Chapter 4

Diagnosis and management of heart failure in COPD

Frans H. Rutten
SUMMARY: Heart failure is common in COPD; however, it is often unrecognised. Tobacco smoking is an important cause of COPD and, indirectly, of heart failure. Heart failure and COPD share common pathways, including systemic inflammation, activation of the neurohumoral system and metabolic modulation resulting in muscle wasting and cachexia. Heart failure is an independent predictor of mortality in COPD. The left ventricle is mainly affected in heart failure, as well as in patients with heart failure and concurrent COPD. Diagnosing heart failure in the presence of COPD is difficult because of an overlap in symptoms and signs. Natriuretic peptides are useful for selecting COPD patients for echocardiography, which is the cornerstone for diagnosing heart failure. Therapy of heart failure in patients with COPD is, in principle, the same as in those without COPD. In patients with COPD and heart failure b2-agonists can be combined with cardioselective b-blockers, but anti-cholinergics seem to be a safer option. Observational data suggest that cardioselective bblockers and statins could reduce the risk of mortality and exacerbations of COPD. However, confirmation with randomised controlled trials is required. KEYWORDS: COPD, diagnosis, heart failure, management, prognosis, treatment
Correspondence: F.H. Rutten, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85060, Stratenum 6.101, 3508 AB Utrecht, The Netherlands. Email: F.H.Rutten@umcutrecht.nl

DIAGNOSIS AND MANAGEMENT OF HEART FAILURE

Eur Respir Monogr 2013; 59: 5063. Copyright ERS 2013. DOI: 10.1183/1025448x.10011412 Print ISBN: 978-1-84984-032-3 Online ISBN: 978-1-84984-033-0 Print ISSN: 1025-448x Online ISSN: 2075-6674

hysicians are often confronted with patients complaining of breathlessness, with approximately 40% of elderly subjects having some degree of shortness of breath [1]. Pulmonary and cardiac diseases are the main causes, and approximately 30% of cases are due to more than one cause of disease [2]. In the elderly, COPD and heart failure are the main reason for breathlessness [2]. Importantly, COPD and heart failure have largely been studied separately, with COPD in the domain of the pulmonologist and heart failure in the domain of the cardiologist. Fortunately, the interest in the interactions between both diseases has grown in the last decade [3]. Tobacco smoking is a strong common risk factor, with lung destruction resulting in COPD and systemic endothelial dysfunction causing ischaemic heart disease. Ischaemic heart disease on its

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own is a major risk factor for developing heart failure. Epidemiological studies suggest that COPD on its own can also increase the risk of ischaemic heart disease, independent of age, sex, and smoking [4, 5]. Moreover, the cause of death in people with COPD is often cardiovascular [6, 7]. Both COPD and heart failure are chronic progressive diseases that lead to systemic inflammation, activation of the neurohumoral system and metabolic modulation, which eventually results in muscle wasting and cachexia [8]. Typically, heart failure develops in the presence of COPD, with COPD starting at an earlier age and having lower mortality rates than heart failure. The prevalence of heart failure is around 25% in patients with COPD aged 65 years or over, which is approximately three times higher than expected in age-matched controls from the general population [9]. Due to overlap in symptoms and signs, as much as 80% of concurrent heart failure in elderly patients with COPD remains unrecognised in daily practice, especially in the early phase of the disease [9]. In this chapter we will provide reasons to further elucidate the complexity of COPD and heart failure and give direction for further research. Moreover, we want to provide clinicians with the tools to further improve everyday clinical management of patients with COPD, hopefully paying more attention to (non-overt) cardiovascular diseases in these patients.

History
Until 2003, heart failure was considered uncommon in patients with COPD and, whenever present, would occur as right-sided heart failure with elevated right arterial pressures, i.e. cor pulmonale [10]. Importantly, however, this view was based on studies performed in the 1970s, with small samples of rather young patients (mean age 5368 years) who mostly had severe COPD and selectively no coronary artery disease (CAD) [11]. In this selected population of COPD patients, left ventricular dysfunction (left ventricular ejection fraction (LVEF) ,4050%) was relatively uncommon with prevalence rates of only 016% [11]. A hint that left ventricular dysfunction was much more common in unselected patients with COPD (i.e. without excluding patients with CAD) came from five studies published between 1975 and 1984, reporting much higher prevalence rates of left ventricular dysfunction, ranging from 10% to 46% [11]. Still, the idea that concomitant heart failure was rare in patients with COPD persisted until 2003 [11]. Then, MCCULLOUGH et al. [12] showed that 21% of 417 patients with self-reported COPD or asthma (mean age 62 years) presenting at the emergency department with acute shortness of breath had previously unknown heart failure. In 2005, similar results were reported from a study among 405 elderly patients (mean age 73 years) with stable COPD [9]. Since then, multiple studies have addressed the occurrence of both diseases and their potential clinical consequences [3, 7, 11, 1316], and international guidelines on both heart failure and COPD have focussed on the impact of one disease in the presence of the other [17, 18].

