Vascular effects of isometric handgrip training in hypertensives

Abstract

The isometric handgrip training (IHT) has been emerging as an alternative approach for blood pressure (BP) reduction in hypertensive patients. However, the mechanisms underlying the reductions in BP after IHT are poorly known. Thus, the aim of this study was to analyze the vascular effects of IHT in hypertensive patients. A randomized controlled trial was conducted with 33 hypertensive patients (61 ± 2 y.o.; 67% female) who were randomly assigned to two groups: IHT or control group. The IHT group has completed three weekly sessions of isometric handgrip (4 × 2 min sets, alternating the hands at 30% of maximal voluntary contraction). Before and after a period of 12 weeks BP, arterial stiffness, central and peripheral pulse wave velocity (PWV) and endothelial function were measured. The IHT approach has significantly decreased systolic (∆ = −16 ± 2 vs. ∆ = −3 ± 3 mmHg, p < 0.001) and diastolic (∆ = −8 ± 2 vs. ∆ = 0 ± 2 mmHg, p = 0.014) BP. Reductions in central PWV (IHT: 9.1 ± 0.5 vs. 8.0 ± 0.3 m/s; Control: 8.8 ± 0.5 m/s, p < 0.05) and shear rate area after occlusion have significantly reduced by using the IHT (37822 ± 6931 vs. 24829 ± 5337 s⁻¹, p < 0.05). In conclusion, 12 weeks of IHT have reduced the BP and arterial stiffness and improved markers of endothelial function in hypertensive patients.

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Clinical and Experimental Hypertension
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Vascular effects of isometric handgrip training in
hypertensives
Sergio L. Cahu Rodrigues, Breno Quintella Farah, Gustavo Silva, Marilia
Correia, Rodrigo Pedrosa, Lauro Vianna & Raphael M. Ritti-Dias
To cite this article: Sergio L. Cahu Rodrigues, Breno Quintella Farah, Gustavo Silva, Marilia
Correia, Rodrigo Pedrosa, Lauro Vianna & Raphael M. Ritti-Dias (2019): Vascular effects of
isometric handgrip training in hypertensives, Clinical and Experimental Hypertension, DOI:
10.1080/10641963.2018.1557683
To link to this article: https://doi.org/10.1080/10641963.2018.1557683
Published online: 09 Jan 2019.
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ORIGINAL RESEARCH
Vascular effects of isometric handgrip training in hypertensives
Sergio L. Cahu Rodrigues
a
, Breno Quintella Farah
a
, Gustavo Silva
b
, Marilia Correia
c
, Rodrigo Pedrosa
d
,
Lauro Vianna
e
, and Raphael M. Ritti-Dias
f
a
Department of Physical Education, Universidade Federal Rural de Pernambuco, Recife, Brazil;
b
Physical Education, Universidade de Pernambuco,
Recife, Brazil;
c
Graduate Program in Medicine, Universidade Nove de Julho, São Paulo, Brazil;
d
Sleep and Heart Laboratory, Pronto Socorro
Cardiológico de Pernambuco, Universidade de Pernambuco, Recife, Brazil;
e
Faculty of Physical Education, Federal University of Brasilia, Brazilia,
Brazil;
f
Graduate Program in Rehabilitation Sciences, Universidade Nove de Julho, São Paulo, Brazil
ABSTRACT
The isometric handgrip training (IHT) has been emerging as an alternative approach for blood pressure
(BP) reduction in hypertensive patients. However, the mechanisms underlying the reductions in BP after
IHT are poorly known. Thus, the aim of this study was to analyze the vascular effects of IHT in
hypertensive patients. A randomized controlled trial was conducted with 33 hypertensive patients
(61 ± 2 y.o.; 67% female) who were randomly assigned to two groups: IHT or control group. The IHT
group has completed three weekly sessions of isometric handgrip (4 × 2 min sets, alternating the hands
at 30% of maximal voluntary contraction). Before and after a period of 12 weeks BP, arterial stiffness,
central and peripheral pulse wave velocity (PWV) and endothelial function were measured. The IHT
approach has significantly decreased systolic (Δ=−16 ± 2 vs. Δ=−3 ± 3 mmHg, p < 0.001) and diastolic
(Δ=−8 ± 2 vs. Δ= 0 ± 2 mmHg, p = 0.014) BP. Reductions in central PWV (IHT: 9.1 ± 0.5 vs. 8.0 ± 0.3 m/s;
Control: 8.8 ± 0.5 m/s, p < 0.05) and shear rate area after occlusion have significantly reduced by using
the IHT (37822 ± 6931 vs. 24829 ± 5337 s
−1
, p < 0.05). In conclusion, 12 weeks of IHT have reduced the
BP and arterial stiffness and improved markers of endothelial function in hypertensive patients.
