LEADING ARTICLE

b-Adrenoceptor Modulation in Chronic Obstructive PulmonaryDisease: Present and Future Perspectives

Maria Gabriella Matera • Luigino Calzetta •

Mario Cazzola

Published online: 15 October 2013

� Springer International Publishing Switzerland 2013

Abstract The common coexistence of chronic obstruc-

tive pulmonary disease (COPD) and cardiovascular disease

(CVD) presents several therapeutic constraints that have

not been comprehensively investigated. Pharmacologic

modulation of b-adrenoceptor (b-AR) function is one of the

critical issues in the treatment of these patients because

inhaled b2-AR agonists may induce adverse events in

patients with COPD, mainly in those with coexisting CVD.

Moreover, the use of b-AR blockers has traditionally been

contraindicated in COPD, mainly because of the potential

for acute bronchospasm and increased airway hyperre-

sponsiveness after their administration. However, there

now appears to be good evidence that b-AR blockers are

not only safe but may have benefits in COPD that extend

beyond a reduction in cardiovascular mortality. This article

starts with a succinct outline of the evolution in our

understanding of b-AR modulation in COPD, touching on

treatment of COPD with b-AR agonists and the issues of

b-AR blockade and cardioselectivity in patients with

comorbid CVD. We then summarize the current evidence

for a COPD benefit from b-AR blockers and hypothesize

on the mode of action. Finally, we provide a view of the

future landscape in terms of therapeutic possibilities and

what still needs to be resolved, based on our opinion.

1 Introduction

There is solid evidence that patients with chronic

obstructive pulmonary disease (COPD) are at increased

risk of cardiovascular disease (CVD) [1]. The underlying

pathophysiologic mechanisms that are responsible for the

increased cardiovascular risk in COPD remain unclear, but

may include arterial stiffness, inflammation, and endothe-

lial dysfunction [2].

The common coexistence of COPD and CVD raises

several therapeutic issues that have not been comprehen-

sively investigated. Pharmacological modulation of

b-adrenoceptor (b-AR) function is one of the critical issues

in the treatment of these patients. In fact, inhaled b2-AR

agonists are one of the mainstays of COPD therapy,

whereas b-AR antagonists, also called b-AR blockers, are

known to improve the survival of patients within a large

spectrum of CVDs, including ischemic heart disease and

heart failure [3].

However, inhaled b2-AR agonists may induce adverse

events in patients with COPD, mainly in those with coex-

isting CVD [4]. Moreover, the use of b-AR blockers has

traditionally been contraindicated in COPD, mainly

because they can potentially cause acute bronchospasm [5]

and increased airway hyperresponsiveness [6].

In this article, we review evidence that supports or

refutes the pharmacologic modulation of b-AR function in

patients with coexisting COPD and CVD, always consid-

ering that ligands interacting with b-ARs have important

differences that influence their final effects (Table 1).

M. G. Matera (&)

Unita di Farmacologia, Dipartimento di Medicina Sperimentale,

Seconda Universita di Napoli, Via Santa Maria di Costantinopoli

16, 80138 Napoli, Italy

e-mail: mariagabriella.matera@unina2.it

L. Calzetta

Department of Pulmonary Rehabilitation, San Raffaele Pisana

Hospital, IRCCS, Rome, Italy

M. Cazzola

Department of Systems Medicine, University of Rome Tor

Vergata, Rome, Italy

Drugs (2013) 73:1653–1663

DOI 10.1007/s40265-013-0120-5

2 The Evolution in Our Understanding of b-

Adrenoceptor Modulation in COPD

Recently, we described the evolution in our understanding of

b-Adrenoceptor modulation in obstructive airway diseases [7, 8].

In humans, sympathetic fibers innervate the submucosal

mucus gland, blood vessels, and the parasympathetic gan-

glia, but sympathetic adrenergic innervation of human

airway smooth muscle (ASM) is sparse and/or nonexistent.

Nonetheless, relaxation and, under some conditions, con-

traction of ASM can be evoked by stimulation of sympa-

thetic nerves. Such contraction and relaxation are attributed

to noradrenaline release, which is capable of acting on

a-ARs and b-ARs.

b-ARs are seven-transmembrane G-protein-coupled

receptors (GPCRs). They couple to the stimulatory G

protein Gs and thereby activate adenylyl cyclase (AC). In

addition, coupling to the inhibitory G protein Gi and G

protein-independent signaling have also been observed [9].

Differential activation of these signaling pathways can be

modulated by biased ligands.

b-ARs are densely located on ASM. Their density

increases with increasing airway generation in humans.

b-ARs are subdivided into three types: b1, b2, and b3.

Binding studies show that approximately 70 % of pul-

monary b-ARs are of the b2-AR subtype.

The activation of b2-ARs increases the intracellular

level of AC, resulting in the conversion of adenosine tri-

phosphate to cyclic adenosine monophosphate (cAMP),

which in turn can activate the effector molecules cAMP-

dependent protein kinase A (PKA) and the exchange factor

directly activated by cAMP (Epac) that acts as guanine-

nucleotide exchange factor for a low-molecular-weight G

protein, the Ras-proximate-1 (Fig. 1). PKA phosphorylates

key regulatory proteins involved in the control of ASM

tone, Epac induces ASM relaxation in a largely PKA-

independent manner through down-regulation of Rho, and

cAMP results in sequestration of intracellular Ca2?, lead-

ing to relaxation of the ASM. However, we are progres-

sively realizing that signaling through AC-coupled

pathways is considerably more complex and sophisticated

than was previously supposed and, in any case, we still

know little about these pathways in airway cells [10].

Prolonged b2-AR activation leads to the receptor

desensitization [11], a normal homeostatic process that

presumably serves to protect cells from excessive stimu-

lation. Agonist binding promotes a process known as

desensitization, which involves rapid phosphorylation of

the receptor at the C terminus and intracellular loops, in

large part by the G-protein-coupled receptor kinases

(GRKs) [12]. The combination of conformational change

and phosphorylation intensely increases the affinity of the

receptor for b-arrestins (b-arrestin-1 and b-arrestin-2),

which are members of a small family of multifunctional

seven-transmembrane receptor regulatory or adaptor pro-

teins. This association blocks subsequent G protein acti-

vation and plays an almost universal role in facilitating

traditional seven-transmembrane receptor desensitization

[12]. More specifically, b-arrestin-2 regulates receptor

desensitization by sterically preventing the interaction

between the receptor and G protein [13], by internalizing

Table 1 Definitions of terms referring to ligands that can interact

with a b-adrenoceptor

Agonist

A ligand that binds to a receptor and activates a process that

follows its binding to the receptor

Partial agonist

An agonist that binds to and activates a receptor, but is not able to

elicit the maximum possible response that is produced by full

agonists

Antagonist

A ligand that binds to a receptor without inducing change in

receptor activity itself but prevents other ligands from activating

the receptor or a specific signal

Inverse agonist

An antagonist that binds to the same receptor-binding site as an

agonist for that receptor but induces a pharmacologic response

opposite to that agonist

Fig. 1 Mechanism of action of b2-adrenoceptor agonists. AC aden-

ylyl cyclase, b2R b2 adrenoceptor, cAMP cyclic adenosine mono-

phosphate, Epac exchange protein directly activated by cAMP, Gs

stimulatory G-protein, HSP-20 heat shock-related protein 20, MLCK

myosin light chain kinase, MLC-P myosin light chain phosphatase,

PDE phosphodiesterase, PKA protein kinase A, SR/RyR Ca2?

sarcoplasmic reticular ryanodine Ca2? channel. Reprinted with

permission of the American Thoracic Society. Copyright � 2013

American Thoracic Society. Cazzola et al. [8]. Official journal of the

American Thoracic Society

1654 M. G. Matera et al.

receptor [14], and by actively recruiting phosphodiester-

ases to degrade the cAMP generated by G protein signaling

[15]. A protein known as a GRK phosphorylates the

receptor on particular residues. This increases its affinity

for b-arrestin that binds to the receptor and prevents it from

associating with a trimeric G-protein. b-Arrestin can target

the receptor for endocytosis, leading to receptor down-

regulation. For this reason, it has been anticipated that a

G-protein-biased ligand that does not promote b-arrestin

recruitment would result in less tachyphylaxis and would

be a more effective therapeutic agent [12]. Persistent

b2-AR activation decreases expression of the regulator of G

protein signaling 5 (an inhibitor of GPCR activity), the

knockdown of which in human ASM increases agonist-

evoked intracellular calcium flux and myosin light chain

phosphorylation, which are prerequisites for contraction.

