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Utilization of Ischemic Preconditioning for Athletes Competing and Training at Altitude: Applications and Perspectives

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Abstract

Acute exposure to altitude negatively impacts exercise tolerance and reduces athletes’ race performance due to lower atmospheric and body tissues oxygen partial pressures. Chronic exposure to altitude has also been used for several decades by athletes to increase training adaptations. However, the decline in arterial oxygen saturation also impacts 'trainability' and athletes are forced to travel to lower altitude for intensified training. For the athlete preparing for altitude, the advantages of properly timed terrestrial acclimatization and/or sea-level hypoxia-based pre-acclimatization recommendations are clear. However, the associated cost, demands, and time investment make these best-practice strategies difficult or impossible to implement for many athletes. This perspective and opinion article summarizes current knowledge on the potency of ischemic preconditioning (i.e., a sequence of transient ischemic episodes followed by reperfusion) to enhance the pulmonary, vascular, and metabolic determinants of performance at altitude with the aim to derive implications to accelerate or facilitate altitude acclimatization for varied goals. We discuss potential applications for athletes and propose innovative questions for future research in this field.

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... Ischemic preconditioning is a local hypoxia method, which corresponds to a sequence of transient ischemic episodes followed by reperfusion. In an attempt to derive implications to accelerate or facilitate altitude acclimatization, Billaut et al. [2] summarized current knowledge on the potency of this practice to enhance the pulmonary, vascular, and metabolic determinants of performance at altitude. ...
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Purpose Main purposes of pre-acclimatization by hypoxia conditioning (HC) are the prevention of high-altitude illnesses and maintenance of aerobic exercise performance. However, robust evidence for those effects or evidence-based guidelines for exposure strategies, including recommendations to ensure safety, are largely lacking. Therefore, we summarize the current knowledge on the physiology of acclimatization to hypoxia and HC with the aim to derive implications for pre-acclimatization strategies before going on high-altitude treks and expeditions. Methods Based on the literature search and personal experience, core studies and important observations have been selected in order to present a balanced view on the current knowledge of high-altitude illnesses and the acclimatization process, specifically focusing on pre-acclimatization strategies by HC. Results and Conclusions It may be concluded that in certain cases even short periods (e.g., 7 h) of pre-acclimatization by HC are effective, but longer periods (e.g., > 60 h) are needed to elicit more robust effects. About 300 h of HC (intermittently applied) may be the optimal preparation for extreme altitude sojourns, although every additional hour spent in hypoxia may confer further benefits. The inclusion of hypobaric exposures (i.e., real altitude) in pre-acclimatization protocols could further increase their efficacy. The level of simulated altitude is progressively increased or individually adjusted ideally. HC should not be terminated earlier than 1–2 weeks before altitude sojourn. Medical monitoring of the pre-acclimatization program is strongly recommended.
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Background: This study assessed the effectiveness of 4 different repeated remote ischaemic preconditioning (RIPC) protocols varying in duration and frequency for preventing acute mountain sickness (AMS) after rapid ascent to high altitude. Methods: In a randomized but not blinded design, participants were assigned to receive either of the four RIPC treatments at low altitude (Group A, once daily for 1 week; Group B, twice daily for 1 week; Group C, once daily for 4 weeks; and Group D, twice daily for 4 weeks) or control (no specific sham treatment). Participants were then flown to a high altitude (3650 m). The primary outcome was the incidence and severity of AMS evaluated by the Lake Louise score (LLS) after arrival; vital signs were collected simultaneously. Results: A total of 250 participants (50 per group; mean age 38.56 ± 0.76 years) were included. The overall AMS incidence was 26.4%. A total of 20 AMS cases (40%) occurred in the control group, 15 cases (30%) both in the RIPC A and RIPC B groups (RR 1.3; 95%CI 0.8-2.3; χ2 = 1.099; p = 0.29), and 8 cases (16%) both in the RIPC C and D groups (RR 2.5; 95%CI 1.2 - 5.2; χ2 = 7.143, p < 0.01), with significantly lower LLSs in the RIPC C and D groups (F = 6.51, p < 0.001). The scores of gastrointestinal symptoms (F = 7.42, p < 0.001) and dizziness (F = 9.82, p < 0.001) but not headache (F = 0.60, p > 0.05) were lower in the RIPC groups compared to control. The blood oxygen saturation level (SpO2) decreased less in the RIPC B, C and D groups compared to control after arrival at a high altitude (F = 11.42, p < 0.001). The number of RIPC treatments received was moderately correlated with SpO2 (R = 0.38, p < 0.001), and SpO2 was moderately inversely correlated with the LLS (R = -0.48, p < 0.001). Conclusion: This study demonstrated that a four-week RIPC intervention but not a one-week regimen reduced AMS incidence and severity; however, a placebo effect might have contributed to these results.
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The aim of the present study was to determine whether ischemic preconditioning (IPC)-mediated effects on neuromuscular function are dependent on tissue oxygenation. Eleven resistance-trained males completed four exercise trials (6 sets of 11 repetitions of maximal effort dynamic single-leg extensions) in either normoxic [fraction of inspired oxygen ( F I O 2 ): 21%) or hypoxic F I O 2 : 14%] conditions, preceded by treatments of either IPC (3 × 5 min bilateral leg occlusions at 220 mmHg) or sham (3 × 5 min at 20 mmHg). Femoral nerve stimulation was utilized to assess voluntary activation and potentiated twitch characteristics during maximal voluntary contractions (MVCs). Tissue oxygenation (via near-infrared spectroscopy) and surface electromyography activity were measured throughout the exercise task. MVC and twitch torque declined 62 and 54%, respectively (MVC: 96 ± 24 N·m, Cohen's d = 2.9, P < 0.001; twitch torque: 37 ± 11 N·m, d = 1.6, P < 0.001), between pretrial measurements and the sixth set without reductions in voluntary activation (P > 0.21); there were no differences between conditions. Tissue oxygenation was reduced in both hypoxic conditions compared with normoxia (P < 0.001), with an even further reduction of 3% evident in the hypoxic IPC compared with the sham trial (mean decrease 1.8 ± 0.7%, d = 1.0, P < 0.05). IPC did not affect any measure of neuromuscular function regardless of tissue oxygenation. A reduction in F I O 2 did invoke a humoral response and improved muscle O2 extraction during exercise, however, it did not manifest into any performance benefit.NEW & NOTEWORTHY Ischemic preconditioning did not affect any facet of neuromuscular function regardless of the degree of tissue oxygenation. Reducing the fraction of inspired oxygen induced localized tissue deoxygenation, subsequently invoking a humoral response, which improved muscle oxygen extraction during exercise. This physiological response, however, did not manifest into any performance benefits.
