Journal of the American College of Cardiology

2007 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 49, No. 2, 2007

ISSN 0735-1097/07/$32.00
doi:10.1016/j.jacc.2006.08.046

STATE-OF-THE-ART PAPER

Diagnostic and Therapeutic Challenges in

Patients With Coexistent Chronic Obstructive
Pulmonary Disease and Chronic Heart Failure
Thierry H. Le Jemtel, MD,* Margherita Padeletti, MD, Sanja Jelic, MD
New Orleans, Louisiana; and New York, New York
Chronic obstructive pulmonary disease (COPD) and heart failure (CHF) are common conditions. The prevalence
of COPD ranges from 20% to 30% in patients with CHF. The diagnosis of CHF can remain unsuspected in patients with COPD, because shortness of breath is attributed to COPD. Measurement of plasma B-type natriuretic
peptide (BNP) levels helps to uncover unsuspected CHF in patients with COPD and clinical deterioration. Noninvasive assessment of cardiac function may be preferable to BNP to uncover unsuspected left ventricular (LV)
systolic dysfunction in patients with stable COPD. Patients with COPD or CHF develop skeletal muscle alterations
that are strikingly similar. Functional intolerance correlates with severity of skeletal muscle alterations but not
with severity of pulmonary or cardiac impairment in COPD and CHF, respectively. Improvement of pulmonary or
cardiac function does not translate into relief of functional intolerance in patients with COPD or CHF unless skeletal muscle alterations concomitantly regress. The mechanisms responsible for skeletal muscle alterations are
incompletely understood in COPD and in CHF. Disuse and low-level systemic inflammation leading to protein
synthesis/degradation imbalance are likely to contribute. The presence of COPD impacts on the treatment of
CHF, as COPD is still viewed as a contraindication to beta-blockade. Therefore, COPD often deprives patients
with CHF due to LV systolic dysfunction of the most beneficial pharmacologic intervention. A large body of
data indicates that patients with COPD tolerate well selective beta-blockade that should not be denied to
CHF patients with concomitant COPD. (J Am Coll Cardiol 2007;49:17180) 2007 by the American College of
Cardiology Foundation

Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are 2 commonly encountered
conditions in clinical practice: 14 million Americans have
COPD and 5 million have CHF (1,2). Notwithstanding the
use of tobacco as a common risk factor, the sheer number of
patients with COPD and CHF accounts for their frequent
coexistence. Among the comorbid conditions commonly
associated with CHF, COPD is the one that most delays
the diagnosis of CHF and is most often advocated for
nonadherence to therapeutic guidelines, especially betablockade (BB) (3). The present review aims to address the
diagnostic and therapeutic problems raised by the coexistence of COPD and CHF. The first aim of the review is to
outline why COPD delays the diagnosis of CHF and how
to avoid any diagnostic delay. The second aim is to
emphasize the important role of skeletal muscle alterations
in limiting functional capacity in patients with COPD and
in patients with CHF and to advocate new therapeutic

From the *Division of Cardiology, Tulane University, New Orleans, Louisiana; and
the Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia
University College of Physicians and Surgeons, New York, New York.
Manuscript received June 19, 2006; revised manuscript received August 14, 2006,
accepted August 14, 2006.

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interventions to manage skeletal muscle alterations in

chronic conditions. The third aim is to summarize the data
that demonstrate the safety and efficacy of BB in patients
with COPD and to promote a greater use of BB in patients
with coexistent COPD and CHF.
Impact of COPD on the Diagnosis of CHF
Overlooked CHF in patients with COPD. Patients without known respiratory disease who complain of dyspnea or
fatigue during exercise undergo noninvasive cardiac imaging
that establishes the diagnosis of heart failure when it
demonstrates left ventricular (LV) dysfunction. When patients with stable COPD complain of dyspnea or fatigue
during exercise, these symptoms are often attributed to
COPD, noninvasive cardiac imaging is not performed, and
LV dysfunction remains undetected (4). In all studies but 1,
the prevalence of COPD ranges from 20% to 32% in
patients with CHF (4 11). The outlier study reported a
10% prevalence of COPD in patients hospitalized for CHF
(10). The risk ratio of developing CHF is 4.5 (95%
confidence interval [CI] 4.25 to 4.95) in COPD patients
compared with age-matched controls without COPD after
adjustments for cardiovascular risk factors (12). The rate-

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Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

adjusted hospital prevalence of

CHF is 3 times greater among
patients discharged with a diagACE angiotensinnosis of COPD compared with
converting enzyme
patients discharged without
BB beta-blockade
mention of COPD (13). FurBNP B-type natriuretic
thermore, the prevalence of hospeptide
pitalization for CHF increased at
CHF chronic heart failure
a much higher rate from 1971 to
CI confidence interval
2001 when discharge coding inCOPD chronic
cluded COPD as primary or secobstructive pulmonary
ondary diagnosis than when
disease
COPD was not mentioned as a
FEV1 forced expiratory
diagnosis (13). The Northern
volume in 1 s
California Kaiser Permanente
LV left ventricular
Medical Program has reported
SM skeletal muscle
an age-adjusted relative rate of
hospitalization for CHF of 5.55
(95% CI 4.71 to 5.73) and an odds ratio of CHF as a
comorbidity of 8.48 (95% CI 7.65 to 9.40) in COPD
patients compared with controls (14).
COPD as a cardiovascular risk. The high prevalence of
CHF in patients with COPD is not surprising, because
COPD patients are at increased risk of cardiovascular
mortality or morbidity independently of other risk factors,
including tobacco use. Forced expiratory volume in 1 s
(FEV1) is as good a predictor of cardiovascular mortality as
Abbreviations
and Acronyms

