Article

Chronic Illness
0(0) 1–15
A randomized controlled trial ! The Author(s) 2020
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DOI: 10.1177/1742395320920700
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muscle training for chronic

heart failure patients with
inspiratory muscle weakness

Zahra Sadek1,2 , Ali Salami2 ,

Mahmoud Youness4, Charifa Awada2,
Malek Hamade4, Wissam H Joumaa2,
Wiam Ramadan2,3 and Said Ahmaidi1

Abstract
Objectives: Chronic heart failure is a major public health problem in which supervised exercise
programs are recommended as part of non-pharmacological management. There are various
reports of the success of high-intensity aerobic interval training (HI-AIT) and inspiratory
muscle training (IMT) in the management of chronic heart failure patients. This study tested
the hypothesis that the combination of HI-AIT and IMT could result in additional benefits over the
IMT and the HI-AIT alone in terms of inspiratory muscle function, exercise capacity, and quality of
life in patients with chronic heart failure and inspiratory muscle weakness.
Methods: Forty patients with ejection fraction
45% and inspiratory muscle weakness
described by maximal inspiratory pressure <70% predicted, underwent three exercise training
sessions per week for 12 weeks. Patients were randomly allocated to one of four groups: the HI-
AIT group, the IMT group, the combined (HI-AIT & IMT) group, and the control group. Before
and after completing their training period, all patients underwent different tests that are men-
tioned above.
3
Lebanese Institutes for Biomedical Research and
Application (LIBRA), Beirut International University (BIU)
and Lebanese International University (LIU), Beirut,
Lebanon
4
1
Laboratory EA-3300 (APERE) « Adaptations Medical Research Center of Beirut Cardiac Institute,
Physiologiques à l’Exercice et R
eadaptation à l’Effort », Beirut, Lebanon
Picardie Jules Verne University, Amiens, France Corresponding author:
2
Rammal Hassan Rammal Research Laboratory, Physio- Mahmoud Youness, Medical Research Center of Beirut
toxicity (PhyTox) Research Group, Faculty of Sciences (V), Cardiac Institute, Beirut, Lebanon.
Lebanese University, Nabatieh, Lebanon Email: myouness55@yahoo.com
2 Chronic Illness 0(0)

Results: No changes were detected in the control group. However, the combined group, when
compared to HI-AITand IMT groups, respectively, resulted in additional significant improvement in
maximal inspiratory training (62%, 24%, 25%), exercise time (62%, 29%, 12%), the 6-minute walk
test (23%, 15%, 18%), and the Minnesota Living with Heart Failure Questionnaire (56%, 47%, 36%).
Conclusion: In patients with chronic heart failure and inspiratory muscle weakness, the com-
bination of the HI-AIT and the IMT resulted in additional benefits in respiratory muscle function,
exercise performance, and quality of life compared to that of HI-AIT or IMT alone.

Trial Registration number: NCT03538249

Keywords
Chronic heart failure, inspiratory muscle training, interval aerobic training, exercise capacity,
quality of life
Received 10 August 2019; accepted 3 February 2020

