Local Ischemic Preconditioning Research Articles

Comparing the protective effects of local and remote ischemic preconditioning against ischemia-reperfusion injury in hepatectomy: a systematic review and network meta-analysis.

Local ischemic preconditioning (LIPC) has been proven to be a protective strategy against hepatic ischemia-reperfusion injury (HIRI) during hepatectomy. Growing evidence suggests remote ischemic preconditioning (RIPC) has the potential to reduce liver injury in hepatectomy. Few studies have directly compared the protective effects of these two mechanical preconditioning strategies. Therefore, we performed a network meta-analysis to compare the efficacy of LIPC and RIPC for hepatic injury during liver resection. We searched Cochrane, PubMed, Embase, and China National Knowledge Infrastructure (CNKI) from the database inception to January 2023. We included studies directly comparing the effectiveness of LIPC and RIPC and those comparing LIPC or RIPC with no-preconditioning in liver resection. Postoperative liver function and surgical events were analyzed. Data were expressed as standardized mean differences (SMDs) or odds ratios (ORs) and analyzed using network meta-analysis with random effects model. Following the screening of 268 citations, we identified 26 eligible randomized clinical trials (RCTs) involving 1,476 participants (LIPC arm: 789, RIPC arm: 859, no-preconditioning arm: 1,072). LIPC and RIPC were superior to no-preconditioning in reducing postoperative serum transaminase levels [aspartate aminotransferase (AST): SMD RIPC versus no-preconditioning: -2.05, 95% confidence interval (CI): -3.39, -0.71; SMD LIPC versus no-preconditioning: -1.10, 95% CI: -2.07, -0.12; alanine aminotransferase (ALT): SMD RIPC versus no-preconditioning: -2.24, 95% CI: -4.15, -0.32; SMD LIPC versus no-preconditioning: -1.32, 95% CI: -2.63, -0.01]. No significant difference was observed between RIPC and LIPC in postoperative liver function and surgical outcomes (AST: SMD RIPC versus LIPC: -0.95, 95% CI: -2.52, 0.62; ALT: SMD RIPC versus LIPC: -0.91, 95% CI: -3.11, 1.28). In addition, the subgroup analysis revealed the potential benefits of RIPC in improving liver function, especially in patients who diagnosed with cirrhosis or underwent major resection. RIPC and LIPC could serve as effective strategies in relieving HIRI during hepatectomy. No significant differences were observed between LIPC and RIPC, however, RIPC may be an easily applicable strategy to relieve liver injury in hepatectomy.

The association between ischemic preconditioning and exercise performance: a systematic review and meta-analysis

Purpose: The present work was performed to provide an updated and comprehensive systematic review and meta-analysis on the potential ergogenic effects associated with ischemic preconditioning (IPC). In this context, this systematic review and meta-analysis aimed to determine the magnitude of the potential ergogenic effect of IPC and the influence of descriptive factors that contribute to the variability of its potential ergogenic effect. We hypothesized that IPC would be associated with improved exercise performance, and putative factors would modulate this association. Methods: On October 17, 2022, a systematic search of three databases (PubMed, Scopus, and Web of Science) was performed. The electronic search yielded 2,876 unique records, of which 79 were included in analyses after abstract and full-text screening. Eligible study designs included within subjects cross-over, sham controlled study, with a randomized or counter balanced study design. Prespecified analyses aimed to determine whether the ergogenic effect of IPC is influenced by: 1) exercise parameters (type of exercise, fraction of inspired oxygen, and muscle group(s) involved in exercise) and 2) IPC parameters (dosage, duration, and timing before onset of exercise). Results: The meta-analysis model demonstrated that exercise performance was improved with IPC compared to the sham control (pooled standard paired difference (SPD), 0.156; 95% confidence interval (CI), 0.084 to 0.227; Z = 4.258; P < 0.001; n = 105). Both remote IPC (pooled SPD, 0.219; 95% CI, 0.071 to 0.368; Z = 2.894; P = 0.004) and local IPC (pooled SPD, 0.159; 95% CI, 0.088 to 0.231; Z = 4.386; P < 0.001) demonstrated ergogenic effects on performance. Subgroup analyses based on the fraction of inspired oxygen level revealed improved exercise performance in normoxic (pooled SPD, 0.169; 95% CI, 0.100 to 0.237; Z = 4.805; P < 0.001) but not hypoxic (pooled SPD, 0.160; 95% CI, -0.029 to 0.349; Z = 1.659; P = 0.097) conditions. The most notable improvement in exercise performance following IPC was demonstrated during cycling (pooled SPD, 0.116; 95% CI, 0.023 to 0.209; Z = 2.454; P = 0.014), running (pooled SPD, 0.180; 95% CI, 0.056 to 0.303; Z = 2.847; P = 0.004), and leg press (pooled SPD, 0.421; 95% CI, 0.034 to 0.808; Z = 2.131; P = 0.033) performance tests. Conclusion: Overall, IPC demonstrated a clear ergogenic effect on exercise performance across various exercise modalities under normoxic environmental conditions. The enhanced exercise performance following IPC was most pronounced in aerobic tests of performance which predominantly recruited large muscle groups in the lower extremities: cycling, running, and leg press. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ischemic Preconditioning Acutely Improves Functional Sympatholysis during Handgrip Exercise in Healthy Males but not Females.

