Comparison of Factors and Effects of Repeated vs. Acute Ischemic Preconditioning on Enhancing Athletic Performance: A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-5035301/v1

Background Repeated ischemic preconditioning (RIPC) has been shown to significantly improve endothelial function, but its effect on enhancing athletic performance remains highly controversial. On the other hand, acute ischemic preconditioning (AIPC) has already been proven to enhance athletic performance. Similar to AIPC, factors such as exercise modality, dosage, training status, and timing of testing are crucial influences on the final effects of RIPC, yet related studies exhibit considerable disagreement. Moreover, the comparison between the effects of repeated ischemic preconditioning and acute ischemic preconditioning has yet to be further clarified.

Objective The primary aim of this meta-analysis is to investigate whether RIPC truly enhances athletic performance while considering exercise modality, dosage, the training status of the tested population, and the timing of observation. It also seeks to compare the effects of RIPC and AIPC on enhancing athletic performance.

Methods A literature search was conducted in five databases. For each outcome, standard error and mean difference or standardized mean difference were calculated. A random-effects model (SMD) with a 95% confidence interval (CI) was used, and analysis was performed using the inverse variance statistical method. The risk of bias was assessed using ROB2 and considerations for randomized controlled trials.

Results RIPC had a small beneficial effect on athletic performance (p = 0.02; SMD = 0.33; 95% CI 0.06–0.60). Regarding exercise modality, RIPC had a small beneficial effect on anaerobic exercise (p = 0.05; SMD = 0.48; 95% CI 0.00–0.97), but no improvement for aerobic exercise (p = 0.12; SMD = 0.26; 95% CI -0.07–0.59). A dosage of RIPC lasting one week or longer was effective (p = 0.006; SMD = 0.37; 95% CI 0.01–0.75). The time interval between RIPC and the start of exercise did not affect the benefit (p > 0.05). RIPC had a greater impact on enhancing athletic performance in the general population (p = 0.06; SMD = 0.36; 95% CI -0.01–0.73; p = 0.001; SMD = 1.03; 95% CI 0.41–1.65) compared to athletes (p > 0.05). The benefit of RIPC compared to AIPC remains unclear (p = 0.1; SMD = 0.22; 95% CI -0.05–0.49).

Conclusion RIPC can effectively improve anaerobic exercise performance and is influenced by RIPC dosage and the training level of the subjects. RIPC dosage lasting one week or longer is most effective in untrained populations and can be observed at any time. However, there are certain limitations in current research, such as the small number of studies available for analysis, and there is insufficient evidence to determine whether repeated or acute IPC application is more effective. Further research is needed to supplement these findings.

PROSPERO registration number CRD42024579390

Repeated ischemic preconditioning

Acute ischemic preconditioning

Athletic performance

Influencing factors

Effect comparison

RIPC can improve athletic performance, but it only enhances anaerobic performance.
The effectiveness of RIPC in enhancing athletic performance is influenced by dosage and the training level of the subjects but is not affected by the timing of observation.
The comparative effects of RIPC and AIPC on enhancing athletic performance remain unclear.

On competition day, in addition to conventional methods, sports scientists and coaches are continuously searching for emerging preconditioning techniques, such as Ischemic Preconditioning (IPC), Morning Resistance Exercise (MRE), Hormonal Preconditioning (HP), and Post-Activation Potentiation (PAP), to enhance athletic performance [1, 2]. Although the effect of IPC on improving athletic performance is small [3], IPC has been increasingly studied in recent years as a simple and non-invasive method. Researchers have also explored whether repeated ischemic preconditioning (RIPC) can enhance the effects of acute ischemic preconditioning (AIPC) [4]. If it is proven that RIPC can indeed enhance athletic performance and has a greater effect compared to AIPC, then IPC could not only be used as a preconditioning strategy on competition days but also as a training method to improve athletic performance in daily training.

Ischemic preconditioning was first introduced by Murray et al. [5], and De Groot et al applied IPC to subjects before an incremental power cycling test, which improved lower limb VO₂max [6]. This sparked research into the effects of IPC in the field of sports. Early studies indicated that IPC effects occur in two phases: the "early" protective phase, which develops within minutes after the initial ischemia and lasts 2 to 3 hours, and the "late" protective phase, which starts 12–24 hours later and lasts 3–4 days [7, 8]. Clinically, the late phase has greater significance for cardiovascular protection [9]. This led researchers to explore the protective effects of repeated IPC in clinical medicine, and it has been proven effective [10, 11]. Starting in 2016, Ferriers [12] and Banks [13] began researching the effects of repeated daily ischemia and reperfusion in the field of sports science. Ferriers applied three sessions of IPC (48h, 24h, and 15min) before repeated sprint swimming tests, which improved athletic performance. Subsequently, various studies confirmed that RIPC can improve skeletal muscle oxidative capacity [14], enhance muscle efficiency [15], induce changes in quadriceps neuromuscular function [16], extend MVIC recovery time [17], and improve anaerobic performance [18], among others. However, many studies have also found that RIPC has no effect on improving athletic performance [4, 13, 19, 20]. Therefore, the effectiveness of RIPC in enhancing athletic performance remains controversial.

Like AIPC, which is influenced by exercise modality, IPC dosage, subject training level, and timing of testing [3], the effectiveness of RIPC in enhancing athletic performance is also affected by these factors. Studies on the effects of RIPC and AIPC on athletic performance primarily focus on physical indicators, making exercise modality a key factor that must be considered. Lindsay and Halley confirmed that RIPC can improve aerobic capacity [21, 22], but RIPC did not improve 1000m running performance [19, 20]. The effects of RIPC on aerobic exercise vary greatly, but it consistently shows improvement in anaerobic exercise [18, 21, 23]. In addition, it may be related to RIPC dosage, subject characteristics, and timing of testing. Addressing these issues, Lindsay studied whether the RIPC dosage, i.e., performing the IPC procedure once or twice daily, would affect the results, and found that more dosage did not enhance the effect[19]. Currently, the dosage differences in related studies are significant, ranging from 7 sessions within a week [21] to 48 sessions over eight weeks [20], and the results also vary. Similarly, the timing of testing varies widely in different studies, with observation times starting from 15 minutes [4], 24 hours [18], to 72 hours [15] after the last RIPC session. RIPC applied to recreationally trained individuals [21] and elite athletes [20] also produced different results.

