Pulmonary dysfunction and disease

Advances in Experimental Medicine and Biology 934
Neuroscience and Respiration

Mieczyslaw Pokorski Editor

Pulmonary
Dysfunction
and Disease


Advances in Experimental Medicine
and Biology
Neuroscience and Respiration

Volume 934
Editorial Board
Irun R. Cohen, The Weizmann Institute of Science, Rehovot, Israel
N.S. Abel Lajtha, Kline Institute for Psychiatric Research, Orangeburg, NY, USA
John D. Lambris, University of Pennsylvania, Philadelphia, PA, USA
Rodolfo Paoletti, University of Milan, Milan, Italy
Subseries Editor
Mieczyslaw Pokorski


More information about this series at />

Mieczyslaw Pokorski
Editor

Pulmonary Dysfunction
and Disease

Editor
Mieczyslaw Pokorski
Public Higher Medical Professional School in Opole
Institute of Nursing
Opole, Poland

ISSN 0065-2598
ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-319-42009-7
ISBN 978-3-319-42010-3 (eBook)
DOI 10.1007/978-3-319-42010-3
Library of Congress Control Number: 2016948844
# Springer International Publishing Switzerland 2016
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Preface

The book series Neuroscience and Respiration presents contributions by
expert researchers and clinicians in the field of pulmonary disorders. The
chapters provide timely overviews of contentious issues or recent advances
in the diagnosis, classification, and treatment of the entire range of pulmonary disorders, both acute and chronic. The texts are thought as a merger of
basic and clinical research dealing with respiratory medicine, neural and
chemical regulation of respiration, and the interactive relationship between
respiration and other neurobiological systems such as cardiovascular function or the mind-to-body connection. The authors focus on the leading-edge
therapeutic concepts, methodologies, and innovative treatments. Pharmacotherapy is always in the focus of respiratory research. The action and
pharmacology of existing drugs and the development and evaluation of
new agents are the heady area of research. Practical, data-driven options to
manage patients will be considered. New research is presented regarding
older drugs, performed from a modern perspective or from a different
pharmacotherapeutic angle. The introduction of new drugs and treatment
approaches in both adults and children also is discussed.
Lung ventilation is ultimately driven by the brain. However, neuropsychological aspects of respiratory disorders are still mostly a matter of conjecture. After decades of misunderstanding and neglect, emotions have been
rediscovered as a powerful modifier or even the probable cause of various
somatic disorders. Today, the link between stress and respiratory health is
undeniable. Scientists accept a powerful psychological connection that can
directly affect our quality of life and health span. Psychological approaches,
by decreasing stress, can play a major role in the development and therapy of
respiratory diseases.
Neuromolecular aspects relating to gene polymorphism and epigenesis,
involving both heritable changes in the nucleotide sequence and functionally
relevant changes to the genome that do not involve a change in the nucleotide
sequence, leading to respiratory disorders will also be tackled. Clinical

advances stemming from molecular and biochemical research are but possible if the research findings are translated into diagnostic tools, therapeutic
procedures, and education, effectively reaching physicians and patients. All
that cannot be achieved without a multidisciplinary, collaborative, bench-tobedside approach involving both researchers and clinicians.
v


vi

Preface

The societal and economic burden of respiratory ailments has been on the
rise worldwide leading to disabilities and shortening of life span. COPD
alone causes more than three million deaths globally each year. Concerted
efforts are required to improve this situation, and part of those efforts are
gaining insights into the underlying mechanisms of disease and staying
abreast with the latest developments in diagnosis and treatment regimens.
It is hoped that the books published in this series will assume a leading role in
the field of respiratory medicine and research and will become a source of
reference and inspiration for future research ideas.
I would like to express my deep gratitude to Mr. Martijn Roelandse and
Ms. Tanja Koppejan from Springer’s Life Sciences Department for their
genuine interest in making this scientific endeavor come through and in the
expert management of the production of this novel book series.
Opole, Poland

Mieczyslaw Pokorski


Contents

Adiponectin and Mortality in Smokers and Non-Smokers
of the Ludwigshafen Risk and Cardiovascular
Health (LURIC) Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Graciela E. Delgado, Rüdiger Siekmeier, Winfried Ma¨rz,
and Marcus E. Kleber
Heart Rate Variability and Arrhythmic Burden
in Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. Witte, J.U. Meyer zur Heide genannt Meyer-Arend, R. Andrie´,
J.W. Schrickel, C. Hammerstingl, J.O. Schwab, G. Nickenig,
D. Skowasch, and C. Pizarro

1

9

Cardiac Vagal Control and Depressive Symptoms
in Response to Negative Emotional Stress . . . . . . . . . . . . . . . . . . . . 23
I. Tonhajzerova, Z. Visnovcova, A. Mestanikova, A. Jurko,
and M. Mestanik
Effect of Simulated Microgravity and Lunar Gravity on Human
Inspiratory Muscle Function: ‘Selena-T’ 2015 Study . . . . . . . . . . . 31
M.O. Segizbaeva, N.P. Aleksandrova, Z.A. Donina,
E.V. Baranova, V.P. Katuntsev, G.G. Tarasenkov,
and V.M. Baranov
Airway Evaluation with Multidetector Computed Tomography
Post-Processing Methods in Asthmatic Patients . . . . . . . . . . . . . . . 41
Mateusz Patyk, Andrzej Obojski, Łukasz Gojny, Bernard Panaszek,
and Urszula Zaleska-Dorobisz
Genotyping of EGFR Mutations from Bronchial Cytological
Specimens in Slovakian Lung Cancer Patients . . . . . . . . . . . . . . . . 49