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Purpose: The ergogenic effect of ischemic preconditioning (IPC) on endurance exercise performed in hypoxia remains debated and has never been investigated with successive exercise bouts. Therefore, we evaluated if IPC would provide immediate or delayed effects during two 5 km cycling time-trials (TTs) separated by ~1 h in hypoxia. Methods: In a counterbalanced randomized cross-over design, thirteen healthy males (27.5 ± 3.6 years) performed two maximal cycling 5 km TTs separated by ~1 h of recovery (TT1 25 min and TT2 2 h post IPC/SHAM), preceded by IPC (3 × 5 min occlusion 220 mmHg/reperfusion 0 mmHg, bilaterally on thighs) or SHAM (20 mmHg) at normobaric hypoxia (inspired fraction of oxygen [FIO2] of 16%). Performance and physiological (i.e., oxyhemoglobin saturation, heart rate, blood lactate, and Vastus Lateralis oxygenation) parameters were recorded. Results: Time to complete (P = 0.011) 5 km TT and mean power output (P = 0.005) from TT1 to TT2 were worse in SHAM, but not in IPC (P = 0.381/P = 0.360, respectively). There were no differences in time, power output or in physiological variables during the two TTs between IPC and SHAM. All muscle oxygenation indices differed (P < 0.001) during the IPC/SHAM with a greater deoxygenation in IPC. During the TTs, there was a greater concentration of total hemoglobin ([tHb]) in IPC than SHAM (P = 0.047) and greater [tHb] in TT1 than TT2. Further, the concentration of oxyhemoglobin ([O2Hb]) was lower during TT2 than TT1 (P = 0.005). Conclusion: In moderate hypoxia, IPC allowed maintaining a higher blood volume during a subsequent maximal exercise, mitigating the performance decrement between two consecutive cycling time-trials.
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Introduction: Ischemic preconditioning (IPC) before exercise has been shown to be a novel approach to improve performance in different exercise modes in normoxia (NORM). Few studies have been conducted examining potential mechanisms behind these improvements, and less has been done examining its influence during exercise in hypoxia (HYP). Oxygen uptake and extraction kinetics are factors that have been implicated as possible determinants of cycling performance. We hypothesized that IPC would lead to improvements in oxygen extraction and peripheral blood flow kinetics, and this would translate to improvements in cycling time trial (TT) performance in both NORM and HYP. Methods: Thirteen men (age, 24 ± 7 yr; V˙O2max, 63.1 ± 5.1 mL·kg·min) participated in the study. Subjects completed trials of each combination of normobaric HYP (FiO2 = 0.16, simulating ~8000 ft/2500 m) or NORM (FiO2 = 0.21) with preexercise IPC protocol (4 × 5 min at 220 mm Hg) or SHAM procedure. Trials included submaximal constant load cycle exercise bouts (power outputs of 15% below gas exchange threshold, and 85% of V˙O2max), and a 5-km cycling performance TT. Results: Ischemic preconditioning significantly improved 5-km TT time in NORM by 0.9% ± 1.8% compared with SHAM (IPC, 491.2 ± 35.2 s vs SHAM, 495.9 ± 36.0 s; P < 0.05). Ischemic preconditioning did not alter 5-km TT performance times in HYP (P = 0.231). Ischemic preconditioning did, however, improve tissue oxygen extraction in HYP (deoxygenated hemoglobin/myoglobin: IPC, 21.23 ± 10.95 μM; SHAM, 19.93 ± 9.91 μM; P < 0.05) during moderate-intensity exercise. Conclusions: Our data confirm that IPC is an effective ergogenic aid for athletes performing 5-km cycling TT bouts in NORM. Ischemic preconditioning did mitigate the declines in tissue oxygen during moderate-intensity exercise in HYP, but this did not translate to a significant effect on mean group performance. These data suggest that IPC may be of benefit for athletes training and competing in NORM.
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Purpose: Research dealing with ischemic preconditioning (IPC) has primarily focused on variables associated to endurance performance with little research about the acute responses of IPC on repeated multidirectional running sprint performance. Here we aimed to investigate the effects of IPC of the arms and the legs on repeated running sprint performance with changes-of-direction (COD) movements. Methods: Thirteen moderately-to-well-trained team-sport athletes (7 males; 6 females; age: 24 ± 2 years, size: 175 ± 8 cm, body mass: 67.9 ± 8.1 kg) performed 16 × 30 m all-out sprints (15 s rest) with multidirectional COD movements on a Speedcourt with IPC (3 × 5 min) of the legs (IPCleg; 240 mm Hg) or of the arms (remote IPC: IPCremote; 180–190 mm Hg) 45 min before the sprints and a control trial (CON; 20 mm Hg). Results: The mean (±SD) time for the 16 × 30 m multidirectional COD sprints was similar between IPCleg (Mean t: 16.0 ± 1.8 s), IPCremote (16.2 ± 1.7 s), and CON (16.0 ± 1.6 s; p = 0.50). No statistical differences in oxygen uptake (mean difference: 0%), heart rate (1.1%) nor muscle oxygen saturation of the vastus lateralis (4.7%) and biceps brachii (7.8%) between the three conditions were evident (all p > 0.05). Conclusions: IPC (3 × 5 min) of the legs (220 mm Hg) or arms (180–190 mm Hg; remote IPC) applied 45 min before 16 × 30 m repeated multidirectional running sprint exercise does not improve sprint performance, oxygen uptake, heart rate nor muscle oxygen saturation of the vastus lateralis muscle when compared to a control trial.
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Introduction: Ischaemic preconditioning (IPC) may enhance endurance performance. No previous study has directly compared distinct IPC protocols for optimal benefit. The aim of this study was to determine whether a specific IPC protocol (i.e. number of cycles, amount of muscle tissue, and local vs remote occlusion) elicits greater performance outcome. Methods: Twelve cyclists performed five different IPC protocols 30-min prior to a blinded 375 kJ cycling time trial (TT) in a laboratory. Responses to traditional IPC (4x5-min legs) were compared to: i. 8x5-min legs and SHAM ("dose-cycles"), ii. 4x5-min unilateral legs ("dose-tissue"), and iii. 4x5-min arms ("remote"). RPE and blood lactate were recorded at each 25% TT completion. Power (watts), heart rate (bpm), and V̇O2 (ml.kg.min(-1)) were measured continuously throughout TT's. Magnitude based inference statistics were employed to compare variable differences to the minimal practically important difference. Results: Traditional IPC was associated with a 17 (0, 34) secs faster TT time compared to SHAM. Applying more "dose-cycles" (8x5-min) had no impact on performance. Traditional IPC was associated with "likely trivial" higher blood lactate and "possibly beneficial" lower V̇O2 responses vs. SHAM. Unilateral IPC was associated with 18 (-11, 48) secs slower performance compared to bilateral ("dose-tissue"). TT times following remote and local IPC were not different [0 (-16, 16) secs]. Conclusion: The traditional 4x5-min (local or remote) IPC stimulus resulted in the fastest TT time compared to SHAM, there was no benefit of applying a greater number of cycles or employing unilateral IPC.
