Heart failure and COPD: Partners in crime?
Jorien Hannink, Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Email: email@example.com
Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both common diseases with major impact and seem to coexist more frequently than expected from their separate population prevalences. However, estimates of combined prevalence must be interpreted carefully because of imperfections and difficulties in assessment of both diseases. This review aims to highlight HF prevalence in patients with COPD and vice versa, with a critical analysis of studies performed. First, definition, diagnosis, and prevalence of COPD and of HF will be discussed. Subsequently, an overview of important studies concerning combined prevalence with their limitations will be presented. Finally, pathogenic mechanisms and diagnostic considerations in clinical practice will be discussed.
Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both common diseases with major impact.1,2 Moreover, HF and COPD seem to coexist more frequently than expected from their separate population prevalences. Assessment of COPD occurrence in HF populations and vice versa is mainly based on hospital discharge diagnoses and/or medication prescription data. These estimates of combined prevalence may be very inaccurate, however. In one study, by Rutten et al., HF occurrence in COPD patients was thoroughly investigated.3 In a general practitioner's population, both COPD and HF were diagnosed according to current definitions.3 Contrarily, concurrent COPD in HF patients seems not so thoroughly investigated. Therefore, data regarding simultaneous COPD and HF remain scarce and results must be interpreted carefully because of imperfections and difficulties in assessment of both diseases.
The prevalence of combined COPD and HF is difficult to determine, because: (i) risk factors, symptoms and signs are overlapping,4; (ii) hyperinflation in COPD may prevent adequate echocardiographic assessment; and (iii) obstructive lung function abnormalities, not to be confused with COPD, may be present in acute HF.5 Although the diagnoses are complex, COPD and HF need a different approach and pharmacotherapy for COPD may interfere with HF (pharmacotherapy) and oppositely. Cardioselective β1-blockers are considered to be safe in COPD patients, but cardiovascular safety of β2-agonists is disputable.6,7 Therefore, an optimal treatment regimen must be carefully determined to balance positive and negative treatment effects in patients with COPD and HF. Knowledge of chances of concurrent COPD and HF facilitates the decision on additional testing in daily practice.
This review aims to highlight HF prevalence in COPD patients, and vice versa, with a critical analysis of performed studies. First, definition, diagnosis and prevalence of COPD and of HF will be discussed separately. Subsequently, an overview of important studies concerning combined prevalence will be presented and limitations discussed. We will end with pathogenic mechanisms, diagnostic considerations in clinical practice and conclusions.
DEFINITION, DIAGNOSIS AND PREVALENCE OF COPD
In the latest American Thoracic Society/European Respiratory Society position paper, COPD is defined as a condition characterized by a not fully reversible airflow limitation, indicated by a post-bronchodilator FEV1/FVC <70%.8 COPD is classified according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.9 Patients usually have symptoms of dyspnoea, cough and/or sputum production and a history of exposure to risk factors, mainly tobacco smoke.8,9
Estimates of prevalence of COPD depend on diagnostic criteria and definitions used.10 In addition, spirometric cut-off points have changed over time.11 Even since the latest guidelines, gender- and age-specific cut-off points for FEV1/FVC instead of a fixed ratio are proposed and have shown essential different results.12 Also, other approaches have been used to assess COPD prevalence, for example, self-reported diagnosis (‘Has a doctor ever told you that you had chronic bronchitis/emphysema?’).1
From the described prevalence studies, we have seen that spirometric assessment resulted in higher prevalence numbers than self-reported diagnosis of COPD.1,11 Furthermore, women do report to have COPD more often than men despite lower prevalence according to spirometry.1 The larger spirometry-determined, compared to self-reported, COPD prevalence might origin from irreversible airflow limitation associated with bronchiectasis, cystic fibrosis and fibrosis due to tuberculosis.8 Furthermore, discrimination between asthma and COPD can be difficult and additional tests might be required (http://www.ginasthma.com).13 On the other hand, patients with a clinical diagnosis of COPD were found to have COPD according to pulmonary function tests in only 61% (general practice) and 71% (tertiary care).3,14 Also, underpresentation, underdiagnosis or misclassification may play a role.13 Clearly, spirometry is essential for COPD diagnosis. Although, even in a tertiary care setting, spirometry was performed in only 31% of COPD patients over the past 8 years.14 For prevalence purposes, self-reported diagnosis is more often used than spirometry, probably because of time and financial limitations.