ARTICLE HISTORY
Received 8 October 2018
Revised 13 November 2018
Accepted 14 November 2018
KEYWORDS
Blood pressure; resistance
exercise; arterial stiffness;
hypertension; vascular
function
Introduction
The isometric handgrip training (IHT) has been emerging as
an alternative approach in the treatment of hypertensive
patients. Several meta-analyses have shown chronic reduc-
tions in systolic blood pressure after few weeks of IHT (1–3).
Interestingly, the mechanisms underlying the reductions in
blood pressure after IHT in hypertensive are poorly known
(4). The effects of IHT in cardiac autonomic modulation,
peripheral sympathetic activity, endothelial function, were
analyzed in previous studies (5–13). Recently, a non-
controlled study (14) showed an improvement in oxidative
stress after training indicating a potential systemic effect of
IHT. However, the effects of IHT in these factors have been
very controversial, and a clearly mechanism altered after IHT
program still need to be found.
A potential factor related to the lack of understanding of
the mechanisms of blood pressure reductions in hypertensives
with IHT is the variability in the responses to training. In fact,
studies (6,14) have shown that 15–40% of patients did not
reduce blood pressure after isometric handgrip training, and
the inclusion of these subjects confound the analysis of the
potential mechanisms involved in the effects of isometric
handgrip training. Thus, in this study was to analyze the
effects of IHT on vascular parameters and stress oxidative
and inflammation biomarkers in hypertensive patients who
were responsive to IHT.
Materials and methods
Trail design
This is a partial analysis of a randomized controlled trial registered
in the www.clinicaltrials.gov database under the registration num-
ber NCT02348138 (6) and is part of the ISOPRESS network (15).
In this study we aimed to describe whether IHT improves arterial
stiffness concomitantly with reductions in blood pressure.
Therefore, only patients that have reduced their blood pressure
after IHT were included in the analysis.
The procedures of this study were approved by the
Institutional Review Board at the University of Pernambuco
in compliance with the Brazilian National Research Ethics
System’s Guidelines. All subjects have provided written con-
sent in accordance with the Declaration of Helsinki.
Subjects
Hypertensive patients were recruited by using local media adver-
tising and flyers that have been distributed in hospitals in the
surrounding area of the University of Pernambuco, Brazil. The
patients would be included if they met the following criteria: a)
hypertensive patient using anti-hypertensive medications b)
>18 years old, c) non-diabetics or with cardiovascular disease, d)
without limitations to performed isometric handgrip training, e) is
not involved in regular physical activity programs; f) reduction in
systolic blood pressure after IHT.
CONTACT Breno Quintella Farah brenofarah@hotmail.com Universidade Federal Rural de Pernambuco, Recife, Brazil
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iceh.
Clinical Trials: NCT02348138
CLINICAL AND EXPERIMENTAL HYPERTENSION
https://doi.org/10.1080/10641963.2018.1557683
© 2018 Taylor & Francis

The patients would be excluded from analysis if they met
any of the following criteria: a) changes in type or dose
antihypertensive medications, b) attendance to an additional
physical exercise program, c) blood pressure reduction lower
than 4 mmHg with the training; and, d) attendance lower
than 80% to sessions in the IHT group.
