Ischemic Preconditioning: The Concept of Endogenous Cardioprotection
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SYSTEMATIC REVIEW
The Effects of Ischemic Preconditioning on Human ExercisePerformance
Anthony V. Incognito1 • Jamie F. Burr1 • Philip J. Millar1
Published online: 8 December 2015
� Springer International Publishing Switzerland 2015
Abstract
Background Ischemic preconditioning (IPC) is the
exposure to brief periods of circulatory occlusion and
reperfusion in order to protect local or systemic organs
against subsequent bouts of ischemia. IPC has also been
proposed as a novel intervention to improve exercise per-
formance in healthy and diseased populations.
Objective The purpose of this systematic review is to
analyze the evidence for IPC improving exercise perfor-
mance in healthy humans.
Methods Data were obtained using a systematic com-
puter-assisted search of four electronic databases (MED-
LINE, PubMed, SPORTDiscus, CINAHL), from January
1985 to October 2015, and relevant reference lists.
Results Twenty-one studies met the inclusion criteria. The
collective data suggest that IPC is a safe intervention that
may be capable of improving time-trial performance.
Available individual data from included studies demon-
strate that IPC improved time-trial performance in 67 % of
participants, with comparable results in athletes and recre-
ationally active populations. The effects of IPC on power
output, oxygen consumption, rating of perceived exertion,
blood lactate accumulation, and cardiorespiratory measures
are unclear. The within-study heterogeneity may suggest
the presence of IPC responders and non-responders, which
in combination with small sample sizes, likely confound
interpretation of mean group data in the literature.
Conclusion The ability of IPC to improve time-trial
performance is promising, but the potential mechanisms
responsible require further investigation. Future work
should be directed toward identifying the individual phe-
notype and protocol that will best exploit IPC-mediated
exercise performance improvements, facilitating its appli-
cation in sport settings.
Key Points
This systematic review examined the effects of
ischemic preconditioning (IPC) on exercise time-
trial performance, power output, and oxygen
consumption in healthy individuals.
Although, large between-study variability exists, the
most consistent benefit of IPC is for an improvement
in time-trial performance in exercise tests of
predominantly lactic anaerobic and aerobic capacity.
Future trials must strive to determine the optimal IPC
and sham-control protocols and to limit the presence
of known confounders.
1 Introduction
Ischemic preconditioning (IPC) is the exposure to brief
periods of circulatory occlusion and reperfusion to protect
local or systemic (remote IPC) organs against subsequent
ischemia-reperfusion injury [1–4]. Since the discovery of this
& Philip J. Millar
1 Department of Human Health and Nutritional Sciences,
University of Guelph, 50 Stone Road East, Guelph, ON
N1G2W1, Canada
123
Sports Med (2016) 46:531–544
DOI 10.1007/s40279-015-0433-5
phenomenon in 1986 [2], research has focused primarily on
the clinical utility of IPC to protect against organ damage and
cellular injury, such as during myocardial infarction or
perioperative periods [5–7]. Although the mechanisms
responsible for these actions are incompletely understood,
IPC has been shown to improve metabolic efficiency by
attenuating ATP depletion [8–10], glycogen depletion [11],
and lactate production [8, 9] during prolonged ischemia. In
addition, IPC may improve skeletal muscle blood flow by
inducing conduit artery vasodilation [12], enhancing func-
tional sympatholysis [13], and preserving endothelial and
microvascular function during stress [1, 14–16]. Based on
these findings, IPC has garnered interest as a novel inter-
vention to improve exercise capacity and performance.
The most common IPC protocol involves three or four
cycles of 5 min circulatory occlusion and reperfusion [2,
17, 18]. As this method is easily administered, non-inva-
sive, and inexpensive, it would represent an attractive
ergogenic aid for athletes to improve exercise performance
and gain a competitive advantage [18–20]. Although the
first proof-of-concept study reported that IPC increased
maximal oxygen consumption (VO2max) and peak power
output in trained cyclists during graded maximal cycling
[17], the benefit of IPC on exercise capacity and perfor-
mance in subsequent studies remains equivocal.
With adherence to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)
guidelines [21, 22], the objective of this systematic review
is to examine the current state of evidence for IPC
improving exercise performance. We investigate both
mean and individual data in order to better capture the
impact of IPC on exercise capacity and performance, and
attempt to elucidate factors delineating responders and
non-responders. In addition, we discuss potential mecha-
nisms responsible for the reported improvements and
conclude with recommendations for future investigations
required for advancing IPC into sport practice.
2 Methods
2.1 Literature Search
Potential studies were identified by two unbiased reviewers
using MEDLINE, PubMed, SPORTDiscus, and CINAHL
databases. Common search terms used to address exercise
performance and IPC were ‘‘sports’’, ‘‘exercise’’, and ‘‘per-
formance’’, and ‘‘ischemic preconditioning’’, ‘‘ischemic
conditioning’’, and ‘‘preconditioning’’, respectively. For both
sets of search terms, relevant predefined database-specific
terms were added to broaden the search. For each database,
the date range was limited to January 1, 1985 (since the first
discovery of IPC was in 1986 [2]) to October 18, 2015. The
language was limited to English. Reference lists of articles
retrieved were manually checked for additional articles.