K. Baluchova, M. Zahradnikova, P. Bakes, S. Trubacova,
H. Novosadova, E. Halasova, I. Majer, and P. Hlavcak
Antiinflammatory Effect of N-Acetylcysteine
Combined with Exogenous Surfactant in Meconium-Induced
Lung Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
P. Mikolka, J. Kopincova, L. Tomcikova Mikusiakova, P. Kosutova,
A. Calkovska, and D. Mokra

vii


viii

Pertussis: History of the Disease and Current
Prevention Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
E. Kuchar, M. Karlikowska-Skwarnik, S. Han, and A. Nitsch-Osuch
Awareness of Influenza and Attitude Toward Influenza
Vaccination Among Medical Students . . . . . . . . . . . . . . . . . . . . . . . 83
A. Banaszkiewicz, E. Talarek, J. S´liwka, F. Kazubski, I. Małecka,
J. Stryczyn´ska-Kazubska, W. Dziubak, and E. Kuchar
Pathogens Causing Upper Respiratory Tract Infections
in Outpatients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
A. Jama-Kmiecik, M. Frej-Ma˛drzak, J. Sarowska,
and I. Choroszy-Kro´l
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Contents


Advs Exp. Medicine, Biology - Neuroscience and Respiration (2016) 25: 1–8

DOI 10.1007/5584_2016_14
# Springer International Publishing Switzerland 2016
Published online: 30 June 2016

Adiponectin and Mortality in Smokers
and Non-Smokers of the Ludwigshafen
Risk and Cardiovascular Health (LURIC)
Study
Graciela E. Delgado, Rüdiger Siekmeier, Winfried Ma¨rz,
and Marcus E. Kleber

Abstract

Cardiovascular diseases (CVD) are an important cause of morbidity and
mortality worldwide. A decreased concentration of adiponectin has been
reported in smokers. The aim of this study was to analyze the effect of
cigarette smoking on the concentration of adiponectin and potassium in
active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen
Risk and Cardiovascular Health (LURIC) Study, and the use of these two
markers for risk prediction. Smoking status was assessed by a questionnaire and measurement of plasma cotinine concentration. The serum
concentration of adiponectin was measured by ELISA. Adiponectin was
binned into tertiles separately for AS and NS and the Cox regression was
used to assess the effect on mortality. There were 777 AS and 1178 NS
among the LURIC patients. Within 10 years (median) of follow-up
221 AS and 302 NS died. In unadjusted analyses, AS had lower

G.E. Delgado
Fifth Department of Medicine, Medical Faculty
Mannheim, Heidelberg University, Heidelberg, Germany
R. Siekmeier

Drug Regulatory Affairs, Pharmaceutical Institute, Bonn
University, Bonn, Germany
W. Ma¨rz
Fifth Department of Medicine, Medical Faculty
Mannheim, Heidelberg University, Heidelberg, Germany
Clinical Institute of Medical and Chemical Laboratory
Diagnostics, Graz Medical University, Graz, Austria
Synlab Academy, Synlab Services LLC, Mannheim,
Germany

M.E. Kleber (*)
Fifth Department of Medicine, Medical Faculty
Mannheim, Heidelberg University, Heidelberg, Germany
Competence Cluster of Nutrition and Cardiovascular
Health (nutriCARD), Halle-Jena-Leipzig, Leipzig,
Germany
Institute of Nutrition, Friedrich Schiller University Jena,
Jena, Germany
Mannheim Institute for Public Health, Social- and
Preventive Medicine, 7-11 Ludolf-Krehl-St, 68167
Mannheim, Germany
e-mail:
1


2

G.E. Delgado et al.

concentrations of adiponectin. However, after adjustment for age and

gender there was no significant difference in adiponectin concentration
between AS and NS. In the Cox regression model adjusted for age and
gender, adiponectin was significantly associated with mortality in AS, but
not in NS, with hazard ratio (95 % CI) of 1.60 (1.14–2.24) comparing the
third with first tertile. In a model further adjusted for the risk factors, such
as diabetes mellitus, hypertension, coronary artery disease, body mass
index, LDL-cholesterol and HDL-cholesterol, adiponectin was significantly associated with mortality with hazard ratio of 1.83 (1.28–2.62)
and 1.56 (1.15–2.11) for AS and NS, respectively. We conclude that
increased adiponectin is a strong and independent predictor of mortality
in both AS and NS. The determination of adiponectin concentration could
be used to identify individuals at increased mortality risk.
Keywords

Adipokines • Biochemical markers • Cardiovascular disease • Smoking •
Mortality • Risk factors

1

Introduction

Cigarette smoking is an addictive habit that has
influenced the behavior of people for more than
four centuries. Worldwide, reductions in the
estimated prevalence of daily smoking have
been observed since 1980, but because of the
population growth, the absolute number of active
smokers has increased from 721 million in 1980
to 967 million in 2012 (Ng et al. 2014). Further, it
was estimated in 2004 that 40 % of children,
33 % of male non-smokers, and 35 % of female

non-smokers are exposed to second-hand smoke
(Oberg et al. 2011). Tobacco continues to be a
major cause of death, leading to 5.7 million
deaths, 6.9 % of years of life lost, and 5.5 %
of disability adjusted life-years (DALYs) (Lim
et al. 2012).
A number of different mechanisms of action
have been proposed that mediate the deleterious
effects of cigarette smoking, e.g., increased
inflammation, increased risk for thrombosis, or
oxidative stress (Ambrose and Barua 2004). In
recent years, it has been reported that smokers
show decreased concentrations of adiponectin
in plasma and tissues (Li et al. 2015; Iwashima
et al. 2005) In vitro experiments have

demonstrated
that
nicotine
significantly
decreases adiponectin secretion by adipocytes,
in part through altering ATP-sensitive potassium
channels (Fan et al. 2015).
Adiponectin is secreted by both white and
brown adipose tissue and circulates in blood in
multimeric forms, such as trimeric, hexameric,
and high molecular mass species (Chakraborti
2015). It has been extensively studied because
of its insulin sensitizing and antiatherogenic
properties. Unlike other adipokines, adiponectin

circulating concentration is decreased not only in
smokers but also in the obese or type 2 diabetics.
Physiological functions of adiponectin are the
following: stimulation of fatty acid (FA) oxidation, reduction of lipid accumulation in muscles,
reduction of plasma FA concentration, and the
improvement of insulin sensitivity. Further,
adiponectin inhibits macrophage activation and
foam cell accumulation, and increases endothelial nitric oxide (NO) production with a reduction
in platelet aggregation (Shehzad et al. 2012).
Therefore, adiponectin may protect against coronary heart disease (CHD), steatohepatitis, and
non-alcoholic fatty liver disease. On the other
hand, no association of adiponectin with CHD
progression has been found, but meta-analyses


Adiponectin and Mortality in Smokers and Non-Smokers of the Ludwigshafen. . .

have shown an association with increased mortality (Wu et al. 2014; Sook Lee et al. 2013).
The aim of this study was to examine the
association of adiponectin with mortality in
active smokers (AS) and life-time non-smokers
(NS) with a medium-to-high risk of coronary
events.