Since both RIPC and AIPC can enhance athletic performance, researchers have begun to explore whether repeated IPC amplifies the effects of AIPC. Mieszkowski found that after ten consecutive days of repeated ischemic preconditioning, upper limb WAnT test output power increased, while acute application did not enhance performance [23]. Slysz also attempted to compare the benefits of three sessions of RIPC with a single acute application of IPC and found that RIPC had no benefit over AIPC in enhancing aerobic performance [4]. Therefore, it is difficult to determine whether RIPC has a greater effect compared to AIPC. In summary, the effects of RIPC on athletic performance remain controversial, with significant differences and disputes regarding the influence of exercise modality, RIPC dosage, timing of testing, and subject characteristics on the final outcome of RIPC application.

To our knowledge, there has been no systematic review or meta-analysis to evaluate the effects of RIPC on athletic performance. Given the current state of research, studies on RIPC are limited, there is no standardized implementation of RIPC protocols, and sample sizes are small, making individual study results less convincing. Therefore, to address the lack of consensus, this study aims to clarify the effects of repeated ischemic preconditioning on athletic performance through a systematic review and meta-analysis. Based on previous research results, we evaluated the effectiveness of RIPC in improving athletic performance in both aerobic and anaerobic exercise modalities. Additionally, we attempted to investigate the influence of various experimental factors used in previous studies (RIPC dosage, timing of testing, and subject training level) and analyzed whether RIPC produces greater benefits compared to AIPC. We hypothesize that RIPC can indeed enhance athletic performance and that it has an enhancing effect on both aerobic and anaerobic exercise. Moreover, the effects of RIPC are expected to be superior to those of AIPC.

Protocol Registration

We searched the Prospero database and the Cochrane Library to ensure that this work would not duplicate existing systematic reviews. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines were followed [24]. This study was prospectively registered on Prospero (Prospero ID: CRD42024579390).

Literature Search Strategy

This study searched the PubMed, Cochrane, WOS, Ebsco, and Scopus databases using the keywords "athletic," "ischemic preconditioning," and "athletic performance." Only English-language journal articles were included. Detailed search strategies and results can be found in the appendix. Blood flow restriction was included in the interventions because it is similar to ischemic preconditioning in that both apply occlusive pressure to limbs to induce endogenous changes in the body to enhance athletic performance. The main difference lies in the level of occlusive pressure and the timing or combination of the procedure with exercise. However, during the exclusion process, it was found that no literature was confused between the two methods.

Inclusion and Exclusion Criteria

The inclusion criteria were established based on the Population, Intervention, Comparison, Outcomes, and Study Design (PICOS) framework:

Participant: Subjects must be healthy individuals or athletes.
Intervention: Studies must have implemented repeated ischemic preconditioning (RIPC) interventions to be eligible for inclusion in this review.
Comparison: The control group must be either a non-RIPC group or a placebo control group.
Outcome: The study must have involved athletic performance testing after RIPC, with results showing performance or physiological indicators.
Study Design: The study design must be a randomized controlled trial. There were no restrictions on the population, age, gender, or type of sport.

Exclusion criteria for this study included:

Non-English language literature.
Systematic reviews and meta-analyses.
Physiological and biochemical mechanism studies (outcome indicators did not include kinematic or physiological indicators reflecting athletic performance).
Studies on the delayed and time-course effects of ischemic preconditioning and studies on repeated blood flow restriction.

Data Extraction

The following data were extracted from the articles: (i) sample size; (ii) participant characteristics (age, height, weight); (iii) duration of intervention; (iv) RIPC intervention details (duration, number of repeated IPC sessions, occlusive pressure, occlusive site, time interval between intervention and testing); (v) type of exercise, outcome indicators; (vi) mean and standard deviation (SD) of test data before and after intervention. If sufficient information to extract mean and SD data was unavailable, the primary authors were contacted to request the data. In the absence of a response, the study was excluded. All study exclusions and data extractions were verified by a second reviewer to minimize potential selection bias and data extraction errors [25]. In case of discrepancies, a third reviewer was involved to reach a decision through voting.

Risk of Bias Assessment

The risk of bias in the included studies was assessed using the second version of the Cochrane Risk of Bias tool for Randomized Trials (RoB2), recommended by Cochrane for assessing the risk of bias in randomized controlled trials [26]. The RoB2 tool provides a framework for assessing the risk of bias in the estimated effects of experimental versus control interventions on specific outcomes in any type of randomized trial. The domains covered by RoB2 include all types of bias currently believed to affect the results of randomized trials: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result.

