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Muscle electrical stimulation improves

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DOI: 10.1177/2047487316654025

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 EURO PEAN
SO CIETY O F
Original scientific paper CARDIOLOGY

European Journal of Preventive

Cardiology

Muscle electrical stimulation 0(00) 110

! The European Society of
Cardiology 2016
improves neurovascular control and Reprints and permissions:
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exercise tolerance in hospitalised DOI: 10.1177/2047487316654025
ejpc.sagepub.com
advanced heart failure patients

Raphaela V Groehs1, Ligia M Antunes-Correa1, Thais S Nobre1,

Maria-Janieire NN Alves1, Maria Urbana PB Rondon2,
Antonio Carlos Pereira Barreto1 and Carlos E Negrao1,2

Abstract
Background: We investigated the effects of muscle functional electrical stimulation on muscle sympathetic nerve
activity and muscle blood flow, and, in addition, exercise tolerance in hospitalised patients for stabilisation of heart failure.
Methods: Thirty patients hospitalised for treatment of decompensated heart failure, class IV New York Heart
Association and ejection fraction  30% were consecutively randomly assigned into two groups: functional electrical
stimulation (n 15; 54  2 years) and control (n 15; 49  2 years). Muscle sympathetic nerve activity was directly
recorded via microneurography and blood flow by venous occlusion plethysmography. Heart rate and blood pressure
were evaluated on a beat-to-beat basis (Finometer), exercise tolerance by 6-minute walk test, quadriceps muscle
strength by a dynamometer and quality of life by Minnesota questionnaire. Functional electrical stimulation consisted
of stimulating the lower limbs at 10 Hz frequency, 150 ms pulse width and 70 mA intensity for 60 minutes/day for 810
consecutive days. The control group underwent electrical stimulation at an intensity of < 20 mA.
Results: Baseline characteristics were similar between groups, except age that was higher and C-reactive protein and
forearm blood flow that were smaller in the functional electrical stimulation group. Functional electrical stimulation
significantly decreased muscle sympathetic nerve activity and increased muscle blood flow and muscle strength. No
changes were found in the control group. Walking distance and quality of life increased in both groups. However, these
changes were greater in the functional electrical stimulation group.
Conclusion: Functional electrical stimulation improves muscle sympathetic nerve activity and vasoconstriction and
increases exercise tolerance, muscle strength and quality of life in hospitalised heart failure patients. These findings
suggest that functional electrical stimulation may be useful to hospitalised patients with decompensated chronic heart
failure.

Keywords
Heart failure, electrical stimulation, sympathetic nerve activity, vasoconstriction, exercise tolerance
Received 27 January 2016; accepted 20 May 2016

Introduction
Heart failure (HF) with reduced ejection fraction is a 1
Heart Institute (InCor), University of Sao Paulo Medical School, Brazil
2
complex syndrome caused by insucient cardiac School of Physical Education and Sport, University of Sao Paulo, Brazil
output to maintain the metabolic demand.1 Exercise
intolerance and dyspnoea are the hallmarks of HF.2 Corresponding author:
Carlos E Negrao, Instituto do Coracao HC/FMUSP, Av. Dr. Eneas de
Despite the advances in the treatment of HF, this syn- Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo SP Brazil,
drome is by far the most predominant cause of death CEP 05403-000.
among patients with cardiovascular disease.1 E-mail: cndnegrao@incor.usp.br