2

Methods

2.1

Study Population

The study was approved by the ‘Landesa¨rztekammer’ Ethics Committee of the RheinlandPfalz state in Germany and all patients gave
written consent at study entry. The
LUdwigshafen RIsk and Cardiovascular Health
(LURIC) study has been an ongoing prospective
study of 3316 patients of German ancestry who
had an indication for coronary angiography.
Patients were recruited between June 1997 and
May 2001 at the Ludwigshafen Cardiac Center
(Winkelmann et al. 2001). All patients were clinically stable, except for acute coronary
syndromes. Information on vital status was
obtained from local registries. Death certificates
were obtained in 97 % of dead participants. Only
were AS and life-time NS included into analysis.
In both groups, there occurred 523 deaths
(26.8 %) during a median follow-up of
10 years. Smoking status was assessed based on
a questionnaire and verified by the measurement
of serum cotinine concentration.

2.2

Laboratory Procedures

Fasting blood samples were taken by venipuncture in the early morning prior to angiography.
Aliquots were frozen at À80  C. Cholesterol and
triglycerides were measured with enzymatic
reagents from WAKO (Neuss, Germany) on an
Olympus AU640 analyser (Center Valley, PA).

Adiponectin serum concentration were measured
by ELISA (Biovendor Laboratory Medicine,
Brno, Czech Republic). Galectin-3 concentration
was measured on an ARCHITECT analyzer

3

(Abbott Diagnostics, Abbott Park, IL). hsCRP
was determined by immunonephelometry on a
Behring Nephelometer II (N High Sensitivity
CRP, Dade Behring, Germany).

2.3

Statistical Analyses

All continuous variables were checked for normality and variables showing a skewed distribution were logarithmically transformed to get a
normal distribution. Continuous variables were
compared between groups by Student’s t-test.
Associations between categorical variables
were examined by chi-squared testing. To
examine the relationship of adiponectin with
mortality, we split AS and NS into tertiles
according to adiponectin concentration and calculated hazard ratios (HR) and 95 % confidence
intervals (95 % CI) using the Cox proportional
hazards model. Multivariable adjustment was
carried out as indicated. IBM SPSS Statistics
v. 21.0 and R statistical software v. 3.2.2
() were used for all
analyses.

3

Results

Among the LURIC patients, there were 777 AS
and 1178 life-time NS. The proportion of men
was higher in the AS group and AS were younger
as compared to NS (Table 1). LDL-C and
HDL-C were lower in AS but the concentrations
of oxidized LDL and triglycerides were higher as
compared to NS. Systemic inflammation, as
measured by the concentration of hsCRP, was
higher in AS, but there was no difference in the
concentration of galectin-3, a marker of fibrosis.
AS had a higher mean estimated glomerular filtration rate (eGFR) and a lower percentage of
hypertension, but there was a higher percentage
of patients suffering from coronary artery
disease and a higher proportion of patients
treated with lipid lowering drugs (mostly statins)
in the AS group as compared to life-time
non-smokers. In unadjusted analyses, AS had
lower concentrations of adiponectin. However,


4

G.E. Delgado et al.

Table 1 Anthropometric characteristics of patients at study onset

Age (yr)
Male sex (%)
BMI (kg/m2)
LDL-C (mg/dl)
Oxidized LDL-C (U/l)
HDL-C (mg/dl)
Triglycerides (mg/dl)
Galectin-3 (ng/ml)
hsCRP (mg/l)
eGFR (ml/min/1.73 m2)
Adiponectin (μg/ml)
Adjusted adiponectin* (μg/ml)
Coronary artery disease (%)
Diabetes mellitus (%)
Hypertension (%)
Lipid lowering therapy (%)

Never smokers (n ¼ 1178)
65.3 Æ 10.1
45.4
27.4 Æ 4.2
119.1 Æ 36.4
73.5 Æ 26.7
41.2 Æ 11.1
136 (102–192)
15.8 Æ 6.3
2.72 (1.17–7.04)
78.7 Æ 19.1
9.7 (6.4–14.8)
11.4 (10.6–12.3)

68.1
38.3
76.6
42.4

Active smokers (n = 777)
56.2 Æ 10.3
77.9
27.0 Æ 4.2
117.5 Æ 32.1
78.4 Æ 25.4
36.2 Æ 10.2
154 (112–218)
15.5 Æ 7.3
4.93 (1.84–10.30)
88.2 Æ 20.1
7.6 (5.2–11.7)
11.2 (10.1–12.3)
80.1
36.0
63.3
52.8

p
<0.001
<0.001
0.833
0.012
<0.001
0.002

<0.001
0.496
<0.001
<0.001
<0.001
0.345
<0.001
0.314
<0.001
<0.001

Data are means Æ SD or median and 25–75th percentile
BMI body mass index, eGFR estimated glomerular filtration rate, HDL-C high density lipoprotein cholesterol, hsCRP
high sensitive C-reactive protein, LDL-C low density lipoprotein cholesterol
*Estimated marginal means (95 % CI) adjusted for age and gender

Table 2 Adiponectin concentration in never smokers and active smokers stratified for gender

Males
Adiponectin (μg/ml)
Females
Adiponectin (μg/ml)

Never smokers
n
Median (25th–75th percentile)

Active smokers
n
Median (25th–75th percentile)

p

520

7.9 (5.4–11.6)

582

6.8 (4.7–10.3)

