Intern Emerg Med (2016) 11:519–527

DOI 10.1007/s11739-015-1319-0

IM - ORIGINAL

Prognostic implications of heart failure with preserved ejection

fraction in patients with an exacerbation of chronic obstructive
pulmonary disease
Robert Marcun1 • Ivan Stankovic2 • Radosav Vidakovic2 • Jerneja Farkas3 •
Sasa Kadivec1 • Biljana Putnikovic2 • Ivan Ilic2 • Aleksandar N. Neskovic2 •
Mitja Lainscak4,5

Received: 14 June 2015 / Accepted: 28 August 2015 / Published online: 30 September 2015
Ó SIMI 2015

Abstract Diagnosing heart failure with preserved ejec- N-terminal pro B-type natriuretic peptide (NT-proBNP)
tion fraction (HFpEF) in patients with chronic obstructive levels (HR 2.79, CI 1.12–6.98) were independent predic-
pulmonary disease (COPD) is difficult due to overlapping tors of long-term survival. HFpEF is present in one-fifth of
pathophysiological pathways, risk factors and clinical patients with exacerbated COPD. Non-invasively diag-
presentations. We investigated the prevalence and prog- nosed HFpEF may not be an independent predictor of all-
nostic implications of coexisting HFpEF in patients hos- cause mortality. Elevated NT-proBNP levels and very
pitalized for acute exacerbation of COPD. A total of 116 severe COPD were independently associated with unfa-
consecutive patients with an acute exacerbation of COPD vorable overall survival.
were evaluated for HFpEF and followed for an average
period of 22 ± 9 months for the occurrence of death from Keywords Chronic obstructive pulmonary disease 
any cause. HFpEF was diagnosed in 22 (19 %) patients Heart failure with preserved ejection fraction  Prevalence 
with COPD, who were older, and also had higher LV mass, Outcome
left atrial size, and mitral E/Ea ratio than those without
HFpEF (p \ 0.05 for all comparisons). HFpEF was not Abbreviations
independently associated with all-cause mortality [hazard COPD Chronic obstructive pulmonary disease
ratio (HR) 1.07, 95 % confidence interval (CI) 0.44–2.62]. HF Heart failure
Global initiative for chronic Obstructive Lung Disease HFpEF Heart failure with preserved ejection
(GOLD) stage (IV vs. I–III, HR 2.37, CI 1.23–4.59) and fraction
FEV1 Forced expiratory volume in 1 s
FVC Forced vital capacity
& Ivan Stankovic GOLD Global initiative on obstructive lung disease
future.ivan@gmail.com LV Left ventricle
Mitja Lainscak LVEF Left ventricular ejection fraction
mitja.lainscak@guest.arnes.si NT-proBNP N-terminal pro B-type natriuretic peptide
1
University Clinic of Respiratory and Allergic Diseases
levels
Golnik, Golnik, Slovenia
2
Department of Cardiology, Faculty of Medicine, Clinical
Hospital Center Zemun, University of Belgrade, Belgrade,
Serbia Introduction
3
Chair of Public Health, Faculty of Medicine, University of
Ljubljana, Ljubljana, Slovenia Chronic obstructive pulmonary disease (COPD) and heart
4
Department of Cardiology, General Hospital Celje, Oblakova failure (HF) are global epidemics associated with unfa-
cesta 5, 3000 Celje, Slovenia vorable long-term prognosis [1–3]. The prevalence of
5
Chair of Internal Medicine, Faculty of Medicine, University COPD is greater in patients with HF than the general
of Ljubljana, Ljubljana, Slovenia population, and a considerable number of patients are