Definition of heart failure

Heart failure can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate proportionate to the requirements of the metabolic tissues [17]. Heart failure can also be defined clinically as a syndrome in which patients have typical symptoms (e.g. breathlessness, ankle swelling and fatigue) and signs (e.g. elevated jugular venous pressure, pulmonary crackles and displaced apex beat) resulting from an abnormality of cardiac function or structure [17]. In heart failure with reduced ejection fraction (REF), the main cardiac abnormality is left ventricular dysfunction with a reduced LVEF ,4050% [17]. In the case of heart failure with preserved ejection fraction (PEF), structural abnormalities of the heart such as left ventricular hypertrophy and left atrial enlargement and/or diastolic dysfunction can be detected with echocardiography in the presence of a LVEF .50% [17]. The main features of diastolic dysfunction on echocardiography are delayed left ventricular relaxation with ventricular stiffness and elevated filling pressures of the left ventricle [17]. For isolated right-sided heart

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failure (cor pulmonale), symptoms and signs suggestive of heart failure are needed but, importantly, typically lack symptoms and signs of left-sided fluid overload, i.e. orthopnoea and pulmonary crackles. This occurs in the presence of a normal left ventricular systolic (LVEF .50%) and diastolic function, but with structural or functional abnormality of the right ventricle, resulting in a calculated systolic pulmonary artery pressure (sPAP) .50 mmHg with echocardiography [17]. However, many of the symptoms of heart failure are nonspecific and do not, therefore, help discriminate between heart failure and other problems [17]. Symptoms that are more specific (i.e. orthopnoea and paroxysmal nocturnal dyspnoea) are less common and are, therefore, infrequently present [17]. Many of the signs of heart failure result from sodium and water retention and are, therefore, also not specific [17]. Peripheral oedema has other causes as well, and is particularly nonspecific. Sodium and water retention resolve quickly with diuretic therapy, i.e. may be absent in patients receiving such treatment, as in hypertension [17]. These points highlight the need to obtain objective evidence, preferably by echocardiography, of a structural or functional cardiac abnormality that is thought to account for the patients symptoms and signs, in order to secure the diagnosis of heart failure. [17] Once the diagnosis of heart failure has been made it is important to establish the cause, particularly specific correctable causes, including non-cardiac causes. The precise aetiology determines whether specific treatment is needed (e.g. valve surgery for valvular disease) [17].

Epidemiology and pathophysiology of heart failure

Approximately 12% of the adult population in developed countries has heart failure with the prevalence increasing to .10% among persons aged 70 years or older [17]. There are many causes of heart failure, with CAD and hypertension being the most important [17]. About half of patients with heart failure have a low ejection fraction (,4050%) and the other half have a PEF (.50%) [17]. Only 1% of patients with heart failure has isolated right-sided heart failure (cor pulmonale), with sPAP of .50 mmHg in the presence of COPD [19]. Heart failure with a PEF seems to have a different epidemiological and aetiological profile from heart failure with REF [17]. Patients with heart failure with PEF are in general older, more often female and obese, and have more concomitant cardiac and non-cardiac problems/diseases (e.g. chronotropic incompetence, atrial fibrillation, anaemia and diabetes) than those with REF. They are less likely to have coronary heart disease and are more likely to have hypertension than those with heart failure with REF [17]. The prognosis of those with heart failure with PEF is somewhat better than those with REF, but still poor with a 5-year mortality of all heart failure cases of around 50% [2022]. In patients with heart failure with REF, the left ventricular systolic dysfunction starts with maladaptive changes occurring in surviving myocytes and extracellular matrix after myocardial injury (e.g. a myocardial infarction) leading to pathological eccentric remodelling of the left ventricle with dilatation and impaired contractility; one measure of which is a reduced LVEF [17]. Over time there is progressive worsening of these changes, with increasing enlargement of the left ventricle and decline in LVEF. Two mechanisms are thought to account for this progression: 1) further events leading to additional myocyte death (e.g. recurrent myocardial infarction); and 2) systemic responses induced by the decline in pumping function [17]. Amongst others, there are two activated key neurohumoral systems that can be targeted with drug treatment; the reninangiotensinaldosterone system and the sympathetic nervous system [17]. Over activation of these systems lead to further myocardial injury and detrimental systemic effects in the blood vessels, as well as the kidneys, muscles, bone marrow, liver and lungs [17]. It creates a pathophysiological vicious circle accounting for many of the clinical features seen in heart failure [17]. This results in episodes of frank decompensation (exacerbations) with hospital admissions and premature death, usually due to pump failure or a ventricular arrhythmia [17]. In heart failure with PEF there is typically a long-lasting low-degree of myocardial injury, e.g. hypertension, resulting in eventual maladaptive changes in surviving myocytes and extracellular matrix with concentric remodelling of the left ventricle [23]. Metabolic adaptation leads to stiffness of the myocytes and fibrotic changes of the extracellular matrix, resulting in delayed