Data Analysis

To compare the outcome measurements of the selected studies, effect sizes with 95% confidence intervals (CI) were calculated. The effect size was calculated as the standardized mean difference between the change in the IPC group and the respective control group, divided by the pooled and weighted estimate of SD. Since the studies included in this review involved different populations, IPC intervention protocols, and a variety of kinematic and physiological indicators, a random-effects model (SMD) was used for the meta-analysis, applying the DerSimonian and Laird inverse variance method. Analysis was performed using Review Manager software (RevMan; Version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). A forest plot was constructed to establish 95% CI, and SMDs were classified according to the following scale: 0–0.19 = negligible effect, 0.20–0.49 = small effect, 0.50–0.79 = moderate effect, ≥ 0.80 = large effect. A chi-square test (χ²) was used to determine the presence of statistical heterogeneity. A lower significance level was selected to verify the effectiveness hypothesis of repeated ischemic preconditioning, and heterogeneity was tested at the α level of p ≤ 0.05. Effects were considered statistically significant at p ≤ 0.05 and approaching significance when 0.05 < p < 0.1. To quantify the percentage of variation between studies due to heterogeneity rather than chance, the I² statistic was used alongside the observed effects. I² values of 25%, 50%, and 75% were interpreted as representing low, moderate, and high levels of heterogeneity, respectively. The significance of the observed I² values was interpreted in relation to the size and direction of the effect and the strength of the evidence of heterogeneity.

Subgroup meta-analyses were used to explore the following potential moderating variables:

Exercise modality: Anaerobic exercise (10–90 seconds) and aerobic exercise (> 90 seconds). The main distinction between aerobic and anaerobic exercise is based on the relative contribution of each energy system during maximal effort over the given duration. The anaerobic exercises in the included studies mainly involved repeated sprint text (RAST) [28] and Wingate tests [25, 33], while the aerobic exercise studies included cycling [27, 32], long-distance running tests [26], and 1000m kayak time trials [34].
IPC Dosage: Dosage was categorized into two parts: duration and the number of IPC procedures applied. In RIPC studies, the duration was mainly categorized as less than one week, one week, and more than one week. Most studies conducted RIPC procedures once daily. Each RIPC procedure included 3, 4, or 5 cycles of ischemia-reperfusion, with 5 minutes of occlusion followed by a 5-minute interval.
Athletes vs. Non-Athletes: Subjects were considered athletes if they were described as trained athletes or engaged in specific forms of exercise. Non-athletes were described as healthy individuals or the general population.
Time Interval between the End of the RIPC Cycle and the Start of the Exercise Test: In most studies, the time interval was 24 hours.
Comparison between RIPC and Acute IPC Effects: Only studies that measured enhancement effects of both RIPC and AIPC within the same study were included.

Study Characteristics

The study selection process and search results are presented in Figure 1. The online database search yielded 11,175 results, which were reduced to 5,440 articles after removing duplicates across databases. Retracted articles and non-journal literature were excluded, and 4,056 articles were further eliminated after carefully reading the titles and abstracts based on predefined exclusion criteria. From the remaining studies (n = 49), full-text reviews were conducted, resulting in the exclusion of repeated blood flow restriction studies (n = 30), ischemic preconditioning time-course studies (n = 5), medical clinical studies (n = 4), studies on exercise injury recovery (n = 1), and studies on neuromuscular function (n = 1). Eventually, 8 studies were included, with 4 additional relevant studies incorporated during the review process. In total, after all screening processes, 12 studies [4,13,15,18–23,27–29](177 participants) met the inclusion criteria and were included in the meta-analysis (Figure 1). Among these 12 studies, 4 included both repeated and acute IPC intervention groups [4,22,23,28].

Risk of Bias

A summary of the methodological assessment of all studies included in the review is presented in Figure 2. There were five instances of disagreement between the two reviewers. Three of these disagreements were resolved through discussion between the reviewers, while the remaining two were resolved by a third reviewer. Of the included studies, eight were evaluated as having a medium to low risk of bias, with 88.3% of the assessed criteria being rated as low risk, leading to an overall low-risk evaluation. This indicates that the results of the meta-analysis are based on high-quality studies. No studies were excluded from the review based on the screening results.

Table 1 Data Extraction Table

References	Exercise protocol	Participants	N	Duration /repetitions	IPC protocol（min）	Ischemia pressure (mmHg)	Limb	Time to test	Test protocol	Variable analyzed
shannon2023[18]	Sprint	recreationally-trained males	8	2 weeks/6	4×5	220/20	thigh	24h	Anaerobic Sprint Test [RAST]	power output heart rate blood lactate fatigue lndex
lindsay2017[21]	Wingate tests cycling	recreationally active sport science students	18	1 week/7	4×5	220/20	thigh	24h	simulated Keirin cycling competition (430 s Wingate tests)	power output heart rate blood lactate fatigue lndex
lindsay2018[19]	cycling	competitive cyclists	24	1 week/7	4×5	220/20	thigh	24h	4000-m cyclingergometer time trial	time trial VO₂max peak power output heart rate RER RPE blood lactate
jeffries2019[15]	cycling	healthy males	20	1 week/7	4×5	220/20	thigh	72h	submaximal cycling incremental exercise test	VO₂max peak Time to exhaustion Wmax delta efficiency

Table 1（continued）

References	Exercise protocol	Participants	N	Duration /repetitions	IPC protocol（min）	Ischemia pressure (mmHg)	Limb	Time to test	Test protocol	Variable analyzed
tanaka2021[27]	cycling	healthy males	10	2 weeks/12	3×5	220	thigh	48/24h	ramp-incremental cycling test repeated moderate-intensity cycling test	VO₂max peak time to task failure heart rate exercise load
slysz2019[20]	Running	highly trained runners	14	8 week/48	3×5	LOP	thigh	unclear	VO₂max test 1-km running performance test	VO₂max peak 1-km time trial time running economy VE RER
slysz2020[4]	cycling	aerobically trained individuals	12	<1 week/1/2/3	3×5	LOP	thigh	15min	5-km running	power output Cadence Velocity 5-km TT
mieszkowski2019[23]	Wingate tests	healthy males	34	>1 week/1/10	4×5	220/20	arm	24h	upper body WAnT	power output