<0.001

618

11.6 (7.9–17.0)

167

10.8 (7.6–15.1)

after adjustment for age and gender, there was no
significant difference in adiponectin concentration anymore. In gender stratified analyses,
adiponectin was significantly higher in females
than in males and only for males there was a
significant difference comparing NS and AS
(Table 2).
In the Cox regression model adjusted for age
and gender, adiponectin was significantly
associated with mortality only in AS with a

hazard ratio of 1.60 (95 % CI 1.14–2.24) comparing the 3rd with 1st tertile (Table 3 and
Fig. 1). In a model additionally adjusted for
the risk factors diabetes mellitus, hypertension,
coronary artery disease, BMI, LDL-C, and
HDL-C adiponectin was significantly associated
with mortality with HR of 1.83 (1.28–2.62) and

0.312

1.56 (1.15–2.11) for AS and NS, respectively.
Hazard ratio plots modeling adiponectin as
restricted cubic spline show an approximately
linear association of adiponectin concentration
with risk in females while in males there was a
steeper risk increase below an adiponectin concentration of 10 μg/ml, and almost three fourth
of all men presented with adiponectin
concentrations in this range (Fig. 2).

4

Discussion

The major finding of this study is that adiponectin
was a strong and independent predictor of
mortality for both life-time non-smokers and
active smokers in a cohort of patients referred


Adiponectin and Mortality in Smokers and Non-Smokers of the Ludwigshafen. . .

5

Table 3 Cox regression analysis of tertiles of adiponectin and all-cause mortality

Model 1
1st tertile
2nd tertile
3rd tertile
Ptrend
Model 2
1st tertile
2nd tertile
3rd tertile
Ptrend

n

Never smokers
HR (95 % CI)

380
380
378

1
0.89 (0.66–1.20)
1.10 (0.83–1.47)

380
380

378

1
1.10 (0.81–1.49)
1.56 (1.15–2.11)

Fig. 1 Cumulative hazard curves showing tertiles of
adiponectin for never-smokers (A + C) and active
smokers (B + D). The two graphs in the upper row
(A + B) show analyses adjusted for age and gender, the

p

0.458
0.501
0.348

0.535
0.004
0.009

n

Active smokers
HR (95 % CI)

250
251
248

1
0.96 (0.67–1.37)
1.60 (1.14–2.24)

249
251
248

1
1.04 (0.72–1.51)
1.83 (1.28–2.62)

p

0.802
0.006
0.003

0.821
0.001
0.001

two graphs in the lower row (C + D) show analyses
additionally adjusted for diabetes mellitus, hypertension,
coronary artery disease, BMI, LDL-C, and HDL-C


6

G.E. Delgado et al.

Fig. 2 Hazard ratio plots showing the association of adiponectin with all-cause mortality stratified by gender in neversmokers and active smokers

for coronary angiography. Adipocytes secret a
variety of so called adipokines that are involved
in the regulation of many physiological processes
in the body, like the metabolism of lipids and
carbohydrates, haemostasis, or inflammation.
The concentration of most adipokines increases
with increasing adipocyte number, except for
adiponectin whose concentration decreases with
obesity (Hajer et al. 2008). A decreased concentration of adiponectin has also been reported in
type 2 diabetics, patients with CHD, or smokers
(Kotani et al. 2012).

Although adiponectin is associated with
mostly beneficial metabolic effects, like insulin
sensitization, higher lipid oxidation, and less
inflammation, no association with the incidence
of CHD has been found (Kanhai et al. 2013).
Worse, adiponectin has been shown to correlate
directly with mortality, especially in CHD
patients (Wu et al. 2014; Sook Lee et al. 2013).
In line with this, Pilz et al. (2006) have reported
a low adiponectin serum concentration in
LURIC participants with CHD, but found no
association with CHD progression. In the present


Adiponectin and Mortality in Smokers and Non-Smokers of the Ludwigshafen. . .

study we set out to compare adiponectin concentration in AS and NS and to investigate its association with 10-year mortality. After adjustment
for age and gender we found no significant difference in adiponectin concentration between AS
and NS. In the Cox regression model using the
same adjustment adiponectin was significantly
associated with mortality only in AS, but not in
NS. After further adjustment for traditional risk
factors, adiponectin was significantly associated
with mortality in both AS and NS. This difference for the never-smokers between both models
is due mainly to the adjustment for diabetes
and CHD. This seems plausible because both
diseases are associated with lower adiponectin
but higher mortality risk.

5

Limitations and Conclusions

All participants were of European ancestry and
were recruited at a tertiary referral center. Therefore our findings may not be representative for a
random population sample or applicable to other
ethnicities. Furthermore, we only investigated
active smokers and life-time non-smokers and
excluded former smokers from the analyses.
Adiponectin concentration has only been
measured once at baseline. The major strength
of the LURIC cohort is, however, the precise
clinical and metabolic characterization of
participants and its cross-sectional and prospective design.
We conclude that adiponectin is an independent risk factor for mortality in active smokers

and life-time non-smokers after adjustment for
coronary heart disease risk factors. In addition,
adiponectin could be determined, as a potentially
useful marker, for risk prediction in active
smokers.
Acknowledgements We extend our appreciation to
the participants of the LURIC study. This article would
not have been written without the participants’ collaboration. We thank the LURIC study team which was
involved in the patient recruitment and data handling,
beside the laboratory staff at the Ludwigshafen General
Hospital and the Universities of Freiburg and Ulm,
Germany. This work was supported by the 7th Framework

7

Program RiskyCAD (grant 305739) of the European
Union.
Conflicts of Interest The authors declare no conflicts of
interest in relation to this article.

