Abstract:
The objective of this review is to identify the acute effects of blood flow
restriction (BFR) with vs without exercise on endothelial function in healthy
individuals and the changes in endothelial function in young and older adults
following different levels of exclusive BFR vs free flow. Systematic searches
were performed in the following databases: PubMed, Web of Science, Scopus, and
Cochrane Library, from inception to July 17, 2021. The studies included healthy
individuals who underwent assessments of endothelial function before and after
experimental protocols through endothelium-dependent flow-mediated dilatation.
In total, 4890 studies were screened, and 6 studies of moderate-to-high
methodological quality (Physiotherapy Evidence Database scores 6 – 10) including
82 subjects (aged 24 – 68 years) were eligible. Overall, flow-mediated
dilatation increased in the non-cuffed arm immediately and 15 minutes after
exercise, with no change in the cuffed arm (BFR of 60 – 80 mmHg). In protocols
without exercise, cuff pressures of 25 – 30 mmHg applied for 30 minutes did not
promote changes in the endothelial function, while those > 50 mmHg induced a
dosedependent attenuation of flow-mediated dilatation only in young individuals.
A moderate level of BFR appears to have no effect on endothelial function after
acute exercise. In non-exercise conditions, reductions in flow-mediated
dilatation seem to result from increased retrograde shear provoked by cuff
pressures ≥ 50 mmHg in young but not in older adults. An exerciserelated
increase in antegrade shear rate leads to a greater nitric oxide-mediated
vasodilator response. However, BFR appears to attenuate this effect in young but
not in older individuals.
PROSPERO: CRD42020219686.
Keywords: Vasodilation, microvascular blood flow, exercise, health.
Resumo:
O objetivo desta revisão foi identificar os efeitos agudos da restrição do fluxo
sanguíneo (RFS) com vs. sem exercício na função endotelial de indivíduos
saudáveis, bem como as alterações na função endotelial em jovens e idosos após
diferentes níveis de RFS vs. fluxo livre. Pesquisas sistemáticas foram
realizadas nas bases United States National Library of Medicine (PubMed), Web of
Science, Scopus e Cochrane Library até 17 de julho de 2021. Os estudos incluíram
indivíduos saudáveis que avaliaram a função endotelial antes e após protocolos
experimentais, por meio da dilatação mediada por fluxo. Foi selecionado o total
de 4.890 estudos, e foram elegíveis seis de moderada a alta qualidade
metodológica (Physioterapy Evidence Database 6 – 10 pontos), incluindo 82
indivíduos (24 – 68 anos). No geral, a dilatação mediada por fluxo aumentou no
braço sem manguito, imediatamente e 15 minutos após o exercício, sem alteração
no braço com manguito (RFS de 60 – 80 mmHg). Em protocolos sem exercício,
pressões do manguito de 25 – 30 mmHg aplicadas por 30 minutos não promoveram
alterações na função endotelial, enquanto aquelas > 50 mmHg induziram uma
atenuação dose-dependente da dilatação mediada por fluxo em indivíduos jovens.
Um nível moderado de RFS parece não ter efeito na função endotelial após uma
sessão de exercício. Em condições sem exercício, as reduções na dilatação
mediada por fluxo parecem resultar do aumento do cisalhamento retrógrado
provocado por pressões do manguito ≥ 50 mmHg em jovens, mas não em idosos. O
aumento da taxa de cisalhamento anterógrado relacionada ao exercício leva a
maior resposta vasodilatadora mediada pelo óxido nítrico. No entanto, a RFS
parece atenuar esse efeito em jovens, mas não em idosos.
PROSPERO: CRD42020219686.
Palavras-chave: Vasodilatação, microcirculação, exercício, saúde.