Introduction Respiratory muscles dysfunction affects

Chronic heart failure (CHF) is a progres-
sive and multifactorial disease that is
mainly characterized by exercise intolerance
and contributes to poor quality of life
(QoL) in diseased patients.1,2 This fact will
usually hinder their daily life routines and
activities.3 In addition, CHF exerts a tre-
mendous health and economic burden on
the healthcare system with an estimated
cost of current treatment that may exceed
108 billion USD, which is about 1–2% of
the global healthcare budget.4
Although central hemodynamic issues
are increasingly appreciated as an impor-
tant pathophysiological factor in CHF
development and progression, alterations
in skeletal muscles constitute a pivotal fea-
ture of CHF.1 In fact, fatigue and dyspnea
that are manifested in the disease are also
correlated with peripheral skeletal muscle
changes,1 such as altered metabolism,
changes in fiber types, decreased capillary
density, and muscle bulk.5 These changes
can directly influence the respiratory
muscle pump performance since the latter
is composed of skeletal muscles.
the ventilation process, gas exchange, and
oxygen delivery to the organs, leading to a
weakness in respiratory muscle strength and
endurance that is common in CHF patients.6
Thus, inspiratory muscle weakness (IMW)
could be explained by poor perfusion of
respiratory muscles and is associated with
sympathetically mediated chemoreflex and
metaboreflex hyperactivity.7 IMW is
described as a maximal inspiratory pressure
(MIP) less than 70% of predicted value.7
Accordingly, non-pharmacological
approaches might be beneficial in improv-
ing a patient’s QoL by improving both skel-
etal and respiratory muscles.1 For instance,
aerobic training has been considered a
highly valuable intervention in CHF
patients. It shows many improvements in
mortality rates,2 aerobic capacity, function-
al class,8 and submaximal exercise endur-
ance.9 The vast majority of aerobic
exercise training adopted in CHF rehabili-
tation programs consists of continuous
training at moderate intensities relative to
the patient’s maximal capacity. However,
in recent years, the high-intensity aerobic
interval training (HI-AIT) has emerged
Sadek et al.
and appears to be safer and more beneficial
to CHF patients.10 HI-AIT consists of
repeated periods of high-intensity exercise
intercepted by periods of low-intensity
one. Its principle is that it permits for recov-
ery periods that make it possible for
patients to reengage in short workouts at
a higher intensity than would be possible
during continuous exercise.
In addition, many authors11–13 demon-
strated that inspiratory muscle training
(IMT) had positive outcomes on the QoL,
as well as the respiratory and peripheral
muscle strength. Indeed, Dall’Ago et al.13
showed that CHF patients, with IMW,
demonstrated an improvement in MIP
upon receiving the IMT for 12 weeks.
Because both aerobic and IMTs are rec-
ommended as useful interventions for CHF
patients, many researchers have performed a
combination of the aerobic continuous train-
ing and the IMT and showed additional ben-
efits in the inspiratory muscle endurance, the
QoL and dyspnea, as well as in the inflamma-
tory and cardiac biomarkers.8 However, all
trials showing the additive benefits of the
combination of these exercise modalities
have included the continuous aerobic train-
ing and not the interval aerobic one,8,13 and
there are no studies that compared the IMT,
the HI-AIT, their combination (IMT & HI-
AIT), and the control group at the same time
using the same given protocol.
Thus, our goal is to evaluate whether the
combination of the HI-AIT and the IMT
would be superior in the improvement of
respiratory muscle function, exercise, and
functional capacity, as well as QoL when
compared with the IMT alone, HI-AIT
alone, and of course the control group.
Methods
Study design
A randomized, single-blinded, parallel con-
trolled study was performed on outpatients,
3
aged between 45 and 65 years, males and
females, who were diagnosed with stable
CHF and IMW (MIP < 70% predicted)
and recruited from Beirut Cardiac
Institute. The predicted value means the
normal value for a healthy person with
the same age, gender, weight, and height.
Eligible subjects must have the below inclu-
sion criteria: (1) Ejection fraction (EF)

45% examined by Echocardiography, (2)
New York Heart Association (NYHA)
class II or III, (3) diagnosed with CHF for
more than 6 months with the absence of any
hospitalization or any change in medica-
tions throughout the previous three
months, and (4) with a sedentary lifestyle
according to the short international physi-
cal activity questionnaire (IPAQ). The
patients were randomized to different
exercising groups, and all sessions were
supervised by a physical therapist and a car-
diologist specialized in cardiac rehabilita-
tion. Excluded subjects suffered from
pulmonary limitation (Forced expiratory
volume (FEV1) and/or vital capacity
<60% of predicted), orthopedic or neuro-
logic disease, had a history of significant
cardiac arrhythmia, had a history of myo-
cardial infarction or a cardiac surgery over
the past 6 months, non-echogenic, unstable,
poorly controlled blood pressure, and/or
end-stage HF. A written informed consent
form was signed and obtained from all the
participating subjects and all of them were
receiving the same type of medication that
included mainly beta-blockers, angiotensin-
converting enzyme inhibitors (ACE-I), or
angiotensin II receptor blockers (ARB), and
Diuretics. Furthermore, an approval for the
experimental protocol was obtained from the
Committee for Ethics in Research of Beirut
Cardiac Institute (IRB, OTLY-P-38F-16).
Protocol
Fifty subjects were block-randomized with
1:1 to different groups as shown in the
4 Chronic Illness 0(0)

Figure 1. Participant flow diagram—CONSORT (Consolidated Standards of Reporting Trials) diagram of

recruitment to the trial. AIT: aerobic interval training; IMT: inspiratory muscle training.