Ischemic preconditioning (IPC), a procedure that involves the cyclic induction of limb ischemia and reperfusion via tourniquet inflation, has been reported to improve exercise capacity and performance, but the underlying mechanisms remain unclear. During exercise, sympathetically mediated vasoconstriction is dampened in active skeletal muscle. This phenomenon, termed functional sympatholysis, plays a critical role in maintaining oxygen delivery to working skeletal muscle and may contribute to determining exercise capacity. Herein, we investigate the effects of IPC on functional sympatholysis in humans. In 20 (10M/10F) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (finger photoplethysmography) were measured during lower body negative pressure (LBNP; -20 mm Hg) applied at rest and simultaneously during rhythmic handgrip exercise (30% maximum contraction) before and after local IPC (4 × 5-min 220 mm Hg) or sham (4 × 5-min 20 mm Hg). Forearm vascular conductance (FVC) was calculated as forearm blood flow/mean arterial pressure and the magnitude of sympatholysis as the difference of LBNP-induced changes in FVC between handgrip and rest. At baseline, LBNP decreased FVC (females [F] = ∆-41% ± 19%; males [M] = ∆-44% ± 10%), and these responses were attenuated during handgrip (F = ∆-8% ± 9%; M = ∆-8% ± 7%). After IPC, LBNP induced similar decreases in resting FVC (F = ∆-37% ± 19%; M = ∆-44% ± 13%). However, during handgrip, this response was further attenuated in males (∆-3% ± 9%, P = 0.02 vs pre) but not females (∆-5% ± 10%, P = 0.13 vs pre), which aligned with an IPC-mediated increase in sympatholysis (M-pre = 36% ± 10% vs post = 40% ± 9%, P = 0.01; F-pre = 32% ± 15% vs post = 32% ± 14%, P = 0.82). Sham IPC had no effect on any variables. These findings highlight a sex-specific effect of IPC on functional sympatholysis and provide evidence of a potential mechanism underlying the beneficial effects of IPC on human exercise performance.

Pathways for Cardioprotection in Perspective: Focus on Remote Conditioning and Extracellular Vesicles

Despite the development of cutting-edge treatments, coronary artery disease (CAD) morbidity and mortality rates remain present at high levels. Therefore, new cardioprotective approaches are crucial to improve the health of patients. To date, experimental investigations of acute ischemia-reperfusion injury (IRI) have generally demonstrated the efficacy of local ischemic preconditioning and postconditioning cardioprotection techniques as well as of remote conditioning. However, application in clinical settings is still highly controversial and debated. Currently, remote ischemic conditioning (RIC) seems to be the most promising method for heart repair. Protective factors are released into the bloodstream, and protection can be transferred within and across species. For a long time, the cross-function and cross-transmission mechanisms of cardioprotection were largely unknown. Recently, it has been shown that small, anuclear, bilayered lipid membrane particles, known as extracellular vesicles (EVs), are the drivers of signal transduction in cardiac IRI and RIC. EVs are related to the pathophysiological processes of cardiovascular diseases (CVDs), according to compelling evidence. In this review, we will first review the current state of knowledge on myocardial IRI and cardioprotective strategies explored over the past 37 years. Second, we will briefly discuss the role of EVs in CVD and the most recent improvements on EVs as prognostic biomarkers, diagnostic, and therapeutic agents. We will discuss how EVs can be used as a new drug delivery mechanism and how they can be employed in cardiac treatment, also from a perspective of overcoming the impasse that results from neglecting confounding factors.