Figure 1

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January 16, 2007:17180

serum cholesterol (15). Ischemic heart disease, and not

respiratory failure, is the leading cause of death in COPD
patients, with only a small fraction dying of respiratory
failure (16). The relationship between COPD and cardiovascular events remains unclear. Patients with COPD are
not at increased risk for hypertension or LV hypertrophy;
however, they consistently show evidence of low-grade
systemic inflammation that plays an increasingly recognized
role in the pathogenesis of atherosclerosis (17). Patients
with severe COPD are 2.18 and 2.74 times more likely to
have elevated and highly elevated, respectively, circulating
C-reactive protein levels than control subjects (18). A
working hypothesis to account for the high prevalence of LV
systolic dysfunction in patients with COPD is that low-grade
systemic inflammation accelerates progression of coronary
atherosclerosis, which ultimately results in ischemic cardiomyopathy. Such a hypothesis fits the clinical observation of a high
incidence of LV wall motion abnormalities noted in patients
with COPD and LV dysfunction (19).
Uncovering CHF during COPD exacerbation. The diagnostic usefulness of measuring B-type natriuretic peptide
(BNP) plasma levels in patients presenting to an emergency
room with dyspnea is now well established and was recently
reviewed (20 22) (Fig. 1). A BNP level of 500 pg/ml in
a patient with known COPD consulting for clinical deterioration alerts to the presence of overt CHF whether or not
the patient is known to have CHF. A BNP level of 500

Evaluation of Heart Failure During COPD Exacerbation

Brain natriuretic peptide (BNP) serum levels and detection of chronic heart failure (CHF) in patients with exacerbation of chronic obstructive pulmonary disease (COPD).
CHF is unlikely when BNP levels are 100 pg/ml. A BNP level of 500 pg/ml indicates overt left-sided (L) CHF and the need for treatment. BNP levels ranging from 100
to 500 pg/ml indicate right-sided (R) heart failure, moderate left-sided heart failure, or both and the need for treatment. Once patients have returned to baseline status,
cardiac imaging needs to be performed and therapy adjusted. 2D 2-dimensional; ACE angiotensin-converting enzyme; RNV radionuclide ventriculography.

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Figure 2

Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

173

Evaluation of Heart Failure in Stable COPD Patients

Two-dimensional (2D) Doppler echocardiography is indicated in patients with stable chronic obstructive pulmonary disease (COPD). A normal (Nl) echocardiogram (echo)
excludes chronic heart failure (CHF). No further therapy () is needed. When left ventricular (LV) ejection fraction (EF) is 40%, full CHF therapy, including beta-blockade,
is recommended. When LVEF is 40%, LV mass is increased, and left atrium is enlarged, the diagnosis of diastolic heart failure needs to be entertained and therapy
with angiotensin-converting enzyme (ACE) inhibitors and diuretics considered. When the echocardiogram is technically (Tech.) inadequate, radionuclide ventriculography
(RNV) is indicated and therapy needs to be adjusted to the findings. Imp. impaired.

pg/ml does not differentiate cardiac from pulmonary deterioration as the cause of clinical worsening but indicates that
CHF therapy should be initiated or upgraded in addition to
treatment of COPD. In contrast, a BNP level of 100
pg/ml argues against CHF decompensation as the cause of
clinical deterioration but does not completely eliminate
acute heart failure as the triggering factor of clinical deterioration (A. Maisel, personal communication, July 2006).
A BNP level between 100 to 500 pg/ml points toward right
ventricular failure, moderate LV failure, or both and the
need to initiate therapy with angiotensin-converting enzyme (ACE) inhibitors and possibly loop diuretics. Once
patients with COPD exacerbation have returned to their
baseline status, cardiac imaging needs to be performed and
therapy adjusted according to the findings.
Ascertaining CHF in patients with stable COPD. Because 20% to 25% of ambulatory patients with CHF have
BNP levels of 100 pg/ml, echocardiography appears more
reliable than BNP levels to detect unsuspected LV systolic
dysfunction in patients with stable COPD (23) (Fig. 2).
Radionuclide ventriculography (RNV) may be obtained
when a poor acoustic window impedes evaluation of LV
function by echocardiography in COPD patients.
Patients with COPD found to have an LV ejection fraction
of 40% need to receive full CHF therapy, including betaadrenergic blockade. Patients with COPD with normal LV
ejection fraction and normal LV mass or LV filling do not
require CHF therapy. The diagnosis of diastolic heart failure is

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particularly difficult to establish in patients with COPD. The

diagnosis of diastolic heart failure needs to be entertained in
COPD patients with LV ejection fraction 40% and abnormal LV mass or enlarged left atrium by echocardiography or
impaired LV filling by RNV, and the response to ACE
inhibitors and loop diuretics needs to be closely monitored.
Standard echocardiographic indices of LV diastolic dysfunction do not reliably permit the diagnosis of diastolic heart
failure, but the diagnosis can be established by comprehensive
Doppler echocardiography and myocardial tissue imaging,
which provide evidence for impaired myocardial relaxation,
decreased LV compliance, and increased LV filling pressure
(24,25).
In summary, COPD is an important risk factor for cardiovascular morbidity and mortality in the general population.
Chronic heart failure is often unrecognized despite its high
prevalence in COPD patients. Elevated BNP plasma levels
should alert to the presence of CHF in patients with COPD
exacerbation. The 20% to 30% prevalence of CHF in ambulatory patients with stable COPD mandates noninvasive assessment of LV function to avoid undue delays in the diagnosis
and therapy of previously unrecognized CHF.
Skeletal Muscle Alterations
in Patients With CHF and COPD
Although CHF and COPD primarily involve different
organs, patients with CHF and COPD develop strikingly

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Figure 3

Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

JACC Vol. 49, No. 2, 2007

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Progression of CHF and COPD

Time course of loss of cardiac or pulmonary function (A), loss of skeletal muscle mass (B), and functional incapacity (C) during the progression of chronic heart failure
(CHF) or chronic obstructive pulmonary disease (COPD). Curves A and C in CHF patients are based on data collected during studies of left ventricular dysfunction (101).
Curve B in CHF patients and curves A, B, and C in COPD patients are based on clinical experience in the absence of quantitative data.