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2 European Journal of Preventive Cardiology 0(00)
Moreover, these statistics tend to get worse with the
increase in the elderly population.3
Observational information shows that the hospital-
isation rate for unstable HF is high. In addition, the
duration of hospitalisation may be long, with serious
economic consequences. Previous studies have shown
that prolonged inactivity exacerbates exercise intoler-
ance worsening patients recovery.4,5 Thus, strategies
to prevent inactivity during hospitalisation for treat-
ment of decompensated HF represent a challenge in
clinical practice.
Neurohumoral activation is a marker of HF with
reduced ejection fraction.6,7 Sympathetic nerve activity,
assessed indirectly by plasma norepinephrine levels8 and
norepinephrine spillover9 or directly by nerve record-
ings,6 is augmented in patients with chronic HF.
Increases in the reninangiotensinaldosterone system
have been consistently reported in HF.10 Although neu-
rohumoral activation exerts an initial compensatory
response on the cardiac level and consequently on under-
perfusion of tissues, the sustained adrenergic and renin
angiotensinaldosterone system hyperactivation leads to
progression and deterioration of the cardiac dysfunction,
worsening patients outcome.6,11 This knowledge raises
the importance of reducing neurohumoral activation in
the treatment of chronic HF.
Sympathetic nerve activation has haemo-
dynamic implications, including vasoconstriction2,12
and impairment in peripheral blood ow distribution.
The vasoconstriction state caused by HF induces
pro-inammation, oxidative stress and protein degrad-
ation.11 More importantly, sympathetic activation is asso-
ciated with an increased mortality rate in HF patients.8,13
Previous studies have shown that exercise training is
safe and, more importantly, markedly benets patients
with HF. Exercise training reduces sympathetic nerve
activity and peripheral vasoconstriction, thereby
improving exercise tolerance and quality of life.12,14,15
However, exercise training is not recommended for
unstable HF patients. Recent studies have demon-
strated that involuntary muscle contraction by elec-
trical stimulation increases muscle strength and
exercise tolerance in outpatients with HF.1619 These
ndings raise the question that muscle functional elec-
trical stimulation (FES) may be useful during hospital-
isation in decompensated chronic HF patients. Despite
previous studies dealing with muscle electrical stimula-
tion lasting for some weeks, this approach may prevent
inactivity and likely the worsening of clinical conditions
even in a short period of hospitalisation. Moreover,
muscle electrical stimulation may improve neurovascu-
lar control. In fact, the eects of FES on sympathetic
nerve activity and peripheral vasoconstriction in hospi-
talised chronic HF patients for stabilisation of cardiac
dysfunction are unknown. This is an important issue,
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because sympathetic nerve activity and muscle blood
ow are independent predictors of mortality in chronic
HF patients.13
We tested the hypothesis that lower limb FES would
decrease muscle sympathetic nerve activity (MSNA)
and would alleviate vasoconstriction in hospitalised
HF patients. In addition, FES would increase muscle
strength, exercise tolerance and quality of life.
Methods
Study population
Thirty patients, New York Heart Association (NYHA)
functional class IV, ejection fraction  30%, aged from
18 to 70 years, admitted to the hospital for treatment
of decompensated HF were recruited to the study.
The exclusion criteria were body mass index >30,
uncontrolled hypertension, lung disease and oxygen-
dependent, neurological and neuromuscular diseases
manifesting as paraesthesia or plegia of the lower
limbs, type I diabetes mellitus, peripheral arterial
obstructive disease, peripheral neuropathy, use of
permanent pacemaker or an implantable cardio-
debrillator because of the possible risk of interference
of the electric current generated by FES in the rhythm
of these devices. The patients were consecutively ran-
domly assigned into two groups: (a) the FES group
(n 15) and (b) the control group (n 15). When the
patients were selected for the study, they were symp-
tomatic and on titration of oral medication.
Medications were prescribed according to patients
needs. They included beta-blockers, angiotensin-con-
verting enzyme inhibitors/angiotensin II receptor
antagonists, diuretics, anticoagulants, digitalis, statins,
vasodilators and antiplatelet agents. At that time, no
intravenous medication was used. Although symptom-
atic, the patients could walk and do daily activities with
limitations. The evaluations were carried out at the
beginning of the titration of oral medication and one
day before discharge. This period lasted a minimum of
8 days and a maximum of 10 days. This study was
performed in accordance with the Declaration of
Helsinki and was approved by the Research
Committee of the Heart Institute (SDC 3354/09/105)
and the Human Subject Protection Committee at the
Clinical Hospital of the School of Medicine of the
University of Sao Paulo (CAPPesq- no. 12/04/09).
The study is the product of a doctoral thesis, which