consort diagram in Figure 1. tests, 6-minute walk test (6MWT), and

Randomization was conducted by using a
research randomizer website (Scott Plous
and Jeff Breil, Lancaster, Pennsylvania).
All the training groups, despite the alloca-
tion, completed three supervised and non-
consecutive exercise sessions per week that
lasted for 12 weeks, performing a total of 36
sessions, in the physical therapy depart-
ment, supervised by a cardiologist special-
ized in cardiac rehabilitation. The control
group patients were allocated to a non-
training-time period, during which they
were told to continue their life the same as
before enrollment. All patients had a seden-
tary lifestyle to avoid bias since some
patients might be following a specific activ-
ity program. Thus, in order to make sure
that all the patients met the criteria, the
short IPAQ was used to assess the level of
each patient’s physical activity.
Assessments of pulmonary function test,
inspiratory muscle function tests, stress
QoL test were completed before (week 0)
and after the intervention (after week 12).
Note that the combined group participants
started with the aerobic training followed
by the inspiratory training, as stated
below, with 5 min rest in-between. All
assessments were achieved by experimenters
blinded to the distribution of patients to
different interventions. All patients were
supervised by nutritionists and psycholo-
gists in order to have a healthy and
smoke-free lifestyle.
High-intensity aerobic interval training
Interval training was used as a training
modality instead of continuous training,
due to its more pronounced effects, as
observed by Wisløff et al.10 To be on the
safe side and to not cause any harmful
effect on patient’s health condition, espe-
cially that all patients had a sedentary
Sadek et al.
lifestyle according to the short IPAQ, work-
load was set at a moderate intensity, at first,
and was increased by 5% every two weeks,
in order to reach 90% of the maximum
workload. HI-AIT included walking on a
treadmill for 30 min at different intensities:
A 1-min warm-up initiated the workout at
low intensity, then followed by a period of
training at 60% to 90% of maximal HR
(MHR), which corresponded to the first
ventilatory threshold on the stress test
when the patient could not continue the
effort, and was terminated by a cooling
down for 1 min at a low intensity too.10
Training consisted of four intervals of
4 min at 60% to 90% of MHR and five
intervals of 2 min at 50% of the maximum
intensity of the workload.
Inspiratory muscle training
Patients established IMT for 20 min, three
times per week, for 12 weeks using the
Power Breathe training device. This hand-
held device strengthens the breathing
muscles (diaphragm and intercostals) by let-
ting them work harder with a level variabil-
ity by generating different pressures.13–15
During exercise, patients were coached to
sustain diaphragmatic breathing, with a
breathing rate at 15 to 20 breaths per
minute. A new study reviewed the literature
and found that the threshold pressure
should be set at 60% of maximal inspirato-
ry mouth pressure to achieve significant
improvements in inspiratory muscle
strength.16 According to these results,
patients in the IMT group were trained at
a training load of 60% of MIP.13 In addi-
tion, exercise loads were adjusted to con-
serve 60% of the MIP every two weeks.17
To start the session, it was made sure
that the patient was sitting upright and feel-
ing relaxed, and then he/she would hold the
device by the handle cover, place
the mouthpiece in her/his mouth so that
the lips would cover the outer shield to
5
make a seal. Then the patient was asked
to take in as much air as he/she could, as
quickly as he/she could, straightening her/
his back and expanding her/his chest. In the
second step, he/she should breathe out
slowly and passively through the mouth
until the lungs are empty, letting the
muscles in the chest and shoulders relax.17
The session is divided into 1 min of warm-
up without resistance, four blocks of work
for 3 min separated by 20 s of rest, and 1
min of cool down without resistance too.18
Pulmonary function test
Digital Spirometer is the standard pulmo-
nary function test used to assess lung func-
tion. The analysis of data was performed
using a program introduced previously by
NHANES II in 1990. The maneuver was
done three consecutive times and the largest
unregistered value was used in the investi-
gation. Forced vital capacity (FVC) and
forced expiratory muscle volume in 1 s
(FEV1) were recorded.
Respiratory muscle test
To assess the respiratory muscle strength,
MIP and the maximal expiratory pressure
(MEP) were recorded using a hand-held
mouth pressure meter (MicroRPM care
fusion) connected to a PUMA PC
Software that offers unique and advanced
features. In addition, sustained maximal
inspiratory pressure (SMIP) was used to
assess the respiratory muscle endurance,
where the time was recorded in the period
during which a patient was asked to main-
tain diaphragmatic breathing at 70% MIP
till exhaustion. This inspiratory effort was
done three times, with 2 min of a rest
period.
Stress test
Bruce treadmill protocol was used for the
assessment of the cardiovascular status
6 Chronic Illness 0(0)
during a progressive incremental exercise.19
This is a maximal exercise test, where the
patient works to complete fatigue as the
treadmill speed and incline are augmented
every 3 min according to Bruce protocol.
The intensity of the exercise was repre-
sented by exercise time and estimated met-
abolic equivalent of a task (METs), which is
equivalent to the oxygen consumption
(VO2).20
The patient would also have a set of ECG
leads placed on her/his chest and a sphyg-
momanometer cuff wrapped around the arm
for BP monitoring. The patient must stop
eating 3 h before performing the test and
no major effort must be made 12 h before
the test; he/she must dress appropriately as
dictated by the needed physical effort.
Functional capacity
Functional capacity in CHF patients was
predicted by using the 6MWT, since a sig-
nificant correlation had been shown to exist
between 6MWT and functional capacity.21
The latter was validated to be reliable and
reproducible. The test was performed in a
60-m corridor under the supervision of a
physical therapist. Initially, the patient
had been familiarized with the corridor
space and the time needed to complete the
test. A stopwatch was used to record the
elapsed time as soon as the subject scurried
from the starting slab. The physical thera-
pist would encourage the patient to walk as
much as he/she can during the 6 min by tell-
ing them “Go on, that is it” and “Great
performance, just keep on track.” The
patient was free to decrease his/her speed
and stop if necessary. HR and blood pres-
sure were monitored at the different effort
stages, and the participants were requested
to self-grade their dyspnea at the end of the
test using Borg scale.12,22 The test was
repeated three times separated by 5 min of
rest, and the best results performed by the
patient were recorded.23
Quality of life
The QoL was evaluated using the Minnesota
Living with Heart Failure Questionnaire
(MLWHF).24 The MLWHFQ assesses a
patient’s perception of the impact of
HF and HF treatment on the physical,
psychological, and social aspects of life.
Statistical analysis
A-priori statistical power examination
showed that n ¼ 10 was the suitable
sample size in order to assess standardized
differences in the main parameters at 0.05
significance level of two-sided hypotheses,
achieving power >95%. All continuous
variables are expressed as mean  standard
deviation of the mean (m  SD). Baseline
comparisons between groups were executed
using the one-way analysis of variance
(ANOVA) test for the normally distributed
variables, the Kruskal–Wallis test for the
non-normally distributed variables, and the
chi-square test for the categorical variables
(gender and medication). The paired t-test
and Wilcoxon signed-rank test were used to
evaluate exercise-induced changes (pre vs.
post) within a particular group. The effect
of intervention between groups, the effect of
time and the effect of group-by-time interac-
tions were evaluated using repeated-measures
ANOVA (RMANOVA). The Friedman test
was used when data is not normally distrib-
uted. Normality was tested using the
Kolmogorov–Smirnov test. The inflation of
type-I error due to multiple comparisons was
controlled using the Bonferroni rule. Finally,
in order to compare the improvement
between groups, the effect size for some
principal parameters was calculated.
The effect size (d) of different parameters
(pre- vs. post-) was calculated using the
following equation: d ¼ l1Sl p
2
, where d is
Cohen’s effect size, l1 and l2 are the pre-
and post-intervention means, and Sp is the
Sadek et al. 7

