Journal of Cardiology 70 (2017) 128–134

Contents lists available at ScienceDirect

Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Review

Total management of chronic obstructive pulmonary disease (COPD)

as an independent risk factor for cardiovascular disease
Katsuya Onishi (MD, PhD, FACC, FESC)*
Onishi Heart Clinic, Mie, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Patients with cardiovascular disease (CVD) often have multiple comorbid conditions that may interact
Received 3 January 2017 with each other, confound the choice of treatments, and reduce mortality. Chronic obstructive
Accepted 5 January 2017 pulmonary disease (COPD) is one of the most important comorbidities of CVD, which causes serious
Available online 18 March 2017
consequences in patients with ischemic heart disease, stroke, arrhythmia, and heart failure. COPD shares
common risk factors such as tobacco smoking and aging with CVD, is associated with less physical
Keywords: activity, and produces systemic inflammation and oxidative stress. Overall, patients with COPD have a 2–
COPD
3-fold increased risk of CVD as compared to age-matched controls when adjusted for tobacco smoking.
Cardiovascular disease
Heart failure
Chronic heart failure (HF) is a frequent and important comorbidity which has a significant impact on
Beta-blocker prognosis in COPD, and vice versa. HF overlaps in symptoms and signs and has a common comorbidity
Bronchodilator with COPD, so that diagnosis of COPD is difficult in patients with HF. The combination of HF and COPD
presents many therapeutic challenges including beta-blockers (BBs) and beta-agonists. Inhaled long-
acting bronchodilators including beta2-agonists and anticholinergics for COPD would not worsen HF.
Diuretics are relatively safe, and angiotensin-converting enzyme inhibitors are preferred to treat HF
accompanied with COPD. BBs are only relatively contraindicated in asthma, but not in COPD. Low doses
of cardioselective BBs should be aggressively initiated in clinically stable patients with HF accompanied
with COPD combined with close monitoring for signs of airway obstruction and gradually up-titrated to
the maximum tolerated dose. Encouraging appropriate and aggressive treatment for both HF and COPD
should be recommended to improve quality of life and mortality in HF patients with COPD.
ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Clinical features of COPD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
COPD on cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Ischemic heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
COPD and HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Diagnosis and assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
The treatment of COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Beta2-agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Anticholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

* Correspondence to: Onishi Heart Clinic, 3431-5 Handa, Tsu, Mie 514-0823, Japan. Fax: +81 59 225 3033.
E-mail address: katsu@clin.medic.mie-u.ac.jp

http://dx.doi.org/10.1016/j.jjcc.2017.03.001
0914-5087/ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
 K. Onishi / Journal of Cardiology 70 (2017) 128–134 129

The treatment of HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
ACE inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Beta-blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Introduction symptomatic management of COPD. The principal bronchodilator