was defended in the cardiology graduate programme
at the School of Medicine, University of Sao Paulo.
All subjects provided written informed consent prior
to participation in the study. This trial is registered at
www.ClinicalTrials.gov (unique identier
#NCT01886430).
Groehs et al.
Measurements and procedures
Muscle sympathetic nerve activity. MSNA was recorded
directly from the peroneal nerve (multiunit post-gang-
lionic) via microneurography as previously described.20
Muscle sympathetic bursts were visually identied by
the principal investigator and two other investigators
(CEN and MUR) in a blinded manner. MSNA was
expressed as burst frequency (bursts per minute) and
burst incidence (bursts per 100 heart beats).
Leg blood flow. Leg blood ow was measured via venous
occlusion plethysmography. The patients were placed
in the supine position. A mercury-lled silastic tube
attached to a low-pressure transducer was placed
around the leg and connected to a plethysmograph
(Hokanson AI6). Sphygmomanometer cus were
placed around the ankle and the thigh. At 10 second
intervals, the upper thigh cu was inated above the
venous pressure for 10 seconds. Leg blood ow was
recorded during all experiments and was expressed in
mL/minute/100 mL. Leg vascular conductance (units)
was calculated by dividing leg blood ow by mean
arterial pressure; this result was multiplied by 100.
Forearm blood flow. Forearm blood ow was measured
via venous occlusion plethysmography as previously
described.21 Forearm vascular conductance (units) was
calculated by dividing forearm blood ow by mean
arterial pressure; this result was multiplied by 100.
Arterial blood pressure and heart rate. Arterial blood pres-
sure was non-invasively evaluated using a nger photo-
plethysmograph (Finometer Pro; Finapress Medical
Systems, Amsterdam, The Netherlands). Heart rate
was evaluated via electrocardiography.
Muscular strength. The isometric maximal voluntary
strength of the knee extensor was measured using a
dynamometer (Dynamometer Kratos DLC model).
The maximal muscle strength was determined as the
greatest maximal voluntary contraction of the quadri-
ceps muscle of three consecutive knee extension
repetitions.
Exercise tolerance. The 6-minute walk test was performed
in a 20 -m-long unobstructed corridor containing mark-
ings on the oor at every metre.22 The patients were
instructed to cover as much distance as possible
during the 6-minute period. The total distance walked
was registered at the end of 6 minutes and was assessed
before and after the 810-day study period.
Quality of life. Patients quality of life was evaluated using
the Minnesota Living with Heart Failure Questionnaire.23
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3
Blood measures. Blood samples were obtained to meas-
ure the plasma B-type natriuretic peptide (BNP), C-
reactive protein (CRP), creatinine, sodium, potassium,
urea and haemoglobin levels.
Muscle FES protocol. The quadriceps and gastrocnemius
muscles of both legs were electrically and simultan-
eously stimulated. On the quadriceps, two self-adhesive
surface electrodes 5  9 cm (ValuTrode) were pos-
itioned on the skin approximately 5 cm below the ingu-
inal fold and 3 cm above the upper patella border. On
the gastrocnemius, two 5  5-cm electrodes
(ValuTrode) were positioned approximately 3 cm
below the popliteal fossa and 5 cm above the Achilles
tendon. The electrical stimulation protocol consisted of
electrical current at 10 Hz frequency, 150 ms pulse
width (Quark Fes Vif 995-Four Quark electrotherapy
device), 20 seconds stimulation time (time on) and
20 seconds resting time (time o) for 60 minutes. The
stimulation intensity was selected according to the dis-
comfort threshold of the patient and was monitored
daily until a maximum amplitude of 70 mA was
achieved to induce visible muscle contractions. The
rst session of electrical stimulation was initiated
using a low amplitude (30 mA), which was gradually
increased by 10 mA/day until a nal amplitude of 70
mA was achieved. FES was conducted during the entire
period of hospitalisation, which lasted a minimum of 8
days and a maximum of 10 days. The control group
was exposed to the same protocol except the intensity
of stimulation that was set to <20 mA, which does not
induce visible contractions. To avoid any motivational
interference, the patients were not informed if they
belonged in the control group or the FES group.
Experimental protocol
The experimental protocol started with blood sample
collection at a fasting condition for at least 8 hours.
Then the patient was fed and 23 hours later submitted
to the experimental protocol, which was performed in a
quiet and thermoneutral room with no interruption of
cardiac medications. In the supine position, electrodes
were placed on the chest for EKG recordings and cus
on the left arm for arterial pressure measures. After
instrumentation, MSNA, blood ow, arterial pressure
and heart rate measures were obtained for 10 minutes.
Then, muscular strength was evaluated and 6-minute
walk test conducted. Finally, patients responded to
the quality of life questionnaire.
Statistical analysis
The primary endpoint was the reduction in MSNA
provoked by lower limb FES for 810 days.
4 European Journal of Preventive Cardiology 0(00)