Carátula del artículo
Acute effects of exercise with blood flow restriction on endothelial
function in healthy young and older populations: a systematic
review
Efeitos agudos do exercício com restrição do fluxo sanguíneo na
função endotelial de jovens e idosos saudáveis: uma revisão
sistemática
Gustavo Gonçalves Cardozo
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Karynne Grutter Lopes kjgolrj@gmail.com
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Daniel Alexandre Bottino
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Maria das Graças Coelho de Souza
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Eliete Bouskela
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Paulo Farinatti
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Ricardo Brandão de Oliveira
Universidade do Estado do Rio de
Janeiro, Brazil
Universidade do Estado do Rio de
Janeiro, Brazil
Geriatrics, Gerontology and Aging, vol. 17, e0230006, 2023
Sociedade Brasileira de Geriatria e Gerontologia,
SBGG
Received: 10 November 2022
Accepted: 17 January 2023
INTRODUCTION
The endothelium plays an important role in the maintenance of vascular homeostasis
and regulates cellular adhesion, smooth muscle cell proliferation, fibrinolysis, and
inflammation.1 Endothelial function is
influenced by several hemodynamic factors, including the direction and magnitude of
shear stress, and exercise has been seen as an important stimulus that alters shear
stress patterns and, consequently, endothelial function, thus reducing
cardiovascular risk.2,3
Acute exposure to oscillatory shear stress, characterized by a large retrograde
component, was associated with increased levels of markers of endothelial cell
apoptosis, eliciting a pro-inflammatory and pro-atherogenic endothelial
phenotype.4 This phenomenon has been
studied in the past few years by means of models that apply inflated tourniquet
pressure around the limbs.4,5,6,7,8,9 Flow-mediated dilatation (FMD) is a commonly
used method to identify endothelial dysfunction, which is considered the earliest
stage of atherogenesis.9 FMD assesses arterial
diameter in response to 5-min ischemia, the so-called reactive hyperemia (ie,
increases in blood flow associated with shear stress),10,11,12 which reflects endothelial-derived nitric
oxide (NO) bioavailability. The dose-response relationship between magnitude of
blood flow restriction (BFR), either associated with exercise or not, and FMD
reduction still needs to be better understood, especially in different age
groups.6,7 Establishing this relationship is important because of the strong
association between aging and endothelial dysfunction.13
Although shear stress has been recognized as an important factor responsible for
exercise-induced vascular adaptations,14,15,16 BFR can disturb blood flow and alter shear stress
patterns,4,5,6,7,8,9 thus mitigating the beneficial effects of physical exercise on
vascular function.17 This is particularly
relevant considering the increased interest in a novel modality of physical training
that combines exercise and BFR. The BFR training has been acknowledged as an
intervention capable of enhancing the metabolic signaling pathways associated with
hypertrophy and strength gain in groups with poor tolerance to exercise with higher
loads, such as older adults,18 patients with
orthopedic diseases,19 and other frail
populations.20,21
Previous trials comparing the effects of different levels and periods of BFR in the
presence or absence of exercise on endothelial function produced divergent
results.22 Some trials have demonstrated
that BFR exercise may lead to enhanced vascular reactivity such as FMD
responses,15 while others failed to
demonstrate benefits to endothelial function.17,23,24 Several factors may help explain those mixed findings, such
as age, sex, exercise modality, BFR protocols, and methods to assess vascular
function.7,15,23
Investigating the acute responses of BFR on the endothelium can provide insight into
the causes of longer-term adaptation, which will expand the knowledge of this type
of intervention and its clinical applications, especially in populations with
limitations to higher loads. Thus, the objective of this systematic review is to
identify the acute effects of BFR with vs without exercise on endothelial function
in healthy individuals. In addition, we examine the changes in endothelial function
in young and older adults following different levels of BFR (without exercise) vs
free flow. For this purpose, the magnitude of endothelium-dependent FMD was adopted
as the main indicator of endothelial health. Our hypothesis is that BFR acutely
promotes negative effects on endothelial function only in young subjects.
Furthermore, when compared to BFR alone, BFR associated with exercise is believed to
lead to less deleterious effects on the vessel.