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affected by both diseases [4]. However, diagnosing con-
comitant HF in patients with COPD is often challenging
due to overlapping pathophysiological pathways, risk
factors and clinical presentations [4]. In the general
population, approximately half of the patients with HF
have a preserved left ventricular (LV) ejection fraction
(HFpEF) and abnormal LV diastolic function, as evi-
denced by invasive hemodynamic assessment, Doppler
echocardiography or elevated natriuretic peptides levels.
On the other hand, recent studies have suggested that
several non-diastolic abnormalities in cardiovascular
function might play a role in the pathophysiology of
HFpEF, and also give rise to the speculation that HFpEF
does not represent a specific disease entity, but rather
merely describes elderly breathless patients with multiple
co-morbidities [5].
Diagnosing HFpEF and assessing its prognostic
importance may, therefore, be even more demanding in
COPD patients due to relatively ambiguous diagnostic
criteria and clustering of age-related co-morbidities in a
typical patient [6, 7]. Patients with COPD may be mis-
diagnosed with HFpEF owing to challenges in non-inva-
sive assessment of LV diastolic function, but also due to
increased levels of natriuretic peptides associated with
conditions other than left-sided heart failure [8, 9]. Fur-
thermore, a number of frequent co-morbidities in patients
with COPD, including diabetes mellitus, hypertension,
coronary artery disease, chronic kidney disease and obe-
sity, are also known risk factors for HFpEF, and may
obscure the relationship of COPD, HFpEF and long-term
survival [10].
In this prospective observational study, we used guide-
line-proposed criteria for HFpEF to investigate the preva-
lence and prognostic implications of HFpEF in patients
hospitalized due to an acute exacerbation of COPD.
Methods
We prospectively enrolled 127 consecutive patients (mean
age 70 ± 10 years, 70 % male) with an exacerbation of
COPD (31 % with first exacerbation), admitted to
University Clinic of Respiratory and Allergic Diseases
Golnik, Slovenia, between December 2009 and October
2011 [11, 12]. There were no prespecified exclusion cri-
teria. Baseline demographics and clinical data were
gathered and a physical examination performed by
attending physicians. The diagnosis of COPD was made
according to European Respiratory Society guidelines,
while the Global Initiative on Obstructive Lung Disease
(GOLD) staging system was used to assess the severity of
COPD [1, 2].
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Intern Emerg Med (2016) 11:519–527
Echocardiographic examination
Standard echocardiographic examination including blood
flow and tissue Doppler imaging (TDI) was performed
within 48 h of admission using Vivid 7 scanner (GE
Healthcare, Wauwatosa, USA). For all acquisitions, image
loops of three consecutive heart cycles (five in patients
with atrial fibrillation) were digitally stored for further off-
line analysis by an EchoPac workstation (GE Healthcare,
Wauwatosa, USA). All measurements were made accord-
ing to American Society of Echocardiography recommen-
dations by a single experienced echocardiographer (RM)
blinded to all other data. [13] Left ventricular mass was
estimated using the Devereux formula [14]. Depending on
the image quality, left ventricular ejection fraction (LVEF)
was assessed using the biplane Simpson’s method, the
Teichholz formula or visual estimation. Transmitral peak
early (E) and atrial (A) velocities, and E-wave deceleration
time were measured, and the E/A velocity ratio was cal-
culated from the pulsed-Doppler recordings made in the
apical four-chamber view (A4C), with the sample volume
placed at the mitral valve leaflet tips during diastole. The
tissue Doppler recordings were acquired in the A4C view,
with the pulse-wave Doppler sample volume placed at the
septal and lateral side of mitral annulus. The ratio of mitral
peak velocity of early filling to early diastolic mitral
annular velocity (E/e0 ) was calculated using the average of
the septal and the lateral e0 wave velocities.
Based on the E/e0 ratio, patients were divided into three
groups: a group with normal LV filling pressures (E/
e0 B 8), a group with elevated LV filling pressures (E/
e0 C 15), and an intermediate group (E/e0 9–14) [15]. Right
ventricular (RV) systolic function was assessed by mea-
suring tricuspid annular plane systolic excursion (TAPSE),
while RV systolic pressure was estimated by measuring the
peak velocity of the tricuspid regurgitant signal with con-
tinuous-wave Doppler, and adding the pressure in the right
atrium [16]. The latter was estimated by measuring the
respiratory variation in size of the inferior vena cava.
N-terminal pro B-type natriuretic peptide (NT-
proBNP) measurement
Venous blood was collected in standard blood collection
tubes containing EDTA. Samples were maintained at 4 °C
for B4 h and then centrifuged for 15 min at 4 °C. Plasma
was then removed and frozen at -80 °C until assays were
performed. Serum NT-proBNP was measured at admission
using electrochemiluminescence immunoassay (ECLIA)
method (Elecsys 2010, Roche Diagnostics, Mannheim,
Germany), and levels \300 pg/ml were considered as
normal [3]. The same cutoff was used to create a
Intern Emerg Med (2016) 11:519–527
dichotomous variable to assess the potential association of
NT-proBNP and all-cause mortality. Independent investi-
gators blinded for the results of the other parameters per-
formed echocardiography and laboratory investigations.
Criteria for the diagnosis of HFpEF
Diagnosis of HFpEF was made according to the European
Association of Cardiology (ESC) consensus statement
criteria [6]. In brief, in addition to the presence of heart
failure symptoms and normal or mildly reduced LVEF
