Sports Medicine

https://doi.org/10.1007/s40279-024-02036-x

REVIEW
ARTICLE

Isometric Exercise Training and Arterial Hypertension: An Updated

Review
Jamie J. Edwards1 · Damian A. Coleman1 · Raphael M. Ritti-Dias2 · Breno Q. Farah3 · David J. Stensel4,5,6,7 ·
Sam J. E. Lucas8 · Philip J. Millar9 · Ben D. H. Gordon10 · Véronique Cornelissen11 · Neil A. Smart12 · Debra J. Carlson13 ·
Cheri McGowan14 · Ian Swaine15 · Linda S. Pescatello16 · Reuben Howden17 · Stewart Bruce-Low18 ·
Christopher K. T. Farmer19 · Paul Leeson20 · Rajan Sharma21 · Jamie M. O’Driscoll1,21

Accepted: 8 April 2024

© The Author(s) 2024

Abstract
Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and
premature mortality. Global initiatives towards the prevention and treatment of arterial
hypertension are centred around non-pharmacological lifestyle modification. Exercise
recommendations differ between professional and scientific organisations, but are generally
unani- mous on the primary role of traditional aerobic and dynamic resistance exercise. In recent
years, isometric exercise training (IET) has emerged as an effective novel exercise intervention
with consistent evidence of reductions in blood pressure (BP) superior to that reported from
traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and
endorsement by select governing bodies, IET remains underutilised and is not widely prescribed
in clinical practice. This expert-informed review critically examines the role of IET as a potential
adjuvant tool in the future clinical manage- ment of BP. We explore the efficacy, prescription
protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological
mechanisms underpinning its anti-hypertensive effects. We end the review with take-home
suggestions regarding the direction of future IET research.

1 Introduction established and defined as non-modifiable

(such as sex, age, and ethnicity) or modifiable
Non-communicable diseases are responsible for (such as body mass index, smoking status,
an estimated 73% of all deaths globally, of alcohol consumption), depending upon the
which cardiovascular disease (CVD) remains capacity for external influence. Elevated blood
the principal culprit [1]. Approximately 31% of pressure (BP), which is clinically termed
all deaths are directly attributable to CVD, hypertension (HTN), is recognised as the
making it the leading cause of mortality leading attributable risk factor for both CVD
worldwide [1, 2]. Specifi- cally, ischaemic heart and mortality [4] (Fig. 1).
disease and cerebrovascular accidents Briefly, BP can be defined as the
collectively account for 84.9% of all CVD measurement of hydrau- lic force exerted on
deaths, with the remaining sum of mortality a the arterial walls by oxygenated blood in the
consequence of other cardiac or vascular systemic circulation [5]. Systolic BP (sBP)
pathology, such as calcific valvular disease refers to the arterial pressure during
and peripheral vascular disease [1, 3]. myocardial contraction, while diastolic BP
The underlying pathophysiology responsible (dBP) describes the state of pressure during
for the development of CVD is dependent upon the relaxation phase of a cardiac contraction.
the complex inter- play of a number of The current classification of BP varies
variables, many of which are unclear, that depending on the guidelines adopted.
intricately interact throughout the course of Guidelines provided by the National Institute
human life. Through generations of empirical for Health and Care Excellence (NICE) and the
investigation, risk fac- tors that contribute to European Soci- ety of Cardiology/European
the progression of CVD have been Society of Hypertension (ESC/ ESH) determine
a diagnosis of HTN at ≥ 140 mmHg sBP, and/or
≥ 90 mmHg dBP [6, 7]. However, the current
Amer-
ican Heart Association/American College of
Cardiology
Extended author information available on the last page of the article
 J. J. Edwards et al.

for BP increased by 50% from 2006 to 2016 in

Key Points England [18]. Despite such prevalence, there
are substantial limita- tions associated with
medication for HTN, which are often
This work presents an expert-informed underestimated in the clinical practice,
review on the role of isometric exercise including adverse effects, economic burden
training in the prevention and treatment of and the risk of prescription errors resulting in
arterial hypertension, covering the efficacy, unintended consequences [19, 20]. Further-
prescription protocols, evidence quality and more, adherence to anti-hypertensive
certainty, acute cardiovascular stimulus, and medication is typi- cally reported at < 50% 1
physiological mecha- nisms underpinning its year following initial prescription [21]. Poor
anti-hypertensive effect. adherence to BP medication is associated with
Data from prospective randomised a 75% increase in the risk of all-cause
controlled trials and meta-analyses indicate mortality [22]. Once a patient is first
that isometric exercise training is capable of prescribed medication, they are also likely to
producing blood pressure reductions greater remain dependent for life, marking an
than that observed following the currently important treatment crossroad for clinicians
recommended exercise guidelines and [23].
possibly even greater, or at least similar to Therefore, establishing effective, adherable,
that of standard anti-hypertensive non-pharma- cological approaches may prove
monother- apy. pivotal in tackling the global HTN crisis. Non-
pharmacological treatment includes weight
Several domains within the literature require loss, smoking cessation, healthy diet, reduced
further empirical attention; however, current intake of dietary sodium, enhanced intake of
evidence supports the clinical dietary potassium, moderation in alcohol and
implementation of IET for the management physical activity [7]. This review critically exam-
of blood pressure. ines the role of isometric exercise training (IET)
as a potential adjuvant tool in the future
clinical management of BP. We explore the
efficacy, acute cardiovascular stimulus, and
physio- logical mechanisms underpinning its
(AHA/ACC) guidelines set a lower treatment anti-hypertensive impact. Despite the BP-
threshold for HTN diagnosis at ≥ 130 mmHg lowering benefits and endorsement by select
sBP and/or ≥ 80 mmHg dBP [8]. Regardless of governing bodies, IET is not widely promoted or
this diagnostic confliction, it is uni- formly prescribed in clinical practice. We end the
accepted that sBP and dBP values of < 120 review with take-home sugges- tions regarding
mmHg and < 80 mmHg are optimal, and the direction of future IET research.
increasing pressure beyond this threshold is
linearly associated with an escalated risk of
CVD [9, 10]. Specifically, the risk of CVD has 2 Isometric Exercise Training: Current
been reported to double for every increase in
sBP by 20 mmHg, with a more recent analysis Evidence
reporting a 13% increase in risk of mortality for
every 10 mmHg increase in sBP [9, 11]. The Isometric exercise refers to a sustained
SPRINT trial of 9361 patients demonstrated muscular contraction in which the length of the
that tar- geting treatment to a sBP of < 120 muscle does not change. In recent years, many
mmHg as opposed to the standard practice of research trials have investigated the effects of
< 140 mmHg resulted in lower rates of fatal IET on BP, employing various protocols and
and nonfatal major cardiovascular events and modes of appli- cation. While no single
all-cause mortality [12]. benchmark protocol has been estab- lished,
HTN is estimated to affect 1.13 billion people the majority of IET research has utilised a
globally, and due to its asymptomatic nature, handgrip (dynamometer) protocol, generally
this figure may be an underestimate [13, 14]. performed at 30% of the participant’s maximal
Given this immense global prev- alence and voluntary contraction (MVC) [24–26].
the sequelae of HTN, approaches to BP man- Conversely, few have investigated bilateral leg
agement have been extensively studied over extension IET, typically applied at an intensity
the past half century. With this, a plethora of of 20% MVC or 85% HRpeak via an isokinetic
anti-hypertensive pharma- cological treatment dynamometer [27, 28]. Finally, more recent
options have been established as highly work has demonstrated the efficacy of IET
efficacious in reducing BP and consequently employed in the variation of a wall squat
improving patient outcomes [15, 16]. As a requiring an incre- mental test to establish
result, the widespread clini- cal application of individualised intensity thresholds of 95%
pharmacotherapy in the management of BP is HRpeak [29, 30]. Regardless of the approach,
vast. For example, survey research shows that the most commonly studied protocols require a
77.3% of Americans diagnosed with HTN are time commitment of approximately 11–20 min
medicated [17], while the number of adults per session. This is significantly less than that
receiving pharmacological treatment of other more conventional exercise modes,
with aerobic and dynamic resistance training
sessions typi- cally ranging from 30 min to > 1
h. In addition to its time efficiency, the appeal
of IET surrounds its practicality with
Isometric Exercise Training and Arterial Hypertension

Fig. 1 Pathophysiological mechanisms of hypertension.

Ang angio- tensin, ANP atrial natriuretic peptide, BNP norepinephrine, NO nitric oxide, PGI prostacyclin, RAAS
brain natriuretic peptide, CA calcium, CO cardiac renin–angi- otensin–aldosterone system, SNS
output, Epi epinephrine, HR heart rate, NE sympathetic nervous system, SV stroke volume, TPR
total peripheral resistance

minimal equipment requirements, wide ‘exercise training’, ‘blood pressure’ and

versatility in appli- cable environments (e.g., ‘hypertension’. Indi- vidual RCTs in this review
home-based and work environ- ments), and were also found through previous meta-
general accessibility. The wall squat protocol analysis research in this area (Table 1). To
can be applied with no equipment and the most effec- tively represent only valid and
handgrip proto- col only requires a rigorous evidence, Table 2 exclusively includes
commercially available dynamometer. The leg only RCTs published from January 1, 2000, to
extension, however, is considerably less April 1, 2023, that have investigated the pre-
accessi- ble, generally requiring a costly and post-BP changes following any IET
isokinetic dynamometer or equivalent and is intervention.
utilised the least of all applications in the IET As detailed in Table 1, there have been
field. several meta- analytic studies collectively
analysing all protocol varia- tions of IET to
2.1 Evidence provide a pooled estimate of its effects on
resting BP. The first of such was performed by
Tables 1 and 2 provide all current meta- Owen et al.
analysis and ran- domised controlled trial [32] and involved a limited analysis of five
(RCT) data recognised in the devel- opment of studies, report- ing significant reductions in
this review. These studies were predominantly resting sBP and dBP by − 10.4 and − 6.7
identified via an update of a systematic search mmHg, respectively. In the decade since, an
which has been detailed previously [31]. This abundance of research trials with greater
search was performed in PubMed (MEDLINE), methodological rigour have been performed,
the Cochrane Library and SPORT- Discus and resulting in the publication of several larger
included MeSH terms, key words and word var- meta-analyses including an individual patient
iants for ‘isometric exercise training’, ‘static data meta-analysis [33]. Specifically, Carlson
contraction’, et al. [34], Jin et al. [35], Inder et al. [36],
Loaiza-Betancur and Chulvi-Medrano [37],
López-Valenciano et al. [38], Smart
 J. J. Edwards et al.

et al. [33], Hansford et al. [39], and Edwards et between increased daytime BP variability and
al. [40] all report pooled resting sBP and dBP early develop- ment of atherosclerosis [57],
reductions of between 5–9 and 1–4 mmHg, target organ damage [58] and cardiovascular
respectively, in varying BP populations. The and stroke mortality [59]. Taylor et al. [44]
differences in effect sizes reported between found that 4 weeks of wall squat IET
particular analyses are likely owing to both the significantly reduced 24-h ambulatory and
year and date in which the systematic search night-time systolic, mean and diastolic average
was performed, as well as strategic real variability, as well as daytime systolic
methodological differences. For example, aver- age real variability. Average real
Edwards et al. variability is a reliable and reproducible index
[40] strictly ensured the omission of papers for BP variability, carrying additional
published prior to the year 2000, thus prognostic information for subclinical organ
excluding Wiley et al. [41] which provided damage and risk of composite cardiovascular
early groundwork for the IET literature, but is events [56].
now outdated with methodological and In summary, there is evidence in support of
statistical limitations. Regardless, it is clear IET as an effective anti-hypertensive
from all meta-analytic evidence thus far that intervention across a range of key BP markers
IET is highly efficacious in the management of including resting office BP, daytime, night-time
rest- ing BP, with mean reductions greater and 24-h ambulatory, morning BP surge and
than that observed following the currently BP variability. However, it is important to note
recommended exercise guidelines and even that these adaptations may be specific to BP-
greater, or at least similar, to that of standard related cardiovascular health with little-to- no
anti- hypertensive pharmacotherapy [42]. evidence regarding the effectiveness of IET in
In addition to resting BP, a smaller number improving wider traditional risk factors, such
of studies [43–47] have also reported the as peak aerobic capacity (VO2), cholesterol, or
effects of IET on ambulatory blood pressure weight management.
monitoring (ABPM). ABPM monitoring is
recognised as a more reliable measure of BP
through its increased precision, elimination of 2.2 IET Protocol
observer bias and supe- rior predictive
effectiveness in determining cardiovascular As discussed, there are various IET protocols
risk [48–50]. Previous work by Taylor et al. [44] which have demonstrated clinically relevant
observed significant reductions in 24-h reductions in resting BP, with no single
ambulatory sBP and dBP by uniformly accepted protocol to date. This has
11.8 and 5.9 mmHg, respectively, following 4 consequently produced a logistical gap
weeks of IET wall squats in unmedicated between the current successful research
hypertensives. Additionally, Tay- lor et al. [44] findings and the practical clini- cal
found significant improvements in daytime and implementation of IET. As with any emerging
night-time sBP, mean BP (mBP) and dBP by − clinical interventional strategy, establishing
13.9/− 9 optimal practices with consideration of
.4 mmHg, − 7.4/− 3.9 mmHg and − 5.6/− 4.9 effectiveness, practicality, safety, and cost
mmHg. While such diurnal changes indicate efficiency is needed.
enhanced BP regulation in response to daily
activities during waking hours, these night-
time ABPM changes are also of considerable 2.3 Mode
importance given the prognostic value of
nocturnal BP as a significant risk factor for Until now, there has been no robust evidence
cardiovascular morbidity and all-cause mor- to support the superiority of one IET mode.
tality in both normotensive and hypertensive However, considering the different stimuli,
populations [50, 51]. Specifically, as denoted such as muscle mass, characteristics of
by the term ‘dipping’, sleeping sBP should be activated muscles, and posture between wall
> 10% lower than daytime sBP [52], a squat, leg extension, and handgrip IET, it has
threshold to which IET may therefore be been long hypothesised that clinically relevant
capable of provid- ing a clinically significant response differences exist. The only
contribution. Although to a lesser magnitude, comparative evidence of IET mode to date is
similar findings have also been demonstrated provided in a recent meta-analysis, where
in leg extension IET studies [43, 45, 53], researchers pooled the magni- tude of BP
showing significant reductions in 24-h, daytime change following the three primarily employed
and night-time ambulatory sBP, as well as IET modes separately, and subsequently
significantly reduced morning sBP surge in compared them as sub-groups [31]. As
both males and females [45]. Conversely, three observed in Fig. 2, this analysis dem- onstrated
studies investigat- ing handgrip IET reported no all three modes to be effective, with sBP and
change, highlighting the need for future dBP reductions following wall squat, leg
research, particularly in unmedicated extension, and handgrip (bilateral or unilateral)
hypertensive individuals [46, 47, 54, 55]. IET by − 11.41/− 5.09, − 9.96/− 3.69 and −
Further to standard daytime and night-time 8.34/− 4.09 mmHg, respectively [31]. Although
ABPM, IET has been demonstrated to not statistically significant, the reduction was >
significantly improve BP variabil- ity [44]. 3 mmHg greater following wall squat IET than
Increased variability in BP is considered a the traditionally employed handgrip mode,
prog- nostic marker for health, independent of which is a magnitude of change considered
mean BP values [56]. Previous evidence has
reported significant associations
Table 1 Systematic review and meta-analytic data on the effects of isometric exercise training on resting blood pressure