2.2 Eligibility Criteria for Potential Studies
Primary research studies published in or accepted by peer
reviewed journals were eligible for review. Animal studies,
case studies, study proposals, and review articles were
excluded. No restrictions were placed on participant age or
fitness level. Studies in disease populations were excluded to
yield a more focused review and to avoid confounding
conclusions that may arise from grouping participants with
different health status. IPC interventions were defined as any
procedure that performed multiple cycles of skeletal muscle
blood flow occlusion and reperfusion prior to exercise. These
protocols have been shown to be effective for cytoprotection
from ischemia-reperfusion injury [2]. Occlusion to both
exercising (IPC) and non-exercising (remote IPC) limbs were
included in the analysis since both have been shown to elicit
comparable cytoprotective effects [1–4]. Further, although
remote IPC requires a neurohumoral signal transduction
factor, considerable overlap in mechanisms between the two
forms of conditioning exist (e.g., triggering stimuli: nitric
oxide, adenosine, bradykinin, opioids; intracellular media-
tors: protein kinase C, hypoxia-inducible factor-1a, reper-fusion injury salvage kinase, microRNA-144; intracellular
effectors: mitochondria ATP-dependent potassium channel;
see Heusch [23]). Studies were only eligible if participants
were randomized into the IPC or control/sham interventions
(i.e., randomized control or crossover designs).
2.3 Study Selection
All studies investigating the effects of IPC on exercise
capacity or performance and meeting the eligibility criteria
indicated above were selected. Studies were first screened
by title and/or abstract, and then the manuscript was
reviewed if the study appeared to satisfy the eligibility
criteria and purpose of this systematic review (Fig. 1). This
process was conducted independently by two reviewers
(A.V.I. and P.J.M).
2.4 Data Collection
The primary study outcomes related to exercise capacity or
performance included measures of time-trial performance,
power output, VO2 [maximal (VO2max) or peak (VO2peak)],
rating of perceived exertion (RPE), and blood lactate
accumulation. Secondary study outcomes included relevant
cardiorespiratory variables (e.g., heart rate, blood pressure,
and ventilation). Studies investigating the effect of IPC on
time-trial performance and power output were classified
532 A. V. Incognito et al.
123
based on the predominant energy systems utilized during
the test. This was determined based on test duration, with
alactic anaerobic capacity predominating between exercise
initiation and 10 s, lactic anaerobic capacity predominating
between 10 and 75 s, and aerobic capacity predominating
for exercise longer than 75 s [24]. An exception was made
for activities requiring breath holds, which were defined as
tests of predominately lactic anaerobic capacity. Studies
investigating the effects of IPC on VO2 were subdivided
into tests of VO2max/peak and tests of submaximal VO2.
Authors were contacted if their article examined time-
trial performance or VO2max/peak but had unreported or
unclear individual participant data on responders and non-
responders. Five [25–29] out of nine contacted authors
responded to our request for individual participant data.
These data are presented in Table 1 and are included in
response rate calculations.
3 Results
3.1 Study Selection
Following article screening, 21 studies were selected for
review, totaling 374 participants (309 men, 65 women).
All major study characteristics are summarized in
Table 2. Twenty studies were designed as randomized
crossover trials, 12 of which used a sham-control and
eight of which used a time-control; the remaining study
was a randomized control trial with a parallel design.
Individual participant responses were obtained from 13 of
the 21 studies (through the article and/or authors) and
used to calculate the proportion of IPC responders and
non-responders (Table 1).
3.2 Effects of Ischemic Preconditioning (IPC)
on Exercise Performance
3.2.1 Time-Trial Performance
3.2.1.1 Tests of Predominantly Alactic Anaerobic Capac-
ity IPC had no effect on 30 m running sprint time [27].
3.2.1.2 Tests of Predominantly Lactic Anaerobic Capac-
ity IPC improved (-1.1 % [18]) and had no effect [30]
on 100 m swim sprint time. IPC also improved under-
water swimming distance (?8.2 % [31]) and mean static
breath hold duration (?17.2 % [31]). IPC had no effect
on three sets of submaximal bilateral knee extension to
failure [32].
Fig. 1 Flow diagram of the
study selection process based on
eligibility criteria for a
systematic review examining
the effects of ischemic
preconditioning (IPC) on
exercise performance
Ischemic Preconditioning and Exercise Performance 533
123
3.2.1.3 Tests of Predominantly Aerobic Capacity IPC
improved 5 km treadmill running time (-2.5 % [19]), 1 km
rowing sprint time (-0.4 % [31]), time to failure during
graded maximal cycling (*?3.6 % [33]) and constant load
cycling (*?15.8 % [28] and ?7.9 % [26]), and time to
failure during submaximal rhythmic handgrip (?10.6 %
[34]). IPC had no effect on 5 km outdoor running time [29],
time to failure during graded maximal cycling [19, 25] or
constant load cycling at 130 % of peak power [33], or time
needed to cycle 100 kJ of total work [35].
3.2.1.4 Overall Findings IPC improved time-trial per-
formance in nine of 17 exercise performance tests. After
examination of the available individual responses,
improvements and no effects in 118 and 57 participants
(Fig. 2a), respectively, were noted, which corresponds to a
67 % response rate [18, 19, 25, 27–31, 33, 34]. Dividing
the studies on the basis of exercise test duration demon-
strated improvements in 11 and no effects in 14 partici-
pants [27], respectively, in tests of predominantly alactic
anaerobic capacity (44 % response rate). There were
improvements in 32 and no effects in 11 participants [18,
31] within tests of lactic anaerobic capacity (74 % response
rate), and 75 and 32 participants [19, 25, 26, 28, 29, 31, 33,
34], respectively, in tests of predominantly aerobic capac-
ity (70 % response rate).