Functional studies have mostly suggested a limited role

for sympathetic adrenergic nerves regulating airway func-

tion in normal human subjects, but relaxation of ASM can

be evoked by stimulation of sympathetic nerves.

Elevated sympathetic nerve activity has been associated

with COPD [16]. Mechanisms that have been proposed to

influence sympathetic activity in patients with COPD

include systemic inflammation, hypoxia, oxidative stress,

physical inactivity, and large intrathoracic pressure chan-

ges [17]. Increased plasma noradrenaline release accom-

panying sympathetic activation induces down-regulation of

b-ARs in the lung, reduction of AC activity, and thus

cAMP-mediated bronchorelaxation [18]. Therefore, it can

be speculated that sympathetic activation might favor

bronchoconstriction [18].

The increased sympathetic activity in COPD patients

might also potentially affect cardiac activity. In fact,

patients with COPD have functional alterations of cardiac

autonomic modulation as reflected in elevated resting heart

rate, reduced baroreflex sensitivity, reduced heart rate

variability [19, 20], reduced respiratory sinus arrhythmia

[21], a direct increase in muscle sympathetic nerve activity

[22, 23], and abnormal heart rate recovery following

exercise [24]. However, there is no direct evidence of a

cause-effect relationship linking increased sympathetic

activity to the evolution of CVD in patients with COPD

[17], although recent data from the Copenhagen City Heart

Study have shown that resting heart rate is a prediction of

median life expectancy in patients with COPD, above and

beyond that of pulmonary function alone, and is associated

with both cardiovascular and all-cause mortality across all

stages of COPD [25].

The presence of b-ARs in the human heart explains why

the modulation of b-AR function is important in influenc-

ing cardiac functions [3, 4], although it must be highlighted

that the heart has a lower b2-AR density than ASM [11].

Bristow et al. [26] demonstrated that the proportions of

b1-AR and b2-AR in normal hearts are 77 and 23 %,

respectively. Functional b1-ARs and b2-ARs coexist on

atria and ventricles with a b1/b2-AR ratio of about

60–70 %/40–30 % in the atria and about 70–80 %/

30–20 % in the ventricles [27]. On human sinoatrial nodes,

total b-AR density is about threefold higher than that in the

adjacent atrial myocardium, with a b2-AR density that is

about 2.5-fold higher in the sinoatrial node than in the right

atrial myocardium, and this is consistent with physiologic

studies that implicate this receptor in regulating cardiac

chronotropism [28]. b2-ARs are also present on adrenergic

nerve terminals in the heart, where they facilitate nor-

adrenaline release [29].

3 Treatment of COPD with b-Adrenoceptor Agonists

Although increased sympathetic nerve activity has been

associated with COPD [17], inhaled long-acting b2-AR

agonists (LABAs) have been suggested to be a mainstay in

the regular treatment of stable COPD since their intro-

duction into the market [30, 31]. Apparently, this seems to

be nonsense. In fact, inhalation of therapeutic doses of

b2-AR agonists even in healthy subjects results in signifi-

cant hemodynamic changes and a shift of sympathovagal

balance towards increased sympathetic tone [32]. Inhaled

b2-AR agonists increase sympathetic activity, as measured

by heart rate variability analysis, in healthy persons, but

they do not change the parasympathetic cardiac modulation

[33, 34]. Moreover, use of b2-AR agonists increases the

sympathetic nervous activity of COPD patients [35].

Nonetheless, a large volume of published evidence

supports the role of LABAs in this disease [7, 8, 36].

LABAs are used either alone or in combination with other

bronchodilators, inhaled corticosteroids, or both. Com-

monly used LABAs include salmeterol and formoterol, and

the new ultra-LABA indacaterol. These agents provide

sustained bronchodilation and, although they are unable to

influence the accelerated decline in lung function that is

characteristic of COPD, at least in terms of clinically

noticeable changes, they offer greater convenience for

patients with COPD [7]. Essentially, they induce significant

improvements in forced expiratory volume in 1 second

(FEV1), reduce dynamic hyperinflation, and improve

exercise tolerance, causing improvements in dyspnea and

health-related quality of life (HRQoL) [7, 8, 36]. More-

over, they reduce the frequency of COPD exacerbations

and offer a potential survival advantage [7, 8, 36].

Inhalational formulations of b2-AR agonists used for

chronic management of COPD are designed for local

application and systemic effects are unintended. Never-

theless, frequent use resulting in higher doses can result in

numerous unfavorable cardiovascular effects such as

b-Adrenoceptor Modulation in COPD 1655

tachycardia, hypokalemia, QTc prolongation, peripheral

vasodilation, disturbed autonomic modulation, and

depressed heart rate variability [3, 4]. Hypoxia, hypercap-

nia, acidosis, and excess sympathetic activity all potentially

amplify these sequelae [3, 4, 37]. A retrospective cohort

case-control analysis of elderly (aged C67 years) Canadian

patients with COPD who developed severe cardiac

arrhythmia compared with those who did not found that the

new use of short-b-agonists (SABAs) or LABAs was

associated with modest increases in the risk of cardiac

arrhythmia (rate ratio: 1.27, 95 % confidence interval [CI],

1.03–1.57; and 1.47, 95 % CI, 1.01–2.15, respectively)

[38], emphasizing the importance of considering CVD

when treating patients with COPD. However, data provided

by the TOwards a Revolution in COPD Health (TORCH)

study [39] suggest that LABAs incur little if any additional

cardiovascular safety signals compared with placebo in the

treatment of COPD. Moreover, the desensitization that

occurs during the first few days of regular use of a b2-AR

agonist results in a reduction in the responsiveness of the

heart, accounting for the commonly observed resolution of

tachycardia [40].

It is crucial to highlight that dyspneic patients are often

treated with inhaled bronchodilators before the cause of the

dyspnea is known. It has been reported that 44 % of COPD

patients with myocardial infarction on the first day of

hospitalization received b-AR agonists [41]. These medi-

cations cause increased myocardial oxygen demand [4] and

may exacerbate dyspnea that is misidentified as an exac-

erbation of COPD. Therefore, it has been recommended

that clinicians should consider greater caution in adminis-

tering large doses of b-AR agonist aerosols (if at all) to

patients with COPD, especially those with documented

coronary artery disease who present with undifferentiated

dyspnea/wheezing because up to 20 % of such episodes

may be cardiac related [41].