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DIAGNOSIS AND MANAGEMENT OF HEART FAILURE

relaxation of the left ventricle [23]. During exercise, the pressure in the left ventricle increases abruptly even with a small increase in blood volume, resulting in insufficient increase in stroke volume and thus symptoms such as breathlessness, chronic incompetence, reduced exercise tolerance and increased recovery time [23].

Systemic effects of heart failure

Ischaemic heart disease and hypertension are the main causes of heart failure and both can be considered as systemic diseases. Ischaemic heart disease develops from coronary and systemic atherosclerosis [24], a major cause of which is tobacco smoking. It leads to elevated levels of lowdensity lipoproteins, increases of free radicals, arterial wall hypoxia and oxidative stress, all negatively affecting the endothelial wall of the arteries [2527]. Hypertension has multiple effects on the heart and vessels, including propagation of systemic atherosclerosis by increasing the formation of hydrogen peroxide, which has pro-inflammatory and atherosclerotic properties [26]. Systemic inflammation is another important feature of heart failure with elevated levels of cytokines and tumour necrosis factor (TNF)-a [28]. Cardiomyocytes and other cells within the myocardium can synthesise TNF-a in response to various forms of cardiac stress, including left ventricular pressure or volume overload, which is present in heart failure [29]. In the disease progression of heart failure, serum levels of the inflammatory cytokines TNF-a, interleukin (IL)-6 and C-reactive protein (CRP) are all elevated and correlated with progression of heart failure, worsening functional condition and poorer survival. To date, treatment of systemic inflammation is uncertain and anti-TNF-a treatment does not result in improved prognosis in heart failure.

Probably the most important pulmonary effect of heart failure is (periods of) increased pulmonary capillary wedge pressure and pulmonary congestion with interstitial and peri-bronchiolar oedema. This can result in a decrease of diffusion capacity and induction of pulmonary vascular bed remodelling resulting in pulmonary arteriolar wall hypertrophy [30, 31]. In addition, an increase in PAP can develop secondary to left-sided heart failure. Acute cardiac decompensations may result in pulmonary obstruction (asthma cardiale) with wheezing and extended expirium on physical examination, which are often difficult to distinguish from asthma attacks.

Effect of heart failure on pulmonary function testing

A reduction of about 20% compared to age-, sex- and height-matched controls in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) can be expected to be caused by heart failure [32]. Fortunately, FEV1 and FVC are affected at an almost similar degree, at least in stabilised patients who are not fluid overloaded. Thus, when in a stable phase of the disease, the FEV1/FVC ratio is not significantly affected in the presence of heart failure [32]. However, the severity of pulmonary obstruction can be over-rated in patients with COPD in the presence of heart failure, because part of the reduction in FEV1 % predicted is caused by heart failure [32]. As already mentioned previously, pulmonary diffusion capacity is lower in the presence of heart failure, more clearly so when patients have signs of water and salt retention on physical examination.

Systemic and cardiovascular effects of COPD

In COPD the most obvious abnormality is the fixed airflow limitation. Importantly, however, this airflow limitation is associated with an abnormal pulmonary and systemic inflammatory response of the lungs to tobacco smoking [3]. Other systemic effects in COPD that are at least partly related to inflammation are (periods of) hypoxaemia, oxidative stress, chronic progressive muscle

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Pulmonary effects of heart failure