Randomization and allocation
The subjects were block randomized by using a random num-
ber table, being stratified for sex and baseline office systolic
blood pressure (performed by a researcher not directly
involved in the recruitment and data collection) into three
different groups: home-based isometric handgrip training,
supervised isometric handgrip training and control group.
The allocation was concealed.
Interventions
Isometric handgrip training group –IHT
The subjects assigned to the IHT group have trained three times
per week, for a total of 12 weeks. Each session consisted of four
sets of 2-min isometric contractions (alternating the hands), by
using a performed handgrip dynamometer (Zhongshan Camry
Electronic Co. Ltd. Zhongshan Guangdong, China) at 30% of
maximal voluntary contraction (16) and of a 1-min rest interval.
In the 6
th
week, load adjustments were performed. The only
difference between home-based isometric handgrip training and
supervised isometric handgrip training was that the later trained
in the University laboratory, whereas the former did their first
session in the laboratory. For analysis, we merged the subjects
who reduced BP in both groups in a single group, increasing the
statistical power for analysis.
Control group
The subjects assigned to the Control group were advised to
maintain dietary habits and physical activity levels, and the
isometric exercise program was provided to them after com-
pleting the study.
Measurements of cardiovascular variables
Prior to all cardiovascular measurements, the patients were
instructed to: eat a light meal before arriving in the laboratory,
avoid moderate-to-vigorous physical activity for at least
24 hours prior to the visit, and avoid smoking, alcohol and
caffeine ingestion for at least 12 hours. Also, in the laboratory,
a rest period of 10 minutes in the supine position was granted
prior to the measurements.
All cardiovascular measurements were taken in the supine
position in a quiet environment, with monitored temperature.
In addition, all data were collected by researchers blinded of
the group allocations.
Blood pressure
The brachial blood pressure was obtained through the Omron
HEM 742 device, using a proper cuff-size to arm-
circumference ratio. For this, three consecutive measurements
were performed in the right-arm, with a one-minute interval
between each of them. The value that has been used was the
average of the last two measurements (17).
Arterial stiffness
The pulse wave velocity was obtained through a high-fidelity
applanation tonometry (Sphygmocor, ATCOR Medical,
Australia) following the guidelines of the Clinical Application
of Arterial Stiffness, Task Force III (18). The central pulse wave
velocity (cPWV) was measured by using the procedures pre-
viously described (19). For the peripheral pulse wave velocity
(pPWV), the distance between the femoral artery and the
suprasternal notch and the dorsalis pedis artery and the supras-
ternal notch were measured through a standard tape. Then, the
distance between the two arteries was divided by the time dif-
ference in both markers. A simultaneous electrocardiogram was
used to assess the heart rate and, according to a “foot-to-foot”
method, the time difference between the points was measured.
Endothelial function
The brachial artery diameter and blood flow velocity were
measured using a high-resolution duplex-Doppler ultrasound
(Apogee 3500, SIUI, China), following the respective recom-
mendations (20). After locating the brachial artery, a 10-MHz
linear transducer was placed on the distal third of the arm
(2–10 cm above the antecubital fossa). The simultaneous
diameter and velocity signals were obtained in duplex mode
corrected with an insonation angle of 60°. The contrast reso-
lution, depth, and gain were adjusted to optimize the long-
itudinal images of the lumen/arterial wall interface.
Baseline diameter and blood velocity waveforms were con-
tinuously recorded over 120 seconds. After that the cuff placed
on the forearm was inflated with a pressure 50 mmHg above the
systolic blood pressure. This occlusion was maintained for five
minutes, being rapidly released after this period. The duplex-
Doppler and images recordings were resumed 30 s before and
maintained for 180 seconds after this release.
The post-occlusion diameter and blood flow velocity of the
brachial artery were obtained. The vasodilatory capacity was
calculated by the flow-mediated dilation, as well as the per-
centage of diameter increase in of the post-occlusion brachial
artery. Recordings of all vascular variables were analyzed off-
line by using a specialized edge-detection software
(Cardiovascular Suite, Quipu, Italy).