The secondary endpoint was the increase in muscle Table 1. Baseline characteristics of the hospitalized advanced
blood ow provoked by FES. The sample size was heart failure patients who underwent muscle functional electrical
based on our previous studies conducted on chronic stimulation or control stimulation.
heart failure patients.15 The data are shown as the Control FES
mean  standard error (SE). A chi-squared (2) test (n 15) (n 15) P value
was used to assess dierences in the categorical data.
The KolmogorovSmirnov and Levenes tests were Age (years) 49  2 54  2 0.05
used to assess the normality of the distribution and BMI (kg/m2) 22  1 25  1 0.07
homogeneity, respectively, of each variable. Baseline Ejection fraction 22  1 22  1 0.94
dierences between the groups were tested using Gender
Students t test for unpaired data. A two-way repeated Male 13 (87%) 14 (93%) 0.54
measures analysis of variance was used to verify the Female 2 (13%) 1 (7%)
between-group dierences pre and post-intervention. Hospitalisation period (days) 91 91 0.55
In case of signicant dierence, the Schee post hoc NYHA functional class IV 15 (100%) 15 (100%) 1.00
analysis was employed. Pearson correlation was used
HF aetiology
to test the association between the changes (delta) in
Idiopathic 5 (33%) 3 (20%) 0.41
cardiovascular, autonomic and functional variable pre
and post-intervention. P < 0.05 was considered to be Ischaemic 3 (20%) 7 (47%) 0.12
signicant. Hypertensive 0 1 (7%) 0.35
Chagasic 7 (47%) 4 (27%) 0.26
BNP (pg/ml) 929  178 1026  157 0.88
Results CRP (mg/l) 15.3  4.4 5.7  1.0 0.04
Serum creatinine (mg/dL) 1.30  0.08 1.37  0.11 0.59
Basal measurements
Serum sodium (mEq/L) 135  1 136  1 0.33
The baseline characteristics of the patients in the control Serum potassium (mEq/L) 4.8  0.1 4.6  0.1 0.17
and FES groups are shown in Table 1. No between-group Serum urea (mg/dL) 71.3  6.7 62.1  6.6 0.34
dierences in body mass index, ejection fraction, gender, Haemoglobin (g/dL) 12.8  0.4 13.4  0.4 0.28
hospitalisation period, functional class or aetiology were
observed. The patients who underwent FES were older The values are presented as the means  SE.
than the control patients. The patients displayed similar FES: muscle functional electrical stimulation;
BMI: body mass index; NYHA: New York Heart Association;
BNP, creatinine, sodium, potassium, urea and haemoglo- HF: heart failure; BNP: plasma B-type natriuretic peptide;
bin levels; however, the CRP level was higher in the con- CRP: C-reactive protein.
trol group. There were no dierences in medications
between the control group and FES group at the begin-
ning and end of treatment (Table 2).
The cardiovascular and autonomic parameters and
exercise tolerance are shown in Table 3. No between-
group dierences in heart rate or systolic, diastolic or Table 2. Medications in control patients and patients submitted
mean arterial pressure were observed. The MSNA burst to functional electrical stimulation at the beginning and end of the
frequency and burst incidence were also similar study.
between the groups. Leg blood ow and vascular con- Control FES
ductance did not dier between the groups. Forearm
blood ow was higher in the control group than in the Pre Post Pre Post
FES group, but no between-group dierence in forearm Beta-blocker 13 (87%) 11 (73%) 15 (100%) 14 (93%)
vascular conductance was observed. The 6-minute ACEI/ARA 13 (87%) 13 (87%) 12 (80%) 13 (87%)
walking distance, knee extensor muscle strength and
Diuretic 13 (87%) 12 (80%) 14 (93%) 11 (73%)
quality of life scores were similar between the FES
Anticoagulant 13 (87%) 9 (60%) 12 (80%) 13 (87%)
and control groups.
Digitalis 1 (7%) 1 (7%) 5 (33%) 5 (33%)
Statin 5 (33%) 5 (33%) 7 (47%) 7 (47%)
Effects of muscle FES Vasodilator 9 (60%) 7 (47%) 9 (60%) 11 (73%)
The FES and control groups caused no changes in Antiplatelet 4 (27%) 4 (27%) 5 (33%) 5 (33%)
heart rate or systolic, diastolic or mean arterial pressure Values are presented as the means  SE.
(Table 4). FES, but not control stimulation, signi- FES: muscle functional electrical stimulation; ACEI/ARA: angiotensin-con-
cantly decreased the MSNA burst frequency verting enzyme inhibitor/angiotensin II receptor antagonist.