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Constantini, Keren, Daniel P. Wilhite, and Robert F. Chapman. A clinician guide to altitude training for optimal endurance exercise performance at sea level. High Alt Med Biol 00:000-000, 2017.-For well over 50 years, endurance athletes have been utilizing altitude training in an effort to enhance performance in sea level competition. This brief review will offer the clinician a series of evidence-based best-practice guidelines on prealtitude and altitude training considerations, which can ultimately maximize performance improvement outcomes.
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Background Repeated-sprint training in hypoxia (RSH) is a recent intervention regarding which numerous studies have reported effects on sea-level physical performance outcomes that are debated. No previous study has performed a meta-analysis of the effects of RSH. Objective We systematically reviewed the literature and meta-analyzed the effects of RSH versus repeated-sprint training in normoxia (RSN) on key components of sea-level physical performance, i.e., best and mean (all sprint) performance during repeated-sprint exercise and aerobic capacity (i.e., maximal oxygen uptake [\(\dot{V}{\text{O}}_{2\hbox{max} }\)]). Methods The PubMed/MEDLINE, SportDiscus®, ProQuest, and Web of Science online databases were searched for original articles—published up to July 2016—assessing changes in physical performance following RSH and RSN. The meta-analysis was conducted to determine the standardized mean difference (SMD) between the effects of RSH and RSN on sea-level performance outcomes. ResultsAfter systematic review, nine controlled studies were selected, including a total of 202 individuals (mean age 22.6 ± 6.1 years; 180 males). After data pooling, mean performance during repeated sprints (SMD = 0.46, 95% confidence interval [CI] −0.02 to 0.93; P = 0.05) was further enhanced with RSH when compared with RSN. Although non-significant, additional benefits were also observed for best repeated-sprint performance (SMD = 0.31, 95% CI −0.03 to 0.89; P = 0.30) and \(\dot{V}{\text{O}}_{2\hbox{max} }\) (SMD = 0.18, 95% CI −0.25 to 0.61; P = 0.41). Conclusion Based on current scientific literature, RSH induces greater improvement for mean repeated-sprint performance during sea-level repeated sprinting than RSN. The additional benefit observed for best repeated-sprint performance and \(\dot{V}{\text{O}}_{2\hbox{max} }\) for RSH versus RSN was not significantly different.
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We recently hypothesized that across the range of normoxia to severe hypoxia the major determinant of central motor drive (CMD) during endurance exercise switches from a predominantly peripheral origin to a hypoxic-sensitive central component of fatigue. We found that peripheral locomotor muscle fatigue (pLMF) is the prevailing factor limiting central motor drive and therefore exercise performance from normoxia to moderate hypoxia (SaO2 > 75 %). In these levels of arterial hypoxemia, the development of pLMF is confined to a certain limit which varies between humans—pLMF does not develop to this limit in more severe hypoxia (SaO2 < 70 %) and exercise is prematurely terminated presumably to protect the brain from insufficient O2 supply. Based on the observations from normoxia to moderate hypoxia, we outlined a model suggesting that group III/IV muscle afferents impose inhibitory influences on the determination of CMD of working humans during high-intensity endurance exercise with the purpose to regulate and restrict the level of exercise-induced pLMF to an “individual critical threshold.” To experimentally test this model, we pharmacologically blocked somatosensory pathways originating in the working limbs during cycling exercise in normoxia. After initial difficulties with a local anesthetic (epidural lidocaine, L3–L4) and associated loss of locomotor muscle strength we switched to an intrathecally applied opioid analgesic (fentanyl, L3–L4). These experiments were the first ever to selectively block locomotor muscle afferents during high-intensity cycling exercise without affecting maximal locomotor muscle strength. In the absence of opioid-mediated neural feedback from the working limbs, CMD was increased and end-exercise pLMF substantially exceeded, for the first time, the individual critical threshold of peripheral fatigue. The outcome of these studies confirm our hypothesis claiming that afferent feedback inhibits CMD and restricts the development of pLMF to an individual critical threshold as observed from normoxia up to moderate hypoxia.
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Acute mountain sickness (AMS) is a neurological disorder occurring when ascending too fast, too high. Remote ischemic preconditioning (RIPC) is a noninvasive intervention protecting remote organs from subsequent hypoxic damage. We hypothesized that RIPC protects against AMS and that this effect is related to reduced oxidative stress. Fourteen subjects were exposed to 18 hours of normoxia (21% oxygen) and 18 h of normobaric hypoxia (12% oxygen, equivalent to 4500 m) on different days in a blinded, randomized order. RIPC consisted of four cycles of lower limb ischemia (5 min) and 5 min of reperfusion, and was performed immediately before the study room was entered. A control group was exposed to hypoxia (12% oxygen, n = 14) without RIPC. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score of the Environmental Symptom Questionnaire. Plasma concentrations of ascorbate radicals, oxidized sulfhydryl (SH) groups, and electron paramagnetic resonance (EPR) signal intensity were measured as biomarkers of oxidative stress. RIPC reduced AMS scores (LLS: 1.9 ± 0.4 vs. 3.2 ± 0.5; AMS-C score: 0.4 ± 0.1 vs. 0.8 ± 0.2), ascorbate radicals (27 ± 7 vs. 65 ± 18 nmol/L), oxidized SH groups (3.9 ± 1.4 vs. 14.3 ± 4.6 μmol/L), and EPR signal intensity (0.6 ± 0.2 vs. 1.5 ± 0.4 × 10(6)) after 5 h in hypoxia (all P < 0.05). After 18 hours in hypoxia there was no difference in AMS and oxidative stress between RIPC and control. AMS and plasma markers of oxidative stress did not correlate. This study demonstrates that RIPC transiently reduces symptoms of AMS and that this effect is not associated with reduced plasma levels of reactive oxygen species. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
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Ischemic preconditioning (IPC) may improve blood flow and oxygen delivery to tissues, including skeletal muscle, and has the potential to improve intense aerobic exercise performance, especially that which results in arterial hypoxemia. The aim of the study was to determine the effects of IPC of the legs on peak exercise capacity (Wpeak), submaximal and peak cardiovascular hemodynamics, and peripheral capillary oxygen saturation (SpO2) in trained males at sea level (SL) and simulated high altitude (HA; 13.3% FIO2, ∼3650 m). Fifteen highly trained male cyclists and triathletes completed 2 Wpeak tests (SL and HA) and 4 experimental exercise trials (10 min at 55% altitude-specific Wpeak then increasing by 30 W every 2 min until exhaustion) with and without IPC. HA resulted in significant arterial hypoxemia during exercise compared with SL (73% ± 6% vs. 93% ± 4% SpO2, p < 0.001) that was associated with 21% lower Wpeak values. IPC did not significantly improve Wpeak at SL or HA. Additionally, IPC failed to improve cardiovascular hemodynamics or SpO2 during submaximal exercise or at Wpeak. In conclusion, IPC performed 45 min prior to exercise does not improve Wpeak or systemic oxygen delivery during submaximal or peak exercise at SL or HA. Future studies must examine the influence of IPC on local factors, such as working limb blood flow, oxygen delivery, and arteriovenous oxygen difference as well as whether the effectiveness of IPC is altered by the volume of muscle made ischemic, the timing prior to exercise, and high altitude acclimatization.