3.2.2 Power Output
3.2.2.1 Tests of Predominantly Alactic Anaerobic Capac-
ity IPC increased (?2.3 % [36]) and had no effect [37,
38] on peak power output during repeated 6 s cycling
sprints.
3.2.2.2 Tests of Predominantly Lactic Anaerobic Capac-
ity IPC had no effect [38] and detrimental effects [39] on
peak power output during a Wingate test.
3.2.2.3 Tests of Predominantly Aerobic Capacity IPC
increased (?3.7 % [17] and ?1.6 % [33]) and had no effect
[40] on peak power output during graded maximal cycling
tests. Additionally, IPC had no effect on submaximal
cycling workload required to reach target heart rate [41].
3.2.2.4 Overall Findings IPC increased peak power in
three of eight exercise tests, and had no effect on sub-
maximal power output in one exercise test.
3.2.3 Oxygen Consumption
3.2.3.1 Tests of Maximal Oxygen Consumption IPC
increased (?2.8 % [17]) and had no effect [33] on VO2max
determined using a graded maximal cycling test. Addi-
tionally, IPC had no effect on VO2max/peak during a graded
maximal treadmill test when tested acutely [19] or after
8 weeks of repeated IPC treatments [42]. IPC was also
shown to increase (?2.8 %) VO2max/peak during constant
load cycling to failure at 100 % peak power [26] but had no
effect at 130 % peak power [33] or at 89 % VO2peak [28].
3.2.3.2 Tests of Submaximal Oxygen Consumption IPC
had no effect on mean VO2 during a 5 km running time
Table 1 Responders vs. non-responders to ischemic preconditioning (IPC) in studies reporting individual differences in time-trial performance
and maximal oxygen uptake
References Effects of IPC IPC benefit IPC null
de Groot et al. [17] : VO2max 12 3
Jean-St-Michel et al. [18] ; 100 m swim time 14 3
Crisafulli et al. [33] : Time to failure 10 7
$ VO2max 6 9
Clevidence et al. [25] $ Time to failure 6 6
Bailey et al. [19] ; 5 km running time 11 2
Gibson et al. [27] $ 30 m sprint time 11 14
Kjeld et al. [31] ; 1 km row time 11 3
: Underwater swim distance 9 2
Tocco et al. [29] $ Mean 5 km running speed 5 6
Barbosa et al. [34] : Handgrip time to failure 9 4
Kido et al. [28] : Time to failure 13 2
Marocolo et al. [30] $ 100 m swim time 9 6
Cruz et al. [26] : Time to failure 10 2
: VO2peak 8 4
: Increase, ; decrease, $ no change, max maximal, VO2 oxygen consumption
534 A. V. Incognito et al.
123
Table
2Summaryofstudycharacteristicsandexercise
perform
ance
andphysiologychanges
withischem
icpreconditioning(IPC)
Study
Studydesign
Population
IPC
protocol
IPC
limb
Exercise
test
EffectsofIPC
deGroot
etal.[17]
Randomized,
controlled
crossover
12M,3F;27±
6years;
trained
cyclists
39
5min
at
220mmHg
Bilateral
upper
leg
Graded
max
cycling
:VO2max
:W
peak
$BL2min
post
cycling
Jean-St-
Michel
etal.[18]
Randomized,sham
-
controlled
crossover
9M,9Ffor100m
swim
;
19±
3years;8M,8Ffor
200m
intervals;
19±
3years;elitesw
immers
49
5min
at15mmHg
aboverestingSBP
Unilateral
upper
arm
100m
swim
;100m
swim
time
79
200m
swim
intervals
$BL2min
post
each
200m
Crisafulli
etal.[33]
Randomized,
controlled
crossover
17M;35±
9years;
recreationally
active
39
5min
at50mmHg
aboverestingSBP
Bilateral
upper
leg
Graded
max
cycling
:Tim
eto
failure
:W
peakandW
total
$VO2max
Alloutcyclesprintat
130%
Wpeakto
failure
(W
determined
byagraded
max
cyclingtest)
$Tim
eto
failure
$VO2max
$W
total
$BLpostcyclesprint
Foster
etal.
[35]
Randomized,
controlled
crossover
6M,2F;39±
10years;
experiencedcyclists
49
5min
at20mmHg
aboverestingSBP
Unilateral
upper
leg
Cyclesprintto
100kJ
$Cyclesprinttime
Clevidence
etal.[25]
Randomized,
controlled
crossover
12M;27±
9years;
competitiveam
ateurcyclists
39
5min
at220
mmHg
Alternate
unilateral
upper
leg
Graded
max
cycling
$Tim
eto
failure
$BL5min
post
cycling
Baileyet
al.
[19]
Randomized,sham
-
controlled
crossover
13M;25±
6years;healthy,
moderatelytrained
49
5min
at220
mmHg
Bilateral
upper
leg
5km
treadmillrun
;5km
runningtime
;RPEduringfirst1000m
;BLduringsubmax
running
Graded
max
treadmillrunning
$Tim
eto
failure
$VO2max
$BL3min
postgraded
max
running
ElMessaoudi
etal.[41]
Randomized,
controlled
crossover
10M,10F;22±
4years;
healthyvolunteers
39
5min
at200
mmHg
Bilateral
upper
arm
70min
cyclingat
80%
HRmax
orreserve;
15min
oruntil
failure
at95%
HRmaxor
reserve
$W
required
fortarget
HR
Gibsonet
al.