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Groehs et al. 5

Table 3. Baseline cardiovascular, autonomic and functional (Figure 1(a), P 0.002) and burst incidence
parameters in hospitalised advanced heart failure patients who (Figure 1(b), P 0.04) and signicantly increased leg
underwent muscle functional electrical stimulation or control blood ow (Figure 2(a), P < 0.001) and leg vascular
stimulation. conductance (Figure 2(b), P < 0.001). Between-group
Control FES comparisons showed that the changes in leg blood
(n 15) (n 15) P value ow (Figure 2(a), P < 0.001) and leg vascular conduct-
ance (Figure 2(b), P < 0.001) were greater in the FES
Cardiovascular parameters group than in the control group. No changes in forearm
Heart rate (bpm) 84  5 82  3 0.81 blood ow or forearm vascular conductance were
SAP (mmHg) 106  5 111  6 0.50 observed between the FES and control groups
DAP (mmHg) 69  3 75  3 0.11 (Table 4).
MAP (mmHg) 81  3 88  3 0.21 Both the FES and control groups increased the 6-
LBF (ml/min/100 ml) 1.09  0.10 0.88  0.09 0.12 minute walking distance (Figure 3, P < 0.001 and
LVC (U) 0.89  0.09 0.80  0.10 0.51 P 0.001, respectively). However, the between-group
FBF (ml/min/100 ml) 2.04  0.19 1.43  0.06 0.05 comparisons indicated that the changes in walking dis-
FVC (U) 1.81  0.19 1.30  0.07 0.12
tance were greater in the FES group than in the control
group (Figure 3, P < 0.001). The knee extensor muscle
Autonomic parameters
strength was signicantly increased (Table 4, P < 0.001)
MSNA frequency (bursts/min) 41  3 49  5 0.28
in the FES group but not in the control group. Thus,
MSNA incidence 45  4 59  6 0.12 the between-group comparisons showed that the knee
(bursts/100 HB)
extensor muscle strength was higher in the FES group
Functional parameters than in the control group (Table 4, P 0.001). The
6-MWT (m) 320  22 304  25 0.66 quality of life score was signicantly increased in the
Knee extensor strength (kgf) 15  2 13  1 0.52 FES (Table 4, P < 0.001) and control groups (Table 4,
Quality of life 70  3 69  5 0.92 P < 0.001). However, the between-group comparisons
The values are presented as the means  SE.
revealed that the quality of life score changes were
FES: muscle functional electrical stimulation; SAP: systolic arterial pres- greater in the FES group than in the control group
sure; DAP: diastolic arterial pressure; MAP: mean arterial pressure; LBF: (Table 4, P 0.001).
leg blood flow; LVC: leg vascular conductance; FBF: forearm blood flow; Further analysis showed a signicant correlation
FVC: forearm vascular conductance; MSNA: muscle sympathetic nerve between the changes in MSNA burst frequency and 6-
activity; 6-MWT: distance walked in a 6-minute walk test.
minute walking distance (Table 5, P < 0.01) and BNP
(Table 5, P < 0.02). There was also correlation between
the changes in knee extensor muscle strength and the
Table 4. Effect of muscle functional electrical stimulation on
cardiovascular parameters, muscle strength and quality of life in
changes in leg blood ow (Table 5, P 0.02), 6-minute
hospitalised advanced heart failure patients. walking distance (Table 5, P < 0.001) and quality of life
score (Table 5, P < 0.001). The changes in leg blood
Control FES ow correlated with the changes in 6-minute walking
distance (Table 5, P < 0.001). Finally, the changes in 6-
Pre Post Pre Post
minute walking distance correlated with the changes in
Heart rate (bpm) 84  5 80  3 82  3 77  2 quality of life scores (Table 5, P < 0.001).
SAP (mmHg) 106  5 107  3 111  6 116  5
DAP (mmHg) 69  3 68  2 75  3 74  4 Follow-up
MAP (mmHg) 81  3 81  2 88  3 90  4
FBF(ml/min/ 2.04  0.19 1.68  0.14 1.43  0.06y 2.06  0.12 Three patients from the control group versus no patient
100 ml) from the FES group were readmitted to the hospital in
FVC (U) 1.81  0.19 1.42  0.11 1.30  0.07 1.89  0.15 a 30-day period for treatment of HF. Moreover, one-
Knee extensor 15  2 16  2 13  1 21  2*y
year follow-up showed that the readmission rate was
strength (kgf) seven patients in the control group and ve patients
Quality of life 70  3 45  3* 69  5 26  3*y
in the FES group.