Oxidative stress and inflammation markers
Oxidative stress was assessed on plasma by the quantification
of the advanced oxidized protein products (AOPP), which
reflects protein oxidation of inflammatory nature and malon-
dialdehyde (MDA), a final product of the lipoperoxidation
reaction. Total thiol levels, was measured to estimate non-
enzymatic antioxidant defenses. AOPP (12–15,17–21) and
MDA (22) levels were assessed by the methods previously
described and plasmatic total thiols were quantified by the
protocol described by Costa et al. (23).
Evaluation of interleukin-1β(IL-1β), interleukin-10 (IL-10),
interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α),
C-reactive protein (CRP) were performed in plasma samples
using available commercial kits, following the manufacturers
instructions (Invitrogen, California USA). For the CRP analysis,
2S. L. CAHU RODRIGUES ET AL.

plasma samples were diluted 4000 times, for the other analysis,
the samples were used without previous dilution.
Statistical analysis
The data were stored and analyzed using the Statistical Package
for the Social Sciences (SPSS Version 17.0 for Windows).
The normality was checked using the Shapiro-Wilk test and the
Levene test was used to analyze the homogeneity of variances.
Continuous variables were summarized as mean and standard
error, whereas categorical variables were summarized as relative
frequencies.
Pre-intervention differences between the groups were
assessed with an independent t-test or with the Qui-square
test. To compare the effects of IHT, Generalized Estimating
Equations (GEE) were used, followed by a post-hoc pairwise
Table 1. General characteristics of experimental groups at baseline (n = 33) .
Variables Control group IHT group p
Age, years 59 ± 2 61 ± 2 0.614
Weight, kg 79.1 ± 5.8 84.2 ± 3.1 0.439
Height, m 1.62 ± 0.02 1.62 ± 0.01 0.894
Body mass index, kg/m
2
29.8 ± 1.7 32.0 ± 1.0 0.290
Systolic blood pressure, mmHg 129 ± 4 135 ± 4 0.336
Diastolic blood pressure, mmHg 73 ± 2 73 ± 2 0.979
Sex, % women 69 65 0.805
Calcium channel blocker, % 19 12 0.576
Diuretic, % 38 59 0.221
ß-blocker, % 19 23 0.576
Angiotensin converting enzyme inibitor, % 6 23 0.166
Angiotensin receptor blockers, % 81 71 0.475
Values are presented as mean ± standard error or frequency.
Figure 1. Flowchart of the hypertensive patients included in the study.
CLINICAL AND EXPERIMENTAL HYPERTENSION 3

comparison using the Bonferroni correction for multiple
comparisons. The Net-Effect of IHT on arterial stiffness was
calculated by: ΔIHT –ΔControl group.
Multiple linear regression analyses were performed to analyze
the relationship between changes on systolic and diastolic blood
pressures with vascular variables being adjusted for sex and age.
The significance level was set at P < 0.05 (two-tailed testing).
Results
The groups were similar at baseline (Table 1), and the study
flowchart is shown in Figure 1.
The systolic and diastolic blood pressures have significantly
reduced after IHT (Table 2). In comparison with men, women
have reduced more diastolic blood pressure. Reductions in cPWV
(IHT: 9.1 ± 0.5 vs. 8.0 ± 0.3 m/s; Control: 8.7 ± 0.5 vs. 8.8 ± 0.5 m/
s, p = 0.043) were also observed, with a net-effect of −1.19 m/s. No
significant changes were observed in pPWV (IHT: 8.4 ± 0.3 vs.
8.5 ± 0.3 m/s; Control: 9.3 ± 0.4 vs. 9.4 ± 0.4 m/s, p = 0,924)
(Figure 2). cPWV reduced only in patients who were responsive to
IHT (responsive: 9.3 ± 0.6 vs. 8.2 ± 0.3 m/s, p = 0.004; non-
responsive: 9.0 ± 0.6 vs. 8.6 ± 0.4 m/s, p = 0.587).
With IHT, it has been observed significant reductions in
shear rate area under the curve after occlusion, whereas no
significant changes were observed in other endothelial func-
tion parameters or biomarkers (Table 3).