similar skeletal muscle (SM) alterations (26,27). In brief,

SM alterations in CHF and COPD include decreased
muscle strength and mass with reduced cross-sectional area,
fiber shift with atrophy of type I oxidative fibers, and relative
increase in glycolytic type IIa and IIb fibers accompanied by
an increase in glycolytic and a decrease in oxidative enzymatic activities (2729). Whether the enzymatic alterations
are the cause or consequence of the fiber shift remains to be
determined. Use of 31-P nuclear magnetic resonance spectroscopy has demonstrated reduced concentration of highenergy phosphate at rest, which becomes more pronounced
during exercise with a faster drop in pH and a slower
rephosphorylation after exercise in patients with CHF or
COPD compared with age-matched controls (27). Loss of
SM mass and the resulting muscle atrophy have major
clinical and therapeutic implications in CHF and COPD.
SM atrophy in CHF and COPD. Muscle atrophy contributes to muscle fatigue during exercise, which leads
patients with CHF or COPD to discontinue exercising
although they have not exhausted their cardiac or pulmonary reserve (30,31). Peak oxygen uptake is linearly related
to SM mass in patients with CHF and or COPD (3234).
As the disease progresses, SM atrophy worsens and patients
with CHF or COPD become increasingly symptomatic
(Fig. 3). Therapeutic interventions that improve LV and
pulmonary function in patients with CHF and COPD,
respectively, do not reliably reverse SM atrophy and thus do
not consistently alleviate functional intolerance (35,36).
Therefore, interventions that primarily aim at reversing SM
atrophy are needed to complement existing interventions
that improve cardiac and pulmonary function in patients
with CHF and COPD, respectively.

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Mechanisms of SM atrophy in CHF or COPD. The

events and mechanisms that lead to SM atrophy are
incompletely understood in patients with CHF and COPD.
Muscle disuse, low-level systemic inflammation, and increased oxidative stress contribute to reduced protein synthesis and accelerated protein degradation and thus to SM
atrophy (37) (Fig 4). Muscle disuse evolves as dyspnea and
fatigue prompt patients to progressively avoid all physical
activities. Patients are often unaware of the progressive
decline in physical activities, which is not readily quantifi-

Figure 4

Mechanisms of Skeletal Muscle

Atrophy in Patients With CHF or COPD

Disuse, low-level systemic inflammation (Inflam.), and increased oxidative

(oxidat.) stress decrease protein synthesis while increasing protein degradation. CHF chronic heart failure; COPD chronic obstructive pulmonary
disease.

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Figure 5

Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

175

Signaling Pathways of Disuse and Inflammation

Reduced insulin growth factor-1 (IGF-1) tissue level and insulin resistance combine to decrease phosphorylation of phospatidyinositol-2-OH kinase (PI3K), which in turn
reduces activation of Akt (protein kinase B), thereby reducing protein synthesis via reduced phosphorylation of mammalian target of rapamycin (mTOR) and glucogen synthase kinase (GSK). Reduced Akt activation increases activity of forkhead box O (FOXO) transcription factors, thereby activating the ubiquitin-proteasome pathway and
promoting protein degradation. Reduced IGF-1 levels and insulin resistance activate caspase-3, resulting in protein breakdown and degradation. Whether activated
caspase-3 results in muscle apoptosis is controversial.

able. However, the overt benefits of a rigorous training

program corroborate the importance of disuse as a cause of
SM atrophy in patients with CHF or COPD (38,39).
Besides SM disuse, low-level systemic inflammation and
increased oxidative stress are responsible for SM atrophy in
CHF and COPD. Circulating levels of proinflammatory
cytokines are elevated in patients with CHF and COPD,
and 8-isoprostanes are elevated in the pericardial fluid of
patients with CHF (40,41). The source of systemic inflammation appears to be in the small airways in COPD and is
unclear in CHF (42,43).
Signaling pathways of disuse and inflammation. Both
disuse and inflammations set off SM atrophy by reducing
protein synthesis, increasing protein degradation, or both
(44) (Fig. 4). Reduced protein synthesis and increased
protein degradation share common pathways (37). Insulin
resistance and reduced tissue concentration of insulin
growth factor (IGF)-1 reduce phosphorylation of the
phosphatidyinositol-3-OH kinase, which in turn lowers
activation of Akt (protein kinase B), thereby decreasing
protein synthesis via dephosphorylation of mTOR, a mammalian target of rapamycin and glucogen synthase kinase
(45 49) (Fig. 5). Reduced Akt activation increases activity
of forkhead box O (FOXO) transcription factors, which in
turn activates the ubiquitin-proteasome pathway, resulting
in protein degradation (48 52) (Fig. 5). In addition, insulin
resistance and reduced tissue IGF-1 concentration activate
caspase-3 (53). After cleavage by activated caspase-3, myofibrillar proteins are degraded by the ubiquitin-proteasome
pathway (54). Whether apoptosis plays a significant role in
SM atrophy remains controversial (55,56). The important
role that the growth hormone (GH)/IGF-1 axis plays in
mediating SM growth provides the rationale for the use of

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ghrelin in patients with CHF or COPD (57). Ghrelin, a

novel GH-releasing peptide acts through a mechanism that
is more potent and independent of hypothalamic GHreleasing hormone (58). Administration of ghrelin for
3 weeks improves functional capacity and alleviates SM
atrophy in patients with CHF and in patients with COPD
(59,60).
In summary, disuse, low-level systemic inflammation,
and increased oxidative stress contribute to SM atrophy by
enhancing protein degradation and hindering protein synthesis. Reduced IGF-1 muscle concentration provides the
rationale for modulation of the GH/IGF-1 axis. Preliminary results with ghrelin, a novel modulator of the GH/
IGF-1 axis, are encouraging.
Emerging therapeutic approaches in CHF and COPD.
Since it was shown to lower mortality 2 decades ago, ACE
inhibition has been the cornerstone of treatment of CHF
(61). More recently, ACE inhibition was shown to prevent
cachexia and SM atrophy and to improve respiratory muscle
strength in patients with CHF (62 64). Because the beneficial effects of ACE inhibition on muscles are partially
mediated by a reduction in angiotensin II levels, which in
turn attenuates the decline in IGF-1 levels, achieving
complete ACE inhibition may be of special interest to
prevent SM atrophy in CHF and potentially in COPD (65).
Modulation of the renin-angiotensin system with ACE
inhibition or angiotensin receptor blockade (ARB) may
have dual benefits in patients with COPD by lowering
cardiovascular risk and preventing lung injury (66,67).
However, ARB failed to improve respiratory or SM
strength in patients with COPD without cardiovascular
diseases nor the exercise capacity or dyspnea score in
patients with COPD and pulmonary hypertension (68,69).