Isometric Exercise Training and Arterial Hypertension

Systematic review with meta-analysis Analysis details Inclusion/exclusion criteria Outcome Subgroup outcome
Owen et al. [110] Published February
2010 5 trials RCTs published ≤ 2009 sBP: − 10.4 N/A
122 participants mmHg dBP: −
6.7 mmHg
Kelly and Kelly [117] Published March RCTs published from 1971 to sBP: − 13.4 N/A
2010 3 trials mmHg dBP: −
Feb 2009 7.8 mmHg
81 participants
≥ 4-week intervention
Cornelissen et al. [118] Published September RCTs published ≤ June 2010 sBP: − 13.5 N/A
2011 3 trials mmHg dBP: −
82 participants 7.8 mmHg
Cornelissen & Smart. [91] Published February RCTs published from 1976 to Feb sBP: − 10.9 N/A
2013 5 trials mmHg dBP: −
150 participants 2012 6.2 mmHg
Carlson et al. [102] Published March ≥ 4-week intervention N/A
2014 9 trials sBP: − 6.77
223 participants RCTs published from 1966 to July mmHg dBP: −
Jin et al. [111] Published January 3.96 mmHg HTN: sBP and dBP significantly
2013 mBP: − 3.94 decreased in NTN, pre-HTN and
2017 6 trials HTN, although greatest reductions
≥ 4-week intervention mmHg
157 participants in pre-HTN
sBP: − 8.33
Inder et al. [112] Published October mmHg dBP: − Sex: greater reduction in males
2016 11 trials RCTs ≤ Nov 2014
Handgrip studies 3.93 mmHg Age: greater reductions in older
302 participants only participants (≥ 45 y)
≥ 4-week intervention sBP: − 5.20 Duration: Greater reductions in
RCTs and cross-over trials published mmHg dBP: − interven- tions ≥ 8 wk
from 1966 to Jan 2015 3.91 mmHg HTN: Greater reductions in hypertensive
mBP: − 3.33 partici- pants
≥ 2-week intervention mmHg Unilateral: greater reductions in unilateral
than bilateral IET
Upper vs lower: greater reductions in
arm vs lower limb IET
Loaiza-Betancur et al. [119] Published March N/A
2020
6 trials
139 participants
RCTs published < 2016 sBP: − 2.83
Normotensive participants only (< mmHg dBP: −
120 mmHg and < 80 mmHg) 2.73 mmHg
mBP: − 3.07
mmHg
Table 1
(continued) review with meta-analysis Analysis details Inclusion/exclusion criteria
Systematic Outcome Subgroup outcome
Loaiza-Betancur et al. [96] Published August
2020 11 trials RCTs published < Jan sBP: − 5.43 HTN: mBP significantly decreased in
311 participants mmHg dBP: − pre-HTN, but sBP and dBP did not. sBP
2018 2.41 mmHg significantly decreased in HTN, but
≤ 50% MVC intensity mBP: − 1.28 not dBP or mBP
mmHg BMI: sBP but not dBP significantly
decreased in healthy BMI participants.
No significant reduc- tions were found
in overweight or obese patients
separately
Age: sBP significantly decreased in ≥
50-year-olds, but not dBP or mBP. BP
did not significantly decrease in < 45-
year-olds
López-Valenciano et al. [113] Published July Medication: patients on anti-
hypertensive medica- tion had
2019 significantly decreased dBP, but not
16 trials RCTs published < Jan sBP: − 5.23 sBP or mBP
mmHg dBP: −
492 participants 2018 1.64 mmHg HTN: greater reductions in normotensive
≥ 2-week intervention mBP: − 2.9 vs hyper- tensives participants
mmHg Other: no significant effects of sex, age,
clinical status, intervention duration,
mode or intensity
Naci et al. [90] Published July RCTs published < Sep 2018 sBP: − 5.65 mmHg N/A
2019 12 trials
Hansford et al. [114] Published August RCTs published < Aug 2020 sBP: − 6.97 HTN: similar statistically significant sBP
2021 24 trials mmHg dBP: − reduc- tions in pre-HTN and HTN.
1143 participants ≥ 3-week intervention 3.86 mmHg Greater dBP reductions in HTN than
pre-HTN, although both statistically
significant
Mode: greater sBP reductions in leg than
handgrip IET, although both statistically
significant.
Edwards et al. [103] Published December Greater dBP reductions in handgrip, with
2021 18 trials RCTs published from Jan 2000 to Sep no significant change in leg IET
2020 Intervention duration 2–12 sBP: − 8.50
672 participants mmHg dBP: − Upper vs lower body IET: no significant
weeks 4.07 mmHg difference No significance moderator
mBP: − 6.46 effects for hyperten- sion diagnosis,
Edwards et al. [120] Published August mmHg medication status or intervention
2022 18 trials duration
RCTs published from 2000 to Dec
628 participants 2021 Intervention duration 2–12 Mode: non-statistically significant
weeks sBP: − 9.34 differences (although clinically
mmHg dBP: − significant) between wall squat, leg
Reported at least 1 mechanistic 4.30 mmHg
parameter along- side the primary mBP: − 5.21 extension and handgrip
BP change mmHg
BMI body mass index, dBP diastolic blood pressure, HTN hypertension, IET isometric exercise training, mBP mean blood pressure, NTN normotension, pre-
HTN pre-hypertension, RCT ran- domised controlled trial, sBP systolic blood pressure

J. J. Edwards et al.
Table 2 Prospective randomised controlled trials investigating the effects of isometric exercise training on resting blood pressure

Isometric Exercise Training and Arterial Hypertension

Randomise Country Duration Participants Hypertensi Include Withdrawal Training Exercise Exercise Pre-IET mean Post-IET mean
d on d sBP/ sBP/
controlled (weeks) (according medica- (n. of frequency mode training dBP (mmHg) dBP (mmHg)
to partici- char-
trial baseline BP tion pants) acteristics
or
medication
status)
Baddeley- UK 4 N = 23 (43% NTN No None 3 × per Isoball 4 × 2 min, Isoball Isoball
week rugby
White et female) handgrip/ bilateral 129.3/70 119.9/65.7
al. mmHg mmHg
(2019) zona plus (alternat- Zona Plus Zona Plus
[77]
handgrip ing hands), 125.5/71.6 114.5/66.6
mmHg mmHg
1-min rest
interval,
30% MVC
(n = 7
isob- all,
n=8
zona, n =
8
control)
Badrov et Canada 8 N = 32 NTN No IET 1 3/5 × per Handgrip 4 × 2 min, 3 days p/w 3 days p/w
al.
(2013) (100% Control 3 week unilateral 94/57 mmHg 88/54 mmHg
[67] female)
4-min rest 5 days p/w 5 days p/w
intervals, 97/57 mmHg 91/57 mmHg
30% MVC
(n = 12
3 × per
week,
n = 11
5 × per
week, n =
9
control)
Badrov et Canada 10 N = 24 (46% HTN Yes None 3 × per Handgrip 4 × 2 min, 129/72 mmHg 121/67 mmHg
al. week
(2013) female) bilateral
[180] (alternat-
ing hands),
1-min rest
interval,
30% MVC
(n = 12
IET, n =
12
control)
Table 2
(continued)
Randomis
ed Country Participants Includ Withdrawa Training Exerci Exercise Pre-IET mean Post-IET mean
controlled ed l (n. of frequen se training sBP/ dBP sBP/ dBP (mmHg)
trial medic partici- cy mode char- (mmHg)
Duration Hypertension a- tion pants) acteristics
(weeks) (according
to baseline
BP or
medication
status)
Baross et
al. UK 8 N = 30 Pre-HTN No None 3 × per week Leg 4 × 2 min, High int High int
(2012) 2-min
[63] (100% exten- 138.7/78.2 127.9/76.6
sion rest mmHg mmHg
male) intervals
(bilat- , 14% Low Low
eral) MVC 137.3/78.3 136.5/79.4
(n = 10
at mmHg mmHg
85%HRpe
ak, n =
10 at
75%HRpe
ak, n =
10
control)
Baross et UK 8 N = 20 Pre-HTN No None 3 × per week Leg 4 × 2 min, 139/85 mmHg 128/83 mmHg
al.
(2013) (100% exten- 2-min
[28] rest
male) sion intervals
(bilat- (85%HRp
eral)
eak n =
10 exer-
cise
group, n 123/70.3 mmHg 118/68.2 mmHg
= 10
Baross et UK 8 N = 25 control)
al. NTN No None 3 × per week Leg
(2022) (36% 4×2
[45] exten-
female) min,
sion
(bilat- 2-min
eral) rest
interval
s
(n = 13
20%
MVC
exer-
cise
group, n
= 12
control)
Rodrigues Brazil 12 N = 72 HTN Yes IET 31 3 × per (n = 17
et al. (67% 30% MVC,
female) Control 8 week Handgrip 4 × 2 min,
(2019) bilateral n = 16
[76] (alternat control)
- ing
hands),
1-min
rest
interval
135/73 mmHg 121/66 mmHg

J. J. Edwards et al.
Table 22 (continued)
Table
(continued)
Randomis
ed Country Participants Includ Withdrawa Training Exerci Exercise Pre-IET mean Post-IET mean
controlled ed l (n. of frequen se training sBP/ dBP sBP/ dBP (mmHg)
trial medic partici- cy mode char- (mmHg)
Duration Hypertension a- tion pants) acteristics
(weeks) (according
to baseline
BP or
medication
status)
Cohen et
al. Colombia 12 N = 77 Pre-HTN No None 3 × per week Handgrip Handgrip: Handgrip:
(2022) (33% : 4×2 140/86.7
[68] female) Handgrip or min, 2- mmHg Wall 128.8/82.7
wall squat min squat: mmHg
rest 141.2/87 Wall squat:
interval 128.3/82.9
s mmHg
(n = 28 mmHg
30%
MVC)
Wall
squat: 4
×2
min, 2-
min
rest
interval
s (n =
27)
22
controls
Carlson et Australia 8 N = 40 (62.5% HTN Yes IET 2 3 × per week Handgrip 4 136/77 mmHg 129/75 mmHg
al. × 2 min,
(2016) [25] female) unilatera
l 1-min
rest
intervals
(n = 18
at 30%
MVC,
n = 20
5% MVC
Correia et Brazil 8 N = 102 (sex HTN Yes IET 21 exercise 142/75 mmHg 136/72 mmHg
control)
al. Con-
3 × per
week Handgrip 4×2
min,
(2020) unknow trol unilater
al, 4-
[72] n) 2 min rest
interval
s (n =
29
30% MVC,
n = 50
control)
Decaux et [65] UK 4 N = 20 (50% Pre-HTN No None 3
al.
(2021) female) × per week Wall squat 4
× 2 min, ( n = 10 131/79.7 mmHg 115.8/75.1 mmHg

Isometric Exercise Training and Arterial Hypertension

2-min HR control)
 Randomise Country Duration Participants Hypertensi Included Withdrawal Training Exercise Exercise Pre-IET mean Post-IET mean
d on sBP/ sBP/
controlled (weeks) (according medica- (n. of frequency mode training dBP (mmHg) dBP (mmHg)
to partici- char-
trial baseline BP tion pants) acteristics
Table 2 or
(continued) medication
status)
Farah et al. USA 12 N = 72 (75% HTN Yes Home IET 6 3 × per Handgrip 4 × 2 min, Home 130/73 Home
week mmHg
(2018) female) Supervised bilateral Supervised 126/71 mmHg
[24]
48 > 50 IET 10 (alternat- 132/71 mmHg Supervised
years
Control 8 ing 120/66 mmHg
hands),
1-min rest
intervals
(n = 18 at
30% MVC
home
based,
n = 14
30% MVC
supervise
d,
n = 16
control)
Fecchio et Brazil 10 N = 35 Pre-HTN Yes IET 3 3 × per Handgrip 4 × 2 min, 128/87 mmHg 125/86 mmHg
al. (100% week
(n = 8(2023)
20%EMG- male) Control 1 unilateral,
peak, n = 9 30%EMG- 110.4/62.1 107.4/58.2 mmHg
peakn= mmHg
18
control
)