[27]
Randomized,sham
-
controlled
crossover
16M,9F;23±
3years;
competitiveteam
sport
athletes
39
5min
at
220mmHg
Alternate
unilateral
upper
leg
39
30m
runningsprints
$30m
sprinttime
Paixao
etal.
[39]
Randomized,sham
-
controlled
crossover
15M;30±
7years;
competitiveam
ateurcyclists
49
5min
at250
mmHg
Alternate
unilateral
upper
leg
3Wingatetestsseparated
by
10min
rest
;W
peakin
thefirstWingateandW
total
infirstandsecondWingatetests
$BL6min
post
each
Wingate
Kjeld
etal.
[31]
Randomized,
controlled
crossover
10M,4F;23years;elite
oarsm
en;10M,1F;
29years;elitefree
divers
49
5min
at40mmHg
aboverestingSBP
Unilateral
upper
arm
1km
row
;1km
row
time
Staticbreathhold;underwater
distance
swim
:Staticbreathhold
timeand
underwater
swim
distance
Ischemic Preconditioning and Exercise Performance 535
123
Table
2continued
Study
Studydesign
Population
IPC
protocol
IPC
limb
Exercise
test
EffectsofIPC
Jones
etal.
[42]
Randomized,
controlled
18M;22±
2years
IPC,
26±
5yearscontrol;healthy
volunteers
49
5min
at
220mmHg,39/
week,8weeks
Unilateral
upper
arm
Graded
max
treadmillrunning
$VO2peak
Patterson
etal.[36]
Randomized,sham
-
controlled
crossover
14M;30±
4years;
recreational
team
sport
athletes
49
5min
at220
mmHg
Bilateral
upper
leg
129
6scyclesprints
:W
peakandW
meanforsprints
1,2,3
$RPE
$BLim
mediately
postsprint4,8,12
Hittinger
etal.[40]
Randomized,
controlled
crossover
15M;30±
7years;
competitivecyclistsand
triathletes
49
5min
at15mmHg
aboverestingSBP
Bilateral
upper
leg
Graded
max
cycling
$W
peak
$RPE
Lalondeand
Curnier
[38]
Randomized,sham
-
controlled
crossover
8M,9F;29±
8years;healthy
students
andam
ateur
triathletes
49
5min
at50mmHg
aboverestingSBP
Unilateral
upper
arm
69
6scyclesprints;Wingate
test
$W
peakandW
meanforeither
test
;RPEduringWingate
Toccoet
al.
[29]
Randomized,sham
-
controlled
crossover
11M;35±
8years;
competitiverunners
39
5min
at50mmHg
aboverestingSBP
Bilateral
upper
leg
5km
run
$5km
runningtime
$BL1min
post
running
Gibsonet
al.
[37]
Randomized,sham
-
controlled
crossover
7M,9F;24±
3years;
competitiveteam
sport
athletes
39
5min
at220
mmHg
Alternate
unilateral
upper
leg
59
6scyclesprints
$W
peakandW
total
$RPE
;BL3min
postfifthsprintin
women
Barbosa
etal.
[34]
Randomized,sham
-
controlled
crossover
13M;25±
4years;
recreationally
active
39
5min
at
200mmHg
Bilateral
upper
leg
Rhythmic
handgripat
45%
MVC
tofailure
(60
contractions/min)
:Tim
eto
failure
Kidoet
al.
[28]
Randomized,
controlled
crossover
15M;24±
1years;habitually
active
39
5min
at
[300mmHg
Bilateral
upper
leg
3min
cyclingat
30W,4min
cyclingat
90%
GET,until
failure
at70%
ofdifference
betweenGETandVO2peak
:Tim
eto
failure
$VO2peak
$BLduringsubmax
and
immediately
post
cycling
Marocolo
etal.[30]
Randomized,sham
-
controlled
crossover
15M;21±
4years;
competitiveam
ateur
swim
mers
49
5min
at220
mmHg
Alternate
unilateral
upper
arm
100m
swim
$100m
swim
time
Cruzet
al.
[26]
Randomized,sham
-
controlled
crossover
12M;20–36years;
recreationally
trained
cyclists
49
5min
at220
mmHg
Bilateral
upper
leg
100%
Wpeakto
failure
(W
determined
byagraded
max
cyclingtest)
:Tim
eto
failure
:VO2peak
;RPE
$BLim
mediately
post
cycling
Marocolo
etal.[32]
Randomized
sham
-
controlled
crossover
13M;26±
5years;resistance
trained
49
5min
at220
mmHg
Alternate
unilateral
upper
leg
3setsofbilateral
legextension
tofailure
(12repetitionmax
load)
$Repetitionsper
set
$RPE
$BL4min
post
set3
Agedataaremean±
SD
:Increase,;decrease,$
nochange,BLbloodlactate,Ffemale,GETgas
exchangethreshold,HRheartrate,M
male,maxmaxim
um/m
axim
al,MVCmaxim
alvolitionalcontraction,postafter,
RPEratingofperceived
exertion,SD
standarddeviation,submaxsubmaxim
al,SBPsystolicbloodpressure,VO2oxygen
consumption,W
workload
orpower
536 A. V. Incognito et al.
123
trial [29], repeated 6 s cycle sprints and associated recov-
ery periods [36], or submaximal VO2 during graded cycling
[17, 25] or during 4 min of cycling at a workload corre-
sponding to *55 % of VO2max [28].