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Remote Ischemic Preconditioning (RIPC) is emerging as a new noninvasive intervention that has the potential to protect a number of organs against ischemia–reperfusion (IR) injury. The standard protocols normally used to deliver RIPC involve a number of cycles of inflation of a blood pressure (BP) cuff on the arm and/or leg to an inflation pressure of 200 mmHg followed by cuff deflation for a short period of time. There is little evidence to support what limb (upper or lower) or cuff inflation pressures are most effective to deliver this intervention without causing undue discomfort/pain in nonanesthetized humans. In this preliminary study, a dose–response assessment was performed using a range of cuff inflation pressures (140, 160, and 180 mmHg) to induce limb ischemia in upper and lower limbs. Physiological changes in the occluded limb and any pain/discomfort associated with RIPC with each cuff inflation pressure were determined. Results showed that ischemia can be induced in the upper limb at much lower cuff inflation pressures compared with the standard 200 mmHg pressure generally used for RIPC, provided the cuff inflation pressure is ~30 mmHg higher than the resting systolic BP. In the lower limb, a higher inflation pressure, (~55 mmHg > resting systolic BP), is required to induce ischemia. Cyclical changes in capillary blood O2, CO2, and lactate levels during the RIPC stimulus were observed. RIPC at higher cuff inflation pressures of 160 and 180 mmHg was better tolerated in the upper limb. In summary, limb ischemia for RIPC can be more easily induced at lower pressures and is much better tolerated in the upper limb in young healthy individuals. However, whether benefits of RIPC can also be derived with protocols delivered to the upper limb using lower cuff inflation pressures and with lesser discomfort compared to the lower limb, remains to be investigated.
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Field-based team sport matches are composed of short, high-intensity efforts, interspersed with intervals of rest or submaximal exercise, repeated over a period of 60-120 minutes. Matches may also be played at moderate altitude where the lower oxygen partial pressure exerts a detrimental effect on performance. To enhance run-based performance, team-sport athletes use varied training strategies focusing on different aspects of team-sport physiology, including aerobic, sprint, repeated-sprint and resistance training. Interestingly, 'altitude' training (i.e. living and/or training in O(2)-reduced environments) has only been empirically employed by athletes and coaches to improve the basic characteristics of speed and endurance necessary to excel in team sports. Hypoxia, as an additional stimulus to training, is typically used by endurance athletes to enhance performance at sea level and to prepare for competition at altitude. Several approaches have evolved in the last few decades, which are known to enhance aerobic power and, thus, endurance performance. Altitude training can also promote an increased anaerobic fitness, and may enhance sprint capacity. Therefore, altitude training may confer potentially-beneficial adaptations to team-sport athletes, which have been overlooked in contemporary sport physiology research. Here, we review the current knowledge on the established benefits of altitude training on physiological systems relevant to team-sport performance, and conclude that current evidence supports implementation of altitude training modalities to enhance match physical performances at both sea level and altitude. We hope that this will guide the practice of many athletes and stimulate future research to better refine training programmes.
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Nuclear magnetic resonance (NMR) imaging and spectroscopy have been applied to assess skeletal muscle oxidative metabolism. Therefore, in-vivo NMR may enable the characterization of ischemia-reperfusion injury. The goal of this study was to evaluate whether NMR could detect the effects of ischemic preconditioning (IPC) in healthy subjects. Twenty-three participants were included in two randomized crossover protocols in which the effects of IPC were measured by NMR and muscle force assessments. Leg ischemia was administered for 20 minutes with or without a subsequent impaired reperfusion for 5 minutes (stenosis model). IPC was administered 4 or 48 hours prior to ischemia. Changes in 31phosphate NMR spectroscopy and blood oxygen level-dependent (BOLD) signals were recorded. 3-Tesla NMR data were compared to those obtained for isometric muscular strength. The phosphocreatine (PCr) signal decreased robustly during ischemia and recovered rapidly during reperfusion. In contrast to PCr, the recovery of muscular strength was slow. During post-ischemic stenosis, PCr increased only slightly. The BOLD signal intensity decreased during ischemia, ischemic exercise and post-ischemic stenosis but increased during hyperemic reperfusion. IPC 4 hours prior to ischemia significantly increased the maximal PCr reperfusion signal and mitigated the peak BOLD signal during reperfusion. Ischemic preconditioning positively influenced muscle metabolism during reperfusion; this resulted in an increase in PCr production and higher oxygen consumption, thereby mitigating the peak BOLD signal. In addition, an impairment of energy replenishment during the low-flow reperfusion was detected in this model. Thus, functional NMR is capable of characterizing changes in reperfusion and in therapeutic interventions in vivo. ClinicalTrials.gov: NCT00883467.
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INTRODUCTION: Repeated ischemic preconditioning (IPC) can improve muscle and pulmonary oxygen on-kinetics, blood flow, and exercise efficiency, but these effects have not been investigated in severe hypoxia. The aim of the current study was to evaluate the effects of 7 d of IPC on resting and exercising muscle and cardio-pulmonary responses to severe hypoxia.METHODS: A total of 14 subjects received either: 1) 7 d of repeated lower-limb occlusion (4 × 5 min, 217 ± 30 mmHg) at limb occlusive pressure (IPC) or SHAM (4 × 5 min, 20 mmHg). Subjects were tested for resting limb blood flow, relative microvascular deoxyhemoglobin concentration ([HHB]), and pulmonary oxygen (Vo2p) responses to steady state and incremental exercise to exhaustion in hypoxia (fractional inspired O₂ = 0.103), which was followed by 7 d of IPC or SHAM and retesting 72 h post-intervention.RESULTS: There were no effects of IPC on maximal oxygen consumption, time to exhaustion during the incremental test, or minute ventilation and arterial oxygen saturation. However, the IPC group had higher delta efficiency based on pooled results and lower steady state Δ[HHB] (IPC ∼24% vs. SHAM ∼6% pre to post), as well as slowing the [HHB] time constant (IPC ∼26% vs. SHAM ∼3% pre to post) and reducing the overshoot in [HHB]: Vo₂ ratio during exercise onset.CONCLUSIONS: Collectively, these results demonstrate that muscle O₂ efficiency and microvascular O₂ distribution can be improved by repeated IPC, but there are no effects on maximal exercise capacity in severe hypoxia.Chopra K, Jeffries O, Tallent J, Heffernan S, Kilduff L, Gray A, Waldron M. Repeated ischemic preconditioning effects on physiological responses to hypoxic exercise. Aerosp Med Hum Perform. 2022; 93(1):13-21.