wasting and increased sympathetic tone. Systemic inflammation negatively affects the endothelial wall of (coronary) arteries, promoting atherosclerotic disease progression. Persistent systemic inflammation is associated with poor clinical outcomes in COPD [33, 34]. Inflammatory markers can be detected irrespective of smoking status and disease stage of COPD [8, 35]. To date, it is unclear whether this is due to spill-over of inflammation from the lungs into the blood, or activation of inflammatory cells in their transit through the pulmonary circulation [36]. The atherosclerotic process is further amplified by pro-inflammatory cytokines, such as TNF-a and IL-8, which are essential elements in the cytokine cascade as they produce increased levels of CRP [37]. In a selfperpetuating way, CRP can even up-regulate production of other inflammatory cytokines and foster leukocyte adhesion to vascular endothelium. In addition, CRP itself may be deposited directly into the arterial wall during atherogenesis [4, 7]. Moreover, neutrophils play a destabilising role in atherosclerotic plaques which may result in their rupture [8]. Thus, the systemic inflammation present in COPD is strongly related to systemic atherosclerosis [38]. This is underlined by epidemiologic studies showing that patients with COPD have an increased incidence of systemic atherosclerosis, independent of age, smoking or other cardiovascular risk factors [4, 5]. As a result, cardiovascular morbidity is common in patients with COPD [38, 39]. Momentarily, it is unknown whether systemic atherosclerosis is just an epiphenomenon associated with COPD or whether it can further induce disease progression of COPD. In patients with COPD and (severe) hypoxaemia, other pathways can affect cardiac function more directly. Alveolar hypoxia and pulmonary vasoconstriction can lead to remodelling of the pulmonary vascular bed by: 1) diversion of blood flow from areas of regional alveolar hypoxia to better ventilated areas of the lung; 2) media hypertrophy of muscular pulmonary arteries; and 3) proliferation of vascular smooth muscle cells into the normally non-muscular vessels of the pulmonary circulation [40]. When extensive parts of the lungs are involved this results in pulmonary arterial hypertension and increased pulmonary vascular resistance, thus, resulting in increased workload for the right ventricle in particular, which can result in dilatation and hypertrophy of the right ventricle and eventually right-sided heart failure (i.e. cor pulmonale) (table 1) [41, 42].

DIAGNOSIS AND MANAGEMENT OF HEART FAILURE

Heart failure in COPD

Common pathophysiological pathways
Apart from the systemic effects of smoking and inflammation, there are other common pathways in COPD and heart failure that cause mutual disease progression. In both diseases, the renin angiotensin system (RAS) is over-activated [17, 43]. Importantly, the RAS is not only active in the systemic circulation but also in organ tissue, including the lungs [43, 44]. Angiotensin-II is a potent pulmonary airway constrictor, has mitogenic effect on lung fibroblasts and can cause apoptosis of lung epithelial cells [45]. In addition, increased levels of angiotensin-II in the lungs have been related to a decrease in alveolar membrane gas exchange and an increase in both pulmonary inflammation and pulmonary vascular constriction [4447]. The other well-established pathway in the disease progression of heart failure is sympathetic overactivity, causing systemic and direct cardiac effects [17]. It results in downregulation and reduction of the density of b1-adrenoreceptors in the myocardium [48]. Sympathetic over-activity can lead to increased heart rates with (short-term) increased contractility and vasoconstriction by activation of the RAS and direct cardiotoxicity with myocyte apoptosis and focal myocardial necrosis [49]. Persistence of the sympathetic over-activity of the heart and vessels and the direct negative myocardial effects lead to fluid retention and increased left ventricular wall stress. In the long run, these changes lead to overloading of the myocytes resulting in overcompensated myocardial hypertrophy, decreased myocardial contractility and eventually myocardial damage [49] and, thus, in a decrease of ventricular function, especially of the dominant left ventricle resulting in heart failure. As a result, b1-selective, but also non-selective b-adrenoreceptor, blockers are now established evidence-based counteracting drugs in heart failure treatment [17].

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Table 1. Pathophysiological changes in COPD that can have an effect on cardiac function
Pulmonary changes in COPD A B C Positive end-expiratory pressure increase Systemic vasodilatation Thoracic pressure increase, respiratory effort increase, hypoxia and hypercapnia Resulting pulmonary and systemic changes Venous blood return decrease Venous blood return decrease Generalised sympathetic over activity and eventually downregulation and density decrease of cardiac b1-adrenoreceptors Cardiac effects Reduced right and left ventricle preload Reduced right and left ventricle preload Increased heart rate and short-term contractility, vasoconstriction, renin-angiotensin system increase, cardiotoxicity eventually leading to myocardial hypertrophy and damage, and decreased contractility High-permeability pulmonary oedema decreased diffusion capacity resulting in hypoxaemia (see pathways E, F and G) Impaired relaxation and contraction of right and left ventricle Right ventricle dilatation and hypertrophy due to increased right ventricle workload, resulting in isolated right ventricular failure and/or left ventricular dysfunction by diastolic flattening of the intraventricular septum Right ventricle dilatation and hypertrophy due to increased right ventricle workload resulting in isolated right ventricular failure and/or left ventricular dysfunction by diastolic flattening of the intraventricular septum

Hyperinflation and increased Pulmonary capillary wall stress lung volume increase and capillary leakage

E F

Hypoxaemia Hypoxaemia

Myocyte hypoxia Polycythaemia leading to serum viscosity increase and pulmonary thromboembolism

In COPD, the nervous system, mainly the parasympathetic system, is also over-activated [18, 43]. However, at least in more severe COPD, several processes can also induce (ortho-) sympathetic over-activity [43]. Such processes include increased thoracic pressures, increased respiratory effort, hypoxaemia and hypercapnia [48]. The exact role of (ortho-) sympathetic over-activity in COPD is still unclear [43]. At a late stage in the disease progression of both COPD and heart failure, there is another important common mechanism. Both diseases share the same type of metabolic modulation with the cellular metabolism shifting from glucose to lipid metabolism, resulting in generalised muscle dysfunction and, eventually, chronic wasting and cachexia in the end stage of both diseases [5052].