treatments to prevent or reduce symptoms are anticholinergics,
Chronic obstructive pulmonary disease (COPD), a common beta2-agonists, or combination therapy. These treatments should
preventable and treatable disease, is characterized by persistent be decided according to each patient’s individual response and
airflow limitation and respiratory symptoms that is usually relative contraindication. Long-acting inhaled bronchodilators are
progressive and associated with airway and/or alveolar abnormal- more convenient and effective for symptom relief, and have fewer
ities caused by significant exposure to noxious particles or gases adverse effects on the cardiovascular system than short-acting
[1]. By 2020, COPD is predicted to cause over 6 million deaths bronchodilators.
annually worldwide, thus becoming the third leading cause of COPD is considered a complex, heterogeneous, and multicom-
death in the world. ponent disease because of many cormobidities and extrapulmon-
Tobacco smoking is the most important cause of COPD. Almost ary manifestations as well as structural and functional abnormality
all smokers experience a progressive decline in lung function in a of the lungs [4]. Extrapulmonary comorbidity should be aggres-
dose- and duration-dependent manner. Tobacco smoking is a sively treated to improve regular physical activity as well as
common risk factor for many comorbidities, including cardiovas- mortality for patients with COPD.
cular disease (CVD) [2]. Many numbers of inflammatory cell types
such as macrophages, neutrophils, and T-cells in the airway and COPD on cardiovascular disease
the lung are involved in the pathophysiology of COPD [3]. In
addition to the lung inflammation, chronic systemic inflammation COPD often coexists with CVD and has a significant impact on
is observed in COPD, but the origin of this inflammation remains prognosis [4]. Overall, patients with COPD have a 2–3-fold
unclear. The systemic inflammation of COPD causes a multisystem increased risk of CVD compared to age-matched controls when
disease associated with the high frequency of major comorbidities adjusted for tobacco smoking [5]. In a multicenter observational
including diagnosed and subclinical CVD independently of the prospective study conducted at 17 cardiology clinics across Japan,
patients’ advanced age and shared risk factors [1]. CVD including the prevalence of airflow limitation compatible with COPD was
hypertension, ischemic heart disease (IHD), stroke, atrial fibrilla- observed in 995 cardiac outpatients with a smoking history (Fig. 1)
tion (AF), and heart failure (HF) is the most frequent and most [6]. The overall prevalence of airflow limitation compatible with
important comorbidity in COPD because of the worsening COPD was 27.0%, and 87.7% of those patients did not have a prior
prognosis in patients with COPD, and vice versa [4]. diagnosis of COPD.
In particular, COPD is a frequent co-morbidity in chronic HF Cardiovascular comorbidities are common at any severity of
with its prevalence ranging between 20% and 30% [2]. Accordingly, COPD and have the most serious consequences in patients with
the objective of this review is to clarify COPD as a main COPD, but they are most frequently undiagnosed and untreated.
comorbidity of CVD, and to discuss the diagnostic and therapeutic [(Fig._1)TD$IG]
approach for HF patients accompanied with COPD.

Clinical features of COPD

40
COPD is a major cause of morbidity and mortality so that its
diagnosis should be considered in any patient who has dyspnea,
chronic cough, or sputum production with a history of smoking 30
[1]. Spirometry is required to make a clinical diagnosis of COPD.
% of COPD

The presence of the ratio of forced expiratory volume in 1 s (FEV1)