J. J. Edwards et al.
Table 2 (continued)

Isometric Exercise Training and Arterial Hypertension

Randomise Country Duration Participants Hypertensi Include Withdrawal Training Exercise Exercise Pre-IET mean Post-IET mean
d on d sBP/ sBP/
controlled (weeks) (according medica- (n. of frequency mode training dBP (mmHg) dBP (mmHg)
to partici- char-
trial baseline BP tion pants) acteristics
or
medication
status)
Gordon et USA 12 N = 22 Pre-HTN/ Yes None 3 × per Handgrip 4 × 2 min, Home Home
al. (sex week
(2018) unknown) HTN unilateral, 137.7/88.4 128/81.6
[84] mmHg mmHg
22 < 50 1-min rest Lab Lab
years
intervals 137.6/87.1 128.5/84.3
(n = 5 mmHg mmHg
30% MVC
home-
based, n
=8
30% MVC
lab-based,
n = 9 con-
trol)
Javidi et al. Iran 8 N = 39 HTN No IHG-60: 3 3 × per Handgrip 3 × 30 s, IHG-60 IHG-60
(100% week
(2022) male) IHG-30: 2 unilateral. 142/91 mmHg 125/84 mmHg
[66]
Control: 1 2-min rest IHG-30 IHG-30
intervals 142/89 mmHg 136/86 mmHg
for IHG-60.
4×2
min,
unilateral,
4-min rest
intervals
for IHG-30
(n = 12
IHG-60,
n = 13
IHG-
30, n =
14
control)
Table 2
Randomise Country Duration
(continued) Participant Hypertensi Included Withdrawal Training Exercise Exercise Pre-IET mean Post-IET mean
d s on sBP/ sBP/
controlled (weeks) (according medica- (n. of frequency mode training dBP (mmHg) dBP (mmHg)
to partici- char-
trial baseline BP tion pants) acteristics
or
medication
status)

Nemoto et
al. Japan 8 N = 53 Pre- Yes None 3 × per week Handgrip 4×2 136.9/81.9 mmHg 134/79.5 mmHg
(2021) HTN/
(43% HTN min,
[80] bilateral
female)
(alternat
- ing
hands),
1-min
rest
intervals
(n = 27
pre- set
resist-
ance
value
closest
to
participa
nts 30%
MVC,
n = 26
control)
O’Driscoll UK 52 N = 24 Pre-HTN No None 3 × per week Wall squat 4 × 132.3/81.7 mmHg 121.8/73.7 mmHg
et al. (100% 2 min,
(2022) male) 2-min
[82] rest
interval
s
(n = 12
95%
HRpeak,
n = 12
control)
Ogbutor et Nigeria 24 days N = 400 (45% Pre-HTN No None 24 Handgrip 2 × 2 min, 133.5/87.7 mmHg 126.1/81.3
al. consecu- mmHg
(2019) female) tive days unilateral,
[73]
5-min rest
interval

J. J. Edwards et al.
(n = 200
30% MVC,
n = 200
control)
Okamoto Japan 8 N = 22 (59% HTN No None 3 × per Handgrip 4 × 2 min, 156/94 mmHg 139/87 mmHg
week
et al. female) bilateral
(2020)
[78] (alternat-
ing hands)
Table 2 (continued)

Isometric Exercise Training and Arterial Hypertension

Randomise Country Duration Participant Hypertensi Included Withdrawal Training Exercise Exercise Pre-IET mean Post-IET mean
d s on sBP/ sBP/
controlled (weeks) (according medica- (n. of frequency mode training dBP (mmHg) dBP (mmHg)
to partici- char-
trial baseline BP tion pants) acteristics
or
medication
status)
Pagonas interv
et al. Germany 12 N = 50 HTN Yes IET 1 5 × per week Handgrip al (n 4 138.4/80.3 mmHg 138.4/79.6 mmHg
(2017) (60% = 25
female) Control 2 × 2 min, 30% MVC,
[47]
1- = 25m
n
in rest
sham
control)
Palmeira Brazil 12 N = 63 (74% HTN Yes IET 16 3 × per Handgrip 4 × 2 min, 129/83 mmHg 121/79 mmHg
week
et al. female) Control 17 1-min rest
(2021)
[71] interval
(n = 15
30% MVC,
n = 16
control)
Punia and India 8 N = 40 (50% HTN Yes None 3 × per Handgrip 4 × 2 min, 144.2/92.7 138.4/87.5
week mmHg mmHg
Kulandaive female) 4-min rest
-
lan (2019) intervals
[74] (n = 20
30% MVC,
n = 20
con-
trol
group)
Stiller-Mol- Canada 8 N = 25 (50% HTN Yes IET 2 3 × per Handgrip 4 × 2 min, 112.5/84.3 111.3/84.6
week mmHg mmHg
dovan et female) Control 3 1-min rest
al.
(2012) interval
[46] (n = 11
30%
MVC, n =
Table 2
(continued)
Randomis
ed Country Participants Includ Withdrawa Training Exerci Exercise Pre-IET mean Post-IET mean
controlled ed l (n. of frequen se training sBP/ dBP sBP/ dBP (mmHg)
trial medic partici- cy mode char- (mmHg)
Duration Hypertension a- tion pants) acteristics
(weeks) (according
to baseline
BP or
medication
status)
Taylor et
al. UK 4 N = 48 Pre-HTN No None 3 × per week Wall squat 4 × 132.4/81.4 mmHg 120.1/75.4 mmHg
(2018)
[29] (100% 2 min,
male) 2- m
in rest
interval
s (n =
24
95%HRpe
ak,
n = 24
control)
Wiles et UK 8 N = 33 NTN No None 3 × per week Leg 4 × 2 High int High int—
al.
(2009) (100% exten- min, -121.5/68.5 116.3/65.8
[27] males) sion 2- mi mmHg mmHg
(bilat- n rest
eral) intervals
(n = 11
HI-
95%HRpe
ak,
n = 11
LO-
75%HRpe
ak,
n = 11
contr
ol
grou
p)
Wiles et UK 4 N = 28 NTN No None 3 × per week Wall squat 4 × 127/79 mmHg 123/76 mmHg
al.
(2016) (100% 2 min,
[30] male) 1-min
rest
interval
(n = 14
95%HRpe
ak,
n = 14
control)
Yamaga Japan 8 N = 20 (sex NTN No None 3 × per week Handgrip 4 107.1/63.3 mmHg 102.5/60.2 mmHg
ta × 2 min,
and unknow 3- mi
Sako n rest
(2020) n) interval
[75] s (n =
10
25%MV
Isometric Exercise Training and Arterial Hypertension

C d p, n =
h g 10 con-
a r trol
n i group)
dBP diastolic blood pressure, EMG electromyography, HTN hypertension, HRpeak peak heart rate, IET isometric exercise training, IHG isometric handgrip,
mBP mean blood pressure, MVC
maximal voluntary contraction, N number, NTN normotension, pre-HTN pre-hypertension, RCT randomised controlled trial, sBP systolic blood pressure

J. J. Edwards et al.
 Table 2
clinically relevant [31]. This work suggests the
wall (continued)
squat may be the most effective form of 2.4 Intensity
IET despite the handgrip protocol being the
most widely studied and the only proto- col Previous research has consistently shown
endorsed in any international guidelines [8]. intensity to be a critical training principle in the
The greater magnitude of effect with the wall prescription of IET. Baross et al. [63]
squat is probably attribut- able to differences demonstrated significant BP improvements fol-
in the extent of recruited muscle mass and lowing 4 weeks of leg extension IET at 14%
thus surface area of compressed vasculature MVC, but found no significant change at 8%. In
when com- pared with handgrip protocols [60], addition, other trials have used lower intensity
while the incorporation of postural and IET to constitute valid sham control groups,
stabilising muscles when holding the squat with Carlson et al. [64] reporting significant BP
position may be an important distinguishing reductions from 30% MVC, but not 5% MVC
factor from leg extension IET [27]. However, handgrip IET, and more recently, Decaux et al.
these results should be inter- preted with [65] reported significant BP improvements
caution given the inherent limitations of such following 95% HRpeak wall squat, but not 75%.
an indirect analysis and the confounding As evidenced by these findings, a minimum
effects of differing heterogeneous participant intensity of IET is required to promote
and study characteristics. Despite the potential cardiovascular benefits, with 95% peak HR for
promise of wall squat IET, direct comparative squat and leg extension IET, and 30% MVC for
RCTs of homogeneous populations and handgrip as the most well-established
consistent study characteristics are required to intensities (Fig. 2). Although numerous trials
conclude such differences. have consistently dem- onstrated the
A limitation of the primary wall squat effectiveness of these intensities, comparative
protocol employed in most of the research is studies investigating novel protocols of
that it requires specialist incremen- tal testing variable intensity and inter-set recovery
to identify an individual intensity prescription periods are needed to truly determine the
based on the squatting knee angle required to optimal IET intensity prescription for the
elicit a 95% peak HR response [31]. This largest magni- tude of effect on BP. Javidi et al.
presents logistical concerns when considering [66] recently compared the traditional
the ultimate objective of widespread clini- cal handgrip 30% MVC protocol (4 × 2 min) versus
implementation, especially given the a novel 60% MVC protocol (8 × 30-s
straightforward pro- cess of prescribing contractions), reporting significant resting BP
handgrip IET at 30% MVC. However, new reductions following both protocols, with
evidence demonstrates the effectiveness of a significantly greater dBP reductions in the 60%
rate of perceived exertion (RPE)-prescribed MVC group. This work may provide promise for
wall squat interven- tion which presents a higher intensity, shorter contraction time IET
more practical prescription approach [61]. protocols and ultimately high- lights the
Interestingly, recent acute research reported importance of continued research into
signifi- cantly higher RPE values during a single unexplored protocol variations.
handgrip session compared with wall squat,
which may carry implications for long-term 2.5 Frequency and Detraining
adherence [62].
Ultimately, while early indirect evidence
suggests that handgrip IET may not produce BP Badrov et al. [67] directly investigated the
changes of the same mag- nitude as that of effects of two different IET training frequencies
lower-body IET, it undoubtedly remains the by comparing the effects of 3-times (3 ×)
most well-investigated mode with the versus 5-times (5 ×) weekly handgrip IET
strongest foundation of supporting evidence, sessions over an 8-week intervention. This
as mentioned previously (Table 2). Handgrip work reported significant resting sBP
IET likely constitutes the most attractive and reductions independently of train- ing
practically implementable mode, with utility in frequency, with no changes in dBP or mBP in
patients with cognitive, mobility or heightened either group. However, the authors reported
cardiovascular risk concerns. Conversely, wall significant mid-train- ing (4 weeks) sBP
squat IET may be capable of pro- ducing larger reductions in the 5 × , but not 3 × weekly
BP improvements but remains more vulner- session group [67]. This finding may indicate
able to implementation limitations in clinical accelerated adaptations with higher training
populations and older frail adults. Leg frequency, which could have implications
extension IET may offer some middle ground respective of the initial training phase and the
regarding magnitude of BP change; however, it potential for a subsequent reduction in training
certainly suffers from limitations regarding dos- age during a maintenance phase. In the
accessibility of specialised equipment. Given first IET study of its kind, Cohen et al. [68]
the importance of train- ing variability for recently demonstrated that BP reductions can
exercise adherence, there is an important be maintained with a single session (hand- grip
argument for the development of multi-modal or wall squat) per week following a standard 3
IET routines. × weekly 12-week IET programme. These
findings suggest that the traditionally
employed 3 × weekly IET frequency may only
be necessary during the initial training phase
with potential to down-titrate frequency in a
maintenance phase. Despite
Isometric Exercise Training and Arterial Hypertension

Fig. 2 Modes of isometric exercise training. dBP diastolic blood pressure, HRpeak peak heart rate, IET isometric
exercise training, MVC maximal voluntary contraction, sBP systolic blood pressure

this, there are very limited data on the detraining period, which is a finding supported
implementation of a maintenance phase, with by the recent findings of Gordon et al. [70].
the optimisation of IET prescrip- tion remaining Evidently, the exact detraining effects
an area for exploration. For example, it is regarding regression toward baseline BP
unclear how the potential for accelerated values fol- lowing IET are not clear and are
adaptations with greater IET session likely influenced via train- ing parameters such
frequency in the training phase (i.e. 5 × as IET mode, intensity and intervention
weekly) may influence the transition from the duration. Therefore, establishing optimal IET
training to maintenance phase. prescription practices in respect to a minimum
Previous work from Howden et al. [69] effective frequency dos- age is not yet feasible
reported a rapid detraining effect of IET where but is critical. Regardless, the current literature
significant reductions in rest- ing BP were is entirely centred around thrice weekly
mitigated within 10 days following the last IET sessions, and thus the significance of any
session [69]. Early data from Wiley et al. [41] wider adjustments to train- ing frequency is
also demon- strated that BP reductions largely unknown with a clear demand for
returned to baseline values fol- lowing a 5- future research.
week detraining period, while Taylor et al. [44]
confirmed the suitability of 3 weeks as a
‘washout’ period to establish baseline BP 2.6 Supervision
levels. Conversely, Baross et al.
[45] found that resting and ambulatory BP An important aspect of IET is its possibility to
reductions seen after an 8-week leg extension be performed with or without (home-based)
intervention remained signifi- cantly lower than supervision. Studies have uti- lised both home-
baseline values following a further 8-week based and supervised IET, depending on the
 J. J. Edwards et al.