3.2.3.3 Overall Findings IPC increased VO2max in two of
seven exercise tests, and had no effect on mean or sub-
maximal VO2 in five exercise tests. Examination of the
available individual responses noted VO2max/peak improve-
ments and no effects in 26 and 16 participants (62 %
response rate; Fig. 2b), respectively [17, 33].
3.2.4 Rating of Perceived Exertion
IPC decreased RPE during a Wingate test (*1 point on a
Borg 1–10 scale [38]), during the first 1000 m of a 5 km
treadmill time trial (*1–2 points on a Borg 6–20 point scale
[19]), and during the first 4 min of cycling to failure at
100 % power output (0.8 points on a Borg 6–20 point scale
[26]), but had no effect during a graded maximal cycling test
[40], three sets of submaximal bilateral knee extension to
failure [32], or repeated 6 s cycling sprints [37, 43].
3.2.5 Blood Lactate
IPC attenuated blood lactate accumulation during sub-
maximal treadmill running (-1.07 mmol-1 or -25.4 %
[19]), but had no effect during submaximal cycling [28].
IPC decreased blood lactate 6 min post cycling exercise in
women (-1.4 mmol-1 or -15.9 % [37]), but had no effect
on post-exercise blood lactate accumulation in all other
studies, though the non-statistically significant mean results
ranged from 7.1 % lower to 8.7 % higher [17–19, 25, 26,
28, 29, 32, 33, 39, 43].
3.3 Effects of IPC on Cardiorespiratory Variables
During Exercise
3.3.1 Heart Rate
IPC increased (*?2.4 % [32]) and had no effect [17, 28]
on maximal heart rate during graded maximal cycling; no
effect on maximal [26, 28] or submaximal [28] heart rate
during constant load cycling to failure; no effect on max-
imal or submaximal heart rate during cycling to 100 kJ of
total work [35]; and no effect on maximal [19] or mean
heart rate [29] during a 5 km running time trial. Similarly,
IPC had no effect on peak heart rate during rhythmic
handgrip exercise to failure [34] or during a 100 m swim
time trial [18]. IPC had no effect on heart rate during
submaximal interval swims [18], submaximal cycling
workloads [17, 28], submaximal treadmill running [19], or
submaximal rhythmic handgrip [34]. IPC did increase heart
rate at a submaximal intensity of 30 % maximal cycling
power output (?5.1 % [25]).
3.3.2 Blood Pressure
IPC had no effect on submaximal mean arterial pressure, but
increased maximal mean arterial pressure (?11 mmHg or
?9.2 % [34]) during rhythmic handgrip exercise to failure,
compared with control conditions. IPC had no effect on
maximal mean arterial pressure [33] or systolic or diastolic
blood pressure [17] during graded maximal cycling. Addi-
tionally, IPC attenuated hypoxia-induced increases in pul-
monary artery systolic pressure at rest (-22.5 % [35]).
3.3.3 Respiratory Variables
IPC had no effect on respiratory exchange ratios during a
5 km running time trial [29], nor during graded maximal
cycling [25]. IPC increased (*?8.1 % [33]) and had no
effect on maximal minute ventilation during graded max-
imal cycling [17, 25], and no effect on maximal or sub-
maximal pulmonary VO2 during submaximal cycling to
failure [28]. Additionally, IPC had no effect on maximal or
submaximal minute ventilation during graded maximal
treadmill running [19] or on mean pulmonary ventilation
during a 5 km running time trial [29].
3.4 Safety and Tolerability
Although no studies sought specifically to investigate the
safety of IPC, no adverse clinical events were reported in
Fig. 2 Number of responders
and non-responders to ischemic
preconditioning (IPC)-mediated
effects on a time-trial
performance, and b maximal
oxygen consumption
Ischemic Preconditioning and Exercise Performance 537
123
any of the reviewed studies. The IPC procedure has been
reported to elicit a score of ‘‘4’’ on a 1–10 pain scale in
healthy participants [38], suggesting it is uncomfortable but
not painful for the average participant.
4 Discussion
4.1 Summary of Findings
IPC has been proposed as a novel intervention to increase
exercise capacity and performance [20, 44]. The results of
this systematic review highlight the considerable equipoise
in the literature and variability in IPC-mediated exercise
benefits between studies. The most consistent evidence was
for an improvement in time-trial performance (nine of 17
exercise tests; 67 % individual response rate), detected
only in exercise modes lasting 10–75 s (three of five
exercise tests; 74 % individual response rate) and [75 s
(six of 11 exercise tests; 70 % individual response rate),
which were characterized in this review as tests of pre-
dominantly lactic anaerobic and aerobic capacity, respec-
tively. The effects on power output, VO2, RPE, and blood
lactate accumulation were less clear; as were changes in
cardiorespiratory measures. An examination of individual
participant data supports the hypothesis that IPC respon-
ders and non-responders may exist [45], which could
explain the large variability observed in exercise perfor-
mance responses within and between studies. The present
results are best used to catalyze future research questions,
study designs, and hypotheses, to establish the utility of
using IPC as an ergogenic aid. Future research must aim to
determine the phenotype most likely to respond to IPC,
optimal IPC protocols, and the mechanisms involved in
mediating the potential beneficial effects on exercise
performance.