pooled estimate of variance calculated as
follows:
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ðn1  1ÞS21 þ ðn2  1ÞS22
Sp ¼
n1 þ n2  2
where n1 and n2 are the pre- and post-
intervention sample sizes, and S1 and
S2 are the pre- and post-intervention stan-
dard deviations.
Also, the percentage of improvement for
each outcome was calculated as follows:
(pre–post)/pre100.
Statistical analyses were achieved in
SPSS software (version 20, SPSS Inc.,
Chicago, IL, USA).
Results
Patient characteristics
Fifty patients were randomized, of which 10
did not complete the program for different
reasons. Finally, a total of 40 patients were
enrolled. Baseline characteristics were mea-
sured and are shown in Table 1. No impor-
tant adverse events were observed in any of
the patients. At baseline, there were no sta-
tistically significant differences between all
the patients comprising the four groups
(Table 1). Participants were on a stable
; pharmacological regimen, and all of them
were taking ACE-I/ARB, beta-blocker,
and a diuretic.
Pulmonary function test
No significant difference between the
groups was observed after the intervention
for FVC (L), FEV1 (L), and FEV1/FVC.
No significant group-by-time interaction
was perceived. The within-group analysis
was also accomplished, and a significant
increase in FVC (L) was shown in the com-
bined group (P ¼ 0.040). Data not shown
here.
Respiratory muscle function
Between-group analysis showed that SMIP
and MIP differed significantly after a
12-week exercise intervention. In particular,
participants in the combined and IMT
groups benefited more from the exercise as
compared to the control group. A signifi-
cant group-by-time interaction was detected

Table 1. Demographic and clinical characteristics of patient population.

Control (n ¼ 10) AIT (n ¼ 10) IMT (n ¼ 10) AIT& IMT (n ¼ 10) P-value

Ages (years) 52.6  11.2 51.6  13.8 52.5  13.7 51.8  8.3 0.998
Males/females 5/5 5/5 5/5 5/5 0.943
BMI 27.3  3.4 28.1  3.7 28.3  1.4 27.7  3.9 0.918
FVC (L) 3.2  0.8 3.2  0.9 2.9  0.7 2.9  0.4 0.809
FEV1 (L) 2.4  0.9 2.7  0.8 2.4  0.6 2.3  0.5 0.748
FEV1/FVC 74.9  11.7 84.8  13.5 81.6  12.9 78.3  11.7 0.439
MIP (mmHg) 35.8  10.5 34.4  11.4 36.4  14.3 33.5  13.1 0.966
SMIP (s) 216.3  91 223.1  69.5 245  102.7 244.3  64.3 0.862
MEP (mmHg) 70.1  16.7 66.3  17.8 61.5  18.8 60.1  19.1 0.679
Minnesota score 29.9  10.6 24  6.5 28.1  11.7 24.8  11.3 0.626
6MWT (m) 455.3  113.1 427.6  153 449.6  96.4 462.8  73.1 0.933
Exercise time (s) 475.5  144.7 516.9  123.6 484.4  164 509.5  180.9 0.941
BMI: body mass index; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; MIP: Maximal inspiratory
pressure; MEP: maximal expiratory pressure; SMIP: sustained maximal inspiratory pressure; 6MWT: six-minute walk test;
AIT: aerobic interval training; IMT: inspiratory muscle training.
8 Chronic Illness 0(0)

for MEP (P ¼ 0.013), PI (P < 0.01), and

MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; SMIP: sustained maximal inspiratory pressure; AIT: aerobic interval training; IMT: inspiratory muscle
34.4  11.4 42.8  13.4 0.012* 36.4  14.3 45.5  13.5 0.001 33.5  13.1 54.4  12.5 0.012* 0.020*
216.9  90.9 184.9  92.3 0.624* 223.13  69.5 249.8  75.7 0.381 245  102.7 369  151.5 0.002 244.3  64.3 418.9  56.1 0.017* 0.016*
66.3  17.8 81.1  25.9 0.011 61.5  18.8 84.8  22.9 0.003 60.1  19.1 84.5  28.4 0.010 0.985
SMIP (P < 0.01). Thus, a within-group