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Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

When they receive ACE inhibitors, patients with COPD

are not at increased risk of cough or bronchospasm (70).
Occurrence of cough in patients with COPD is more likely
to be related to unsuspected CHF than to ACE inhibition.
Human menopausal gonadotropin-CoA reductase inhibition with simvastatin inhibits development of emphysema, inflammation, and pulmonary hypertension in a rat
model of smoking-induced lung injury (71). Simvastatin
also reverses pulmonary hypertension in a rat model of toxic
injury to the pulmonary vasculature (72). The pleiotropic
effects and, especially, the anti-inflammatory action of
simvastatin are likely to mediate its benefits in experimental
models. Administration of simvastatin for 14 weeks improves LV ejection fraction and functional status in patients
with CHF due to idiopathic cardiomyopathy (73). These
preliminary findings with simvastatin contrast with the
negative experience with tumor necrosis factor antibodies
(74,75). A nested case-control study of elderly COPD
patients with and without known CAD who were receiving
statins, ACE inhibitors, or ARBs alone or a combination of
statins with either ACE inhibitors or ARBs advocates that
these agents may have cardiopulmonary protective properties (76). Statins alone and in combination with either ACE
inhibitors or ARBs reduced hospitalizations for COPD
(76). Because only a minority of patients with CHF (4%)
were included in that case-control COPD study, one cannot
extrapolate the results to patients with coexistent CHF and
COPD. Whether these agents have dual cardiac and pulmonary protective properties needs to be confirmed in
randomized clinical trials.
BB in Patients With CHF and COPD
Long-term BB is underused in CHF patients (3,77). Underuse of BB in CHF is largely due to the entrenched belief
that it may precipitate respiratory deterioration when
COPD coexists with CHF. Few reports of acute bronchospasm after initiation of BB lead to exclusion of patients
with coexistent CHF and COPD from large BB trials (78).
Beta-blockers remain underprescribed to patients with
CHF and COPD despite extensive safety data in patients
with moderate to severe COPD (77,79,80).
Selective beta-1 adrenergic blockade. Respiratory symptoms and FEV1 are not significantly worsened by selective
beta-1 blockade (B1B) in COPD patients (80 86). Selective B1B with metoprolol succinate or tartrate was well
tolerated for 3 months by 50 patients with coexistent
ischemic cardiac disease and mild to severe COPD (87).
Patients remained free of adverse respiratory effects, and
FEV1 was unchanged. Selective B1B does not attenuate
beta-2 receptor (B2R) agonist-induced bronchodilatation
(82). The cumulative evidence from trials and meta-analysis
indicates that selective B1B should not be withheld when
COPD coexists with cardiovascular diseases, because the
benefits of selective B1B in cardiac patients with COPD far
outweigh the risks (80,88).

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Nonselective BB combined with alpha-blockade. The

safety profile of carvedilol and labetalol that combine
alpha-adrenergic blockade with nonselective BB is not as
well-established as that of selective B1B in COPD. Labetalol at maximal dose does not affect FEV1 in COPD (79).
Among 89 patients with coexistent COPD and CHF who
received carvedilol for at least 3 months, only 13 did not
tolerate carvedilol (89). The reasons for intolerance and the
presence of reversible airway obstruction were not specified.
Thirty-one patients with coexistent CHF and COPD
without reversible airflow obstruction receiving a mean dose
of 29 19 mg daily carvedilol were followed for a mean
duration of 2.4 years (90). Only 1 patient did not tolerate
carvedilol because of COPD exacerbation. Cardiac size and
function improved similarly in patients with coexistent
CHF and COPD and in patients with CHF alone after
receiving nonselective beta- and alpha-adrenergic blockade
for 24 months (89,91). Data regarding the use of carvedilol in
COPD patients with reversible airflow obstruction are not
available. In contrast to selective B1B, nonselective blockade
attenuates B2R agonist-induced bronchodilatation.
Clinical experience with selective B1B and combined
nonselective and alpha-blockade in COPD. Betablockade with selective and nonselective agents does not
affect the rate of hospitalization for COPD exacerbation in
patients with recent myocardial infarction, whereas it beneficially impacts mortality (92,93). Although case studies
have documented nonselective BB-triggered bronchospasm,
BB with selective and nonselective agents does not appear to
affect the rate of hospitalization for COPD exacerbation
(94). Therefore, current guidelines from the Heart Failure
Society of America recommend BB in all patients with
coexistent COPD and CHF (88). The use of BB in patients
with COPD and CHF can be substantially and safely
increased by a structured outpatient program (95). The
clinical experience and pulmonary effects of the 3 betablockers currently approved for the treatment of CHF are
summarized in Table 1.
Lastly, 3 issues regarding BB in COPD patients will be
briefly reviewed. They are time dependence of pulmonary
effects, receptor selectivity, and concomitant use of BB and
beta-2 agonists.
Time dependence of BB-induced pulmonary effects. As
observed with LV function, acute and long-term BB appears to have opposite effects on lungs. Airway hyperresponsiveness (AHR), as defined by an FEV1 decline of
20% after inhalation of metacholine, is associated with
increased mortality in patients with COPD (96). Acutely
administered selective or nonselective BB increases AHR in
patients with COPD (82). However, after an initial increase, long-term administration of carvedilol or nadolol
reduces AHR in a murine model of asthma (97). No data
are presently available regarding the effects of long-term BB
on AHR in patients. Similarly, beta-receptor (BR) density,
although unaffected by acute BB, increases during longterm BB (97). Increased BR density may be beneficial as

Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

89

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FEV1 forced expiratory volume in 1 second; NA not applicable; NS not significant.