([50 %), the evidence of abnormal LV relaxation, filling,
diastolic distensibility and diastolic stiffness was obliga-
tory for establishing the HFpEF diagnosis. The latter cri-
terion was considered fulfilled if the patient had either E/
e0 C 15 or NT-proBNP [300 pg/ml and E/e0 ratio in the
range of 9–14. For patients with unobtainable E/e0 due to
poor quality of tissue Doppler recordings, an LV wall mass
index [149 g/m2 ([122 g/m2 for female) was considered
sufficient for the diagnosis of HFpEF if NT-proBNP levels
were also elevated [6]. Patients were followed for an
average period of 22 ± 9 months for the occurrence of
death from any cause. Data on mortality were collected
from medical records, by contacting the patients’ general
practitioner or relatives, and from Central population
Registry.
Lung function testing
Forced expiratory volume in 1 s (FEV1), forced vital
capacity (FVC) and single breath-hold carbon monoxide
diffusing capacity (DLCO) were measured in all patients.
Statistical analysis
Continuous data are expressed as mean ± standard devi-
ation (SD) or median and interquartile range while cate-
gorical data were summarized by their observed
frequencies and percentages. Normally distributed data
were compared between groups using unpaired t test for
continuous variables and Fisher’s exact test for categori-
cal variables. Levels of NT-proBNP exhibited a skewed
distribution, and were transformed, using the natural
logarithms, before t tests and linear regression analysis
were conducted, to satisfy the prerequisite assumptions of
normality. Linear regression analysis was used to evaluate
relations between E/e0 ratio, TAPSE and NT-proBNP
levels. Survival rates were assessed with Kaplan–Meier
analysis, while differences in survival were compared
between groups by a log-rank test. Univariate Cox
regression was used to assess the effect of demographic,
echocardiographic, biomarker and clinical parameters on
521
long-term survival. In addition, a multivariable Cox
regression model comprising the predictors with p \ 0.10
in univariate analysis was used to assess independent
predictors of all-cause mortality. All statistical tests were
two tailed, and a p value \0.05 was considered signifi-
cant. Statistical analysis was performed using commer-
cially available software (PASW Statistics 18, version 18,
SPSS, Inc., and Chicago, IL, USA).
Results
From the 127 consecutive patients, 11 patients (9 %) were
excluded from further analyses due to reduced LVEF. Of
the remaining 116 patients, 22 patients (19 %) met the
criteria for HFpEF. Characteristics of the study population
are summarized in Table 1. Our study population was
comprised of elderly COPD patients (mean age
70 ± 10 years), more frequently male (78 %), previously
often diagnosed with arterial hypertension (43 %), diabetes
mellitus (20 %) and atrial fibrillation (16 %). Patients with
coexisting HFpEF and COPD were older, more frequently
had arterial hypertension and atrial fibrillation than those
without HFpEF, and were more often receiving diuretics,
beta-blockers, angiotensin-converting-enzyme inhibitors
(ACEi)/angiotensin II receptor blockers (ARB) and cal-
cium channel blockers.
Echocardiographic data are shown in Table 2. Patients
with HFpEF and COPD had similar LV end-diastolic
dimension and LVEF as those without HFpEF, but LV
mass and indexed LA diameter and area were greater in
patients with HFpEF, as were the mitral E-wave velocity
and E/e0 ratio. Right ventricular end-diastolic dimension
and RV systolic pressure estimate were also higher in
patients with coexisting COPD and HFpEF than in those
with COPD alone, while TAPSE showed similar values in
both groups. However, RV systolic dysfunction, as indi-
cated by TAPSE \16 mm, was observed in 15 (13 %)
patients who had higher NT-proBNP levels than patients
with normal RV systolic function (log-transformed NT-
proBNP values: 6.9 ± 1.4 vs. 5.9 ± 1.56 pg/ml, respec-
tively; p = 0.025).
Patients with HFpEF also had higher levels of NT-
proBNP than those without HFpEF (log-transformed NT-
proBNP values: 8.0 ± 0.9 vs. 5.6 ± 1.3 pg/ml, respec-
tively; p \ 0.001). NT-proBNP levels above the cutoff
point were observed in 21 patients (95 %) with HFpEF and
COPD versus 39 patients (41 %) with COPD, but without
HFpEF (p \ 0.001). Baseline clinical and echocardio-
graphic data of these two subgroups of patients with ele-
vated NT-proBNP levels are shown in Table 3. Patients
with elevated NT-proBNP levels, but no HFpEF had lower
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Table 1 Characteristics of
All patients (n = 116) HFpEF (n = 22) No HFpEF (n = 94) p value
study population
Age (years) 70 ± 10 75 ± 10 69 ± 10 0.009
Female sex, n (%) 37 (32) 5 (23) 32 (34) 0.446
Hypertension, n (%) 50 (43) 15 (68) 35 (37) 0.012
Atrial fibrillation, n (%) 18 (16) 11 (50) 7 (7) \0.001
Diabetes mellitus, n (%) 23 (20) 6 (27) 17 (18) 0.375
Dyslipidemia, n (%) 10 (9) 3 (14) 7 (7) 0.287
Smoking, n (%) 26 (22) 4 (18) 22 (23) 0.779
NT-proBNP median (IQR) 377 (123–1336) 3755 219 (106–549) \0.001
(pg/ml) (1862–4560)
DLCO (% predicted) 57 ± 17 55 ± 15 58 ± 18 0.596
FVC (% predicted) 61 ± 20 55 ± 18 62 ± 20 0.145
FEV1 (% predicted) 35 ± 15 36 ± 14 34 ± 15 0.629
Chronic therapy
Diuretics, n (%) 25 (22) 17 (77) 8 (8) \0.001
ACEi/ARB, n (%) 56 (48) 17 (77) 39 (42) 0.004
Beta-blockers (%) 22 (19) 10 (46) 12 (13) 0.001
Calcium antagonists, n (%) 18 (16) 10 (46) 8 (9) \0.001
Statins, n (%) 22 (19) 6 (27) 16 (17) 0.363
LTOT, n (%) 22 (19) 5 (23) 17 (18) 0.563
ACEi/ARB Angiotensin-converting-enzyme inhibitor/Angiotensin II receptor blocker, DLCO diffusing
capacity of the lung for carbon monoxide, FEV1 forced expiratory volume in 1 s, FVC forced vital
capacity, HFpEF heart failure with preserved ejection fraction, NT-proBNP N-terminal pro B-type natri-
uretic peptide, IQR interquartile range, LTOT long-term oxygen therapy