References	Exercise protocol	Participants	N	Duration /repetitions	IPC protocol（min）	Ischemia pressure (mmHg)	Limb	Time to test	Test protocol	Variable analyzed
halley2020[22]	kayaking	kayak athletes	8	<1 week/1/2	4×5	220	thigh	40/20min	two 1,000-m TTs	Time power output VO₂max peak stroke rate
seeley2022[28]	submaximal graded exercise	healthy males	15	1 week/1/7	4×5	220	thigh	45min	submaximal hypoxic exercise	heart rate
chopra2022[29]	cycling	recreationally-trained males	14	1 week/7	4×5	LOP/20	thigh	72h	incremental test	VO₂max peak time to exhaustion heart rate O2pulse
Banks2016[13]	cycling	Sedentary young adults	10	1 week/9	4×5	200	right arm	24h	Cardiopulmonary exercise testing	power output heart rate blood lactate Exercise test duration

Table 1（continued）

Participant Characteristics

In all the studies, the median number of participants was 17 (ranging from 8 to 34), the median age was 24 years (ranging from 18 to 41), the median height was 178 cm (ranging from 170.4 to 183 cm), and the median weight was 78.3 kg (ranging from 65.9 to 87.5 kg). The number of studies focused on elite athletes, amateur trained individuals, and healthy populations were 3, 5, and 4, respectively.

RIPC Interventions

Most studies had IPC interventions lasting 1 week, with a repetition of 7 sessions, meaning the interventions were conducted daily over a week (n = 5). Four studies had IPC durations exceeding one week, with repetitions of 9 [13], 10 [23], or 12 [27] sessions. In Slysz's study, the IPC duration extended to 8 weeks, with a total of 42 sessions [20]. Additionally, two studies had IPC intervention durations of less than one week, with only 2 to 3 sessions [4,22]. Regarding each IPC session, most included studies involved bilateral or alternating occlusion at the proximal thighs, with occlusion pressures of 220 mmHg [22,28] or higher than LOP [29]. Banks[13] and Mieszkowski's[23] studies conducted ischemic preconditioning on the upper limbs, with only Banks' study employing remote ischemic preconditioning [13].

Effect of RIPC on Athletic Performance

The results are shown in Figure 4. RIPC had a small but significant effect on improving VO₂max (p = 0.02; SMD = 0.33; 95% CI 0.06–0.60), as derived from a pooled analysis of 106 samples from 84 individuals across 8 studies. Although the effect size was small, the large sample size and lack of heterogeneity between studies make the results more reliable.

RIPC had a moderate and significant effect on improving heart rate (p = 0.001; SMD = 0.70; 95% CI 0.27–1.13), as derived from a pooled analysis of 147 samples from 77 individuals across 8 studies. However, there was heterogeneity between studies (I² = 69%). This suggests that repeated ischemic preconditioning has a significant impact on physiological changes, but there is considerable heterogeneity between studies. The reason for this heterogeneity is that the study by Seeley (2022) examined the effect of RIPC on exercise in a hypoxic environment (as shown in Figure 5, with I² = 0% after excluding Seeley's study). The heart rate data in this study differed significantly from those in studies conducted in normoxic and normobaric conditions [28]. The large heterogeneity observed in subsequent subgroup analyses on heart rate indicators was also due to this study.

RIPC did not have a significant effect on improving blood lactate levels or VO₂max(p > 0.05). The likely reason is the limited number of references and small sample sizes (n = 51, n = 53). Additionally, in studies involving maximal oxygen uptake, the results explicitly indicated that there was no significant change in VO₂max before and after the intervention [15].

Subgroup Analysis

In the current research on the effects of RIPC on enhancing athletic performance, the primary considerations include the impact on different types of athletic performance, the duration and dosage of IPC application, the timing of testing, the characteristics of the subjects and their responses to IPC, and the comparison of effects with acute IPC application.

Therefore, this study's subgroup analysis is divided into five subgroups. Each subgroup focuses on similar types of outcomes, exploring whether RIPC is more effective in enhancing aerobic or anaerobic performance in activities dominated by different energy systems. The analysis also examines the impact of RIPC dosage, the interval between RIPC application and the start of testing, and the training level of the subjects on the final results. Due to the limited number of studies on blood lactate and VO₂max, with only one or two studies allocated to different subgroups, the subgroup analysis mainly compares VO₂max and heart rate outcomes. The greater heterogeneity observed in heart rate outcomes is primarily due to the inclusion of studies conducted in hypoxic environments [28]. In contrast, the heterogeneity among studies on power outcomes is lower, leading to higher credibility in these results.

Comparison of the Effects of RIPC on Aerobic vs. Anaerobic Performance

After confirming that RIPC is effective in enhancing athletic performance, the studies primarily focus on aerobic and anaerobic exercises. Given the number of studies and the specific outcomes, a subgroup analysis was feasible for the VO₂max outcome.

In the subgroup analysis, which compares RIPC's effects on aerobic and anaerobic exercises using VO₂max as the outcome measure, the combined results indicate that RIPC has no significant effect on aerobic performance (p > 0.05). Even under the assumption of significant differences, the enhancement effect of RIPC on aerobic performance is minimal (p = 0.12; SMD = 0.26; 95% CI -0.07–0.59). However, the impact of RIPC on anaerobic performance shows a small but significant difference (p = 0.05; SMD = 0.48; 95% CI 0.00–0.97). Therefore, the effect size of RIPC on enhancing anaerobic performance is greater than that on aerobic performance.

Dose-Response Analysis of RIPC

In terms of power outcomes, studies with RIPC doses exceeding one week showed a nearly significant but small IPC effect (p = 0.06; SMD = 0.37; 95% CI -0.01–0.75), while those with RIPC doses of one week or less did not show a significant effect (p > 0.05).

For heart rate outcomes, RIPC administered for one week displayed a significant and large IPC effect (p = 0.002; SMD = 0.89; 95% CI 0.31–1.46), whereas RIPC administered for more than one week did not show a significant effect (p > 0.05).