Pb
analysis was also done, and a significant
increase in MEP, MIP, and SMIP was

Pa
shown in the combined and IMT groups.
Patients in the HI-AIT group significantly
improved their MEP and MIP, but not

Post
their SMIP (Table 2). Post hoc analysis
showed that there was a significant differ-

AIT & IMT

ence for MIP between the “HI-AIT” and
the control group (P ¼ 0.011) and between

Pre
the “IMT” group and the control group
(P ¼ 0.011). To compare the degree of

Pa
improvement between the groups, the
effect size was calculated (Figure 2), and
the highest improvement was observed in
the combined group.

Stress test Post

P-Values derived using paired Student’s t-test, after checking for the normality of the distributions.
The between-group analysis showed that
IMT

Pre

P-Values between groups derived using repeated measures analysis of variance (RMANOVA).
METs and exercise time varied significantly
after a 12-week exercise intervention. In
particular, significant improvements were
Pa

observed in the combined, HI-AIT, and

IMT groups compared to the control
group. A significant group-by-time interac-
Post

tion was detected for METs (P < 0.01) and

exercise time (P < 0.01). Thus, a within-
group analysis was also performed, and a
significant increase in METs and exercise
AIT

Pre

time was shown in the combined, HI-AIT,

*Pb-Values between groups derived using Friedman test.

and IMT groups (Table 3). Post hoc analy-

36  11.5 0.895

sis revealed a significant difference between

Pa

MEP (mmHg) 70.1  16.7 70.1  18.4 1

“HI-AIT & IMT” and control groups for

*Pa derived using Wilcoxon signed-rank test.
Table 2. Respiratory muscle function.

METs (P ¼ 0.011) and exercise time

(P ¼ 0.009). To compare the degree of
Post

improvement between groups, the effect

size was calculated (Figure 3), and the high-
MIP (mmHg) 35.8  10.5

est improvement was observed in the com-

Control

bined group.
Pre

Functional capacity and QoL

The between-group analysis indicated that
SMIP (s)

training.

6MWT and Minnesota varied significantly

after a 12-week exercise intervention.
b
a
 Sadek et al.

Figure 2. Effect size on respiratory muscle function. MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; SMIP: sustained maximal
inspiratory pressure; AIT: aerobic interval training; IMT: inspiratory muscle training.

Table 3. Stress test.

Control AIT IMT AIT & IMT

Pre Post Pa Pre Post Pa Pre Post Pa Pre Post Pa Pb

METs 8.1  2.1 7.7  2.2 0.424 9.9  1.9 11.7  1.9 0.001 8  2.9 9.7  2.2 0.010 9.9  2.4 13.3  2.9 0.001 0.009
Exercise 474.5  144.7 448.1  168.3 0.889* 516.9  123.6 669.1  144.9 0.001 484.4  164 542.5  157.3 0.047 500.9  180.9 812.8  172.9 <0.001 0.048
time (s)
METs: metabolic equivalent of a task; AIT: aerobic interval training; IMT: inspiratory muscle training.
a
P-Values derived using paired Student’s t-test, after checking for the normality of the distributions.
b
P-Values between groups derived using repeated measures analysis of variance (RMANOVA).
*Pa derived using Wilcoxon signed-rank test.
*Pb-Values between groups derived using Friedman test.
9
 10

Figure 3. Effect size on stress test: METs and exercise time. METs: metabolic equivalent of a task; AIT: aerobic interval training; IMT: inspiratory muscle
training.

Table 4. Functional capacity and quality of life.