Similarly, many acute decompensated heart failure

patients without a history of COPD receive inhaled bron-

chodilators [42], but it must be mentioned that inhaled

bronchodilators may have a role in the management of

patients with chronic heart failure because of their potential

to improve pulmonary function, especially in those with

airway obstruction. Airway narrowing associated with

heart failure has a reversible component, as almost 40 % of

patients without a history of COPD or asthma who have

pre-bronchodilator airway obstruction fully recover after

bronchodilation [43]. In effect, these patients have some

degree of reversible airway hyperresponsiveness or reac-

tive airway disease likely because of congestion of the

bronchial vessels leading to thickening and edema of the

airway wall, accumulation of paracrine bronchoconstrictor

agents due to extravasation of plasma, and vagally medi-

ated bronchoconstriction [44].

It should be noted that the data that link the use of

b2-AR agonists and heart failure in the literature are still

relatively few and conflicting. Coughlin et al. [45] identi-

fied an association between b2-AR agonists and the

development of idiopathic dilated cardiomyopathy, with an

adjusted odds ratio for developing cardiomyopathy asso-

ciated with inhaled b2-AR agonist use that was 3.2 (95 %

CI 1.1–11). Two large-scale retrospective analyses exam-

ined the impact of b2-AR agonist use on heart failure

outcomes. Au et al. [46] demonstrated that b2-AR agonist

use is associated with excess heart failure hospitalizations

as well as an increased risk of all-cause mortality in

patients with left ventricular dysfunction. Moreover, a

retrospective analysis of the Candesartan in Heart Failure:

Assessment of Reduction in Mortality and morbidity

(CHARM) dataset showed a concerning 26 % excess risk

of mortality when using bronchodilators [47].

Conversely, Sengstock et al. [48] did not find any

association between b2-AR agonist use and the develop-

ment of idiopathic dilated cardiomyopathy. Moreover, a

retrospective cohort study of patients attending a heart

failure disease management program showed that that

inhaled b2-AR agonists are not associated with increased

mortality in community-managed heart failure patients

when adjusted for B-type natriuretic peptide (BNP) as well

as other clinical, demographic, and medication variables

[49]. These data suggest that the previously reported

mortality risk attributed to b2-AR agonists may be

accounted for by other factors and particularly heart failure

severity as measured by BNP.

Whatever the case may be, it has been suggested that the

characteristics of the single b2-AR agonist may influence

its impact on the heart [37, 40]. In effect, in view of the low

b2-AR density in the heart, it might be expected that full

b-AR agonists (formoterol, indacaterol) would elicit a

greater cardiac response than partial agonists (salmeterol).

However, a 2006 clinical trial in patients with COPD

reported that formoterol did not increase arrhythmia fre-

quency as assessed by Holter monitoring [50]. Moreover,

indacaterol demonstrated no apparent potential for increased

cardiovascular risk even with the highest evaluated dose of

600 lg and its cardiovascular safety profile was similar to

placebo and comparable to formoterol and salmeterol [51].

4 b-Adrenoceptor Blockers in COPD

Although there is no direct evidence of a cause-effect

relationship linking increased sympathetic activity to the

evolution of CVD in patients with COPD [17], b-AR

blockers could theoretically exert beneficial effects by

tempering the sympathetic nervous system or by reducing

the ischemic burden [18]. In fact, these agents have

1656 M. G. Matera et al.

relatively little effect on heart rate and contractility in an

individual at rest but slow heart rate and decrease cardiac

contractility when the sympathetic nervous system is acti-

vated [52]. Nonetheless, the use of b-AR blockers has

traditionally been contraindicated in COPD, mainly

because of anecdotal evidence and case reports from small

trials in the 1970s and 1980s citing acute bronchospasm [5]

or increased airway hyperresponsiveness [6] after their

administration. Airway obstruction during treatment with

b-AR blockers is mediated through interference with

b2-AR mediated bronchodilatation [3].

b-AR blockers can be broadly classified into (a) non-

selective, those producing a competitive blockade of

both b1-ARs and b2-ARs and (b) those with much higher

affinity for the b1-ARs than for the b2-ARs usually

called b1-AR selective (cardioselective) [52]. However,

although highly selective b1-AR compounds do exist, the

b-AR blockers currently available for clinical use do not

show much selectivity between the b-ARs [53]. In any

case, selectivity is dose dependent and decreases or

disappears when larger doses are used. Moreover, the

pharmacokinetic profile of the drugs, the absorption,

metabolism, tissue distribution, and elimination of the

drugs, as well as their longevity of action at the given

receptors, are also important [53]. Many b-AR blockers

are not neutral antagonists, but have some agonist and

inverse agonist actions of their own at the different

b-ARs (Table 1). In fact, paradoxically, some b-AR

blockers can exert a weak agonist response (intrinsic

sympathomimetic activity), and can stimulate and block

the b-AR. The agonist and inverse agonist effects of the

different b-AR blockers may explain some of the dif-

ferences between drugs and their mode of action in

conditions where b1-AR antagonism does not seem to be

the whole explanation [53]. It must also be mentioned

that several b-AR blockers have peripheral vasodilator

activity mediated via a1-AR blockade (carvedilol,

labetalol), b2-AR agonism (celiprolol), or via mecha-

nisms independent of the AR blockade (nebivolol). In

addition, b-AR blockers can be classified as lipophilic or

hydrophilic.

In patients with mild to moderate COPD, propranolol

(non-selective), but not celiprolol or metoprolol (both

cardioselective), inhibited the bronchodilating effect of

formoterol compared with placebo, although the 15

patients included in this study had no increase in respira-

tory symptoms [6]. However, owing to pharmacological

properties, bronchospasm or increased airway hyperre-

sponsiveness is more frequent but not limited to non-car-

dioselective agents [3]. Chang et al. [54] recently

documented that both non-selective b-AR blockers and

high doses of cardioselective b-AR blockers may inhibit

the bronchodilator response to b2-AR agonists in patients

with COPD. b-AR blockers were also associated with

lower oxygen saturation during exercise.

We believe that the clinical significance of these adverse

effects is uncertain mainly because the evidence is still

rudimentary, although COPD is listed as a ‘‘compelling

contraindication’’ in the Joint British Societies’ 2005

guidelines on the prevention of CVD in clinical practice

[55]. However, the expert consensus document on b-AR

blockers, published by the Task Force on b-AR blockers of

the European Society of Cardiology in 2004 [52], and the

National Institute for Health and Care Excellence guideline

on heart failure, published in 2010 [56], recommend such

therapy for all patients, specifically including those with

concomitant COPD without significant airways reversibil-

ity. Moreover, international guidelines for coronary artery

disease [57] and hypertension [58] support the benefit of

treatment with b-AR blockers in most patients, including

COPD patients.

Unfortunately, most large-scale cardiovascular trials

excluded patients with COPD, thus evidence on efficacy or

safety of b-AR blockers used for cardiovascular conditions

in people who also have COPD is largely derived from

observational studies. The cumulative evidence from trials

and meta-analyses suggests that cardioselective b1-AR

blockers should not be routinely withheld from patients

with COPD, because the benefits of selective b1-AR

blockers in patients with COPD who also have cardiac

disease far outweigh the risks [59]. However, owing to the

observational nature of the included studies, the possibility

of confounding affecting these results cannot be excluded.

Therefore, the long-term influence of b-AR blockade on

pulmonary function, symptoms, and HRQoL in patients

with COPD is still unclear.