Studies with RIPC doses exceeding one week approached a significant enhancement effect on power outcomes, but not on heart rate outcomes. The difference is primarily due to the study by Mieszkowski (2019), which only measured power outcomes. In that study, the effect size for VO₂max was substantial, with Cohen's d = 0.8, indicating a large effect size [23], resulting in an overall effect size on the right side of the forest plot, which is considered reliable.

In studies with IPC doses administered consecutively for seven days within one week, fewer studies measured VO₂max, whereas more data were collected on heart rate outcomes. The combined results showed a larger enhancement effect size, but with significant heterogeneity among studies (I² = 73%). There were only two studies investigating whether repeated IPC doses of two to three sessions had an impact on athletic performance, and the conclusions of Halley (2020) and Slysz (2020) were contradictory [4,22].

In summary, RIPC doses lasting one week or more, with six or more sessions, have been proven effective, whereas the effects of fewer IPC doses remain unclear due to the limited literature and require further research.

Is the Time Interval Between RIPC and the Start of Exercise a Key Indicator?

Slysz's study did not specify the time interval between the RIPC procedure and the outcome measures, so it was excluded from this subgroup analysis [20]. In Tanaka's study, the Ramp Incremental Cycling Test and Repeated Moderate-Intensity Cycling Test were conducted 48 hours and 24 hours, respectively, after the RIPC procedure, resulting in the data being categorized into different subgroups [27]. For heart rate outcomes, Seeley's study measured maximum heart rate 45 minutes after RIPC [28], but due to the lack of similar studies for comparison, this study was excluded, which caused the overall combined effect size for heart rate to differ from other subgroups, showing no significant effect.

In both groups, no significant enhancement effect was observed (p > 0.05). Therefore, it can be concluded that the time interval between the RIPC procedure and the start of exercise is not a key factor influencing the enhancement of athletic performance by RIPC. The benefits of RIPC can be observed immediately after the procedure and may persist for up to 48 or 72 hours.

Comparison of RIPC Effects Between Athletes and Healthy Individuals

Due to the limited comparable data available in studies focusing on elite athletes, highly trained elite athletes and recreationally trained athletes were combined into a single trained group. For both power and heart rate outcomes, RIPC did not show a significant effect in the trained group (p > 0.05). However, in healthy individuals, the enhancement effect was nearly significant for power (p = 0.06; SMD = 0.36; 95% CI -0.01–0.73) and significant for heart rate (p = 0.001; SMD = 1.03; 95% CI 0.41–1.65). There was considerable heterogeneity among the studies on heart rate outcomes (I² = 75%). Therefore, RIPC appears to have a more pronounced enhancement effect on healthy individuals compared to trained individuals.

This finding supports the current prevailing view. In Lindsay's study, a 7-day RIPC protocol improved both aerobic and anaerobic capacity [21]. However, no improvement effects were observed in subsequent studies by Lindsay in 2018 and Slysz in 2019, which involved subjects with higher levels of training[19,20]. The subjects in Lindsay's 2017 study were recreationally trained, which may explain the difference in results. This suggests that the training level of the subjects is an important factor influencing the effect of RIPC on athletic performance.

Comparison of the Effects of RIPC)Versus AIPC on Athletic Performance

The comparison between RIPC and AIPC regarding their effects on enhancing athletic performance was conducted using the VO₂max outcome measure. The results showed no significant enhancement effect (p > 0.05). Although a p-value of 0.1 could be considered as approaching significance, the effect size was small (p = 0.1; SMD = 0.22; 95% CI -0.05–0.49). Most studies supported the notion that RIPC has a greater enhancement effect compared to AIPC. However, the study by Slysz (2020) reported the opposite conclusion, significantly influencing the final results[4].

Therefore, it remains unclear whether RIPC has a more substantial impact on athletic performance than acute IPC, although it is close to showing an enhancement effect.

RIPC Can Enhance Athletic Performance

Consistent with our hypothesis, RIPC can enhance athletic performance. The results of the meta-analysis show that RIPC improves VO₂max. The ability to optimize muscle power output is considered fundamental to success in many sports and physical activities. As a result, numerous studies have investigated methods to increase power output and its transfer to athletic performance[30]. For instance, the performance of trained cyclists in a 40-kilometer time trial can be most accurately predicted by adjusting VO₂max relative to body weight (W/kg)[31]. For activities requiring high power and speed generation in a short time, such as jumping, sprinting, and throwing, improvements in VO₂max may have a significant impact on performance. These activities often demand a high rate of force development (RFD) from athletes. Previous studies designed multivariate regression models to analyze the determinants of VO₂max, identifying oxygen transport capacity as the primary factor[32]. Therefore, the improvement in VO₂max induced by RIPC may be a key factor in enhancing athletic performance. In the studies included in our analysis, increases in VO₂max were consistently accompanied by significant improvements in athletic performance. Jeffries' study observed a 9% increase in VO₂max after seven consecutive days of IPC, along with a 3.1% improvement in muscle efficiency[15]. Halley's study reported increases in VO₂max of 6.8% and 9.6%[22], which were followed by significant improvements in 1000-meter kayak time trial performance. The effect of RIPC on VO₂max was even greater in anaerobic exercise, with increases of 11%[21]and 12%[18], along with improvements in the fatigue index during maximum aerobic capacity tests by 12.8% and 9%. In summary, RIPC may primarily enhance VO₂max by improving muscle efficiency, rate of force development, or oxygen transport capacity, thereby influencing athletic performance.

