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Background Intermittent hypoxia applied at rest or in combination with exercise promotes multiple beneficial adaptations with regard to performance and health in humans. It was hypothesized that replacing normoxia by moderate hyperoxia can increase the adaptive response to the intermittent hypoxic stimulus. Objective Our objective was to systematically review the current state of the literature on the effects of chronic intermittent hypoxia–hyperoxia (IHH) on performance- and health-related outcomes in humans. Methods PubMed, Web of Science™, Scopus, and Cochrane Library databases were searched in accordance with PRISMA guidelines (January 2000 to September 2021) using the following inclusion criteria: (1) original research articles involving humans, (2) investigation of the chronic effect of IHH, (3) inclusion of a control group being not exposed to IHH, and (4) articles published in peer-reviewed journals written in English. Results Of 1085 articles initially found, eight studies were included. IHH was solely performed at rest in different populations including geriatric patients ( n = 1), older patients with cardiovascular ( n = 3) and metabolic disease ( n = 2) or cognitive impairment ( n = 1), and young athletes with overtraining syndrome ( n = 1). The included studies confirmed the beneficial effects of chronic exposure to IHH, showing improvements in exercise tolerance, peak oxygen uptake, and global cognitive functions, as well as lowered blood glucose levels. A trend was discernible that chronic exposure to IHH can trigger a reduction in systolic and diastolic blood pressure. The evidence of whether IHH exerts beneficial effects on blood lipid levels and haematological parameters is currently inconclusive. A meta-analysis was not possible because the reviewed studies had a considerable heterogeneity concerning the investigated populations and outcome parameters. Conclusion Based on the published literature, it can be suggested that chronic exposure to IHH might be a promising non-pharmacological intervention strategy for improving peak oxygen consumption, exercise tolerance, and cognitive performance as well as reducing blood glucose levels, and systolic and diastolic blood pressure in older patients with cardiovascular and metabolic diseases or cognitive impairment. However, further randomized controlled trials with adequate sample sizes are needed to confirm and extend the evidence. This systematic review was registered on the international prospective register of systematic reviews (PROSPERO-ID: CRD42021281248) ( https://www.crd.york.ac.uk/prospero/ ).
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Behrendtetal. Sports Medicine - Open (2022) 8:70
https://doi.org/10.1186/s40798-022-00450-x
SYSTEMATIC REVIEW
Eects ofIntermittent Hypoxia–Hyperoxia
onPerformance- andHealth-Related Outcomes
inHumans: ASystematic Review
Tom Behrendt1* , Robert Bielitzki1 , Martin Behrens1,2 , Fabian Herold3 and Lutz Schega1
Abstract
Background: Intermittent hypoxia applied at rest or in combination with exercise promotes multiple beneficial
adaptations with regard to performance and health in humans. It was hypothesized that replacing normoxia by mod-
erate hyperoxia can increase the adaptive response to the intermittent hypoxic stimulus.
Objective: Our objective was to systematically review the current state of the literature on the effects of chronic
intermittent hypoxia–hyperoxia (IHH) on performance- and health-related outcomes in humans.
Methods: PubMed, Web of Science, Scopus, and Cochrane Library databases were searched in accordance with
PRISMA guidelines (January 2000 to September 2021) using the following inclusion criteria: (1) original research
articles involving humans, (2) investigation of the chronic effect of IHH, (3) inclusion of a control group being not
exposed to IHH, and (4) articles published in peer-reviewed journals written in English.
Results: Of 1085 articles initially found, eight studies were included. IHH was solely performed at rest in different
populations including geriatric patients (n = 1), older patients with cardiovascular (n = 3) and metabolic disease
(n = 2) or cognitive impairment (n = 1), and young athletes with overtraining syndrome (n = 1). The included stud-
ies confirmed the beneficial effects of chronic exposure to IHH, showing improvements in exercise tolerance, peak
oxygen uptake, and global cognitive functions, as well as lowered blood glucose levels. A trend was discernible that
chronic exposure to IHH can trigger a reduction in systolic and diastolic blood pressure. The evidence of whether IHH
exerts beneficial effects on blood lipid levels and haematological parameters is currently inconclusive. A meta-analysis
was not possible because the reviewed studies had a considerable heterogeneity concerning the investigated popu-
lations and outcome parameters.
Conclusion: Based on the published literature, it can be suggested that chronic exposure to IHH might be a promis-
ing non-pharmacological intervention strategy for improving peak oxygen consumption, exercise tolerance, and cog-
nitive performance as well as reducing blood glucose levels, and systolic and diastolic blood pressure in older patients
with cardiovascular and metabolic diseases or cognitive impairment. However, further randomized controlled trials
with adequate sample sizes are needed to confirm and extend the evidence. This systematic review was registered on
the international prospective register of systematic reviews (PROSPERO-ID: CRD42021281248) (https:// www. crd. york.
ac. uk/ prosp ero/).
© The Author(s) 2022. Open Access This ar ticle is licensed under a Creative Commons Attr ibution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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Open Access
*Correspondence: tom.behrendt@ovgu.de
1 Department of Sport Science, Chair for Health and Physical Activity, Otto-
von-Guericke University Magdeburg, Universitätsplatz 2, 39104 Magdeburg,
Germany
Full list of author information is available at the end of the article
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Behrendtetal. Sports Medicine - Open (2022) 8:70
Key Points
• Current evidence indicates that chronic exposure to
intermittent hypoxic–hyperoxic periods at rest can be
considered an efficient non-pharmacological interven-
tion strategy to improve physical and cognitive perfor-
mance and reduce cardiometabolic risk factors in older
patients with cardiovascular and metabolic diseases or
cognitive impairment, when an intervention with 3–5
sessions per week over 3–6weeks is conducted.
• Although the optimal hypoxic and hyperoxic dose and
mode of application (i.e. at rest or in combination with
exercise) are still unknown, from the available literature
it can be inferred that 4–8 cycles of hypoxic–hyperoxic
periods with moderate intensity (i.e. inspired fraction
of oxygen of 0.10–0.12 and 0.30–0.40, respectively) and
durations of 2–6 or 1–4 min per single hypoxic and
hyperoxic period, respectively, are safe and well tolerated
in older and younger adults.
• Still, there is no strong evidence that intermittent
exposure to hypoxic–hyperoxic periods is more efficient
than intermittent exposure to hypoxic–normoxic periods
to improve performance- and health-related outcomes or
reduce the session duration by shortening the reoxygena-
tion periods.
Introduction
Intermittent hypoxia (IH) is traditionally characterized
by periodic and alternating cycles of hypoxia and nor-
moxia. With the development and widespread availability
of devices inducing a systemic or local hypoxic environ-
ment (e.g. hypobaric chambers, hypoxia rooms and tents,
hypoxicators, or pneumatic cuffs), the “live low-train
high” approach has gained considerable popularity as an
effective and efficient training modality for a variety of
professional athletes [13] as well as a non-pharmacolog-
ical approach for the prevention and therapy of patients
with various diseases or healthy adults, respectively [4, 5].
To date, different “live low-train high” methods exist
(see Fig.1). Commonly, systemic hypoxia can be gener-
ated in two ways: (1) by reducing the barometric pressure
Keywords: Hypoxic conditioning, Cognitive impairment, Metabolic disease, Cardiovascular disease, Geriatrics,
Therapy
Fig. 1 Graphical panorama of different “live low-train high” methods (modified from Girard et al. [2]). Please note that in the current literature the
term “intermittent hypoxic–hyperoxic training” (IHHT ) is commonly used for both passive and active applications. To avoid terminological ambiguity
with respect to the term intermittent hypoxic–hyperoxic periods, we recommend to use the term "intermittent hypoxic–hyperoxic training" for active
and “intermittent hypoxic–hyperoxic exposure” for passive applications
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Behrendtetal. Sports Medicine - Open (2022) 8:70
(BP, hypobaric hypoxia) or (2) by reducing the oxygen
fraction in the inspired air (FiO2) via oxygen filtration or
nitrogen dilution (normobaric hypoxia) [6]. Despite the
ongoing debate whether different combinations of BP
and FiO2 produce the same partial pressure of oxygen
and trigger similar or different physiological responses
[714], both types of hypoxia reduce arterial oxygen sat-
uration (SaO2) [15, 16], which, in turn, stimulates specific
biological signal cascades that promote hypoxia-induced
adaptations. In particular, the reduction in SaO2 trig-
gers the stabilization of hypoxia-inducible factors (HIF),
which are the key oxygen sensors and master regula-
tors of oxygen homeostasis regulating cellular adapta-
tions to hypoxia [17, 18]. For example, the activation of
the α-subunit of HIF (HIF-1α) upregulates genes that are
responsible for erythropoiesis [19, 20], angiogenesis [20],
and metabolic adaptations [21, 22] contributing to an
increase in physical performance after long-term expo-
sure to hypobaric and normobaric hypoxia [23]. From
a practical point of view, inducing normobaric hypoxia
is a more convenient, efficient, and less expensive form
compared to hypobaric hypoxia [5], i.e. the creation
of hypobaric hypoxia requires hypobaric chambers or
expeditions to natural altitudes. As shown in Fig.1, IH
using normobaric hypoxia can be performed at rest or
in combination with exercise, e.g. continuous or interval
hypoxic training, (repeated) sprint interval training in
hypoxia, or resistance training in hypoxia [2]. IH at rest
refers to the use of either brief alternating hypoxic and
normoxic periods (e.g. 3–6min hypoxia and normoxia,
respectively) of moderate- to relatively severe-intensity
hypoxia (typically reported as FiO2 = 0.15–0.08, intermit-
tent hypoxic exposure) or prolonged hypoxic exposures
(0.5–4h/session) at hypoxia intensities of FiO2 = 0.164–
0.090 (prolonged hypoxic exposure) [4, 5, 2426].
Studies involving normoxic control groups have revealed
that neither intermittent nor prolonged hypoxic exposure
could induce significant changes in haematological param-
eters or aerobic and anaerobic performance in elite athletes
[1, 2729]. Although IH at rest does not seem to improve
sea-level performance of elite athletes, it might be a useful
pre-acclimatization strategy for athletes or mountaineers
before traveling to high altitudes [3032]. However, high-
intensity training under hypoxic conditions (e.g. repeated
sprint training in hypoxia) [3336] or a combination of
hypoxic methods [1, 37] seems a promising approach for
performance enhancement in moderately to well-trained
populations and elite athletes. Nevertheless, it has also been
stated that the use of hypoxic training methods (whether at
rest or in combination with exercise) has been strongly pro-
moted in elite athletes for many years without any evidence
for their justification, which is still under debate [36, 38].
Studies conducted with healthy non-athletic populations
have shown that IH at rest or in combination with physi-
cal exercises can be a valuable strategy to improve cogni-
tive functions (e.g. selective attention and information
processing speed [39, 40]) and health-related outcomes
(e.g. vascular function [41] and glucose homeostasis [42]).
Additionally, IH has been proposed as a promising non-
pharmacological intervention for patients with, for example,
cardiovascular, metabolic, and neurodegenerative diseases
[4347], as well as overweight and obese people [48]. In this
context, studies have shown that intermittent hypoxic expo-
sure improved aerobic capacity and exercise tolerance in
elderly males with coronary artery disease [49] and reduced
systolic and diastolic blood pressure in young adults with
stage I hypertension [50]. Furthermore, prolonged hypoxic
exposure performed over 22 days has been found to
improve blood lipid profiles in patients with severe coro-
nary artery disease [51] as well as aerobic capacity, skeletal
muscle strength, quality of life, and left ventricular ejection
fraction in patients with heart failure and reduced ejection
fraction ( 35%) [52]. In addition, 3–8weeks of intermittent
hypoxic exposure also had positive effects in patients with
prediabetes (i.e. reduction in fasting and 2h post-oral blood
glucose levels during a glucose tolerance test) [53], chronic
obstructive pulmonary disease (i.e. increase in exercise
tolerance, improved baroreflex sensitivity, and enhanced
hypocapnic ventilatory response) [54, 55], and mild cogni-
tive impairment (i.e. increase in cognitive functions and
cerebral tissue oxygenation) [56]. Nevertheless, there is evi-
dence that the combination of physical training (continuous
cycling) and hypoxic exposure (continuous hypoxic train-
ing) provides some additional benefits compared to physical
training in normoxia (i.e. a higher increase in peak oxygen
consumption and maximal power output during cycling) in
overweight and obese people [57].
In the last decade, a new IH-method was developed
combining hypoxic and hyperoxic (FiO2 = 0.30–0.40)
periods. Intermittent hypoxic–hyperoxic periods can be
applied as a passive intervention modality with the sub-
jects at rest (referred to as intermittent hypoxic–hyper-
oxic exposure, IHHE) or during physical exercise (referred
to as intermittent hypoxic–hyperoxic training, IHHT). It
has been hypothesized that replacing normoxia by mod-
erate hyperoxia can increase the adaptive response to the
intermittent hypoxic stimulus by upregulating reactive
oxygen species (ROS) [58] and hypoxia-inducible genes
[59]. While HIF-1α is stabilized when cellular oxygen con-
tent decreases [17], ROS is generated in the initial period
of reoxygenation [60]. Although the excess of ROS is
associated with cell damage and the pathogenesis of vari-
ous diseases, a moderate ROS formation is also linked to
beneficial physiological processes including (1) oxidation
of damaged molecules, (2) synthesis of messenger mol-
ecules, and (3) extra- and intracellular signalling [61]. In
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Behrendtetal. Sports Medicine - Open (2022) 8:70
particular, ROS triggers intracellular redox signal cascades,
which activate transcription factors such as nuclear factor
erythroid 2-related factor 2 (Nrf2)and HIF-1α by inacti-
vating Kelch-like ECH-associated protein 1 (Keap1) and
prolyl hydroxylase (PHD), respectively [62]. ese factors
are known to induce the expression of antioxidant and
anti-inflammatory genes, heat shock proteins (HSP), iron
regulation proteins, repair enzymes, erythropoietin (EPO),
vascular endothelial growth factor (VEGF), and glycolytic
enzymes promoting cell survival, erythropoiesis, blood
vessel formation, and maintaining adenosine triphosphate
level [58, 61, 63]. erefore, the production of protective
proteins and those responsible for the adaptations might
be increased by replacing normoxia by hyperoxia periods
without the need to increase hypoxia intensity. us, the
application of intermittent hypoxia–hyperoxia, either pas-
sive or in combination with physical exercise, seems to be
a promising intervention strategy for various populations.
Recently, placebo-controlled trials examined the effects of
IHHE and IHHT [6466]. For instance, Serebrovska etal.
[66] investigated the effects of IHHE, intermittent hypoxic
exposure, and sham hypoxia on carbohydrate and lipid
metabolism as well as hypoxia resistance in 55 prediabetic
patients (5 sessions per week for 3 weeks). e authors
observed the same positive effect for both IHHE and inter-
mittent hypoxic exposure [66]. However, it was concluded
that IHHE leads to a faster reoxygenation resulting in a
shorter session duration compared to intermittent hypoxic
exposure (IHHE: 4 cycles of 5 min hypoxia and 3 min
hyperoxia, intermittent hypoxic exposure: 4cycles of 5min
hypoxia and 5min normoxia). Another study compared the
acute responses to IHHT, continuous hypoxic training, and
sham hypoxia during aerobic exercise consisting of 40min
of moderate cycling in overweight non-insulin-dependent
type 2 diabetic patients [64]. e authors revealed that both
IHHT and continuous hypoxic training induced a greater
up-regulation of pro-angiogenetic factors (e.g. VEGF and
matrix metalloproteinase-9) than the sham hypoxia aero-
bic training without significant differences between the
hypoxic modalities [64]. However, the authors noted that
exercising under hypoxia–hyperoxia might be more toler-
able than hypoxia–normoxia given the observed tendency
for less exertion in IHHT (i.e. assessed with Borg’s Rating of
Perceived Exertion scale) [64]. Consequently, there is some
preliminary evidence that exercising under intermittent
hypoxic–hyperoxic conditions may be a convenient, effi-
cient, and less demanding training strategy to achieve
similar positive effects as seen after training in hypoxia or
intermittent hypoxic–normoxic conditions. is might
be relevant for specific populations characterized by a low
exercise tolerance and fitness level (e.g. sedentary individu-
als or patients with cardiovascular diseases).
Conclusively, IH at rest or in combination with physical
exercise has been shown to be an effective intervention strat-
egy to induce beneficial adaptations in several body systems
that can positively influence the performance and health
status of elite athletic or non-athletic people with or without
disease. In order to enhance the IH effectiveness, research-
ers hypothesized that normoxia should be replaced by mod-
erate hyperoxia [58, 67]. Indeed, in some studies promising
effects of IHHE and IHHT on different performance- and
health-related outcomes have been observed in healthy and
preclinical populations [6466]. However, to the best of our
knowledge, the literature on the effects of IHHE and IHHT
have yet not been systematically reviewed and summarized.
To advance research and practical application of IHHE and
IHHT, a systematic review and critical discussion of the
results as well as methodology of IHHE and IHHT studies
are required. erefore, the present systematic review aimed
to provide an overview and critical discussion of studies that
have investigated the influence of IHHE and IHHT on per-
formance- and health-related outcomes in humans.
Methods
Search Strategy andProcess
is systematic review was conducted in accordance with
the PRISMA guidelines (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) [68, 69]. Two
independent researchers (T.B. and F.H.) performed a sys-
tematic literature search in the following electronic data-
bases [applied specifications/filters]: (1) PubMed [all fields/
non]; (2) Scopus [all fields/source type: journal, document
type: article]; (3) Web of Science [all fields/non]; and (4)
Cochrane Library [all text/non]. e literature search
included studies published from January 2000 to Septem-
ber 2021. To optimize the identification of relevant arti-
cles, the terms were combined with Boolean operators
(“OR” and “NOT”). Terms combined with “NOT” were
only searched for in the title and abstract.
To identify relevant articles, we used the following search
terms in all electronic databases mentioned above:
hypoxia
hyperoxia OR hyperoxia
hypoxia OR hypoxic OR hyperoxic
hypoxic OR hypoxia/hyperoxia OR hyperoxia/hypoxia
NOT
sleep apnoea OR sleep apnea OR neonates OR mice OR rats OR rabbits OR zebrafish
OR dog
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Furthermore, references of the included studies (cross
references) were checked for further potential articles.
Any disagreements between the literature searchers were
resolved through discussion and agreement.
e results of the systematic literature search were
imported into a reference manager (Citavi 6.8, Swiss
Academic Software GmbH, Switzerland) to analyse the
retrieved studies (e.g. to remove duplicates, screen for
relevant studies). e procedure is displayed in the flow
chart shown in Fig.2.
In‑ andExclusion Criteria
As recommended by the PRISMA guidelines [68, 69], we
used the PICOS-principle [70] to define the eligibility
criteria (i.e. specific exclusion and inclusion) for relevant
studies. e inclusion and exclusion criteria are listed
below.
Participants
We included all studies regardless of the sex and health
status of the participants. Studies that have included par-
ticipants with an age < 18years or investigated animals
were excluded.
Intervention
We included only studies that investigated the chronic
effects of IHHE or IHHT on human performance or
health. us, IHHE or IHHT had to be conducted regu-
larly in a planned, structured, and purposed manner with
Fig. 2 Flow chart of study selection. Please note that the term “inappropriate” refers to the inclusion and exclusion criteria used in this systematic
review
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Behrendtetal. Sports Medicine - Open (2022) 8:70
the objective to affect one or multiple fitness or health
dimensions. Studies that have investigated (1) the effects
of acute IHHE or IHHT (i.e. a single IHHE or IHHT
session), (2) only the effects of intermittent normoxia–
hypoxia (i.e. without an IHHE or IHHT condition), and
(3) the effects of permanent or long-term stay in hypoxia
(e.g. long-term stay in high mountain regions) were
excluded.
Comparison
We included all studies that involved a control group that
was not exposed to IHHE or IHHT (e.g. placebo/sham
control group).
Outcomes
We included all studies that assessed at least one or mul-
tiple performance- or health-related outcome(s).
Study Design
We included all longitudinal intervention studies that
complied with the above-stated inclusion criteria and
were published in English in a peer-reviewed scientific
journal.
Data Extraction
We extracted the following information from the
included studies: (1) bibliographic information (first
author and year of publication), (2) design information
(study design and comparison group), (3) participants’
characteristics (health status, sex, age, body height,
body mass, and body mass index), (4) characteristics of
any additional exercise program if applicable (type and
description of exercise, single session duration, train-
ing duration, training frequency, training density, and
training setting), (5) characteristics of the IHHE or
IHHT (hypoxia intensity, intra-session frequency [num-
ber of cycles], intra-session density [duration of a single
hypoxic/hyperoxic period], total time of a single session,
participants’ mean SpO2 at hypoxic condition, interven-
tion duration, inter-session frequency of the intervention
sessions, inter-session density of the intervention ses-
sions, and number of total sessions across the interven-
tion duration), and (6) main outcomes.
Check forDuplicate Publication
To check for duplicate publication, we analysed each study
using the decision tree for identification of patterns of
duplicate publication by von Elm etal. [71]. e two crite-
ria were similarity of study samples and similarity of study
outcomes. Four duplicate patterns were defined: (1) pat-
tern one = identical samples and identical outcomes, (2)
pattern two = identical samples and different outcomes, (3)
pattern three = different samples and identical outcomes,
and (4) pattern four = different samples and different out-
comes [71]. Studies matching one of these combinations
were excluded from this systematic review. ree studies
[7274] were identified as duplicate category pattern three
and were thus excluded from the final analysis (Fig.2).