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8
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Nauck M, Boehm BO, Winkelmann BR, Mangge H,
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Advs Exp. Medicine, Biology - Neuroscience and Respiration (2016) 25: 9–22
DOI 10.1007/5584_2016_18
# Springer International Publishing Switzerland 2016
Published online: 31 May 2016

Heart Rate Variability and Arrhythmic
Burden in Pulmonary Hypertension
C. Witte, J.U. Meyer zur Heide genannt Meyer-Arend,
R. Andrie´, J.W. Schrickel, C. Hammerstingl, J.O. Schwab,
G. Nickenig, D. Skowasch, and C. Pizarro
Abstract

A growing body of evidence indicates that sudden cardiac death
constitutes a major cause of mortality in pulmonary hypertension (PH).
As validated method to evaluate cardiac autonomic system dysfunction,
alterations in heart rate variability (HRV) are predictive of arrhythmic
events, particularly in left ventricular disease. Here, we sought to determine the clinical value of HRV assessment in PH. Sixty-four patients were
allocated to different PH-subgroups in this prospectively conducted trial:
25 patients with pulmonary arterial hypertension (PAH), 11 patients with
chronic thromboembolic PH (CTEPH), and 28 patients with COPDinduced PH. All patients underwent 24-h Holter electrocardiogram for
HRV assessment by time- and frequency-domain analysis. Arrhythmic
burden was evaluated by manual analysis and complementary automatic
measurement of premature atrial and ventricular contractions. The results
were compared to 31 healthy controls. The PAH patients offered a significantly higher mean heart rate (78.6 Æ 10.4 bpm vs. 70.1 Æ 10.3 bpm,

p ¼ 0.04), a higher burden of premature ventricular contractions
(p < 0.01), and decreases in HRV (SDNN: p < 0.01; SDANN:
p < 0.01; very low frequency: p < 0.01; low frequency/high frequency
ratio: p < 0.01; total power: p ¼ 0.02). In CTEPH patients, only the
amount of premature ventricular contractions differed from controls
(p < 0.01), whereas in COPD both premature atrial contraction count
and frequency-domain-based HRV manifested significant differences.
C. Witte, J.U. Meyer zur Heide genannt Meyer-Arend,
R. Andrie´, J.W. Schrickel, C. Hammerstingl, G. Nickenig,
D. Skowasch, and C. Pizarro (*)
University Hospital Bonn, Department of Internal
Medicine II, Cardiology, Pneumology and Angiology, 25
Sigmund-Freud-Straße, Bonn 53105, Germany
e-mail:
J.O. Schwab
Beta Clinic, Department of Cardiology, 15 JosephSchumpeter-Allee, Bonn 53227, Germany
9


10

C. Witte et al.

In conclusion, PAH appears to be primarily affected by HRV alterations
and ventricular arrhythmic burden, indicating a high risk for malignant
arrhythmic events.
Keywords

Atrial fibrillation • Echocardiography • Frequency-domain analysis •
Right heart catheterization • Sudden cardiac death • Systolic pulmonary

arterial pressure • Time-domain analysis

1

Introduction

Pulmonary hypertension represents a complex
and heterogeneous disorder characterized by a
multifactorial pathogenesis. In pulmonary arterial hypertension (PAH), proliferative pulmonary
vasculopathy, triggered by vasoconstriction,
fibrosis and thrombosis, induces vascular obliteration and elevation in pulmonary vascular resistance. In chronic thromoembolic pulmonary
hypertension (CTEPH) and pulmonary hypertension due to lung disease, the underlying pathogenic mechanisms are less well defined. A
common entity of the last-mentioned subgroup
of pulmonary hypertension is chronic obstructive
pulmonary disease (COPD) – caused PH, in which
both hypoxia-induced vasoconstriction and obliteration of the vascular bed are the primary drivers
of pulmonary vascular resistance increase (Seeger
et al. 2013). The disease course is progressive,
disabling, frequently fatal and highly dependent
on the underlying type of pulmonary hypertension, with PAH offering the poorest survival
rates (Chung et al. 2015). Right heart failure
with consecutive circulatory and respiratory collapse constitutes the main cause of death. Right
heart dilatation and hypertrophy provoke sinoatrial stretch and reduction in myocardial perfusion, which, in turn, increases the risk of cardiac
dysrhythmia. In PAH, approximately 30 % of
mortality has recently been reported to be attributable to sudden cardiac death (Bandorski
et al. 2015). Hoeper et al. (2002) have investigated
the frequency and outcome of cardiopulmonary
resuscitation in 132 patients with PAH and
demonstrated only a modest survival rate of 6 %,

with baseline hemodynamics showing no
association with resuscitation outcomes. In that
study, initial electrocardiogram at the time of
resuscitation revealed ventricular fibrillation
present in 8 % of cases.
The autonomic nervous system, which
encompasses the sympathetic and parasympathetic neural parts, substantially influences the
onset and sustainment of malignant ventricular
arrhythmias. Alterations in autonomic nervous
system function are evaluable by different
approaches, with assessment of heart rate
variability (HRV) being of major clinical feasibility. HRV describes the fluctuations of
normal heart beat intervals (NN) during ECGmonitoring. In heart failure, atrial fibrillation,
stable coronary heart disease and postmyocardial infarction, decreased HRV predicts
worse clincial outcome (Valencia et al. 2013),
but its diagnostic and prognostic value in pulmonary hypertension still needs to be determined. In
the present study we aimed at prospectively
evaluating the utility of HRV assessment in pulmonary hypertension by including different pulmonary hypertension classes and comparing the
results to controls. Moreover, the respective
arrhythmic burden, as assessed by Holtermonitoring, was examined.