Values are presented as the means  SE.

FES: muscle functional electrical stimulation; SAP: systolic arterial pres-
sure; DAP: diastolic arterial pressure; MAP: mean arterial pressure;
FBF: forearm blood flow; FVC: forearm vascular conductance.
*Within-group comparison, P < 0.05;
y
Between-group comparison, P < 0.05.
Discussion
The main and new ndings of this study are that muscle
electrical stimulation reduces MSNA and increases
muscle blood ow in hospitalised patients with

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6 European Journal of Preventive Cardiology 0(00)

(a) * (b) *
80 100

MSNA (bursts/100HB)
90
MSNA (bursts/min)

70
80
60
70
50 60
40 50
30 40
30
20
20
10 10
0 0

Pre Post Pre Post Pre Post Pre Post

Control FES Control FES
60 70

MSNA (bursts/100HB)
50 60 *
MSNA (bursts/min)

* 50
40
40
30
30
20
20
10 10

0 0
Control FES Control FES

Figure 1. Muscle sympathetic nerve activity (MSNA) burst frequency (bursts/minute) (a) and burst incidence (bursts/100 heart
beats) (b) in hospitalised heart failure (HF) patients subjected to 810-day control stimulation (controls, n 9) or muscle functional
electrical stimulation (FES, n 12). Note that the patients who received FES, but not the control patients, exhibited a marked
reduction in the MSNA burst frequency and burst incidence. *Within-group comparison, P < 0.05.

(a) (b)

3.5 3.5
LBF (ml/min/100ml)

3 3
2.5 2.5
LVC (U)

2 2
1.5 1.5
1 1
0.5 0.5
0 0
Pre Post Pre Post Pre Post Pre Post
Control FES Control FES

1.8 1.8
1.6
LBF (ml/min/100ml)

1.6
1.4 1.4
1.2 1.2
LVC (U)

1 1
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0 0
Control FES Control FES

Figure 2. Leg blood flow (LBF) (a) and leg vascular conductance (LVC) (b) in hospitalised heart failure (HF) patients subjected to 8
10-day control stimulation (controls, n 15) or muscle functional electrical stimulation (FES, n 14). Note that FES, but not the
control stimulation, markedly increased LBF and LVC. *Within-group comparison, P < 0.05; yBetween-group comparison, P < 0.05.

