our main analysis could depend on the choice of age cut point. Furthermore, limitations regarding our asthma definition should be acknowledged. Both heavy smoking history and airflow limitation were exclusion criteria in this group, thereby excluding individuals with a major cardiovascular risk factor or with obstructive lung function impairment.3 7 34 35 We thus recognise that our results may not apply to individuals with asthma and presence of airflow limitation, although the majority of individuals with asthma in the general population do not show presence of obstruction on spirometry.
Previous studies have indicated that presence of allergy could be associated with increased risk of cardiovascular disease.12 Therefore, we did a sensitivity analysis dividing asthmatic individuals by presence of allergy. In this analysis, we observed that only asthma with presence of allergy associated significantly with the risk of coronary heart disease. A possible explanation could be cellular pathways such as mast cell release linking allergy in asthma with coronary heart disease.36 The hypothesis of inflammatory pathways as a possible common mechanism is compatible with at recent finding of an increased risk only present in individuals with active asthma37 and also in line with observed associations between atopic dermatitis and myocardial infarction.38 Furthermore, the observed association between presence of allergy in asthma and coronary heart disease could be dependent on the late-phase reaction and chronic allergic inflammation involving mediators such as transforming growth factor α,39 a cytokine that has been associated with coronary heart disease.40 However, many complex mechanisms and mediators are involved in chronic inflammation in allergic asthma,39 and future studies are needed to investigate whether there could be particular inflammatory links between presence of allergy in asthma and cardiovascular comorbidity since our subgroup sensitivity analysis showed no association between presence of allergy without presence of asthma and prospective risk of cardiovascular disease.
As expected, we observed that diabetes and hypertension were strongly associated with the prospective risk of cardiovascular disease. These risk factors can be easily assessed at regular pulmonary examinations in an ambulatory setting by measuring glycated haemoglobin and blood pressure in other to facilitate targeted treatment. Our analyses also showed reduction in risk of coronary heart disease and heart failure associated with increased physical activity in leisure time, also when adjusting for several other important covariates. Considering that many previous studies have corroborated the importance of pulmonary rehabilitation in COPD, physical activity seems particularly important in patients with presence of both obstructive airway disease and comorbid cardiovascular disease.
In addition, while increased body mass index, as expected, associated with increased risk of both coronary heart disease and heart failure, previous research has shown that an increased body mass index is, in fact, associated with a lower risk of exacerbations in COPD.41 This seems like a paradox as several studies have shown a strong association between increased risk of exacerbations in COPD and increased risk of cardiovascular events.42 We therefore also call for future studies of associations between body mass index, weight changes, and body composition and risk of exacerbations in individuals with obstructive airway disease and cardiovascular comorbidity.
Our study seems to corroborate and supplement previous findings on the strong association between COPD, disease severity assessed by lung function impairment, and future risk of coronary heart disease and heart failure.4 5 A major strength of our study was inclusion of important clinical respiratory and cardiovascular characteristics. After adjusting for established risk factors, we observed that even mild-to-moderate COPD was associated with coronary heart disease and heart failure. Severity of FEV1 impairment seemed important in our study, thus, individuals with FEV1 below 50% of predicted had a higher risk than those with FEV1 above 50% p. A potential limitation is that our spirometries are prebronchodilator only. However, we believe that our findings support the notion that severity of lung function impairment plays the most important role in the risk of hospitalisations with coronary heart disease and heart failure in COPD. These results are in line with a previous study from the Copenhagen City Heart Study,43 and also in line with a study using the UK-based General Practice Research Database, where the investigators used COPD treatment as a proxy for disease severity and observed a higher risk among those patients with COPD with most severe disease.44
Most individuals with COPD have a history of smoking and therefore, we included pack-years in our definition of COPD phenotype. This explains why smoking was a weakly associated variable in multivariable modelling. We are aware of the fact that the way we defined our subgroups of airway disease phenotypes may significantly affect our findings and interpretation such as exclusion of individuals with light smoking COPD and heavy smoking asthma. However, our classification used both elements from the Global Initiative for Asthma and GOLD documents, and also elements commonly employed to define inclusion criteria for drug trials in asthma and COPD.45 46
It should also be acknowledged that we lack further characterisation of types of airway inflammatory process in our individuals with different phenotypes of obstructive airway disease. Furthermore, as another possible limitation, we only had access to information on self-reported asthma, and a physician-based diagnosis would likely be more reliable. Nevertheless, the use of self-reported asthma is well established for identification of asthma in population-based settings,47 48 as well as reported age of asthma onset.49
Strengths to the present study include the high number of enrolled participants and a complete follow-up in nationwide registries of diagnoses with a high specificity.24 25 We also consider the quite comprehensive information on both established cardiovascular and respiratory risk factors and an objectively verified presence of airflow limitation an important advantage that allows new clinical information on the associations between obstructive airway disease phenotypes and prospective risk of coronary heart disease and heart failure.
Despite our findings, we acknowledge that whether obstructive airway disease phenotypes should be considered as genuine cardiovascular risk factors is still a matter of dispute. Recently, a large randomised trial of treatment with inhaled corticosteroids and long-acting β2-agonists, the SUMMIT Study, aiming at reducing risk of cardiovascular mortality in individuals with COPD, failed to show any effect.50 Considering the importance of low lung function as a major risk factor both for cardiovascular disease and mortality, and considering that the SUMMIT Study did not show an effect of inhaled maintenance medications on mortality in subjects with COPD at increased cardiovascular risk, we suggest that cardiovascular as well as metabolic concomitant diseases should be not only carefully searched for in subjects with impaired lung function, but also appropriately treated with cardiovascular and metabolic agents. All together, we therefore suggest that, presence of asthma, COPD and ACO should lead to an increased focus on established cardiovascular risk factors in this population and result in relevant interventions if indicated.
In conclusion, risks of coronary heart disease and heart failure were increased in COPD, even in mild-to-moderate disease. We also observed similar increased risks in individuals with ACO, that seemed largely explained by the severity of lung function impairment. Asthma also associated with risks of coronary heart disease and heart failure, with an increased risk of coronary heart disease only present in individuals who also reported presence of allergy. We suggest that cardiovascular risk factors should be assessed systematically in obstructive airway disease with the potential to facilitate targeted treatments.