20
to forced vital capacity (FVC) < 0.70 with a post-bronchodilator
indicates airflow limitation caused by COPD. Tobacco smoking is
the most important cause of COPD, which causes lung inflamma- 10
tion that induces parenchymal tissue destruction, leading to air
trapping and progressive airflow limitation. (n=995)
COPD should be treated based on an individualized assessment 0
<2 2<, <10 10> (per month)
of disease in order to reduce current symptoms, reduce the
Lung function tests performed in cardiology clinic
frequency and severity of exacerbations, and improve health status
and exercise tolerance. Smoking cessation, non-pharmacologic
therapies including pulmonary rehabilitation, and pharmacologic
therapies are recommended based on an individual patient’s Fig. 1. The prevalence of airflow limitation and a previous diagnosis of COPD in
symptoms, airflow limitation, and severity of exacerbations. cardiology clinic. The amount of airflow limitation and a previous diagnosis of COPD
observed in 995 cardiac outpatients with a smoking history. Lung function tests
Pharmacologic therapies for COPD are used to reduce symp- performed in cardiology clinic often (10), less often (2, <10), and seldom (<2).
toms, avoid exacerbations, and improve health status and exercise Color squares show airflow limitation, and white squares a previous diagnosis of
tolerance. Inhaled bronchodilator medications are indicated for the COPD. COPD, chronic obstructive pulmonary disease.
130 K. Onishi / Journal of Cardiology 70 (2017) 128–134
Studies have reported that about 40% of patients with mild to
moderate COPD died due to CVD, which is 8–10 times more than
due to respiratory failure [4,5]. Over 5 years of follow-up, patients
with COPD had higher rates of hospitalization and death due to
IHD, stroke, and HF.
CVD may be causally related to COPD either with shared risk
factors or by systemic inflammation. CVD and COPD share the
same main risk factors, i.e. tobacco smoking and aging which cause
endothelial dysfunction [1]. Systemic inflammation and increased
oxidative stress as important and unique features of COPD cause
atherosclerosis leading to the CVD. Exacerbation of respiratory
symptoms (acute exacerbation of COPD: AECOPD) often occur in
patients with COPD triggered by airway infection. AECOPD would
get even more activated systemic inflammation leading to the
increased total systemic resistance [7].
Ischemic heart disease
IHD should be considered in all COPD patients with smoking,
and vice versa [8]. The epidemiological link between COPD and IHD
has been well established because they share smoking and aging as
the same risk factors. The metabolic syndrome is highly prevalent
in patients with COPD, and is associated with less daily physical
activity. After adjustment for age, gender, smoking status, race,
body mass index (BMI), and educational level, IHD increased by
COPD probably due to the chronic inflammation and oxidative
stress. For every 10% decrease in FEV1, cardiovascular mortality
increases by 28% and the frequency of non-fatal coronary events
increases by 20% [9]. The link between COPD and IHD is
independent of any other confounding coronary risk factors,
namely smoking status, cholesterol, hypertension, and BMI.
Patients with COPD often have hypoxia during exercise, high
resting heart rates, impaired vasodilatory capacity, and peripheral,
cardiac, and neurohumoral sympathetic stress, which may cause
and/or worsen IHD. The activation of immune cells in the
atheromatous plaque observed in IHD induces the production of
cytokines [interferon-g, interleukin (IL)-1, tumor necrosis factor
(TNF)-a, and IL-6], and acute-phase inflammatory proteins
[fibrinogen, C-reactive protein (CRP) and amyloid protein], which
are involved in the inflammatory reaction observed in the
bronchus in COPD [3,10].
Concomitant COPD increases morbidity and mortality among
patients with IHD. Endothelial and myocardial injury are over-
looked and IHD is therefore under-diagnosed in COPD patients. The
presence of symptoms of simple chronic bronchitis increases the
risk of death due to a coronary event by 50%. Moreover, during
AECOPD, there is an increased risk of myocardial damage in
patients with concomitant IHD. The treatment of IHD should be
according to the IHD guideline irrespective of the presence of
COPD.
Stroke
Strokes are more prevalent in COPD compared with the general
population [4,5,11]. COPD patients are reported to have an
increased risk of approximately 20% for both ischemic and
hemorrhagic strokes. This risk is estimated to be up to 7-fold
higher following an AECOPD compared with stable COPD.
However, there is no association between the presence of COPD
and stroke severity or short-term mortality. The reduced FEV1 is
associated with an increased incidence of both ischemic and
hemorrhagic stroke independent of smoking status.
The pathophysiological mechanisms of stroke in COPD patients
are complex. Smoking and aging share risk factors between stroke
and COPD. Systemic inflammation and oxidative stress caused by
COPD can alter the structure and function of cerebral artery by
promoting vascular remodeling, stiffness, atherosclerosis, and
brain-blood barrier disruption, which may contribute to the
increased risk of intracerebral hemorrhage and microbleeds in
COPD. The systemic inflammation in COPD also induces a ‘‘pro-
coagulant’’ state [12]. Systemic inflammation is associated with
increased platelet aggregation and triggers the coagulation cascade
with further activation occurring during AECOPD. Furthermore,
COPD modulates stroke risk by increasing the propensity for
atherosclerotic plaque rupture.
Arrhythmias
Cardiac arrhythmias are common in COPD and vice versa.
Pathophysiological changes in COPD related to arrhythmias seem
to be delayed after depolarizations leading to triggered activity,
changed cardiac repolarization represented by QT interval
abnormalities, and increased sympathetic tone or reduced vagal
tone indicated by a reduced heart rate variability [13]. Other
studies have reported that COPD is associated with baroreceptor
sensitivity abnormalities, heart rate variability abnormalities, and
a direct increase in muscle sympathetic nerve activity.
AF is frequently and directly associated with FEV1 [14]. AECOPD
may be a trigger of AF, and AF may cause AECOPD. COPD is a risk
factor for sudden cardiac death independent of cardiovascular risk
profile, both in cohorts of cardiovascular patients and in
community-based studies.
The presence of AF does not alter the treatment of COPD.
Bronchodilators have been previously described as potentially pro-
arrhythmic agents, however, available evidence suggests an
overall acceptable safety profile for long-acting beta2-agonists
[7_TD$IF]and [8_TD$IF]anticholinergic [9_TD$IF]drugs [15]. Nevertheless, caution is advised for
using short-acting beta2-agonists which may precipitate AF and
make control of the ventricular response rate difficult. Oral
macrolide antibiotics, which are often prescribed for COPD
exacerbations, are known QT-prolonging drugs, and suspected of
increasing the risk of ventricular arrhythmias and sudden cardiac
death.
COPD and HF
Left ventricular failure rather than right ventricular failure is a
frequent and important comorbidity which has a significant
impact on prognosis in COPD [1,2]. Some cases of HF arise
independently of COPD, whereas others may be related to shared
risk factors (i.e. smoking, aging, physical inactivity) and/or with
COPD itself accompanied by systemic inflammation and oxidative
stress.
Prevalence
As a comorbidity of HF in community-based surveys, COPD is
detected in one third of outpatients. The Japanese Cardiac Registry
of Heart Failure in Cardiology (JCARE-CARD), a prospective
observational study in a broad sample of patients hospitalized
with worsening HF, shows the prevalence of COPD in patients with
HF was 6.5% because of the absence of aggressive performing of
spirometry [16]. Overall, the prevalence of COPD has been reported
to range from 6.5 to 40% in patients with chronic HF. The risk ratio
of developing HF is 2.8–8 in COPD patients compared with age-
matched controls without COPD after adjustments for cardiovas-
cular risk factors. Compared with the non-COPD population in the
meta-analyses, patients with COPD were more likely to be
diagnosed with HF with a three times higher risk.
On the other hand, the prevalence of HF in COPD patients ranges
from 20 to 70%, and its annual incidence between 3 and 4%
[17]. Importantly, incident HF is a significant and independent
 K. Onishi / Journal of Cardiology 70 (2017) 128–134 131