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Groehs et al. 7

600

500

6MWT (m) 400

300

200

100

Pre Post Pre Post

Control FES

500
450
400
350
6MWT (m)

300
250
200
150
100
50
0
Control FES

Figure 3. Walking distance on the 6-minute walk test (6-MWT) in hospitalised heart failure (HF) patients subjected to 810-day
control stimulation (controls, n 13) or muscle functional electrical stimulation (FES, n 14). Note that FES, but not the control
stimulation, markedly increased the walking distance. *Within-group comparison, P < 0.05; yBetween-group comparison, P < 0.05.

Table 5. Association between the changes in cardiovascular, autonomic and functional parameters in hospitalized advanced heart
failure patients.

BNP
Quality
6-MWT
LBF
Knee extensor
MSNA frequency

(pg/ml) of life (m) (ml/min/100 ml) strength (kgf) (bursts/min)

MSNA frequency (bursts/min) 0.56* 0.07 0.58* 0.35 0.22 1

Knee extensor strength (kgf) 0.09 0.54* 0.70* 0.44* 1

LBF (ml/min/100 ml) 0.01 0.35 0.63* 1

6-MWT (m) 0.07 0.61* 1

Quality of life 0.20 1

BNP (pg/ml) 1
MSNA: muscle sympathetic nerve activity; LBF: leg blood flow; 6-MWT: distance walked in a 6-minute walk test; BNP: plasma B-type natriuretic
peptide. *P < 0.05.

decompensated chronic HF. In addition, this type of
approach increases the 6-minute walking test distance.
Sympathetic nerve activity has been associated with
poor prognosis in HF patients. In a classic study, Cohn
and collaborators24 demonstrated that plasma
norepinephrine concentration guides prognosis in
chronic HF patients. More recently, we found that
MSNA is an independent predictor of mortality in
chronic HF patients.13 Thus, approaches to reduce
sympathetic activation are of great interest in the