The meta-analysis also revealed that RIPC increased maximum heart rate during equivalent task exercises, although significant heterogeneity among the studies was observed, likely due to the inclusion of research conducted in hypoxic environments[28, 29]. This may indicate an improvement in cardiovascular health, where the heart becomes stronger and more efficient at pumping blood after RIPC, allowing it to work at a higher heart rate during equivalent tasks, thus suggesting improved endurance and efficiency of the heart[33]. Additionally, an increase in heart rate is commonly associated with sympathetic nervous system activation, which may suggest that RIPC leads to greater activation of the autonomic nervous system during exercise[34]. Heart rate changes in athletes are often used to reflect adaptation to exercise load. When RIPC leads to an increase in maximum heart rate under the same task level, it may suggest a decreased adaptation to the current load, implying a potential decrease in performance. However, because our study included research conducted in hypoxic environments, where exercise-induced heart rate changes may follow entirely different mechanisms, the increase in heart rate observed after RIPC under equivalent task levels in hypoxic environments may indicate an increase in cardiac output or ventilation[28].

However, our study did not observe significant changes in blood lactate or VO₂max. This could be due to the limited number of available studies and small sample sizes. Additionally, most of the included studies measured aerobic exercise, with fewer studies focusing on anaerobic exercise (see Fig. 6). As a result, the combined data did not show significant changes in blood lactate. Studies specifically investigating the impact of RIPC on VO₂max generally concluded that RIPC does not lead to any beneficial changes in VO₂max [15, 19, 20, 27]. Given that one of our subgroup analyses found that RIPC was ineffective in improving aerobic performance, the lack of significant changes in VO₂max is reasonable and supports the consistency of the study results.

Exercise Modality and Subject Training Level

Our meta-analysis results indicate that RIPC significantly enhances anaerobic performance but provides insufficient evidence to reject the null hypothesis for aerobic training, suggesting that RIPC may be ineffective in improving aerobic performance. This finding contradicts our initial hypothesis. Additionally, our results show that RIPC significantly enhances athletic performance in untrained individuals, while the effect is not significant in trained elite athletes. We believe these two points are related and can be explained through the physiological mechanisms of RIPC.

In the field of research on the physiological mechanisms by which RIPC enhances athletic performance, few studies have focused on the myocardium, with most concentrating on changes in the vascular system. In the limited mechanistic studies available, improvements in vascular structure and function were consistently observed. Kimura found that repeated late-phase IPC stimulation enhanced endothelium-dependent vasodilation in humans by increasing local nitric oxide production and the number of endothelial progenitor cells (EPCs) under localized conditions[9]. Luca et al. also found that seven consecutive days of IPC provided sustained protection against ischemia-reperfusion injury in the peripheral artery endothelium[35]. Jones observed that seven days of repeated IPC improved vascular structure and function, increasing endothelium-dependent vasodilation (+ 9%) and vascular conductance (+ 14%)[36]. In fact, eight weeks of RIPC also enhanced brachial artery flow-mediated dilation (FMD)[37]. Jeffries observed an increase in microvascular oxygenation[14].

The vascular structure and functional improvements induced by RIPC are primarily due to the increased production of circulating factors such as NO and VEGF, resulting from occlusive pressure, tissue ischemia, and the shear stress and hypoxia generated during reperfusion. Bolli et al. proposed that NO plays an essential role in the initiation of the late phase of IPC[38]. These findings suggest that the beneficial effects of repeated IPC are due to the activation of endothelial nitric oxide synthase (eNOS), leading to increased NO production. The increased shear stress caused by increased blood flow can stimulate NO release in isolated blood vessels and cultured cells[39]. Repeated IPC can upregulate eNOS mRNA and eNOS protein levels. It is believed that mechanosensors on the endothelial cell membrane (such as caveolae, G proteins, ion channels, and integrins) can sense shear stress and convert the stimulus into biochemical signals, which then activate several pathways, including the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) and c-Src pathways, leading to increased eNOS activity[40–42].

It is noteworthy that RIPC also has a remote effect, with shear stress being unlikely to be the primary mechanism behind the remote effects of IPC, as the increase in shear stress in remote areas is minimal[36]. The systemic stimuli or circulating markers activated by IPC are more likely to explain the remote improvement in conduit artery endothelial function. For example, IPC leads to an increase in VEGF and EPCs, which may improve endothelial function in remote areas. During the IPC process, the prominent tissue ischemia and shear stress are key stimuli for releasing EPCs from the bone marrow into circulation[36]. Under hypoxic conditions, VEGF gene expression is upregulated, inducing hypoxia-inducible factor-1 (HIF-1)[43], leading to an increase in EPCs. Endothelial function has been found to correlate with the number of circulating EPCs. IPC is believed to enhance endothelial function by increasing EPCs[44]. Studies have shown that VEGF-induced and ischemia-induced mobilization of bone marrow-derived EPCs contributes to angiogenesis[45], resulting in increased capillary density.

RIPC also enhances the antioxidative stress capacity and oxidative capacity of skeletal muscles, another physiological mechanism of RIPC. Previous work has demonstrated the anti-inflammatory effects of repeated RIPC, improving antioxidant defense mechanisms (e.g., increased superoxide dismutase activity), with 10 days of RIPC reducing neutrophil adhesion[46]. RIPC improves antioxidant defense mechanisms and/or reduces the production of oxidative stress. Lindsay observed a reduction in oxidative stress biomarkers, indicating an enhanced ability to scavenge free radicals and reduce the production of reactive oxygen species (ROS) during exercise. Smaller disturbances in inflammation and oxidative stress would reduce the impact on skeletal muscle contraction characteristics, allowing for more sustainable and repeatable anaerobic performance[21].