A Cochrane meta-analysis suggested that cardioselec-

tive b1-AR blockers neither adversely affect the FEV1 nor

induce respiratory symptoms compared with placebo,

independent of the severity of the COPD [60]. A single

dose of a cardioselective b-AR blocker may produce a

small decrease in FEV1, especially in patients with reactive

airway disease, but as therapy is continued over days to

weeks, there is no significant change in symptoms or FEV1

and no increase in the need for b-AR agonist inhalers.

Nevertheless, a later meta-analysis indicated that both non-

selective and cardioselective b-AR blockers produced a

slight reduction in FEV1 (by 0.14 and 0.03 l, respectively)

in patients with COPD, but only non-selective b-blockers

also produced a significant reduction in the responsiveness

of the FEV1 to b-AR agonist administration [61]. More-

over, a very recent study that has been performed within

the Rotterdam Study, a prospective population-based

cohort study, has shown that both non-selective and car-

dioselective b-AR blockers had a clinically relevant effect

on both FEV1 and forced vital capacity (FVC) [62]. In

b-Adrenoceptor Modulation in COPD 1657

contrast to cardioselective b-AR blockers, use of non-

selective b-AR blockers was associated with a significantly

lower FEV1/FVC. These findings suggest that b-blockers,

particularly cardioselective b-blockers, should not be

contraindicated in patients who have COPD because of

their presumed bronchoconstrictive properties.

A systematic review examined the association between

b-AR blocker use and all-cause mortality in patients with

COPD in nine retrospective cohort studies [63]. The pooled

relative risk of COPD-related mortality secondary to b-AR

blocker use was 0.69 (95% CI 0.62–0.78; I2 = 82 %).

However, the authors of this systematic review pointed out

that studies unable to find a protective association for b-AR

blockers and mortality in COPD patients were less likely to

be published.

A large, well-designed, observational cohort study using

data from the electronic medical records of 23 general

practices in the Netherlands has shown that treatment with

b-AR blockers may reduce the risk of exacerbations and

improve survival in patients with COPD, the adjusted hazard

ratios being 0.68 (0.56–0.83) and 0.71 (0.60–0.83), respec-

tively [64]. Intriguingly, cardioselective b1-AR blockers had

larger beneficial effects on mortality than nonselective ones

but similar effects on the risk of exacerbations of COPD.

Moreover, the study reported that the benefit on mortality

seen with b-AR blockers was preserved in those individuals

who were using inhaled b2-AR agonists.

A later retrospective and observational Scottish study

has shown that b-AR blockers (predominantly cardiose-

lective) may confer reductions in mortality, exacerbations,

and hospital admissions in patients with COPD, in addition

to the benefits attributable to addressing cardiovascular

risk. These additive benefits were seen across a spectrum of

inhaled stepwise therapy, including LABAs, and did not

result in any worsening of pulmonary function in the study

cohort [65]. The additive benefits of b-AR blockers were

independent of other cardiovascular drugs and history of

overt CVD, which suggests that b-AR blockers have an

independent effect on COPD itself.

A more recent retrospective cohort study of patients with

COPD from two academic primary care practice sites sug-

gested that patients with COPD prescribed a b-AR blocker

were significantly less likely to have a COPD exacerbation

and had fewer mild COPD exacerbations [66]. Interestingly,

there was no significant difference in COPD exacerbations

based on b-AR blocker cardioselectivity.

These two studies support the use of b-AR blockers in

COPD patients and suggest that up-regulation of b2-ARs

by chronic b-AR blockade may improve the effectiveness

of b2-AR agonists. However, while it could be argued that

the reduction observed in all-cause mortality with b-AR

blockers is attributable to their cardiovascular effect, the

reduction in the risk of acute exacerbations of COPD by

these agents cannot easily be explained by this effect alone

[67].

In effect, a very new prospective cohort study, con-

ducted over 12 months for lung function and respiratory

symptom measures, and over 6 years for survival and

exacerbation data, in a cohort of cardiac patients, docu-

mented that long-term b-AR blocker treatment did not

adversely affect lung function, respiratory symptom scores,

or survival, but was associated with an increased risk of

respiratory exacerbations [68].

In any case, Dransfield et al. [69] examined a large

population of in-patients admitted for acute exacerbations

of COPD and found that b-AR blocker use was associated

with reduced in-hospital mortality. Moreover, they

observed that b-AR blockers did not reduce the beneficial

effects of SABAs when they were used concomitantly

during acute exacerbations. However, the very large effect

estimate (b-AR blocker use during a COPD hospitalization

was associated with a 61 % reduction in mortality and a

92 % reduction associated with SABA use) may have been

due to immortal time bias, as well as selection of the last

hospitalization for acute exacerbations of COPD, over-

representing hospitalizations resulting in death [70].

More recently, a retrospective large cohort study of

35,082 patients aged C40 years, with ischemic heart dis-

ease, congestive heart failure, or hypertension and hospi-

talized for an acute exacerbation of COPD documented that

the 29 % of patients who received b-AR blockers during

the first 2 days of the hospital stay, including 22 % with

b1-AR selective blockers and 7 % with non-selective b-AR

blockers, did not have an increased risk of in-hospital

mortality, readmission within 30 days, or mechanical

ventilation, compared with COPD patients who did not

receive b-AR blockers [71]. This is not an unexpected

finding because, apparently, there is no evidence that b-AR

blocker selectivity is associated with differences in out-

comes for patients with heart failure with COPD versus

those without.

The Organized Program to Initiate Lifesaving Treatment

in Hospitalized Patients With Heart Failure (OPTIMIZE-

HF), which explored the interaction between b-AR blocker

selectivity and outcomes in patients with COPD after

admission for heart failure in patients with systolic dys-

function, documented that both non-selective and cardio-

selective b-AR blockers were associated with lower

risk-adjusted mortality in patients with and without COPD

[72]. Similar findings have been demonstrated in the Heart

Failure and A Controlled Trial Investigating Outcomes of

Exercise TraiNing (HF-ACTION) [73], which, however,

found that patients with COPD more often received car-

dioselective b-AR blockers compared with patients without

COPD, although those with COPD still tended to receive

lower doses of cardioselective b-AR blockers.

1658 M. G. Matera et al.

It has been suggested that reducing the sympathetic

tone and up-regulation of b2-ARs in the lungs could be

possible mechanisms by which b-AR blockers exhibit

pulmonary beneficial effects in the long term [74]. Long-

term use of b-AR blocker can up-regulate b2-ARs in the

lungs and thus reduce the need for b-AR agonists [75]. It

has been documented that chronic treatment with nadolol

increases cellular cAMP levels by mechanisms that

include the upregulation of b2-AR and Gas [76]. This

effect could be secondary to the increase in b2-AR

numbers, in that G proteins are likely to be more stable

when present in a macromolecular complex with a GPCR.

By the same argument, AC levels may be increased, or

phosphodiesterase activities reduced by nadolol treatment

as well.

Another intriguing possibility has been documented

recently. Non-selective b-AR blockers, but not selective

b1-AR blockers, seem to be associated with a decrease in

membrane diffusing capacity (DM), a very sensitive marker

of fluid accumulation within the interstitial lung compart-

ment, likely because of a blockade of the alveolar b2-ARs

known to control the active Na? transport of fluid out of

the alveolar and interstitial lung compartments [77]. The

decrease in DM was associated with an increase in the

minute ventilation versus carbon dioxide production slope

during exercise, thus suggesting that fluid accumulation

within the interstitial lung compartment may contribute to

trigger hyperventilation during exercise, thus reducing the

ventilator efficiency [65]. These findings may represent the

basis for a more physiologically oriented b-AR blocker use

in COPD patients with heart failure.