90
1/31 patients

13/89 patients
12.525 mg twice daily

Beta-1
Beta-2
Alpha-1
Carvedilol

3.12525 mg twice daily

Excluded
NA

NA

29 19 mg daily

Not specified

85

84
None

None

Not specified

Not specified

2 (reversed with beta-agonist), NS

2 (reversed with beta-agonist)

50 mg three times daily

Beta-1
Metoprolol (Toprol-XL)

12.5200 mg daily

NA
20 mg daily
1.2510 mg daily
Beta-1
Bisoprolol

Doses in Heart Failure

100 mg twice daily

83

82
None

None
Not specified
NA
100 mg twice daily

Excluded
NA
100 mg twice daily

86

81
1/6 patients
NA
NA
200 mg daily

None
NA

Long-Term FEV1 Treatment

Effect in Reversible
Airway Disease
Long-Term FEV1 Treatment
Effect in Irreversible
Airway Disease
Doses Used in
Referenced Trials
Adrenergic
Receptor-Blocking
Activity

Effects of Beta-Blockers Approved for Treatment of Heart Failure on Lung Function and Symptoms in Patients With COPD
Table 1

Effects of Beta-Blockers Approved for Treatment of Heart Failure on Lung Function and Symptoms in Patients With COPD

Respiratory
Symptoms

Reference

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177

experimental over-expression of B2R increases adenyl cyclase activity in airway smooth muscle and reduces
AHR (98).
In summary, the detrimental effects of acute BB on AHR
may with time convert into beneficial effects. Accordingly,
early mild deterioration in pulmonary symptoms or FEV1 in
patients with coexistent CHF and COPD should not
prompt BB discontinuation. Close observation is recommended and BB discontinuation is warranted when pulmonary symptoms persist or worsen.
Receptor selectivity of BB. Selective B1Bs have a 20-fold
higher affinity for B1R than for B2R. Selective B1Bs are
presumably less likely to induce bronchoconstriction than
nonselective BBs (99). However, the receptor selectivity of
BBs varies in experimental models (100). Receptor selectivity varies for the following reasons: 1) B2Rs predominate in
bronchial smooth muscle, whereas B1Rs account for 10%
and 30% of beta-receptors in submucosal glands and alveolar walls, respectively (101); 2) selective B1Bs appear to
lose selectivity at the high end of dose ranging; 3) several
polymorphisms of beta-receptor have been reported; and 4)
exposure to agonists may alter B2Rs such that the affinity
for ligands is reduced 10-fold (102). Consequently, prior
exposure to beta agonists may reduce binding of antagonists
to B2Rs. It may explain the high tolerance for BB in COPD
patients who routinely inhale B2R agonists.
In summary, BB receptor selectivity varies in experimental settings. Whether such variability has therapeutic implications remains unclear in patients with COPD.
Concomitant use of BB and inhaled beta-agonists. Owing
to the cardiovascular risks associated with the use of inhaled
B2R agonists, nonselective BB may be particularly beneficial
in patients with CHF and COPD. Deleterious cardiovascular effects of inhaled B2R agonists, the mainstay of
COPD therapy, are now increasingly recognized. Recent
meta-analysis of 5 single-dose and 6 longer-duration trials
of B2R agonists has underlined their adverse cardiovascular
effects in COPD patients (103). Therapy with inhaled B2R
agonists is associated with an increased risk for CHF
decompensation (adjusted OR 3.42, 95% CI 1.99 to 5.86)
and all-cause mortality in patients with CHF (104,105).
Inhaled B2R agonists induced adverse cardiac effects in
COPD patients with pre-existing cardiovascular disease
(106). The adverse effects of B2R agonists are likely to be
exacerbated in COPD patients with coexistent CHF. The
efficacy of concomitant BB to offset the adverse cardiovascular effects of B2R agonists in COPD patients with
coexistent CHF has not yet been assessed in clinical trials.
In summary, BB therapy should be attempted with selective
beta-1 adrenergic blockade or combined nonselective beta- and
alpha-adrenergic blockade in all CHF patients with concomitant stable COPD who do not have reversible airway obstruction. Selective BB is recommended in patients with CHF and
COPD who have reversible airway obstruction in the absence
of safety data regarding combined nonselective beta- and
alpha-adrenergic blockade. Both selective beta-1 and com-

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Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

bined nonselective beta- and alpha-adrenergic blockade are to

be avoided during COPD exacerbation until safety data are
available.
Reprint requests and correspondence: Dr. Thierry H. Le Jemtel,
Section of Cardiology, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-48, New
Orleans, Louisiana 70112-2699. E-mail: [email protected].

REFERENCES

1. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med

2000;343:269 80.
2. Jessup M, Brozena S. Medical progress: heart failure. N Engl J Med
2003;348:200718.
3. Egred M, Shaw S, Mohammad P, Waitt P, Rodriguez E. Under-use
of beta-blockers in patients with ischaemic heart disease and concomitant chronic obstructive pulmonary disease. Q J Med 2005;98:
4937.
4. Rutten FH, Cramer MJ, Grobbee DE, et al. Unrecognized heart
failure in elderly patients with stable chronic obstructive pulmonary
disease. Eur Heart J 2005;261:88794.
5. Havranek EP, Masoudi FA, Westfall KA, Wolfe P, Ordin DL,
Krumholz HM. Spectrum of heart failure in older patients: results
from the National Heart Failure Project. Am Heart J 2002;143:
4127.
6. OConnor CM, Stough WG, Gallup DS, Hasselblad V, Gheorghiade M. Demographics, clinical characteristics, and outcomes of
patients hospitalized for decompensated heart failure: observations
from the IMPACT-HF registry. J Card Fail 2005;11:200 5.
7. Braunstein JB, Anderson GF, Gerstenblith G, et al. Noncardiac
comorbidity increases preventable hospitalizations and mortality
among Medicare beneficiaries with chronic heart failure. J Am Coll
Cardiol 2003;42:1226 33.
8. Gustafsson F, Torp-Pedersen C, Burchardt H, et al., DIAMOND
Study Group. Female sex is associated with a better long-term
survival in patients hospitalized with congestive heart failure. Eur
Heart J 2004;25:129 35.
9. Dahlstrom U. Frequent noncardiac comorbidities in patients with
chronic heart failure. Eur J Heart Fail 2005;7:309 16.
10. Ni H, Nauman D, Hershberger RE. Managed care and outcomes of
hospitalization among elderly pateints with congestive heart failure.
Arch Int Med 1998;158:1231 6.
11. Render ML, Weinstein AS, Blaustein AS. Left ventricular dysfunction in deteriorating patients with chronic obstructive pulmonary
disease. Chest 1995;107:162 8.
12. Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in
patients with chronic obstructive pulmonary disease, Saskatchewan
Canada cardiovascular disease in COPD patients. Ann Epidemiol
2006;16:6370.
13. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and
mortality in COPD-related hospitalizations in the United States,
1979 to 2001. Chest 2005;128:200511.
14. Sidney S, Sorel M, Quesenberry CP Jr., DeLuise C, Lanes S, Eisner
MD. COPD and incident cardiovascular disease hospitalizations and
mortality: Kaiser Permanente Medical Care Program. Chest 2005;
128:2068 75.
15. Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and
women: findings from the Renfrew and Paisley prospective population study. BMJ 1996;313:7115.
16. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, GOLD
Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
NHLBI/WHO Global Initiative for Chronic Obstructive Lung
Disease (GOLD) workshop summary. Am J Respir Crit Care Med
2001;163:1256 76.
17. Sin DD, Hogg J. Are Patients with chronic obstructive pulmonary
disease at increased risk of cardiovascular morbidity and mortality?
CVR&R 2004;25:168 70.