Control AIT IMT AIT& IMT

Pre Post Pa Pre Post Pa Pre Post Pa Pre Post Pa Pb

6MWT 455.3  113.1 457.2  104.9 0.905 427.6  153 491.5  170 <0.001 449.6  96.4 532.1  113.9 0.022 462.8  73.1 567.5  75.9 0.017* 0.042*
Minnesota 29.9  10.6 31.6  13.8 0.348 24  6.5 12.8  10.4 0.002 28.1  11.7 18  9.7 0.012* 24.8  11.3 10.8  5.8 0.001 0.002*
6MWT: six-minute walk test; AIT: aerobic interval training; IMT: inspiratory muscle training.
a
P-Values derived using paired Student’s t-test after checking for the normality of the distributions.
b
P-Values between groups derived using repeated measures analysis of variance (RMANOVA).
*Pa derived using Wilcoxon signed-rank test.
*Pb-Values between groups derived using Friedman test.
Chronic Illness 0(0)
Sadek et al.
Figure 4. Effect size on functional capacity and quality of life. 6MWT: six-minute walk test; AIT: aerobic
interval training; IMT: inspiratory muscle training.
In particular, patients in the combined, HI-
AIT, and IMT groups benefited more from
the exercise as compared to the control
group. A significant group-by-time interac-
tion was perceived for 6MWT (P < 0.01)
and Minnesota (P < 0.01). Thus, a within-
group analysis was executed and a signifi-
cant increase in 6MWT and a significant
decrease in Minnesota were shown in the
combined, HI-AIT, and IMT groups
(Table 4). The post hoc analysis indicated
that there was a significant difference
between “HI-AIT & IMT” and control
groups for 6MWT (P ¼ 0.008). For
Minnesota, there was a significant differ-
ence between “HI-AIT & IMT” and control
groups (P ¼ 0.012) and between HI-AIT
and control groups (P ¼ 0.012). To compare
the degree of improvement between
groups, the effect size was calculated
(Figure 4) and the highest improvement
was observed in the combined group.
Discussion
The present study aimed to examine the
additional benefits of the combination of
HI-HI-HI-AIT and IMT over the IMT
and the HI-AIT alone in terms of inspira-
tory muscle function, exercise capacity, and
QoL in patients with CHF and IMW. The
11
results showed that combined training of
HI-AIT and IMT is superior to HI-AIT
alone and IMT alone in all parameters,
especially in respiratory muscle function,
exercise performance, and QoL.
Respiratory muscle function
Both MIP and MEP were significantly
improved in all three groups, compared to
the control group. However, SMIP, which
reflects the inspiratory muscle endurance, is
only increased in the IMT and HI-
AIT&IMT groups.
In our study, the combined exercise was
the most beneficial among all groups regard-
ing MIP, MEP, and SMIP, with an increase
of 62%, 40%, and 72%, respectively.
The increase in respiratory muscle
strength and endurance allow us to hypoth-
esize that IMT can result in an increased
proportion of type I fibers and reduced
type IIb fibers in the external intercostal
muscles. In addition, strengthening inspira-
tory muscles by performing IMT reduces
the amount of oxygen respiratory muscles
require during exercise, resulting in more
oxygen being available to other muscles,
which reduces dyspnea and fatigue.
The findings related to MIP confirm the
claims made by Adamopoulos et al.8 where
12
MIP has improved in HI-AIT and HI-
AIT&IMT groups. These results suggest
that the aerobic training, although it does
not train the respiratory muscles directly,
can improve the inspiratory muscle perfor-
mance, possibly by its “anti-inflammatory”
effect. Concerning SMIP, the 72%
improvement shown for the combined
group might be more attributed to the
IMT, since an incremental increase (51%)
was shown for the IMT group versus no
improvement shown for the HI-AIT
group. Note that the benefits credited to
the IMT were approved in previous stud-
ies.11,13,25 Dall’Ago et al.13 and Bosnak-
Guclu et al.11 reported a 115% and 50%
increase in MIP, respectively, which is
greater than the increase reported in our
IMT group (25%). Possible reasons include
longer IMT duration, different training
regimes, or different HF populations.
Previous HF studies have shown that
improvements in respiratory muscle func-
tion may be attributed to a reduced activity
of inspiratory chemoreflex and metabore-
flex.25 In fact, chemoreflexes are related to
the impacts of the central and peripheral
chemoreceptors on pulmonary ventilation.
However, a metaboreflex is triggered by
skeletal muscle abnormalities, resulting in
metaboreceptors activation. It is also medi-
ated by stimulations that can discharge
group III and IV muscle afferents.7
Alternatively, such improvements may be
due to reduced activity of chemo and metab-
oreflexes that may have been caused by
decreased oscillatory ventilation, desensiti-
zation of the type III/IV afferents secondary
to a reduced metabolite accumulation, or an
increased oxidative capacity of the respira-
tory muscles.26
Stress test
The analysis of the variables measured
during the “Stress Test” gives an important
evaluation of cardiovascular fitness and
Chronic Illness 0(0)
functional capacity. Most important is the
exercise time27 since it was mostly improved
in the combined groups where a synergetic
effect between HI-AIT and IMT was
enough for exerting this amelioration in
the exercise duration. In our study, this
effect is reflected by a mean increment of