predictor of all-cause mortality in patients with COPD. There are
few data on the impact of COPD in patients with HF. The studies
based on the Norwegian Heart Failure Registry, including 4132 HF
patients followed for 8 years, demonstrated a significantly higher
proportion of deaths in patients with concomitant COPD (32.6% vs.
37.0%) [18]. Consecutive 378 patients admitted for HF with
coexistent moderate COPD (GOLD stage II) had higher cardiac and
non-cardiac mortality (Fig. 2) [19]. COPD therefore appears to be a
truly independent risk factor for death in compromised HF patients,
and the coexistence of COPD can delay the diagnosis of HF.
Pathophysiology
Patients with COPD and HF are exposed to important
cardiovascular risk factors, i.e. smoking, physical inactivity, an
unhealthy diet, obesity, metabolic syndrome, and aging (Fig. 3)
[1,4,5]. These risk factors may relate to the coexistence of COPD
and HF.
Hyperinflated lungs due to emphysema may disturb left
ventricular filling in severe COPD, but not mild to moderate COPD.
It is likely that COPD induces chronic [10_TD$IF]systemic inflammation and
oxidative stress from the early stage, which impairs cardiomyo-
cytes as well as endothelial cells. These factors may directly or
indirectly through IHD cause HF. Myocardial perfusion reserve,
which reflects microcirculation of the heart, was impaired in COPD
patients without IHD compared to age-matched healthy volun-
teers with or without tobacco smoking (Fig. 4) [20].
AECOPD might further increase the incidence of HF because of
hypoxia, tachycardia, activation of neurohumoral sympathetic
stress, increased total systemic resistance due to arterial stiffness,

[(Fig._2)TD$IG]

Fig. 2. Kaplan–Meier analyses for all-cardiac events (cardiac death and progressive heart failure) and all-cause mortality along GOLD II, GOLD I, and non-COPD groups. COPD,

[(Fig._3)TD$IG]
chronic obstructive pulmonary disease.