Risk ofBias Assessment
Risk of bias assessment of the included studies was per-
formed with the modified version of the Downs and
Black checklist [75] used to assess the methodological
quality of randomized controlled as well as non-rand-
omized studies taking various aspects of the study design
into account, e.g. reporting (Items 1–10), external valid-
ity (Items 11–13), internal validity (Items 14–26), and
statistical power (Item 27). Given the specificity of stud-
ies investigating the chronic effect of IH, the importance
of the hypoxic dose [25, 76], and the individual internal
response to a hypoxic stimulus [77], we modified the
checklist by adjusting Item 4 (description of the inten-
sity of hypoxia and hyperoxia, number of hypoxic and
hyperoxic periods per session [intra-session frequency],
duration of hypoxic and hyperoxic periods [intra-ses-
sion density]), Item 23 (homogeneity in main outcomes
between groups at post-test), and by adding a further
Item (Item 28: reporting of internal intensity of hypoxia
[e.g. SpO2]). Each Item, except Item 5, was scored with
one point if the criterion was met and with zero points
if the criterion was not satisfied or could not be deter-
mined. Item 5 was scored with two points if all main
confounders (i.e. sex, age, disability, training status, and
body mass) were described, with one point if four of the
five main confounders plus one secondary confounder
(i.e. the moment of testing during the intervention or
test mode) were described and with zero points if the
described criterion was not met or was not appropriately
acknowledged. Studies were classified based on the sum
score as being of “good quality” (21–29 points), “mod-
erate quality” (11–20 points), and “poor quality” (< 11
points) [78]. ree researchers (T.B., R.B., and M.B.)
independently evaluated the risk of bias of the included
studies and any case of disagreement in the ratings was
resolved by discussion or consultation with a fourth
author (F.H.).
Results
Study Selection
e systematic literature search revealed 1085 poten-
tially relevant articles. One additional study was iden-
tified through the manual search of secondary data
sources. After duplicates were removed, 887 stud-
ies remained and were assessed in the initial screen-
ing process. Of these 887 studies, titles or abstracts
were screened, which resulted in the exclusion of 847
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Behrendtetal. Sports Medicine - Open (2022) 8:70
studies. us, 40 studies were examined for eligibility.
Of these, 32 studies were excluded due to the following
reasons: non-English full-text [7982], duplicate data
[7274], investigating effects of IHHE or IHHT in ani-
mals [8385], or did not meet the inclusion criteria with
respect to the intervention (investigating only acute
effects of IHHE or IHHT [64, 65, 8688] or the effects
of permanent or long-term stay in hypoxia or hyperoxia
[8992]), or the article type (i.e. not original article: nar-
rative review [93, 94], book chapter [95], or a confer-
ence abstract [96105]). After the full-text assessment,
eight studies [66, 106112] met our inclusion criteria
and were qualitatively analysed. e study selection
process is shown in Fig.2. A meta-analysis was not pos-
sible because the included studies had a considerable
heterogeneity concerning the investigated populations
and outcome parameters.
Risk ofBias Assessment
e average quality of the studies included in the qual-
itative analysis was rated as moderate. e median
quality rating score on the modified Downs and Black
checklist was 19 of the possible 29 points (range 17–22).
Five studies [107111] were rated as being of moder-
ate quality, whereas the other three studies [66, 106,
112] were considered to be of good quality (Table1).
All studies scored zero points (i.e. the criterion was not
satisfied or unable to determine) for Item 15 (blinding
those measuring the main outcomes), Item 19 (report-
ing participants’ compliance with the intervention), Item
22 (recruiting participants over the same period of time),
Item 24 (concealing randomized intervention assign-
ment from patients and health care staff), and Item 28
(SpO2 values during hypoxia periods). Item 27 (sample
size calculation) [109] was satisfied in only one of the
eight studies.
Participants’ Characteristics andStudy Designs
All reviewed studies [66, 106112] used IHHE. IHHE was
performed in different populations, including geriatric
patients [106], older patients with coronary arterial dis-
ease [107, 110], young track and field athletes with over-
training syndrome [108], older cardiology outpatients
[109], older patients with prediabetes [66], older patients
with mild cognitive impairment [111], and patients with
metabolic syndrome [112]. Detailed information about
the number of participants, sex distribution, and partici-
pants’ characteristics (e.g. age, height, weight, and body
mass index) is provided in Table2.
Five studies [66, 106, 109, 110, 112] were classified as
randomized controlled trials, one study [107] as a non-
randomized controlled trial, and two studies [108, 111]
were described as pilot studies. In seven studies [66,
106, 107, 109112], the IHHE intervention group was
Table 1 Results of risk of bias assessment using the modified checklist by Downs and Black [76]
References Reporting External validity Internal validity
1234567891011121314151617181920
Bayer et al. [106] 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 0 1
Glazachev et al. [107] 1 1 1 1 2 1 1 1 1 0 1 1 1 1 0 1 1 1 0 0
Susta et al. [108] 1 1 1 1 2 1 1 0 1 1 1 1 1 1 0 1 1 1 0 1
Dudnik et al. [109] 1 0 1 1 0 1 1 1 1 1 1 1 1 1 0 1 1 1 0 0
Glazachev et al. [110] 1 1 1 1 0 1 1 1 0 1 1 1 0 1 0 1 1 1 0 1
Serebrovska et al. [66] 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 0 1
Serebrovska et al. [111] 1 1 1 1 1 1 1 0 0 1 1 1 1 1 0 1 1 1 0 1
Bestavashvili et al. [112] 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 0 1
References Internal validity—confounder Power Hypoxia
intensity Total score
21 22 23 24 25 26 27 28
Bayer et al. [106] 1010110 0 22
Glazachev et al. [107] 1000010 0 19
Susta et al. [108] 0000010 0 19
Dudnik et al. [109] 1010011 0 19
Glazachev et al. [110] 1010000 0 17
Serebrovska et al. [66]1010010 0 21
Serebrovska et al. [111]1010010 0 19
Bestavashvili et al. [112]1010110 0 22
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Behrendtetal. Sports Medicine - Open (2022) 8:70
Table 2 Summary of study designs, participants’ characteristics, and characteristics of the interventions of the reviewed studies
References Design Participants Training characteristics Characteristics of IHHE
(1) Study design
(2) Comparison groups (1) Participants’ characteristics
(2) Number of participants (f/m)
(3) Mean age ± SD in years
(4) Mean height ± SD in cm/mean
weight ± SD in kg/mean BMI ± SD in
kg/m2
(1) Type and description of exercise
(2) Single session duration
(3) Training duration
(4) Training frequency
(5) Training density
(6) Training setting
(1) Intensity of hypoxia/hyperoxia (FiO2)
(2) Intra-session frequency (number of
cycles)
(3) Intra-session density (Duration of a
single hypoxic/hyperoxic period)
(4) Total time of IHHE procedure
(5) Participants’ mean SpO2 at IHHE
(hypoxic condition)
(6) Intervention duration
(7) Inter-session frequency of IHHE sessions
(8) Inter-session density of IHHE sessions
(9) Number of total sessions across the
intervention duration
Bayer et al. [106] (1) Randomized controlled trial
(2) 2 groups
[1] IHHE (normobaric IHHE and individual
multimodal rehabilitation training)
[2] Sham IHHE (simulated IHHE (nor
mobaric normoxic air) and individual
multimodal rehabilitation training)
(1) Geriatric patients
(2) IHHE: 18 (13/5)
Sham IHHE: 16 (14/2)
(3) IHHE: 80.9 ± 7.8
Sham IHHE: 83.4 ± 5.5
(4) IHHE: 163.7 ± 8.3/72.0 ± 9.3/27.0 ± 3.9
Sham IHHE: 163.2 ± 8.5/66.8 ± 12.3/2
5.0 ± 6.6
(1) Individual multimodal traininga
(2) N.R.
(3) 5–6 weeks
(4) 2–3 sessions/week (16–20 sessions)
(5) N.R.
(6) 30 min physiotherapy (balance train
ing, coordination training, and exer-
cises to stimulate energy metabo-
lism), 60 min occupational therapy
(motor functional training, perceptual
training, mental training, and cogni-
tive training), and 20 min cycling
(1) 0.12/0.35
(2) N.R.
(3) 4–6 min/1–2 min
(4) 35–45 min
(5) N.R.
(6) 5–6 weeks
(7) 2–3 sessions/week
(8) N.R.
(9) 14–15 sessions
Glazachev et al. [107 ] (1) Controlled trial
(2) 2 groups
[1] IHHE (normobaric IHHE)
[2] Sham IHHE (patients were enrolled
after completing a standard cardiac
rehabilitation program (8 weeks,
2 days/week), simulated IHHE (normo-
baric normoxic air))
(1) Patients with coronary arterial disease
(NYHA functional class II and III)
(2) IHHE: 27 (18/9)
Sham IHHE: 19 (10/9)
(3) IHHE: 63.9 ± 13.9
Sham IHHE: 79.1 ± 12.5
(4) IHHE: N.R./81.6 ± 13.9/N.R.
Sham IHHE: N.R./79.1 ± 12.5/N.R.
(1) N.A.
(2) N.A.
(3) N.A.
(4) N.A.
(5) N.A.
(6) N.A.
(1) 0.10–0.12/0.30–0.35
(2) 5–7 cycles
(3) 4–6 min/3 min
(4) N.R.
(5) N.R.
(6) 5 weeks
(7) 3 sessions/week
(8) N.R.
(9) 15 sessions
Susta et al. [108] (1) Pilot study
(2) 2 groups
[1] IHHE (normobaric IHHE and low-
intensity running performed by ath-
letes with overtraining syndrome)
[2] Control group (healthy athletes per
forming training as usual)
(1) Young track and field athletes with
and without overtraining syndrome
(2) IHHE: 15 (8/7)
CG: 19 (12/7)
(3) Overall: 18–20
(4) Overall: 176.4 ± 14.6/71.4 ± 6.9/N.R.
(1) 2 bouts of 30 min running at 40%
VO2max with 10 min resta
(2) 70 min
(3) 4 weeks
(4) 3 days/week
(5) N.R.
(6) Low-intensity running
(1) 0.11/0.30
(2) 6–8 cycles
(3) 5–7 min/2–6 min
(4) 40–50 min
(5) N.R.
(6) 4 weeks
(7) 3 sessions/week
(8) N.R.
(9) 12 sessions
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Table 2 (continued)
References Design Participants Training characteristics Characteristics of IHHE
Dudnik et al. [109] (1) Randomized controlled trial
(2) 2 groups
[1] IHHE (normobaric IHHE)
[2] Sham IHHE (simulated IHHE (normo
baric normoxic air) and exercise
program)
(1) Cardiology outpatients
(2) IHHE: 15 (N.R.)
Sham IHHE: 14 (N.R.)
(3) IHHE: 66.7 ± 5.7
Sham IHHE: 65.0 ± 6.2
(4) IHHE: N.R./N.R./27.7 ± 2.3
Sham IHHE: N.R./N.R./28.9 ± 2.0
(1) Standard tailored cardiopulmonary
exercise program according to the
European Society of Cardiologyb
(2) N.R.
(3) 8 weeks
(4) 150 min/week
(5) N.R.
(6) 12–13 at Borg scale and/or 64–75% of
maximal heart rate
(1) 0.11–0.12/0.30–0.33
(2) 5–7 cycles
(3) 4–6 min/3 min
(4)N.R.
(5)
Glazachev et al. [110] (1) Randomized controlled trial
(2) 2 groups
[1] IHHE (normobaric IHHE)
[2] Sham IHHE (simulated IHHE (normo
baric normoxic air))
(1) Patients with chronic coronary artery
disease and angina pectoris of func-
tional class II–III
(2) Overall: 36 (26/10)
IHHE: 17 (N.R.)
Sham IHHE: 19 (N.R.)
(3) Overall: 68.2 ± 6.1
(4) N.R./N.R./N.R.
(1) N.A.
(2) N.A.
(3) N.A.
(4) N.A.
(5) N.A.
(6) N.A.
(1) 0.11–0.12/0.35
(2) N.R.
(3) 2–6 min/1–2 min
(4) 45–50 min
(5) N.R.
(6) 3 weeks
(7) 5 sessions/week
(8) 1 session per day for 5 days and 2 days
rest (e.g. Monday to Friday: training,
Saturday and Sunday: rest)
(9) 15 sessions
Serebrovska et al. [66] (1) Randomized controlled trial
(2) 3 groups
[1] IHHE (normobaric IHHE)
[2] IHE (normobaric intermittent hypoxic
exposure)
[3] Sham IHHE (simulated IHHE (normo
baric normoxic air))
(1) Patients with prediabetes
(2) IHHE: 17 (13/4)
IHE: 22 (15/7)
Sham IHHE: 16 (10/6)
(3) IHHE: 67.7 ± 7.7
IHE: 64.2 ± 6.6
Sham IHHE: 67.5 ± 8.7
(4) IHHE: 163 ± 6.0/84.9 ± 12.8/32.2 ± 4.6
IHE: 164 ± 9.5/86.3 ± 14.2/32.5 ± 6.7
Sham IHHE: 163 ± 6.0/84.9 ± 12.8/32
.2 ± 4.6
(1) Intermittent hypoxic exposureb
(2) N.R.
(3) 3 weeks
(4) 5 sessions/week (15 sessions)
(5) N.R.
(6) Intermittent hypoxic exposure (5 min
of hypoxia (12% FiO2) and 5 min of
normoxia (~ 21% FiO2))
(1) 0.12/0.33
(2) 4 cycles
(3) 5 min/3 min
(4) N.R.
(5) N.R. (lowest: ~ 79%)
(6) 3 weeks
(7) 5 sessions/week
(8) N.R.
(9) 15 sessions
Serebrovska et al. [111] (1) Pilot study
(2) 3 groups
[1] IHHE (patients with mild cognitive
impairments performing normobaric
IHHE)
[2] Sham IHHE (patients with mild cogni
tive impairments performing simu-
lated IHHE (normobaric normoxic air))
[3] Control group (healthy participants
performing either IHHE nor Sham
IHHE)
(1) Patients with mild cognitive impair
ments
(2) IHHE: 8 (6/7)
Sham IHHE: 6 (6/0)
Control group: 7 (6/1)
(3) IHHE: 68.2 ± 7.2
Sham IHHE: 72.6 ± 6.9
Control group: 63.0 ± 10.0
(4) IHHE: N.R./N.R./27.7 ± 2.0
Sham IHHE: N.R./N.R./26.3 ± 5.5
Control group: N.R./N.R./26.5 ± 3.6
(1) N.A.
(2) N.A.
(3) N.A.
(4) N.A.
(5) N.A.
(6) N.A.
(1) 0.12/0.33
(2) 4 cycles
(3) 5 min/3 min
(4) N.R.
(5) N.R.
(6) 3 weeks
(7) 5 sessions/week
(8) N.R.
(9) 15 sessions
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Behrendtetal. Sports Medicine - Open (2022) 8:70
Table 2 (continued)
References Design Participants Training characteristics Characteristics of IHHE
Bestavashvili et al. [112] (1) Randomized controlled trial
(2) 2 groups
[1] IHHE (normobaric IHHE)
[2] Sham IHHE (simulated IHHE (normo
baric normoxic air))
(1) Patients with metabolic syndrome
(2) IHHE: 32 (18/14)
Sham IHHE 33 (14/19)
(3) IHHE: 60.0 (45.5; 65.5)
Sham IHHE: 61.5 (56.2; 66.0)
(4) IHHE: N.R./92.0 (81.0; 114.0)/34.3 (30.2;
38.0)
Sham IHHE: N.R./92.5 (82.8; 104.0)/32.4
(30.8; 35.8)
(1) N.A.
(2) N.A.
(3) N.A.
(4) N.A.
(5) N.A.
(6) N.A.
(1) 0.11–0.12/0.30–0.35
(2) N.R.
(3) 4–7 min/2–4 min
(4) 40–45 min
(5) N.R.
(6) 3 weeks
(7) 5 sessions/week
(8) One session per day for 5 days and
2 days rest (e.g. Monday to Friday: train-
ing, Saturday and Sunday: rest)
(9) 15 sessions
BMI body mass index, CAD coronary artery disease, CG control group, f female, FiO2 fraction of inspired oxygen, IHE intermittent hypoxic exposure, IHHE intermittent hypoxia–hyperoxia exposure, m male, N.A. not
available, N.R. not reported, NYHA New York Heart Association, RIP remote ischaemic preconditioning, SD standard deviation, SPO2 blood oxygen saturation measured with nger pulse oximeter
a Describes the characteristics of an additional training that is carried out in addition to the IHHE
b Describes the characteristics of the training that is performed by an control group
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Behrendtetal. Sports Medicine - Open (2022) 8:70
compared to at least one control group performing a
sham IHHE. One study [108] compared IHHE with a
physically active healthy control group. Additionally, in
some studies, IHHE was further compared with intermit-
tent hypoxic exposure [66] as well as a physically active
[109] or inactive control group [111]. In two studies,
IHHE was performed in addition to an individualized
multimodal training program (consisting of 30 min of
physiotherapy procedures, 60min of occupational ther-
apy, and 20min of aerobic training) [106] or low-inten-
sity aerobic exercise (consisting of two bouts of 30min
running at 50% of maximum oxygen uptake, with 10min
rest between bouts) [108].
Characteristics oftheIntermittent Hypoxia–Hyperoxia
Protocols
All studies used normobaric hypoxia and hyperoxia
(Table 2). e hypoxic and hyperoxic gas mixture was
administered via face masks connected to hypoxia gen-
erators. e intensity of hypoxia and hyperoxia ranged
from FiO2 = 0.10–0.12 and FiO2 = 0.30–0.40, respe ctively.
e mean SpO2 value of the patients during the hypoxia
cycles was not reported in the studies. Five studies [66,
107109, 111] reported the number of hypoxic–hyperoxic
cycles per session. e number of cycles in these studies
ranged from 4 to 8 cycles per session. e cycle duration
for the hypoxia and hyperoxia periods ranged from 2 to
7min and 1 to 6min, respectively. Four studies [106, 108,
110, 112] reported the total time taken for a single IHHE
procedure with a minimum of 35 and a maximum of
50min. Based on the number of cycles and the duration
of the hypoxic and hyperoxic periods, it can be assumed
that the entire training session lasted approximately
35–63min [107, 109] and 32min [66, 111] in the stud-
ies not reporting the total duration. IHHE was performed
with a frequency of 2–5 sessions per week, over an inter-
vention period of 3–6weeks (12–15 sessions in total) [66,
106112]. e inter-session density of the IHHE interven-
tion (i.e. distribution of IHHE sessions across a distinct
time interval with regard to recovery time in-between
the IHHE sessions) was reported in the study from Gla-
zachev etal. [110] and Bestavashvili etal. [112] (5 weekly
IHHE sessions and 2days of rest per week). In seven stud-
ies, [66, 106110, 112] the patients’ individual reaction to
a hypoxic stimulus was determined with a hypoxia test
that was conducted prior to the IHHE intervention. e
hypoxia test consisted of breathing a hypoxic gas mixture
(FiO2 = 0.10–0.12) for 10–20min under constant moni-
toring of heart rate or SpO2 or both. Six studies [106110,
112] stated that the IHHE protocol (i.e. duration or inten-
sity of hypoxia and hyperoxia periods) was individually
adjusted based on the results of the hypoxia test and the
individual responses (heart rate and SpO2). Two studies
[66, 111] used fixed parameters (i.e. hypoxia and hyper-
oxia intensity, inter-session density [i.e. cycle duration],
inter-session frequency [i.e. number of cycles]).
Eects ofIntermittent Hypoxia–Hyperoxia onPhysical
andCognitive Performance aswell asHaematological,
Metabolic, andHaemodynamic Parameters
e included studies investigated the effect of IHHE on
different outcomes including physical [106110] and
cognitive performance [106, 111] as well as metabolic
[66, 107, 110, 112], haemodynamic [106109], and hae-
matological parameters [107109]. e main findings
of the eight included studies are summarized in Table3.