type of isometric exercise. For instance, all

studies assessing wall squat IET have utilised From a scientific standpoint, the
home-based training, whereas leg-extension implementation of uni- lateral exercises is
IET has been conducted under supervision. intriguing as it allows for the differentia- tion of
Handgrip IET has demonstrated positive potential local and systemic effects of IET.
effects on resting BP through both home-based Given that no study has yet examined
and supervised training [54, 55, 71, 72]. unilateral IET with leg exercises, this remains
In order to compare the potential influence of an important gap that should be addressed in
home-based or supervised IET on resting BP, future studies.
Farah et al. [54] conducted a randomised trial
with three groups: supervised handgrip IET, 2.8 Duration and Adherence
home-based IET, and a control group. Handgrip
IET was performed using a commercially As shown in Table 2, all except one IET RCT
available handgrip dynamometer. The published to date are ≤ 12 weeks in duration.
observed results showed that only super- vised The only study to meas- ure the longitudinal
handgrip IET training reduced resting and effects of IET is a 1-year unsuper- vised wall
central BP in medicated hypertensive squat intervention by O’Driscoll et al. [82].
individuals. Unfortunately, the device used to This investigation reported significant
perform the handgrip IET was not able to reductions in sBP, mBP and dBP by − 10.5, −
record data regarding the completion and 9.9 and − 8 mmHg, respectively (all p <
intensity of exer- cise sessions. However, it is 0.001). Although the study sample size was
possible to speculate that the differences lim- ited, this work provides the first evidence
between supervised and home-based of long-term adherence to IET with 77%
exercises occurred due to the absence or adherence to sessions across all participants.
inadequate performance of the exercise at This finding supports the hypothesis that
home. adherence to IET is likely to be greater than
Despite the potential simplicity and short other anti- hypertensive interventions,
duration of the handgrip IET protocol, a particularly considering the well cited report
previous study [72] using a hand- grip device that 50% of people who start an exer- cise
able to record the information regarding programme will fail to adhere within 6 months
exercise sessions observed 37% of patients [83]. Unfortunately, there are otherwise limited
with peripheral artery disease did not data on longi- tudinal adherence to IET, which
adequately complete the 8-week home- based remains a fundamental gap in the current
training. Therefore, increased adherence literature. Data from short-term studies have
monitoring and supervision (virtual or other) is reported good adherence to IET [64, 66, 73,
necessary to ensure the effectiveness of 77, 80,
handgrip IET when prescribing it for home- 84, 85]. Palmeira et al. [71] demonstrated an
based training. immediately concerning dropout rate of 50%;
however, this value was similar to that
2.7 Bilateral Versus Unilateral observed in the control group (48%), which
indicates factors other than IET (e.g., difficulty
Leg extension IET and handgrip IET can both attending exercise sessions, city traffic, etc.)
be performed in either a unilateral or bilateral were related to the poor adherence.
fashion. All studies of leg extension IET have Given the lack of longer-term IET studies,
adopted bilateral training, while the handgrip the impor- tance of intervention duration on
IET studies have used both unilateral [64, 66, the magnitude of BP reduction is not clear.
67, 72–75] and bilateral [46, 47, 54, 71, 76–80] Research from Millar et al. [86] effectively
approaches. In a study directly comparing demonstrated linear negative trends in resting
unilateral and bilateral approaches, McGowan sBP and dBP over an 8-week intervention with
et al. [81] demonstrated that both unilateral no plateau in reductions over this timeframe.
and bilateral handgrip IET training were able to Although this work indi- cates greater
reduce the rest- ing sBP of medicated reductions from a longer intervention dura-
hypertensive patients. In contrast, in a tion, how this trendline may continue to adapt
systematic review and meta-analysis following an IET intervention of > 8 weeks is
conducted by Inder et al. [36], it was observed largely unknown. The magnitude of change
that participants undertak- ing unilateral found in the O’Driscoll et al. [82] longitudinal
handgrip IET showed a larger reduction in study may support a larger resting dBP effect
resting sBP than those undergoing bilateral with longer intervention duration when
handgrip IET (− 8.92 mmHg vs − 4.58 mmHg). observationally compared with previously
No significant differences in resting dBP or mBP published identical 4-week interventions [44,
were observed between unilateral and bilateral 65]; however, direct research is needed.
IET. Therefore, while the bilateral approach Separate meta-analysis work has offered
may be considered superior, the unilateral intervention dura- tion as a potential
approach remains open to discussion. moderator in meta-regression analyses, but no
However, the significant effects of unilateral IET significant effect of the number of training
on resting BP increase the possibility of using weeks on duration has been detected [31].
this mode of training for several populations Regarding minimum duration, trials have
that may be unable to per- form bilateral demonstrated clinically significant reductions
training (e.g., post-stroke patients). in resting BP following as
Isometric Exercise Training and Arterial Hypertension

little as 3 weeks of IET [87]. To our knowledge,

no research has examined the effects of a < 3- variance is commonly overlooked with some
week IET intervention; however, given the individuals deemed ‘non-responders’ to an IET
substantial changes commonly seen at 3–4 intervention. While inter-individual variability is
weeks, it may be pragmatic to suggest that inherent to any anti-hyper- tensive treatment,
clinically significant changes occur much identifying likely non-responders at an early
before this point. With this in mind, future stage (ideally before initiation of IET) is
research is required to understand the mini- important in the context of personalised
mum effective duration of IET before BP medicine [88]. The reasons for such inter-
adaptations begin to plateau. Combined with individual variability may be linked to dif-
the minimum effective frequency of IET, this ferences in physical activity status, stress
information would allow for enhanced IET pre- levels, sex, age, ethnicity, complex pre-
scription by establishing the minimum existing comorbidities and diseases, genetics,
necessary duration and frequency of training rapid versus delayed responses and current
required to achieve maximal BP reductions and phar- macotherapy. However, it is also
then subsequently maintain these changes. important to consider the common pitfalls of
Ultimately, a lack of longitudinal and non-responder identification consider- ing
minimum effective duration IET data limit the random variability, as discussed by Atkinson et
ability to generate specific effi- cacy and al. [89]. As detailed, the complexity of BP
adherence inferences from the current IET regulation is itself an inherent limitation to the
duration literature. However, it can be underlying literature of any anti- hypertensive
concluded that interventions of ≥ 3 weeks to 1 intervention, adding a broad layer of intricacy
year in duration can produce clinically to the interpretation and inferences that can
important reductions in resting BP. be made from the available IET data. The two
primary confounders which are historically
understood to moderate the degree to which
2.9 Protocol Summary BP changes following exercise are baseline BP
and medica- tion status.
Figure 2 presents the most well-supported IET Like pharmacological anti-hypertensive
protocol practices based on the current treatment, a higher baseline resting BP is
literature. In summary, the present evidence generally associated with greater reductions in
base supports 95% HRpeak wall squat and leg BP with exercise training [90]. Indeed, as
extension, and 30% MVC handgrip protocols, shown in Table 2, the greatest BP reductions
performed 3 × per week for ≥ 3 weeks, in observed fol- lowing IET tend to be in
sessions of 4 × 2-min bouts with rest intervals unmedicated hypertensive cohorts [36, 44].
of 1–4 min (see ESM for full IET exercise This is traditionally linked to a lower
prescription details). However, RPE protocols threshold of BP response in hypertensives,
are emerg- ing as more practical for the whereas normotensive reductions may be
prescription of wall squat IET. RCTs are needed limited by counter-regulatory processes
to truly discern the comparative efficacy and designed to prevent BP reductions below
clinical utility of each IET mode; however, homeostatic clinical levels (hypotension) [91].
early, indi- rect work suggests the wall squat While baseline BP may therefore constitute a
may be more efficacious than the traditionally significant portion of inter-study and inter-
employed handgrip IET mode, while leg individual variance, IET has also been largely
extension IET is often excluded on the basis of success- ful in multiple RCTs of normotensive
poor practicality/accessibility. It is also cohorts, as demon- strated in a recent
important to consider that these traditionally systematic review and meta-analysis by
recommended protocols of 4 × 2-min bouts at Loaiza-Betancur et al. [92]. This therefore
the discussed intensities have rarely been supports IET in not only the treatment of HTN,
challenged and are largely rooted in original but as a potential protective and preventative
work from Wiley et al. [41] and others (see intervention for those with normotensive or
Table 2). As such, research trials such as Javidi pre-hypertensive status. However, the potency
et al. [66], which pilot new IET protocols of this requires confirmation in prospective
against the traditional protocols, are to be studies with long-term follow-up.
encouraged. The involvement of ongoing anti-
hypertensive pharmaco- therapy complicates
interpretation of the current IET litera- ture.
Although the individual participant data meta-
3 Considerations in the analysis by Smart et al. [33] reported no
evidence of a medication effect, the BP
Interpretation of the Current response to IET in medicated hypertensives is
Literature often lower than that seen in unmedicated
hypertensives, which is likely, at least in part,
3.1 Outcome Moderators attributable to overlapping mechanisms
between IET and anti-hypertensive drug-
induced BP reductions [40, 44, 67]. As a
Substantial heterogeneity and complexity in limited example of this, four studies have
individual phys- iological profiles complicate measured pre- and post-IET inflam- matory
the interpretation of the current IET literature. biomarkers, with differing results depending on
Despite consistent and reproducible mean med- ication status, which may provide some
reductions in resting BP following IET, inter- mechanistic insight.
individual
 J. J. Edwards et al.

In unmedicated pre-hypertensive or
hypertensive cohorts, Taylor et al. 2018 [44], completion rates are not reported. The
Javidi et al. [66] (IHG-30 group) and Ogbutor et majority of published IET research also fails to
al. [93] all found anti-inflammatory changes effectively control for non-specific factors, such
with reductions in interleukin-6 following IET, as the placebo effect. Controlling for non-spe-
whereas Rodrigues et al. [76], who studied a cific factors in IET is complicated by the
medicated hyperten- sive population, found no inability to blind participants (i.e. participants
change. Although these conflicting results are are likely to be aware that they are, or they
probably influenced by a plethora of other are not, receiving IET); however, the inclusion
meth- odological variables, the hypothesis that of a sham control group who unknowingly
IET shares common mechanistic ground with perform IET at an intensity proven to be
anti-hypertensive medication is certainly ineffective is a useful technique to improve
plausible and one that remains largely general methodological rigour. This design has
unexplored [94–97]. Thus, given the expansive been effectively employed in some previous
number of varying anti- hypertensive drug handgrip [47, 64, 102] and wall squat IET
classes, each constituting different mecha- studies [65]. Combining these outlined
nistic effects, future IET research requires limitations, sometimes in the form of
participant strati- fication based on medication uncontrolled and non-randomised designs,
class. However, this line of research remains some of the weaker evidence is likely to suffer
complicated by limited real-world clinical from regression toward the mean, which is a
transferability due to the common scenario of concept not exclusive to IET, but applies to all
polypharmacy. While the outlined inter- interventional research with repeated
individual differences in response to IET measures [103].
appear pragmatically linked to the moderators Regarding population numbers, studies
dis- cussed (baseline BP and medication from Ogbutor et al. [73] and Correia et al. [72]
status), it is important to consider the findings have included impressive sample sizes of 400
of a recent meta-analysis by Kelly et al. [98] and 102 initially randomised partici- pants,
who found random variability as opposed to respectively; however, these numbers are not
true inter-individual response differences common across a literature that is largely
accounted for any dif- ferences in sBP and dBP limited by small sample size trials. Indeed,
changes following IET. Thus, while future larger-scale research, ideally applied in a clini-
research on inter-individual response cal setting using ABPM methods, and
differences to IET is undoubtedly needed, this compared against the present exercise
work suggests confounding moderators are guidance, would be of immeasurable benefit to
less important than traditionally believed in the current evidence landscape. In that sense,
influencing BP responses to IET. larger-scale feasibility studies, such as the
IsoFIT-BP study currently applied in an NHS
primary care setting, may constitute important
3.2 Evidence Quality steps forward [104].
Table 3 presents an authorship panel
There are some notable concerns regarding consensus on the certainty of evidence. We
the methodo- logical quality of the current IET applied the constructs of the GRADE (Grading
literature. In a recent meta-analysis of RCTs of Recommendation, Assessment, Devel-
[40], all trials were scored via the ‘Tool for the opment, and Evaluation) approach following
assEssment of Study qualiTy and reporting in the narrative summarisation of the information
Exercise’ (TESTEX), which is a 15-point quality provided in this work from all studies in Table
assessment tool designed for the direct 2. This rating should provide decision makers,
application to exercise interven- tional particularly those involved in the development
research [99]. Examining this quality of exercise guidelines, with information
assessment, the TESTEX scores of these regarding the certainty of the current IET
papers primarily ranged from 7 to 10 out of a literature and its effects on resting blood
possible 15, with one study scoring 13 [64]. pressure.
Although arbitrary cut-off points are debated,
previous work has suggested > 12 points as 3.3 Comparative Research: IET Versus Exercise
‘high quality’, 7–11 points as ‘good quality’, Guideline Recommendations
and < 6 points as ‘low quality’ [100, 101].
Thus, while the IET literature may be
interpreted as primar- ily being of ‘good Despite a plethora of indirect analyses [88, 90,
quality’, there are several quality points that 105–107], there are limited direct data on the
are frequently neglected and need addressing comparative effects of IET against traditionally
in future IET research. In particular, the recommended aerobic exercise on BP and
majority of research fails to blind assessors related cardiovascular parameters. Of note,
(which could be counteracted with ABPM the distinctive characteristics of these exercise
approaches), conceal allocation from the modes make it challenging to draw accurate
participants eligi- ble for inclusion (i.e. acquire comparisons, primarily due to the absence of
consent prior to the randomi- sation process), standardised parameters in key training
perform intention-to-treat analysis where variables like volume and intensity. While Yoon
appropriate, or monitor control group activity. et al. [108] found similar reductions in BP and
In some severely limited studies, there are pulse wave velocity between handgrip IET and
statistically significant differences in BP at aerobic brisk walking, the wider comparative
baseline, and adherence and/or session literature appears to provide less support for
Isometric Exercise Training and Arterial Hypertension

IET. Preliminary training work by Ash et al.