Fig. 3. Temporal and spatial influences of COPD on heart failure. COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; HR, heart rate; HTN, hypertension; LVH,
left ventricular hypertrophy; IHD, [5_TD$IF]ischemic heart disease.
[(Fig._4)TD$IG]
132
Myocardial Perfusion Reserve
P < 0.05
4.0
3.0
3.7±0.3
2.0
1.0
0 QTc prolongation, peripheral vasodilation, disturbed autonomic
Control
Never-smokers
(n=20)
Fig. 4. Impaired myocardial perfusion reserve in COPD patients (a magnetic
resonance imaging study). COPD, chronic obstructive pulmonary disease.
right ventricular pressure overload due to pulmonary hyperten-
sion, impaired left ventricular filling, increased platelet activation,
and use of high-dose beta2 agonists.
Non-cardiovascular comorbidities of COPD should not be
ignored [1,4,5]. Anemia is one of the important comorbidities of
COPD caused by chronic inflammation and malnutrition. Although
smokers would have polycythemia, anemia is reported to be more
common than polycythemia (a prevalence range: 12.3–23% vs 6%).
Anemia and decreased hematocrit would increase cardiac work
leading to HF.
Skeletal muscle dysfunction is another important comorbidity
in COPD. Skeletal muscle dysfunction in COPD is characterized by
alterations in fiber type, capillarization, reduced oxidative enzyme
capacity, and altered energy metabolism. Skeletal muscle dys-
function reduces exercise tolerance, and increases hospitalization
and mortality.
Diagnosis and assessment
HF overlaps in symptoms and signs and has the common
comorbidity with COPD, so that diagnosis of COPD may be delayed
in patients with HF. When patients with HF complain of dyspnea
during exercise, the symptom may be considered due to HF
without further assessment for COPD. Patients with a history of
smoking should be evaluated for the existence of COPD. Pulmonary
function tests and spirometry are essential, but there are
limitations to consider. The interpretation of spirometry in
patients with pulmonary congestion should be cautious because
interstitial edema causes external, partial obstruction of alveoli
and bronchioles, and increased bronchial sensitivity leading to
over diagnosis. FEV1/FVC is reduced by about 10–20% in pulmonary
congestion [21]. This partially or fully resolves after the treatment
for HF including diuretics. Spirometry to make a final diagnosis of
COPD should be performed when patients have been stable and
euvolemic for at least 6–8 weeks after pulmonary congestion.
B-type natriuretic peptide (BNP) is useful to distinguish HF from
COPD, and to discover the existence of HF in patients with COPD
(Fig. [1_TD$IF]5) [2]. The study, which examined patients presenting to the
emergency department with acute dyspnea, showed that BNP
measurements could be used to accurately differentiate HF from
respiratory disease including COPD [22].
K. Onishi / Journal of Cardiology 70 (2017) 128–134
The treatment of COPD
P < 0.001
The combination of HF and COPD presents many therapeutic
P < 0.05 challenges including beta-blockers (BBs) and beta-agonists [23].
Bronchodilator is useful to reduce symptoms, reduce the
frequency of acute exacerbations, and improve health status and
exercise tolerance even in patients with HF. Long-acting inhaled
beta2-agonists, anticholinergics, or combination therapy are
chosen dependent on each patient’s individual response to these
treatments as well as the degree of symptom relief and adverse
effects [1].
3.1±0.3
2.3±0.2
Beta2-agonists
In general, beta2-agonists [12_TD$IF]may cause tachycardia, hypokalemia,
Control COPD modulation, and depressed heart rate variability [21]. Although
Smokers Patients
most of the clinical trials of beta-agonists have systematically
(n=20) (n=20)
excluded patients with HF, the adverse effects of long-acting but
not short-acting inhaled beta-agonist on HF would be minimized
for several reasons. The affinity for beta-receptor of the latest long-
acting beta2-agonist is enough selective not to affect the heart.
Standard metered-dose, long-acting beta2-agonist inhalers pro-
duce only minor systemic and biochemical abnormalities. To
compare to long-acting bronchodilator, short-acting broncho-
dilator is often used in an as-needed manner which may lead to
over-use.
Anticholinergics
The anticholinergic agents principally act as a bronchodilator
via the cholinergic system. The results of the UPLIFT study show
that tiotropium improved lung function, quality of life, and
exacerbations during a 4-year period in patients with COPD
[24]. POET-COPD has reported that tiotropium was more effective
than salmeterol in preventing exacerbations and has demonstrated
relatively neutral safety outcomes in 7376 patients with moderate-
to-very-severe COPD [25]. The [13_TD$IF]treatment [14_TD$IF]with a long-acting
anticholinergic agent would appear to be the appropriate strategy
for patients with HF until further clinical trial information is available.
Corticosteroids
The effects of corticosteroids on pulmonary and systemic
inflammation in patients with COPD are controversial. Oral
steroids can produce intense sodium retention, potentially leading
to worsening of HF, and thus should be considered carefully.
Inhaled steroids appear to have a relatively neutral safety profile,
but their use in the management of stable COPD should be limited.
Others
Non-invasive ventilation, added to conventional therapy,
improves the outcome of patients with acute respiratory failure
due to hypercapnic exacerbation of COPD or HF in situations of
acute pulmonary edema. Pulmonary rehabilitation can stabilize
and/or reverse several features of skeletal muscle dysfunction in
HF patients with COPD.
The treatment of HF
Acute HF should be treated according to usual HF guidelines
regardless of COPD because there is no evidence to support an
alternative management strategy [2]. There is also little evidence
that chronic HF should be treated differently in the presence of
COPD. [15_TD$IF]Unfortunately, among the comorbid conditions commonly
 [(Fig._5)TD$IG]
K. Onishi / Journal of Cardiology 70 (2017) 128–134 133