Worldwide prevalence of COPD according to the current spirometric definition ranges from 7.8% to 26.1% (Table S1 in the online supporting information) and is higher with increasing age, in smokers and in men, although prevalence in women is increasing.1,11,15,16
DEFINITION, DIAGNOSIS AND PREVALENCE OF CHRONIC HEART FAILURE
Many different definitions of HF have been used in the past. According to the most recent guidelines, HF is a complex clinical syndrome with symptoms and signs typical of HF and objective evidence of a structural or functional abnormality of the heart at rest (physical examination, echocardiography or natriuretic peptide concentration).17,18 Typical symptoms are dyspnoea, fatigue and typical signs are rales and oedema.17,18 There is no single diagnostic test, although the most useful test in the evaluation of patients with HF is the comprehensive two dimensional echocardiogram together with Doppler flow studies.17
Although many disorders may result in HF, main causes are coronary artery disease and hypertension.19 Various descriptive terms of HF are used, for example, systolic and diastolic HF.18 More recently, instead of systolic and diastolic HF, HF with reduced and normal left ventricular ejection fraction (LVEF) is preferred, since diastolic dysfunction occurs in diastolic HF as much as in systolic HF.20,21 Whether these two are ends of the spectrum or two distinct syndromes is still matter of debate.21 Although HF with reduced LVEF has been studied mostly, about half of all patients with HF have normal LVEF.20,21 Anyhow, prevalence of HF also depends on diagnostic criteria and definition and ranges from 2.2% to 3.9% (Table S2 in the online supporting information). Also, prevalence increases with increasing age.2,22,23
Left ventricular dysfunction is objective evidence of cardiac dysfunction and not necessarily HF. Whether these abnormalities are preclinical or patients adapt their activities to their symptoms and do not experience them or do not go to a doctor is unclear. Left ventricular systolic dysfunction (LVSD) is generally defined as LVEF <40–50%, although there is no consensus concerning the cut-off.18 LVSD prevalence ranges from 2.0% to 7.7% with different cut-off points for LVEF.2,22,23 In contrast to the relatively straightforward method to diagnose LVSD, many different parameters are used to describe left ventricular diastolic dysfunction (LVDD) and criteria have changed recently.21,24 According to the most recent criteria, LVDD is indicated by LVEF >50% and left ventricular end-diastolic volume index <97 mL/m2, plus invasively measured left ventricular end-diastolic pressure >16 mm Hg, or mean pulmonary capillary wedge pressure >12 mm Hg, or time constant of left ventricular relaxation >48 ms, or constant of left ventricular chamber stiffness >0.27; or plus by tissue Doppler determined E/E′ >15 (E: early mitral valve flow velocity; E′: early diastolic lengthening velocity of mitral annulus).21 When 15 > E/E′ > 8, additional echo (Doppler), blood or electrocardiographic investigations are necessary to prove diastolic dysfunction.21 Described prevalences of mild, moderate and severe LVDD are 20.8, 6.6 and 0.7% respectively.23
PREVALENCE OF HEART FAILURE IN COPD
Heart failure in stable COPD
In a cross-sectional study in elderly COPD patients from general practice, prevalence of unrecognized HF turned out to be 21%.3 Patients were subjected to a diagnostic work-up including questionnaires, physical examination, chest radiography, electro- and echocardiography and pulmonary function tests. COPD was confirmed according to the GOLD criteria. An expert panel decided about the existence of HF using all available diagnostic information. Half had systolic, half isolated diastolic and none right-sided HF. Age and smoking history were similar, but a history of ischaemic heart disease, hypertension or diabetes mellitus was more frequently seen in COPD patients with concurrent HF compared with those without. Because signs and symptoms between these groups were comparable, patients with asymptomatic left ventricular dysfunction might have been included in the HF group. As this study was performed in general practice, conclusions regarding other populations cannot be drawn.