Diagnostic considerations
In any patient with shortness of breath, heart failure should be considered, as well as in patients with known COPD. Importantly, signs and symptoms and additional investigations, such as natriuretic peptide measurements, ECG and chest radiographs, are more difficult to interpret in patients with COPD. Key symptoms of heart failure are breathlessness, ankle swelling and fatigue [17], another common feature in patients with COPD, certainly in the elderly, is chronic venous insufficiency of the legs. Even the more typical symptoms of heart failure, i.e. paroxysmal nocturnal dyspnoea and orthopnoea can also be present in COPD. Other overlapping symptoms between heart failure and COPD are nocturnal cough, wheezing and loss of appetite [17]. Key signs of heart failure are an elevated jugular venous pressure, peripheral oedema and pulmonary crepitations; however, these are all related to fluid retention, a laterally displaced apical impulse and a cardiac murmur, respectively [17]. Importantly, signs of fluid retention can be absent,

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Hypoxaemia induces hypoxic pulmonary vasoconstriction and pulmonary vascular bed remodelling

Pulmonary hypertension and pulmonary vascular resistance increase

especially in patients who use diuretics and in early stages of heart failure with PEF [17]. Additional investigations to increase the likelihood of heart failure include electrocardiography, serum measurements of natriuretic peptides and chest radiographs [17]. A completely normal electrocardiogram in patients with COPD makes heart failure unlikely [17, 53]. However, there are no typical ECG abnormalities for heart failure [17]. In addition, a B-type natriuretic value below the exclusionary cut-off point of 125 pg?mL-1 for N-terminal pro-brain natriuretic peptide (NTproBNP) and 35 pg?mL-1 for brain natriuretic peptide (BNP) in the nonacute setting makes heart failure unlikely [17]. The same holds true for patients with COPD [53], although patients with severe COPD and pulmonary arterial hypertension have, in general, elevated levels of natriuretic peptides reaching above the aforementioned exclusion cut-off points, and higher cut-off points could be used with similar good exclusionary capacity [17]. In the acute setting, when assessing patients with acute breathlessness, higher exclusion cut-off points of natriuretic peptides should be used; 300 pg?mL-1 for NT-proBNP and 100 pg?mL-1 for BNP [17]. A chest radiograph is, generally speaking, not very useful in the diagnostic assessment of heart failure in either setting, certainly not in patients with COPD, risking misinterpretation of abnormalities and underestimation of the cardiothoracic ratio [11]. In conclusion, signs and symptoms, together with natriuretic peptide measurements, ECG and chest radiographs, can only increase (or reduce) the likelihood of heart failure, irrespective of the presence or absence of COPD. Echocardiography is the cornerstone investigation and is necessary in order to confirm the diagnosis of heart failure. In general, highquality echocardiographic images can be made in the vast majority of COPD patients [53]. Cardiovascular magnetic resonance imaging is an alternative to echocardiography in patients with unclear views due to COPD [17]. To date, only one study has developed a prediction model to detect (or exclude) heart failure in patients with COPD [53]. The model was derived from patients with a diagnosis of COPD, aged 65 years and older, and in a stable phase of their disease [53]. Independent predictors of heart failure were: 1) a history of ischaemic heart disease (prior myocardial infarction, angina pectoris, coronary bypass grafting and percutanous coronary intervention); 2) obesity (body mass index (BMI) .30 kg?m-2); 3) a laterally displaced or broadened/sustained apex beat; 4) a heart rate .90 beats?minute-1; 5) an NT-proBNP level .125 pg?mL-1 (,15 pmol?L-1); and 6) an abnormal electrocardiogram [53]. Combining these variables in a clinical decision rule, the points for the aforementioned items were 2, 3, 3, 2, 4 and 3, respectively. With a score of 0, the risk of heart failure was 5%. With a score of 2 to 5, the risk was 24%, and for scores 69 and 1014, the risk of heart failure was 35% and 57%, respectively. Importantly, however, this model needs external validation in another cohort of COPD patients before it can be applied in everyday clinical practice.