5 Future Landscape in Terms of Therapeutic

Possibilities

Animal data suggest decreased airway responsiveness and

inflammation after chronic b-AR blockade [78, 79]. A

small pilot study in patients with asthma supports this

observation [80]. Despite initial acute bronchospasm,

chronic escalating doses of b-AR blockers reduced airway

responsiveness. It could, therefore, be assumed that chronic

b-AR blockade may exert positive effects also in COPD

[81]. However, it must be highlighted that data from animal

studies [78, 79] came from mouse models of asthma

(T-helper (Th)2 inflammation) and not COPD (Th1 and

Th17 inflammation). Consequently, it is not known whe-

ther the same effects can be seen in COPD.

Intriguingly, inhibition of the constitutive b2-AR activ-

ity (rather than b-AR blockade) was the mechanism con-

tributing to the beneficial effects seen with b-AR blockers,

ICI118.551 and nadolol, in the airway [78, 79]. These

results suggested that ICI118.551 and nadolol are also

inverse agonists [82].

Inverse agonists are a class of antagonists that not only

block the ability of agonists to bind and activate a receptor

but also lock a receptor in a ‘closed’ conformation and

thereby block any (unliganded) constitutive or spontaneous

activity of the receptor [83]. This mechanism is in contrast

to that of neutral antagonists, which can only block access

of agonists to the receptor [83]. Inverse agonist activity is

important for b-AR regulation when b-ARs are downreg-

ulated because of chronic sympathetic activation. Inacti-

vation of b-ARs by inverse agonists inhibits

phosphorylation of receptors, and thus desensitization and

downregulation [83] (Fig. 2). Chronic administration of an

inverse agonist has the effect of upregulating the popula-

tion of active b-ARs [84]. The increase in the number of

b2-AR signaling components could potentially offset the

blocking effect of b-AR and lead to a decrease in the

contractility in airways [76]. However, a recent study has

suggested that this effect cannot be observed if a patient is

receiving regular corticosteroid treatment because con-

comitant corticosteroids might cause up-regulation of

b2-ARs and mask any subtle effects due to b-AR blocker-

induced up-regulation, at least in asthmatic patients [85].

Unfortunately, among the studies investigating the effi-

cacy and safety of LABAs in COPD patients, there are no

definitive data for the development of tolerance, as those

studies were not designed to examine this phenomenon.

Consequently, it is difficult to determine how important is

the effect of upregulating the population of active b-ARs

induced by inverse agonists in patients with COPD.

However, we must note that some studies suggest that

tachyphylaxis occurs when LABAs are used for the man-

agement of COPD [86, 87]. Moreover, there are many

COPD patients who exhibit airway responsiveness [88, 89].

For this reason, we can hypothesize that there is a role for

inverse agonists, at least in a subgroup of patients with

COPD.

Regrettably, no randomized prospective study has

evaluated the impact of a b-AR blocker that is also an

inverse agonist in COPD. However, a Cochrane meta-

analysis, which examined the impact of cardioselective

b-AR blockers in COPD patients and included both classic

b-AR blockers and b-AR inverse agonists, suggested that

chronic administration of cardioselective b-AR inverse

agonists do not change pulmonary function in patients with

congestive heart failure and COPD [60]. FEV1 was

unchanged in patients treated with cardioselective b-AR

inverse agonists. This information is intriguing, but it does

not allow us to understand the extent to which the use of a

b-AR inverse agonist is really useful in COPD compared

with a classic b-AR blocker.

b-Adrenoceptor Modulation in COPD 1659

Apparently, only b-AR blockers that are b2-AR inverse

agonists, those that could also inactivate the spontaneously

active b2-ARs, exert their beneficial effects on airway

epithelial cells and immune cells, at least in a murine

model of asthma [78], by inhibiting constitutive proin-

flammatory signaling through non-canonical b-arrestin-2-

mediated signaling [78] (Fig. 2). b-Arrestin-2 exerts its

regulatory effect proximal to the recruitment of activated

Th2 cells into the lung. This finding suggests that chronic

administration of b2-AR inverse agonists might reduce

inflammation and mucous production, at least in asthmatic

patients.

It is important to note that the inflammatory process of

COPD is likely to be quite different than that in asthma

and, as such, the free extrapolation of the experience in

asthma to COPD may not be warranted [90]. However, in

COPD patients, an allergic profile of inflammation can

occur, particularly during exacerbation [91]. It seems that

the minimization of eosinophilic airway inflammation is

associated with a reduction in severe COPD exacerbation

[92]. As already mentioned, b-AR blockers may reduce the

risk of exacerbations in patients with COPD [65, 67], but

data that are present in literature do not allow us to

establish if this is an effect that is limited to inverse ago-

nists or can be generalized to all b-AR blockers.

In any case, inflammation in asthma results from an

exuberant inflammatory response to allergens. Therefore,

reducing mucous production should improve patient

symptoms. In contrast, blocking the production of mucus

in COPD has more potential to be detrimental because

normal mucus helps to eliminate bacteria from the air-

ways [93].

6 Conclusion

Regarding the use of b2-AR agonists, there is still no solid

proof that supports or denies their use in the treatment of

patients that also have CVD, although some evidence

suggests that therapy with inhaled b2-AR agonists is

associated with an increased risk for chronic heart failure

decompensation and all-cause mortality in patients with

chronic heart failure [45, 94]

Although b-AR blockers are often indicated in patients

with CVD, clinicians are reluctant to prescribe these drugs

to patients with co-existing COPD for fear of inducing

Fig. 2 b2-adrenoceptor inverse agonists, which could inactivate the

spontaneously active b2-adrenoceptors, exert their beneficial effects on

airway epithelial cells and immune cells by inhibiting constitutive

proinflammatory signaling through non-canonical b-arrestin-2-mediated

signaling (based on information from Ref. [83]). Moreover, inactivation

of b2-adrenoceptors by inverse agonists inhibits phosphorylation of

b2-adrenoceptors, and thus desensitization and down-regulation.

b2R b2-adrenoceptor, MAPK mitogen-activated protein kinase, AHR

airway hyperresponsiveness, GRK G-protein receptor kinase, AC adenylyl

cyclase, cAMP cyclic adenosine monophosphate, Epac exchange protein

directly activated by cAMP, Gs stimulatory G-protein, HSP-20 heat shock-

related protein 20, MLCK myosin light chain kinase, MLC-P myosin light

chain phosphatase, PDE phosphodiesterase, PKA protein kinase A, SR/

RyR Ca2? sarcoplasmic reticular ryanodine Ca2? channel

1660 M. G. Matera et al.

bronchospasm and worsening their health status. We

completely agree with Rutten and Hoes [74] that the time

has come for physicians to place their trust in b-AR

blockers in patients with CVD and COPD.

Future randomized trials are needed to confirm the long-

term positive results of b-AR blockers in patients with

COPD, even in those without overt CVD. In particular, it

will be important to establish whether a beneficial effect is

achievable with all b-AR blockers or if we must only

prescribe inverse agonists.

If the first hypothesis is correct, we must determine

whether the beneficial effect of b-AR blockers can be

explained only by the cardioprotection exerted by these

drugs or also by other properties that are not yet clear, but

are probably related to the sympathetic nerve activity

associated with COPD.