2

Methods

2.1

Study Population

The study was approved by the local Ethics

Committee and performed in accordance with


Heart Rate Variability and Arrhythmic Burden in Pulmonary Hypertension

the Declaration of Helsinki. Between January
2014 and August 2015, 95 participants,
subdivided into four groups, were included in
this prospectively conducted trial at the outpatient pneumological department of the University
Hospital Bonn (Germany). There were
36 patients with invasively confirmed
pre-capillary pulmonary hypertension, of whom
25 patients appertained to group 1 (PAH) and
11 patients to group 4 (CTEPH); the division
was made according to the current European
Society of Cardiology/European Respiratory
Society’s guidelines for the diagnosis and treatment of pulmonary hypertension (Galie`
et al. 2016; Simonneau et al. 2013). A third
subgroup consisted of 28 patients with
echocardiographically diagnosed pulmonary
hypertension and spirometrically and clinically
confirmed advanced, emphysematous chronic
obstructive pulmonary disease (COPD). Finally,
an age- and gender-matched healthy control
group of 31 individuals was included. Controls
had no history of cardiac or pulmonary disease.
All participants underwent 24-hour Holter
electrocardiogram,
recorded
by

the
SpiderView™ Ambulatory Electrocardiographic
Recorder (Sorin Group; Milan, Italy). A trained
professional applied five electrodes to the
subject’s chest. Two electrodes were placed
parasternal right and left between the second
and third rib. One was positioned in the right
mid-clavicular line between the seventh and
eighth rib, another was positioned on the contralateral left side. The last electrode was placed
directly at the xiphoid. An experienced cardiologist analyzed the Holter ECG data using
SyneScope™ Software (Sorin Group; Milan,
Italy).
Additionally, transthoracic echocardiography
was performed the day after Holter monitoring
by experienced cardiac sonographers on conventional equipment (iE 33, Philips Medical
Systems; Koninklijke N.V., Hamburg, Germany)
in line with the recommendations of the American Society of Echocardiography (American Col
lege of Cardiology Foundation Appropriate Use
Criteria Task Force 2011). In PAH/CTEPH

11

patients, right heart catheterization values were
recorded just before the Holter monitoring. A
standardized questionnaire-based survey was
performed to assess the use of medication.

2.2

Supraventricular and Ventricular

Arrhythmias

The SyneScope™ Software analyzes supraventricular und ventricular premature beats and
divides them into three groups: single ectopic
beats, couplets, and salvos/non-sustained supraventricular and ventricular tachycardias. Additionally, it combines all recognized premature
beats to a total number, denominated as premature atrial and ventricular contractions (PAC and
PVC, respectively) which were used for statistical analysis.

2.3

Time-Domain Analysis

SyneScope™ Software enables time-domain
analysis of HRV. All NN intervals qualify for
analysis when in sinus rhythm. All ectopic beats,
non-sinus rhythm beats or artifacts are excluded.
We analyzed a number of indices: The mean
standard deviation of NN intervals (SDNN, in
milliseconds) was analyzed over a 24-h period
as it is influenced by the circadian rhythm.
SDNN values below 100 ms are predictive of
increased cardiovascular mortality (Nolan
et al. 1998). The mean standard deviation of the
average NN intervals (SDANN, in milliseconds)
was analyzed for all of the 5-min intervals of
24-h Holter monitoring. The root mean square
of differences between successive NN intervals
(RMSSD, in milliseconds) is the average absolute value of the variation in NN intervals
between single beats. Finally, there is a percentage of NN intervals that differ from the prior
interval by at least 50 ms (pNN50%). The indices

were correlated to the echocardiographically
assessed pulmonary arterial systolic pressure
(PASP).


12

2.4

C. Witte et al.

Frequency-Domain Analysis

Spectral analysis of RR intervals was conducted
with the fast Fourier transform. The range of the
spectral analysis was 0.00–0.40 Hz. All frequency bands were expressed in ms2, except for
the HF/LF ratio that has no unit. The
SyneScope™ Software calculates three frequency bands. There are very low frequencies
(VLF), comprising 0.00–0.04 Hz, which represent the parasympathetic branch of the autonomic nervous system and are influenced by the
renin-angiotensin-system (Taylor et al. 1998).
The low frequency (LF) spectrum ranges from
0.04 Hz to 0.15 Hz and represents the efferent
activity of both vagal and sympathetic nervous
system. The high frequency (HF) spectrum
ranges from 0.15 Hz to 0.40 Hz and represents
the efferent parasympathetic activity. The LF/HF
ratio is a marker of sympathetic activity; the total
power (TP) illustrates the total HRV over 24 h.

2.5

Statistical Analysis

Categorical variables were expressed as total
numbers and percentages. Continuous variables
were presented as means Æ SD and tested for
normal distribution. For comparison between
groups, the Mann-Whitney U test was
performed. Correlation between values was
analyzed by linear regression. A p-value < 0.05
was considered statistically significant. Statistical analysis was performed with the IBM SPSS
Statistics Software Ver. 23.0 (Armonk, NY) for
Macintosh.

3

Results

3.1

Clinical and Echocardiographic
Characteristics

Demographic, clinical and echocardiographic
data are presented in Table 1. The participants
were
predominantly
late
middle-aged
(64.3 Æ 13.3 years) and of male gender

(52.6 %), with no significant differences among
groups. In the PAH group, 68.0 % of subjects
had idiopathic PAH. Associated PAH-classes
were present in 28.0 %; one patient (4.0 %) suffered from pulmonary veno-occlusive disease
(PVOD), as depicted in Table 2. The majority
of patients were in WHO functional class II and
III (80.0 %). Pre-capillary pulmonary hypertension was confirmed by invasive recordings; mean
pulmonary arterial pressure (PAPM) was elevated to 48.0 Æ 14.9 mmHg. Left ventricular
function was preserved as shown by echocardiography, with a mean left ventricular ejection
fraction (LVEF) of 62.6 Æ 7.7 %. Only two
patients had diastolic dysfunction ! grade II.
CTEPH patients were likewise mainly in
WHO functional class II and III (81.8 %), with
a mean pulmonary arterial pressure of
45.3 Æ 12.3 mmHg and echocardiographically
confirmed preserved left ventricular function.
With regard to right heart catheterization, there
were no significant differences between the
PAH- and CTEPH-subgroups, as depicted in
Table 2. When both subgroups were combined,
correlation analysis of echocardiographically
assessed systolic pulmonary arterial pressure
(PASP) and invasively measured PAPM showed
a significant association of values (r ¼ 0.51,
p < 0.01; Fig. 1), underlining accuracy of echocardiographic measurements.
With a view to pulmonary hypertensionspecific treatment in PAH patients, endothelin
receptor antagonists were preferentially prescribed (66.7 % of all pulmonary hypertension
cases), followed by phosphodiesterase-5
inhibitors (55.6 %); 8.3 % received prostanoids.