No significant correlation was observed between the
changes in systolic and diastolic blood pressures after IHT
and the changes in arterial stiffness and markers of endothe-
lial function (Table 4).
Discussion
The main finding of this study was related to improvements
in vascular function that have occurred concomitantly with
reductions in blood pressure after IHT in hypertensive
patients. More specifically, improvements in central arterial
stiffness and shear area under the curve after occlusion were
observed. Surprisingly, the changes in these was vascular
parameters were not correlated with the changes in blood
pressure after the IHT.
The main novelty of this study is the improvement in arter-
ial stiffness after IHT. The net observed reductions were greater
than 1.19 m/s, which are similar to the ones the observed after
aerobic-like training programs (24). From a clinical point of
view, these reduction represent a decrease of 14%, 15%, and
15% in the risk of cardiovascular events, cardiovascular mor-
tality, and all-cause mortality, respectively (25).
Figure 2. Effects of isometric handgrip training on arterial stiffness in hypertensive.
Table 2. Effects of isometric handgrip training on blood pressure in hypertensives (n = 33).
Isometric Handgrip Training Control
Pre Post ΔPre Post ΔGroup Effect Time Effect Interaction Effect
Systolic BP, mmHg 135 ± 4 121 ± 3* −16 ± 2 129 ± 5 126 ± 4 −3 ± 3 0.974 <0.001 <0.001
Diastolic BP, mmHg 73 ± 2 66 ± 2* −9±273±273±2−1 ± 2 0.168 0.011 0.014
Values are presented as mean ± standard error; BP –blood pressure; IHT –isometric handgrip training; *significant difference from pre-intervention (p < 0.05).
4S. L. CAHU RODRIGUES ET AL.

The link between blood pressure and arterial stiffness have
been widely discussed in the literature (26,27). Functional
changes in cardiovascular parameters including increases in
anti-oxidant agents (14) and improvement of endothelial func-
tion (9,28) are potentially involved in the decreases in arterial
stiffness after IHT. Supporting this hypothesis, we have also
observed reductions in shear rate area under curve after cuff
release which indicates an improvement in endothelial function.
On the other hand, unlike the Peters’study, we did not observe
improvement of the inflammatory markers and oxidative stress.
In addition, interestingly, the changes in blood pressure after
IHT did not correlate with the changes in arterial stiffness and
endothelial function, indicating an absence of a dose-response
relationship among these variables. Therefore, other mechan-
isms might also have acted to reduce blood pressure with IHT.
There were no changes in peripheral arterial stiffness (mea-
sured by pPWV in the leg) with IHT. This is aligned to previous
studies on dynamic resistance training that has not observed
alterations in this variable after training (29,30). These results
indicate that IHT has no effect on distal elastic and muscular
arteries, suggesting that local stimulus might be necessary to
improve stiffness in peripheral arteries. Therefore, future stu-
dies are required to understand whether lower limb isometric
training may improve peripheral arterial stiffness.
The main limitation of this study is the inclusion of patients
using of different anti-hypertensive medications, and an exercise-
medication interaction cannot be discarded. The peripheral arter-
ial stiffness was assessed only in lower limbs, but whether local
changes in arterial stiffness have occurred in upper limbs or not, it
has not been assessed.
In conclusion, we have observed improvements in vascular
function after 12 weeks of IHT, indicating that reductions in
Table 4. Correlation between change systolic and diastolic blood pressure and
vascular variables in hypertensives after isometric handgrip training.
ΔSystolic BP, % ΔDiastolic BP, %
Baseline cPWV, m/s r = 0.224
p = 0.455
r = 0.053
p = 0.846
Baseline pPWV, m/s r = −0.004
p = 0.988
r=−0.226
p = 0.337
ΔcPWV, m/s r = −0.124
p = 0.652
r=–0.119
p = 0.623
ΔpPWV, m/s r = −0.199
p = 0.448
r = 0.250
p = 0.289
Baseline Shear rate AUC, s
−1
r=–0.580
p = 0.305
r = 0.725
p = 0.166
ΔShear rate AUC, s
−1
r = 0.663
p = 0.337
r=−0.834
p = 0.166
BP–blood pressure. Adjusted for sex and age.