Physical Performance
Five of the eight included studies measured physical
performance outcomes [106110]. In three of these
studies, a cardiopulmonary exercise test was performed
before and after 3 [110] or 5weeks [107, 109] of the
IHHE intervention. In two studies, exercise tolerance
(i.e. time until exhaustion while performing the Bruce
or modified Bruce protocol) was increased at the end
of the intervention [110] or 1-month follow-up [107]
in patients who performed IHHE but not in those who
performed sham IHHE. Significant improvements
in peak oxygen consumption have been observed in
older patients with coronary artery disease (+ 12.6%;
pre: 14.3 ± 4.2 ml-O2/min/kg; post: 16.1 ± 4.2 ml-O2/
min/kg) [107] and cardiology outpatients (+ 43.2%;
pre: 13.9 ± 2.5 ml-O2/min/kg; post: 19.9 ± 6.1 ml-O2/
min/kg) [109] after 5weeks of IHHE when compared
to baseline. In the study by Glazachev etal. [110], peak
oxygen consumption (+ 26.1%; pre: 13.4 ± 2.5 ml-O2/
min/kg; post: 16.9 ± 1.4 ml-O2/min/kg) and oxygen
uptake at the first ventilatory threshold (+ 11.3%; pre:
11.5 ± 1.3 ml-O2/min/kg; post: 13.8 ± 2.0 ml-O2/min/
kg) were increased in older patients with coronary
artery disease who conducted 3weeks of IHHE. Fur-
thermore, the increase in peak oxygen consumption
was higher in the IHHE group compared to the patients
who had performed sham IHHE. Susta etal. [108] have
found that the physical work capacity of young athletes
with overtraining syndrome (i.e. the power at a heart
rate of 170 beats/min, PWC 170) was improved after
4weeks of IHHE which was performed 1.5–2h after
low-intensity aerobic exercise (two bouts of 30 min
running at 50% of maximum oxygen uptake, with
10min rest between bouts). In one study, older geriat-
ric patients performed the six-minute walk test prior
to and after 5–6 weeks of real or sham IHHE com-
bined with a multimodal training program [106]. e
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Behrendtetal. Sports Medicine - Open (2022) 8:70
Table 3 Summary of assessed outcomes and main results of the reviewed studies
References Assessed outcomes Main results
Bayer et al. [106]Cognitive functions
Dementia detection test
(DemTect)
Clock drawing test (CDT)
Physical functions
Six-minute Walk Test (6MWT)
Cardiovascular hemodynamic
parameters
Resting heart rate
Resting systolic and diastolic
blood pressure
Resting oxygen saturation
Within-group comparisons (pre-test vs. post-test)
DemTect in IHHE (11.2 ± 3.5 points vs. 14.2 ± 3.7 points)
CDT in IHHE (7.8 ± 2.9 points vs. 8.4 ± 3.0 points)
6MWT in IHHE and sham IHHE (234.3 ± 94.7 m vs. 290.7 ± 83.1 m; 250.6 ± 94.3 m vs. 277.7 ± 96.3 m)
Between-group comparisons
DemTect in IHHE compared to sham IHHE (post-test: 14.2 ± 3.7 points vs. 11.3 ± 3.6 points)
CDT in IHHE compared to sham IHHE (post-test: 8.4 ± 3.0 points vs. 6.8 ± 2.6 points)
6MWT in IHHE compared to sham IHHE (post-test: 290.7 ± 83.1 m vs. 277.7 ± 96.3 m)
Correlations
Δ-DemTect Δ-6MWT (r = + 0.57)
Δ-CDT Δ-6MWT (r = + 0.42)
Glazachev et al. [107]Physical functions
Cardiopulmonary exercise test
Cardiovascular hemodynamic
parameters
Resting heart rate
Resting systolic and diastolic
blood pressure
Resting left ventricular ejection
fraction
Blood markers
Haemoglobin concentration,
reticulocytes, total cholesterol,
high- and low-density lipopro-
tein, and glucose
Atherogenic index ((total choles-
terol high-density lipoprotein)
÷ high-density lipoprotein)
Quality of life
Seattle Angina Questionnaire
(SAQ)
Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)
Angina as a reason to stop cardiopulmonary exercise test in IHHE (12 vs. 6 vs. 3b, c)
Time to exhaustion in cardiopulmonary exercise test (modified Bruce protocol) in IHHE (354 ± 194
s vs. 383 ± 141 s vs. 395 ± 130 sb)
Time to exhaustion in cardiopulmonary exercise (Bruce protocol) in IHHE (280 ± 126 s vs. 295 ± 79
s vs. 332 ± 113 sb)
VO2peak in IHHE (14.3 ± 4.2 ml-O2/min/kg vs. 16.1 ± 4.2 ml-O2/min/kga vs. 15.4 ± 4.5 ml-O2/min/
kga)
Systolic blood pressure in IHHE (151 ± 19 mmHg vs. 130 ± 13 mmHga vs. 129 ± 11 mmHgb)
Diastolic blood pressure in IHHE (85 ± 11 mmHg vs. 73 ± 7 mmHga vs. 75 ± 9 mmHgb)
Resting heart rate in IHHE (71.5 ± 11.4 beats/min vs. 67.7 ± 8.3 beats/mina vs. 66.6 ± 10.0 beats/
minb)
Maximum heart rate in IHHE (122 ± 19 beats/min vs. 120 ± 14 beats/mina vs. 116 ± 14 beats/
minb)
Left ventricle ejection fraction in IHHE (14.3 ± 4.2% vs. 16.1 ± 4.2%a vs. 15.4 ± 4.5%b)
Reticulocytes in IHHE (9.0 ± 4.5% vs. 11.3 ± 6.2%a vs. 9.2 ± 4.8%b)
Total cholesterol in IHHE (5.6 ± 1.4 mmol/L vs. 5.1 ± 1.2 mmol/La vs. 5.5 ± 1.4 mmol/Lb)
Low-density lipoprotein in IHHE (3.5 ± 1.2 mmol/L vs. 3.2 ± .9 mmol/La vs. 2.6 ± 1.3 mmol/Lb, c)
Atherogenic index in IHHE (4.7 ± 1.8 vs. 3.4 ± 1.3a vs. 3.5 ± 1.5c)
Glucose in IHHE (7.1 ± 2.3 mmol/L vs. 6.5 ± 1.7 mmol/L vs. 6.2 ± 1.7 mmol/Lc)
SAQ physical limitation subscale in IHHE (43.3 ± 17.7 vs. 51.6 ± 13.1a vs. 53.7 ± 17.8b)
SAQ angina stability subscale in IHHE (56.5 ± 27.4 vs. 78.3 ± 23.3a vs. 79.6 ± 22.7b)
SAQ angina frequency subscale in IHHE (59.6 ± 27.6 vs. 81.1 ± 17.9a vs.80.9 ± 18.2b)
SAQ treatment satisfaction subscale in IHHE (60.7 ± 16.2 vs. 77.4 ± 16.8a vs. 80.5 ± 17.7b)
SAQ disease perception subscale in IHHE (47.2 ± 18.9 vs. 60.8 ± 17.8 vs. 63.4 ± 17.4b)
Between-group comparisons
Angina as a reason to stop cardiopulmonary exercise test in IHHE compared to sham IHHE
(1-month follow-up: 3 vs. 6)
Exercise time (modified Bruce protocol) in IHHE compared to sham IHHE (post-test: 383 ± 141 s vs.
280 ± 92)
VO2peak in IHHE compared to sham IHHE (1-month follow-up: 15.4 ± 4.5 ml-O2/min/kg vs. 17.8 ±
4.9 ml-O2/min/kg)
Reticulocytes in IHHE compared to sham IHHE (post-test: 11.3 ± 6.2% vs. 6.4 ± 3.6%; 1-month
follow-up: 9.2 ± 4.8% vs. 5.11 ± 3.13%)
Total cholesterol in IHHE compared to sham IHHE (post-test 5.1 ± 1.2 mmol/L vs. 5.5 ± 0.9 mmol/L)
Low-density lipoprotein in IHHE compared to sham IHHE (post-test: 3.2 ± .9 mmol/L vs. 3.6 ± 0.8
mmol/L; 1-month follow-up: 2.6 ± 1.3 mmol/L vs. 3.5 ± 0.8 mmol/L)
Atherogenic index in IHHE compared to sham IHHE (post-test: 3.4 ± 1.3 vs. 3.6 ± 1.1)
Atherogenic index in IHHE compared to sham IHHE (1-month follow-up: 3.5 ± 1.5 vs. 3.4 ± 1.0)
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Table 3 (continued)
References Assessed outcomes Main results
Susta et al. [108]Physical functions
Cardiopulmonary exercise test
Cardiovascular hemodynamic
parameters
Inotropic reserve index (IRI,
(maximal systolic blood pres-
sure resting systolic blood
pressure) ÷ resting systolic blood
pressure)
Chronotropic reserve index (CRI,
(maximal heart rate resting
heart rate) ÷ resting heart rate)
Resting heart rate and heart rate
variability
Cardiovascular hemodynamic
parameters
Inotropic reserve index (IRI,
(maximal systolic blood pres-
sure resting systolic blood
pressure) ÷ resting systolic blood
pressure)
Chronotropic reserve index (CRI,
(maximal heart rate resting
heart rate) ÷ resting heart rate)
Resting heart rate and heart rate
variability
Blood markers
Red blood cell count, reticulo-
cyte, haemoglobin concentra-
tion, and haematocrit
Hypoxia test (10 min at FiO2 =
0.10)
Oxygen saturation (SpO2) Maxi-
mal heart rate (HRmax)
Within-group comparisons (pre-test vs. post-test)
PWC170 in IHHE (170.8 ± 44.8 W vs. 191.9 ± 26.9 W)
IRI in IHHE (65.8 ± 3.6% vs. 54.8 ± 5.4%)
CRI in IHHE (50.0 ± 5.3% vs. 38.0 ± 5.9%)
SpO2 during hypoxic test in IHHE (77.9 ± 6.8% vs. 84.2 ± 5.7%)
HRmax during hypoxic test in IHHE (82.2 ± 14.6 beats/min vs. 76.6 ± 11.0 beats/min)
Standard deviation of R–R intervals in IHHE (54.0 ± 24.7 ms vs. 76.0.2 ± 26.8 ms)
Low frequency power in IHHE (1300 ± 661 ms2 vs. 801 ± 673 ms2)
High frequency power in IHHE (277 ± 188 ms2 vs. 624 ± 468 ms2)
Low frequency to high frequency index in IHHE (8.01 ± 7.51 vs. 1.45 ± 1.71)
Between-group comparisons
PWC170 in IHHE compared to control group (pre-test: 170.8 ± 44.8 W vs. 204.2 ± 13.8 W; post-test:
191.9 ± 26.9 W v6s. 278.0 ± 19.3 W)
IRI in IHHE compared to control group (pre-test: 65.8 ± 3.6% vs. 50.8 4.1%; post-test: 54.8 ± 5.4%
vs. 49.6 3.8%)
CRI in IHHE compared to control group (pre-test: 50.0 ± 5.3% vs. 37.5 ± 4.9%)
SpO2 during hypoxic test in IHHE compared to control group (pre-test: 77.9 ± 6.8% vs. 83.7 ± 9.0%)
HRmax during hypoxic test in IHHE compared to control group (pre-test: 82.2 ± 14.6 beats/min vs.
79.7 ± 13.1 beats/min)
R–R intervals in IHHE compared to control group (post-test: 890 ± 160 ms vs. 990 ± 180 ms)
Standard deviation of R–R intervals in IHHE (54.0 ± 24.7 ms vs. 82.0 ± 24.8 ms)
HRrest in IHHE compared to control group (post-test: 67.1 ± 13.7 beats/min vs. 60.4 ± 4.6 beats/
min)
High frequency in IHHE compared to control group (pre-test: 277 ± 188 ms vs. 1100 ± 344 ms2;
post-test: 624 ± 468 ms2 vs. 1167 ± 501 ms2)
Low frequency to high frequency index in IHHE compared to control group (pre-test: 8.01 ± 7.51
vs. 2.2 ± 1.0)
Dudnik et al. [109]Physical functions
Cardiopulmonary exercise test
Cardiovascular hemodynamic
parameters
Resting heart rate
Resting systolic and diastolic
blood pressure
Blood markers
Red blood cells count, white
blood cell count, platelets,
haemoglobin concentration,
reticulocytes
Within-group comparisons (pre-test vs. post-test)
VO2peak in IHHE (13.9 ± 2.5 ml-O2/min/kg vs. 19.9 ± 6.1 ml- O2/min/kg)
Between-group comparisons
Reticulocytes in IHHE compared to sham IHHE (post-test: 1.1 ± 0.5% vs. 0.6 ± 0.3%)
Interaction effects (group × time)
Diastolic blood pressure in IHHE compared to sham IHHE (pre-test: 82.1 ± 11.1 mmHg vs.
77.9 ± 9.7 mmHg; post-test: 74.7 ± 8.9 mmHg vs. 82.0 ± 9.3 mmHg)
Glazachev et al. [110]Physical functions
Cardiopulmonary exercise test
Blood markers
Total cholesterol, high and low-
density lipoprotein, triglycerides,
and glucose
Quality of life
Medical Outcome Study 36-item
Short Form Health Survey (MOS
SF-36)
Seattle Angina Questionnaire
(SAQ)
Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)
Time to exhaustion in cardiopulmonary exercise test (modified Bruce protocol) in IHHE (303 ± 147 s
vs. 362 ± 124 sa vs. 342 ± 113 s)
Metabolic equivalent in IHHE (3.5 ± 1.2 vs. 39.1 ± 1.0 s vs. 4.2 ± 1.2 s)
VO2 at anaerobic threshold in IHHE (11.5 ± 1.3 ml-O2/min/kg vs. 13.8 ± 2.0 ml-O2/min/kga vs.
13.8 ± 0.3 ml-O2/min/kgb)
MOS SF-36 physical functioning subscale in IHHE (84.2 ± 13.0 vs. 55.7 ± 12.0a vs. 51.7 ± 14.0)
MOS SF-36 role physical subscale in IHHE (47.0 ± 17.8 vs. 61.7 ± 18.8a vs. 55.8 ± 19.0)
MOS SF-36 body pain subscale in IHHE (22.0 ± 39.4 vs. 48.5 ± 43.7 vs.58.8 ± 39.0b)
MOS SF-36 vitality subscale in IHHE
Between-group comparisons
MOS SF-36 physical functioning subscale in IHHE compared to sham IHHE (post-test: 61.7 ± 18.8 vs.
47.5 ± 11.9)
MOS SF-36 body pain subscale in IHHE compared to sham IHHE (post-test: 48.5 ± 43.7 vs.
27.3 ± 8.9)
metabolic equivalent in IHHE compared to sham IHHE (post-test: 3.5 ± 0.9 vs. 3.8 ± 1.0)
VO2peak in IHHE compared to sham IHHE (post-test: 16.9 ± 1.4 ml-O2/min/kg vs. 12.0 ± 6.3 ml-O2/
min/kg)
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Behrendtetal. Sports Medicine - Open (2022) 8:70
Table 3 (continued)
References Assessed outcomes Main results
Serebrovska et al. [66]Blood markers
Total cholesterol, high- and
low-density lipoprotein, and
triglycerides
Fasting glucose level and 2 h
post-oral glucose tolerance test
glucose level
Hypoxia test (20 min at
FiO2 = 0.10)
Oxygen saturation (SpO2)
Maximal heart rate (HRmax)
Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)
Minimum SpO2 during hypoxic test in IHHE (79.4 ± 3.8% vs. 81.5 ± 3.9a % vs N.R.b)
Fasting glucose in IHHE and IHE (IHHE: 6.3 ± 0.5 mmol/L vs. 5.8 ± 0.7 mmol/La vs. 5.3 ± 0.8 mmol/Lb;
IHE: 6.5 ± 0.4 mmol/L vs. 5.4 ± 0.5 mmol/La vs. 5.1 ± 0.6 mmol/Lb)
2-h post-oral glucose tolerance test glucose level in IHHE and IHE (IHHE: 7.9 ± 0.9 mmol/L
vs. 6.8 ± 1.0 mmol/La vs. 6.4 ± 1.3 mmol/Lb; IHE: 8.3 ± 1.0 mmol/L vs. 7.0 ± 1.9 mmol/La vs.
6.4 ± 1.1 mmol/Lb)
Total cholesterol in IHHE and IHE (IHHE: 6.3 ± 1.1 mmol/L vs. 5.7 ± 1.0 mmol/La vs. 6.1 ± 1.3 mmol/L;
IHE: 6.2 ± 1.2 mmol/L vs. 5.3 ± 0.9 mmol/La vs. 5.8 ± 1.2 mmol/L)
Low-density lipoprotein cholesteral in IHHE and IHE (IHHE: 4.2 ± 1.3 mmol/L vs. 3.5 ± 1.0 mmol/La
vs. 3.5 ± 1.3 mmol/Lb; IHE: 4.0 ± 1.3 mmol/L vs. 3.3 ± 1.0 mmol/La vs. 3.4 ± 1.0 mmol/L)
Between-group comparisons
Fasting glucose in IHHE compared to sham IHHE (1-month follow-up: 5.3 ± 0.8 mmol/L; vs
6.1 ± 0.8 mmol/L)
Fasting glucose in IHE compared to sham IHHE (post-test: 5.4 ± 0.5 mmol/L vs. 6.12 ± 0.8 mmol/L;
1-month follow-up: 5.1 ± 0.6 mmol/L vs. 6.1 ± 0.8 mmol/L)
2-h post-oral glucose tolerance test glucose level in IHHE compared to sham IHHE (post-test:
6.8 ± 1.0 mmol/L vs. 8.3 ± 1.1 mmol/L; 1-month follow-up: 6.4 ± 1.3 mmol/L vs. 8.2 ± 1.2 mmol/L)
2-h post-oral glucose tolerance test glucose level in IHE compared to sham IHHE (post-test:
7.0 ± 1.9 mmol/L vs. 8.3 ± 1.1 mmol/L; 1-month follow-up: 6.4 ± 1.1 mmol/L vs. 8.2 ± 1.2 mmol/L)
Total cholesterol in IHE compared to sham IHHE (1-month follow-up: 5.3 ± 0.9 mmol/L vs.
6.2 ± 0.9 mmol/L)
Serebrovska et al. [111]Cognitive functions
Montreal Cognitive Assessment
Test (MoCA)
Long latency cognitive event-
related potential (P300, N200)
Blood markers
Amyloid-β and amyloid precur-
sor protein (APP130, APP110, and
APP110/APP130 ratio)
Beta-site amyloid precursor pro-
tein cleaving enzyme 1 (BACE1)
Stimulated neutrophil extracellu-
lar traps formation in peripheral
blood (NETst)
Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)
MoCA test score in IHHE (19.6 ± 1.6% vs. 22.1 ± 1.7%a vs. 21.3 ± 1.6%)
APP130 in IHHE (0.4 ± 0.1 r.U. vs. 0.7 ± 0.1 r.U.a vs. 0.6 ± 0.1 r.U.b)
APP110 in IHHE (0.6 ± 0.1 r.U. vs. 0.7 ± 0.1 r.U.a vs. 0.8 ± 0.1 r.U.b)
APP-ratio in IHHE (0.7 ± 0.1 vs. 0.9 ± 0.1a vs. 0.8 ± 0.1)
Amyloid-β in IHHE (2.6 ± 0.3 r.U. vs. 2.2 ± 0.4 r.U.a vs. 2.1 ± 0.4 r.U.b)
NETst in IHHE (12.7 ± 6.2% vs. 8.8 ± 3.3% vs. 6.1 ± 3.5%b)
NETns in IHHE (9.5 ± 2.1% vs. 4.5 ± 1.1%a vs. 4.2 ± 1.3%b)
BACE1 in IHHE (85.3 ± 55.6 r.U. vs. 36.8 ± 34.6 r.U.a vs. 45.6 ± 32.8 r.U.)
Between-group comparisons
APP130 in IHHE compared to sham IHHE (post-test: 0.7 ± 0.1 r.U. vs. 0.4 ± 0.1 r.U.; 1-month follow-
up: 0.6 ± 0.1 r.U. vs. 0.4 ± 0.1 r.U.)
APP110 in IHHE compared to sham IHHE (post-test: 0.7 ± 0.1 r.U. vs. 0.5 ± 0.1 r.U.; 1-month follow-
up: 0.8 ± 0.1 r.U. vs. 0.5 ± 0.1 r.U.)
APP-ratio in IHHE compared to sham IHHE (post-test: 0.9 ± 0.1 vs. 0.8 ± 0.1)
Amyloid-β in IHHE compared to sham IHHE (post-test: 2.2 ± 0.4 r.U. vs. 2.8 ± 0.4 r.U.; 1-month
follow-up: 2.1 ± 0.4 r.U. vs. 2.8 ± 0.2 r.U.)
NETst in IHHE (1-month follow-up: 6.1 ± 3.5% vs. 11.2 ± 3.6%)
NETns in IHHE (post-test: 4.5 ± 1.1% vs. 9.22 ± 3.9%; 1-month follow-up: 4.2 ± 1.3% vs. 8.25 ± 2.0%)
BACE1 in IHHE (85.3 ± 55.6 r.U. vs. 36.8 ± 34.6 r.U.a vs. 45.6 ± 32.8 r.U.)
Bestavashvili et al.
[112]
Anthropometric parameters
Body mass index (BMI)
Waist circumference
Hip circumference
Blood markers
Total cholesterol, high- and
low-density lipoprotein, and
triglycerides
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Galectin-3
Nitric oxide synthase 2 (NOS2)
Heat shock proteins (Hsp70)
Transforming growth factor
beta-1 (TGF beta-1)
Heart-type fatty acid binding
protein (H-FABP)
High-sensitive C-reactive protein
(CRP-hs)
N-Terminal pro-hormone of brain
natriuretic peptide (NTproBNP)
Within-group comparisons (pre-test vs. post-test)
BMI in IHHE (34.2 ± 5.2 kg/m2 vs. 33.3 ± 5.2 kg/m2)
Waist circumference in IHHE (116.2 ± 11.2 cm vs. 111.0 ± 10.6 cm)
Hip circumference in IHHE (114.1 ± 9.4 cm vs. 110.3 ± 9.4 cm)
Total cholesterol in sham IHHE (4.8 ± 1.2 mmol/L vs. 5.1 ± 1.1 mmol/L)
ALT in IHHE (37.3 ± 26.1 u/L vs. 29.0 ± 15.3 u/L)
HSP70 in IHHE (0.963 ± 0.316 ng/mL vs. 0.865 ± 0.334 ng/mL)
CRP-hs in IHHE (3.608 ± 3.448 mg/L vs. 2.237 ± 1.527 mg/L)
NTproBNP in IHHE (27.5 ± 45.1 pmol/L vs. 20.4 ± 34.2 pmol/L)
Between-group comparisons
ALT in IHHE compared to sham IHHE (post-test: 29.0 ± 15.3 u/L vs. 36.2 ± 21.5 u/L)
NTproBNP in IHHE compared to sham IHHE (post-test: 20.4 ± 34.2 pmol/L vs. 34.9 ± 62.1 pmol/L)
Δ-BMI in IHHE compared to sham IHHE (-0.9 ± 0.5 vs. 0.3 ± 0.6)
Δ-Waist circumference in IHHE compared to sham IHHE ( 5.2 ± 2.4 vs. 0.7 ± 1.8)
Δ-Hip circumference in IHHE compared to sham IHHE ( 3.8 ± 1.7 vs. 3.4 ± 1.0)
Δ-Total cholesterol in IHHE compared to sham IHHE ( 0.8 ± 0.8 vs. 0.3 ± 0.1)
Δ-Triglyceride in IHHE compared to sham IHHE ( 0.3 ± 0.4 vs. 0.1 ± 0.5)
Δ-Low-density lipoprotein in IHHE compared to sham IHHE ( 0.8 ± 0.7 vs. 0.3 ± 0.8)
Δ-ALT in IHHE compared to sham IHHE ( 8.3 ± 14.6 vs. 5.4 ± 9.2)
Δ-AST in IHHE compared to sham IHHE ( 4.5 ± 12.1 vs. 3.2 ± 6.3)
Δ-NTproBNP in IHHE compared to sham IHHE ( 7.1 ± 13.6 vs. 9.0 ± 18.0)
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Behrendtetal. Sports Medicine - Open (2022) 8:70
improvement in the six-minute walk distance at the end
of the intervention was higher in patients who com-
pleted the IHHE in combination with the multimodal
training program than in patients who received sham
IHHE plus multimodal training [106].