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8 European Journal of Preventive Cardiology 0(00)
treatment of chronic HF. Exercise training has been
shown to provoke a remarkable reduction in MSNA
in patients with chronic HF.15,25 More recently,
Labrunee et al.26 described that an acute session of
neuromuscular electrostimulation (muscle and sensorial
stimulation) and transcutaneous electrical nerve stimu-
lation (sensorial stimulation) decreases MSNA levels in
outpatients with chronic HF. Our study extends this
knowledge. We found that muscle electrical stimulation
for an 810-day period during hospitalisation to com-
pensate chronic HF signicantly decreased MSNA.
An increase in muscle blood ow after weeks of FES
in outpatients with HF has been reported.18,27 The nov-
elty of our study is that this improvement in muscle
circulation can be achieved during hospitalisation to
treat decompensated HF. An 810-day period of
lower limbs electrical stimulation increases muscle
blood ow in hospitalised chronic HF patients. The
mechanisms involved in this response are out of the
scope of our study. However, the mediation of sympa-
thetic nerve activity in the peripheral vasoconstriction
in HF28,29 suggests that the reduction in MSNA plays a
role in the amelioration of muscle blood ow in the
present study. Of course, we cannot rule out other
mechanisms. Improved endothelial function has been
described in exercise-trained HF patients.30,31
Likewise, increases in capillary density and neoangio-
genesis have been reported.32,33
Another nding of great interest in our study is the
increase in exercise tolerance in patients who underwent
FES. In fact, this nding has clinical implications. The
6-minute walking test distance is associated with clin-
ical outcome and quality of life in patients with HF.34
Moreover, the increase in leg strength and 6-minute
walking distance are evidence that muscle electrical
stimulation counteracts muscle strength lost and exer-
cise intolerance provoked by long periods of hospital-
isation. Improvement in exercise tolerance after weeks
of FES in outpatients with HF has previously been
reported.17,35,36 Our study conrms these ndings in
hospitalised chronic HF patients. There is no denitive
explanation for this response. However, someone could
suggest that the improvement in neurovascular control
contributed to the increase in exercise tolerance. The
rational for this theory is that the reduction in sympa-
thetic nerve activity increases muscle blood ow, which,
in turn, facilitates substrate supply and energy produc-
tion in the skeletal muscle. The association between
reduction in MSNA and increase in muscle blood
ow and 6-minute walking distance support this idea.
Alternatively, the increased performance in the 6-
minute walking test is linked to an improvement in
the recruitment of motor units. Moreover, there is evi-
dence that FES improves muscle structure such as the
number of muscle oxidative bres,37 expression of slow
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myosin isoform and oxidative enzymes,38 mitochon-
drial volume39 and neoangiogenesis and capillary dens-
ity.32,33 All these muscle adaptations contributed to the
increase in muscle strength and 6-minute walking
distance.
Denitely, the present study was not designed to
prove the benecial eect of FES on hospitalisation
and mortality. However, the hospital readmission rate
to treatment of decompensated HF in a 30-day period
and one-year follow-up suggests that FES may play a
role in the patients outcome. This is an interesting
topic for future investigation.
Limitations
We recognise many limitations in our study. We studied
hospitalised unstable class IV HF patients who were
using many dierent medications according to their
needs. Thus, someone could raise the question that
the dierences in physiological responses were inu-
enced by medications among patients. This is unlikely,
because there were no signicant dierences in medica-
tions between control patients and patients with FES at
baseline and one day before discharge (Table 2). The
blood ow measurements were limited to skeletal
muscle. Thus, it is unknown whether the eects of
FES also occurred in other vascular beds with more
prominent haemodynamic implications. The eects of
FES might have been more apparent if the experimen-
tal protocol included a longer period of time. Muscle
biopsy could provide interesting data regarding the
molecular basis of the FES-induced improvement in
exercise tolerance. One control group treated with
standard optimal medical therapy but without interven-
tion could rule out the dose-dependent eects of the
FES. Finally, the present ndings need to be conrmed
in large trials also including older HF patients.
Perspectives
The present study provides evidences of the safety of
FES in hospitalised patients with decompensated
chronic HF. More importantly, FES causes benets
to these patients. The improvement in neurovascular
control and exercise tolerance provoked by muscle elec-
trical stimulation suggests that this approach has
the potential to be associated with standard clinical
therapy in hospitalised patients with decompensated
chronic HF.
In conclusion, FES reduces sympathetic nerve activ-
ity and muscle vasoconstriction and improves exercise
tolerance in hospitalised patients with decompensated
chronic HF. These ndings suggest that this approach
may be useful during hospitalisation to treat decom-
pensated HF.
Groehs et al.
Acknowledgment
This trial is registered at www.ClinicalTrials.gov (unique
identier #NCT01886430).
Author contribution
RVG and CEN contributed to the conception or design of the
work. RVG, LMAC, TSN, MJNNA, MUPBR and CEN
contributed to the acquisition, analysis, or interpretation of
data for the work. RVG and CEN drafted the manuscript.
MJNNA, MUPBR, ACPB and CEN critically revised the
manuscript. All gave nal approval and agree to be account-
able for all aspects of work ensuring integrity and accuracy.
Declaration of conflicting interests
The authors declared no potential conicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The authors disclosed receipt of the following nancial sup-
port for the research, authorship, and/or publication of this
article: This study was supported by the Fundacao de
Amparo a Pesquisa do Estado de Sao Paulo (FAPESP
#2010/50048-1) and, in part, by Fundacao Zerbini. RVG
was supported by Coordenacao de Aperfeicoamento de
Pessoal de Nvel Superior(CAPES). LMAC was supported
by CNPq and FAPESP (#142366/2009-9 and #2013/15651-
7, respectively). TSN, MUPBR and CEN were supported by
CNPq (#142367/2009-5, #308068/2011-4 and # 301867/2010-
0, respectively).
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