[109] supports aerobic training over handgrip

Concerns about certain

IET, but is limited by a total sample size of 11
participants. Goessler et al. [55] performed a
trial of greater scale, randomising 60
participants to an 8-week aerobic, IET

MODERATEa ⊕ ⊕ ⊕ O (due to serious risk

handgrip or control group interven- tion. While
this study found larger reductions in sBP fol-

reductions in systolic and diastolic blood pressure were reported in most trials with different sample suspected

suspected

suspected
lowing handgrip IET (− 5.5 mmHg; p < 0.01)

domains
than aerobic (− 3.9 mmHg; p = 0.07), dBP was

Seriou
significantly reduced fol- lowing aerobic

no evidence of indirectness The sample size of all studies was ~ 1400 subjects. Significant Not

Not

Although unclear, we did not strongly suspect publication bias because most registered trials were Not
training (− 4.4 mmHg; p = 0.006) but not

s
following IET (− 1.8 mmHg; p > 0.05);

concealment. Blinding of outcome assessors was not reported in most of the studies. However, this

Assessment of blood pressure was performed directly using validated methods. We judged there is
although it should be noted that these

failed to adequately account for all patients in the analysis. Selective outcome reporting and other
differences between the two modes were not

to − 4.5 mmHg). The inter-study variability in the magnitude of effect is considered primarily
limitation was mitigated using automatic devices for blood pressure assessments. Some studies
statistically significant. Furthermore, aerobic

Number of participants/Certainty in the

limitations were not disclosed. Approximately 30% of the studies exhibited a high risk of bias

were no variations in the direction of the estimated effect. The mean magnitude of
effect for systolic blood pres- sure was − 8.1 mmHg (95% CI − 6.5 to − 9.7 mmHg) and for
Many of the studies, despite randomisation, provided unclear information regarding allocation
train- ing, but not IET handgrip, produced

Serious risk of bias across studies because of unclear or inadequate allocation concealment, blinding and adequately
significant changes in daytime ABPM [55].
Perhaps the most notable compara- tive
research is that by Pagonas et al. [47], who

systolic and diastolic randomised controlled of bias)

randomised 75 hypertensive patients to either
5 × weekly IET handgrip training, 5 × weekly
sham handgrip training, or 3–5 × weekly
aerobic exercise training. Intriguingly, while
aerobic train- ing significantly reduced resting
and 24-h ambulatory sBP, this study firmly
conflicts with the wider scientific literature by

reductions in both 1424 subjects (28

reporting no BP changes following IET. In Table 3 Isometric exercise training and resting blood pressure: author panel consensus on the
response to this publication, Smart et al. [110]
provided a commen- tary citing various
methodological criticisms of the study, which

show evidence
studies
were individually countered by Pagonas and

trials)
diastolic blood pressure was − 3.7 mmHg (95% CI − 2.9
Westhoff [111]. Interestingly, it should be
noted that further analysis of this trial recently
demonstrated significant reductions in central

attributable to protocol and population differences

aortic sBP in the IET group, although no
change in BP variability; however, this work
was not powered for this analysis and the
finding may simply reflect a type 1 error [112].

blood pressure
In summary, while some limitations of Pagonas

studies
et al. [47] are clearly valid, the immediate
dismissal of these findings based on the
presented criticisms is still a point of debate.
Indeed, combined with the findings of Goessler
Effect
Most
et al. [55], this work effectively highlights the
uncertainty of IET, particularly in the form of
handgrip, to produce reductions that are
clinically and statistically significantly greater
than that seen with traditionally recommended
aerobic training as was previously
hypothesised. The important outcome of this
correspondence and the wider literature is the accounting for all patients in the analysis
need for future trials of larger sample sizes
investigating the effects of IET (handgrip and
published
Resting systolic and diastolic blood
Judgeme

wall squat) versus or in combination with

There

aerobic training on resting and ambulatory BP.

sizes

Future research may even consider reframing

nt
certainty rating of evidence

the research approach to IET, whereby

researchers investigate non-inferiority as
opposed to superiority when making such
comparisons.
limitations of the

Recently, Fecchio et al. [85] compared the effects of

Methodological

10 weeks of dynamic resistance training,

handgrip IET, and their combination on resting
BP in treated hypertensive men. The net
bias Outcome
studies

pressure

reduction in systolic blood pressure (sBP) in

the dynamic resistance training, IET, and
Inconsisten

Publication
Indirectne

combined train- ing groups was − 8 mmHg, −

domain
GRADE

5 mmHg and − 11 mmHg, respectively, when

a

compared with the control group. Among these,

only the dynamic resistance training group
cy
ss

showed
 J. J. Edwards et al.

statistically significant results and also

demonstrated a net increase in peak blood to 2019, HTN rates in women have nearly
flow during reactive hyperaemia, indicating doubled from 331 to 626 million people, with
improved microvascular function. However, the age-standardised global prevalence similar
pairwise comparisons did not reveal any to men (32 vs 34%, respectively) [118]. As
significant differ- ences among the three such, the importance of anti-hypertensive
groups, making it uncertain whether dynamic interventions in females should not be
training is superior to IET. To clarify this, future overlooked as was traditionally the case, and
studies should not only compare dynamic therefore greater quality sex-focused IET
training with other forms of IET but also include research is encouraged [119]. Indeed, the
both hypertensive men and women in the same applies for those of different ethnic
sample. populations who are at varying degrees of
predisposed cardiovascular risk [120].
3.4 Sex-Based Research 3.5 Evidence Reviewal Summary
IET research has been predominantly
performed in a mix of male to female, or male- In summary, this section aims to provide
only cohorts (Table 2). Therefore, the efficacy insight and contex- tualisation of the specific
of IET exclusively in females, as well as any details that remain important when
potential sex differences are not well known. interpreting the broad literature and
Evidence from acute studies indicates considering the direc- tion of future research.
potential sex dif- ferences in responses to a The outlined gaps and limitations of the IET
single session of IET. In female- exclusive literature provide important context, but it
research, O’Driscoll et al. [96] investigated the should be noted that many of these are true
acute responses to a single IET wall-squat for any anti-hypertensive intervention,
session, finding significant improvements in including pharmacotherapy, which remains the
haemodynamic control, with cardiac most prevalent treatment option in clinical
autonomic power-spectral heart rate variability practice [18]. Despite many ongoing studies
(HRV) analysis data returning to baseline addressing these gaps, there remains a lack of
readings during recovery. Interestingly, large-scale clinical IET studies as the main
following an identical protocol in males, prior source of evidence quality disparity between
research from Taylor et al. [97] found HRV to established interventions such as medical
increase following an acute bout of IET and therapy and IET.
exceed that of baseline measures. These
differences are further supported by the
findings of Teixeira et al. [113], who measured
the acute effects of IET handgrip training and 4 Safety
showed larger cardiac autonomic responses
during recovery in males com- pared with Traditionally, IET has been commonly
females. Although unknown, there appears to overlooked due to concerns over safety. These
be differences in the baroreflex pressor concerns have been largely cen- tred around
response as a pri- mary mediator of these historical work on left ventricular and
differences in post-IET autonomic response haemody- namic responses to IET [121–127].
between males and females, with males Subsequently, a notion followed that IET
receiving a 16-fold increase in baroreceptor induces drastic acute increases in sBP, dBP
sensitivity (BRS) follow- ing IET, compared with and rate pressure product (RPP), which may
a 3.6-fold increase in females [96, 113, 114]. theoreti- cally contraindicate such training for
In training studies, Baross et al. [53] and certain clinical popula- tions. Indeed, the safety
Somani et al. of IET in clinical populations with specific risks
[43] both found similar statistically significant concerning acute BP changes is an imperative
reductions in systolic ABPM between men and consideration and highlights the need for
women. Badrov et al. appropriate patient screening prior to the
[115] found that resting BP, as well as the prescription of IET. For example, IET is strongly
mechanistic investigation of endothelial- contraindicated (although on the basis of low-
dependent vasodilation, did not differ quality evidence) in those with connective
between young, normotensive men and tissue disorders (such as Marfan syndrome)
women, a finding also supported by Smart et [128] or thoracic aortic disease [129].
al. [33]. Furthermore, a systematic review However, wider claims for the contraindication
and narrative synthesis by Bentley et al. of IET in otherwise healthy hypertensive
[116] also found no significant differences in patients are unfounded and confuse clinicians
BP reductions following a handgrip IET and clinical exercise professionals. With
intervention between men and women. respect to safety and appropriate application,
Interestingly, when simultaneously ana- lysed the afore- mentioned claims are ultimately
with age, older women experienced the largest prohibitive of adoption and IET remains
mean reductions, indicating a potential ignored.
sex/age interaction in the effects of IET [116]. Physiologically, the static nature of IET
Although HTN remains less common in younger results in the compression (and occlusion in
women than men (< 60 years of age), rates of some individuals) of the active muscle
HTN are greater in elderly women than men vasculature, eliciting increases in cardiac
[117]. From 1990 output ( Q ̇) without the same magnitude of
concurrent
Isometric Exercise Training and Arterial Hypertension

reductions in total peripheral resistance (TPR)

that would generally be seen during other to IET are relatively small, even when
modes of exercise [96, 97]. Given the role of Q̇ compared with that of routine exercise testing
and TPR as the fundamentals of BP regulation in clinically vulnerable patients. For example,
(see Fig. 1), such changes would suggest an the highest RPP response observed in Wiles et
exag- gerated response during IET, specifically al. [130] was 20,681 ± 2911 mmHg⋅bpm−1,
in regard to dBP and especially in those with whereas that reported in high-risk patients
HTN [60, 130]. referred for clinical exer- cise testing for the
Considering that the contracting muscle evaluation of ischaemic heart disease was
mass is a cru- cial factor contributing to 27,729 ± 5018 mmHg⋅bpm−1 [135]. These low
increases in BP and the subse- quent RPP responses are further evidenced in Carlson
compression of blood vessels, there are et al. [136] with handgrip IET. In addition, the
greater con- cerns regarding elevations in BP increase in dBP is also a driver of coronary
during exercises involving large muscle groups flow, which may reduce the risk of myo- cardial
(such as squats and leg presses) com- pared ischemia.
with handgrip exercise. Aside from the wall Intensity is another important determinant of
squat, a recent modified Delphi study reported the BP response to IE. A systematic review
that handgrip and leg extension IET produce [132] observed that acute BP responses
BP responses of > 30 mmHg sBP or 20 mmHg following IET were dependent on inten- sity
dBP, with smaller RPP increases com- pared with higher MVC handgrip IET (> 60%) eliciting
with aerobic training [131]. Comparatively, a more exaggerated responses than lower
recent systematic review and meta-analysis intensity IET. In contrast, duration did not
[132] reported mean sBP responses of squat, appear a primary mediator for acute BP
leg extension and handgrip IET by + 46 responses to IET. Although this review is
mmHg, + 64 mmHg and + 33 mmHg. The limited by inter- study heterogeneity regarding
differ- ences in BP response between leg a lack of standardisation in which BP was
extension and handgrip IET were statistically recorded in response to an IET contraction,
significant. overall, this work confirms that IET involving
Examining the evidence, Wiles et al. [130] larger muscle groups, such as leg extension
measured the acute BP and RPP responses to and wall squat IET, appear to induce a more
wall squat IET in 26 hypertensive patients and exaggerated BP response. This therefore
reported sBP and dBP responses of 171 mmHg provides a loose framework on which clinicians
and 113 mmHg respectively. Importantly, the can indi- vidualise IET prescription, with
American College of Sports Medicine (ACSM) handgrip more likely to be suitable for those at
thresh- olds for acute BP safety are set at > higher risk.
250 mmHg sBP, and > 115 mmHg dBP [133]. To ensure the safe prescription of IET, it has
While no single participant recorded an sBP > been sug- gested that clinicians and
250 mmHg, dBP reached > 115 mmHg in six researchers ensure patients and participants
participants, presenting some concern. These maintain frequent uninterrupted breathing
dBP responses indicate the need for selective throughout a contraction to avoid
individualised IET prescription through the unintentionally perform- ing the Valsalva
manipulation of programme variables to manoeuvre [131]. The Valsalva manoeuvre
achieve lower BP responses. However, the refers to forced expiration against a closed
relative applicability of the ACSM guidelines glottis and is well known to produce significant
which were originally developed for aerobic acute increases in BP [137]. Previous work has
exercise testing remains unknown, especially acknowledged its importance with respect to
given that these thresholds were arbitrarily cardiovascular risk, particularly in the context
established by clinicians in the absence of data of straining for bowel movement [138].
[133]. Notably, the time spent above these Combined with the acute BP response to an IET
ACSM dBP guidelines was 4% (~ 19 s), which contraction, incorrect breathing practices
does not represent one single time period, but resulting in the performance of an
was instead spread across the train- ing unintentional Valsalva manoeuvre may
session and is therefore unlikely to elicit any increase BP beyond absolute contraindica- tion
signifi- cant cardiovascular risk given the short thresholds, particularly in those with pre-
time period over which these participants were established HTN. This communication from
subjected to this ‘extreme’ pressor response clinician/researcher to patient/participant is
[134]. The RPP, calculated as HR × sBP, crucial as those performing IET often have a
provides an effective non-invasive index of proclivity to naturally begin holding their
myocardial oxygen consumption. HR responses breath dur- ing a contraction.
to IET are generally much lower than that of As an interesting caveat to the safety
other exercise modes and certainly do not literature, IET is well established to produce a
achieve that of the ACSM exercise test post-exercise hypotensive response, which
attainment threshold of 85% predicted generally appears in relation to the hyper-
maximum HR [133]. To con- textualise this, the tensive response during IET [139–141].
Wiles et al. [130] population would have Although there are no direct comparative data,
needed to achieve an HR response of 149 the post-exercise hypotension following IET
b⋅min−1, whereas they only observed a (particularly lower-body IET) appears larger
response of 105 b⋅min−1. As such, the RPP and than that of other exercise modes and may
thus myocardial oxygen consumption offer a positive counteraction to the acute BP
responses rise that occurs during an IET contraction,
particularly when combined with the chronic
 J. J. Edwards et al.