Heart failure in COPD exacerbations
Patients with a history of asthma or COPD (self-report and medical record) and without a history of HF presenting to the emergency department with acute dyspnoea were evaluated for HF.25 In 21%, congestive HF was diagnosed after discharge by two independent cardiologists using all obtainable information (blinded for natriuretic peptide levels).25 The group with HF was older than the group without (71 vs 60 years). In patients with HF, a history of coronary heart disease, atrial fibrillation and diabetes mellitus was more common than in those without. Unfortunately, no smoking data were presented. Some severe limitations of this study need to be taken into consideration. Namely, no distinction between asthma and COPD was made, and no spirometry was performed to verify the diagnoses. Furthermore, echocardiography was performed in only 29% of the study population.
In another study, patients admitted for a severe acute exacerbation of their COPD without obvious cause were studied by an expert panel.26 In 51% echocardiographic left ventricular dysfunction was found, of which 64% was systolic, 23% diastolic and 13% both. After discharge, an expert panel could confirm in 31% of the acute exacerbations a definite association with left ventricular dysfunction. The limitation of this study was that COPD was not validated by pulmonary function testing.
Heart failure hospitalization in COPD
In database studies, hospitalization for congestive HF was reported to be approximately three times higher in COPD patients compared with matched controls (Table S3 in the online supporting information).27–29 COPD and HF were assessed by discharge diagnoses and/or medication prescriptions, which might be very inaccurate to make a diagnosis. Furthermore, it might be that patients with COPD and HF are more often hospitalized for HF than those with HF but without COPD.
Left ventricular dysfunction in COPD
The prevalence of LVSD was reviewed in COPD patients without overt coronary artery disease and hypertension and varied from 0% to 16% (5 out of 8 studies found a prevalence of 0%).30 When LVSD was found, it was generally mild and mainly in patients with a history of cor pulmonale. In patients with a COPD exacerbation, prevalence varied from 0% to 32%.30 In groups without exclusion of patients with cardiovascular disease, LVSD varied from 10% to 46%.30 Surprisingly, the lowest prevalence was reported in COPD patients with clinically suspected left ventricular dysfunction.31 In summary, LVEF seems to be normal in COPD patients without recognized cardiovascular comorbidity31–37 (Table S4 in the online supporting information). In those with an affected right heart, generally lower but still normal ejection fractions were found.32,34,36,37
In a large cohort of stable emphysema patients without a history of cardiovascular disease, mean pulmonary capillary wedge pressure was 14 mm Hg,35 indicating mild LVDD. Some smaller studies showed no LVDD in comparable patients32,36,38 (Table S5 in the online supporting information). Boussuges et al. compared clinically stable patients with severe COPD and without a history of hypertension or heart disease with healthy subjects.39 They found a correlation between left atrium and left ventricular filling pattern on the one hand and right ventricle pressure and diameter on the other hand, so-called ventricular interdependence, which has been described earlier.40 Comparable findings were observed by others, especially in patients with elevated pulmonary artery pressure41,42 (Table S5 in the online supporting information). LVDD during COPD exacerbation ranged from 0% to 41%.43–45
Instead of discriminating between LVSD and LVDD, a myocardial performance index ((isovolumetric contraction time + isovolumetric relaxation time)/ejection time) was used as an index of global ventricular function in non-cardiovascular affected COPD subjects. Left ventricular myocardial performance index was increased in patients with COPD and pulmonary hypertension compared with those without pulmonary hypertension and with controls.37
PREVALENCE OF COPD IN HEART FAILURE
COPD prevalence according to GOLD criteria of 39% was reported in HF patients with reduced LVEF.46 Initial assessment in an outpatient HF clinic included spirometry with reversibility testing, and retrospectively COPD prevalence was determined.46 Although patients were reported to be stable, it is questionable whether patients were optimally treated at initial assessment. Because obstructive lung function abnormalities may be present in acute HF and may disappear with treatment,5 this might have influenced their reported COPD prevalence.