62% in the combined group, compared to
29% in the HI-AIT and 10% in the IMT. In
previous reports, Laoutaris et al.17 showed
a 9% increment in the exercise duration,
which is lower than the one recorded in
this study. This is probably due to the fact
that interval training is more effective in
improving exercise time than continuous
training.
However, Adamopoulos et al.8 have
shown that the combined group improved
exercise time by 17%, which was not seen
with the aerobic training group. They pro-
posed that this improvement might be due
to the amelioration in dyspnea and the IMT
symptomatic relief.
Another finding is the additive effect
between the HI-AIT and the IMT concern-
ing METs. Actually, the combined training
resulted in a 34% increment in METs. Such
a benefit could be related to the improved
cardiorespiratory fitness of HF patients.
A possible explanation for the improve-
ment in exercise performance might be
because of the inhibition of the inspiratory
metaboreflex hyperactivity that is usually
shown in HF patients during physical exer-
cise. This fact decreases sympathetic activi-
ty and peripheral vasoconstriction, leading
to increased blood flow to the active skele-
tal muscles.7,28
Functional capacity and QoL
It has been shown that the IMT improves
functional capacity in patients with CHF or
with IMW,13,26 whereas aerobic training
partially improves functional capacity and
QoL in those patients.2
Sadek et al.
Patients in both IMT and HI-AIT
groups increased their walking distance sig-
nificantly (18.3% and 14.9%, respectively).
But a greater benefit was shown for the
combined group (22.6%) and this can be
explained by the significant amelioration
in exercise performance.
In this study, we have shown that exer-
cise training can improve the quality of
CHF patients’ life. Each exercise training
program, IMT, HI-AIT, and combined
protocols resulted, respectively, in a 36%,
46%, and 56% decrease in the Minnesota
score, which reflects amelioration in the
daily living limitations, mainly for the com-
bined groups.
Consequently, an improvement was
shown in both 6MWT and QoL for the
IMT and the combined groups, with a
greater benefit for the latter, suggesting
that the HI-AIT may provide important
symptomatic relief and improve the daily
life activities.
Clinical implications
Finally, these findings may have important
implications for exercise training in cardiac
rehabilitation programs. Interval aerobic
training and IMT appear to be well-
tolerated, easy, and safe to use for clinical
practice in heart failure patients.
In addition, combining of IMT to inter-
val aerobic training has been promising and
has proved to be more beneficial than each
training modality taken alone in heart fail-
ure patients.
Finally, both IMT and HI-AIT can be
considered as simple, inexpensive, and
harmless interventions that could be imple-
mented in home-based exercise programs.
Conclusion and limitations
This randomized clinical trial verified that
in patients with CHF and IMW, the com-
bination of the HI-AIT and the IMT results
13
is an additional improvement in the inspi-
ratory muscle function, which could be
mediated by reduced activity of metabore-
flex and chemoreflex. This effect may be
related to the reduced functional capacity
and the exercise intolerance observed in
our study. Since it was not possible to
assess aerobic capacity through measuring
peak oxygen consumption (VO2max), we
have used the prognostic outcome
“METs” as alternative option. METs have
been approved to be used instead of direct
measurement of oxygen uptake.20,29
Acknowledgements
The authors would like to thank Professor
Hassan Khachfe for constructive criticism of
the manuscript and for comments that greatly
improved the manuscript.
Contributorship
ZS and WR contributed to the conception and
the design of the work. ZS and CA drafted the
manuscript. AS contributed to the analysis and
the interpretation of data for the work. MY and
MH contributed to the patient recruitment,
examination and medical follow-up. WHJ, WR
and SA critically revised the manuscript. All
gave final approval and agree to be accountable
for all aspects of work ensuring integrity and
accuracy.
Declaration of conflicting interests
The author(s) declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
Ethical approval
An approval for the experimental protocol was
obtained from the Committee for Ethics in
Research of Beirut Cardiac Institute OTLY-P-
38F-16.
Funding
The author(s) disclosed receipt of the following
financial support for the research, authorship,
and/or publication of this article: This work
14
was supported by the National Council for
Scientific Research (CNRS), Beirut, Lebanon
(2015–2018) and the Islamic Center Association
for Guidance and Higher Education, Beirut,
Lebanon (2014–2018).
Guarantor
ZS.
Informed consent
A written informed consent form was signed and
obtained from all the participating subjects.
ORCID iDs
Zahra Sadek https://orcid.org/0000-0003-
4985-8465
Ali Salami https://orcid.org/0000-0003-3343-
4035
References
1. Clark AL, Poole-Wilson PA and Coats A.
Exercise limitation in chronic heart failure:
central role of the periphery. J Am Coll
Cardiol 1996; 28: 1092–1102.