4.2 Potential IPC Responders and Non-Responders
The responsiveness to any therapy or treatment can vary
between individuals on the basis of genetic, pathological,
and/or environmental profiles. It is acknowledged that such
heterogeneity even exists in the responsiveness to exercise
training [46]. Whether a similar range of responsiveness
exists to IPC has recently been postulated [45] to explain
the discrepancy between the widespread cytoprotective
success in experimental models [2, 4, 8–11] and the
inconsistency of benefits in clinical trials [47, 48]. Exam-
inations of clinical IPC responsiveness have reported
reduced or absent cardioprotection in women, diabetics,
and older patients with coronary artery disease [48, 49],
suggesting a phenotype for ‘‘responders’’ and ‘‘non-re-
sponders’’ may exist. This could explain the large
variability observed in exercise performance responses
within and between studies (Table 1 and 2) and highlights
the potential limitation of conventional statistical approa-
ches based on aggregate data.
4.3 Potential Sources of Between-Study Variability
In addition to potential differences in IPC responsiveness,
it is difficult to compare results between studies as partic-
ipant characteristics (e.g., sex, training status) and study
methods (e.g., exercise mode, pre-study restrictions, IPC
protocol) differ widely. The following sections will assess
the potential impact that this between-study variability may
have on the results.
4.3.1 Study Participants
Participant characteristics differed widely between stud-
ies. Females were not included in eight of 21 studies and
only represent 17 % of participants overall, raising the
question of whether a sex-based difference in IPC
responsiveness may exist. To our knowledge, this has not
been investigated formally in humans. Peak exercise
capacity and training status were also highly variable. We
attempted to classify the studies into categories based on
one or a combination of participant VO2max/peak, peak
power output, and author-reported fitness status. We
identified five studies with highly trained participants [18,
29, 31, 39, 40], 12 studies with trained participants [17,
19, 25–27, 30, 32, 33, 35–38], and four studies with
recreationally active participants [28, 34, 41, 42]. Within
the highly trained population, two of five studies (40 %)
reported improvements in exercise performance following
IPC [18, 31], compared with five of 12 studies (42 %) in
the trained population [17, 19, 26, 33, 36] and two of four
studies (50 %) in the recreationally active population [28,
34]. Available individual participant time-trial response
rates were 81, 57, and 79 % for the highly trained, trained,
and recreationally active population, respectively. It must
be acknowledged that although we attempted to catego-
rize participant fitness status, we only identified two elite
athlete populations [18, 31]. Broadening the continuum of
fitness status is required to understand the role of fitness
and/or sport-specific training status on IPC efficacy.
Understanding these potential trends may explain vari-
ability in results and give insight into the IPC responder
phenotype.
4.3.2 Exercise Mode
The mode of exercise performed differed dramatically
between studies (Table 2). To help stratify the results, we
538 A. V. Incognito et al.
123
grouped exercise mode by duration and predominant
energy systems. With respect to time-trial performance, the
results demonstrate clearly that the majority of observed
benefits were in exercise tests lasting longer than 10 s,
although no differences in IPC responsiveness were
observed between tests of predominantly lactic anaerobic
and aerobic capacity. While the large variability in exercise
modes makes it difficult to compare directly between
studies, the reported benefits across a variety of tests pro-
vide support for a generalized effect.
4.3.3 IPC Protocols
The optimal methodology for implementing IPC is
unknown [50], with variability in the size (muscle mass)
of the occluded limb, the number of ischemia-reperfusion
cycles or cycle length, and the time lag between IPC and
the start of exercise. The protective effects of remote IPC
against brachial artery endothelial ischemia-reperfusion
injury have been shown to be similar when occlusion was
completed three times in the arms and legs [51]; however,
whether the effects on exercise performance are propor-
tional to the muscle mass is uncertain. No clear rela-
tionships were evident from the present data as time-trial
performance was improved by implementing IPC to the
arm [18, 31] or leg [19, 26, 33, 34]. The number of
ischemia-reperfusion cycles may also be important, and
interact with the amount of muscle mass. Two cycles of
5 min circulatory occlusion in the legs, but not the arms,
prevents brachial artery endothelial ischemia-reperfusion
dysfunction [51]. All of the studies included in this review
completed either three or four cycles of 5 min occlusion
and reperfusion; however, no clear relationships with
exercise performance were present. Lastly, IPC is known
to exert an early (1–2 h) and late (12–72 h) window of
effectiveness on ischemia-reperfusion injury [52]. The
optimal time lag between IPC and the start of exercise has
not been investigated. Current studies ranged from 5–105
min, with no clear relationships with exercise perfor-
mance. Future investigations establishing optimal proto-
cols for the implementation of IPC prior to exercise are
warranted.
4.3.4 Pre-Study Restrictions
A notable limitation of the existing literature is the
inconsistency in limiting confounders known to modulate
the effects of IPC, such as caffeine, alcohol, and physical
activity [33, 53–55]. Of the 21 studies, only 14 reported
pre-study instructions, 13 restricted caffeine, 12 restricted
alcohol, and 11 restricted physical activity. The timelines
for these restrictions were also not standardized.
With respect to caffeine, studies implemented 48 h
(n = 2), 24 h (n = 7), 12 h (n = 1), 6 h (n = 2), and 2 h
(n = 1) restrictions. A plasma concentration of *6 mg/L,
the equivalent of drinking two to four cups of coffee, has
been shown to abolish the cytoprotective effects of IPC
compared with plasma concentrations of *0.2 mg/L,
achieved by asking participants to abstain from caffeine for a
minimum of 24 h [55]. Given that caffeine is reported to
have a half-life in plasma of roughly 5.5 h [56], two to four
cups of coffee would take roughly 27.5 h to reduce to con-
centrations of 0.2 mg/L. This information should encourage
caffeine restriction for at least 24 h prior to IPC testing.