Cognitive Performance
e effect of IHHE on cognitive performance was inves-
tigated by two studies [106, 111] using different popu-
lations. With regard to older patients undergoing a
multimodal training program (2–3 times per week for
5–6weeks, consisting of 30min of physiotherapy, 60min
of occupational therapy, and 20min of aerobic exercise)
in a geriatric day care unit, the additional application of
IHHE led to improvements in global cognitive functions
(i.e. operationalized by Dementia Detection Test score
and Clock Drawing Test score) when compared with
older patients performing the same multimodal train-
ing program combined with sham IHHE [106]. In older
people with mild cognitive impairments, but not healthy
controls, global cognitive functions (i.e. Montreal Cogni-
tive Assessment Test) increased after 3weeks of IHHE,
whereas sham IHHE did not lead to a change in cognitive
test performance [111]. However, 3weeks of IHHE had
no effect on N200 and P300 latency in both older peo-
ple with mild cognitive impairments and healthy older
people [111]. In the same study, participantswith mild
cognitive impairment who performed a 3-week IHHE
intervention, showed an increase of neuroprotective
proteins (i.e. amyloid precursor proteins) and a decrease
in circulating biomarkers of Alzheimer’s disease (i.e.
amyloid-beta, neutrophil extracellular traps, and beta-
site amyloid precursor protein cleaving enzyme 1) in the
peripheral blood [111].
Haematological, Metabolic, andHaemodynamic Parameters
In three studies, changes in haematological parameters
were evaluated after 4–5weeks of IHHE in older patients
with coronary artery disease [107] and cardiac comor-
bidities [109] as well as young athletes with overtraining
syndrome [108]. Increases in reticulocytes were found
in patients with coronary heart disease after 3weeks of
IHHE when compared with patients who conducted
8 weeks of the standard rehabilitation program and
3weeks of sham IHHE [107]. However, two other stud-
ies did not observe such a change in patients with car-
diac comorbidities [109] as well as young athletes with
overtraining syndrome [108]. All three studies [107109]
that investigated IHHE-related changes in red blood cell
count and haemoglobin concentration did not find evi-
dence for a change in response to the intervention. In a
comparable manner, IHHE also had no effect on haema-
tocrit level [108] or white blood cell count and platelets
[109].
e patients’ metabolic status was assessed in four
studies [66, 107, 110, 112] and in one of these studies
[107], investigating older patients with coronary arte-
rial disease, a reduction in total cholesterol level was
observed compared with patients who had performed a
standard rehabilitation program and sham IHHE. In two
studies investigating the effects of IHHE in older patients
with coronary arterial disease [110] and prediabetes [66],
a reduction in total cholesterol levels was observed after
3weeks of IHHE, while total cholesterol levels remained
unchanged in those patients who had conducted sham
IHHE. In another study [112], no change in total choles-
terol was observed in older patients with metabolic dis-
ease. Two studies including older patients with coronary
arterial disease [107] or prediabetes [66], reported reduc-
tions in low-density lipoprotein cholesterol after 3weeks
of IHHE compared to baseline, whereas only one of these
studies [107] reported a reduced low-density lipoprotein
cholesterol level compared to a sham IHHE group. Only
one study [110] noticed a tendency towards a decrease
in low-density lipoprotein cholesterol in patients with
coronary arterial disease. With regard to patients with
metabolic syndrome, 3weeks of IHHE did not result in
a reduction in low-density lipoprotein cholesterol blood
concentration [112]. High-density lipoprotein cholesterol
was increased after 3 weeks of IHHE in patients with
coronary arterial disease compared to baseline [110],
whereas the levels remained unchanged in patients with
Table 3 (continued)
ALT Alanine aminotransferase, APP amyloid precursor protein, AST Aspartate aminotransferase, BACE1 beta-site amyloid precursor protein cleaving enz yme 1, BMI
body mass index, CDT Clock-drawing Test, CRI chronotropic reserve index, CRP-hs High-sensitive C-reactive protein DemTect Dementia Detection Test, FiO2 fraction of
inspired oxygen, H-FABP Heart-type fatty acid binding protein, Hsp70 Heat shock proteins, HRmax maximum heart rate, HRrest resting heart rate, IRI inotropic reser ve
index, IHE intermittent hypoxic exposure, IHHE intermittent hypoxia–hyperoxia exposure, IQR interquartile range, MoCA Montreal-Cognitive-Assessment, MOS SF-36
Medical Outcome Study 36-item Short Form Health Survey, NETst stimulated neutrophil extracellular traps formation, NETns not stimulated neutrophil extracellular
traps formation, NOS2 Nitric oxide synthase 2, N.R. not reported, NTproBNP N-terminal pro-hormone of brain natriuretic peptide, PWC130 physical work capacity at a
heart rate of 130 beats min1, r.U. relative units, SAQ Seattle Angina Questionnaire, TGF beta-1 Transforming growth factor beat-1, VO2peak peak oxygen uptake, 6MWT
Six-minute Walk Test
a p values < .05 for dierences between pre-test and post-test (time eect)
b p values < .05 for dierences between pre-test and 1-month follow-up (time eect)
c p values < .05 for dierences between post-test and 1-month follow-up (time eect)
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Behrendtetal. Sports Medicine - Open (2022) 8:70
prediabetes [66] and metabolic syndrome [112]. Moreo-
ver, in the study of Glazachev etal. [107], areduction in
the atherogenic index (i.e. [total cholesterol – high-den-
sity lipoprotein cholesterol] ÷ high-density lipoprotein
cholesterol) was found in patients with coronary arterial
disease who had conducted IHHE over 5 weeks com-
pared to those who had performed 8weeks of the stand-
ard rehabilitation program and 3weeks of sham IHHE.
Moreover, one study [110] reported a decrease in triglyc-
eride levels compared to baseline in response to 3weeks
of IHHE, but three other studies [66, 107, 112] did not
reveal such an effect. In patients with prediabetes, fasting
blood glucose concentration was reduced at the 1-month
follow-up assessment and 2 h post-oral glucose toler-
ance test glucose levels were decreased 1 day after and
remained decreased 1month after a 3-week IHHE inter-
vention when compared with patients with prediabetes
conducting sham IHHE [66]. Additionally, Bestavashvili
etal. [112] reported a decrease in body mass index, waist
and hip circumference, and inflammatory markers in
patients with metabolic syndrome after 3weeks of IHHE
compared to a sham IHHE group.
Four studies [106109] evaluated the effect of IHHE on
haemodynamic indices. In two studies that measured the
effect of IHHE on blood pressure and heart rate recorded
at rest in geriatric patients [106] and cardiac outpatients
[109], no changes in systolic and diastolic blood pres-
sure as well as heart rate were observed. In one study
[107], both resting systolic and diastolic blood pres-
sure as well as heart rate were decreased after 5weeks
of IHHE in patients with coronary artery disease when
compared with baseline. Susta etal. [108] reported that
4weeks of IHHE plus low-intensity aerobic exercise (2
bouts of 30 min) improved the inotropic reserve index
(i.e. [maximum systolic blood pressure resting systolic
blood pressure] ÷ resting systolic blood pressure) and
the chronotropic reserve index (i.e. [maximum heart
rate resting heart rate] ÷ resting heart rate) in healthy
athletes with overtraining syndrome. In addition, the
parasympathetic drive was increased (i.e. high-frequency
power of heart rate variability), while the sympathetic
tone was decreased (i.e. low-frequency power of heart
rate variability and low-frequency power high-frequency
power ratio) after 4 weeks of IHHE. One study [107]
found an increase in left ventricular ejection fraction
after 5weeks of IHHE in patients with coronary arterial
disease when compared to baseline. However, left ven-
tricular ejection fraction did not differ between patients
who conducted 5weeks of IHHE and patients who per-
formed 8weeks of the standard rehabilitation program
and 3weeks of sham IHHE [107].
Discussion
In this systematic review, we included eight studies that
have investigated the chronic effects of intermittent
hypoxia–hyperoxia on physical and cognitive perfor-
mance as well as haemodynamic, metabolic, or haema-
tological parameters in humans. All of the reviewed
studies [66, 106112] have performed intermittent
hypoxia–hyperoxia at rest (i.e. IHHE), with intervention
durations ranging from 3 to 6weeks. Two studies imple-
mented a physical training program in addition to the
IHHE intervention [106, 108]. e parameters that were
most frequently assessed included changes in (1) physical
performance [106110], (2) haemodynamic parameters
[106109], and (3) parameters of the metabolic state [66,
107, 110, 112]. Two of the reviewed studies [106, 111]
have investigated the effects of IHHE on (4) cognitive
performance and three studies [107109] have investi-
gated (5) haematological parameters. e results of some
studies included in this systematic review seem conflict-
ing and are difficult to compare due to the heterogeneity
in study population and design.
Eects ofIntermittent Hypoxia–Hyperoxia Exposure
onPhysical Performance
e findings of our systematic review indicate that IHHE
might have positive effects on physical performance in
specific populations, such as in geriatric patients [106].
e improvements in physical performance could be
explained by specific cardiovascular and muscular adap-
tations to IHHE, e.g. the regulation of inflammatory
response, angiogenesis, improved glycolysis, glucose
transport, and vasodilatation as well as mitochondrial
functioning [4, 113]. Furthermore, it is assumed that
physical exercise in hypoxia (e.g. aerobic exercise under
continuous hypoxia) might be a great promise for
successful geriatric rehabilitation by inducing lower
mechanical stress compared to a similar training in
normoxia (i.e. when the exercise intensity is equal and
operationalized by a marker of internal load [e.g. heart
rate]) [114]. An increased physical performance was also
observed in young track and field athletes with overtrain-
ing syndrome, evidenced by an improved physical work
capacity and balance of the autonomic nervous system
(evaluated by changes in heart rate variability frequency
measurements, i.e. low- and high-frequency power, and
low- to high-frequency power ratio) [108]. e authors
assumed that a recovered autonomic nervous system and
an increased antioxidant capacity might partially explain
these results [108]. However, this hypothesis remains
speculative, since the authors did not measure the anti-
oxidant status. Unfortunately, the control group con-
sisted of healthy athletes who kept their training routine
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Page 17 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
constant, and thus, the results could not be compared
to a “real” control group in this pilot study, i.e. athletes
with overtraining syndrome who have trained without an
additional IHHE program or a sham IHHE. erefore, no
robust conclusions can be drawn concerning the syner-
gistic effects of IHHE executed after low-intensity run-
ning in athletes with overtraining syndrome.
ree studies [107, 109, 110] imply that IHHE might
be an effective intervention to increase peak oxygen
consumption in patients with cardiovascular disease
by 12.6–43.2% (~ 1.8–6.0ml-O2/min/kg). In general, an
increase of 3.5ml-O2/min/kg is considered as the mini-
mum important difference in cardiac rehabilitation [115].
Moreover, it was shown that an increase in peak oxygen
consumption of 6% is associated with a 5% lower risk of
all-cause mortality and morbidity in patients with heart
failure [116]. Accordingly, the improvements in peak
oxygen consumption observed after IHHE can be con-
sidered as clinically meaningful. A previous study [52]
in which prolonged hypoxic exposures of 10 sessions of
3–4h per session (FiO2= 0.175–0.150) were used over a
period of 22days demonstrated a significant increase in
peak oxygen consumption (~ 5%; pre: 13.5 ± 1.8 ml-O2/
min/kg; post: 14.2 ± 1.9 ml-O2/min/kg) in patients with
heart failure and reduced ejection fraction. However, this
study included only 12 patients without a control group
[52]. Another study by Burtscher etal. [49] included eight
elderly, physically active males with New York Heart
Association class I to II heart failure who were exposed
to intermittent hypoxia (5 times per week, FiO2= 0.14–
0.10) and eight subjects of the same population who
received an equivalent sham condition. e authors
observed a significant increase in peak oxygen consump-
tion from 2333 ± 586 ml-O2/min to 2475 ± 546 ml-O2/
ml (~ 6%) after 3 weeks of intermittent hypoxic expo-
sure without changes in the subjects who completed the
sham condition [49]. However, the findings of a system-
atic review [26] suggest that passive hypoxia applica-
tion can enhance exercise tolerance during submaximal
exercise, but changes in maximal exercise capacity (e.g.
peak oxygen consumption) were somewhat difficult to
detect in healthy physically active individuals. is can
be explained by the already high level of cardiorespira-
tory fitness when compared to patients with cardiovas-
cular disease [49, 52, 117, 118]. Moreover, it should be
noted that the participants in the studies [107, 109, 110]
included in our systematic review were all of higher age
(mean age from 63.9 to 68.2years) and had cardiovas-
cular diseases as well as low peak oxygen consumption
values at baseline (13.4–14.3 ml-O2/min/kg). us, the
observed effects of IHHE cannot be generalized to other
populations such as healthy individuals.
Eects ofIntermittent Hypoxia–Hyperoxia Exposure
onCognitive Performance
e beneficial effects of a well-dosed application of
intermittent hypoxia–normoxia or hypoxia–hyperoxia
on neurocognitive health have recently been discussed
by several authors [45, 67, 119, 120]. ese reviews
have summarized the evidence from research in vari-
ous populations suggesting that IH can be applied as a
therapeutic modality in order to preserve or enhance
brain functions. Hence, the development and progres-
sion of age- or disease-dependent cognitive impairments
such as mild cognitive impairments or dementia might
be mitigated. For instance, investigations in animals and
humans have found an improved cerebrovascular func-
tion (e.g. augmented cerebral blood flow due to enhanced
endothelial-dependent vasodilatation and vascularisa-
tion) [121123], reduced vascular risk factors (e.g. hyper-
tension, hypercholesterolaemia, obesity) [50, 124, 125]
and inflammation (e.g. due to the anti-inflammatory
effect of erythropoietin [126, 127]), prevented neuronal
degeneration [128], as well as stimulated neurogenesis
and neuroregeneration [129, 130]. However, the results
of our review suggest that clinical evidence on the neu-
rocognitive effects of intermittent hypoxia–hyperoxia
is currently limited. Bayer etal. [106] found that global
cognitive performance only improved in those patients
who underwent the combination of the multimodal
training program and the IHHE. e authors concluded
that the lack of improvements in cognitive perfor-
mance in patients who conducted the multimodal train-
ing program in combination with sham IHHE might be
explained by their low initial fitness level, which made it
impossible to undergo training with an exercise inten-
sity sufficient to induce measurable improvements in
cognitive performance. Consequently, improvements in
cognitive performance could be related to the effects of
IHHE. However, more well-controlled studies are neces-
sary to confirm these promising findings. Furthermore,
Serebrovska etal. [111] reported a better cognitive per-
formance one day after the last IHHE session, which
was associated with a decrease in non-stimulated neuro-
trophic extracellular traps and amyloid-beta expression.
Neurotrophic extracellular traps are released by neutro-
phils to initiate immune defence mechanisms [131] and
increased formation of neurotrophic extracellular traps
has been observed in patients with Alzheimer’s disease
[132, 133]. In general, neurotrophic extracellular traps
formation and amyloid-beta accumulation are suggested
to play a role in the pathogenesis of Alzheimer’s disease,
which offers an approach for the treatment of this dis-
ease [134, 135]. Given the finding that IHHE influenced
the formation of neurotrophic extracellular traps and
amyloid-beta expression, IHHE could be an interesting
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Behrendtetal. Sports Medicine - Open (2022) 8:70
intervention for future studies aiming to prevent or
decelerate cognitive decline. Furthermore, there is some
evidence that intermittent hypoxic exposure alone [56]
or in combination with resistance training [40] and pro-
longed hypoxic exposure in combination with endurance
training [39] can improve cognitive performance in older
patients with mild cognitive impairment or in healthy
older people. Even if these results seem promising, fur-
ther studies are urgently needed to investigate the effects
of IHHE or IHHT on various domains of cognitive func-
tions (e.g. inhibition, working memory, cognitive flexibil-
ity) because previous studies [106, 111] only investigated
global cognitive functions with a total of 26 participants.
Furthermore, future studies should investigate the neu-
robiological mechanisms driving these cognitive perfor-
mance enhancements by assessing changes on the (1)
molecular and cellular level (e.g. changes in brain-derived
neurotrophic factor), (2) structural and functional level
(e.g. using magnetic resonance imaging (MRI), functional
MRI, functional near-infrared spectroscopy), and (3)
socioemotional level (e.g. sleep quality) [136, 137].
Eects ofIntermittent Hypoxia–Hyperoxia Exposure
onHaematological, Metabolic, andHaemodynamic
Parameters
ree studies [107109] focussed on haematological
parameters without detecting changes in haemoglobin
concentration. Comparable results have been observed
in healthy older males receiving intermittent hypoxic
exposure (5min of hypoxia [FiO2= 0.12] separated by
5min of normoxia, 4 times a day, daily for 10days) [138],
whereas other studies reported an increase in haemo-
globin concentration [49] (3–5min of hypoxia [FiO2=
0.15–0.12] separated by 3 min of normoxia, 5–6 times
a day, 5 sessions per week for 3weeks) or total haemo-
globin mass (same protocol as [49]) [54]. However, a
growing amount of evidence suggests that the hypoxia
intensity, total duration of hypoxic exposure, and inter-
session density (in particular the duration of the single
hypoxic exposure per day) are crucial factors for haema-
tological adaptations to hypoxia [139]. It can be assumed
that haemoglobin mass increases on average by 1.1% per
100h of hypoxia [140] and that the minimum duration
to reach an acclimatization effect and trigger haemato-
logical responses would be at least 12 h per day with a
hypoxia intensity corresponding to altitudes of 2500–
3000 m (FiO2= ~ 0.155–0.145) [141]. Furthermore,
Wilber et al. [142] stated that lower hypoxia intensi-
ties corresponding to altitudes of 2000–2500m (FiO2=
~ 0.165–0.155) would require a daily hypoxic duration
of more than 22 h to achieve haematological changes.
In three of the reviewed studies [107109], the total
hypoxic duration and the single hypoxic exposure per
day were considerably lower than these values (i.e. 22h).
us, it can be assumed that the hypoxic dose was not
sufficient to increase erythropoiesis. As a consequence,
the improvements in exercise capacity were likely due
to non-haematological adaptations such as respiratory
(e.g. increased ventilatory efficiency), cardiovascular (e.g.
increased stroke volume), or muscular or metabolic (e.g.
improved mitochondrial efficiency and muscle pH-regu-
lation) adaptations [4, 113]. Although one study [107] has
shown that IHHE was associated with an improved car-
diac function (i.e. increased left ventricular ejection frac-
tion), the underlying mechanisms for the improvements
in exercise capacity in response to IHHE are still not fully
clarified and should be further investigated in additional
studies in more detail.
e individual blood lipid profile (e.g. total choles-
terol, high-density lipoprotein cholesterol, low-density
lipoprotein cholesterol, and triglyceride concentration),
blood glucose level, and blood pressure are important
indicators concerning the assessment and management
of health-related risk factors. Among other factors, their
purposeful modification (e.g. due to interventions) may
have a great importance for the prevention of metabolic
and cardiovascular diseases [143145].
In theory, hypoxia could induce positive effects on
blood lipid levels by the modification of transcriptional
factors that are responsible for the regulation of appe-
tite (e.g. acylated ghrelin) [125, 146] as well as the glu-
cose and lipid metabolism (e.g. proliferator-activated
receptor gamma coactivator 1-α) [147149]. However,
none of the included studies [66, 110, 112] provide evi-
dence for a robust effect of IHHE on blood lipid levels,
except one [107]. Total cholesterol was significantly
reduced in three studies [66, 107, 110] and remained
unchanged in one study [112]. However, only Glazachev
et al. [107] have demonstrated significant differences
between patients who underwent IHHE and patients
who underwent sham IHHE. In the same study [107], the
atherogenic index (i.e. [total cholesterol high-density
lipoprotein cholesterol]÷high-density lipoprotein cho-
lesterol) was significantly reduced in patients conduct-
ing IHHE compared to those who performed a standard
rehabilitation program and sham IHHE. High-density
lipoprotein cholesterol was significantly increased and
triglycerides were significantly decreased over time
but without differences between groups (e.g. in the lat-
ter study by Glazachev etal. [110]), while IHHE had no
influence on these parameters in other studies [66, 112].