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Remote ischemic conditioning (RIC) confers protection on major organs from hypoxic/ischemic injuries; however, its impacts on attention network function and blood oxygen levels in unacclimatized adults exposed to high altitudes have yet to be elucidated. In this study, we recruited 120 healthy male volunteers, of which one was exposed to high altitude and the other was exposed to low altitude. The two cohorts were further divided into RIC and sham control groups. The attentional network test (ANT) was performed to evaluate cognitive function before and after RIC treatment. Other outcomes such as heart rate, blood pressure, blood oxygen saturation, cerebral tissue oxygenation index (CTOI), and cerebrovascular hemodynamic indices were also evaluated. Prior to RIC treatment, there were no significant differences in orienting or executive function between the treatment and control arms of either cohort. Alerting function was significantly lower in the high-altitude cohort than in the low-altitude cohort. There were significant reductions in both blood oxygen and CTOI in the high-altitude cohort relative to the low-altitude cohort, while the pulse index (PI) of the former cohort was significantly increased. After RIC treatment, there was a significant difference in alerting function between the high-altitude RIC group and its associated control. The CTOI of the treatment group increased from 60.39±3.40% to 62.78±4.40%, and blood oxygenation also improved. Furthermore, this group showed a significant reduction in its PI. Exposure to high-altitude environments had a significant impact on alerting function, blood oxygen, CTOI, and PI. RIC ameliorated changes in attentional function, as well as blood oxygen and CTOI, suggesting that it potentially alters cerebrovascular compliance upon exposure to high altitude.
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Fracture healing in elderly patients is an emerging public health concern. As non-drug treatments, intermittent hypoxia training (IHT) and remote ischemic preconditioning (RIPC) are considered to have substantial advantages and to aid fracture healing in elderly patients. The purpose of the present study was to evaluate and compare the effects of IHT and RIPC on fracture healing. Micro-computed tomography (micro-CT) and biomechanical testing were used to assess the morphology and structural properties of bone callus dissected from aged rats with tibial fractures. In addition, hypoxia-inducible factor-1α (HIF-1α) and its target gene, associated with the healing process, were investigated by reverse transcription-quantitative polymerase chain reaction and western blot analyses. The micro-CT-based parameters, including bone mineral density and trabecular number, were measured, and significant differences were identified between the experimental and control groups. The IHT group exhibited superior bone formation and mineralization rates compared with the RIPC group. The biomechanical testing revealed that the ultimate loading and stiffness values were significantly higher in the IHT group compared with those in the RIPC group. In accordance with previous studies, RIPC exerted a similar effect in increasing the expression of HIF-1α, and its downstream genes, throughout the course of healing. In addition, the IHT group exhibited increased expression levels of HIF-1α compared with the RIPC group. Taken together, the results suggested that IHT and RIPC significantly enhanced fracture healing; however, IHT exhibited superior bone formation and healing effects compared with RIPC.
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Objective: To quantify the effects of acute hypoxic exposure on exercise capacity and performance, which includes continuous and intermittent forms of exercise. Design: A systematic review was conducted with a three-level mixed effects meta-regression. The ratio of means method was used to evaluate main effects and moderators providing practical interpretations with percentage change. Data Sources: A systemic search was performed using 3 databases (Google scholar, PubMed and SPORTDiscus). Eligibility criteria for selecting studies: Inclusion was restricted to investigations that assessed exercise performance (time trials, sprint, and intermittent exercise tests) and capacity (time to exhaustion test (TTE)) with acute hypoxic (< 24 hrs) exposure and a normoxic comparator. Results: Eighty-two outcomes from 53 studies (N = 798) were included in this review. The results show an overall reduction in exercise performance/capacity -17.8 ± 3.9% (95% CI -22.8% to -11.0%), which was significantly moderated by -6.5 ± 0.9% per 1000 m altitude elevation (95% CI -8.2% to -4.8%) and oxygen saturation (-2.0 ± 0.4% 95% CI -2.9% to -1.2%). Time trial (-16.2 ± 4.3%; 95% CI -22.9% to -9%) and TTE (-44.5 ± 6.9%; 95% CI -51.3% to -36.7%) elicited a negative effect, whilst indicating a quadratic relationship between hypoxic magnitude and both TTE and TT performance. Furthermore, exercise < 2-min exhibited no ergolytic effect from acute hypoxia. Summary/ Conclusion: This review highlights the ergolytic effect of acute hypoxic exposure; which is curvilinear for TTE and TT performance with increasing hypoxic levels, but short-duration intermittent and sprint exercise seem to be unaffected.
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Purpose: Endurance athletes often compete and train at altitude where exercise capacity is reduced. Investigating acclimation strategies is therefore critical. Ischemic preconditioning (IPC) can improve endurance performance at sea level through improved O2 delivery and utilization, which could also prove beneficial at altitude. However, data are scarce and there is no study at altitudes commonly visited by endurance athletes. Methods: In a randomized, crossover study, we investigated performance and physiological responses in thirteen male endurance cyclists during four 5-km cycling time trials (TT), preceded by either IPC (3x5-minutes ischemia/5-minutes reperfusion cycles at 220 mmHg) or SHAM (20 mmHg) administered to both thighs, at simulated low (FIO2 0.180, ~1200 m) and moderate (FIO2 0.154, ~2400 m) altitudes. Time to completion, power output, cardiac output (Q), arterial O2 saturation (SpO2), quadriceps tissue saturation index (TSI) and ratings of perceived exertion (RPE) were recorded throughout the TT. Differences between IPC and SHAM were analyzed at every altitude using Cohen's effect size (ES) and compared to the smallest worthwhile change. Results: At low altitude, IPC possibly improved time to complete the TT (-5.2sec, -1.1%, Cohen's ES ± 90% confidence limits -0.22, -0.44;0.01), power output (2.7%, ES 0.21, -0.08;0.51) and Q (5.0%, ES 0.27, 0.00;0.54), but did not alter SpO2, muscle TSI and RPE. At moderate altitude, IPC likely enhanced completion time (-7.3sec, -1.5%, ES -0.38, -0.55;-0.20) and power output in the second half of the TT (4.6%, ES 0.28, -0.15;0.72), increased SpO2 (1.0%, ES 0.38, -0.05;0.81), and decreased TSI (-6.5%, ES -0.27, -0.73;0.20) and RPE (-5.4%, ES -0.27, -0.48;-0.06). Conclusion: IPC may provide an immediate and effective strategy to defend SpO2 and enhance high-intensity endurance performance at moderate altitude.