On the contrary, if the second hypothesis is factual, we

must determine whether the inverse agonists may be

effective in COPD because they can up-regulate the pop-

ulation of active b-ARs or because of the anti-inflamma-

tory mechanism that has been suggested for asthma [80]. In

the latter case, it will be important to verify if there is a

specific phenotype of COPD patients who is particularly

sensitive to inverse agonists.

We believe that a positive result of a randomized clin-

ical trial with an inverse agonist on important COPD

clinical endpoints (symptoms, lung function, exacerba-

tions, and mortality) would cause a paradigm shift com-

parable to b-AR blocker use in patients with heart failure in

the 1990s.

Acknowledgments M. Matera, L. Calzetta, and M. Cazzola declare

that they have no conflicts of interest relevant to this article. No

sources of funding were used to support the writing of the manuscript.

All authors contributed to the writing of the manuscript.

References

1. Cazzola M, Calzetta L, Bettoncelli G, Cricelli C, Romeo F,

Matera MG, Rogliani P. Cardiovascular disease in asthma and

COPD: a population-based retrospective cross-sectional study.

Respir Med. 2012;106:249–56.

2. Cockcroft JR, Pedersen ME. b-blockade: benefits beyond blood

pressure reduction? J Clin Hypertens (Greenwich).

2012;14:112–20.

3. Matera MG, Martuscelli E, Cazzola M. Pharmacological modu-

lation of b-adrenoceptor function in patients with coexisting

chronic obstructive pulmonary disease and chronic heart failure.

Pulm Pharmacol Ther. 2010;23:1–8.

4. Cazzola M, Matera MG, Donner CF. Inhaled b2-adrenoceptor

agonists: cardiovascular safety in patients with obstructive lung

disease. Drugs. 2005;65:1595–610.

5. Cazzola M, Noschese P, D’Amato G, Matera MG. The pharma-

cologic treatment of uncomplicated arterial hypertension in

patients with airway dysfunction. Chest. 2002;121:230–41.

6. van der Woude HJ, Zaagsma J, Postma DS, Winter TH, van Hulst

M, Aalbers R. Detrimental effects of b-blockers in COPD: a

concern for nonselective b-blockers. Chest. 2005;127:818–24.

7. Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and

therapeutics of bronchodilators. Pharmacol Rev.

2012;64:450–504.

8. Cazzola M, Page CP, Rogliani P, Matera MG. b2-Agonist therapy

in lung disease. Am J Respir Crit Care Med. 2013;187:690–6.

9. Billington CK, Hall IP. Novel cAMP signalling paradigms:

therapeutic implications for airway disease. Br J Pharmacol.

2012;166:401–10.

10. Brueckner F, Piscitelli CL, Tsai CJ, Standfuss J, Deupi X,

Schertler GF. Structure of b-adrenergic receptors. Methods

Enzymol. 2013;520:117–51.

11. Johnson M. The b-adrenoceptor. Am J Respir Crit Care Med.

1998;158:S146–53.

12. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of

b-arrestin- and G protein-biased agonists. Trends Mol Med.

2011;17:126–39.

13. Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ. Beta-

arrestin: a protein that regulates beta-adrenergic receptor func-

tion. Science. 1990;248:1547–50.

14. Ahn S, Nelson CD, Garrison TR, Miller WE, Lefkowitz RJ.

Desensitization, internalization, and signaling functions of beta-

arrestins demonstrated by RNA interference. Proc Natl Acad Sci

USA. 2003;100:1740–4.

15. Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang

KL, Miller WE, McLean AJ, Conti M, Houslay MD, Lefkowitz

RJ. Targeting of cyclic AMP degradation to beta 2-adrenergic

receptors by beta-arrestins. Science. 2002;298:834–6.

16. Canning BJ. Reflex regulation of airway smooth muscle tone.

J Appl Physiol. 2006;101:971–85.

17. van Gestel AJ, Kohler M, Clarenbach CF. Sympathetic overac-

tivity and cardiovascular disease in patients with chronic

obstructive pulmonary disease (COPD). Discov Med.

2012;14:359–68.

18. Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohormonal

activation as a link to systemic manifestations of chronic

obstructive pulmonary disease. Chest. 2005;128:3618–24.

19. Volterrani M, Scalvini S, Mazzuero G. Decreased heart rate

variability in patients with chronic obstructive pulmonary dis-

ease. Chest. 1994;106:1432–7.

20. Steward RI, Lewis M. Cardiac output during exercise in patients

with COPD. Chest. 1986;89:199–205.

21. Patakas D, Louridas G, Kakavelas E. Reduced baroreceptor

sensitivity in patients with chronic obstructive pulmonary dis-

ease. Thorax. 1982;37:292–5.

22. Heindl S, Lehnert M, Criee CP. Marked sympathetic activation in

patients with chronic respiratory failure. Am J Respir Crit Care

Med. 2001;164:597–601.

23. Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de

Borne P. Increased sympathetic nerve activity in pulmonary

artery hypertension. Circulation. 2004;110:1308–12.

24. Poirier P, Lacasse Y, Marquis K, Jobin J, LeBlanc P. Post-

exercise heart rate recovery and mortality in chronic obstructive

pulmonary disease. Respir Med. 2005;99:877–86.

25. Jensen MT, Marott JL, Lange P, Vestbo J, Schnohr P, Nielsen

OW, Jensen JS, Jensen GB. Resting heart rate is a predictor of

mortality in COPD. Eur Respir J. 2013;42:341–9.

26. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W,

Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson

EB. b1- and b2-adrenergic-receptor subpopulations in nonfailing

and failing human ventricular myocardium: coupling of both

receptor subtypes to muscle contraction and selective b1-receptor

down-regulation in heart failure. Circ Res. 1986;59:297–309.

b-Adrenoceptor Modulation in COPD 1661

27. Brodde OE. b1- and b2-adrenoceptors in the human heart: prop-

erties, function and alterations in chronic heart failure. Pharmacol

Rev. 1991;43:203–42.

28. Rodefeld MD, Beau SL, Schuessler RB, Boineau JP, Saffitz JE.

b-Adrenergic and muscarinic cholinergic receptor densities in the

human sinoatrial node: identification of a high b2-adrenergic

receptor density. J Cardiovasc Electrophysiol. 1996;7:1039–49.

29. Newton GE, Parker JD. Acute effects of b1-selective and non-

selective b-adrenergic receptor blockade on cardiac sympathetic

activity in congestive heart failure. Circulation. 1996;94:353–8.

30. Cazzola M, Donner CF, Matera MG. Long acting b2 agonists and

theophylline in stable chronic obstructive pulmonary disease.

Thorax. 1999;54:730–6.

31. Cazzola M, Matera MG. Should long-acting b2-agonists be

considered an alternative first choice option for the treatment of

stable COPD? Respir Med. 1999;93:227–9.

32. Cekici L, Valipour A, Kohansal R, Burghuber OC. Short-term

effects of inhaled salbutamol on autonomic cardiovascular con-

trol in healthy subjects: a placebo-controlled study. Br J Clin

Pharmacol. 2009;67:394–402.

33. Silke B, Hanratty CG, Riddell JG. Heart-rate variability effects of

beta-adrenoceptor agonists (xamoterol, prenalterol, and salbuta-

mol) assessed nonlinearly with scatterplots and sequence meth-

ods. J Cardiovasc Pharmacol. 1999;33:859–67.

34. Hanratty CG, Silke B, Riddell JG. Evaluation of the effect on

heart rate variability of a beta2-adrenoceptor agonist and antag-

onist using non-linear scatterplot and sequence methods. Br J

Clin Pharmacol. 1999;47:157–66.

35. Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic

responses to the intracoronary infusion of a b2-receptor agonist: a

human in vivo study. Circulation. 1999;99:2402–7.

36. Cazzola M, Calzetta L, Matera MG. b2-adrenoceptor agonists:

current and future direction. Br J Pharmacol. 2011;163:4–17.

37. Cazzola M, Imperatore F, Salzillo A, Di Perna F, Calderaro F,

Imperatore A, Matera MG. Cardiac effects of formoterol and

salmeterol in patients suffering from COPD with preexisting

cardiac arrhythmias and hypoxemia. Chest. 1998;114:411–5.

38. Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bron-

chodilator use and the risk of arrhythmia in COPD: part 2.

Reassessment in the larger Quebec cohort. Chest.

2012;142:305–11.

39. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,

Jones PW, Crim C, Willits LR, Yates JC, Vestbo J. Cardiovas-

cular events in patients with COPD: TORCH study results.

Thorax. 2010;65:719–25.

40. Hanania NA, Sharafkhaneh A, Barber R, Dickey BF. b-agonist

intrinsic efficacy: measurement and clinical significance. Am J

Respir Crit Care Med. 2002;165:1353–8.

41. Parker H, Brenya R, Zarich S, Manthous CA. b-agonists for

patients with chronic obstructive pulmonary disease and heart

disease? Am J Emerg Med. 2008;26:104–5.

42. Singer AJ, Emerman C, Char DM, Heywood JT, Kirk JD, Hol-

lander JE, Summers R, Lee CC, Wynne J, Kellerman L, Peacock

WF. Bronchodilator therapy in acute decompensated heart failure

patients without a history of chronic obstructive pulmonary dis-

ease. Ann Emerg Med. 2008;51:25–34.

43. Minasian AG, van den Elshout FJ, Dekhuijzen PN, Vos PJ,

Willems FF, van den Bergh PJ, Heijdra YF. Bronchodilator

responsiveness in patients with chronic heart failure. Heart Lung.

2013;42:208–14.

44. Maak CA, Tabas JA, McClintock DE. Should acute treatment

with inhaled beta agonists be withheld from patients with dyspnea

who may have heart failure? J Emerg Med. 2011;40:135–45.

45. Coughlin SS, Metayer C, McCarthy EP, Mather FJ, Waldhorn

RE, Gersh BJ, DuPraw S, Baughman KL. Respiratory illness,

beta-agonists, and risk of idiopathic dilated cardiomyopathy: the

Washington, DC, Dilated Cardiomyopathy Study. Am J Epi-

demiol. 1995;142:395–403.

46. Au DH, Udris EM, Fan VS, Curtis JR, McDonell MB, Fihn SD.

Risk of mortality and heart failure exacerbations associated with

inhaled beta-adrenoceptor agonists among patients with known

left ventricular systolic dysfunction. Chest. 2003;123:1964–9.

47. Hannink JD, van Helvoort HA, Dekhuijzen PN, Heijdra YF.

Heart failure and COPD: partners in crime? Respirology.

2010;15:895–901.

48. Sengstock DM, Obeidat O, Pasnoori V, Mehra P, Sandberg KR,

McCullough PA. Asthma, beta-agonists, and development of

congestive heart failure: results of the ABCHF study. J Card Fail.

2002;8:232–8.

49. Bermingham M, O’Callaghan E, Dawkins I, Miwa S, Samsudin

S, McDonald K, Ledwidge M. Are beta2-agonists responsible for

increased mortality in heart failure? Eur J Heart Fail.

2011;13:885–91.

50. Campbell SC, Criner GJ, Levine BE, Simon SJ, Smith JS, Or-

evillo CJ, Ziehmer BA. Cardiac safety of formoterol 12 microg

twice daily in patients with chronic obstructive pulmonary dis-

ease. Pulm Pharmacol Ther. 2006;20:571–9.

51. Worth H, Chung KF, Felser JM, Hu H, Rueegg P. Cardio- and

cerebrovascular safety of indacaterol vs formoterol, salmeterol,

tiotropium and placebo in COPD. Respir Med. 2011;105:571–9.

52. Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggi-

oni AP, Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat

P, Torp-Pedersen C. Expert consensus document on b-adrenergic

receptor blockers. Eur Heart J. 2004;25:1341–62.

53. Baker JG. The selectivity ofb-adrenoceptor antagonists at the human

b1, b2 and b3 adrenoceptors. Br J Pharmacol. 2005;144:317–22.

54. Chang CL, Mills GD, McLachlan JD, Karalus NC, Hancox RJ.

Cardio-selective and non-selective beta-blockers in chronic

obstructive pulmonary disease: effects on bronchodilator

response and exercise. Intern Med J. 2010;40:193–200.

55. British Cardiac Society, British Hypertension Society, Diabetes

UK, HEART UK, Primary Care Cardiovascular Society, The

Stroke Association. JBS 2: Joint British Societies’ guidelines on

prevention of cardiovascular disease in clinical practice. Heart

2005; 91:v1–52.

56. National Clinical Guidelines Centre 2010. Chronic heart failure:

national clinical guideline for diagnosis and management in pri-

mary care [online]. August 2010. http://www.nice.org.uk/

nicemedia/live/13099/50514/50514.pdf. Accessed 16 May 2013.

57. Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow

GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L,

Pasternak RC, Pearson T, Pfeffer MA, Taubert KA. AHA/ACC,

National Heart Lung and Blood Institute: AHA/ACC guidelines

for secondary prevention for patients with coronary and other

atherosclerotic vascular disease: 2006 update: endorsed by the

National Heart, Lung, and Blood Institute. Circulation.

2006;113:2363–72.

58. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R,

Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S,

Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Stru-

ijker Boudier HA, Zanchetti A. ESH-ESC practice guidelines for

the management of arterial hypertension: ESH-ESC task force on

the management of arterial hypertension. J Hypertens.

2007;2007(25):1105–87.

59. Cazzola M, Matera MG. b-Blockers are safe in patients with

chronic obstructive pulmonary disease, but only with caution. Am

J Respir Crit Care Med. 2008;178:661–2.

60. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta blockers

for chronic obstructive pulmonary disease. Cochrane Database

Syst Rev. 2005; (19):CD003566.

61. Ni Y, Shi G, Wan H. Use of cardioselective b-blockers in patients

with chronic obstructive pulmonary disease: a meta-analysis of

1662 M. G. Matera et al.

randomized, placebo-controlled, blinded trials. J Int Med Res.

2012;40:2051–65.

62. Loth DW, Brusselle GG, Lahousse L, Hofman A, Leufkens HG,

Stricker BH. Beta-blockers and pulmonary function in the general

population: the Rotterdam Study. Br J Clin Pharmacol. 2013.

doi:10.1111/bcp.12181.

63. Etminan M, Jafari S, Carleton B, FitzGerald JM. Beta-blocker use

and COPD mortality: a systematic review and meta-analysis.

BMC Pulm Med. 2012;12:48.

64. Rutten F, Zuithoff N, Hak E, Grobbee D, Hoes A. b-blockers may

reduce mortality and risk of exacerbations in patients with

chronic obstructive pulmonary disease. Arch Intern Med.

2010;170:880–7.

65. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ.

Effect of beta blockers in treatment of chronic obstructive pul-

monary disease: a retrospective cohort study. BMJ.

2011;342:d2549.