DIAGNOSIS AND MANAGEMENT OF HEART FAILURE

Prognosis of heart failure in COPD

Newly detected heart failure in community-dwelling elderly patients with COPD doubles the mortality rates (25.6% versus 12.1%, p50.002 during meanSD 4.21.4 years follow-up), also independent of other factors [54]. Also, in newly diagnosed hospitalised heart failure patients, those with COPD had higher all-cause 5-year mortality compared to those without COPD [55]. Although not extensively investigated, there seems to be no significant difference in prognosis between heart failure with REF and PEF patients with coexisting COPD [56].

Pharmacological treatment considerations

Therapy of heart failure in patients with COPD is in principle the same as in those without COPD, including cardioselective b-blockers [18]. For patients truly intolerant to b-blockers, ivabradine (when heart rate is .70 beats?minute-1) or digoxin can be considered to reduce the risk of heart failure hospitalisation (fig. 1) [17].

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Diuretics relieve breathlessness and oedema in heart failure patients with signs and symptoms of congestion, irrespective of ejection fraction, but the effect of diuretics on mortality and morbidity is unclear [17]. In heart failure with REF patients, angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers (ARBs) when intolerated), b-blockers and mineralocorticoid/aldosterone receptor antagonists are all evidence-based morbidity and mortality reducing drugs and should, when possible, be prescribed and up-titrated in any patients with heart failure with REF [17]. For patients with heart failure with PEF, no treatment has yet been shown to convincingly reduce morbidity and mortality [17]. Diuretics are used in heart failure with PEF to control sodium and water retention. Adequate treatment of hypertension and myocardial ischaemia is also considered important, as is control of ventricular rate in heart failure with PEF patients with atrial fibrillation [17]. Importantly, statins are not effective in heart failure with REF [57, 58], and whether they are effective in heart failure with PEF needs to be further studied [59]. Nowadays, digoxin and other digitalis glycosides are infrequently used in heart failure with the exception of patients with concurrent atrial

Diuretics to relieve symptoms/signs of congestion# ACE inhibitor (or ARB if not tolerated) Add -blocker Still NYHA class IIIV? Yes Add an MR antagonist, Still NYHA class IIIV? No+

Yes

No

LVEF 35% Yes No

Sinus rhythm and heart rate 70 beatsmin-1 Yes Add ivabradine Still NYHA class IIIV and LVEF 35%? Yes QRS duration 120 ms? Yes Consider CRT-P/CRT-D## No Consider ICD No No

Still NYHA class IIIV? Yes No+ No further specific treatment+ Continue in disease-management programme

Consider digoxin++ and/or H-ISDN If end stage, consider LVAD and/or transplantation

Figure 1. Treatment options for patients with chronic symptomatic heart failure (New York Heart Association
(NYHA) class IIIV) and reduced ejection fraction irrespective of presence of COPD. ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; MR: mineralocorticoid receptor; LVEF: left ventricular ejection fraction; CRT-P: cardiac resynchronisation therapy-pacemaker; CRT-D: cardiac resynchronisation therapy-defibrillator; ICD: implantable cardioverter-defibrillator; H-ISDN: hydralazine and isosorbide dinitrate; LVAD: left ventricular assistant device. #: diuretics may be used as needed to relive the signs and symptoms of congestion but they have not been shown to reduce hospitalisation or death; ": should be titrated to evidence-based dose or maximum tolerated dose below the evidence-based dose; +: asymptomatic patients with an LVEF f35% and a history of myocardial infarction should be considered for an ICD; 1: if MR antagonist not tolerated an ARB may be added to an ACE inhibitor as an alternative; e: European Medicines Agency has approved ivabradine for use in patients with a heart rate o75 beats per minute, may also be considered in patients with a contraindication to a b-blocker or b-blocker intolerance; ##: indication differs according to heart rhythm, NYHA class, QRS duration, QRS morphology and LVEF; "" : not indicated in NYHA class IV; ++: digoxin may be used earlier to control the ventricular rate in patients with atrial fibrillation, usually in conjunction with a b-blocker; 11: the combination of hydralazine and isoorbide dinitrate may also be considered earlier in patients unable to tolerate an ACE inhibitor or an ARB. Reproduced from [17] with permission from the publisher.

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fibrillation [17]. For more information refer to the therapeutic flow chart of the recent European Society of Cardiology guidelines on heart failure [17].