associated with HF, COPD is most often advocated for nonadher-

ence to therapeutic guidelines, especially BBs.

Diuretics

Diuretics are recommended to reduce the signs and symptoms

of congestion in HF patients. Loop diuretics can be used safety and
efficiently for most patients with HF and COPD even though
diuretics have limited data because of the limited enrollment of HF
patients in COPD trials. Overuse of diuretics may cause metabolic
alkalosis which can suppress the respiratory drive. The dose of the
diuretic must be adjusted according to the individual needs over
time with the lowest achievable dose.

ACE inhibitors

ACEIs have been shown to reduce symptoms, improve quality of

life and functional capacity, prolong survival, and prevent disease
progression in HF patients [2]. ACEIs have potential effects on Fig. 5. Differential diagnosis of heart failure (HF) and COPD. BNP, B-type natriuretic
peptide; COPD, chronic obstructive pulmonary disease; FEV1%, the ratio of forced
pulmonary and pulmonary arterial inflammation related to the
expiratory volume in 1 s (FEV1) to forced vital capacity; [6_TD$IF]HFpEF, heart failure with
constriction of the airway and pulmonary arteries, improvements
in the alveolar membrane gas conductance abnormality, respira-
[(Fig._6)TD$IG]
preserved ejection fraction; LVD, left ventricular dysfunction.

tory drive and respiratory muscle function, the efficacy of

peripheral use of oxygen, and improvements in skeletal muscle Beneficial effects Unfavorable effects
functional capacity [26]. ACEIs must be initiated and up-titrated to Mortality LV contractility (early phase)
the maximum tolerated dose in order to achieve adequate Morbidity Bradycardia
Exercise tolerance General fatigue or weakness
inhibition of the renin–angiotensin–aldosterone system. Hospitalization Exacerbated AV block
HF LV remodeling Hypotension
LV contractility (late phase)
Beta-blockers Arrhythmia
Ischemia
BBs reduce symptoms, improve functional capacity, reduce Heart rate