METHODS
This systematic review is consistent with the Preferred Reporting Items for
Systematic Reviews and Meta-Analysis (PRISMA)25 and was registered on the International Prospective Registry of
Systematic Reviews (PROSPERO) database under number CRD42020219686. Because it is a
systematic review, this study did not involve human subjects and did not require
ethical committee approval.
Search strategy and data sources
For the identification of relevant studies, multiple electronic databases
(PubMed, Web of Science, Scopus, and Cochrane Library) were searched from
inception until July 17, 2021. A search strategy using the terms “blood flow
restriction” OR “vascular occlusion” OR “kaatsu” OR “blood occlusion” OR “blood
flow occlusion” OR “venous restriction” OR “restricted blood flow” OR
“restricted venous blood flow” AND “vascular” OR “endothelial” OR “retrograde”
AND “exercise” identified potentially relevant reports written in English.
Selection criteria
Qualifying trials complied with the PICOS (acronym for patient, intervention,
comparison, outcome, and study design) strategy and included the following:
adult populations (> 18 years); at least one group performing an acute dynamic
handgrip exercise with BFR (until 60 min after cessation of the exercise) and a
non-exercise control or comparison group; and endothelial function assessed by
FMD before and after intervention for the BFR and control groups. We excluded
animal, epidemiological, pharmacological, and review studies; trials including
samples under medication influencing vascular function or blood flow; trials
involving smokers, alcoholics, or drug addicts; and trials involving diet, drug,
environmental, or supplemental interventions in addition to BFR and/or exercise.
Since endothelial dysfunction rarely occurs alone (ie, clusters of metabolic or
cardiovascular risk factors), studies that included populations exhibiting
clinical conditions related to cardiovascular risk (eg, cancer, HIV/AIDS) were
excluded. We adopted the same exclusion criteria for studies including samples
of young and older individuals.
Data extraction and study outcomes
Potentially relevant reports were screened in duplicate (by KGL and GGC) first by
title, then by title and abstract, and lastly by full-text review. Reference
lists of included studies, recent reviews, and meta-analyses were searched for
additional qualifying reports. A third investigator (RBO) arbitrated any
disagreements in coding. To assess the reliability of study inclusion, double
coding for 20 randomly selected abstracts was assessed by Cohen’s kappa (κ =
1.0; p < 0.05). Excluded studies were re-screened as a quality control
measure.
Extracted data included (but were not restricted to) variables of age,
sex/gender, clinical status, exercise characteristics (intensity, duration, and
mode), BFR characteristics (magnitude of cuff pressure, duration, and cuff
placement), FMD outcomes, and study quality. Study quality was assessed by the
Physiotherapy Evidence Database (PEDro) scale, a 10-point checklist with higher
scores indicating better study quality.26
Two coders independently performed data extraction and exhibited high
inter-rater reliability (mean Cohen’s κ = 1.0).
RESULTS
Study selection and quality
Figure 1 shows how reports were selected for
the systematic review. Of the initially identified 4890 studies, only 6 trials
reporting BFR and FMD at pre- and post-intervention conditions satisfied the
eligibility criteria. Of those, one was conducted in Brazil, two in the
Netherlands, and three in the United Kingdom.6,7,9,17,27,28 The trials were of moderate methodological study quality (all
studies scored 6 points on PEDro scale), mostly because of the nature of BFR
intervention – in general, groups were not randomized, and participants or
researchers were not blinded to the BFR or exercise interventions.
FIGURE 1
Flow diagram for the inclusion of trials in the review.
Study characteristics and major outcomes
Table 16,7,9,17,27,28 depicts the characteristics and outcomes of the studies included
in the systematic review. Two studies compared changes in endothelial function
following exercise with vs without BFR and included, in total, 19 young men
(aged 28 ± 7 years) who were healthy (no cardiovascular or metabolic disease
and/or no use of any medication that could influence the cardiovascular system)
and recreationally active (< 150 min/week of moderate-intensity physical
activity or 75 min/week of high-intensity physical activity).17,27 Both trials applied low-intensity dynamic handgrip exercise (1 to
2 kg or 60% of maximum voluntary contraction), used moderate levels of BFR (60
or 80 mmHg) through cuffs placed on the forearms, and assessed the brachial
artery vasodilation response. Cuff pressure duration ranged from 20 to 30 min,
and the non-cuffed arm served as a control limb. FMD in the non-cuffed arm
increased immediately27 and 15 min after
exercise,17 while no significant
change occurred in the cuffed arm.17,27 After 60 min, FMD
returned to baseline values with no difference between limbs.17 No adverse effects were reported during
exercise sessions.17,27
TABLE 1
Summary of studies included in the systematic review.