With regard to low-density lipoprotein cholesterol, both
time- and group-effects were only observed in an ear-
lier study conducted by Glazachev etal. [107], which has
shown a decrease in low-density lipoprotein cholesterol
after performing IHHE. In a comparable manner, Tin’kov
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Behrendtetal. Sports Medicine - Open (2022) 8:70
et al. [51] have demonstrated that 22 daily sessions of
continuous hypoxic exposure (3h per session, FiO2=
~ 0.135) resulted in a significant decrease in total cho-
lesterol, low-density lipoprotein cholesterol, and triglyc-
erides, whereas high-density lipoprotein cholesterol was
increased in male patients with coronary artery disease.
However, the study did not contain a control group that
was not exposed to hypoxia. In general, the findings of
the studies that have investigated the effect of continuous
hypoxic training on blood lipid levels are relatively heter-
ogeneous [124, 150152]. Hence, there is currently little
evidence supporting a positive effect of IHHE on blood
lipid profile. us, further research is needed to draw
robust conclusions.
A previous invitro study has shown an increased insu-
lin-independent glucose uptake in overweight or obese
humans after 7 consecutive days of intermittent hypoxic
exposure (3 cycles of 2h exposures to hypoxia [FiO2=
0.15], interspersed with 1 h of normoxia) [153]. e
authors concluded that intermittent hypoxic exposure led
to increases in glucose uptake via adenosine monophos-
phate-activated protein kinase-dependent pathways pri-
marily in the myotubes but not in adipocytes. Moreover,
activation of the HIF-1α subunit led to the induction of
several genes involved in the glucose metabolism such
as glucose transporter 1 and phosphofructokinase [154,
155]. In particular, increasing evidence suggests that
long- and short-time IH (passive or in combination with
exercise) may improve glucose uptake and insulin sensi-
tivity in patients with diabetes mellitus type 2, metabolic
syndrome, and overweight or obese patients [42, 156].
Based on the evidence mentioned above, intermittent
hypoxic exposure or training might be an efficient, non-
pharmacological therapeutic strategy to improve glucose
metabolism in metabolically compromised individu-
als. e results of the present review point in the same
direction as such positive effects were also observed after
IHHE. However, this evidence has to be regarded as pre-
liminary because only two studies [66, 110] have inves-
tigated fasting blood glucose concentration before and
after an IHHE intervention. Serebrovska etal. [66] have
shown that fasting blood glucose and 2h post-oral glu-
cose tolerance test glucose concentrations in patients
with prediabetes were reduced one day after a 3-week
IHHE intervention (5 sessions per week). Furthermore,
glucose levels were still reduced at the 1-month follow-
up assessment and were significantly lower compared
to a sham IHHE group. Although no significant group
differences were observed between IHHE and intermit-
tent hypoxic exposure, the authors concluded that IHHE
is more advantageous due to the reduction in session
duration resulting from shorter reoxygenation peri-
ods (3min during IHHE and 5min during intermittent
hypoxic–normoxic exposure). However, the authors did
not investigate the effect of intermittent hypoxic expo-
sure with shorter normoxic periods (e.g. 3min). Indeed,
previous studies have shown that intermittent hypoxic
exposure can be effective to improve physical perfor-
mance (i.e. peak oxygen consumption [49] and peak
power [54]) in patients with heart failure or chronic
obstructive pulmonary disease and to reduce blood
pressure in hypertensive patients [50] even with shorter
normoxic reoxygenation periods of 3min. Considering
these deficits, further studies are required to examine
the effects of IHHE and IHHT on glucose metabolism in
metabolically compromised persons.
In addition to the effects on blood lipid and glucose
concentration, the influences of IHHE on resting sys-
tolic and diastolic blood pressure were also investigated
[106, 107, 109]. e prevalence and absolute burden of
hypertension is rising worldwide [157] and represents
one of the leading modifiable risk factors for cardiovas-
cular diseases being indirectly involved in the devel-
opment of, for instance, kidney diseases and dementia
[157, 158]. ere is rather solid evidence supporting the
assumption that intermittent and continuous hypoxia at
rest or in combination with exercise is generally effec-
tive to reduce blood pressure [49, 50, 138, 159] and posi-
tively influence vascular health [41]. e mechanisms
associated with an antihypertensive effect of moderate
hypoxia may include vascular adaptions (e.g. increased
vascularisation and endothelium-dependent vasodila-
tation) as well as adaptations in the autonomic nervous
system (e.g. reduced sympathetic activity) [159]. From
a physiological point of view, acute exposure to hypoxia
is associated with an increase in blood flow, which is
accompanied by higher endothelial shear stress and
thereby endothelium-dependent increase in nitric oxide
[160]. It is well known that nitric oxide causes vasodilata-
tion [161], which reduces total peripheral resistance and
thus blood pressure. Moreover, the hypoxia-mediated
factor HIF-1α is also associated with antihypertensive
mechanisms due to the upregulation of transcriptional
genes such as nitric oxide synthase [162] (i.e. vasodila-
tation) and vascular endothelial growth factor [17] (i.e.
vascularisation). ree studies have found that IHHE can
decrease systolic ( 2.9% to 13.9%) and diastolic blood
pressure ( 9.0% to 14.0%) [106, 107, 109], although the
changes did not always reach statistical significance [106,
109]. With regard to studies using intermittent hypoxia–
normoxia, Lyamina etal. [50] exposed young males with
stage I hypertension to 20 consecutive days of intermit-
tent hypoxic exposure (4–10 cycles per session, 3 min
of hypoxia [FiO2 = 0.10] interspersed by 3 min of nor-
moxia) and found a decrease of 22mmHg in systolic and
16.6mmHg in diastolic blood pressure. In a more recent
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Behrendtetal. Sports Medicine - Open (2022) 8:70
study, Muangritdech et al. [163] reported significant
reductions in systolic blood pressure (-11.0 ± 9.7 mmHg)
after 6weeks of intermittent hypoxic interval training (2
sessions per week, 8 cycles per session, 3min of hypoxia
[SpO2 = 90.8 ± 2.31% to 87.7 ± 1.89%] interspersed by
3min of normoxia combined with continuous treadmill
walking at 35–50% of the participants’ individual heart
rate reserve). Moreover, Serebrovska etal. [159] reported
decreases of 10–30mmHg in systolic and 10–15mmHg
in diastolic blood pressure in patients with stage I to II
hypertension after intermittent or prolonged hypoxic
exposure in their review. Recent meta-analyses have
shown that every reduction of 10 mmHg in systolic or
5mmHg in diastolic blood pressure reduced the risk of
major cardiovascular events by 20%, the genesis of car-
diovascular diseases by 17–40%, and all-cause mortality
by 13% [164, 165]. Indeed, a decrease of even 2mmHg
in systolic blood pressure would involve a 10% lower
stroke mortality and about 7% lower mortality for cardio-
vascular heart diseases or other vascular causes in mid-
dle age [166]. Given the evidence that IHHE can trigger
a reduction in systolic and diastolic blood pressure in
older patients with and without cardiovascular diseases,
IHHE can be considered as a promising therapeutic strat-
egy to reduce systemic blood pressure in this population.
erefore, the hypotensive effect of IHHE is practically
relevant to prevent the genesis or exacerbation of cardio-
vascular diseases and ensure a healthy life.
Hypoxia Dose
In general, the acute and chronic responses to hypoxia are
complex and could be either adaptive/beneficial or mala-
daptive/pathological depending, among other factors, on
the hypoxic dose. e hypoxic dose can be adjusted by
modulating various variables (Table4) including the (1)
intensity of hypoxia (hyperoxia), (2) duration of a single
hypoxic period as well as (3) intra-session frequency, and
(4) intra-session density [25, 76]. Indeed, the variables
mentioned above are relevant factors for the acute effects
in response to a single IH session. In order to provide a
more detailed explanation of the effects of the hypoxic
dose on chronic adaptations, we suggest consideration
of three additional variables (Table4) which are relevant
in an IH training program (i.e. when IH sessions are con-
ducted regularly in a planned, structured, and purposive
manner with the objective to increase or maintain at least
Table 4 Overview of the general variables determining the hypoxic dose and preliminary synopsis for the application of intermittent
hypoxic–hyperoxic exposure (IHHE) interventions
a Please note that the displayed variables were frequently reported in the reviewed studies and can serve as starting point for future investigations. However, currently
no specic recommendations concerning the dose being most suitable for a distinct population can be provided since there is not enough evidence in the literature
allowing us to draw robust and reliable conclusions in this direction
Variable and description IHHE protocola
Main variables relevant for a single IHHE session (acute effects)
Intensity of hypoxia
Level of hypoxemia, typically reported as oxygen saturation of the blood (SpO2, internal intensity) or fraction of
inspired oxygen (FiO2, external intensity) FiO2 = 0.10–0.12
Intensity of hyperoxia
Fraction of inspired oxygen (FiO2, external intensity) during hyperoxic periods FiO2 = 0.30–0.40
Duration of a single hypoxic period
Time spent in hypoxia before the onset of reoxygenation period (i.e. onset of normoxia or hyperoxia period) 2–6 min
Intra-session frequency
Number of hypoxic periods that are interspersed with hyperoxic or normoxic periods (cycle) within a single session
or day 4–8 cycles
Intra-session density
Distribution of hypoxic periods across a distinct time interval with regard to reoxygenation time (i.e. duration of
normoxia or hyperoxia period) within a single session or day 1–4 min
Main variables relevant for a IHHE training program (chronic effects)
Inter-session frequency
The number of IHHE sessions across a distinct time interval 3–5 sessions per week
Inter-session density
Distribution of IHHE sessions across a distinct time interval with regard to recovery time in-between the IHHE ses-
sions Every second day until daily
for 5 days interspersed with 2
days rest
Duration
IHHE intervention duration 3 weeks
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Behrendtetal. Sports Medicine - Open (2022) 8:70
one fitness or health dimension). ese variables include
the (5) inter-session frequency, (6) inter-session density,
and (7) duration over which the IH intervention is car-
ried out. In a review, Navarrete-Opazo and Mitchell [25]
concluded that the intensity and the intra-session fre-
quency of the hypoxic stimulus are the most important
variables with regard to the acute and chronic responses
to IH. Accordingly, the authors recommended “low-
dose” IH protocols with an intensity of FiO2 = 0.09–0.16
and intra-session frequency of 3–15 cycles per session
or day to achieve positive effects on multiple structures
such as the cardiovascular, respiratory, musculoskel-
etal, neuronal, and immune systems [25]. Although the
recommendations refer to IH sessions with normoxic
reoxygenation periods, the studies in our review gener-
ally point in a comparable direction. Based on the cur-
rent literature, we propose general recommendations for
planning IHHE interventions in Table4. However, given
the evidence showing that acute and chronic responses to
hypoxia are complex, specific, and inter-individual [167,
168], we also advocate for the conduction of additional
high-quality studies investigating the acute and chronic
dose–response relationship of IHHE and IHHT. Further-
more, we suggest that the administration of hypoxia and
hyperoxia requires an individually tailored approach [77].
With regard to the intensity of the hypoxic stimulus, it
is crucial to differentiate between internal (e.g. individuals’
SpO2) and external intensity (e.g. FiO2). Reductions in SpO2
at a fixed FiO2 vary widely within and between individu-
als due to different compensatory processes especially with
increasing hypoxia intensity [168]. Knowing that internal
intensity but not the external intensity determines the
individuals’ physiological stress, it is suggested that the
administration of hypoxia requires an individually tailored
approach [77, 169]. To deal with this issue, the majority of
the studies included in this systematic review [106110,
112] performed a hypoxic test in order to examine patients’
individual response to hypoxia (i.e. changes in SpO2 and
heart rate). Subsequently, the hypoxia intensity and intra-
session density of the IHHE program was individually
tailored based on the results of this hypoxia test [170]. Fur-
thermore, to control and adjust the hypoxia intensity and
duration during the IHHE session, the patients’ heart rate
and SpO2 were monitored and the IHHE session was con-
trolled via biofeedback (i.e. when reaching the individual
minimum of SpO2, the hypoxic switched to the hyperoxic
period until the initial SpO2 was reached).
Of note, the main difference of IHHE or IHHT com-
pared to other IH methods is the replacement of nor-
moxic periods by hyperoxic periods. is modification
is hypothesized to up-regulate specific transcription fac-
tors [58, 59, 67], which can, in turn, cause adverse (e.g.
cell damage) or beneficial (e.g. redox signalling) effects
depending on the dose of the stimuli [25, 76]. In this
regard, it has been shown that chronic exposure to hyper-
oxia can increase oxidative stress, which may have a neg-
ative impact on normal cellular mechanisms [171]. us,
hyperoxia should be carefully administered even in IHHE
or IHHT. With regard to the included studies, no adverse
effects being directly attributable to the hyperoxic peri-
ods were reported. However, further research is neces-
sary to better understand the biological consequences
and possible health risks (e.g. for specific populations
such as patients with chronic obstructive pulmonary
disease) of the replacement of normoxic periods with
hyperoxic periods. Unfortunately, due to the low number
of studies and the heterogeneity in study population and
design, a more detailed sub-analysis regarding the influ-
ence of the hypoxia and hyperoxia dose was not possible.
Limitations
e first limitation is that four studies were excluded
because they were not written in English. ese studies
were published between 2010 and 2017 and have inves-
tigated the effect of IHHE on different performance- and
health-related outcomes in patients with metabolic and
cardiovascular diseases. Unfortunately, the full-texts of
all of these studies were published in Russian and could
not be completely analysed as none of the authors of this
systematic review understands Russian sufficiently well.
Secondly, according to our quality assessment (modified
Downs and Black checklist [75]), the majority of stud-
ies were classified as moderate quality. us, our findings
should be viewed with respect to this limitation. In this
context, a major point of concern is the insufficient jus-
tification of the sample size since only the study by Dud-
nik et al. [109] calculated and reported the sample size
and effects size measures. e sample size calculation is a
critical element of interventional studies as most of these
studies aim to determine the effect (size) of different inter-
vention approaches on a primary outcome parameter
[172]. erefore, the sample size calculation is a crucial
part of the study planning being related to ethical, medi-
cal, and statistical considerations. In line with established
recommendations [173], researchers are advised to pay
more attention to an appropriate sample size calculation
to improve the quality and transparency of their studies
which, in turn, can enhance the robustness and trustwor-
thiness of their findings. Furthermore, all of the reviewed
studies lacked important methodological descriptions
concerning Items 15, 19, 22, 24, and 28 of the modified
Downs and Black checklist (see Risk of bias assessment
[75]). In particular, the lack of reporting of the patients’
compliance with the intervention is worth mentioning,
given that reduced or marked inter-group differences in
the patients’ compliance could have biased the effects of
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Behrendtetal. Sports Medicine - Open (2022) 8:70
IHHE on performance- and health-related outcomes. In
addition, the intervention was primarily applied in older
patients with various diseases such as cognitive, cardiovas-
cular, or metabolic disorders. Finally, the studies showed
a strong heterogeneity with regard to their primary out-
come parameters making a meta-analytical approach not
possible.
Conclusion andPerspective
Despite a somewhat limited number of studies included
in our qualitative analysis, the current systematic review
provides first hints that IHHE can be a non-pharmacolog-
ical intervention strategy for improving peak oxygen con-
sumption, exercise tolerance, and cognitive performance
as well as reducing cardiometabolic risk factors (particu-
larly blood glucose level, systolic and diastolic blood pres-
sure) in older patients with cardiovascular and metabolic
diseases or cognitive impairment. Importantly, although
the results appear promising, more high-quality rand-
omized controlled trials with a detailed description of the
hypoxia dose and population (i.e. specific disease pheno-
type) are warranted before robust conclusions for the use
of IHHE in therapy or clinical practice can be drawn. e
evidence concerning the effects of IHHE on total choles-
terol, high- and low-density lipoprotein cholesterol, and
triglyceride blood level as well as erythropoiesis and hae-
moglobin mass is still inconclusive. Moreover, there is no
evidence that replacing normoxic periods with hyperoxic
periods enhances hypoxia-related adaptations in humans.
is is mainly due to the fact that only one study directly
compared the effect of IHHE and intermittent hypoxic
exposure on blood glucose and lipoprotein cholesterol
level in older patients with prediabetes.
Given the relatively low number of studies investigating
the chronic effects of IHHE on performance- and health-
related outcomes, there are some important aspects that
should be addressed in future studies. ese include
the direct comparison of the effectiveness of IHHE or
IHHT and hypoxic–normoxic exposure or training on,
for example, changes in physical performance (e.g. exer-
cise tolerance), cognitive performance (e.g. working
memory), or cardiometabolic risk factors (e.g. systolic
and diastolic blood pressure). Moreover, the cellular
and molecular changes (e.g. nitric oxide, erythropoie-
tin, HIF-1α) driving the adaptations to IHHE or IHHT
should be examined. Furthermore, to better individualize
IHHE or IHHT interventions, the optimal combination
of variables that determine the dose–response relation-
ship needs to be investigated with respect to physiologi-
cal and structural adaptations as well as their importance
for physical and cognitive performance improvements.
ese variables include the intensity of hypoxia and
hyperoxia, the duration of a single hypoxic period, the
intra-session frequency (i.e. the number of cycles), the
intra-session density (i.e. duration of a single hyperoxic
period), the inter-session frequency, the inter-session
density, and the duration over which the IHHE or IHHT
intervention is carried out (see Table4). Finally, there are
no studies available that have investigated the chronic
effects of IHHT on performance- and health-related out-
comes in humans. To address this gap, future studies are
needed that investigate the combination of intermittent
exposures to hypoxic and hyperoxic periods with differ-
ent types of exercise, such as intermittent or continu-
ous aerobic exercise or resistance exercise, to elucidate
whether synergistic effects occur. In particular, it should
be noted that the functional and structural adaptations
in response to acute or chronic IHHT are not necessarily
the same as those that occur during exercise in continu-
ous hypoxia or intermittent hypoxia–normoxia. ere-
fore, current recommendations for exercise and training
in hypoxic conditions should be re-evaluated for IHHT.
As a consequence, it could be necessary to introduce spe-
cific recommendations for IHHT.
Abbreviations
EPO: Erythropoietin; FiO2: Oxygen fraction in the inspired air; HIF: Hypoxia-
inducible factors; HIF-1α: α-Subunit of HIF; HSP: Heat shock proteins; IH:
Intermittent hypoxia; IHH: Intermittent hypoxia–hyperoxia; IHHE: Intermittent
hypoxic–hyperoxic exposure; IHHT: Intermittent hypoxic–hyperoxic training;
Keap1: Kelch-like ECH-associated protein 1; NF-κB: Nuclear factor kappa B;
Nrf2: Nuclear factor erythroid 2-related factor; 2PHD: Prolyl hydroxylase; PiO2:
Oxygen partial pressure in the atmosphere; PRISMA: Preferred reporting items
for systematic reviews and meta-analyses; ROS: Reactive oxygen species; SaO2:
Arterial oxygen saturation; SpO2: Peripheral oxygen saturation; VEGF: Vascular
endothelial growth factor.
Acknowledgements
Not applicable.
Author contributions
TB had the idea and wrote the first draft of the manuscript. TB and FH estab-
lished the search strategy, did the search, and identified the studies to be
included. TB, RB, and MB carried out the quality assessment. TB, RB, MB, and FH
collectively interpreted the results of the systematic review. RB, MB, FH, and LS
critically read and revised the manuscript. All authors read and approved the
final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No sources of
funding were used to assist in the preparation of this article.
Availability of data and materials
The data within this systematic review are secondary data and are available
through the relevant articles referenced throughout.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
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Page 23 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
Competing of interests
Tom Behrendt, Robert Bielitzki, Martin Behrens, Fabian Herold, and Lutz
Schega declare that they have no conflicts of interest relevant to the content
of this review.
Author details
1 Department of Sport Science, Chair for Health and Physical Activity, Otto-
von-Guericke University Magdeburg, Universitätsplatz 2, 39104 Magdeburg,
Germany. 2 Department of Orthopaedics, Rostock University Medical Center,
Doberaner Str. 142, 18057 Rostock, Germany. 3 Research Group Degenerative
and Chronic Disease, Movement, Faculty of Health Sciences, University of Pots-
dam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany.
Received: 14 December 2021 Accepted: 17 April 2022
References
1. Millet GP, Roels B, Schmitt L, Woorons X, Richalet JP. Combining hypoxic
methods for peak performance. Sports Med. 2010;40:2–25.
2. Girard O, Brocherie F, Goods PSR, Millet GP. An updated panorama of
“living low-training high” altitude/hypoxic methods. Front Sports Act
Living. 2020;2:26. https:// doi. org/ 10. 3389/ fspor. 2020. 00026.
3. Girard O, Brocherie F, Millet GP. Effects of altitude/hypoxia on single-
and multiple-sprint performance: a comprehensive review. Sports Med.
2017;47:1931–49. https:// doi. org/ 10. 1007/ s40279- 017- 0733-z.
4. Verges S, Chacaroun S, Godin-Ribuot D, Baillieul S. Hypoxic condition-
ing as a new therapeutic modality. Front Pediatr. 2015;3:58. https:// doi.
org/ 10. 3389/ fped. 2015. 00058.
5. Serebrovsk aya TV, Xi L. Intermittent hypoxia training as non-pharmaco-
logic therapy for cardiovascular diseases: practical analysis on methods
and equipment. Exp Biol Med (Maywood). 2016;241:1708–23. https://
doi. org/ 10. 1177/ 15353 70216 657614.
6. Feriche B, García-Ramos A, Morales-Ar tacho AJ, Padial P. Resistance
training using different hypoxic training strategies: a basis for hyper-
trophy and muscle power development. Sports Med Open. 2017;3:12.
https:// doi. org/ 10. 1186/ s40798- 017- 0078-z.