Downloaded From: http://content.onlinejacc.org/ on 08/18/2016

JACC Vol. 49, No. 2, 2007

January 16, 2007:17180
18. Sin DD, Man SF. Why are patients with chronic obstructive
pulmonary disease at increased risk of cardiovascular diseases? The
potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514 19.
19. Steele P, Ellis JH, Van Dyke D, Sutton F, Creagh E, Davies H. Left
ventricular ejection fraction in severe chronic obstructive airways
disease. Am J Med 1975;59:21 8.
20. Maisel A, Hollander JE, Guss D, et al. Primary results of Rapid
Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels,
emergency department decision making, and outcomes in patients
presenting with shortness of breath. J Am Coll Cardiol 2004;44:
1328 33.
21. Steg PG, Joubin L, McCord J, et al. B-type natriuretic peptide and
echocardiographic determination of ejection fraction in the diagnosis
of congestive heart failure in patients with acute dyspnea. Chest
2005;128:219.
22. Mueller C, Laule-Kilian K, Frana B, et al. Use of B-type natriuretic
peptide in the management of acute dyspnea in patients with
pulmonary disease. Am Heart J 2006;151:4717.
23. Tang WH, Girod JP, Lee MJ, et al. Plasma B-type natriuretic
peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation 2003;108:2964 66.
24. Petrie MC, Hogg K, Caruana L, McMurray JJ. Poor concordance of
commonly used echocardiographic measures of left ventricular diastolic function in patients with suspected heart failure but preserved
systolic function: is there a reliable echocardiographic measure of
diastolic dysfunction? Heart 2004;90:5117.
25. Oh JK, Hatle L, Tajik J, Little W. Diastolic heart failure can be
diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500 6.
26. American Thoracic Society, European Respiratory Society. Skeletal
muscle dysfunction in chronic obstructive pulmonary disease. Am J
Respir Care Med 1999;159:S1 40.
27. Gosker HR, Wouters EF, van der Vusse GJ, Schols AM. Skeletal
muscle dysfunction in chronic obstructive pulmonary disease and
chronic heart failure: underlying mechanisms and therapy perspectives. Am J Clin Nutr 2000;71:1033 47.
28. Gosker HR, Lencer NH, Franssen FM, van der Vusse GJ, Wouters EF,
Schols AM. Striking similarities in systemic factors contributing to
decreased exercise capacity in patients with severe chronic heart failure or
COPD. Chest 2003;123:1416 24.
29. Whittom F, Jobin J, Simard PM, et al. Histochemical and morphological characteristics of the vastus lateralis muscle in patients with
chronic obstructive pulmonary disease. Med Sci Sports Exerc 1998;
30:146774.
30. Jondeau G, Katz SD, Zohman L, et al. Active skeletal muscle mass
and cardiopulmonary reserve. Failure to attain peak aerobic capacity
during maximal bicycle exercise in patients with severe congestive
heart failure. Circulation 1992;86:1351 6.
31. Killian KJ, Leblanc P, Martin DH, Summers E, Jones NL, Campbell
EJ. Exercise capacity and ventilatory, circulatory, and symptom
limitation in patients with chronic airflow limitation. Am Rev Respir
Dis 1992;146:935 40.
32. Harrington D, Anker SD, Chua TP, et al. Skeletal muscle function
and its relation to exercise tolerance in chronic heart failure. J Am
Coll Cardiol 1997;30:1758 64.
33. Cicoira M, Zanolla L, Franceschini L, et al. Skeletal muscle mass
independently predicts peak oxygen consumption and ventilatory
response during exercise in noncachectic patients with chronic heart
failure. J Am Coll Cardiol 2001;37:2080 5.
34. Yoshikawa M, Yoneda T, Takenaka H, et al. Distribution of muscle
mass and maximal exercise performance in patients with COPD.
Chest 2001;119:93 8.
35. Grove A, Lipworth BJ, Reid P, et al. Effects of regular salmeterol on
lung function and exercise capacity in patients with chronic obstructive airways disease. Thorax 1996;51:689 93.
36. Ennezat PV, Ennezat CA, Vijayaraman P, et al. Dissociation
between improvement in left ventricular performance and functional
class in patients with chronic heart failure. J Cardiovasc Pharmacol
2005;46:577 85.
37. Jackman RW, Kandarian SC. The molecular basis of skeletal muscle
atrophy. Am J Physiol Cell Physiol 2004;287:C834 43.