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Remote ischemic preconditioning (RIPC) has been shown to protect remote organs, such as the brain and the lung, from damage induced by subsequent hypoxia or ischemia. Acute mountain sickness (AMS) is a syndrome of nonspecific neurologic symptoms and in high-altitude pulmonary edema excessive hypoxic pulmonary vasoconstriction (HPV) plays a pivotal role. We hypothesized that RIPC protects the brain from AMS and attenuates the magnitude of HPV after rapid ascent to 3,450 m. Forty nonacclimatized volunteers were randomized into two groups. At low altitude (750 m) the RIPC group (n = 20) underwent 4 × 5 min of lower-limb ischemia (induced by inflation of bilateral thigh cuffs to 200 mmHg) followed by 5 min of reperfusion. The control group (n = 20) underwent a sham protocol (4 × 5 min of bilateral thigh cuff inflation to 20 mmHg). Thereafter, participants ascended to 3,450 m by train over 2 h and stayed there for 48 h. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score. Systolic pulmonary artery pressure (SPAP) was assessed by transthoracic Doppler echocardiography. RIPC had no effect on the overall incidence (RIPC: 35%, control: 35%, P = 1.0) and severity (RIPC vs. Control: P = 0.496 for LLS; P = 0.320 for AMS-C score) of AMS. RIPC also had no significant effect on SPAP [maximum after 10 h at high altitude; RIPC: 33 (SD 8) mmHg; controls: 37 (SD 7) mmHg; P = 0.19]. This study indicates that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate AMS and the magnitude of high-altitude pulmonary hypertension.NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) has been reported to improve neurologic and pulmonary outcome following an acute ischemic or hypoxic insult, yet the effect of RIPC for protecting from high-altitude diseases remains to be determined. The present study shows that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate acute mountain sickness and the degree of high-altitude pulmonary hypertension. Therefore, RIPC cannot be recommended for prevention of high-altitude diseases.
Article
Application of repeated short duration bouts of ischemia to the limbs, termed remote ischemic preconditioning (RIPC), is a novel technique that may have protective effects on vascular function during hypoxic exposures. In separate parallel-design studies, at sea-level (SL; n = 16), and after 8-12 days at high-altitude (HA; n = 12; White Mountain, 3800 m), participants underwent either a sham protocol or one session of 4 × 5 minutes of dual-thigh cuff occlusion with 5 minutes recovery. Brachial artery flow-mediated dilation (FMD; ultrasound), pulmonary artery systolic pressure (PASP; echocardiography), and internal carotid artery flow (ICA; ultrasound) were measured at SL in normoxia and isocapnic hypoxia [end-tidal PO₂ (PETO₂) maintained to 50 mmHg], and during normal breathing at HA. The hypoxic ventilatory response (HVR) was measured at each location. All measures at SL and HA were obtained at baseline (BL), 1 hour, 24 hours, and 48 hours post-RIPC or sham. At SL, RIPC produced no changes in FMD, PASP, ICA flow, end-tidal gases or HVR in normoxia or hypoxia. At HA, although HVR increased 24 hours post RIPC compared to BL (2.05 ± 1.4 vs. 3.21 ± 1.2 l min(-1) ·%SaO2 -1, P < 0.01), there were no significant differences in FMD, PASP, ICA flow, resting end-tidal gases. Accordingly, a single session of RIPC is insufficient to evoke changes in peripheral, pulmonary, and cerebral vascular function in healthy adults. Although chemosensitivity may increase following RIPC at HA, this did not confer any vascular changes. The utility of a single RIPC session seems unremarkable during acute and chronic hypoxia. This article is protected by copyright. All rights reserved.
Article
Ischemic preconditioning (IPC) enhances whole-body exercise endurance. However, it is poorly understood whether the beneficial effects originate from systemic (e. g., cardiovascular system) or peripheral (e. g., skeletal muscle) adaptations. The present study examined the effects of IPC on local muscle endurance during fatiguing isometric exercise. 12 male subjects performed sustained isometric unilateral knee-extension exercise at 20% of maximal voluntary contraction until failure. Prior to the exercise, subjects completed IPC or control (CON) treatments. During exercise trial, electromyography activity and near-infrared spectroscopy-derived deoxygenation in skeletal muscle were continuously recorded. Endurance time to task failure was significantly longer in IPC than in CON (mean±SE; 233±9 vs. 198±9 s, P<0.001). Quadriceps electromyography activity was not significantly different between IPC and CON. In contrast, deoxygenation dynamics in the quadriceps vastus lateralis muscle was significantly faster in IPC than in CON (27.1±3.4 vs. 35.0±3.6 s, P<0.01). The present study found that IPC can enhance muscular endurance during fatiguing isometric exercise. Moreover, IPC accelerated muscle deoxygenation dynamics during the exercise. Therefore, we suggest that the origin of beneficial effects of IPC on exercise performance may be the enhanced mitochondrial metabolism in skeletal muscle. © Georg Thieme Verlag KG Stuttgart · New York.
Article
Although the amount of evidence demonstrating the beneficial effects of ischemic preconditioning (IPC) on exercise performance is increasing, conclusions about its efficacy cannot yet be drawn. Therefore, the purposes of this review were to determine the effect of IPC on exercise performance and identify the effects of different IPC procedures, exercise types, and subjects' characteristics on exercise performance. The analysis comprised 19 relevant studies from 2000-2015, 15 of which were included in the meta-analyses. Effect sizes (ES) were calculated as the standardized mean difference. Overall, IPC had a small beneficial effect on exercise performance (ES = 0.43; 90% confidence interval [CI], 0.28-0.51). The largest ES were found for aerobic (ES = 0.51; 90% CI, 0.35 - 0.67) and anaerobic (ES = 0.23; 90% CI, -0.12 - 0.58) exercise. In contrast, an unclear effect was observed in power and sprint performance (ES = 0.16; 90% CI, -0.20 - 0.52). In conclusion, IPC can effectively enhance aerobic and anaerobic exercise performance.
Article
Preconditioning refers to exposure to brief episodes of potentially adverse stimuli, which protects from injury during subsequent exposures. This was first described in the heart, where episodes of ischemia/reperfusion render the myocardium resistant to subsequent ischemic injury, which is likely caused by reactive oxygen species (ROS) and pro-inflammatory processes. Protection of the heart was also found when preconditioning was performed in an organ different from the target, which is called remote ischemic preconditioning (RIPC). The mechanisms causing protection seem to include stimulation of nitric oxide synthase, increase in anti-oxidant enzymes, and down-regulation of pro-inflammatory cytokines. These pathways are also thought to play a role in high altitude diseases: High altitude pulmonary edema (HAPE) is associated with decreased bioavailability of nitric oxide and increased generation of ROS, whereas mechanisms causing acute mountain sickness (AMS) and high altitude cerebral edema (HACE) seem to involve cytotoxic effects by ROS and inflammation. Based on these apparent similarities between ischemic damage and AMS, HACE, and HAPE, it is reasonable to assume that RIPC might be protective and improve altitude tolerance. In studies addressing high altitude/hypoxia tolerance, RIPC has been shown to decrease pulmonary arterial systolic pressure in normobaric hypoxia (13% O2) and at high altitude (4342m). Our own results indicate that RIPC transiently decreases the severity of AMS at 12% O2. Thus, preliminary studies show some benefit, but clearly further experiments to establish the efficacy and potential mechanism of RIPC are needed. Copyright © 2015, Journal of Applied Physiology.