7. Girard O, Koehle MS, MacInnis MJ, Guenette JA, Verges S, Rupp T,
Jubeau M, Perrey S, Millet GY, Chapman RF, Levine BD, Conkin J, Wessel
JH, Nespoulet H, Wuyam B, Tamisier R, Levy P, Casey DP, Taylor BJ, Snyder
EM, Johnson BD, Laymon AS, Stickford JL, Weavil JC, Loeppky JA, Pun M,
Schommer K, Bartsch P, Vagula MC, Nelatury CF. Comments on point:
counterpoint: hypobaric hypoxia induces/does not induce different
responses from normobaric hypoxia. J Appl Physiol. 2012;112:1788–94.
https:// doi. org/ 10. 1152/ jappl physi ol. 00356. 2012.
8. Millet GP, Faiss R, Pialoux V. Last word on point: counterpoint: hypobaric
hypoxia induces different responses from normobaric hypoxia. J Appl
Physiol. 2012;112:1795. https:// doi. org/ 10. 1152/ jappl physi ol. 00338.
2012.
9. Millet GP, Faiss R, Pialoux V. Point: hypobaric hypoxia induces different
physiological responses from normobaric hypoxia. J Appl Physiol.
2012;112:1783–4. https:// doi. org/ 10. 1152/ jappl physi ol. 00067. 2012.
10. Mounier R, Brugniaux JV. Counterpoint: hypobaric hypoxia does not
induce different responses from normobaric hypoxia. J Appl Physiol.
2012;112:1784–6. https:// doi. org/ 10. 1152/ jappl physi ol. 00067. 2012a.
11. Mounier R, Brugniaux JV. Last word on counterpoint: hypobaric hypoxia
does not induce different physiological responses from normobaric
hypoxia. J Appl Physiol. 2012;112:1796. https:// doi. org/ 10. 1152/ jappl
physi ol. 00355. 2012.
12. DiPasquale DM. Moving the debate forward: Are normobaric and hypo-
baric hypoxia interchangeable in the study of altitude? Curr Sports Med
Rep. 2017;16:68–70. https:// doi. org/ 10. 1249/ JSR. 00000 00000 000337.
13. Millet GP, Debevec T. CrossTalk proposal: barometric pressure, inde-
pendent of PO2, is the forgotten parameter in altitude physiology and
mountain medicine. J Physiol (Lond). 2020;598:893–6. https:// doi. org/
10. 1113/ JP278 673.
14. Richalet J-P. CrossTalk opposing view: barometric pressure, independ-
ent of PO2, is not the forgotten parameter in altitude physiology and
mountain medicine. J Physiol (Lond). 2020;598:897–9. https:// doi. org/
10. 1113/ JP279 160.
15. Mourot L, Millet GP. Is maximal heart rate decrease similar between nor-
mobaric versus hypobaric hypoxia in trained and untrained subjects?
High Alt Med Biol. 2019;20:94–8. https:// doi. org/ 10. 1089/ ham. 2018.
0104.
16. Coppel J, Hennis P, Gilbert-Kawai E, Grocott MP. The physiological
effects of hypobaric hypoxia versus normobaric hypoxia: a systematic
review of crossover trials. Extrem Physiol Med. 2015;4:2. https:// doi. org/
10. 1186/ s13728- 014- 0021-6.
17. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease
pathophysiology. Annu Rev Pathol. 2014;9:47–71. https:// doi. org/ 10.
1146/ annur ev- pathol- 012513- 104720.
18. Greer SN, Metcalf JL, Wang Y, Ohh M. The updated biology of hypoxia-
inducible factor. EMBO J. 2012;31:2448–60. https:// doi. org/ 10. 1038/
emboj. 2012. 125.
19. Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors.
Blood Rev. 2013;27:41–53. https:// doi. org/ 10. 1016/j. blre. 2012. 12. 003.
20. Wahl P, Schmidt A, Demarees M, Achtzehn S, Bloch W, Mester J.
Responses of angiogenic growth factors to exercise, to hypoxia and to
exercise under hypoxic conditions. Int J Sports Med. 2013;34:95–100.
https:// doi. org/ 10. 1055/s- 0032- 13148 15.
21. Choi JH, Park MJ, Kim KW, Choi YH, Park SH, An WG, Yang US, Cheong J.
Molecular mechanism of hypoxia-mediated hepatic gluconeogenesis
by transcriptional regulation. FEBS Lett. 2005;579:2795–801. https:// doi.
org/ 10. 1016/j. febsl et. 2005. 03. 097.
22. Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible
factor 1. Physiology (Bethesda). 2009;24:97–106. https:// doi. org/ 10.
1152/ physi ol. 00045. 2008.
23. Saugy JJ, Schmitt L, Hauser A, Constantin G, Cejuela R, Faiss R, Wehrlin
JP, Rosset J, Robinson N, Millet GP. Same performance changes after
live high-train low in normobaric vs. hypobaric hypoxia. Front Physiol.
2016;7:138. https:// doi. org/ 10. 3389/ fphys. 2016. 00138.
24. Bär tsch P, Gibbs JSR. Effect of altitude on the hear t and the lungs. Circu-
lation. 2007;116:2191–202. https:// doi. org/ 10. 1161/ CIRCU LATIO NAHA.
106. 650796.
25. Navarrete-Opazo A, Mitchell GS. Therapeutic potential of intermittent
hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol.
2014;307:R1181–97. https:// doi. org/ 10. 1152/ ajpre gu. 00208. 2014.
26. Lizamore CA, Hamlin MJ. The use of simulated altitude techniques for
beneficial cardiovascular health outcomes in nonathletic, seden-
tary, and clinical populations: a literature review. High Alt Med Biol.
2017;18:305–21. https:// doi. org/ 10. 1089/ ham. 2017. 0050.
27. Bär tsch P, Dehnert C, Friedmann-Bette B, Tadibi V. Intermittent hypoxia
at rest for improvement of athletic performance. Scand J Med Sci
Sports. 2008;18(Suppl 1):50–6. https:// doi. org/ 10. 1111/j. 1600- 0838.
2008. 00832.x.
28. Lundby C, Millet GP, Calbet JA, Bärtsch P, Subudhi AW. Does “altitude
training” increase exercise performance in elite athletes? Br J Sports
Med. 2012;46:792–5. https:// doi. org/ 10. 1136/ bjspo rts- 2012- 091231.
29. Wilber RL. Application of altitude/hypoxic training by elite athletes.
JHSE. 2011;6:271–86. https:// doi. org/ 10. 4100/ jhse. 2011. 62. 07.
30. Bur tscher M, Millet GP, Burtscher J. Hypoxia conditioning for high-
altitude pre-acclimatization. J Sci Sport Exerc. 2022;8:133. https:// doi.
org/ 10. 1007/ s42978- 021- 00150-0.
31. Treml B, Kleinsasser A, Hell T, Knotzer H, Wille M, Burtscher M. Carry-
over quality of pre-acclimatization to altitude elicited by intermittent
hypoxia: a participant-blinded, randomized controlled trial on ante-
dated acclimatization to altitude. Front Physiol. 2020;11:45. https:// doi.
org/ 10. 3389/ fphys. 2020. 00531.
32. Khodaee M, Grothe HL, Seyfert JH, VanBaak K. Athletes at high altitude.
Sports Health. 2016;8:126–32. https:// doi. org/ 10. 1177/ 19417 38116
630948.
33. Millet GP, Girard O, Beard A, Brocherie F. Repeated sprint training in
hypoxia—an innovative method. Dtsch Z Sportmed. 2019;2019:115–22.
https:// doi. org/ 10. 5960/ dzsm. 2019. 374.
34. Lundby C, Robach P. Does “altitude training” increase exercise perfor-
mance in elite athletes? Exp Physiol. 2016;101:783–8. https:// doi. org/ 10.
1113/ EP085 579.
35. Brocherie F, Girard O, Faiss R, Millet GP. Effects of repeated-sprint train-
ing in hypoxia on sea-level performance: a meta-analysis. Sports Med.
2017;47:1651–60. https:// doi. org/ 10. 1007/ s40279- 017- 0685-3.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 24 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
36. Millet GP, Brocherie F. Hypoxic training is beneficial in elite athletes. Med
Sci Sports Exerc. 2020;52:515–8. https:// doi. org/ 10. 1249/ MSS. 00000
00000 002142.
37. Brocherie F, Millet GP, Hauser A, Steiner T, Rysman J, Wehrlin JP, Girard
O. “Live high-train low and high” hypoxic training improves team-sport
performance. Med Sci Sports Exerc. 2015;47:2140–9. https:// doi. org/ 10.
1249/ MSS. 00000 00000 000630.
38. Siebenmann C, Dempsey JA. Hypoxic training is not beneficial in elite
athletes. Med Sci Sports Exerc. 2020;52:519–22. https:// doi. org/ 10. 1249/
MSS. 00000 00000 002141.
39. Schega L, Peter B, Brigadski T, Leßmann V, Isermann B, Hamacher D,
Törpel A. Effect of intermittent normobaric hypoxia on aerobic capacity
and cognitive function in older people. J Sci Med Sport. 2016;19:941–5.
https:// doi. org/ 10. 1016/j. jsams. 2016. 02. 012.
40. Schega L, Peter B, Törpel A, Mutschler H, Isermann B, Hamacher D.
Effects of intermittent hypoxia on cognitive performance and quality of
life in elderly adults: a pilot study. Gerontology. 2013;59:316–23. https://
doi. org/ 10. 1159/ 00035 0927.
41. Montero D, Lundby C. Effects of exercise training in hypoxia versus
normoxia on vascular health. Sports Med. 2016;46:1725–36. https:// doi.
org/ 10. 1007/ s40279- 016- 0570-5.
42. van Hulten V, van Meijel RLJ, Goossens GH. The impact of hypoxia expo-
sure on glucose homeostasis in metabolically compromised humans:
a systematic review. Rev Endocr Metab Disord. 2021;22:471–83. https://
doi. org/ 10. 1007/ s11154- 021- 09654-0.
43. Bur tscher J, Maglione V, Di Pardo A, Millet GP, Schwarzer C, Zangrandi
L. A rationale for hypoxic and chemical conditioning in huntington’s
disease. Int J Mol Sci. 2021. https:// doi. org/ 10. 3390/ ijms2 20205 82.
44. Bur tscher J, Syed MMK, Lashuel HA, Millet GP. Hypoxia conditioning
as a promising therapeutic target in Parkinson’s disease? Mov Disord.
2021;36:857–61. https:// doi. org/ 10. 1002/ mds. 28544.
45. Bur tscher J, Mallet RT, Burtscher M, Millet GP. Hypoxia and brain
aging: Neurodegeneration or neuroprotection? Ageing Res Rev.
2021;68:101343. https:// doi. org/ 10. 1016/j. arr. 2021. 101343.
46. Millet GP, Debevec T, Brocherie F, Malatesta D, Girard O. Therapeutic
use of exercising in hypoxia: promises and limitations. Front Physiol.
2016;7:224. https:// doi. org/ 10. 3389/ fphys. 2016. 00224.
47. Mallet RT, Manukhina EB, Ruelas SS, Caffrey JL, Downey HF. Cardio-
protection by intermittent hypoxia conditioning: evidence, mecha-
nisms, and therapeutic potential. Am J Physiol Heart Circ Physiol.
2018;315:H216–32. https:// doi. org/ 10. 1152/ ajphe art. 00060. 2018.
48. Camacho-Cardenosa A, Camacho-Cardenosa M, Brooks D, Timón R,
Olcina G, Brazo-Sayavera J. Effects training in hypoxia on cardiometa-
bolic parameters in obese people: a systematic review of randomized
controlled trial. Aten Primaria. 2019;51:397–405. https:// doi. org/ 10.
1016/j. aprim. 2018. 03. 011.
49. Bur tscher M, Pachinger O, Ehrenbourg I, Mitterbauer G, Faulhaber
M, Pühringer R, Tkatchouk E. Intermittent hypoxia increases exercise
tolerance in elderly men with and without coronary artery disease. Int J
Cardiol. 2004;96:247–54. https:// doi. org/ 10. 1016/j. ijcard. 2003. 07. 021.
50. Lyamina NP, Lyamina SV, Senchiknin VN, Mallet RT, Downey HF,
Manukhina EB. Normobaric hypoxia conditioning reduces blood
pressure and normalizes nitric oxide synthesis in patients with arterial
hypertension. J Hypertens. 2011;29:2265–72. https:// doi. org/ 10. 1097/
HJH. 0b013 e3283 4b5846.
51. Tin’kov AN, Aksenov VA. Effects of intermittent hypobaric hypoxia on
blood lipid concentrations in male coronary heart disease patients.
High Alt Med Biol. 2002;3:277–82.
52. Saeed O, Bhatia V, Formica P, Browne A, Aldrich TK, Shin JJ, Maybaum
S. Improved exercise performance and skeletal muscle strength after
simulated altitude exposure: a novel approach for patients with chronic
heart failure. J Card Fail. 2012;18:387–91. https:// doi. org/ 10. 1016/j. cardf
ail. 2012. 02. 003.
53. Serebrovska TV, Portnychenko AG, Drevytska TI, Por tnichenko VI, Xi L,
Egorov E, Gavalko AV, Nask alova S, Chizhova V, Shatylo VB. Intermittent
hypoxia training in prediabetes patients: beneficial effects on glucose
homeostasis, hypoxia tolerance and gene expression. Exp Biol Med
(Maywood). 2017;242:1542–52. https:// doi. org/ 10. 1177/ 15353 70217
723578.
54. Bur tscher M, Haider T, Domej W, Linser T, Gatterer H, Faulhaber M,
Pocecco E, Ehrenburg I, Tkatchuk E, Koch R, Bernardi L. Intermittent
hypoxia increases exercise tolerance in patients at risk for or with mild
COPD. Respir Physiol Neurobiol. 2009;165:97–103. https:// doi. org/ 10.
1016/j. resp. 2008. 10. 012.
55. Haider T, Casucci G, Linser T, Faulhaber M, Gatterer H, Ott G, Linser A,
Ehrenbourg I, Tkatchouk E, Burtscher M, Bernardi L. Interval hypoxic
training improves autonomic cardiovascular and respiratory control in
patients with mild chronic obstructive pulmonary disease. J Hypertens.
2009;27:1648–54. https:// doi. org/ 10. 1097/ HJH. 0b013 e3283 2c0018.
56. Wang H, Shi X, Schenck H, Hall JR, Ross SE, Kline GP, Chen S, Mallet RT,
Chen P. Intermittent hypoxia training for treating mild cognitive impair-
ment: a pilot study. Am J Alzheimers Dis Other Demen. 2020. https://
doi. org/ 10. 1177/ 15333 17519 896725.
57. Chacaroun S, Borowik A, Vega-Escamilla Y, Gonzalez I, Doutreleau S,
Wuyam B, Belaidi E, Tamisier R, Pepin JL, Flore P, Verges S. Hypoxic exer-
cise training to improve exercise capacity in obese individuals. Med Sci
Sports Exerc. 2020;52:1641–9. https:// doi. org/ 10. 1249/ MSS. 00000 00000
002322.
58. Sazontova TG, Bolotova AV, Bedareva IV, Kostina NV, Arkhipenko YV.
Adaptation to intermittent hypoxia/hyperoxia enhances efficiency of
exercise training. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia
and human diseases. London: Springer; 2012. p. 191–205. https:// doi.
org/ 10. 1007/ 978-1- 4471- 2906-6_ 16.
59. Arkhipenko YV, Sazontova TG, Zhukova AG. Adaptation to periodic
hypoxia and hyperoxia improves resistance of membrane structures in
heart, liver, and brain. Bull Exp Biol Med. 2005;140:278–81. https:// doi.
org/ 10. 1007/ s10517- 005- 0466-0.
60. Clanton TL. Hypoxia-induced reactive oxygen species formation in
skeletal muscle. J Appl Physiol. 2007;102:2379–88. https:// doi. org/ 10.
1152/ jappl physi ol. 01298. 2006.
61. Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxy-
gen species. Mol Cell. 2012;48:158–67. https:// doi. org/ 10. 1016/j. molcel.
2012. 09. 025.
62. Malec V, Gottschald OR, Li S, Rose F, Seeger W, Hänze J. HIF-1 alpha
signaling is augmented during intermittent hypoxia by induction of
the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells. Free
Radic Biol Med. 2010;48:1626–35. https:// doi. org/ 10. 1016/j. freer adbio
med. 2010. 03. 008.
63. He F, Ru X, Wen T. NRF2, a transcription factor for stress response and
beyond. Int J Mol Sci. 2020. https:// doi. org/ 10. 3390/ ijms2 11347 77.
64. Brinkmann C, Metten A, Scriba P, Tagarakis CVM, Wahl P, Latsch J, Brixius
K, Bloch W. Hypoxia and Hyperoxia affect serum angiogenic regulators
in T2DM men during cycling. Int J Sports Med. 2017;38:92–8. https://
doi. org/ 10. 1055/s- 0042- 116823.
65. Susta D, Glazachev OS, Zapara MA, Dudnik EN, Samartseva VG. Redox
homeostasis in humans exposed to intermittent hypoxia–normoxia
and to intermittent hypoxia–hyperoxia. High Alt Med Biol. 2020;21:45–
51. https:// doi. org/ 10. 1089/ ham. 2019. 0059.
66. Serebrovska TV, Grib ON, Portnichenko VI, Serebrovska ZO, Egorov E,
Shatylo VB. Intermittent hypoxia/hyperoxia versus intermittent hypoxia/
normoxia: comparative study in prediabetes. High Alt Med Biol.
2019;20:383–91. https:// doi. org/ 10. 1089/ ham. 2019. 0053.
67. Mallet RT, Burtscher J, Manukhina EB, Downey HF, Glazachev OS,
Serebrovskaya TV, Burtscher M. Hypoxic–hyperoxic conditioning and
dementia. In: Martin CR, Preedy VR, editors. Diagnosis and management
in dementia. Amsterdam: Elsevier; 2020. p. 745–60.
68. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. J Clin
Epidemiol. 2009;62:1006–12. https:// doi. org/ 10. 1016/j. jclin epi. 2009. 06.
005.
69. Rethlefsen M, Kirtley S, Waffenschmidt S, Ayala AP, Moher D, Page MJ,
Koffel J. PRISMA-S: an extension to the PRISMA statement for reporting
literature searches in systematic reviews. Syst Rev. 2021;10:1–19.
70. Harris JD, Quatman CE, Manring MM, Siston RA, Flanigan DC. How to
write a systematic review. Am J Sports Med. 2014;42:2761–8. https://
doi. org/ 10. 1177/ 03635 46513 497567.
71. von Elm E, Poglia G, Walder B, Tramèr MR. Different patterns of duplicate
publication: an analysis of articles used in systematic reviews. JAMA.
2004;291:974–80. https:// doi. org/ 10. 1001/ jama. 291.8. 974.
72. Bayer U, Likar R, Pinter G, Stettner H, Demschar S, Trummer B,
Neuwersch S, Glazachev O, Burtscher M. Effects of intermittent
hypoxia–hyperoxia on mobility and perceived health in geriatric
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 25 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
patients performing a multimodal training intervention: a randomized
controlled trial. BMC Geriatr. 2019;19:167. https:// doi. org/ 10. 1186/
s12877- 019- 1184-1.
73. Bayer U, Likar R, Pinter G, Stettner H, Demschar S, Trummer B, Neuw-
ersch S, Glazachev O, Burtscher M. Intermittent hypoxic–hyperoxic
training on cognitive performance in geriatric patients. Alzheimers
Dement (N Y). 2017;3:114–22. https:// doi. org/ 10. 1016/j. trci. 2017. 01. 002.
74. Glazachev OS, Susta D, Dudnik E, Zagaynaya E. Intermittent hypoxia–
hyperoxia exposures improve cardiometabolic profile, exercise toler-
ance and quality of life: a preliminary study in cardiac patients. Ind J
Publ Health Res Dev. 2018;9:208. https:// doi. org/ 10. 5958/ 0976- 5506.
2018. 00039.6.
75. Downs SH, Black N. The feasibility of creating a checklist for the
assessment of the methodological quality both of randomised and
non-randomised studies of health care interventions. J Epidemiol Com-
munity Health. 1997;52:377–84.
76. Serebrovska TV, Serebrovska ZO, Egorov E. Fitness and therapeutic
potential of intermittent hypoxia training: a matter of dose. Fiziol Zh.
2016;62:78–91.
77. Soo J, Girard O, Ihsan M, Fairchild T. The use of the SpO2 to FiO2 ratio to
individualize the hypoxic doxe in sport science, exercise, and health set-
tings. Front Physiol. 2020. https:// doi. org/ 10. 3389/ fphys. 2020. 570472.
78. Davies T, Orr R, Halaki M, Hackett D. Effect of training leading to
repetition failure on muscular strength: a systematic review and
meta-analysis. Sports Med. 2016;46:487–502. https:// doi. org/ 10. 1007/
s40279- 015- 0451-3.
79. Glazachev OS, Zvenigorodskaia LA, Dudnik EN, Iartseva LA, Mishchen-
kova TV, Platonenko AV, Spirina GK. Interval hypoxic–hyperoxic training
in the treatment of the metabolic syndrome. Eksp Klin Gastroenterol.
2010;7:51–6.
80. Syrkin AL, Glazachev OS, Kopylov FY, Dudnik EN, Zagaynaya EE, Tuter
DS. Adaptation to intermittent hypoxia–hyperoxia in the rehabilitation
of patients with ischemic heart disease: exercise tolerance and quality
of life. Kardiologiia. 2017;57:10–6.