The captured studies implemented a 48 h (n = 2) and
24 h (n = 10) abstinence from alcohol. The protective
effects of IPC against myocardial ischemia have been
shown to be abolished when blood ethanol concentrations
were between 16 and 34 mg/dL, 30 min after oral admin-
istration of 40 g of ethanol (approximately three standard
alcoholic drinks in North America) compared with the
placebo group [54]. As alcohol has a clearance rate of
*13 mg/dL/h [57], the commonly used 24 h abstinence
prior to IPC testing is likely sufficient.
With regards to physical activity, studies implemented a
pre-study restriction of 5 days (n = 1), 48 h (n = 2), and
24 h (n = 7). One study restricted physical activity for 1
week between crossover study visits, but did not commu-
nicate a pre-study restriction. Since physical activity may
elicit a similar preconditioning response to IPC [33, 53],
and the effects of IPC can persist for up to 48 h [1],
restrictions on physical activity should extend for a mini-
mum of 48 h prior to IPC testing.
It is acknowledged that the implementation of these
restrictions may compromise the practicality of research in
athletes. For example, caffeine represents a common
ergogenic aid employed by endurance athletes to improve
performance [58], while restricting exercise for 48 h (or
longer) would likely alter the training schedule of most
athletes and lead to sub-optimal performances during
subsequent testing. It is recommended that careful docu-
mentation of these confounders be collected and reported
in all future research.
4.4 Potential Mechanisms for IPC-Mediated
Improvements in Exercise Performance
Whether the factors regulating the clinical benefits of IPC
for protecting organs against prolonged ischemia are
the same as those needed for potential improvements in
exercise performance is unclear. In animal models testing
ischemic tolerance, IPC acts via a blood-borne sub-
stance(s) that requires the presence of adenosine [59, 60],
nitric oxide [60], and an intact nervous system [60,
61]. The following sections briefly review potential
Ischemic Preconditioning and Exercise Performance 539
123
mechanisms that may be responsible for IPC’s ability to
alter exercise performance.
4.4.1 Metabolic Efficiency
With the exception of Patterson et al. [43], IPC-mediated
improvements were observed in exercise performance tests
classified as predominantly utilizing lactic anaerobic or
aerobic energy systems [17–19, 28, 31, 33, 34]. This sug-
gests that IPC may not have as strong of an impact on
alactic anaerobic capacity [24]. In support of a metabolic
mechanism, animal-based investigations using prolonged
ischemia of skeletal muscle have demonstrated that IPC
attenuates ATP depletion [8–10, 62] secondary to mito-
chondrial ATP-sensitive potassium (mKATP) channel
opening [51, 62], skeletal muscle opioid receptor activation
[8], and preservation of ischemia-induced reductions in
muscle energy charge potential [9]. IPC has also been
shown to attenuate ischemia-induced mitochondrial dys-
function [63, 64]. This may be the result of IPC-mediated
increases in nitric oxide [65–67], as nitrate supplementa-
tion in humans has been shown to improve basal mito-
chondrial efficiency through enhancement of ADP
sensitivity [68]. Furthermore, IPC has been observed to
reduce ischemia-induced glycogen depletion [11] and lac-
tate production [8, 9] in skeletal muscle. These studies
suggest that IPC can reduce muscle energy demand and
improve metabolic efficiency in times of ischemic stress.
Evidence of IPC improving metabolic efficiency in
humans is scarce. Bailey et al. [19] reported attenuations in
submaximal exercise blood lactate accumulation in healthy
participants, but whether this was due to reduced produc-
tion or increased clearance is unclear. IPC has been shown
to increase peak forearm deoxygenation during handgrip
exercise to failure [34] and mean forearm deoxygenation
during a static breath hold [31], which may represent
increased oxygen extraction by the muscle. However, both
of these investigations also reported increased time to task
failure following IPC; therefore, the enhanced deoxy-
genation reported with IPC may reflect the greater time
available for oxygen extraction [31, 34]. When compared
at equal time points during submaximal exercise, IPC does
not alter the magnitude of deoxygenation, rather, it alters
the kinetics, speeding up deoxygenation at the onset of
moderate cycling exercise [28], which would reduce the
oxygen deficit. In addition, IPC has recently been shown to
increase VO2peak partially through increasing the amplitude
(not the delay) of the slow component of whole body VO2
[26]. This change may have been driven by the recruitment
of additional motor units towards the end of exercise [26].
Overall, human evidence for IPC improving metabolic
efficiency requires further investigation.
4.4.2 Blood Flow
IPC has been observed to increase muscle oxygen satura-
tion during 6 s cycle sprints [43] and rhythmic handgrip
exercise at 25 % maximal volitional contraction [13],
reflecting a disproportional increase in muscle blood flow
compared with oxygen demand. IPC-mediated increases in
muscle blood flow during exercise are likely secondary to
the ability of IPC to protect against exercise-induced and
ischemia-induced endothelial [1, 15, 19] and microvascular
[16] dysfunction. Additionally, IPC can induce conduit
artery vasodilation of the contralateral limb [12]. IPC can
also enhance functional sympatholysis [13], likely medi-
ated by increases in nitric oxide [65–67] or decreases in
sympathetic activity [12, 69]. Therefore, IPC may improve
skeletal muscle blood flow by preserving endothelial and
microvascular function, as well as attenuating neurogenic
restraint on peripheral vasculature. Since endothelial and
microvascular function and sympathetic activity are
impacted by nitric oxide [16, 65, 70], these mechanisms
may work in concert to enhance skeletal muscle blood flow
during exercise. Arguing against increases in blood flow,
remote IPC failed to increase brachial artery diameter or
blood flow compared with control during rhythmic hand-
grip, even though time to failure was increased [34]. Fur-
ther work in humans is required to confirm that IPC-
mediated vascular effects are involved in improving exer-
cise performance.