In Mieszkowski's study, repeated IPC on the arms led to a significant increase in ferritin gene expression. Given that ferritin is a crucial component of antioxidant defense, it can be hypothesized that this leads to higher resistance to oxidative stress in PBMCs and other cells[23]. The enhanced oxidative capacity is primarily due to the improved ability of mitochondria to produce ATP through oxidation. Jeffries' experiment confirmed that by performing four 5-minute arterial occlusions and equivalent durations of reperfusion over seven days, skeletal muscle oxidative capacity increased by 13%, and resting muscle metabolism decreased by 16%[14]. The improved mitochondrial efficiency is speculated to result from enhanced mitochondrial capacity induced by hypoxia itself, improving oxidative function at rest and after exercise. Another explanation is that repeated ischemic exercise increased PGC-1α mRNA levels and oxidative stress markers, leading to enhanced mitochondrial function through ROS production and subsequent AMPK pathway activation. The increase in muscle efficiency brought about by RIPC observed in Jeffries' study corroborates previous findings, further suggesting that increased mitochondrial efficiency leads to improved muscle efficiency[15].

From the perspective of exercise modality, aerobic exercise can improve endothelial function by increasing nitric oxide (NO) production[47], particularly by enhancing flow-mediated dilation (FMD). The potential mechanisms by which aerobic exercise improves vascular endothelial function include increasing NO bioavailability and reducing inflammatory factors[48]. It can be seen that the mechanism by which aerobic exercise enhances endothelial function is similar to that of RIPC, and aerobic-trained athletes, with their well-developed slow-twitch muscle fibers, contain a greater number of mitochondria and capillaries, resulting in adaptive changes in the vascular system. There is less research on the effects of anaerobic exercise on vascular structure and function. A meta-analysis by Cortes (2023) on the effects of aerobic and anaerobic training on endothelial function in overweight and obese individuals found that the evidence for anaerobic training was insufficient to reject the null hypothesis, indicating no improvement in endothelial function[49]. Research in this area is conflicting. Some studies suggest that aerobic and anaerobic exercise may have similar effects on improving vascular function. For example, a randomized controlled trial found that both aerobic exercise, anaerobic exercise, and their combination significantly improved vascular endothelial-dependent dilation (FMD) and reduced blood pressure[50]. Anaerobic exercise may promote vascular adaptation by increasing blood flow shear stress. However, other studies have indicated that aerobic exercise may be more effective than anaerobic exercise in improving FMD[51]. Therefore, the effects of RIPC on vascular structure and function may be overshadowed by the effects of aerobic training, while anaerobic exercise, compared to aerobic exercise, does not produce these effects, making the benefits of RIPC more apparent in anaerobic performance.

The production of oxidative stress depends on the exercise modality and intensity[52]. Anaerobic exercise may generate more ROS, requiring a more effective antioxidant defense system to prevent damage. While anaerobic training also increases mitochondrial density, it focuses more on the muscle cells' ability to generate energy quickly. Anaerobic athletes have fewer mitochondria in their fast-twitch muscle fibers compared to slow-twitch fibers, but these mitochondria are more efficient at producing ATP through oxidation. Jeffries' study also observed that RIPC improved muscle oxidative capacity, reduced resting metabolism, and enhanced muscle efficiency[14, 15]. Moreover, our research reported that RIPC improved VO₂max and enhanced anaerobic performance (11%, 12%)[18, 21]more than aerobic performance (9%, 6.8%, and 9.6%)[15, 22]. In summary, these changes may be more beneficial for anaerobic performance.

The adaptive changes in vascular function and the enhanced oxidative and antioxidative stress capacity induced by RIPC also explain why RIPC has a less significant effect on enhancing athletic performance in trained athletes but a more pronounced effect in untrained individuals. Prolonged exercise training leads to adaptive changes in vascular structure and function, as well as increased oxidative capacity and antioxidative stress levels. Research suggests that RIPC may also provide greater benefits in improving exercise capacity for sedentary individuals, those with reduced physical activity, or those recovering from training cessation[14].

It is worth noting that the studies included in our analysis all mentioned the importance of responders in interpreting the results. Jeffries noted that their study had a responder rate of up to 70% among participants[15], which may have influenced the final results. Lindsay's study concluded that RIPC did not enhance athletic performance, but there were 2 and 3 responders in the two groups, respectively[19]. A review of 17 IPC studies reported a responder rate of approximately 67%[53]. Slysz specifically studied the response to RIPC and found that the majority (75%) of participants improved their cycling performance, with no gender differences in response[4]. Interestingly, all three of these studies involved athletes, suggesting that differences in individual responses may be due to physiological differences resulting from varying levels of training. Future research is needed to confirm this.

Dose and Timing

Our meta-analysis results indicate that RIPC doses lasting one week or more, with more than six sessions, show a combined overall effect that is sufficient to reject the null hypothesis. Thus, it is considered effective to use an IPC dose lasting more than one week to enhance athletic performance. Moreover, the results did not show significant differences regardless of the testing time after RIPC completion, suggesting that the timing between the RIPC procedure and the start of exercise is not a critical factor. This can be explained by another mechanism of RIPC.

The enhancement of athletic performance through RIPC may be due to the combination of early and late protective effects of IPC. Studies have shown that the infarct protection effect of IPC is present 1–2 hours after the onset of IPC (early phase) and recurs 24 hours later, lasting for 3–4 days (late phase)[8]. Although this description relates to the protection of ischemic myocardium, this pattern may also affect peripheral blood vessels[54]. Therefore, repeated IPC cycles can be spaced 24–72 hours apart to ensure that tissues are exposed to both the early and late phases of protection. Combining these effects may have clinical relevance, as the early and late phases may involve different protective mechanisms[55]. Considering the relatively long duration of the late protection phase, Jones (2015) explored whether less frequent RIPC exposure could induce vascular adaptation and found that eight weeks of IPC (three cycles per week) significantly improved athletic performance[37]. Shannon applied RIPC three times a week for two weeks and observed significant improvements in anaerobic capacity[18]. Thus, the repeated activation of these effects may explain the benefits of RIPC[54].