benefits generally observed (which may be

mediated by the acute response) [141, 142]. disease. Current research is limited in
Despite the well-recognised role of post- providing any conclu- sions on the safety of IET
exercise hypo- tension in patients with HTN, in wider and often more complex populations,
significantly rapid decreases in BP, especially including no available evidence in patients with
dBP, can pose risks in patients with coro- nary obesity, diabetes, or populations wherein HTN
artery disease. During the diastolic phase of and mobil- ity limitations are prominent.
the car- diac cycle, blood flow supplies the Regardless of the health sta- tus of the
cardiac muscle. Rapid decreases in dBP can participating individual, the Valsalva
reduce the flow to the myocardium, leading to manoeuvre should be avoided through the
transient myocardial ischemia and a encouragement and teaching of appropriate
consequent increase in cardiovascular risk breathing techniques.
[143]. Therefore, caution is advised for
patients with coronary artery disease when
performing IET involving larger muscle mass, 5 Isometric Exercise Training: Acute
due to an abrupt decrease in dBP [144]. Physiological Responses
Separate to cardiovascular risk, specific IET
modalities can carry some less notable safety
considerations. Mobility concerns, particularly in 5.1 Physiological Responses During Isometric
frail older patients, carry an additional risk of Exercise
falls and musculo- skeletal injury with the wall
squat. As such, the application of wall squat The acute physiological responses of any anti-
IET may be limited or even contraindicated in a hypertensive intervention remain the
subgroup of patients who cannot safely hold a groundwork on which an under- standing of
wall squat position due to various reasons, long-term adaptations can be developed.
such as knee pathology, obe- sity and lack of Interestingly, research from Somani et al. [145]
sufficient musculoskeletal fitness or general has dem- onstrated that the acute sBP
frailty-related mobility problems. The acute responses to handgrip and leg extension IET
hypotensive effects could also pose a risk in can effectively predict the sBP reduc- tions
older participants prone to vasovagal following a 10-week intervention in healthy
syncope. Handgrip IET specifically may also young adults. Although the advanced cellular
cause hand cramping and skin events underlying the acute responses are
irritation/discomfort with common reports of unknown, research on the sys- temic
blisters and calluses from the sustained cardiovascular and autonomic responses to IET
pressure. However, there may be room for has advanced over several decades [146–148].
improvement here in targeting the historically The elevation in BP during IET is primarily
rigid design of handgrip dynamometers with the result of an increase in Q̇ via a
alternative devices, such as a squeeze ball chronotropic response, while SV generally
dynamometer. Acute local paraesthesia, likely remains stable or decreases due to venous
attribut- able to metabolite build-up, is also return impairment and increases in cardiac
commonly reported with IET. This most afterload [96, 97, 146, 147]. TPR has been
commonly presents in the form of an uncom- previously suggested to provide a less active
fortable burning sensation which subsides contribution to this BP rise, although the
shortly following the cessation of a contraction. limited previous data have been largely based
The only adverse event data of any on transitory meas- ures as opposed to
significant scale were continuous recording which may not be
reported in a systematic review and meta- sufficient to effectively capture the true
analysis [39]. Combining findings from pre- pressor response [130, 147, 149, 150].
hypertensive IET studies to form a pooled Examining the current continuous data,
sample size of 964 participants, Hansford et handgrip research has demonstrated a small
al. [39] reported a sum of eight events increase in TPR that remains above baseline
following IET and one in the control group. when measured throughout a single
These data were subsequently extrapolated to contraction [151], as well as when measured
equate to one adverse event per 28,428 bouts throughout a 4 × 2-min protocol session [62].
of IET [39]. While this contextualises the Conversely, the wall squat appears to produce
current best avail- able evidence, the limited an initial rise in TPR, followed by a stepwise
quality of research this finding is extracted reduction throughout each interval [96, 97].
from, combined with various other Regardless of these small response differences
confounders such as IET mode, the health between modes, the conclusion is that IET
status of participants in the analysed trials and does not appear to produce reductions in TPR
reporting bias severely impede the real clinical to the same extent as seen at the onset of
inferences that can be made from such dynamic modes including moderate intensity
analysis. It is encouraged that all future IET continuous [142] and high-intensity interval
trials closely monitor and appropriately report exercise [141], which is certainly a large
adverse event data. media- tor in the BP response to IET.
Overall, as summarised in the recent expert Mechanistically, this may be linked to the
consensus Delphi study [131], the current IET differences reported in flow mediated dilation
data support the safety of IET in healthy between IET and other exercise modes within
people, patients with pre-HTN, stage 1 HTN, an acute setting [30, 97, 152]. In particular, IET
some cardiovascular diseases and peripheral acutely produces a
artery
Isometric Exercise Training and Arterial Hypertension

mechanical response via contraction-induced

compression of the relevant vasculature with which is associated with the withdrawal of
resulting reactive hyper- aemia and a pressure parasympathetic activation as previously
undershoot on relaxation [115]. This reactive measured via high frequency HRV. This
hyperaemia subsequently enhances shear significant reduction in BRS during IET
stress as a mechanical stimulus to facilitate represents the resetting of the baroreceptors
increases in endothe- lial intracellular calcium to allow for a higher BP and HR as demanded
via potassium channel activa- tion, ultimately by the exercise; a response commonly seen in
promoting endothelial NO synthase [153]. other forms of exercise [141, 156]. Irrespective
Given that such a mechanism only occurs on of the con- fliction surrounding the validity of
cessation of an IET contraction, the short rest frequency domain HRV, evidence from
intervals between each sustained contraction, differing methodological approaches such as
combined with the short total dura- tion of an muscle sympathetic nerve activity (MSNA) and
IET session, may be speculated to be responsi- plasma noradrenaline spillover support a
ble for the lesser acute TPR reductions during sympathetic response dur- ing IE [154, 157–
IET than seen with standard exercise 159].
hyperaemia in other exercise modes Broadly, the acute BP responses during IET
(sustained vs rhythmic contractions). Without appear pro- portional to the relative intensity
the sustained vasculature compression unique and duration of contrac- tion, as well as
to IET, these other exercise modes may have important programme variables such as rest
this flow mediated dilation mechanism period between each contraction, number of
continuously functioning throughout a single contractions per session and of course, the IET
session, resulting in more consistently mode performed [130, 160, 161]. Recent
elevated shear rates at the site of the local comparative research has shown wall squat IET
vessels, consequently promot- ing TPR to elicit larger bout-to-bout elevations in BP
reductions during exercise and thus a lower BP than that of handgrip as a result of a greater
response [96, 97]. HR and thus Q̇ response [62]. Despite variance
These acute BP and haemodynamic changes in the magnitude of change [162], the general
with IET are regulated by complex interactions trend of these during-IET BP, haemodynamic
between central com- mand, the exercise and autonomic changes appear consistent
pressor reflex, the arterial baroreflex and the across males and females performing either
cardiopulmonary baroreflex [154]. Specifically, handgrip or wall squat IET [62, 96, 97].
an IET contraction-compression affects group
III/IV afferents sensi- tive to mechanical and 5.2 Physiological Responses Post-isometric Exercise
metabolic stimuli which subsequently triggers
cardio-acceleratory central command The acute physiological responses typically
responses in the form of increased seen after IE are depicted in Fig. 3. As
sympathetic activation and concur- rent observed, cessation of an IE contrac- tion
parasympathetic withdrawal. Such changes in allows for rapid reperfusion of blood to the
auto- nomic balance are implicated in the previously compressed vasculature in a period
outlined haemodynamic responses to IET, of post-IET reactive hyperaemia [163]. This
including the release of catecholamines which reactive hyperaemia results in an elevated
promote positive chronotropy, inotropy, shear rate against the localised endothelial
dromotropy and lucitropy via β-adrenoceptors. lining to stimulate the secretion of flow-
While the chronotropic effects are clearly induced vasoactive sub- stances such as NO,
evidenced through an increase in HR, the prostaglandins, potassium, adenosine
inotropic effects of this sympathetic triphosphate and other important vasodilatory
predominance are attenuated by concurrent mechanisms that are not well established in
changes in afterload and preload [97]. This has the context of IE [164, 165]. Simultaneously,
been evidenced through a reduction in SV there are fundamental autonomic and
seen during IET [97], which differs from the baroreflex changes immediately following IE,
response com- monly observed with other with shifts towards parasympathetic
modes of exercise training [141]. Investigating predominance, sympathetic with- drawal, and
such cardiac autonomic changes during IET, concurrent increases in BRS [243, 244]. Asso-
frequency domain HRV analyses in both males ciated with this vagal action, the increase in
[97] and females [96] have reported a BRS during recovery suggests a post-exercise
stepwise reduction in the total power spectrum resetting of the barorecep- tors as HR and
of HRV at the onset of an IE contraction with a subsequently blood pressure begin to reduce
greater proportion of the frequency domain [166, 167]. As previously reported [97, 144],
within the low frequency band. Commonly, this venous return is increased post-IE, resulting in
observation would be associated with a a reinstated preload. Com- bined with a
sympathetic response during IET; how- ever, reduction in afterload, this increase in preload
methodological limitations in the interpretation contributes towards acute cardiac functional,
of low frequency as an accurate measure of structural and mechanical improvements via
sympathetic tone have been commonly the Frank-Starling law, ulti- mately increasing
presented, with Goldstein et al. [155] sug- SV and Q̇ to slightly above baseline [166, 167].
gesting that low frequency serves as an index Specifically, IET elicits statistically significant
of baroreflex function rather than sympathetic acute improvements in cardiac systolic and
tone [141]. Conversely, BRS appears to diastolic function, relative wall thickness,
significantly decrease during IET [96, 97], fractional shortening, and cardiac
 J. J. Edwards et al.

mechanics (global longitudinal strain and

untwisting) [144]. With Q̇ remaining near an obvious moderator, with Swift et al. [62]
baseline irrespective of these acute cardiac demonstrating greater post-exercise
adaptations, the post-IET hypotensive changes hypotensive responses following wall squat
must be predominantly driven by TPR compared with handgrip IET. Interestingly,
reductions. while the wall squat group produced the
Acute post-IET hypotensive effects are largest reductions 10 min fol- lowing IE with
generally sup- ported, particularly for the wall steady attenuation of this response at 1 h, the
squat, with previous research showing acute handgrip group demonstrated the greatest BP
statistically significant sBP reductions below reductions at 1 h following IE, suggesting a
baseline by − 23.2 mmHg in males, and − more sustained response. Undoubtedly, future
17.3 mmHg in females [97] [216–218]. research with standardised and compa- rable
However, the post-exercise hypo- tensive methodologies are needed to comprehensively
effects of handgrip protocols have been less under- stand the acute BP responses and
clear, with some studies even reporting no subsequently sustained post-exercise
change in cohorts of older women [168] and hypotension following IE amongst different
medicated hypertensive patients [169, 170]. participant populations and IET protocols.
Certainly, the acute post-IET BP responses Regardless of the conflicting literature findings,
reported in different trials are dependent on it is a common theme that greater exercise BP
various meth- odological factors. Those studies and haemodynamic responses during IE often
measuring more imme- diate values (≤ 10 produce the greatest post-IE changes,
min) tend to report larger reductions [62, 96, highlighting the need to generate a sufficient
97] than more delayed measures (≥ 30 min) acute stimulus for a response. This may serve
[169, 170]. Indeed, some work suggests that a as evidence for the integral role of IET inten-
single acute IET handgrip bout may produce sity and protocol prescription in eliciting the
immediate BP reductions, but without any necessary acute responses which may
sustained post-exercise hypotension as deter- subsequently translate into the desired chronic
mined through ABPM [109, 171]. IET mode adaptations.
appears to be

IET

ReInstated
Venous Return

Parasympathetic
Dominance

LV Remodelling

Fig. 3 Acute physiological responses post-isometric

exercise. ATP adenosine triphosphate, BEI baroreflex factor, IET isometric exercise training, K potassium, LV
effectiveness index, BRS baroreflex sensitivity, EDHF left ventricu- lar, NTS nucleus tractus solitarius, TPR total
endothelium-derived hyperpolarising peripheral resistance
Isometric Exercise Training and Arterial Hypertension

Similar to the responses during IE, the post-

IE responses and underlying mechanisms are 6.2 Central Adaptations: Stroke Volume
dependent on a variety of moderators that
remain heterogeneous from study to study. There are several documented central
These may include IET mode, protocol, age, adaptations to an IET intervention. Similar to
sex, ethnicity, disease, medication and the outlined acute cardiac responses, recent
methodology, which should all be considered work has demonstrated statistically and
independently and collectively as factors when clinically significant improvements in cardiac
implementing IET. structure, function and mechanics following 4
weeks of home-based wall squat IET [172]. In
particular, wall squat IET improved key
6 Isometric Exercise Training: Chronic measures of systolic performance such as
Physiological Mechanisms global longitudinal strain and left ventricular
ejection fraction, as well as markers of diastolic
function including tissue doppler parameters
6.1 Mechanistic Overview and estimated filling pressures [172]. These
cardiac parameters are almost all understood
As demonstrated in Fig. 1, BP is fundamentally as ‘load-dependent’ parameters, suggesting
regulated by Q̇ and TPR. Therefore, any acute that such adaptations are primarily a basic
or chronic BP changes following IET must con- sequence of the observed simultaneous
involve either or both of these integral factors. reduction in rest- ing BP and thus cardiac
The advanced details regarding these afterload. This is further supported by
underlying mechanisms, particularly on a improvements in cardiac time intervals with
cellular level, are still largely unknown with the same intervention [173], highlighting the
most research based on small-scale work. An favourable LV and aor- tic pressure–volume
overlap in mechanisms between IET and anti- changes that occur with a reduction in BP from
hypertensive medical therapy-induced BP IET. Interestingly, this work also found
reductions complicates clinical interpretation independ- ent improvements in measures of
of this literature. global myocardial work (global wasted work
The largest-scale mechanistic work to date is and global work efficiency), which represents a
a systematic review and meta-analysis [31] of novel approach to assessing cardiac function
all IET RCTs in which BP changes were by incorporating afterload into its algorithm to
reported alongside at least one mecha- nistic generate less load-dependent indices [172,
variable. With a pooled analysis of 18 RCTs 174]. Inter-linked with these cardiac
(628 participants), this work found a adaptations is the role of ventricular filling and
statistically significant reduction in resting HR preload, with IET inducing significant
by − 1.55 b⋅min−1 (95% CI − 0.14 to 2.96; p = improvements in end- diastolic volume, likely
0.031), concurrent with a statistically sig- due to improvements in LV relaxa- tion [172]
nificant increase in SV by 6.35 mL (95% CI which has drawn speculation on the potential
0.35–12.60; p = 0.038). There was role of IET in heart failure with preserved
consequently no change in Q̇ across these ejection fraction in an ongoing clinical trial
studies. Conversely, TPR significantly [175]. This increase in preload has implications
decreased by − 100.38 dyne⋅s−1⋅cm5 (95% CI relating to the Frank-Starling law as well as LV
− 14.16 to − 186.61; p = 0.023) alongside stretch-induced NO stimulation relating to
significant improvements in the low frequency cardiac exci- tation–contraction coupling [176–
to high frequency HRV by − 0.41 (95% CI − 178]. Collectively, these afterload- and
0.09 to − 0.73; p = 0.013) and BRS by 7.43 preload-dependent cardiac adaptations are
ms⋅mmHg−1 (95% CI 4.29–10.57; p < 0.001). likely responsible for small increases in SV
Ultimately, this analysis concluded a reduction often (but not always) seen following IET [31].
in TPR, potentially mediated through enhanced
autonomic vasomotor control, to be primarily 6.3 Central Adaptations: Resting Heart Rate
responsible for the observed reductions in BP
with IET [31]. While the findings of this work Although some research has evidenced
provide a strong base for understand- ing the statistically signifi- cant and mechanistically
gross mechanistic adaptations to IET, relevant reductions [30, 63, 179], resting HR is
performing a pooled analysis of several not traditionally understood as a primary
heterogeneous studies that are not statistically mediator of BP changes following IET,
powered to examine these mechanisms as the especially given that several studies have
primary outcome is inherently limited. reported substantial BP reductions with little or
Furthermore, this work is restricted to gross- no change in resting HR [44, 64, 65, 67, 77,
level changes without the scope to draw on 78, 82, 94, 180, 181]. Considering the limited
more advanced fine-level physiological adapta- diversity in recruited populations and small
tions. Therefore, an in-depth exploration of sample sizes often used in these IET trials,
each mechanistic domain is necessary to combined with the complexity and potential for
effectively understand and encapsu- late the measurement error if not appropriately
wider mechanistic literature. controlled for in methodological design (e.g.,
female menstrual cycle), it is not clear if a
change in resting HR has a different active
mechanistic contribution towards BP reductions
in particular
 J. J. Edwards et al.