Cardiovascular drugs and their pulmonary implications in patients with COPD b-blockers
Patients with heart failure and COPD should not be denied cardioselective b-blockers (e.g. metoprolol succinate, bisoprolol and nebivolol), although low-dose initiation and gradual uptitration (start low, go slow) seems even more important than in heart failure patients without COPD [14, 60]. For heart failure patients with more severe COPD the efficacy of b-blockade has not been extensively studied [14]. Nonselective b-blockers are not recommended because of the higher risk of bronchospasm, especially in the initial phase, although scarce data suggest that carvedilol (also a-blocking activity) can be used safely [14]. It is well-known that b-blockers initially have negative inotropic effects, while over time gradually displaying their cardiovascular beneficial effects. This also seems to occur in heart failure patients with COPD [14]. In a post hoc analysis of participants in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) programme, HAWKINS et al. [61] showed that b-blockers seem to be capable of counter-balancing possible negative effects of bronchodilators, including b-agonists on survival, although, the authors were not able to adjust for the severity of COPD. Considering always continuing b-blockers in patients with heart failure and COPD is also underpinned by the potential beneficial pulmonary effects of long-term b-blocker use, based on animal models. Long-term use of b-blockers can upregulate b2-receptors in the lungs and, thus, reduce the need for b-agonists and reduce inflammation [62, 63]. Interestingly, recent large observational studies provide some evidence that long-term use of cardioselective b-blockers, in particular, may reduce mortality rates and the risk of pulmonary exacerbations in patients with COPD, even in the subgroup of patients who are not known to have cardiovascular disease, and irrespective of the use of b-agonist inhalers [6466]. Residual confounding in these studies could dilute beneficial effect of b-blockers, because b-blockers are typically prescribed to patients with increased mortality risks (i.e. with hypertension and cardiovascular disease). However, confounding by contraindication threatens the validity of the aforementioned observational pharmaco-epidemiological studies because b-blockers could knowingly be withheld by a clinician in patients with more severe COPD due to concerns that the drug may worsen the patients condition [66]. Clinicians may reserve prescription of b-blockers to those with a less severe form of COPD who may have a lower risk of mortality. This can result in confounding by contra-indication and therefore overestimation of the effect of b-blockers [66].

DIAGNOSIS AND MANAGEMENT OF HEART FAILURE

ACE inhibitors or ARBs

ACE inhibitors and ARBs may improve pulmonary obstruction by decreasing angiotensin-II levels [4346]. Moreover, ACE inhibitors can also ameliorate the alveolar membrane gas exchange and decrease pulmonary inflammation and pulmonary vascular constriction [44]. A single, small randomised controlled trial (RCT) evaluated angiotensin-II blockers in patients with COPD and without obvious cardiovascular disease, evaluating surrogate end-points after 4 months of follow-up. This study showed that treatment with irbesartan resulted in an increase in total lung capacity (TLC) [67]. Two recently published observational studies showed potential benefit of ACE inhibitors for patients with COPD [68, 69]; however, these results should be interpreted cautiously, as with the observational data with (cardioselective) b-blockers and statins because of the risk of confounding.

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Mineralocorticoid/aldosterone receptor antagonists: spironolactone and eplerenone

There is a lack of studies evaluating the pulmonary effects of these drugs. Importantly, they also have some angiotensin-II blocking effects. These drugs seem to improve pulmonary gas diffusion and exercise capacity in patients with heart failure [70].

Diuretics
High dosages of diuretics can cause acidbase disturbances (metabolic alkalosis) in patients with COPD and this may blunt the respiratory drive, but at normal dosages pulmonary function is not affected by diuretics [46]. Acute exacerbations of COPD can go along with water and salt retention and (intravenous) loop diuretics could possibly have a beneficial role as one of the initial treatments, reducing the left ventricular cardiac wall stress and, as a result, lower the elevated levels of natriuretic peptides [71].

Digoxin
Digitalis glycosides may reduce lung function by pulmonary vasoconstriction [46].

Statins
In addition to their cholesterol-lowering ability, statins have been shown to have pleiotropic antiinflammatory and immune modulatory effects. Statins may be able to reduce neutrophil numbers, reduce T-cell activation and differentiation, increase apoptosis of eosinophils and regulate inflammation by enhancing phagocytosis of apoptotic cells [72, 73]. Animal studies have shown that statins inhibit the progression of emphysema in both murine and rat models [74]. Observational data show a reduction in rate of decline in FEV1 and FVC and, thus, suggest that statins directly exert a protective effect on the pulmonary system and abrogate the adverse effects of smoking on lung function, even in those who no longer smoke [75, 76]. Multiple observational studies in human populations show a reduction in frequency of COPD exacerbations, hospitalisations and all-cause mortality by statin therapy [77]. Whether the beneficial effects of statins in COPD patients are due to pulmonary, systemic or cardiovascular effects, or a combination of the three, remains unclear [77]. Despite the encouraging results, randomised interventional trials are needed with clinical relevant outcomes, such as lung function, number of exacerbations and hospitalisations, and mortality [77].