A notable exception is Halley (2020), who only applied two RIPC sessions but still observed significant improvements in athletic performance, greater than those achieved with a single IPC session. This study does not contradict our conclusions because the two IPC sessions occurred on the same day, with a 60-minute interval between them, likely representing an accumulation of the early IPC effects. Mechanistically, RIPC produces its enhancement effects primarily by inducing physiological adaptations in the body. Therefore, a duration of less than one week with only two or three RIPC sessions is insufficient to induce these changes and, consequently, unable to enhance athletic performance.

However, this study did not explore the relationship between the duration of RIPC and the number of repeated sessions, as no standardized protocol exists. In studies lasting more than one week but less than two weeks, IPC procedures were conducted daily. In contrast, Shannon and Tanaka's studies lasted two weeks, with Shannon conducting only six IPC sessions, resulting in improved anaerobic performance. This is consistent with previous research[37], which suggests that the late phase of IPC lasts long enough that daily continuous intervention may not be necessary to achieve the benefits of RIPC. Thus, continuous daily IPC may not be the optimal method for obtaining the enhancement benefits of RIPC.

The timing between the end of the RIPC procedure and the start of exercise can also be explained by the early and late effects. The benefits observed immediately after the last RIPC procedure and lasting for 1–2 hours may represent the early IPC effects, while the benefits observed at later time points may be due to the late phase effects or physiological adaptations of the body. Therefore, enhancement effects can be observed with time intervals as short as less than 1 hour[22, 28], 24 hours[18, 21], or even up to 72 hours[15].

Comparison Between RIPC and AIPC

Our meta-analysis shows that the evidence comparing the effects of RIPC and AIPC does not allow us to reject the null hypothesis, although there is a trend toward showing an effect. It remains unclear whether RIPC provides a greater enhancement effect than acute IPC, as the research evidence does not fully support our hypothesis. Even when assuming a significant effect, the magnitude of the enhancement was small. Upon analyzing each study's data, we found that Slysz's study was a key factor influencing the final result. Slysz applied RIPC three times (48h, 24h, 15min intervals) and found no greater enhancement with RIPC compared to a single application[4]. However, we believe that the three consecutive days of RIPC in that study may have only included 1–2 overlapping windows of early and late effects, making it difficult to fully manifest the cumulative benefits of both phases. Due to the limited number of relevant studies—only four—along with small doses in the studies by Halley and Slysz, and Seeley's study being conducted in a unique hypoxic environment, the current results should be viewed with caution. The enhancement effect of RIPC compared to acute IPC is still inconclusive and requires further research. We believe that with more evidence, it may become clearer that RIPC has a greater enhancement effect than AIPC.

Limitations

Due to the limited number of studies, this paper did not investigate the effects of gender, age, and application site as influencing factors. Subgroup analyses were conducted based on power and heart rate outcomes, but due to the limited data, we could not compare blood lactate and maximal oxygen uptake, leading to potential selection bias that could affect the final results. Our study also included research on RIPC conducted in unique environments, resulting in significant heterogeneity. The small number of included studies highlights the need for further research.

The current meta-analysis demonstrates that repeated ischemic preconditioning (RIPC) can indeed improve athletic performance. Moreover, RIPC is effective for anaerobic performance but not for aerobic performance, likely because the mechanisms of RIPC are better suited to anaerobic performance enhancement. An IPC dose lasting one week or more, with more than six sessions, can produce effective improvements without the need for daily continuous application. The timing between the end of the RIPC procedure and the start of the exercise protocol is not a critical factor for achieving the enhancement effects; improvements can be observed at any time after the last IPC session. RIPC appears to offer no significant benefits for trained individuals, but it shows clear benefits for healthy, untrained individuals, indicating that the training level of the subjects is a key factor. Our study also suggests that RIPC may have a higher enhancement effect compared to AIPC, which could potentially be applied as a training method in daily routines, pending further confirmation through future research.

RIPC Repeated ischemic preconditioning

AIPC acute ischemic preconditioning

FMD Flow-Mediated Dilation

EPCs endothelial progenitor cells

VEGF Vascular Endothelial Growth Factor

NO nitric oxide

eNOS endothelial nitric oxide synthase

ROS reactive oxygen species

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and material

The data sets generated during and/or analysed during the current study are

available from the corresponding author upon reasonable request. The data sets suporting the conclusions of this article are included within the additional files.

Competing interests

The authors declare that they have no competing interests.

Funding

The present study was funded by the Department of Science and Technology of Zhejiang Province (No. 2023C03197 and No.2024C03260).

Authors' contributions

LC and ZYH contributed to the study concept and design. LC, ZYH and ZZ performed the literature search. LC, ZYH and ZZ performed the data extraction, LC, ZYH and ZZ performed full-text screening, risk-of-bias analysis, and review and editing of first draft and final draft. LC wrote the first draft of the manuscript. ZZ, HJP and HWZ critically revised the draft of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

Authors' information

¹College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, 321000, China

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AdditionalFiles.docx

Comparison of Factors and Effects of Repeated vs. Acute Ischemic Preconditioning on Enhancing Athletic Performance: A Systematic Review and Meta-Analysis

Status:

Version 1

Abstract

Figures

Key Points

Background

Methods

Protocol Registration

Literature Search Strategy

Inclusion and Exclusion Criteria

Data Extraction

Risk of Bias Assessment

Data Analysis

Results

Discussion

RIPC Can Enhance Athletic Performance

Exercise Modality and Subject Training Level

Dose and Timing

Comparison Between RIPC and AIPC

Limitations

Conclusion

Abbreviations

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and material

Competing interests

Funding

Authors' contributions

Acknowledgements

Authors' information

References

Supplementary Files

Status:

Version 1