Article
Abstract Foster, Gary P., Paresh C. Giri, Douglas M. Rogers, Sophia R. Larson, and James D. Anholm. Ischemic preconditioning improves oxygen saturation and attenuates hypoxic pulmonary vasoconstriction at high altitude. High Alt Med Biol 15, 000-000. 2014.-Exposure to hypoxic environments is associated with decreased arterial oxygen saturation and increased pulmonary artery pressures. Ischemic preconditioning of an extremity (IPC) is a procedure that stimulates vasoactive and inflammatory pathways that protect remote organ systems from ongoing or future ischemic injury. To test the effects of IPC on oxygen saturation and pulmonary artery pressures at high altitude, 12 healthy adult volunteers were evaluated in a randomized cross-over trial. IPC was administered utilizing a standardized protocol. IPC or placebo was administered daily for 5 days prior to ascent to altitude. All participants were evaluated twice at 4342 m altitude (placebo and IPC conditions separated by 4 weeks, randomized). The pulmonary artery systolic pressure (PASP) at 4342 m was significantly lower in the IPC condition than the placebo condition (36±6.0 mmHg vs. 38.1±7.6 mmHg, respectively, p=0.035). Oxygen saturation at 4342 m was significantly higher with IPC compared to placebo (80.3±8.7% vs. 75.3±9.6%, respectively, p=0.003). Prophylactic IPC treatment is associated with improved oxygen saturation and attenuation of the normal hypoxic increase in pulmonary artery pressures following ascent to high altitude.
Article
Ischemic preconditioning (IPC) protects tissue against ischemia-induced injury inside and outside ischemic areas. The purpose was to examine the hypothesis that daily IPC leads to improvement in endothelial function and skin microcirculation not only in the arm exposed to IPC but also in the contralateral arm. Thirteen healthy, young, normotensive male individuals (aged 22±2 years) were assigned to 7-day daily exposure of the arm to IPC (4×5 minutes). Assessment of brachial artery endothelial function (using flow-mediated dilation (FMD)) and forearm microcirculation (cutaneous vascular conductance (CVC) at baseline and during local heating) was performed before and after 7 days to examine the local (i.e., intervention arm) and remote (i.e., control arm) effect of IPC. We repeated the assessment tests 8 days after the intervention (Post+8). FMD increased after repeated IPC (P = 0.03) and remained significantly elevated at Post+8 in the intervention (5.0±2.2%, 6.1±2.2%, and 6.6±2.3%) and contralateral arms (5.4±2.2%, 6.0±2.2%, and 7.5±2.2%). Forearm CVC also increased following repeated IPC (P = 0.006) and remained elevated at Post+8 in both arms (intervention: 0.12±0.03, 0.14±0.04, 0.16±0.04 mV/mm Hg; contralateral: 0.14±0.04, 0.015±0.04, 0.17±0.07). No interaction between IPC arm and time was evident for FMD and CVC (both P > 0.05). IPC intervention did not alter CVC responses to local heating (P > 0.05). Daily exposure to IPC for 7 days leads to local and remote improvements in brachial artery FMD and resting skin microcirculation that remain after cessation of the intervention and beyond the late phase of protection. These findings may have clinical relevance for micro- and macrovascular improvements.
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Abstract Chapman, Robert F., Abigail S. Laymon, and Benjamin D. Levine. Timing of arrival and pre-acclimatization strategies for the endurance athlete competing at moderate to high altitudes. High Alt Med Biol 14:319-324, 2013.-With the wide array of endurance sport competition offerings at moderate and high altitudes, clinicians are frequently asked about best practice recommendations regarding arrival times prior to the event and acclimatization guidelines. This brief review will offer data and current advice on when to arrive at altitude and various potential sea level-based pre-acclimatization strategies in an effort to maximize performance and minimize the risk of altitude sickness.
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Remote ischemic preconditioning (RIPC) has emerged as a feasible and attractive therapeutic procedure for heart protection against ischemia/reperfusion (I/R) injury. However, its molecular mechanisms remain poorly understood. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that plays a key role in the cellular adaptation to hypoxia and ischemia. This study's aim was to test whether RIPC-induced cardioprotection requires HIF-1α upregulation to be effective. In the first study, wild-type mice and mice heterozygous for HIF1a (gene encoding the HIF-1α protein) were subjected to RIPC immediately before myocardial infarction (MI). RIPC resulted in a robust HIF-1α activation in the limb and acute cardioprotection in wild-type mice. RIPC-induced cardioprotection was preserved in heterozygous mice, despite the low HIF-1α expression in their limbs. In the second study, the role of HIF-1α in RIPC was evaluated using cadmium (Cd), a pharmacological HIF-1α inhibitor. Rats were subjected to MI (MI group) or to RIPC immediately prior to MI (R-MI group). Cd was injected 180minutes before RIPC (Cd-R-MI group). RIPC induced robust HIF-1α activation in rat limbs and significantly reduced infarct size (IS). Despite Cd's inhibition of HIF-1α activation, RIPC-induced cardioprotection was preserved in the Cd-R-MI group. RIPC applied immediately prior to MI increased HIF-1α expression and attenuated IS in rats and wild-type mice. However, RIPC-induced cardioprotection was preserved in partially HIF1a-deficient mice and in rats pretreated with Cd. When considered together, these results suggest that HIF-1α upregulation is unnecessary in acute RIPC.
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Field-based team sport matches are composed of short, high-intensity efforts, interspersed with intervals of rest or submaximal exercise, repeated over a period of 60–120 minutes. Matches may also be played at moderate altitude where the lower oxygen partial pressure exerts a detrimental effect on performance. To enhance run-based performance, team-sport athletes use varied training strategies focusing on different aspects of team-sport physiology, including aerobic, sprint, repeated-sprint and resistance training. Interestingly, ‘altitude’ training (i.e. living and/or training in O2-reduced environments) has only been empirically employed by athletes and coaches to improve the basic characteristics of speed and endurance necessary to excel in team sports. Hypoxia, as an additional stimulus to training, is typically used by endurance athletes to enhance performance at sea level and to prepare for competition at altitude. Several approaches have evolved in the last few decades, which are known to enhance aerobic power and, thus, endurance performance. Altitude training can also promote an increased anaerobic fitness, and may enhance sprint capacity. Therefore, altitude training may confer potentially-beneficial adaptations to team-sport athletes, which have been overlooked in contemporary sport physiology research. Here, we review the current knowledge on the established benefits of altitude training on physiological systems relevant to team-sport performance, and conclude that current evidence supports implementation of altitude training modalities to enhance match physical performances at both sea level and altitude. We hope that this will guide the practice of many athletes and stimulate future research to better refine training programmes.