A very recent review showed a prevalence of COPD in HF hospitalization populations of 9–51% and in stable outpatients of 7–13%, with diagnoses based on disease codes and medication use,47 which may be imprecise, as stated before.
Pulmonary function disorders in heart failure
To assess the effects of HF on spirometry, pulmonary function was assessed serially during a mean follow-up of 310 days in 28 patients with acute HF and without a history of COPD.5 As expected, a restrictive, but also an obstructive lung function disorder with a mean pre-bronchodilatory FEV1/FVC of 66% was found initially. After the treatment of HF, this ratio improved to normal only in non-smokers (smokers mean FEV1/FVC 64%, but in 5 of the 13 smokers ≥70%). The persisting obstruction in smokers after treatment of HF might be due to undiagnosed COPD or asthma. In this study, it is not clear whether non-smokers had a smoking history. Also, reversibility was only tested in 64% of the subjects and in these patients no reversibility was found.
Similarly, hospitalized patients with severe HF showed FEV1/FVC ratios (without reversibility testing) before and after HF treatment of 63% and 78% respectively.48 Furthermore, flow limitation (measured by negative expiratory pressure), especially in supine position, has been demonstrated in acute HF patients.49,50 This was shown to disappear after treatment with diuretics and vasodilators.50 It is suggested that this flow limitation is caused by airway obstruction due to intrathoracal blood shift with compression of peripheral airways by the distended pulmonary arteries.5,50 Subsequently, interstitial oedema is thought to develop and ultimately alveolar oedema.5
In stable congestive HF patients without a history of COPD or asthma, no obstruction was demonstrated, although some found large standard deviations (FEV1/FVC 73–80 ± 7–20%).51–53 After bronchodilation, FEV1/FVC improved from 80 ± 7% to 83 ± 6% in non-smokers and from 75 ± 11% to 77 ± 9% in smokers with severe congestive HF52 (Table S6 in the online supporting information).
The conclusion from the presented studies might be that HF may cause an obstructive pulmonary function pattern in the acute phase, disappearing with treatment of HF.
SHORTCOMINGS OF STUDIES CONCERNING SIMULTANEOUS COPD AND HEART FAILURE
Substantial variation in prevalence of concurrent HF and COPD is reported and this seems to have several reasons. Different definitions have been applied, for example, based on objective measurements, self-report or drug exposure. In case of objective measurements, the two conditions were usually defined according to established criteria; however, they have changed over time. Furthermore, on the basis of a single lung function measurement, it is impossible to discriminate between asthma and COPD. Also, left ventricular function has been assessed by different techniques, such as catheterization, echocardiography and radionuclide ventriculography, and different cut-off points have been applied. Additionally, a considerable number of patients have been excluded in several studies because of poor echogenicity due to hyperinflation. Finally, patients with varying disease severity and, in case of COPD, with and without concomitant cardiovascular diseases have been studied. Conclusions are therefore hard to draw. To elucidate prevalence of HF in COPD and vice versa, prospective studies should be performed.