Table 2 Echocardiographic
All patients HFpEF No HFpEF p value
data
(n = 116) (n = 22) (n = 94)

LA size (mm) 40 ± 8 47 ± 7 38 ± 6 \0.001

LA/BSA (mm/m2) 21 ± 4 25 ± 5 20 ± 3 \0.001
LA area/BSA( mm/m2) 11 ± 4 15 ± 5 10 ± 3 \0.001
LVEDD (mm) 51 ± 4 52 ± 5 50 ± 4 0.097
LVEF (%) 65 ± 8 66 ± 7 65 ± 8 0.431
Septum (mm) 9.9 ± 1.2 10.6 ± 1.4 9.2 ± 1.2 0.008
Posterior wall (mm) 10.0 ± 1.3 10.6 ± 1.6 9.8 ± 1.2 0.012
LV mass/BSA (g/m2) 100 ± 21 111 ± 25 97 ± 20 0.006
Mitral E-wave (cm/s) 79 ± 28 104 ± 36 73 ± 22 \0.001
E-wave deceleration time 222 ± 63 229 ± 79 221 ± 59 0.569
(ms)
Mitral E/A ratio 0.9 ± 0.4 1.0 ± 0.6 0.9 ± 0.4 0.225
0
Septal e wave (cm/s) 8.1 ± 2.8 10.9 ± 4.7 8.1 ± 2.8 0.638
Lateral e0 wave (cm/s) 9.2 ± 3.6 10 ± 36 8.7 ± 3.1 0.055
Mitral E/e0 (average) 9.0 ± 2.5 12.2 ± 7.1 9.2 ± 2.5 0.047
RVEDD (mm) 32 ± 7 39 ± 8 31 ± 5 \0.001
RVSP (mmHg) 70 ± 10 48 ± 16 45 ± 16 0.009
TAPSE (mm) 20 ± 4 19 ± 5 20 ± 3 0.409
HFpEF heart failure with preserved ejection fraction, LA left atrium, BSA body surface area, LVEDD left
ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, RVEDD right ventricular end-
diastolic diameter, RVSP right ventricular systolic pressure, TAPSE tricuspid annular plane systolic
excursion