mortality and morbidity, and reverse ventricular remodeling in
patients with HF treated with ACEIs [2]. There is consensus that
BBs and ACEIs are complementary, and recommended to be started
together in patients with HF. However, BBs are underprescribed in
HF patients with COPD because of the concern that BBs might
trigger bronchoconstriction leading to the worsening of symptoms
of COPD. However, BBs are only relatively contraindicated in
asthma according to the 2015 GINA global strategy report, but not
in COPD [27]. In fact, beta-1 selective BBs are well tolerated in most
COPD patients with the development of agents with extremely
high affinity for beta-1 adrenergic receptors over beta-2 adrenergic
receptors (bisoprolol, or metoprolol succinate). Switching from
beta-1 selective BBs such as bisoprolol to the nonselective BB
carvedilol results in significant reduction in airway function [28].
Attention has been paid to the beneficial effects of BBs on COPD.
In a subgroup analysis of 2712 patients from a cohort who had
serial spirometry measures over 4 years, there was no deleterious
effect of long-term BB use (88% were cardioselective) on FEV1,
even among patients with severe COPD taking triple inhaled
therapy, and BBs reduced AECOPD and mortality [29]. Large
population-based analyses have shown that BBs reduced the risk of
mortality in patients with COPD and concomitant HF after
propensity matching. Almost all large clinical trials evaluating
the effect of BBs on HF excluded patients with COPD. In MERIT-HF
study in which 5.3% of HF patients enrolled into this study had
documented COPD, the incidence of respiratory adverse events
was similar in the metoprolol and placebo groups [30].
Thus, BBs reduce mortality and exacerbations in patients with
COPD due to improved cardiac function, reduced heart rate, anti-
arrhythmic effects, protection against sympathetic drive, protec-
tion against adverse effect of short-acting beta2-agonists, inhibi-
tion of endothelin-1 release, reduction in circulating pro-
inflammatory cytokines, inhibition of neutrophil chemotaxis and
respiratory burst, and reduction in goblet cell number and mucus
release (Fig. [16_TD$IF]6) [4,31]. Patients with COPD often have high resting
Hypoxic sympathetic drive Bronchoconstriction
Adverse effects of beta2-agonist Airway sensitivity
Endothelin-1 release
COPD Circulating pro-inflammatory cytokines
Neutrophil chemotaxis
Goblet cell number and mucus release
Fig. 6. Beneficial and unfavorable effects of beta-blockers on heart failure (HF) and
COPD. AV, atrioventricular; COPD, chronic obstructive pulmonary disease; LV, left
ventricular.
heart rates, and a decrease in them is associated with a reduction in
overall mortality, which was shown in the study comparing If
inhibitor ivabradine to placebo [32][4_TD$IF].
At present, BBs should be aggressively initiated in clinically
stable patients with HF accompanied with COPD. Low doses of
cardioselective BBs should be started combined with close
monitoring for signs of airway obstruction such as wheezing
and gradually up-titrated to the maximum tolerated dose. Mild
deterioration in pulmonary function and symptoms should not
lead to prompt discontinuation because BBs are essential for both
HF and COPD. If symptoms worsen, a reduction of the dosage or
withdrawal may be necessary. Inhaled beta2-agonists should be
administered as required in patients with COPD and HF, who are
treated with BBs.
Summary
COPD is a frequent comorbidity in CVD, and is related to
mortality as well as reduced physical activity and exercise
tolerance. The diagnosis of COPD in patients with HF is challenging
134 K. Onishi / Journal of Cardiology 70 (2017) 128–134
due to overlap in symptoms and signs, but also problems in the
interpretation of spirometry. Treatments for HF accompanied with
COPD should be targeted toward maximizing evidence-based
dosages. The majority of HF patients with COPD can safely tolerate
BBs. Encouraging appropriate and aggressive treatment for HF and
COPD together should be recommended to improve quality of life
and mortality in HF patients with COPD.
Funding
None.
Disclosures
None.
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