66. Farland MZ, Peters CJ, Williams JD, Bielak KM, Heidel RE, Ray

SM. b-Blocker use and incidence of chronic obstructive pul-

monary disease exacerbations. Ann Pharmacother.

2013;47:651–6.

67. Matera MG, Calzetta L, Rinaldi B, Cazzola M. Treatment of

COPD: moving beyond the lungs. Curr Opin Pharmacol.

2012;12:315–22.

68. Cochrane B, Quinn S, Walters H, Young I. Investigating the

adverse respiratory effects of beta-blocker treatment: six years of

prospective longitudinal data in a cohort with cardiac disease.

Intern Med J. 2012;42:786–93.

69. Dransfield MT, Rowe SM, Johnson JE, Bailey WC, Gerald LB.

Use of b blockers and the risk of death in hospitalised patients

with acute exacerbations of COPD. Thorax. 2008;63:301–5.

70. Suissa S, Ernst P. Biases in the observational study of beta

blockers in COPD. Thorax. 2008;63:1026–7.

71. Stefan MS, Rothberg MB, Priya A, Pekow PS, Au DH, Linden-

auer PK. Association between b-blocker therapy and outcomes in

patients hospitalized with acute exacerbations of chronic

obstructive lung disease with underlying ischaemic heart disease,

heart failure or hypertension. Thorax. 2012;67:977–84.

72. Mentz RJ, Wojdyla D, Fiuzat M, Chiswell K, Fonarow GC,

O’Connor CM. Association of beta-blocker use and selectivity

with outcomes in patients with heart failure and chronic

obstructive pulmonary disease (from OPTIMIZE-HF). Am J

Cardiol. 2013;111:582–7.

73. Mentz RJ, Schulte PJ, Fleg JL, Fiuzat M, Kraus WE, Pina IL,

Keteyian SJ, Kitzman DW, Whellan DJ, Ellis SJ, O’Connor CM.

Clinical characteristics, response to exercise training, and out-

comes in patients with heart failure and chronic obstructive

pulmonary disease: findings from Heart Failure and A Controlled

Trial Investigating Outcomes of Exercise TraiNing (HF-

ACTION). Am Heart J. 2013;165:193–9.

74. Rutten FH, Hoes AW. Chronic obstructive pulmonary disease: a

slowly progressive cardiovascular disease masked by its pul-

monary effects? Eur J Heart Fail. 2012;14:348–50.

75. Lin R, Peng H, Nguyen LP, Dudekula NB, Shardonofsky F, Knoll

BJ, Parra S, Bond RA. Changes in b2-adrenoceptor and other

signaling proteins produced by chronic administration of ‘b-

blockers’ in a murine asthma model. Pulm Pharmacol Ther.

2008;21:115–24.

76. Peng H, Bond RA, Knoll BJ. The effects of acute and chronic

nadolol treatment on b2AR signaling in HEK293 cells. Naunyn

Schmiedebergs Arch Pharmacol. 2011;383:209–16.

77. Paolillo S, Pellegrino R, Salvioni E, Contini M, Iorio A, Bovis F,

Antonelli A, Torchio R, Gulotta C, Locatelli A, Agostoni P. Role

of alveolar b2-adrenergic receptors on lung fluid clearance and

exercise ventilation in healthy humans. PLoS One.

2013;8:e61877.

78. Nguyen LP, Omoluabi O, Parra S, Frieske JM, Clement C,

Ammar-Aouchiche Z, Ho SB, Ehre C, Kesimer M, Knoll BJ,

Tuvim MJ, Dickey BF, Bond RA. Chronic exposure to beta-

blockers attenuates inflammation and mucin content in a murine

asthma model. Am J Respir Cell Mol Biol. 2008;38:256–62.

79. Nguyen LP, Lin R, Parra S, Omoluabi O, Hanania NA, Tuvim

MJ, Knoll BJ, Dickey BF, Bond RA. b2-adrenoceptor signaling is

required for the development of an asthma phenotype in a murine

model. Proc Natl Acad Sci USA. 2009;106:2435–40.

80. Hanania NA, Singh S, El-Wali R, Flashner M, Franklin AE,

Garner WJ, Dickey BF, Parra S, Ruoss S, Shardonofsky F,

O’Connor BJ, Page C, Bond RA. The safety and effects of the

beta-blocker, nadolol, in mild asthma: an open-label pilot study.

Pulm Pharmacol Ther. 2008;21:134–41.

81. Kazani S, Israel E. Treatment with b blockers in people with

COPD. BMJ. 2011;342:d2655.

82. Page C. Paradoxical pharmacology: turning our pharmacological

model upside down. Trends Pharmacol Sci. 2011;32:197–200.

83. Dickey BF, Walker JKL, Hanania NA, Bond RA. b-Adrenoceptor

inverse agonists in asthma. Curr Opin Pharmacol. 2010;10:254–9.

84. Penn RB. Embracing emerging paradigms of G protein-coupled

receptor agonism and signaling to address airway smooth muscle

pathobiology in asthma. Naunyn Schmiedebergs Arch Pharma-

col. 2008;378:149–69.

85. Short PM, Williamson PA, Anderson WJ, Lipworth BJ. Ran-

domized placebo-controlled trial to evaluate chronic dosing

effects of propranolol in asthma. Am J Respir Crit Care Med.

2013;187:1308–14.

86. Donohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating

effects of salmeterol in COPD. Respir Med. 2003;97:1014–20.

87. Tsagaraki V, Amfilochiou A, Markantonis SL. Evidence of

tachyphylaxis associated with salmeterol treatment of chronic

obstructive pulmonary disease patients. Int J Clin Pract.

2006;60:415–21.

88. Tashkin DP, Altose MD, Bleecker ER, Connett JE, Kanner RE,

Lee WW, Wise R. The lung health study: airway responsiveness

to inhaled methacholine in smokers with mild to moderate airflow

limitation. The Lung Health Study Research Group. Am Rev

Respir Dis. 1992;145:301–10.

89. van den Berge M, Vonk JM, Gosman M, Lapperre TS, Snoeck-

Stroband JB, Sterk PJ, Kunz LI, Hiemstra PS, Timens W, Ten

Hacken NH, Kerstjens HA, Postma DS. Clinical and inflamma-

tory determinants of bronchial hyperresponsiveness in COPD.

Eur Respir J. 2012;40:1098–105.

90. Irvin CG. Neutrophils, airway hyperresponsiveness and COPD:

true, true and related? Eur Respir J. 2012;40:1067–9.

91. Zhu J, Qiu YS, Majumdar S, Gamble E, Matin D, Turato G,

Fabbri LM, Barnes N, Saetta M, Jeffery PK. Exacerbations of

bronchitis: bronchial eosinophilia and gene expression for inter-

leukin-4, interleukin-5, and eosinophil chemoattractants. Am J

Respir Crit Care Med. 2001;164:109–16.

92. Siva R, Green RH, Brightling CE, Shelley M, Hargadon B,

McKenna S, Monteiro W, Berry M, Parker D, Wardlaw AJ,

Pavord ID. Eosinophilic airway inflammation and exacerbations

of COPD: a randomised controlled trial. Eur Respir J.

2007;29:906–13.

93. Cohn L. Mucus in chronic airway diseases: sorting out the sticky

details. J Clin Invest. 2006;116:306–8.

94. Au DH, Udris EM, Curtis JR, McDonell MB, Fihn SD. Associ-

ation between chronic heart failure and inhaled b-2-adrenoceptor

agonists. Am Heart J. 2004;148:915–20.

b-Adrenoceptor Modulation in COPD 1663