JACC Vol. 49, No. 2, 2007

January 16, 2007:17180
38. Sala E, Roca J, Marrades RM, et al. Effects of endurance training on
skeletal muscle bioenergetics in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:1726 34.
39. Sullivan MJ, Higginbotham MB, Cobb FR. Exercise training in
patients with severe left ventricular dysfunction. Hemodynamic and
metabolic effects. Circulation 1988;78:506 15.
40. Mallat Z, Philip I, Lebret MD, et al. Elevated levels of 8-isoprostaglandin F2alpha in pericardial fluid of patients with heart
failure: a potential role for in vivo oxidant stress in ventricular
dilatation and progression to heart failure. Circulation 1998;97:
1536 9.
41. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between
chronic obstructive pulmonary disease and systemic inflammation: a
systematic review and a meta-analysis. Thorax 2004;59:574 80.
42. Vernooy JH, Kucukaycan M, Jacobs JA, et al. Local and systemic
inflammation in patients with chronic obstructive pulmonary disease:
soluble tumor necrosis factor receptors are increased in sputum. Am J
Respir Crit Care Med 2002;166:1218 24.
43. Testa M, Yeh M, Lee P, et al. Circulation levels of cytokines and
their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease and hypertension.
J Am Coll Cardiol 1996;28:964 71.
44. Le Jemtel TH, Farr M, Moskowitz R. Alterations in skeletal muscle.
In: Mann DL, editor. Heart Failure. Philadelphia, PA: Saunders,
2004:291302.
45. Hambrecht R, Schulze PC, Gielen S, et al. Reduction of insulin-like
growth factor-I expression in the skeletal muscle of noncachectic patients
with chronic heart failure. J Am Coll Cardiol 2002;39:1175 81.
46. Niebauer J, Pflaum CD, Clark AL, et al. Deficient insulin-like
growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.
J Am Coll Cardiol 1998;32:3937.
47. Guttridge DC. Signaling pathways weigh in on decisions to make or
break skeletal muscle. Curr Opin Clin Nutr Metab Care 2004;7:44350.
48. Glass DJ. Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol 2003;5:8790.
49. Latres E, Amini AR, Amini AA, et al. Insulin-like growth factor-1
(IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/
Akt/mTOR) pathway. J Biol Chem 2005;280:2737 44.
50. Sandri M, Sandri C, Gilbert A, et al. FOXO transcription factors
induce the atrophy-related ubiquitin ligase atrogin-1 and cause
skeletal muscle atrophy. Cell 2004;117:399 412.
51. Sacheck JM, Ohtsuka A, McLary SC, Goldberg AL. IGF-I stimulates muscle growth by suppressing protein breakdown and expression
of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J
Physiol Endocrinol Metab 2004;287:E591 601.
52. Jagoe RT, Goldberg AL. What do we really know about the
ubiquitin-proteasome pathway in muscle atrophy? Curr Opin Clin
Nutr Metab Care 2001;4:18390.
53. Du J, Wang X, Miereles C, et al. Activation of caspase-3 is an initial
step triggering accelerated muscle proteolysis in catabolic conditions.
J Clin Invest 2004;113:11523.
54. Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role
of the ubiquitin-proteasome pathway. N Engl J Med 1996;335:1897
905.
55. Libera LD, Vescovo G. Muscle wastage in chronic heart failure,
between apoptosis, catabolism and altered anabolism: a chimaeric
view of inflammation? Curr Opin Clin Nutr Metab Care 2004;7:
435 41.
56. Persinger R, Janssen-Heininger Y, Wing SS, Matthews DE,
LeWinter MM, Toth MJ. Effect of heart failure on the regulation of
skeletal muscle protein synthesis, breakdown, and apoptosis. Am J
Physiol Endocrinol Metab 2003;284:E1001 8.
57. Florini JR., Ewton DZ., Cooligan SH. Growth hormone and the
insulin-like growth factor system in myogenesis. Endocr Rev 1996;
17:481517.
58. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev
2005;85:495522.
59. Nagaya N, Moriya J, Yasumura Y, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle
wasting in patients with chronic heart failure. Circulation 2004;110:
3674 9.

Downloaded From: http://content.onlinejacc.org/ on 08/18/2016

Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

179

60. Nagaya N, Itoh T, Murakami S, et al. Treatment of cachexia with

ghrelin in patients with COPD. Chest 2005;128:118793.
61. The SOLVD Investigators. Effect of enalapril on survival in patients
with reduced left ventricular ejection fractions and congestive heart
failure. N Engl J Med 1991;325:293302.
62. Jones A, Woods DR. Skeletal muscle RAS and exercise performance.
Int J Biochem Cell Biol 2003;35:855 66.
63. Anker SD, Negassa A, Coats AJ, et al. Prognostic importance of
weight loss in chronic heart failure and the effect of treatment with
angiotensin-converting-enzyme inhibitors: an observational study.
Lancet 2003;361:1077 83.
64. Coirault C, Hagege A, Chemla D, Fratacci MD, Guerot C,
Lecarpentier Y. Angiotensin-converting enzyme inhibitor therapy
improves respiratory muscle strength in patients with heart failure.
Chest 2001;119:1755 60.
65. Maggio M, Ceda GP, Lauretani F, et al. Relation of angiotensinconverting enzyme inhibitor treatment to insulin-like growth factor-1
serum levels in subjects 65 years of age (the InCHIANTI study).
Am J Cardiol 2006;97:15259.
66. Mancini GB. The double dip hypothesis: simultaneous prevention of
cardiovascular and pulmonary morbidity and mortality using angiotensin
II type 1 receptor blockers. Can J Cardiol 2005;21:519 23.
67. Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme 2
in lung diseases. Curr Opin Pharmacol 2006;6:271 6.
68. Morrell NW, Higham MA, Phillips PG, Shakur BH, Robinson PJ,
Beddoes RJ. Pilot study of losartan for pulmonary hypertension in
chronic obstructive pulmonary disease. Respir Res 2005;6:88.
69. Andreas S, Herrmann-Lingen C, Raupach T, et al. Angiotensin II
blockers in obstructive pulmonary disease: a randomised controlled
trial. Eur Respir J 2006;27:9729.
70. Packard KA, Wurdeman RL, Arouni AJ. ACE inhibitor-induced
bronchial reactivity in patients with respiratory dysfunction. Ann
Pharmacother 2002;36:1058 67.
71. Lee JH, Lee DS, Kim EK, et al. Simvastatin inhibits cigarette
smoking-induced emphysema and pulmonary hypertension in rat
lungs. Am J Respir Crit Care Med 2005;172:98793.
72. Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from
fatal pulmonary hypertension by inducing apoptosis of neointimal
smooth muscle cells. Circulation 2003;108:1640 5.
73. Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin
therapy improves cardiac function and symptoms in patients with
idiopathic dilated cardiomyopathy. Circulation 2003;108:839 43.
74. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine
therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation
2004;109:1594 602.
75. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT,
Anti-TNF Therapy Against Congestive Heart Failure Investigators.
Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha,
in patients with moderate-to-severe heart failure: results of the
Anti-TNF Therapy Against Congestive Heart Failure (ATTACH)
trial. Circulation 2003;107:3133 40.
76. Mancini G, Etminan M, Zhang B, et al. Reduction of morbidity and
mortality by statins, angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers in patients with chronic obstructive
pulmonary disease. J Am Coll Cardiol 2006;47:2554 60.
77. Bellotti P, Badano LP, Acquarone N, et al., OSCUR Investigators.
Specialty-related differences in the epidemiology, clinical profile,
management and outcome of patients hospitalized for heart failure;
the OSCUR study. Eur Heart J 2001;22:596 604.
78. Popio KA, Jackson DH Jr., Utell MJ, Swinburne AJ, Hyde RW.
Inhalation challenge with carbachol and isoproterenol to predict
bronchospastic response to propranolol in COPD. Chest 1983;83:
1759.
79. George RB, Manocha K, Burford JG, Conrad SA, Kinasewitz GT.
Effects of labetalol in hypertensive patients with chronic obstructive
pulmonary disease. Chest 1983;83:457 60.
80. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for
chronic obstructive pulmonary disease. Cochrane Database Syst Rev
2005;4:CD003566.
81. Fenster PE, Hasan FM, Abraham T, Woolfenden J. Effects of
metoprolol on cardiac and pulmonary function in chronic obstructive
pulmonary disease. Clin Cardiol 1983;6:1259.