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Table 3 Characteristics of
Elevated NT-proBNP & p value
patients with elevated NT-
proBNP levels with respect to HFpEF (n = 21) No HFpEF (n = 39)
the presence of HFpEF
Age (years) 74 ± 8 75 ± 10 0.515
Female sex, n (%) 4 (19) 10 (26) 0.751
Hypertension, n (%) 14 (67) 11 (28) 0.006
Atrial fibrillation, n (%) 11 (52) 4 (10) 0.001
NT-proBNP median (IQR) (pg/ml) 4863 (1862–4560) 1996 (435–1630) \0.001*
DLCO, % predicted 56 ± 16 54 ± 16 0.804
FVC (% predicted) 55 ± 18 58 ± 19 0.606
FEV1 (% predicted) 37 ± 14 32 ± 12 0.202
LA/BSA (mm/m2) 25 ± 5 21 ± 3 0.001
LA area/BSA (mm/m2) 15 ± 5 11 ± 2 0.001
LVEDD (mm) 52 ± 5 51 ± 4 0.469
Mitral E/e0 (average) 12.1 ± 7.3 10.1 ± 2.7 0.253
RVEDD (mm) 39 ± 8 32 ± 6 \0.001
RVSP (mmHg) 48 ± 16 46 ± 18 0.694
TAPSE (mm) 19 ± 5 19 ± 3 0.599
BSA body surface area, DLCO diffusing capacity of the lung for carbon monoxide, FEV1 forced expiratory
volume in 1 s, FVC forced vital capacity, IQR interquartile range, HFpEF heart failure with preserved
ejection fraction, LA left atrium, LVEDD left ventricular end-diastolic diameter, NT-proBNP N-terminal
pro B-type natriuretic peptide, RVEDD right ventricular end-diastolic diameter, RVSP right ventricular
systolic pressure, TAPSE tricuspid annular plane systolic excursion
* From the t test, after values being transformed using the natural logarithms

prevalence of arterial hypertension and atrial fibrillation,

NT-proBNP ≤300 pg/ml
smaller LA diameters and LA areas and lower NT-proBNP
levels than those with HFpEF. The mitral E/e0 ratio,
TAPSE and RVSP were similar in both groups.
Univariate linear regression analysis revealed that both
E/e0 ratio (B = 0.151, 95 % CI 0.082–0.221, p \ 0.001)
and TAPSE (B = -x00.087, 95 % CI x0.172 to -x0.002,
p = 0.045) were associated with NT-proBNP levels.
Kaplan–Meier analysis showed that patients with coex-
NT-proBNP >300 pg/ml
isting HFpEF and COPD had worse long-term survival
than those without HFpEF (log rank p = 0.002). In addi-
tion, patients with normal E/e0 ratio (B8) had a signifi-
cantly better long-term survival than both patients with
intermediate E/e0 ratio (9–15) and patients with severe LV n=113
diastolic dysfunction, as indicated by the E/e0 ratio C15 Log rank P<0.001
(log rank p \ 0.05). Likewise, patients with NT-proBNP
levels above the cutoff value of 300 pg/ml had significantly
worse survival than those with NT-proBNP levels within
normal limits (log rank p \ 0.001, Fig. 1). Univariate
NT-proBNP ≤300 pg/ml
regression analysis revealed that HFpEF, age, NT-proBNP,
53 52 51 47 31 7 0
E/e0 ratio, very severe GOLD stage and diuretic therapy
NT-proBNP >300 pg/ml
were associated with all-cause mortality (Table 4). How- 60 47 40 35 25 4 0
ever, in multivariate analysis by the Cox proportional
hazard model, GOLD stage and NT-proBNP remained Fig. 1 Long-term survival with respect to the N-terminal pro B-type
natriuretic peptide (NT-proBNP) levels. Patients with NT-proBNP
independently associated with long-term all-cause mortal-
B300 pg/ml have a better long-term survival than those with NT-
ity, whereas HFpEF did not. proBNP [300 pg/ml