PATHOGENIC MECHANISMS OF CONCURRENT COPD AND HEART FAILURE
Apart from smoking as a common risk factor, COPD patients are suggested to have an additional cardiovascular risk factor.54,55 Like cardiovascular diseases, stable COPD is associated with low-grade systemic inflammation.56,57 Sin and Man analysed the relation between COPD, systemic inflammation and cardiovascular disease.58 Risk of underlying ischaemic heart disease was greatest in patients with moderate or severe airflow obstruction and highly elevated C-reactive protein, suggesting an additional effect of this inflammatory marker on cardiac risk. Furthermore, several markers of cardiovascular risk are associated with airflow limitation.59–61 In addition, C-reactive protein concentrations were found to be correlated with vascular structure and function in COPD patients,59,62,63 although not consistently.64 Cardiovascular diseases in turn are the main cause of HF.19 On the other hand, pulmonary hypertension is common in severe COPD65 and finally leads to right HF.66 Right HF in turn is associated with left HF.39,40 In summary, COPD patients seem to be at higher risk for cardiovascular disease, including HF, caused by the same pathogenic mechanism.
DIAGNOSTIC CONSIDERATIONS IN CLINICAL PRACTICE
In patients with COPD, plasma levels of natriuretic peptides, simple and relatively cheap diagnostic tests, can be useful. In stable elderly COPD patients in a primary care setting, optimal cut-off values of 35 pg/mL for B-type natriuretic peptide (BNP) and of 125 pg/mL for aminoterminal-proBNP (NT-proBNP) were found with sensitivities of 71% and 78% and specificities of 58% and 58%, respectively.67 Therefore, these tests perform better in excluding than detecting HF. For detecting HF in stable COPD patients imaging techniques appear more suitable.4 Different cut-off values apply to COPD patients with acute dyspnoea. Cut-off values of BNP and NT-proBNP derived from large studies in patients presenting with acute dyspnoea to the emergency department68,69 were tested in a subgroup of patients with a history of COPD.25,70 A single cut point for BNP to exclude/detect HF was </≥100 pg/mL, with a sensitivity of 93% and a specificity of 77%.25 Although not specifically tested in patients with a history of COPD, BNP >500 pg/mL is suggested by others to indicate acute HF in COPD.4 However, they emphasized that it does not necessarily differentiate between a cardiac and pulmonary cause of clinical deterioration but indicates that HF therapy should be initiated, and cardiac imaging should be performed when stable.4 Finally, in COPD patients with BNP levels of 100–500 pg/mL, cor pulmonale (right ventricular stretch) might be the source (or moderate left ventricular failure).4,71 For NT-proBNP, a value of <300 pg/mL to exclude HF, and of >450 pg/mL for patients <50 years and of >900 pg/mL for those ≥50 years to detect HF was tested in patients with previous COPD presenting with acute dyspnoea.70 For excluding HF sensitivity was 94% and for detecting HF specificity was 84%. In COPD patients with previous HF these values were 97% and 47%, respectively, and in those without previous HF 90% and 90%, respectively.70 When natriuretic peptides were added to clinical judgment, 95–100% of the patients were correctly diagnosed.25,70 In a group admitted to the intensive care unit for severe exacerbation of COPD, much higher levels of NT-proBNP levels of <1000 pg/mL to exclude (sensitivity 94%) and ≥2500 pg/mL to detect (specificity 86%) HF were found to be optimal.26 Thus, generally, values derived in patients with acute dyspnoea are also applicable to patients with a history of COPD, and the combination of clinical judgment together with natriuretic peptides provides a good diagnostic framework. In case of doubt, cardiac imaging techniques should be applied.
To investigate simultaneous COPD in stable HF patients, repeated spirometry with reversibility testing should be performed. In the acute situation, it might be impossible to perform spirometry reliably and concurrent COPD can only be determined after the acute phase.
Based on recent studies, COPD and HF seem to coexist more often than expected from its separate prevalences. However, reported numbers should be interpreted cautiously, because there are generally shortcomings according to definition and assessment of both diseases. LVSD does not seem to play an important role in COPD patients without concomitant cardiovascular disease, in contrast to LVDD, which is suggested to be mediated by ventricular interdependence. Future studies should be directed at determining more precise estimates of coexistence of COPD and HF and optimal diagnosis and treatment.
In clinical practice, there should be awareness of increased combined prevalence of COPD and HF. At least in patients with excessive symptoms despite optimal treatment, additional investigations should be performed.