populations. For example, moderator analysis

from a recent systematic review and meta- controlling the vasculature and subsequently
analysis [40] suggested that studies including BP to a larger degree [262, 264]. Additionally,
medicated participants observed sig- nificantly there are limited data to support the role of
larger resting HR reductions following IET than BRS in long-term BP control [186]. Despite
unmedicated. With the effectiveness of HR- some promising findings, there remains a
modulating anti- hypertensive substan- tial degree of confliction amongst IET
pharmacotherapy such as β-blockers, it is pos- trials measuring cardiovascular autonomic
sible that resting HR may assume a more modulation [27, 102]. Studies by Wiles et al.
central position as a mechanistic co-ordinator [27], Ray and Carrasco et al. [102] and Badrov
in different sub-populations, particularly in et al. [67] have all observed significant BP
traditional essential HTN patients with auto- reductions with no change in cardiac
nomic dysfunction and thus an elevated autonomic metrics, as summarised in a small-
baseline resting HR. It is likely that a reduction scale handgrip IET meta-analysis by Farah et
in resting HR following IET is mediated via al. [187]. Intriguingly, these studies have
autonomic vagal tone improvements [44, 94, primarily incor- porated younger,
181]. normotensive, active populations and in
theory, hypertensive, older, inactive cohorts
are much more likely to have an impaired
6.4 Central Adaptations: Cardiac Output baseline sympathovagal balance and therefore
a greater capacity for adaptation in such a
With small improvements or no change seen in domain [264]. It is plausible that some of the
both SV and resting HR, Q̇ tends to remain cur- rent confliction in autonomic findings in
stable after an IET interven- tion. This is the IET literature may be explained, at least in
demonstrated after both short term and longi- part, by participant charac- teristic differences.
tudinal IET interventions, with a recent IET For example, a subset of studies that include
intervention evidencing no change in Q,̇ but medicated HTN patients have shown no
significant reductions in rest- ing BP and TPR improve- ments in HRV measures of cardiac
[82]. Despite this, some studies [30] have autonomic function fol- lowing IET, as
found significant reductions in resting Q̇ demonstrated in Millar et al. [181], Farah et
without changes in TPR. The relevance of this al. [54], Correia et al. [72] and Palmeira et al.
finding in the context of the wider literature is [71]. As such, it may be speculated that
not known, but it is worth noting that this improvements in autonomic modulation are
research was performed in rather young, most distinguished in those with poorly
physically active, normotensive participants controlled BP, which may help mechanistically
who have a different physiologi- cal and risk explain the larger magnitude of reduction
factor profile to those studies recruiting older often seen in these popula- tions. Alternatively,
patients with essential HTN. in younger normotensive individuals and those
with well controlled medicated HTN, it is likely
6.5 Cardiac Autonomic Adaptations that alternative adaptations are predominantly
responsible for the reductions in BP.
It is also important to note that this line of
Autonomic dysfunction, as characterised by an research may
impaired sympathovagal balance, has been
long implicated in the mul- tifactorial aetiology also be complicated by the application of
of HTN [182–184]. Numerous studies have different auto- nomic measures across these
demonstrated improvements in autonomic studies, which may have het- erogeneous
cardiovas- cular control following an IET sensitivities in detecting more subtle changes.
intervention as measured by frequency- For example, in those studies that only
domain HRV metrics [44, 65, 94] and non- demonstrated modest BP adaptations following
linear heart rate complexity (sample entropy) IET, traditional HRV parameters may be too
[181]. The theoreti- cal translation of IET- insensitive to detect such small changes in car-
induced autonomic adaptations into clinically diac autonomic modulation, as supported by
relevant reductions in BP is likely seen through Millar et al. [181]. Furthermore, methodological
the complex interacting effects of several BP concerns regarding insufficiently powered
modulating influences, such as vascular sample sizes and the overall robust- ness of
vasomotor activity and possi- ble effects on HRV as an indirect measure of cardiac
the renin-angiotensin aldosterone system, as autonomic modulation remain. There also
illustrated in Fig. 1 [183, 185]. remains substantial inherent bias regarding
the effects of HR change on HRV, which has
Two studies [44, 65] have evidenced not been adequately addressed in any IET
improvements in cardiac BRS after 4 weeks of
wall squat IET, although Decaux et al. [65] was work to date.
not powered to show a significant difference. In summary, the results of studies
The baroreflex is a vagally mediated inte- examining change in autonomic function have
gral regulator of BP, with an increase in BRS conflicting results. Although unclear,
serving to improve both BP and BP variability improvements may be dependent on
[44]. However, these measures are local to participant characteristics, with more
cardiac BRS and do not reflect the sympathetic pronounced improvements in uncontrolled HTN
arm of the baroreflex, which is responsible for and a notable absence of such adaptations
following IET in young normotensive
individuals or those with controlled HTN. This
domain of literature is compli- cated by
differing measures and sub-measures of
autonomic
Isometric Exercise Training and Arterial Hypertension

modulation and methodological limitations.

Ultimately, at best, cardiac autonomic shear rate) was not sufficient to trigger
measures represent a surrogate of autonomic adaptations in the brachial artery [190].
nervous system modulation as a plausibly Finally, a meta-analysis of 23 trials
impli- cated mechanistic change following IET. demonstrated that both dynamic resistance
However, cardiac autonomic parameters such training and IET increase flow-mediated
as HRV cannot provide any fur- ther detail on dilation in healthy individuals and subjects with
whether BP changes are Q̇ or TPR driven. cardiovascular and metabolic diseases, with no
difference between the types of exercise [191].
It is important to consider that, despite the
well-estab- lished notion that BP is regulated at
6.6 Vascular Adaptations the level of the resist- ance vessels [67], most
IET trials investigating functional vascular
Given the frequent reports of no change in Q̇, it changes have been applied at the conduit
is likely that reductions in BP following IET are vessel level (brachial or femoral artery
primarily mediated by vascular changes. In measures). Considering this, Badrov et al. [67]
support of this, studies applying non- invasive investigated the effects of an 8-week hand- grip
measures of TPR have demonstrated IET intervention on forearm reactive
significant improvements after an IET hyperaemic blood flow in normotensive
intervention on several occasions [44, 65, 82], participants, demonstrating significant
as highlighted in a recent meta-analysis [31]. increases by 42% and 57% in 3 × and 5 ×
Despite this, the current literature has not weekly IET groups. Combined with the earlier
comprehensively addressed the degree to findings of McGowan et al. [192] that
which these vascular changes fol- lowing IET evidenced a larger post-reactive hyperaemic
are locally regulated via endothelial-depend- response, these data support the effects of IET
ent mechanisms, or systemically modulated on resistance vessel function further to that of
via structural remodelling and/or functional conduit vessel function. However, it should be
adaptations in autonomic vasomotor control. noted that, despite a significant reduction in
resting BP mid-intervention (4 weeks), changes
6.7 Vascular Adaptations: Local in forearm blood flow trended towards an
increase but were not statisti- cally significant
Endothelium-Dependent Mechanisms [67].
A promising study abstract was published
Improvements in conduit artery endothelial which reported findings of improvements in
function are mechanistically plausible as a resistance vessel endothe- lial function in the
consequence of repeated bouts of acute contralateral arm following a 4-week handgrip
endothelial stimulation with IET. As a gold- IET intervention [193]. However, there is other-
standard non-invasive measure of endothelial wise limited evidence to suggest these
func- tion, previous studies have investigated adaptations extend beyond the locally trained
the effects of IET on flow-mediated dilation, vasculature [272]. The localisa- tion of these
demonstrating mostly positive results. Early adaptations may also help explain the differ-
work from McGowan and colleagues [81, 188] ence in magnitude of BP reduction between
reported improvements in endothelium- handgrip and lower body IET, with wall squat
dependent, but not endothelium- and leg extension protocols involving larger
independent, vasodilation following 8 weeks muscle groups and thus a greater degree of
of handgrip IET in medicated HTN participants. functionally adapted vasculature.
While some discrepancies exist [54, 189], Overall, IET is associated with improvements
these improve- ments in endothelial function in local conduit and resistance vessel
have been more recently rep- licated in endothelial function; however, the vascular
medicated, (majority hypertensive) peripheral mechanisms responsible for reductions in BP
artery disease patients [72] and unmedicated following IET are likely multi-factorial and the
HTN patients [66]. However, as evidenced in exact contri- bution of these local functional
the work from McGowan et al. [81, 188], flow- adaptations remains unclear. The roles of
mediated dilation improvements after IET only population, medication status and a possible
occur in the trained arm, suggesting that such ceiling effect are also unknown.
endothelium-dependent vasodilation
adaptations are lim- ited to the locally 6.8 Vascular Adaptations: Neural Vasomotor
stimulated vasculature [81, 188]. This is Control
further supported in the findings of Baross et
al. [63] who found significant improvements in
femoral artery blood flow, blood velocity, Changes in the neural regulation of vascular
diameter and vascular conductance after 8 tone may con- stitute an important
weeks of leg extension IET, but no changes in mechanistic pathway for BP reduc- tions
bra- chial artery measures. Recent knee following IET, as supported in the findings of a
extension resistance training also echoes recent meta-analysis [31]. Ray and Carrasco et
these findings with localised improve- ments al. [102] measured MSNA, which is a direct
in femoral artery endothelial function but measure of vasoconstrictor neural activity to
citing that the mechanical stimulus (increase skeletal muscle, finding no significant change
in Q̇ and in turn, in MSNA following handgrip IET. While further
research into MSNA following IET is warranted,
it may be considered a
 J. J. Edwards et al.

measure that primarily contributes to short-

term BP modu- lation as opposed to long-term with peripheral artery disease complicate the
control [194]. Despite con- fliction, current possible infer- ences made from such data.
data support a reduction of vasomotor tone Despite one finding of central (but not
following IET. peripheral) pulse wave velocity improvements
in medicated participants [76], the general
literature tends to suggest a confounding
6.9 Vascular Adaptations: Structural effect of baseline medication status on the
Vascular Remodelling efficacy of IET in improving arterial stiffness. It
is also important to consider that most studies
It has been suggested that vascular employ standard carotid-femoral pulse-wave
adaptations following IET are biphasic, with velocity measures as opposed to the localised
shorter duration interventions associated with limb.
the aforementioned functional changes, While the underlying mechanisms driving
whereas longer duration IET interventions have arterial stiff- ness improvements are unclear, it
been linked to structural vascular remodelling. has been previously hypothesised that
Following this concept, the major- ity of IET structural changes through an improve- ment
data, including the discussed mechanistic in the synthesis and degradation of collagen
meta- analysis [31], only reflect short-term and elas- tin, which remain the key scaffolding
functional changes with limited information on proteins of arterial structure and stiffness
longitudinally stimulated structural [197], are implicated. This hypothesis is
mechanistic adaptations. Baross et al. [53] and supported by evidence of chronic
Gordon et al. enhancements in clinical markers of
[70] have both recently evidenced a sustained inflammation and oxidative stress following an
effect of IET on BP after a detraining period IET intervention [44, 66]. However, to date
following 8 and 12 weeks of IET, respectively. there are no lon- gitudinal (> 12 weeks) data
Given that a rapid detraining effect would be on measures of arterial stiffness with IET.
expected if the mechanisms driving such BP Therefore, the current literature is likely
reductions were purely functional, this work reflective of functional changes underlying
may therefore imply some degree of sustained arterial stiffness improve- ments following IET,
structural [70] adaptation. Furthermore, a with any discussion of systemic struc- tural
recent study [82] documented the longest IET vascular remodelling remaining mostly
intervention to date of 1 year and reported a speculative.
significantly reduced TPR as the primary Overall, as evidenced in the recent large-
mechanism for the maintained BP reductions. scale mechanis- tic meta-analysis recently
While the mechanisms responsible for these published [31], it is important to note that data
TPR reductions were not further explored, such on vascular adaptations following IET, be it
intervention duration war- rants the functional or structural, remain limited.
consideration of structural changes. Although it is clear that reduced TPR is
Unfortunately, little work to date has directly fundamental to the BP reductions seen with
investigated vessel structure following IET, the exact mechanistic underpinnings of
longitudinal IET. Previous work from Baross et this are inconclusive with a likely dependency
al. [63] found a significant increase in femo- ral on population/patient characteristics, IET mode
mean arterial diameter following an 8-week leg and intervention duration. Func- tional
extension IET intervention, but no change in improvements in endothelial function and
brachial diameter. Given the previously vasomotor tone are mechanistically implicated,
demonstrated localisation of these functional while hypotheses of structural vascular
changes, these adaptations likely reflect remodelling are still speculative.
endothelial-medi- ated dilatory adaptations,
rather than evidence of a sustained structural 6.9.1 Inflammation and Oxidative Stress
enlargement [195]. Other studies measuring
con- duit vessel diameter following short-term A small number of IET studies have provided
IET observed little or no change [72, 76, 153]. small-scale data on biomarkers which may
Several studies have investigated the effects provide further information on the
of IET on arterial stiffness, with mixed results. physiological underpinnings of BP responses to
Okamoto et al. [78] included a cohort of IET. Inflammation and oxidative stress have
unmedicated physically inactive par- ticipants been long implicated in the pathophysiology of
and reported improvements in augmentation HTN and remain key mechanistic areas of
index following 8 weeks of IET, a finding the interest [198]. Changes in inflammation and
authors have recently reproduced [196]. oxida- tive stress following IET are likely
Differently, in a group of medi- cated attributable to the dis- cussed improvements
hypertensives, Farah et al. [54] found no in NO-dependent conduit and resist- ance
significant pulse wave velocity or vessel vasodilation by this strong anti-
augmentation index changes after 12 weeks inflammatory and antioxidant molecule [199].
of IET. More recently, Correia et al. [72] Indeed, a recent acute study demonstrated
recruited a cohort of medicated patients with significant increases in NO and antioxidant
peripheral artery disease and also reported no defence after a session of IE bench and leg
effect on pulse wave velocity or aug- press [200].
mentation index from an 8-week IET As outlined above, IET is capable of
intervention. However, the vascular improving inflamma- tory markers, particularly
abnormalities and arterial stiffness in patients IL-6 [44, 66, 73], although these adaptations
appear dependent on medication status [76].
Recent pilot research from Bennett et al.
[201] is the first
Isometric Exercise Training and Arterial Hypertension