180

Le Jemtel et al.
Diagnosis and Therapy of Coexistent COPD and CHF

82. van der Woude HJ, Zaagsma J, Postma DS, Winter TH, van Hulst M,
Aalbers R. Detrimental effects of beta-blockers in COPD: a concern for
nonselective beta-blockers. Chest 2005;127:818 24.
83. Lammers JW, Folgering HT, van Herwaarden CL. Ventilatory
effects of long-term treatment with pindolol and metoprolol in
hypertensive patients with chronic obstructive lung disease. Br J Clin
Pharmacol 1985;20:20510.
84. Tivenius L. Effects of multiple doses of metoprolol and propranolol
on ventilatory function in patients with chronic obstructive lung
disease. Scand J Respir Dis 1976;57:190 6.
85. Wunderlich J, Macha HN, Wudicke H, Huckauf H. Betaadrenoceptor blockers and terbutaline in patients with chronic obstructive lung disease. Effects and interaction after oral administration. Chest 1980;78:714 20.
86. Dorow P, Bethge H, Tonnesmann U. Effects of single oral doses of
bisoprolol and atenolol on airway function in nonasthmatic chronic
obstructive lung disease and angina pectoris. Eur J Clin Pharmacol
1986;31:1437.
87. Camsari A, Arikan S, Avan C, et al. Metoprolol, a beta-1 selective
blocker, can be used safely in coronary artery disease patients with
chronic obstructive pulmonary disease. Heart Vessels 2003;18:
188 92.
88. The Heart Failure Society of America. Executive summary: HFSA
2006 comprehensive heart failure practice guideline. J Card Fail
2006;12:10 38.
89. Kotlyar E, Keogh AM, Macdonald PS, Arnold RH, McCaffrey DJ,
Glanville AR. Tolerability of carvedilol in patients with heart failure
and concomitant chronic obstructive pulmonary disease or asthma.
J Heart Lung Transplant 2002;21:1290 5.
90. Krum H, Ninio D, MacDonald P. Baseline predictors of tolerability
to carvedilol in patients with chronic heart failure. Heart 2000;84:
6159.
91. Macdonald P, Keogh A, Aboyoun C, Lund M, Amor R, McCaffrey
D. Tolerability and efficacy of carvedilol in patients with New York
Heart Association class IV heart failure. J Am Coll Cardiol 1999;33:
924 31.
92. Chen J, Radford MJ, Wang Y, Marciniak TA, Krumholz HM.
Effectiveness of beta-blocker therapy after acute myocardial infarction
in elderly patients with chronic obstructive pulmonary disease or
asthma. J Am Coll Cardiol 2001;37:1950 6.
93. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on
mortality among high-risk and low-risk patients after myocardial
infarction. N Engl J Med 1998;339:489 97.

Downloaded From: http://content.onlinejacc.org/ on 08/18/2016

JACC Vol. 49, No. 2, 2007

January 16, 2007:17180
94. Barnett MJ, Milavetz G, Kaboli PJ. Beta-blocker therapy in veterans
with asthma or chronic obstructive pulmonary disease. Pharmacotherapy 2005;25:1550 9.
95. Shelton RJ, Rigby AS, Cleland JG, Clark AL. Effect of a community
heart failure clinic on uptake of beta blockers by patients with
obstructive airways disease and heart failure. Heart 2006;92:331 6.
96. Hospers JJ, Postma DS, Rijcken B, Weiss ST, Schouten JP. Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study. Lancet 2000;356:13137.
97. Callaerts-Vegh Z, Evans KL, Dudekula N, et al. Effects of acute and
chronic administration of beta-adrenoceptor ligands on airway function
in a murine model of asthma. Proc Natl Acad Sci U S A 2004;101:
4948 53.
98. McGraw DW, Fukuda N, James PF, et al. Targeted transgenic
expression of beta(2)-adrenergic receptors to type II cells increases
alveolar fluid clearance. Am J Physiol Lung Cell Mol Physiol
2001;281:L895903.
99. Wellstein A, Palm D, Belz G, Butzer R, Polsak R, Pett B. Reduction
of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy. Eur Heart J
1987;8 Suppl M:3 8.
100. Baker JG. The selectivity of beta-adrenoceptor antagonists at the
human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol
2005;144:31722.
101. Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization
of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis
1985;132:5417.
102. Baker JG, Hall IP, Hill SJ. Influence of agonist efficacy and receptor
phosphorylation on antagonist affinity measurements: differences
between second messenger and reporter gene responses. Mol Pharmacol 2003;64:679 88.
103. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of
beta-agonists in patients with asthma and COPD: a meta-analysis.
Chest 2004;125:2309 21.
104. Martin RM, Dunn NR, Freemantle SN, Mann RD. Risk of nonfatal
cardiac failure and ischaemic heart disease with long acting beta 2
agonists. Thorax 1998;53:558 62.
105. 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.
106. Cazzola M, Imperatore F, Salzillo A, et al. Cardiac effects of
formoterol and salmeterol in patients suffering from COPD with
preexisting cardiac arrhythmias and hypoxemia. Chest 1998;
114:4115.