FMD: flow-mediated dilatation; EXP: experimental; CON: control; MVC:
maximum voluntary contraction; ↑: increased; ↔: maintained; ↓:
decreased.
Four studies evaluated changes in endothelial function at different levels of BFR
without exercise, including, in total, 48 young subjects (aged 24 to 27
years)6,9,28 and 15 older subjects
(aged 68 ± 9 years)7 who were healthy and recreationally active. The older
adults had a body mass index of 26.2 ± 3.4 kg/m2 and no diagnosis of
cardiovascular disease or severe hypertension. The studies applied
low-to-moderate levels of BFR (25–75 mmHg) on the forearms, upper arm, or
thigh.6,7,9,28 Cuff pressure lasted 30 min, and the non-cuffed arm was
used as a control limb.6,7,9,28 All trials assessed FMD
in the brachial artery, and two studies performed additional assessments on the
femoral artery.6,7 Overall, cuff pressures below 30 mmHg did not alter FMD,
while pressures greater than 50 mmHg induced a dose-dependent reduction in
endothelial function in young6,9,28
but not in older individuals.7
DISCUSSION
This systematic review summarizes the results of trials investigating the acute
effects of BFR applied at different magnitudes with and without exercise on
endothelial function in young and older individuals. Although limited in number, the
studies accumulated evidence indicating that an acute increase in anterograde shear
rate promoted by exercise leads to improvements in FMD in healthy young individuals.
Conversely, exercise performed with BFR seems to attenuate the transient vascular
benefits of acute exercise alone. Finally, increases in retrograde shear rate
promoted by cuff inflation over 50 mmHg seem to provoke a dose-dependent decline in
endothelium- mediated vasodilation, at least in young individuals.
It is widely accepted that exercise-induced increases in arterial blood flow and
shear stress play an important role in vascular health.16,29 Exercise is a key
factor for NO release from the endothelium. In addition to its vasodilator effects,
NO is a potent mediator inhibiting vascular smooth muscle contraction, platelet
aggregation, and leukocyte adhesion.30
Several previous studies reported increases in brachial artery FMD following acute
and chronic exercise.31,32,33 Exercise training
is known to improve peripheral vascular function and structure (reflected by
increased FMD),16 inducing clinically relevant benefits for different
populations.34,36,36
Cuff inflation appears to promote modifications in brachial artery shear stress and
oscillatory flow patterns, reducing the antegrade/retrograde ratio in the
experimental exercised arm and impairing the exercise-related benefits. Acute
studies showed that FMD increased immediately and 15 min after exercise in the
non-cuffed arm, with no changes in the cuffed arm.17,27 In addition, at least one
trial showed that endothelium- independent vasodilation in the brachial artery
followed by the administration of sublingual glyceryl trinitrate remained unaffected
after exercise performed with and without cuff inflation.14 These results reinforce that the manipulation of
antegrade/retrograde flow during a single session of exercise can result in distinct
responses in vascular function and that intraluminal shear stress stimulates
NO-mediated endothelium-dependent dilation, not affecting the smooth muscle response
reflected by endothelium-independent vasodilatation.
Physiological mechanisms underlying vascular damage or dysfunction are complex.