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Table 4 Univariate and

Univariate Multivariable
multivariate regression analyses
to identify predictors of all- HR (95 % CI) P value HR (95 % CI) p value
cause mortality
HFpEF 2.782 (1.421–5.446) 0.003 1.071 (0.437–2.621) 0.881
Male sex 1.924 (0.881–4.199) 0.100 – –
Age 1.070 (1.029–1.112) 0.001 1.036 (0.992–1.082) 0.113
Arterial hypertension 1.201 (0.635–2.271) 0.573 – –
Atrial fibrillation 1.859 (0.879–3.931) 0.105 – –
NT-proBNPa 4.301 (1.969–9.393) \0.001 2.792 (1.116–6.984) 0.028
Mitral E/e0 ratio 1.089 (1.029–1.152) 0.003 1.056 (0.984–1.135) 0.132
TAPSE 0.935 (0.848–1.032) 0.182 – –
RVSP 1.014 (0.993–1.035) 0.198 – –
GOLD stage (IV vs. I–III) 2.043 (1.073–3.890) 0.030 2.374 (1.228–4.588) 0.010
Beta-blockers (yes/no) 1.564 (0.759–3.221) 0.225 – –
ACEi/ARBs (yes/no) 1.271 (0.672–2.403) 0.461 – –
Diuretics (yes/no) 2.780 (1.434–5.391) 0.002 1.226 (0.508–2.959) 0.650
Calcium antagonists (yes/no) 1.212 (0.534–2.754) 0.646 – –
ACEi/ARB Angiotensin-converting-enzyme inhibitor/Angiotensin II receptor blocker, CI confidence
interval, HR hazard ratio, HFpEF heart failure with preserved ejection fraction, NT-proBNP N-terminal pro
B-type natriuretic peptide, TAPSE tricuspid annular plane systolic excursion, RVSP right ventricular sys-
tolic pressure, GOLD Global Initiative on Obstructive Lung Disease
a
As a dichotomous variable (with a predefined cutoff of 300 pg/ml)

Discussion
In our cohort of patients hospitalized due to newly diag-
nosed or worsening COPD, HFpEF was diagnosed in 19 %
of patients who were older and also had higher LV mass,
left atrial size and mitral E/Ea ratio than those without
HFpEF. Very severe COPD and elevated NT-proBNP, but
not HFpEF were independent predictors of all-cause mor-
tality (Table 4).
Cardiovascular co-morbidities are common in patients
with COPD, influencing approximately a half of all hospi-
talizations and 20–30 % of all deaths [17–20]. It has also
been shown that subclinical LV filling impairment is fre-
quently found in COPD patients at an earlier stage of the
disease even in the absence of any other cardiovascular
dysfunction [21]. Coexistence of both HF and COPD fre-
quently delays the diagnosis of each other, which may have
therapeutic and prognostic implications. In a series of 405
stable COPD patients aged C65 years, one-fifth have
coexisting HF, and half of them with preserved EF [22].
During the mean follow-up of 4.2 years, mortality risk of
these patients is twofold higher compared to those without
HF [23]. In another study comparing cardiovascular and
pulmonary event-free survival of patients with coexisting
COPD and HF with reduced or preserved ejection fraction,
no significant difference during 3-year follow-up is found
[10]. Prior studies report a variable prevalence of LV
diastolic dysfunction, ranging from 30 to 90 %, depending
on echocardiographic criteria [24–28]. By contrast, our
study did not aim to identify patients with isolated with LV
diastolic dysfunction, but those with definite diagnosis of
HFpEF according to guideline-proposed criteria [6]. The
prevalence of HFpEF in patients with COPD also varied
considerably in the previous reports, which can be at least
partially explained by different inclusion criteria and
diagnostic algorithms for HFpEF. [10, 22] We did not apply
any preselection criteria and applied strict guideline-pro-
posed criteria for diagnosing HFpEF. Although present in
almost one-fifth of the study population, HFpEF was not
identified as an independent predictor of all-cause mortality.
There are several pathophysiologic mechanisms involved
in developing LV diastolic dysfunction and HFpEF in COPD.
One of the main COPD characteristics, systemic inflamma-
tion, can promote coronary atherosclerosis with subsequent
ischemia and increase in myocardial stiffness [29]. Also, the
presence of pulmonary hypertension due to chronic lung
hyperinflation, hypoxia, and pulmonary capillary vasocon-
striction can promote the development of cor pulmonale with
diastolic interventricular septal flattening or bulging towards
left ventricle, altering its filling and compliance [30].
Nonetheless, chronic lung hyperinflation increases negative
intrathoracic pressure, with a consequent LV preload decrease
and afterload increase, both leading to subendocardial ische-
mia [30]. It should also be noted that our patients were
assessed for HFpEF during the hospitalization for clinical
worsening of COPD, and that therefore it is possible that the
results would have been different if the assessment had taken
place during the stable phase of the disease.