No patient received calcium channel blockers.
Two out of 11 CTEPH patients suffered from
recurrent or persistent pulmonary hypertension
despite pulmonary endarterectomy; 9 patients
were rejected from surgical treatment. Given
their symptomatology, medication in CTEPH
comprised both guanylate cyclase stimulators
(riociguat) and off-label endothelin receptor
antagonists and prostanoids.
The COPD group had a mean age of
67.1 Æ 10.9 years and was composed of patients
in advanced COPD stages: 75.0 % were


n
Age (years)
Echocardiographic parameters
PASP (mmHg)
TAPSE (cm)
Tricuspid insufficiency:
No tricuspid insufficiency, n (%)
Grade I, n (%)
Grade II, n (%)
Grade III, n (%)
Grade IV, n (%)
EF (%)
Diastolic dysfunction:
No diastolic dysfunction, n (%)
Grade I, n (%)
Grade II, n (%)

Grade III, n (%)
Cardiovascular medication, n (%)
Diuretics
CCB
RAAS inhibitors
Beta blockers
PH-specific medication, n (%)
PDE5 inhibitors/guanylate cyclase
stimulator
ERA
Prostanoids
2 PH drugs
3 PH drugs
54.7 Æ 20.1
1.8 Æ 0.7
0
4 (36.4
5 (45.4
2 (18.2
0
63.1 Æ
2 (18.2 %)
8 (72.7 %)
0
1 (9.1 %)
9 (81.8 %)
0
4 (36.4 %)
4 (36.4 %)
6 (54.6 %)

4 (36.4 %)
1 (9.1 %)
2 (18.2 %)
0

55.1 Æ 24.7
2.1 Æ 0.6
5 (20.0 %)
11 (44.0 %)
6 (24.0 %)
2 (8.0 %)
1 (4.0 %)
62.6 Æ 7.7
3 (12.0 %)
20 (80.0 %)
1 (4.0 %)
1 (4.0 %)
20 (80.0 %)
5 (20.0 %)
7 (28.0 %)
11 (44.0 %)
14 (66.0 %)
20 (80.0 %)
2 (8.0 %)
9 (36.0 %)
2 (8.0 %)

9.4

%)

%)
%)

CTEPH
11
66.4 Æ 12.3

PAH
25
65.8 Æ 12.2

0
0
0
0

0

18 (66.6 %)
6 (16.3 %)
15 (55.6 %)
11 (40.7 %)

8 (28.6 %)
18 (64.3 %)
0
2 (7.1 %)

8 (28.6 %)
12 (42.8 %)

8 (28.6 %)
0
0
60.5 Æ 11.5

32.3 Æ 12.3
2.2 Æ 0.7

COPD
28
67.1 Æ 10.9

0
0
0
0

0

0
0
0
0

7 (22.6 %)
21 (67.7 %)
3 (9.7 %)
0

16 (51.6 %)

14 (45.2 %)
1 (3.2 %)
0
0
64.9 Æ 5.6

20.8 Æ 6.1
2.5 Æ 0.5

Controls
31
59.9 Æ 15.6

Table 1 Demographic, echocardiographic and clinical characteristics of the study population

%)
%)
%)
%)

24 (25.3 %)
3 (3.2 %)
11 (11.6 %)
2 (2.1 %)

20 (21.1 %)

47 (49.5
11 (11.6
26 (27.4

26 (27.4

20 (20.7 %)
67 (70.7 %)
4 (4.3 %)
4 (4.3 %)

29 (30.5 %)
41 (43.2 %)
20 (21.1 %)
4 (4.2 %)
1 (1.0 %)
62.8 Æ 8.7

37.4 Æ 21.8
2.2 Æ 0.6

All
participants
95
64.3 Æ 13.3

NS

<0.0001
NS

NS

PAH/

Controls
p-value

NS

<0.0001
0.02

NS

CTEPH/
Controls
p-value

NS

(continued)

<0.0001
NS

NS

COPD/
Controls
p-value

Heart Rate Variability and Arrhythmic Burden in Pulmonary Hypertension
13

COPD
26 (96.3 %)
23 (85.2 %)
22 (81.5 %)
5 (18.5 %)

CTEPH
8 (72.7 %)
3 (27.3 %)
7 (63.6 %)
0

0
0
0
0

Controls
49 (51.6 %)
38 (40.0 %)
38 (40.0 %)
6 (6.3 %)

All
participants

PAH/
Controls
p-value

CTEPH/
Controls
p-value

COPD/
Controls
p-value

PH pulmonary hypertension, CTEPH chronic thromboembolic pulmonary hypertension, COPD chronic obstructive pulmonary disease, PASP systolic pulmonary arterial
pressure, PAH pulmonary arterial hypertension, TAPSE tricuspid annular plane systolic excursion, TI tricuspid insufficiency, EF ejection fraction, CCB calcium channel
blockers, ERA endothelin receptor antagonists, RAAS inhibitors renin angiotensin aldosterone system, PDE5 inhibitors phosphodiesterase-5 inhibitors, PDE4 inhibitors
phosphodiesterase-4 inhibitors

PAH
Anti-obstructive/anti-inflammatory medication, n (%)
Long-acting beta 2 agonists
15 (60.0 %)
Long-acting anticholinergics
12 (48.0 %)
Inhaled glucocorticoids
9 (36.0 %)
PDE4 inhibitor (roflumilast)
1 (4.0 %)

Table 1 (continued)

14
C. Witte et al.

Heart Rate Variability and Arrhythmic Burden in Pulmonary Hypertension

15

Table 2 Clinical characteristics and right heart catheterization data in PAH and CTEPH patients

n
PAH subgroups
IPAH
Associated with:
HIV
Congenital heart disease
Portal hypertension
PVOD
WHO functional class, n (%)
Class I
Class II
Class III
Class IV
Parameters of right heart catheterization
PAWP (mmHg)
PAP systolic (mmHg)
PAP diastolic (mmHg)
PAP mean (mmHg)
Cardiac output (l/min)
PVR (WU)