Pulmonary drugs and their potential cardiovascular implications b2-agonists

For b2-agonists, short- and long-term effects may differ [14]; especially for orally administered bagonists in patients with heart failure who have demonstrated acute haemodynamic improvements with an increase in LVEF and cardiac index, a decrease in pulmonary wedge pressure and even an improvement in symptoms and exercise tolerance [14]. In the longer term, however, b-agonists exert numerous unfavourable cardiovascular effects that are possibly even more pronounced when prescribed orally and in patients with heart failure because of the increased chronotropic and inotropic responsiveness and vulnerability to arrhythmias of the failing myocardium to b-agonists [14]. These negative effects include tachycardia and disturbed autonomic modulation with depressed heart rate variability and, in susceptible patients, could exert ischaemic events [14]. Importantly, standard metered-dose b-agonist inhalers produce only minor systemic and biochemical abnormalities [14]. Although, observational studies reported that b-agonist inhalers in patients with heart failure and COPD may increase mortality and heart failure hospitalisations [16], adjustment for confounders showed that purported adverse effects of b-agonists may be attributable to underlying pulmonary disease [14]. RCTs have established the safety of inhalation of long-acting b-agonists in patients with COPD; however, concerns remain regarding the safety of these drugs in patients with asthma [14, 78].

Inhaled anti-cholinergics 59
The long-acting anti-cholinergic bronchodilator tiotropium is as equally effective as the longacting b-agonist salmeterol, and has reassuring cardiovascular safety data [14, 79, 80]. Potentially,

F.H. RUTTEN

anti-cholinergics can reduce acetylcholine release over a short period and thus, potentially exert adverse cardiac effects conform atropine, such as atrial and ventricular tachycardias [81]. Until now, such negative cardiac effects have not been shown [80, 81].

Inhaled and oral corticosteroids

Oral corticosteroids cause sodium and water retention, potentially leading to worsening of heart failure [17]. This effect can be expected with long-term use and, in general, does not occur with pulsed-dosing for 710 days. Inhaled corticosteroids have not yet shown any cardiovascular problems [17].

Nonpharmacological treatment of heart failure and COPD

Aerobic exercise training is evidence-based treatment in both COPD and heart failure [17, 18], with a large overlap in training programmes [51]. Smoking cessation should also be considered in patients with either or both diseases [17, 18]. Devices such as cardiac resynchronisation therapy or an implantable cardioverter defibrillator could be implanted in patients with heart failure with REF when needed, irrespective of the presence or absence of COPD [17].

Conclusions
Heart failure and COPD are very common, especially in the elderly. Tobacco smoking is a strong common risk factor. Both diseases are chronic and progressive and share important pathophysiological pathways, notably, systemic inflammation, activation of the neurohumoral system and metabolic modulation. In heart failure and the presence of COPD the left ventricle is mainly affected. In only approximately 1% of all heart failure cases, the right ventricle is the main cause of heart failure (cor pulmonale). Physicians should think of the possibility of heart failure in any patient with shortness of breath and fatigue, irrespective of the presence of COPD. Detecting heart failure has a major impact on prognosis and treatment. Diagnosing heart failure in patients with COPD is difficult because of the common cardinal symptoms of breathlessness and fatigue, and the difficulty of distinguishing certain signs (i.e. abnormal pulmonary breathing sounds). Elevated natriuretic peptides help to select those who need echocardiography to definitely establish or reject the diagnosis of heart failure. In COPD patients aged 65 years and over who are overweight with a history of ischaemic disease, a pulse rate above 90 beats?minute-1 and a laterally displaced or broadened/sustained apex beat, or any combination of these clinical items, physicians should consider concurrent presence of heart failure. A dual diagnosis of COPD and heart failure means an increase in burden of care with complex polypharmacy and the risk of miscommunication between multiple care providers. Cardiovascular drugs focused on atherosclerosis and neurohumoral over-activation could become new treatment options in COPD. The time has come where physicians should not withhold cardioselective b-blockers in patients with COPD who need these drugs for any comorbid condition. Future randomised trials could possibly confirm the long-term beneficial effects of cardiovascular drugs, notably b-blockers and statins, as seen in patients with COPD in observational pharmaco-epidemiological studies. A positive result on clinically important end-points of cardiovascular drugs in patients with COPD in such an RCT would cause a major paradigm shift in the treatment of COPD.

DIAGNOSIS AND MANAGEMENT OF HEART FAILURE

Statement of Interest
F.H. Rutten has received assays of N-terminal brain natriuretic peptides at a reduced price from Roche Diagnostics for a diagnostic study in patients with breathlessness.

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