4.5 Potential Clinical Benefits
The value of IPC for improving exercise performance in
clinical populations remains largely unstudied. In patients
with coronary [44] or peripheral artery disease [71, 72], IPC
had no effect on exercise time to failure or oxygen uptake,
but did alter clinically relevant markers, such as increasing
time to claudication [71] and cardiac ischemia [44], and
lowering peak systolic blood pressure and rate pressure
product [44]. The ability of IPC to prolong the onset of
myocardial ischemia during exercise [44] may be due to
improved metabolic efficiency and increases in myocardial
blood flow, similar to the above mechanisms described in
skeletal muscle. Compared with control conditions, remote
IPC was shown to preserve mitochondrial respiration in
atrial [73] and ventricular [74] tissue after aortic cross-
clamping in patients undergoing coronary artery bypass graft
surgery. Furthermore, remote IPC has been shown to
increase coronary artery blood flow in animals [75] and
humans [76]. Together, these results suggest that prolonged
onset of exercise-induced cardiac ischemia following IPC
may be due to improved myocardial oxygen utilization or
delivery.
540 A. V. Incognito et al.
123
One important unanswered question is whether clinical
patients fully respond to IPC. In patients with heart failure
[77], IPC had no effect on VO2peak, exercise duration, or
power output. Blood drawn from these heart failure
patients following IPC did not attenuate infarct size in a
mouse heart Langendorff model of infarction [77], com-
pared with a 38.6 % reduction previously reported with
healthy athletes [18]. Further, IPC does not protect against
endothelial ischemic-reperfusion injury in heart failure
patients [78]. The reduced efficacy in patients with heart
failure with reduced ejection fraction may highlight the fact
that these patients are already preconditioned due to
chronic exposure to a low flow state. Although potential
disease-specific differences in IPC responsiveness may
exist, the therapeutic benefits of IPC on exercise capacity
and performance for clinical populations warrant further
study. It is known that exercise capacity is a strong marker
of overall mortality in cardiovascular disease [79–82] and
that the benefits of exercise rehabilitation are dose/volume
dependent [83]. Interventions to increase exercise duration
or tolerance may allow patients to perform more exercise
and reap greater overall benefits.
4.6 Future Directions
To better establish the effects of IPC on human exercise
performance, more strictly controlled and mechanistic
studies are needed. Overall, sample sizes need to be
increased to account for the large variability in between-
subject IPC responsiveness and to detect the modest 1–3 %
improvements in exercise performance that have been
reported to date. Additionally, there is a need for a direct
comparison between different IPC protocols, exercise
modalities, individual fitness levels, and sport-specific
backgrounds to determine if these factors play a role in IPC
effectiveness and to better understand the potential IPC
responder and non-responder phenotypes. Pre-study
restrictions on caffeine, alcohol, and physical activity are
recommended to be implemented for a minimum of 24, 12,
and 48 h, respectively. In athletes, these restrictions may
not be practical, and it is recommended that careful data
collection on these confounders be reported. Further, a
major confounder with all human studies remains the
inability to effectively sham-control IPC treatments.
Highlighting the potential influence of placebo effects on
results, a recent study noted that 67 % of participants
improved 100 m swim time following a sham-IPC condi-
tion compared with a time-controlled condition when they
were told that sham-IPC would improve exercise perfor-
mance [30]. At a minimum, studies should seek to record
participants’ knowledge of IPC-mediated exercise effects
[38], while the use of deception may be required.
5 Conclusion
Current evidence suggests that IPC may be efficacious as
an ergogenic aid to improve exercise performance and gain
a competitive advantage. Of the 21 investigations
reviewed, 10 reported statistically significant exercise
performance benefits such as improved time-trial perfor-
mance, increased VO2max/peak, increased power output, or
reduced ratings of perceived exertion. The mechanisms
responsible for these improvements are unknown, but
likely involve changes in both metabolic and vascular
pathways. However, despite these positive findings, 11
studies demonstrated no effect of IPC on exercise perfor-
mance, three of which were completed with short-duration
exercise modes utilizing predominantly alactic anaerobic
metabolism. The large between-subject variability of
results may be impacted by populations of IPC responders
and non-responders, and therefore caution should be used
in the interpretation of mean group changes in exercise
performance. Future IPC research should focus on (1)
increasing the statistical power to detect the modest
changes in exercise performance and account for the
variability in IPC responsiveness, (2) improving our
understanding of the physiological mechanisms involved,
(3) identifying the participant phenotype or IPC protocol
mediating beneficial exercise responses, and (4) deter-
mining the applicability for clinical populations engaged in
exercise rehabilitation. Overall, the application of IPC as
an ergogenic aid and adjunct clinical rehabilitation therapy
is promising, but requires further investigation.
Compliance with Ethical Standards
Funding Anthony Incognito is supported by a Fredrick Banting and
Charles Best Canada Graduate Scholarship. Jamie Burr and Philip
Millar are both supported by National Science and Engineering
Research Council (NSERC) Discovery Grants.
Conflicts of interest Anthony Incognito, Jamie Burr, and Philip
Millar declare that they have no conflicts of interest relevant to the
content of this review.
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