Table 3. Effects of isometric handgrip training on vascular function and biomarkers in hypertensives.
Pre Post G T Gvs.T
Resting blood flow, ml/min 0.344 0.781 0.518
Control 74 ± 9 77 ± 13
Isometric handgrip training 93 ± 15 88 ± 16
Resting brachial artery, cm 0.987 0.529 0.376
Control 0.39 ± 0.02 0.41 ± 0.02
Isometric handgrip training 0.40 ± 0.02 0.40 ± 0.02
Peak shear rate, s
−1
0.595 0.266 0.317
Control 481 ± 35 475 ± 41
Isometric handgrip training 586 ± 128 462 ± 108
Time to maximum dilation, s 0.447 0.988 0.138
Control 87 ± 14 66 ± 12
Isometric handgrip training 80 ± 22 102 ± 16
FMD brachial artery, cm 0.470 0.918 0.383
Control 0.47 ± 0.03 0.45 ± 0.03
Isometric handgrip training 0.48 ± 0.04 0.51 ± 0.05
Shear rate area under curve, s
−1
0.945 0.001 0.049
Control 31914 ± 2075 29990 ± 3630
Isometric handgrip training 37822 ± 6931 24829 ± 5337*
AOPP (µM) 0.623 0.005 0.475
Control 67 ± 27 11 ± 3
Isometric handgrip training 62 13 29 8
MDA (µM) 0.793 <0.001 0.331
Control 1.53 ± 0.18 1.20 ± 0.06
Isometric handgrip training 1.67 0.15 1.15 0.15
Total Thiols (µM) 0.095 0.847 0.599
Control 281 ± 14 310 ± 76
Isometric handgrip training 233 28 220 27
IL-6 (pg/mL) 0.691 0.042 0.838
Control 1.36 ± 0.25 1.57 ± 0.15
Isometric handgrip training 1.27 ± 0.06 1.51 ± 0.15
IL-10 (pg/mL) 0.728 0.751 0.600
Control 4.74 ± 0.58 4.41 ± 0.47
Isometric handgrip training 4,72 0,41 4.80 .050
IL-1b (pg/mL) 0.085 0.198 0.412
Control 0.36 ± 0.05 0.43 ± 0.04
Isometric handgrip training 0.33 0.02 0.35 0.03
CRP (pg/mL) 0.644 0.397 0.630
Control 1126 ± 226 1188 ± 322
Isometric handgrip training 919 166 1143 218
TNF-alpha (pg/mL) 0.045 0.762 0.198
Control 9.59 ± 3.81 6.56 ± 1.10
Isometric handgrip training 3.33 0.32 5.20 0.65
Values are presented as mean ± standard error; *significant difference from pre-intervention (p < 0.05). G –Group effect; T –Time effect; GxT –Interation effect.
CLINICAL AND EXPERIMENTAL HYPERTENSION 5

arterial stiffness and improvement on endothelial function occurs
concomitantly with reductions in blood pressure after IHT.
Funding
Supported by grants from ‘Conselho Nacional de Desenvolvimento Científico
eTecnológico–CNPQ’(#448759/2014-4), ‘Fundação de Amparo à Ciência
eTecnologiadoEstadodePernambuco’–FACEPE (#APQ-1177-4.09/14),
and ‘Coordenação de Aperfeiçoamento de Pessoal de Nível Superior –
CAPES’.
ORCID
Breno Quintella Farah http://orcid.org/0000-0003-2286-5892
Gustavo Silva http://orcid.org/0000-0001-6341-345X
Marilia Correia http://orcid.org/0000-0002-8983-3433
Rodrigo Pedrosa http://orcid.org/0000-0001-9078-3296
Lauro Vianna http://orcid.org/0000-0002-5747-0295
Raphael M. Ritti-Dias http://orcid.org/0000-0001-7883-6746
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