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Being typically higher in patients with worse outcome,
natriuretic peptides have been used for screening purposes,
and for establishing the diagnosis and prognosis of HF [31]. In
the general patient population, N-terminal pro B-type natri-
uretic peptide accurately detects the presence of isolated LV
diastolic dysfunction in symptomatic patients, correlates
strongly with indices of LV filling pressure as determined by
invasive measurements and tissue Doppler imaging, and is an
useful tool to rule out non-cardiac origin of reduced exercise
tolerance [32]. In addition, natriuretic peptides have an
established role in algorithms for distinguishing the cause of
dyspnea in patients with known COPD [33]. These biomark-
ers may accurately identify the exacerbation trigger, and
provide both short- and long-term prognostic information of
hospitalized patients. Wang et al. show that COPD patients
with HF have significantly higher level of NT-proBNP than
those without HF or stable controls [34]. They report that NT-
proBNP values of 935 pg/ml may serve as the optimal cutoff
for identifying HF in COPD patients, with an excellent sen-
sitivity of 94 % and negative predictive value of 98 %.
Almost the same cutoff value of NT-proBNP (1000 pg/ml),
associated with a sensitivity of 94 % and negative predictive
value of 94 %, has been proposed by Abroug et al. [24]. In
subjects admitted to the hospital with an acute exacerbation of
COPD, elevated NT-proBNP levels are associated with a
significantly higher 30-day mortality [35]. We also recently
reported that increased NT-proBNP levels, measured on
hospital admission of patients with COPD, are associated with
an unfavorable outcome during a 6-month follow-up [36].
The present study, however, gives rise to speculation that
increased NT-proBNP levels in patients with COPD may not
only be attributable to LV diastolic dysfunction, but also to RV
dysfunction. This hypothesis was not directly investigated in
the present study, but is in line with the close relationship of
NT-proBNP, RV dysfunction and patients’ outcomes
observed in the setting of acute pulmonary embolism [37, 38].
Furthermore, elevated NT-proBNP levels in the absence of
HFpEF might also be explained by RV dysfunction or
increased PA pressure—in our study, this subgroup of patients
has a smaller LA size and area (i.e., a surrogate marker of
chronic LA pressure elevation), while RV systolic pressure is
comparable to patients with HFpEF. Therefore, it is not sur-
prising that severe COPD and NT-proBNP levels, both fre-
quently associated with RV dysfunction, are independent
predictors of all-cause mortality, whereas HFpEF is not.
Study limitations
We investigated a relationship of HFpEF and all-cause
mortality, while it would also be of interest to assess the
association between HFpEF and cardiovascular mortality.
Finally, invasive measurement of LV filling pressures was
525
not a part of the present study and the percentage of
patients meeting guideline-criteria for HFpEF and actually
having elevated LV filling pressures remains unknown.
Conclusions
HFpEF is present in one-fifth of patients with exacerbated
COPD. Non-invasive detection of HFpEF may guide more
appropriate treatment of these patients, but may not be an
independent predictor of all-cause mortality. Elevated NT-
proBNP levels and very severe GOLD stage are indepen-
dently associated with an unfavorable overall survival.
Acknowledgments BP and ANN are partially supported by the
Grant No. 175099 of the Ministry of Science, Republic of Serbia.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict
of interest.
Statement of human and animal rights The study was conducted
in accordance with the Declaration of Helsinki Principles, it was
approved by the National Ethics Committee.
Informed consent Written informed consent was obtained from all
patients.
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