to report inflammatory changes to be linked to

sBP changes following 6 weeks of IET. inter-individual and inter-population variation
Regarding oxidative stress, an early in mechanis- tic findings complicates our
uncontrolled trial by Peters et al. [202] current understanding, with par- ticular
reported reduc- tions in aerobic exercise- consideration of baseline BP and medication
induced oxygen-centred radicals and status. Future well-powered research with a
improvements in the ratio of whole blood mechanistic focus is likely to help clarify the
glutathione to oxidised glutathione, current confusion and uncertainty in the
simultaneous to significant reduc- tions in sBP literature. Finally, the effect of IET on other
after 6 weeks of IET in unmedicated HTN. More potentially important external mechanistic
recently, Javidi et al. [66] assessed both domains, including renin- angiotensin
inflammatory and oxidative stress responses aldosterone system factors and other
to an 8-week 30% or 60% MVC handgrip mediators of vasodilation such as endothelin,
intervention. This work found improve- ments prostaglandin, vasopres- sin and brain
in endothelin-1 (although this has limited natriuretic peptide, remain undetermined and
inferences) and carbonyl protein following thus have not been discussed. This review and
handgrip IET at 60% MVC, but not 30%, with the outlined gaps in the literature should be
no improvements in malondialdehyde, or total incorporated into the stra- tegic planning of
antioxidant capacity at either intensity. future mechanistic investigatory research.
Conversely, 30% MVC but not 60% MVC IET Figure 4 illustrates our current understanding
elicited consistent anti- inflammatory effects of the mecha- nistic adaptations following IET.
with reductions in IL-6 and tumour necrosis
factor-α. As both intensities produced
significant BP reductions concurrent with 7 Conclusion
inconsistent changes in oxi- dative stress and
inflammation, Javidi et al. [66] concluded that This review summarises the potential role of
IET may produce BP reductions independently IET as an anti- hypertensive intervention with
of anti- oxidant and anti-inflammatory consideration of its efficacy, acute
changes. As is the case for almost all IET cardiovascular stimulus, and physiological
mechanistic data, these studies are powered mechanistic underpinnings. Data from
to detect BP changes as the primary outcome prospective RCTs and meta-anal- yses indicate
so it is possible that a lack of consistent IET is capable of producing reductions greater
changes in the selected markers of than that observed following the currently
inflammation and oxidative stress is the recommended exercise guidelines and possibly
consequence of lim- ited statistical power. even greater, or at least sim- ilar to that of
Thus, while IET is capable of produc- ing standard anti-hypertensive monotherapy. The
favourable changes in inflammation and current evidence primarily supports protocols of
oxidative stress, future well-powered research, 95% HRpeak for wall squat and leg extension,
ideally of longer intervention duration, is and 30% MVC for hand- grip, performed three
needed to ascertain the mechanistic or more times per week for ≥ 3 weeks, in
importance of these changes in regard to the sessions of 4 × 2-min bouts with rest intervals
adjacent reductions in BP. of 1–4 min. Handgrip protocols in particular
have received endorsement in previous
6.9.2 Mechanistic Summary international guidelines [8].
It is important to acknowledge that these
protocols have rarely been challenged and
In summary, the mechanistic changes driving thus research piloting novel IET protocols are
reductions in BP following IET are complicated encouraged. The effectiveness of IET may be
and still largely unclear. With little or no dependent on the magnitude of muscle mass
change in Q̇, it appears that adaptations to the recruited, with wall squat and leg extension IET
vascular system, which ultimately produce a appearing more effective than the traditionally
reduction in TPR, are key. Of these, IET has employed handgrip mode. However, the
been previously associated with improvements convenience and reach of handgrip IET in
in locally regulated conduit and resist- ance populations with mobility or risk limitations
vessel endothelial-dependent vasodilation, cannot be ignored, nor the anti-hypertensive
functional adaptations in autonomic vasomotor effects overstated. IET appears safe in patients
control, and systemi- cally modulated with pre-HTN, stage 1 HTN, some
structural vascular remodelling. While it is cardiovascular diseases and peripheral artery
probable that multiple vascular mechanistic disease, although the current literature is
pathways are involved simultaneously, this limited in providing any conclusions on the
review highlights the short intervention safety of IET in wider and often more complex
duration of studies currently available, thereby populations, such as those with aortic
suggesting functional improvements in pathology or connective tissue dis- orders. The
localised endothelial- dependent vasodilation acute haemodynamic and autonomic
and vasomotor tone are most likely implicated, responses to IE are largely understood and
while hypotheses of structural vascular may be useful in predict- ing chronic changes
remodel- ling are still speculative with and providing advanced mechanistic insight.
longitudinal mechanistic data needed. Chronically, the mechanisms driving changes
Although this section provides an overview in BP following an IET intervention are still
of the lit- erature findings, it is not clear if elusive, but appear primarily dependent on
these mechanistic changes are the same changes in TPR. Vascular changes in
amongst differing populations. Certainly,
 J. J. Edwards et al.

Isometric Exercise Training

Diastology

sBP
GLS
dBP
mBP
SV
.
Q

HR

Autonomic
Function

Functional
TPR Sympatholysis

Local vessel
Structural
endothelial
remodelling
BRS
function

Strong Evidence Conflicted/Moderate Evidence Speculative/Weak Evidence

Fig. 4 Chronic mechanistic changes seen with isometric

exercise training. BRS baroreflex sensitivity, dBP sure, Q̇ cardiac output, sBP systolic blood pressure, SV
diastolic blood pressure, GLS global longitudinal strain, stroke vol- ume, TPR total peripheral resistance
HR heart rate, mBP mean blood pres-
Isometric Exercise Training and Arterial Hypertension

locally regulated conduit and resistance vessel

endothelial- dependent vasodilation and
•
Longitudinal IET study designs with
functional adaptations in auto- nomic consideration of clinical and economic
vasomotor control are implicated, while a lack outcomes.
of longitudinal data limits the possibility to
•
Due to confounding variables with RCTs,
generate accurate inferences regarding the wait-list design research trials where
mechanistic role of systemically modulated participants represent as their own control
structural vascular remodelling. The should be explored. Greater focus on
mechanisms responsible for BP reductions with methodo- logical rigour through control
IET are almost certainly multi-factorial and group monitoring, assessor blinding,
narrowing the exact contribution of each controlling for non-specific factors and mini-
potential pathway is complicated by an mising measurement error through a
underdeveloped body of evidence and inter- prioritisation of 24-h ambulatory, awake
study variation. daytime and asleep night-time measures is
Given that IET has only been investigated as needed.
an anti- hypertensive intervention for a
relatively short period of time, there are still Direction:
several domains within the literature that
require attention. Importantly, IET research is •
Further direct research comparing IET in
still mostly limited to small sample sizes and combination with and against traditional
thus there remains a need for large-scale RCTs exercise guideline recom- mendations.
ideally applied in a clinical setting and •
Investigation into inter-individual and inter-
compared against the present exercise population heterogeneous BP responses to
guideline recom- mendations. Indeed, a lack of IET.
large-scale clinical IET stud- ies remains the •
Research into adoption and adherence and
main source of evidence quality disparity individualised exercise prescription of IET.
between established interventions such as •
Exploration of IET in differing clinical
medical therapy, traditional exercise, and IET. conditionsand ethnic populations;
Future investigation into inter- individual and generation of female-specific data.
inter-population heterogeneity regarding BP •
Investigation of the effects of IET on
response to IET is also needed, with particular cerebrovascular health.
emphasis on participant stratification based •
Investigation of effectiveness of IET prior to
on sex, baseline BP and active medical initiation of pharmacotherapy or in
therapy. Furthermore, adequately powered combination with medical therapy and in
studies investigating important mechanistic those with resistant HTN and other BP
variables, ide- ally of longitudinal intervention pheno- types.
designs, are warranted. The methodological •
Quantifying health-system level feasibility
rigour of future IET trials may benefit from an (e.g., patient and physician burden).
improved implementation of assessor blinding, •
Understanding the impact of timing of IET
appropri- ate concealing of group allocation therapy (morning vs evening) on non-
from participants eligible for inclusion, dippers, morning surge, and sleep.
monitoring of control group activity and con-
trolling for non-specific factors such as the
placebo effect (i.e., employing a sham control Declarations
protocol).
Funding No sources of funding were used to assist in
the preparation of this article.
7.1 Future Research Direction: Key Considerations
Conflict of Interest The authors declare that they have no
conflicts of interest relevant to the content of this
The following take-home points represent review.
summarised areas of research design and
direction, identified through this review and as Ethics Approval and Consent to Participate Not applicable.
general recommendations by the author team,
Author Contributions JE and JO’D contributed to the
that are most in need of future investigatory conception and design of the study. JE and JO’D were
attention. the principal writers of the manuscript. All authors
Design: contributed to the drafting and revision of the final
article. All authors approved the final submitted version
of the manuscript.
•
RCTs with adequately powered sizes are
needed to gen- erate the same quality of Consent for Publication Not applicable.
evidence as that of traditional training
modes. Availability of Data and Materials Not applicable.
•
Multi-centre RCTs applied in a clinical
setting through personalised exercise
referral to match ethnic and soci-
odemographic diversity.
•
RCTs sufficiently powered to investigate
underlying mechanistic variables behind the
success of IET in reduc- ing resting BP.
 J. J. Edwards et al.

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Authors and Affiliations

Jamie J. Edwards1 · Damian A. Coleman1 · Raphael M. Ritti-Dias2 · Breno Q. Farah3 · David J. Stensel4,5,6,7 ·
Sam J. E. Lucas8 · Philip J. Millar9 · Ben D. H. Gordon10 · Véronique Cornelissen11 · Neil A. Smart12 · Debra J. Carlson13 ·
Cheri McGowan14 · Ian Swaine15 · Linda S. Pescatello16 · Reuben Howden17 · Stewart Bruce-Low18 ·
Christopher K. T. Farmer19 · Paul Leeson20 · Rajan Sharma21 · Jamie M. O’Driscoll1,21

 Jamie M. O’Driscoll 11
[email protected] Department of Rehabilitation Sciences, KU
Leuven, Leuven, Belgium
1
School of Psychology and Life Sciences, 12
School of Science and Technology, University of
Canterbury Christ Church University, Kent CT1 New England, Armidale, NSW, Australia
1QU, UK 13
2
School of Health, Medical and Applied Sciences,
Graduate Program in Rehabilitation CQ University, North Rockhampton, QLD,
Sciences, University Nove de Julho, São Australia
Paulo, Brazil 14
3
Department of Kinesiology, University of
Department of Physical Education, Windsor, Windsor, ON, Canada
Universidade Federal Rural de Pernambuco, 15
Recife, Brazil Sport Science, University of Greenwich, London, UK
16
4
National Centre for Sport and Exercise Department of Kinesiology, University of
Medicine, School of Sport, Exercise and Connecticut, Storrs, CT 06269, USA
Health Sciences, Loughborough University, 17
Department of Applied Physiology, Health and
Loughborough, UK Clinical Sciences, UNC Charlotte, Charlotte, NC
5
NIHR Leicester Biomedical Research Centre, 28223, USA
University Hospitals of Leicester NHS Trust 18
Department of Applied Sport and Exercise
and the University Science, University of East London, London, UK
of Leicester, Leicester, UK 19
6
Centre for Health Services Studies, University of
Faculty of Sport Sciences, Waseda University, Kent, Canterbury, UK
Tokyo, Japan 20
Oxford Clinical Cardiovascular Research
7
Department of Sports Science and Physical Facility, Department of Cardiovascular
Education, The Chinese University of Hong Medicine, University of Oxford, Oxford, UK
Kong, Hong Kong, China 21
Department of Cardiology, St George’s
8
School of Sport, Exercise and University Hospitals NHS Foundation Trust,
Rehabilitation Sciences, University of Blackshaw Road, Tooting,
Birmingham, Birmingham, UK London SW17 0QT, UK
9
Human Cardiovascular Physiology Laboratory,
Department of Human Health and Nutritional
Sciences, College
of Biological Sciences, University of Guelph,
Guelph, ON, Canada
10
Department of Health and Human
Development, University of Pittsburgh,
Pittsburgh, PA, USA