81. Tuter DS, Komarov RN, Glazachev OS, Syrkin AL, Severova LP, Ivanova EV,
Kopylov FY. Application of intervalic hypoxic–hyperoxic entrainment to
prevention of intraand early postoperational complications in coronary
bypass grafting. Russ J Cardiol. 2018;23:166–72. https:// doi. org/ 10.
15829/ 1560- 4071- 2018-6- 166- 172.
82. Glazachev OS, Pozdnyakov YM, Urinskyi AM, Zabashta SP. Hypoxia–
hyperoxia adaptation and increased exercise capacity in patients with
coronary heart disease. Cardiovasc Ther Prev (Russ Fed). 2014;13:16–21.
https:// doi. org/ 10. 15829/ 1728- 8800- 2014-1- 16- 21.
83. Sazontova TG, Glazachev OS, Bolotova AV, Dudnik EN, Striapko NV,
Bedareva IV, Anchishkina NA, Arkhipenko IV. Adaptation to hypoxia
and hyperoxia improves physical endurance: the role of reactive
oxygen species and redox-signaling. Ross Fiziol Zh Im I M Sechenova.
2012;98:793–807.
84. Sazontova TG, Stryapko NV, Arkhipenko YV. Addition of hyperoxic
component to adaptation to hypoxia prevents impairments induced
by low doses of toxicants (free radical oxidation and proteins of HSP
family). Bull Exp Biol Med. 2016;160:304–7. https:// doi. org/ 10. 1007/
s10517- 016- 3157-0.
85. Zhang X, Li J, Sejas DP, Pang Q. Hypoxia–reoxygenation induces
premature senescence in FA bone marrow hematopoietic cells. Blood.
2005;106:75–85. https:// doi. org/ 10. 1182/ blood- 2004- 08- 3033.
86. Barratt SL, Blythe T, Ourradi K, Jarrett C, Welsh GI, Bates DO, Millar AB.
Effects of hypoxia and hyperoxia on the differential expression of VEGF-
A isoforms and receptors in idiopathic pulmonary fibrosis (IPF). Respir
Res. 2018;19:9. https:// doi. org/ 10. 1186/ s12931- 017- 0711-x.
87. Debevec T, Keramidas ME, Norman B, Gustafsson T, Eiken O, Mekjavic IB.
Acute short-term hyperoxia followed by mild hypoxia does not increase
EPO production: resolving the “normobaric oxygen paradox.” Eur J Appl
Physiol. 2012;112:1059–65. https:// doi. org/ 10. 1007/ s00421- 011- 2060-7.
88. Tuter DS, Kopylov PY, Syrkin AL, Glazachev OS, Komarov RN, Katkov
AI, Severova LP, Ivanova EV, Zhang Y, Saner H. Intermittent systemic
hypoxic–hyperoxic training for myocardial protection in patients under-
going coronary artery bypass surgery : first results from a single-centre,
randomised controlled trial. Open Heart. 2018;5:e000891. https:// doi.
org/ 10. 1136/ openh rt- 2018- 000891.
89. Thomson AJ, Drummond GB, Waring WS, Webb DJ, Maxwell SR. Effects
of short-term isocapnic hyperoxia and hypoxia on cardiovascular
function. J Appl Physiol. 2006;101:809–16. https:// doi. org/ 10. 1152/ jappl
physi ol. 01185. 2005.
90. Young P, Bailey M, Bellomo R, Bernard S, Dicker B, Freebairn R,
Henderson S, Mackle D, McArthur C, McGuinness S, Smith T, Swain A,
Weatherall M, Beasley R. HyperOxic therapy or normoxic therapy after
out-of-hospital cardiac arrest (HOT OR NOT): a randomised controlled
feasibility trial. Resuscitation. 2014;85:1686–91. https:// doi. org/ 10.
1016/j. resus citat ion. 2014. 09. 011.
91. Xu F, Liu P, Pascual JM, Xiao G, Lu H. Effect of hypoxia and hyperoxia on
cerebral blood flow, blood oxygenation, and oxidative metabolism. J
Cereb Blood Flow Metab. 2012;32:1909–18. https:// doi. org/ 10. 1038/
jcbfm. 2012. 93.
92. Hermand E, Pichon A, Lhuissier F, Richalet J-P. Oscillatory pattern of
breathing in healthy humans at exercise: effects of hypoxia, hyperoxia
and hypercapnia. FASEB J. 2015;29:1012–8.
93. Hermand E, Lhuissier FJ, Pichon A, Voituron N, Richalet J-P. Exercising in
hypoxia and other stimuli: heart rate variability and ventilatory oscilla-
tions. Life (Basel). 2021. https:// doi. org/ 10. 3390/ life1 10706 25.
94. Hadanny A, Efrati S. The hyperoxic–hypoxic paradox. Biomolecules.
2020. https:// doi. org/ 10. 3390/ biom1 00609 58.
95. Aisenpreis PM. The improvement of the parasympathetic response and
the O2 intake at rest of stress-exposed patients through a HRV con-
trolled application of intermittent hypoxia/hyperoxia therapy (IHHT): a
pilot study out of therapeutic practice. Appl Psychophysiol Biofeed-
back. 2018;43:93.
96. Di Giulio C. Carotid Body as a model for aging studies: the hypoxia–
hyperoxia aging interaction. Acta Physiol. 2019;227:185.
97. Di Marco P, Priori A, Finoia MG, Petochi T, Marino G, Lemarie G, Alexis
M, Alberti A, Macciantelli D. Plasma total oxidant/antioxidant status in
Dicentrarchus labrax after exposure to experimental hypoxia, hyper-
oxia and hypercapnia. Comp Biochem Physiol A Mol Integr Physiol.
2008;151:S15. https:// doi. org/ 10. 1016/j. cbpa. 2008. 05. 030.
98. Khan M, Basye A, Chen C-A, Angelos M. Intermittent hypoxic/
hyperoxic cycling improves survival of human inducible pluripotent-
derived cardiomyocytes subjected to prolonged hypoxia. Circulation.
2014;130:A168.
99. Yu S-H, Chen P-W. Effects of systemic hypoxia–hyperoxia precondition-
ing on acute heavy resistance exercise-induced muscle damage in
athletes. Med Sci Sports Exerc. 2019;51:403. https:// doi. org/ 10. 1249/ 01.
mss. 00005 61707. 11042. 08.
100. Zhang H, Han B, DeLisser HM. The role of TGF beta in hyperoxia/
hypoxia-induced delay in alveolarization and endothelial dysfunction.
Am J Respir Crit Care Med. 2009;179:A3277.
101. Glazachev OS, Mischenkova T, Dudnik H, Zvenigorodskaya L, Pla-
tonenko A, Spirina G. The effect of hypoxic–hyperoxic preconditioning
on cardiometabolic risk-factors and gut hormones in patients with the
metabolic syndrome. Obes Facts. 2012;5:229. https:// doi. org/ 10. 1159/
00025 8190.
102. Glazachev OS, Urinskiy A, Pozdnyakov Y, Dudnik E. Interval normobaric
hypoxic–hyperoxic training increases exercise tolerance in patients
with coronary artery disease. Eur J Prev Cardiol. 2013;20:S109. https://
doi. org/ 10. 1177/ 20474 87314 530052.
103. Glazachev OS, Dudnik E, Zagaynaya E, Susta D. Intermittent
hypoxia–hyperoxia training is as effective as a standard rehabilita-
tion programme in improving cardiorespiratory fitness in comorbid
cardiac outpatients: a randomised controlled trial. Eur J Prev Cardiol.
2018;25:S42.
104. Glazachev OS, Kopylov F, Zagaynaya E, Dudnik E. Adaptation to interval
hypoxia–hyperoxia improves exercise tolerance and cardiometabolic
profile in patients with coronary artery diseases. Eur J Prev Cardiol.
2015;22:S126. https:// doi. org/ 10. 1177/ 20474 87315 586744.
105. Susta D, Zagaynaya E, Glazachev OS. Intermittent hypoxia–hyperoxia
training is effective in improving cardiopulmonary fitness in FC II–III
CAD patients: a randomised controlled trial. Eur J Cardiovasc Nurs.
2017;16:S12. https:// doi. org/ 10. 1177/ 14745 15117 700580.
106. Bayer U, Glazachev OS, Likar R, Burtscher M, Kofler W, Pinter G, Stettner
H, Demschar S, Trummer B, Neuwersch S. Adaptation to intermittent
hypoxia–hyperoxia improves cognitive performance and exercise
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 26 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
tolerance in the elderly. Adv Gerontol. 2017;7:214–20. https:// doi. org/
10. 1134/ S2079 05701 70300 31.
107. Glazachev OS, Kopylov P, Susta D, Dudnik E, Zagaynaya E. Adaptations
following an intermittent hypoxia–hyperoxia training in coronary artery
disease patients: a controlled study. Clin Cardiol. 2017;40:370–6. https://
doi. org/ 10. 1002/ clc. 22670.
108. Susta D, Dudnik E, Glazachev OS. A programme based on repeated
hypoxia–hyperoxia exposure and light exercise enhances performance
in athletes with overtraining syndrome: a pilot study. Clin Physiol Funct
Imaging. 2017;37:276–81. https:// doi. org/ 10. 1111/ cpf. 12296.
109. Dudnik E, Zagaynaya E, Glazachev OS, Susta D. Intermittent hypoxia–
hyperoxia conditioning improves cardiorespiratory fitness in older
comorbid cardiac outpatients without hematological changes: a
randomized controlled trial. High Alt Med Biol. 2018;19:339–43. https://
doi. org/ 10. 1089/ ham. 2018. 0014.
110. Glazachev OS, Dudnik EN, Zapara MA, Samarceva VG, Kofler WW. Adap-
tation to dosed hypoxia–hyperoxia as a factor in the improvement of
quality of life for elderly patients with cardiac pathology. Adv Gerontol.
2019;9:453–8. https:// doi. org/ 10. 1134/ S2079 05701 90400 52.
111. Serebrovska ZO, Serebrovska TV, Kholin VA, Tumanovska LV, Shysh AM,
Pashevin DA, Goncharov SV, Stroy D, Grib ON, Shatylo VB, Bachinskaya
NY, Egorov E, Xi L, Dosenko VE. Intermittent hypoxia–hyperoxia training
improves cognitive function and decreases circulating biomarkers of
Alzheimer’s disease in patients with mild cognitive impairment: a pilot
study. Int J Mol Sci. 2019. https:// doi. org/ 10. 3390/ ijms2 02154 05.
112. Bestavashvili AA, Glazachev OS, Bestavashvili AA, Ines D, Suvorov AY,
Vorontsov NV, Tuter DS, Gognieva DG, Yong Z, Pavlov CS, Glushenkov
DV, Sirkina EA, Kaloshina IV, Kopylov PY. The effects of intermittent
hypoxic–hyperoxic exposures on lipid profile and inflammation in
patients with metabolic syndrome. Front Cardiovasc Med. 2021. https://
doi. org/ 10. 3389/ fcvm. 2021. 700826.
113. Gore CJ, Clark SA, Saunders PU. Nonhematological mechanisms of
improved sea-level performance after hypoxic exposure. Med Sci
Sports Exerc. 2007;39:1600–9. https:// doi. org/ 10. 1249/ mss. 0b013 e3180
de49d3.
114. Pramsohler S, Burtscher M, Faulhaber M, Gatterer H, Rausch L, Eliasson
A, Netzer NC. Endurance training in normobaric hypoxia imposes less
physical stress for geriatric rehabilitation. Front Physiol. 2017;8:514.
https:// doi. org/ 10. 3389/ fphys. 2017. 00514.
115. Myers J, Prakash M, Froelicher V, Do D, Par tington S, Atwood JE. Exercise
capacity and mortality among men referred for exercise testing. N Engl
J Med. 2002;346:793–801. https:// doi. org/ 10. 1056/ NEJMo a0118 58.
116. Swank AM, Horton J, Fleg JL, Fonarow GC, Keteyian S, Goldberg L,
Wolfel G, Handberg EM, Bensimhon D, Illiou M-C, Vest M, Ewald G,
Blackburn G, Leifer E, Cooper L, Kraus WE. Modest increase in peak VO2
is related to better clinical outcomes in chronic heart failure patients:
results from heart failure and a controlled trial to investigate outcomes
of exercise training. Circ Heart Fail. 2012;5:579–85. https:// doi. org/ 10.
1161/ CIRCH EARTF AILURE. 111. 965186.
117. Fu T-C, Yang N-I, Wang C-H, Cherng W-J, Chou S-L, Pan T-L, Wang J-S.
Aerobic interval training elicits different hemodynamic adaptations
between heart failure patients with preserved and reduced ejection
fraction. Am J Phys Med Rehabil. 2016;95:15–27. https:// doi. org/ 10.
1097/ PHM. 00000 00000 000312.
118. Carbone S, Kim Y, Kachur S, Billingsley H, Kenyon J, de Schutter A,
Milani RV, Lavie CJ. Peak oxygen consumption achieved at the end
of cardiac rehabilitation predicts long-term survival in patients with
coronary heart disease. Eur Heart J Qual Care Clin Outcomes. 2021.
https:// doi. org/ 10. 1093/ ehjqc co/ qcab0 32.
119. Manukhina EB, Downey HF, Shi X, Mallet RT. Intermittent hypoxia
training protects cerebrovascular function in Alzheimer’s disease. Exp
Biol Med (Maywood). 2016;241:1351–63. https:// doi. org/ 10. 1177/
15353 70216 649060.
120. Iyalomhe O, Swierczek S, Enwerem N, Chen Y, Adedeji MO, Allard
J, Ntekim O, Johnson S, Hughes K, Kurian P, Obisesan TO. The
role of hypoxia-inducible factor 1 in mild cognitive impairment.
Cell Mol Neurobiol. 2017;37:969–77. https:// doi. org/ 10. 1007/
s10571- 016- 0440-6.
121. Mashina SY, Aleksandrin VV, Goryacheva AV, Vlasova MA, Vanin
AF, Malyshev IY, Manukhina EB. Adaptation to hypoxia prevents
disturbances in cerebral blood flow during neurodegenerative
process. Bull Exp Biol Med. 2006;142:169–72. https:// doi. org/ 10. 1007/
s10517- 006- 0318-6.
122. Ambrose CT. A therapeutic approach for senile dementias: neuroan-
giogenesis. J Alzheimers Dis. 2015;43:1–17. https:// doi. org/ 10. 3233/
JAD- 140498.
123. Pichiule P, LaManna JC. Angiopoietin-2 and rat brain capillary remod-
eling during adaptation and deadaptation to prolonged mild hypoxia.
J Appl Physiol. 2002;93:1131–9. https:// doi. org/ 10. 1152/ jappl physi ol.
00318. 2002.
124. Bailey DM, Bruce D, Baker J. Training in hypoxia: modulation of
metabolic and cardiovascular risk factors in men. Med Sci Sports Exerc.
2000;32:1058–66.
125. Bailey DP, Smith LR, Chrismas BC, Taylor L, Stensel DJ, Deighton K,
Douglas JA, Kerr CJ. Appetite and gut hormone responses to moderate-
intensity continuous exercise versus high-intensity interval exercise, in
normoxic and hypoxic conditions. Appetite. 2015;89:237–45. https://
doi. org/ 10. 1016/j. appet. 2015. 02. 019.
126. Meng R, Zhu D, Bi Y, Yang D, Wang Y. Erythropoietin inhibits gluconeo-
genesis and inflammation in the liver and improves glucose intolerance
in high-fat diet-fed mice. PLoS ONE. 2013;8:e53557. https:// doi. org/ 10.
1371/ journ al. pone. 00535 57.
127. Sifringer M, Genz K, Brait D, Brehmer F, Löber R, Weichelt U, Kaindl AM,
Gerstner B, Felderhoff-Mueser U. Erythropoietin attenuates hyperoxia-
induced cell death by modulation of inflammatory mediators and
matrix metalloproteinases. Dev Neurosci. 2009;31:394–402. https:// doi.
org/ 10. 1159/ 00023 2557.
128. Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA,
Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA, Maly-
shev IY. Prevention of neurodegenerative damage to the brain in
rats in experimental Alzheimer’s disease by adaptation to hypoxia.
Neurosci Behav Physiol. 2010;40:737–43. https:// doi. org/ 10. 1007/
s11055- 010- 9320-6.
129. Paltsyn AA, Manukhina EB, Goryacheva AV, Downey HF, Dubrovin IP,
Komissarova SV, Kubatiev AA. Intermittent hypoxia stimulates formation
of binuclear neurons in brain cortex—A role of cell fusion in neuropro-
tection? Exp Biol Med (Maywood). 2014;239:595–600. https:// doi. org/
10. 1177/ 15353 70214 523898.
130. Zhu X-H, Yan H-C, Zhang J, Qu H-D, Qiu X-S, Chen L, Li S-J, Cao X,
Bean JC, Chen L-H, Qin X-H, Liu J-H, Bai X-C, Mei L, Gao T-M. Intermit-
tent hypoxia promotes hippocampal neurogenesis and produces
antidepressant-like effects in adult rats. J Neurosci. 2010;30:12653–63.
https:// doi. org/ 10. 1523/ JNEUR OSCI. 6414- 09. 2010.
131. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health
and inflammation. Nat Rev Immunol. 2013;13:159–75. https:// doi. org/
10. 1038/ nri33 99.
132. Dong Y, Lagarde J, Xicota L, Corne H, Chantran Y, Chaigneau T, Crestani
B, Bottlaender M, Potier M-C, Aucouturier P, Dorothée G, Sarazin M,
Elbim C. Neutrophil hyperactivation correlates with Alzheimer’s disease
progression. Ann Neurol. 2018;83:387–405. https:// doi. org/ 10. 1002/ ana.
25159.
133. Kretzschmar GC, Bumiller-Bini V, Gasparetto Filho MA, Zonta YR, Yu KST,
de Souza RLR, Dias-Melicio LA, Boldt ABW. Neutrophil extracellular
traps: a perspective of neuroinflammation and complement activation
in Alzheimer’s disease. Front Mol Biosci. 2021;8:630869. https:// doi. org/
10. 3389/ fmolb. 2021. 630869.
134. Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui
S, Turano E, Rossi B, Angiari S, Dusi S, Montresor A, Carlucci T, Nanì S,
Tosadori G, Calciano L, Catalucci D, Berton G, Bonetti B, Constantin G.
Neutrophils promote Alzheimer’s disease-like pathology and cognitive
decline via LFA-1 integrin. Nat Med. 2015;21:880–6. https:// doi. org/ 10.
1038/ nm. 3913.
135. Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alz-
heimer’s disease: from synapses toward neural networks. Nat Neurosci.
2010;13:812–8. https:// doi. org/ 10. 1038/ nn. 2583.
136. Herold F, Müller P, Gronwald T, Müller NG. Dose–response matters!—A
perspective on the exercise prescription in exercise-cognition research.
Front Psychol. 2019;10:2338. https:// doi. org/ 10. 3389/ fpsyg. 2019. 02338.
137. Stillman CM, Cohen J, Lehman ME, Erickson KI. Mediators of physical
activity on neurocognitive function: a review at multiple levels of analy-
sis. Front Hum Neurosci. 2016;10:626. https:// doi. org/ 10. 3389/ fnhum.
2016. 00626.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 27 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
138. Shatilo VB, Korkushko OV, Ischuk VA, Downey HF, Serebrovskaya TV.
Effects of intermittent hypoxia training on exercise performance,
hemodynamics, and ventilation in healthy senior men. High Alt Med
Biol. 2008;9:43–52. https:// doi. org/ 10. 1089/ ham. 2007. 1053.
139. Płoszczyca K, Langfort J, Czuba M. The effects of altitude training on
erythropoietic response and hematological variables in adult athletes:
a narrative review. Front Physiol. 2018;9:375. https:// doi. org/ 10. 3389/
fphys. 2018. 00375.
140. Gore CJ, Sharpe K, Gar vican-Lewis LA, Saunders PU, Humberstone
CE, Robertson EY, Wachsmuth NB, Clark SA, McLean BD, Friedmann-
Bette B, Neya M, Pottgiesser T, Schumacher YO, Schmidt WF. Altitude
training and haemoglobin mass from the optimised carbon monoxide
rebreathing method determined by a meta-analysis. Br J Sports Med.
2013;47(Suppl 1):i31–9. https:// doi. org/ 10. 1136/ bjspo rts- 2013- 092840.
141. Rusko HK, Tikkanen HO, Peltonen JE. Altitude and endurance training. J
Sports Sci. 2004;22:928–44. https:// doi. org/ 10. 1080/ 02640 41040 00059
33.
142. Wilber RL, Stray-Gundersen J, Levine BD. Effect of hypoxic “dose” on
physiological responses and sea-level performance. Med Sci Sports
Exerc. 2007;39:1590–9. https:// doi. org/ 10. 1249/ mss. 0b013 e3180
de49bd.
143. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS,
Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R,
Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N,
Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L,
Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/
AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood
cholesterol: executive summary. J Am Coll Cardiol. 2019;73:3168–209.
https:// doi. org/ 10. 1016/j. jacc. 2018. 11. 002.
144. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M,
Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F,
Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent
S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE,
Shlyakhto E, Tsioufis C, Aboyans V, Desormais I. 2018 ESC/ESH guide-
lines for the management of arterial hypertension: the task force for
the management of arterial hypertension of the European Society of
Cardiology and the European Society of Hypertension: The Task Force
for the management of arterial hypertension of the European Society
of Cardiology and the European Society of Hypertension. J Hypertens.