PAH
25

CTEPH
11

PAH/CTEPH
p-value

17 (68.0 %)
3 (12.0 %)
3 (12.0 %)
1 (4.0 %)
1 (4.0 %)
1 (4.0 %)
14 (56.0 %)
6 (24.0 %)
4 (16.0 %)

2 (18.2 %)
3 (27.3 %)
6 (54.5 %)
0

NS

12.3 Æ 6.6
76.0 Æ 23.5
29.1 Æ 10.2
48.0 Æ 14.9
5.0 Æ 1.7
8.4 Æ 5.5

11.3 Æ 4.0
73.9 Æ 19.5
27.7 Æ 7.9
45.3 Æ 12.3
4.8 Æ 1.6
8.1 Æ 4.7

NS
NS
NS
NS
NS
NS

PAH pulmonary arterial hypertension, CTEPH chronic thromboembolic pulmonary hypertension, IPAH idiopathic
pulmonary arterial hypertension, PVOD pulmonary veno-occlusive disease, PAWP pulmonary artery wedge pressure,
PAP pulmonary artery pressure, PVR pulmonary vascular resistance, WU wood unit
Fig. 1 Correlation of
mean pulmonary artery
pressure (PAPM), assessed
echocardiographically,
versus systolic pulmonary
artery pressure (PASP),
measured invasively. Line
is a linear regression line;
r ¼ 0.51; p < 0.01;
y ¼ 29.41 + 0.34*x

classified as GOLD stages C and D (Table 3).

Pulmonary function showed a mean FEV1
evinced FEV1 of 1.1 Æ 0.7 l in absolute terms
and 40.7 Æ 20.0 % of the predicted value. Like

PAH/CTEPH patients, transthoracic echocardiography in COPD excluded major left ventricular
dysfunction and revealed right ventricular
impairment (Table 1). Anti-obstructive and


16

C. Witte et al.

Table 3 Clinical and pulmonary function characteristics
of COPD patients
n
GOLD classification, n (%)
A
B
C
D
Pulmonary function testing
FEV1 (l)
FEV1 (% predicted)
FVC (l)
FVC (% predicted)
RV (l)
RV (% predicted)

28

0
7 (25.0 %)
9 (32.1 %)
12 (42.9 %)
1.1 Æ 0.7
40.7 Æ 20.0
2.0 Æ 0.9
54.8 Æ 16.4
4.5 Æ 1.9
204.0 Æ 86.5

FEV1 forced expiratory volume in 1 s, FVC forced vital
capacity, RV residual volume

cardiovascular medication use is depicted in
Table 1.
Echocardiographic evaluation of the age- and
gender-matched controls, in whom no cardiopulmonary pathology had been previously
diagnosed, revealed a preserved right and left
ventricular function with mean values for LVEF
and
PASP
of
64.9 Æ 5.6 %
and
20.8 Æ 6.1 mmHg, respectively.
Comparison of PASP values showed significant differences between the groups studied, as
specified in Table 1. As might be expected, PAH
and CTEPH patients presented the highest
values, followed by COPD patients, whereas the

control’s mean PASP value was within normal
range.

3.2

Heart Rate and Arrhythmic
Burden

The arrhythmic burden, assessed by 24-h Holter
ECG, is displayed in Table 4. PAH patients had a
significantly higher average heart rate (PAH:
78.6 Æ 10.4 bpm; controls: 70.1 Æ 10.3 bpm;
p ¼ 0.04) and mean PVC burden (PAH:
1203.6 Æ 2992.6
beats/day;
controls:
62.3 Æ 118.4 beats/day; p < 0.01). The number
of premature atrial contractions was statistically

balanced between PAH patients and controls
(PAH: 746.8 Æ 1737.8 beats/day, controls:
540.3 Æ 1562.3 beats/day; p ¼ NS).
There were no significant differences between
the CTEPH and control group with regard to the
average (CTEPH: 78.0 Æ 11.0 bpm; controls:
70.1 Æ 10.3 bpm) and the total number of PAC
(CTEPH: 216.5 Æ 215.9 beats/day; controls:
540.3 Æ 1562.3 beats/day). However, CTEPH
patients presented a higher total count of PVC
(CTEPH: 1031.5 Æ 1803.6 beats/day; controls:

62.3 Æ 118.4 beats/day; p < 0.01).
There were no significant differences between
the COPD and control group with regard to the
average heart rate (COPD: 77.8 Æ 13.6 bpm;
controls: 70.1 Æ 10.3 bpm) and PVC burden
(COPD: 1454.4 Æ 4686.9 beats/day; controls:
62.3 Æ 118.4 beats/day). Nonetheless, premature atrial contractions were significantly more
frequent in COPD patients than in controls
(COPD: 1395.7 Æ 2413.4 beats/day; controls:
540.3 Æ 1562.3 beats/day; p ¼ 0.01).
Paroxysmal atrial fibrillation occurred in
22.1 % of the whole study population, with
COPD patients showing the highest incidence
(35.7 % of patients), followed by PAH and
CTEPH patients (32.0 % and 27.3 %, respectively). The mean cumulative duration of atrial
fibrillation for all subgroups is given in Table 4
and differed significantly between each of the
pulmonary hypertension group as compared to
controls (PAH vs. controls: p ¼ 0.001; CTEPH
vs. controls: p < 0.01; COPD vs. controls:
p < 0.0001).

3.3

Time-Domain Analysis

Results obtained by time-domain analysis are
summarized in Table 4. PAH patients had significantly
lower
mean

SDNN
(PAH:
100.4 Æ 38.1 ms, controls: 126.8 Æ 37.5 ms;
p < 0.01) and SDANN (PAH: 79.2 Æ 28.3 ms,
controls: 105.2 Æ 39.0 ms; p < 0.01). Both
RMSSD (PAH: 54.6 Æ 53.6 ms, controls:
36.8 Æ 38.2 ms; p ¼ NS) and PNN50%