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Ischemic preconditioning enhances ergometer cycling and swimming performance. We evaluated whether ischemic preconditioning of one forearm (4 times 5 min) also affects static breath-hold and underwater swimming, while the effect of similar preconditioning on ergometer rowing served as control since the warm-up for rowing regularly encompasses intense exercise and therefore reduced muscle oxygenation. Six divers performed a dry static breath-hold, 11 divers swam underwater in an indoor pool, and 14 oarsmen rowed "1000 m" on an ergometer. Ischemic preconditioning reduced the spatial resulted near-infrared determined forearm oxygen saturation from 65 ± 7% to 19 ± 7% (mean±SD; P<0.001). During the breath-hold (315 s, range 280 to 375 s) forearm oxygenation decreased to 29 ± 10% and in preparation for rowing, right thigh oxygenation decreased from 66 ± 7% to 33 ± 14% (P<0.05). Ischemic preconditioning prolonged the breath-hold from 279 ± 72 to 327 ± 39 s and the underwater swimming distance from 110 ± 16 to 119 ± 14 m (P<0.05) and also the rowing time was reduced (from 186.5 ± 3.6 to 185.7 ± 3.6 s; P<0.05). We conclude that while the effect of ischemic preconditioning (of one forearm) on ergometer rowing was minimal, probably because of reduced muscle oxygenation during the warm-up, ischemic preconditioning does enhance both static and dynamic apnea, supporting that muscle ischemia is an important preparation for physical activity.
Article
Hypoxia can have profound influences on the circulation. In humans, acute exposure to moderate hypoxia has been demonstrated to result in vasodilatation in the coronary, cerebral, splanchnic and skeletal muscle vascular beds. The combination of submaximal exercise and hypoxia produces a "compensatory" vasodilatation and augmented blood flow in contracting skeletal muscles relative to the same level of exercise under normoxic conditions. This augmented vasodilatation exceeds that predicted by a simple sum of the individual dilator responses to hypoxia alone and normoxic exercise. Additionally, this enhanced hypoxic exercise hyperaemia is proportional to the hypoxia-induced fall in arterial oxygen (O2) content, thus preserving muscle O2 delivery and ensuring it is matched to demand. Several vasodilator pathways have been proposed and examined as likely regulators of skeletal muscle blood flow in response to changes in arterial O2 content. The purpose of this review is to put into context the present evidence regarding mechanisms responsible for the compensatory vasodilatation observed during hypoxic exercise in humans. Along these lines, this review will highlight the interactions between various local metabolic and endothelial derived substances that influence vascular tone during hypoxic exercise.
Article
Strenuous exercise is associated with an immediate decrease in endothelial function. Repeated bouts of ischemia followed by reperfusion, known as remote ischemic preconditioning (RIPC), is able to protect the endothelium against ischemia-induced injury beyond the ischemic area. We examined the hypothesis that RIPC prevents the decrease in endothelial function observed after strenuous exercise in healthy men. In a randomized, crossover study, 13 healthy men performed running exercise preceded by RIPC of the lower limbs (4 × 5-min 220-mmHg bilateral occlusion) or a sham intervention (sham; 4 × 5-min 20-mmHg bilateral occlusion). Participants performed a graded maximal treadmill running test, followed by a 5-km time trial (TT). Brachial artery endothelial function was examined before and after RIPC or sham, as well as after the 5-km TT. We measured flow-mediated dilation (FMD), an index of endothelium-dependent function, using high-resolution echo-Doppler. We also calculated the shear rate area-under-the-curve (from cuff deflation to peak dilatation; SR(AUC)). Data are described as mean and 95% confidence intervals. FMD changed by <0.6% immediately after both ischemic preconditioning (IPC) and sham interventions (P > 0.30). In the sham trial, FMD changed from 5.1 (4.4-5.9) to 3.7% (2.6-4.8) following the 5-km TT (P = 0.02). In the RIPC trial, FMD changed negligibly from 5.4 (4.4-6.4) post-IPC and 5.7% (4.6-6.8) post 5-km TT (P = 0.60). Baseline diameter, SR(AUC), and time-to-peak diameter were all increased following the 5-km TT (P < 0.05), but these changes did not influence the IPC-mediated maintenance of FMD. In conclusion, these data indicate that strenuous lower-limb exercise results in an acute decrease in brachial artery FMD of ∼1.4% in healthy men. However, we have shown for the first time that prior RIPC of the lower limbs maintains postexercise brachial artery endothelium-dependent function at preexercise levels.
Article
Ischemic pre-condition of an extremity (IPC) induces effects on local and remote tissues that are protective against ischemic injury. To test the effects of IPC on the normal hypoxic increase in pulmonary pressures and exercise performance, 8 amateur cyclists were evaluated under normoxia and hypoxia (13% F(I)O(2)) in a randomized cross-over trial. IPC was induced using an arterial occlusive cuff to one thigh for 5 min followed by deflation for 5 min for 4 cycles. In the control condition, the resting pulmonary artery systolic pressure (PASP) increased from a normoxic value of 25.6±2.3 mmHg to 41.8±7.2 mmHg following 90 min of hypoxia. In the IPC condition, the PASP increased to only 32.4±3.1 mmHg following hypoxia, representing a 72.8% attenuation (p=0.003). No significant difference was detected in cycle ergometer time trial duration between control and IPC conditions with either normoxia or hypoxia. IPC administered prior to hypoxic exposure was associated with profound attenuation of the normal hypoxic increase of pulmonary artery systolic pressure.
Article
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS transcription factor consisting of HIF-1 alpha and HIF-1 beta subunits. HIF-1 alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O2 delivery or allow metabolic adaptation to reduced O2 availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia. HIF-1 expression is increased in tumor cells by multiple mechanisms and may mediate adaptation to hypoxia that is critical for tumor progression. HIF-1 thus appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.
Article
Brief episodes of nonlethal ischemia, commonly known as "ischemic preconditioning" (IP), are protective against cell injury induced by infarction. Moreover, muscle IP has been found capable of improving exercise performance. The aim of the study was the comparison of standard exercise performances carried out in normal conditions with those carried out following IP, achieved by brief muscle ischemia at rest (RIP) and after exercise (EIP). Seventeen physically active, healthy male subjects performed three incremental, randomly assigned maximal exercise tests on a cycle ergometer up to exhaustion. One was the reference (REF) test, whereas the others were performed after the RIP and EIP sessions. Total exercise time (TET), total work (TW), and maximal power output (W(max)), oxygen uptake (VO(2max)), and pulmonary ventilation (VE(max)) were assessed. Furthermore, impedance cardiography was used to measure maximal heart rate (HR(max)), stroke volume (SV(max)), and cardiac output (CO(max)). A subgroup of volunteers (n = 10) performed all-out tests to assess their anaerobic capacity. We found that both RIP and EIP protocols increased in a similar fashion TET, TW, W(max), VE(max), and HR(max) with respect to the REF test. In particular, W(max) increased by ∼ 4% in both preconditioning procedures. However, preconditioning sessions failed to increase traditionally measured variables such as VO(2max), SV(max,) CO(max), and anaerobic capacity(.) It was concluded that muscle IP improves performance without any difference between RIP and EIP procedures. The mechanism of this effect could be related to changes in fatigue perception.