2. O’Connor CM, Whellan DJ, Lee KL, et al.
Efficacy and safety of exercise training in
patients with chronic heart failure: HF-
ACTION randomized controlled trial.
JAMA 2009; 301: 1439–1450.
3. Roger VL, Weston SA, Redfield MM, et al.
Trends in heart failure incidence and surviv-
al in a community-based population. JAMA
2004; 292: 344–350.
4. Lesyuk W, Kriza C and Kolominsky-Rabas
P. Cost-of-illness studies in heart failure: a
systematic review 2004-2016. BMC
Cardiovasc Disord 2018; 18: 1–11.
5. Coats AJS, Clark AL, Piepoli M, et al.
Symptoms and quality of life in heart failure:
the muscle hypothesis. Br Hear J 1994; 72:
36–39.
6. Mancini DM, Henson D, Manca J, et al.
Benefit of selective respiratory muscle train-
ing on exercise capacity in patients with
chronic congestive heart failure. Am Hear
Assoc 1995; 91: 320–329.
Chronic Illness 0(0)
7. Harms CA. Insights into the role of the
respiratory muscle metaboreflex. J Physiol
(Lond) 2007; 584: 711.
8. Adamopoulos S, Schmid J-P, Dendale P,
et al. Combined aerobic/inspiratory muscle
training vs. aerobic training in patients with
chronic heart failure. Eur J Heart Fail 2014;
16: 574–582.
9. Kiilavuori K, N€averi H, Salmi T, et al. The
effect of physical training on skeletal muscle
in patients with chronic heart failure. Eur J
Hear Fail J Work Gr Hear Fail Eur Soc
Cardiol 2000; 2: 53–63.
10. Wisløff U, Støylen A, Loennechen JP, et al.
Superior cardiovascular effect of aerobic
interval training versus moderate continuous
training in heart failure patients: a random-
ized study. Circulation 2007; 115: 3086–3094.
11. Bosnak-Guclu M, Arikan H, Savci S, et al.
Effects of inspiratory muscle training in
patients with heart failure. Respir Med
2011; 105: 1671–1681.
12. Weiner P, Waizman J, Magadle R, et al. The
effect of specific inspiratory muscle training
on the sensation of dyspnea and exercise tol-
erance in patients with congestive heart fail-
ure. Clin Cardiol 1999; 22: 727–732.
13. Dall’Ago P, Chiappa GRS, Guths H, et al.
Inspiratory muscle training in patients with
heart failure and inspiratory muscle weak-
ness: a randomized trial. J Am Coll Cardiol
2006; 47: 757–763.
14. Winkelmann ER, Chiappa GR, Lima COC,
et al. Addition of inspiratory muscle training
to aerobic training improves cardiorespira-
tory responses to exercise in patients with
heart failure and inspiratory muscle weak-
ness. Am Heart J 2009; 158: 768.e1–768.e7.
15. Menzes KKP. A review on respiratory
muscle training devices. J Pulm Respir Med
2018; 8: 451.
16. Sadek Z, Salami A, Joumaa WH, et al. Best
mode of inspiratory muscle training in heart
failure patients: a systematic review and
meta-analysis. Eur J Prev Cardiol. 2018; 25:
1691–1701.
17. Laoutaris ID, Adamopoulos S, Manginas A,
et al. Benefits of combined aerobic/resis-
tance/inspiratory training in patients with
chronic heart failure. A complete exercise
Sadek et al.
model? A prospective randomised study. Int
J Cardiol 2013; 167: 1967–1972.
18. Laoutaris ID, Dritsas A, Brown MD, et al.
Immune response to inspiratory muscle
training in patients with chronic heart fail-
ure. Eur J Cardiovasc Prev Rehabil 2007; 14:
679–685.
19. Bruce RA, Kusumi F and Hosmer D.
Maximal oxygen intake and nomographic
assessment of functional aerobic impairment
in cardiovascular disease. Am Heart J 1973;
85: 546–562.
20. Wicks JR, Oldridge NB, Nielsen LK, et al.
HR index—a simple method for the predic-
tion of oxygen uptake. Med Sci Sports Exerc
2011; 43: 2005–2012.
21. Beatty AL, Schiller NB and Whooley MA.
Six-minute walk test as a prognostic tool in
stable coronary heart disease: data from the
Heart and Soul Study. Arch Intern Med
2012; 172: 1096–1102.
22. Grant S, Aitchison T, Henderson E, et al.
A comparison of the reproducibility and
the sensitivity to change of visual analogue
scales, Borg scales, and Likert scales in
normal subjects during submaximal exercise.
Chest 1999; 116: 1208–1217.
23. Laoutaris I, Dritsas A, Brown MD, et al.
Inspiratory muscle training using an incre-
mental endurance test alleviates dyspnea
and improves functional status in patients
15
with chronic heart failure. Eur J Cardiovasc
Prev Rehabil 2004; 11: 489–496.
24. Bilbao A, Escobar A, Garc
ıa-Perez L, et al.
The Minnesota living with heart failure ques-
tionnaire: comparison of different factor
structures. Health Qual Life Outcomes 2016;
14: 23.
25. Meirelles L. D, Matsuura C, Resende A. D C,
et al. Chronic exercise leads to antiaggregant,
antioxidant and anti-inflammatory effects in
heart failure patients. Eur J Prev Cardiol
2013; 21: 1225–1232.
26. Ribeiro JP, Chiappa GR and Callegaro CC.
The contribution of inspiratory muscles
function to exercise limitation in heart fail-
ure: pathophysiological mechanisms. Rev
Bras Fisioter 2012; 16: 261–267.
27. Miller TD. The exercise treadmill test: esti-
mating cardiovascular prognosis. Cleve Clin
J Med 2008; 75: 424–430.
28. Witt JD, Guenette JA, Rupert JL, et al.
Inspiratory muscle training attenuates the
human respiratory muscle metaboreflex.
J Physiol 2007; 584: 1019–1028.
29. Miyamoto S, Nagaya N, Satoh T, et al.
Clinical correlates and prognostic signifi-
cance of six-minute walk test in patients
with primary pulmonary hypertension. Am
J Respir Crit Care Med 2000; 161(2 Pt 1):
487–492.