Hemodynamic changes, greater sympathetic activity, increase in oxidative
stress/inflammation, or dysfunction of vascular smooth muscle cells37,38,39,40 are possible explanations for FMD decrease and require more
detailed investigation. It is important to consider that the time points of
post-exercise measurements in presently reviewed studies (immediate, 15 min, and 30
min after exercise)17,27 do not assess a possible biphasic change in FMD and,
therefore, a transient exercise-related decrease in vasodilation.30 Although the application of moderate
restrictive pressure in association with low loads may induce considerable
hypertrophy and strength gain,41 the
potential occurrence of negative effects on endothelial function14,17,24,27 should be considered when prescribing this training
method.
In experimental protocols without exercise, cuff pressures ≥ 50 mmHg increased the
retrograde shear rate, impairing endothelial function in young subjects,6,9,30 but FMD decreases were not detected in a
single trial including older individuals.7
Albeit limited, this evidence is suggestive of an age-dependent response of
endothelial function to similar arterial hemodynamic occlusion forces. Oscillatory
shear stress patterns can induce a pro-atherogenic vascular phenotype.42 Previous studies demonstrated a reduction in
endothelial NO synthase (eNOS) expression43
and an increased expression of adhesion molecules,44 inflammatory mediators,42
endothelin-1,43 and oxidative stress45 as a consequence of increased shear stress.
Moreover, the retrograde blood flow has been associated with a greater release of
cellular markers of endothelial activation or apoptosis,4 reinforcing its relationship with endothelial dysfunction.
The absence of endothelial function impairment in older subjects after restrictive
pressures could be related to an attenuated ability to adapt in response to shear
rate resulting in a priori lower FMD. Decreased NO bioavailability contributes to
lower endothelium-dependent vasodilation among older individuals.46 In addition, reduced vascular smooth muscle
responsiveness,47 increased arterial
stiffness,48 and/or hyperactive
sympathetic system49 may be associated with
these findings. Finally, the magnitude or duration of the retrograde shear stimulus
was insufficient to compromise endothelial function in that specific older
sample.4 Additional research is needed to
clarify the underlying physiological mechanisms associated with the lower
responsiveness to retrograde shear induced by BFR observed in older individuals when
compared to younger ones.
Limitations and practical implications
Some limitations of current research investigating the acute effects of BFR
exercise on endothelial function in healthy individuals should be acknowledged.
Firstly, the trials included mostly healthy young men, while factors such as age
and sex-related hormonal variations and cardiometabolic diseases may influence
endothelial function.50,51 However, this seems to reflect a
limitation of the current literature rather than one of the present review. In
addition, albeit limited, the studies investigating the impact of BFR on
endothelial function are heterogeneous regarding methodology (intensity of
exercise, cuff placement site, reference artery, and assessments), which
precluded further inferences about the determinants of changes in FMD. Trials
applying multiple post-exercise measurements are warranted for determining
whether a biphasic and transient decrease in vascular function occurs in
different age groups and clinical populations subject to BFR with and without
exercise.
The major limitation of our study is the small number of trials included,
especially when we consider the number of studies of older adults (only one). In
addition, those studies included small sample sizes (82 individuals) and showed
moderate methodological quality (6 in the PEDro scale for all studies). This
occurred especially in relation to the absence of group randomization and
blinding of participants or researchers to the blood restriction or exercise
interventions. However, this is not feasible because of the type of
intervention.
With regard to practical implications, the result of the systematic review
suggests that the increasing levels of BFR appear to attenuate the vascular
benefits promoted by physical exercise in young but not in older adults.
Although additional studies are needed to determine acute safety, our results
suggest that older adults may benefit from BFR training to improve muscle mass
and strength as well as physical capacity while preserving vascular health.
CONCLUSION
The available evidence suggests that an exercise-related increase in shear stress
leads to greater NO release and FMD. The addition of BFR appears to attenuate this
response. A dose-response relationship between retrograde blood flow elicited by BFR
and reduction in endothelial function seems to occur in healthy and recreationally
active young subjects, but not in older individuals. Future research needs to
elucidate the determinants of FMD changes associated with exercise (type, duration,
and intensity) and BFR (magnitude and duration) in different clinical populations as
well as the potentially involved underlying mechanisms.