2018;36:1953–2041. https:// doi. org/ 10. 1097/ HJH. 00000 00000 001940.
145. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M,
Christiaens T, Cifkova R, de Backer G, Dominiczak A, Galderisi M, Grob-
bee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson
PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber
B, Zannad F, Burnier M, Ambrosioni E, Caufield M, Coca A, Olsen MH,
Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H,
Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Ferrari R, Hasdai D, Hoes AW,
Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF,
Ponikowski P, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker
S, Clement DL, Gillebert TC, Rosei EA, Anker SD, Bauersachs J, Hitij JB,
Caulfield M, de Buyzere M, de Geest S, Derumeaux GA, Erdine S, Farsang
C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Jordan
J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Ostergren J, Parati G,
Perk J, Polonia J, Popescu BA, Reiner Z, Rydén L, Sirenko Y, Stanton A,
Struijker-Boudier H, Vlachopoulos C, Volpe M, Wood DA. 2013 ESH/ESC
guidelines for the management of arterial hypertension: the Task Force
for the Management of Arterial Hypertension of the European Society
of Hypertension (ESH) and of the European Society of Cardiology (ESC).
Eur Heart J. 2013;34:2159–219. https:// doi. org/ 10. 1093/ eurhe artj/
eht151.
146. Debevec T. Hypoxia-related hormonal appetite modulation in humans
during rest and exercise: mini review. Front Physiol. 2017;8:366. https://
doi. org/ 10. 3389/ fphys. 2017. 00366.
147. O’Hagan KA, Cocchiglia S, Zhdanov AV, Tambuwala MM, Tambawala
MM, Cummins EP, Monfared M, Agbor TA, Garvey JF, Papkovsky DB,
Taylor CT, Allan BB. PGC-1alpha is coupled to HIF-1alpha-dependent
gene expression by increasing mitochondrial oxygen consumption in
skeletal muscle cells. Proc Natl Acad Sci USA. 2009;106:2188–93. https://
doi. org/ 10. 1073/ pnas. 08088 01106.
148. Zoll J, Ponsot E, Dufour S, Doutreleau S, Ventura-Clapier R, Vogt M,
Hoppeler H, Richard R, Flück M. Exercise training in normobaric hypoxia
in endurance runners. III. Muscular adjustments of selected gene tran-
scripts. J Appl Physiol. 2006;100:1258–66. https:// doi. org/ 10. 1152/ jappl
physi ol. 00359. 2005.
149. Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism.
Adv Physiol Educ. 2006;30:145–51. https:// doi. org/ 10. 1152/ advan.
00052. 2006.
150. Wiesner S, Haufe S, Engeli S, Mutschler H, Haas U, Luft FC, Jordan J. Influ-
ences of normobaric hypoxia training on physical fitness and metabolic
risk markers in overweight to obese subjects. Obesity (Silver Spring).
2010;18:116–20. https:// doi. org/ 10. 1038/ oby. 2009. 193.
151. Haufe S, Wiesner S, Engeli S, Luft FC, Jordan J. Influences of normobaric
hypoxia training on metabolic risk markers in human subjects. Med
Sci Sports Exerc. 2008;40:1939–44. https:// doi. org/ 10. 1249/ MSS. 0b013
e3181 7f1988.
152. Gatterer H, Haacke S, Burtscher M, Faulhaber M, Melmer A, Ebenbichler
C, Strohl KP, Högel J, Netzer NC. Normobaric intermittent hypoxia over 8
months does not reduce body weight and metabolic risk factors–a ran-
domized, single blind, placebo-controlled study in normobaric hypoxia
and normobaric sham hypoxia. Obes Facts. 2015;8:200–9. https:// doi.
org/ 10. 1159/ 00043 1157.
153. van Meijel RLJ, Vogel MAA, Jocken JWE, Vliex LMM, Smeets JSJ, Hoebers
N, Hoeks J, Essers Y, Schoffelen PFM, Sell H, Kersten S, Rouschop KMA,
Blaak EE, Goossens GH. Mild intermittent hypoxia exposure induces
metabolic and molecular adaptations in men with obesity. Mol Metab.
2021;53:101. https:// doi. org/ 10. 1016/j. molmet. 2021. 101287.
154. Lee J-W, Bae S-H, Jeong J-W, Kim S-H, Kim K-W. Hypoxia-inducible factor
(HIF-1)alpha: its protein stability and biological functions. Exp Mol Med.
2004;36:1–12. https:// doi. org/ 10. 1038/ emm. 2004.1.
155. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1
mRNA by hypoxia-inducible factor-1. Interaction between H-ras and
hypoxia. J Biol Chem. 2001;276:9519–25. https:// doi. org/ 10. 1074/ jbc.
M0101 44200.
156. Kim S-W, Jung W-S, Chung S, Park H-Y. Exercise intervention under
hypoxic condition as a new therapeutic paradigm for type 2 diabetes
mellitus: a narrative review. World J Diabetes. 2021;12:331–43. https://
doi. org/ 10. 4239/ wjd. v12. i4. 331.
157. Mills K T, Stefanescu A, He J. The global epidemiology of hyperten-
sion. Nat Rev Nephrol. 2020;16:223–37. https:// doi. org/ 10. 1038/
s41581- 019- 0244-2.
158. Burnier M, Egan BM. Adherence in hypertension. Circ Res.
2019;124:1124–40. https:// doi. org/ 10. 1161/ CIRCR ESAHA. 118. 313220.
159. Serebrovskaya TV, Manukhina EB, Smith ML, Downey HF, Mallet RT.
Intermittent hypoxia: Cause of or therapy for systemic hypertension?
Exp Biol Med (Maywood). 2008;233:627–50. https:// doi. org/ 10. 3181/
0710- MR- 267.
160. Paniagua OA, Bryant MB, Panza JA. Role of endothelial nitric oxide
in shear stress-induced vasodilation of human microvasculature:
diminished activity in hypertensive and hypercholesterolemic patients.
Circulation. 2001;103:1752–8. https:// doi. org/ 10. 1161/ 01. CIR. 103. 13.
1752.
161. Vedam H, Phillips CL, Wang D, Barnes DJ, Hedner JA, Unger G, Grun-
stein RR. Short-term hypoxia reduces arterial stiffness in healthy
men. Eur J Appl Physiol. 2009;105:19–25. https:// doi. org/ 10. 1007/
s00421- 008- 0868-6.
162. Hu R, Dai A, Tan S. Hypoxia-inducible factor 1 alpha upregulates the
expression of inducible nitric oxide synthase gene in pulmonary arter-
ies of hyposic rat. Chin Med J (Engl). 2002;115:1833–7.
163. Muangritdech N, Hamlin MJ, Sawanyawisuth K, Prajumwongs P, Saeng-
jan W, Wonnabussapawich P, Manimmanakorn N, Manimmanakorn A.
Hypoxic training improves blood pressure, nitric oxide and hypoxia-
inducible factor-1 alpha in hypertensive patients. Eur J Appl Physiol.
2020. https:// doi. org/ 10. 1007/ s00421- 020- 04410-9.
164. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J,
Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for preven-
tion of cardiovascular disease and death: a systematic review and
meta-analysis. Lancet. 2016;387:957–67. https:// doi. org/ 10. 1016/ S0140-
6736(15) 01225-8.
165. Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease.
Hypertension. 2020;75:285–92. https:// doi. org/ 10. 1161/ HYPER TENSI
ONAHA. 119. 14240.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 28 of 28
Behrendtetal. Sports Medicine - Open (2022) 8:70
166. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies
Collaboration. Age-specific relevance of usual blood pressure to vascu-
lar mortality: a meta-analysis of individual data for one million adults in
61 prospective studies. Lancet. 2002;360:1903–13. https:// doi. org/ 10.
1016/ S0140- 6736(02) 11911-8.
167. Manimmanakorn AHMJ. Live high-train low altitude training: respond-
ers and non-responders. J Athl Enhancement. 2015. https:// doi. org/ 10.
4172/ 2324- 9080. 10001 93.
168. Costello JT, Bhogal AS, Williams TB, Bekoe R, Sabir A, Tipton MJ, Corbett
J, Mani AR. Effects of normobaric hypoxia on oxygen saturation vari-
ability. High Alt Med Biol. 2020;21:76–83. https:// doi. org/ 10. 1089/ ham.
2019. 0092.
169. Törpel A, Peter B, Hamacher D, Schega L. Dose-response relationship
of intermittent normobaric hypoxia to stimulate erythropoietin in the
context of health promotion in young and old people. Eur J Appl Phys-
iol. 2019;119:1065–74. https:// doi. org/ 10. 1007/ s00421- 019- 04096-8.
170. Glazachev OS. Optimization of clinical application of interval hypoxic
training. Biomed Eng. 2013;47:21–4.
171. Dean JB, Mulkey DK, Henderson RA, Potter SJ, Putnam RW. Hyperoxia,
reactive oxygen species, and hyperventilation: oxygen sensitivity of
brain stem neurons. J Appl Physiol. 2004;96:784–91. https:// doi. org/ 10.
1152/ jappl physi ol. 00892. 2003.
172. Jones SR, Carley S, Harrison M. An introduction to power and sample
size estimation. Emerg Med J. 2003;20:453–8. https:// doi. org/ 10. 1136/
emj. 20.5. 453.
173. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ,
Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elab-
oration: updated guidelines for reporting parallel group randomised
trials. BMJ. 2010;340:c869. https:// doi. org/ 10. 1136/ bmj. c869.
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Purpose Main purposes of pre-acclimatization by hypoxia conditioning (HC) are the prevention of high-altitude illnesses and maintenance of aerobic exercise performance. However, robust evidence for those effects or evidence-based guidelines for exposure strategies, including recommendations to ensure safety, are largely lacking. Therefore, we summarize the current knowledge on the physiology of acclimatization to hypoxia and HC with the aim to derive implications for pre-acclimatization strategies before going on high-altitude treks and expeditions. Methods Based on the literature search and personal experience, core studies and important observations have been selected in order to present a balanced view on the current knowledge of high-altitude illnesses and the acclimatization process, specifically focusing on pre-acclimatization strategies by HC. Results and Conclusions It may be concluded that in certain cases even short periods (e.g., 7 h) of pre-acclimatization by HC are effective, but longer periods (e.g., > 60 h) are needed to elicit more robust effects. About 300 h of HC (intermittently applied) may be the optimal preparation for extreme altitude sojourns, although every additional hour spent in hypoxia may confer further benefits. The inclusion of hypobaric exposures (i.e., real altitude) in pre-acclimatization protocols could further increase their efficacy. The level of simulated altitude is progressively increased or individually adjusted ideally. HC should not be terminated earlier than 1–2 weeks before altitude sojourn. Medical monitoring of the pre-acclimatization program is strongly recommended.
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Background: Patients with metabolic syndrome (MS) tend to suffer from comorbidities, and are often simultaneously affected by obesity, dysglycemia, hypertension, and dyslipidemia. This syndrome can be reversed if it is timely diagnosed and treated with a combination of risk factors-reducing lifestyle changes and a tailored pharmacological plan. Interval hypoxic-hyperoxic training (IHHT) has been shown as an effective program in reducing cardiovascular risk factors in patients with MS even in the absence of exercise. However, the influence of IHHT on the lipid profile and inflammation in this clinical population remains relatively unknown. Methods: A prospective, single-center, randomized controlled trial was conducted on 65 (33 men) patients with MS aged 29–74 years, who were randomly allocated to the IHHT or control (sham) experimental groups. The IHHT group completed a 3-week, 5 days/week intermittent exposure to hypoxia and hyperoxia. The control (sham) group followed the same protocol but was breathing room air instead. The primary endpoints were the lipid profile (concentrations of total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TG]) and the inflammatory factors such as high-sensitivity C-reactive protein (hs-CRP), galectin-3, heat shock proteins (Hsp70). The secondary endpoints were alanine aminotransferase (ALT), aspartate aminotransferase (AST), N-terminal pro-hormone of brain natriuretic peptide level (NTproBNP), transforming growth factor beta-1 (TGF-beta1), heart-type fatty acid-binding protein (H-FABP), and nitric oxide synthase 2 (NOS2). Results: There were no differences between the two groups but the different baseline values have affected these results. The IHHT group demonstrated pre-post decrease in total cholesterol ( p = 0.001), LDL ( p = 0.001), and TG levels ( p = 0.001). We have also found a decrease in the CRP-hs ( p = 0.015) and Hsp70 ( p = 0.006) in IHHT-group after intervention, and a significant decrease in pre-post (delta) differences of NTproBNP ( p < 0.0001) in the IHHT group compared to the control group. In addition, the patients of the IHHT group showed a statistically significant decrease in pre-post differences of ALT and AST levels in comparison with the control group ( p = 0.001). No significant IHHT complications or serious adverse events were observed. Conclusions: The IHHT appears to improve lipid profile and anti-inflammatory status. It is a safe, well-tolerated procedure, and could be recommended as an auxiliary treatment in patients suffering from MS, however, the experiment results were limited by the baseline group differences. Clinical Trial Registration: ClinicalTrials.gov , identifier [NCT04791397]. Evaluation of the effect of IHHT on vascular stiffness and elasticity of the liver tissue in patients with MS.
Article
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Background: Literature searches underlie the foundations of systematic reviews and related review types. Yet, the literature searching component of systematic reviews and related review types is often poorly reported. Guidance for literature search reporting has been diverse and, in many cases, does not offer enough detail to authors who need more specific information about reporting search methods and information sources in a clear, reproducible way. This document presents the PRISMA-S (Preferred Reporting Items for Systematic reviews and Meta-Analyses literature search extension) checklist, and explanation and elaboration. Methods: The checklist was developed using a three-stage Delphi survey process, followed by a consensus conference and public review process. Results: The final checklist includes sixteen reporting items, each of which is detailed with exemplar reporting and rationale. Conclusions: The intent of PRISMA-S is to complement the PRISMA Statement and its extensions by providing a checklist that could be used by interdisciplinary authors, editors, and peer reviewers to verify that each component of a search is completely reported and, therefore, reproducible.
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Objective: Recent studies suggest that hypoxia exposure may improve glucose homeostasis, but well-controlled human studies are lacking. We hypothesized that mild intermittent hypoxia (MIH) exposure decreases tissue oxygen partial pressure (pO2) and induces metabolic improvements in people who are overweight/obese. Methods: In a randomized, controlled, single-blind crossover study, 12 men who were overweight/obese were exposed to MIH (15 % O2, 3 × 2 h/day) or normoxia (21 % O2) for 7 consecutive days. Adipose tissue (AT) and skeletal muscle (SM) pO2, fasting/postprandial substrate metabolism, tissue-specific insulin sensitivity, SM oxidative capacity, and AT and SM gene/protein expression were determined. Furthermore, primary human myotubes and adipocytes were exposed to oxygen levels mimicking the hypoxic and normoxic AT and SM microenvironments. Results: MIH decreased systemic oxygen saturation (92.0 ± 0.5 % vs 97.1 ± 0.3, p < 0.001, respectively), AT pO2 (21.0 ± 2.3 vs 36.5 ± 1.5 mmHg, p < 0.001, respectively), and SM pO2 (9.5 ± 2.2 vs 15.4 ± 2.4 mmHg, p = 0.002, respectively) compared to normoxia. In addition, MIH increased glycolytic metabolism compared to normoxia, reflected by enhanced fasting and postprandial carbohydrate oxidation (pAUC = 0.002) and elevated plasma lactate concentrations (pAUC = 0.005). Mechanistically, hypoxia exposure increased insulin-independent glucose uptake compared to standard laboratory conditions (~50 %, p < 0.001) and physiological normoxia (~25 %, p = 0.019) through AMP-activated protein kinase in primary human myotubes but not in primary human adipocytes. MIH upregulated inflammatory/metabolic pathways and downregulated extracellular matrix-related pathways in AT but did not alter systemic inflammatory markers and SM oxidative capacity. MIH exposure did not induce significant alterations in AT (p = 0.120), hepatic (p = 0.132) and SM (p = 0.722) insulin sensitivity. Conclusions: Our findings demonstrate for the first time that 7-day MIH reduces AT and SM pO2, evokes a shift toward glycolytic metabolism, and induces adaptations in AT and SM but does not induce alterations in tissue-specific insulin sensitivity in men who are overweight/obese. Future studies are needed to investigate further whether oxygen signaling is a promising target to mitigate metabolic complications in obesity. Clinical trial registration: This study is registered at the Netherlands Trial Register (NL7120/NTR7325).
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Periodic breathing is a respiratory phenomenon frequently observed in patients with heart failure and in normal subjects sleeping at high altitude. However, until recently, periodic breathing has not been studied in wakefulness and during exercise. This review relates the latest findings describing this ventilatory disorder when a healthy subject is submitted to simultaneous physiological (exercise) and environmental (hypoxia, hyperoxia, hypercapnia) or pharmacological (acetazolamide) stimuli. Preliminary studies have unveiled fundamental physiological mechanisms related to the genesis of periodic breathing characterized by a shorter period than those observed in patients (11~12 vs. 30~60 seconds). A mathematical model of the respiratory system functioning under the aforementioned stressors corroborated these data and pointed out other parameters, such as dead space, later confirmed in further research protocols. Finally, a cardiorespiratory interdependence between ventilatory oscillations and heart rate variability in the low frequency band may partly explain the origin of the augmented sympathetic activation at exercise in hypoxia. These nonlinear instabilities highlight the intrinsic “homeodynamic” system that allows any living organism to adapt, to a certain extent, to permanent environmental and internal perturbations.
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Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer’s disease, or the most common neurodegenerative motor disorder, Parkinson’s disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle–brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle–brain axis in neurodegenerative diseases are outlined.
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Humans living at a higher altitude are less prone to suffer from impaired glucose homeostasis and type 2 diabetes mellitus (T2DM), which might at least partly be explained by lower oxygen availability at higher altitudes. The present systematic review aimed to provide an overview of the current literature on the effects of hypoxia exposure on glucose homeostasis in metabolically compromised humans. Several databases were searched up to August 10 th , 2020. The search strategy identified 368 unique records. Following assessment for eligibility based on the selection criteria, 16 studies were included in this review. Six studies (2 controlled studies; 4 uncontrolled studies) demonstrated beneficial effects of hypoxia exposure on glucose homeostasis, while 10 studies (8 controlled studies; 2 uncontrolled studies) reported no improvement in glucose homeostasis following hypoxia exposure. Notably, passive hypoxia exposure seemed to improve glucose homeostasis, whereas hypoxic exercise training (2–8 weeks) appeared to have no additional/synergistic effects on glucose homeostasis compared to normoxia exposure. Due to the heterogeneity in study populations and intervention duration (acute studies / 2–8 wks training), it is difficult to indicate which factors may explain conflicting study outcomes. Moreover, these results should be interpreted with some caution, as several studies did not include a control group. Taken together, hypoxia exposure under resting and exercise conditions might provide a novel therapeutic strategy to improve glucose homeostasis in metabolically compromised individuals, but more randomized controlled trials are warranted before strong conclusions on the effects of hypoxia exposure on glucose homeostasis can be drawn.
Article
Background Cardiac rehabilitation (CR) improves survival in patients with coronary heart disease (CHD), which is largely mediated by the improvements in cardiorespiratory fitness (CRF) defined as peak oxygen consumption (VO2). Therefore, measuring CRF is essential to predict long-term outcomes in this population. It is unclear, however, whether peak VO2 achieved at the end of CR (END-peak VO2) predicts survival or whether the changes of CRF achieved during CR provide a greater prognostic value. Objectives To determine whether END-peak VO2 independently predicts long-term survival in patients with CHD undergoing CR. We also aimed at identifying cut-offs for END-peak VO2 that could be used in clinical practice. Methods Retrospective analysis of 853 patients with CHD referred to CR who completed a maximal cardiopulmonary exercise test. Survival analysis was performed to examine the risk of all-cause mortality (average follow-up years: 6.65) based on peak VO2. The Contal and O’Quigley’s method was used to determine the optimal cutoff of END-peak VO2 based on the log-rank statistic. Results END-peak VO2 was inversely associated with mortality risk (hazard ratio [HR]=0.84; 95% CI = 0.78-0.90), independent of changes in peak VO2 adjusted for the baseline peak VO2. The estimated cutoff of end-peak VO2 at ≥ 17.6 mL/kg/min best predicted the survival with high predictive accuracy and patients with END-peak VO2 under the cutoff had a greater risk of mortality (HR = 2.93; 95% CI = 1.81–4.74). Conclusions In patient with CHD undergoing CR, END-peak VO2 is an independent predictor for long-term survival. Studies utilizing higher intensity CR programs, with and without pharmacologic strategies, to increase peak VO2 to a greater degree in those achieving a suboptimal END-peak VO2, are urgently needed.
Article
The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable to hypoxia, whether at high altitude or in clinical settings of anemia or pulmonary disease. Hypoxia is pivotal to the pathogeneses of myriad neurological disorders, including Alzheimer’s, Parkinson’s and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e.g. sojourns or residing at high altitudes, may impart favorable effects on aging and mortality. Moreover, controlled hypoxia exposure may represent a treatment strategy for age-related neurological disorders. This review discusses evidence of hypoxia’s beneficial vs. detrimental impacts on the aging brain and the molecular mechanisms that mediate these divergent effects. It draws upon an extensive literature search on the effects of hypoxia/altitude on brain aging, and detailed analysis of all identified studies directly comparing brain responses to hypoxia in young vs. aged humans or rodents. Special attention is directed toward the risks vs. benefits of hypoxia exposure to the elderly, and potential therapeutic applications of hypoxia for neurodegenerative diseases. Finally, important questions for future research are discussed.