Remote and local ischemic preconditioning increases isometric strength and muscular endurance in recrea-tional trained individuals

The aim of the present study was to verify the acute effect of remote and local IPC application before isometric strength, lumbar and lower limbs manual grip, and upper limbs and trunk muscle endurance tests in recreationally trained individuals. The volunteers were 22 men (age: 26.2 ± 6.9 years, weight: 83.4 ± 11.6 kg, height: 175.4 ± 5.8 cm, BMI: 27.1 ± 3.5 kg.m-2) recreationally trained (4.6 ± 3.3 years) in resistance exercise (RE) that performed three visits on non-consecutive days (three to seven days apart). This was a crossover and randomized study. In the first visit, the Informed Consent Form (ICF) was signed, according to the Declaration of Helsinki, and the PAR-Q was completed. Immediately after, anthropometrics was assessed, followed by familiarization with the tests. At the second and third visits, the volunteers were randomly assigning to the following experimental protocols: a) IPC protocol with 220 mmHg + isometric strength and muscular endurance tests (IPC); or b) control protocol (CON) isometric strength and muscular endurance tests. Isometric handgrip strength was significantly higher in IPC compared to CON (61.59±10.18 vs. 58.95±10.84, 4.47Δ%, p=0.01). Lumbar isometric strength was significantly higher in IPC compared to CON (165.36±22.56 vs. 156.77±22.81, 5.48Δ%, p= 0.01) and lower limbs isometric strength was significantly higher in IPC compared to CON (163.09±22.92 vs. 154.86±21.55, 5.31Δ%, p=0.01). Push-up repetitions were significantly higher in IPC compared to CON (43±12.80 vs. 38.91±13.03,10.51Δ%, p=0.01). The trunk flexion repetitions were significantly higher in the IPC compared to the CON (46.05±13.28 vs. 40.23±11.18, 14.46Δ%, p=0.01). In conclusion, local IPC significantly increased upper limb isometric strength and muscle endurance compared to the control protocol. Remotely, IPC significantly increased lower limb isometric strength, lumbar and trunk flexion muscular endurance compared to the control protocol. Keywords: Ischemic preconditioning, Isometric strength, Muscular endurance

Effect of ischemic preconditioning on maximum accumulated oxygen deficit in 400-meter runners

ABSTRACT The main aim of this study was to examine the influence of ischemic preconditioning (IPC) on maximal accumulated oxygen deficit (MAOD). We conducted a three-arm and assessor-blinded randomized, controlled crossover study. Sixteen 400-meter running male athletes (19.9 ± 1.3 years; 1.78 ± 0.05 m; 67.9 ± 5.5 kg) completed three supramaximal intensity tests separated with Control, Local (legs), and Remote (arms) IPC interventions. IPC was induced on the limbs on both sides (4×5 min alternating unilateral occlusion 220 mmHg and reperfusion; arms or thighs; right side first) before participants performed the supramaximal intensity test on a treadmill at 110% VO2max intensity to exhaustion. During each test, indices of respiratory gas exchange, blood lactate, and heart rate were determined. The MAOD was calculated as the difference between the theoretical VO2 demand and the actual VO2 during the supramaximal intensity test. Differences from three trials were analyzed using ANOVA with repeated measures. IPC increased MAOD (RIPC, 59 ± 17 ml/kg/min, p = 0.018; LIPC, 57 ± 15 ml/kg/min, p = 0.037; p < 0.05) compared with Control (49 ± 9 ml/kg/min). Time to exhaustion was enhanced after IPC (Control: 257.2 ± 69.5 s, RIPC, 292.3 ± 66.6 s, p = 0.048; LIPC, 291.6 ± 79.2 s, p = 0.042; p < 0.05). In contrast, the enhancements of RIPC and LIPC trials were similar (p = 1.000). Blood lactate concentrations were similar across the three intervention conditions (p > 0.05). Acute IPC improved MAOD and supramaximal intensity exercise capacity in 400-meter running athletes. The increased MAOD indicated greater anaerobic capacity, which can be the potential mediator for improvement in exhaustion time. HIGHLIGHTS Ischemic preconditioning may improve the exhaustion time of supramaximal intensity running in well-trained 400-meter middle distance athletes. Acute IPC may be beneficial to anaerobic exercise capacity as the maximal accumulated oxygen deficit increases after IPC. Acute IPC occlusion on the upper arms or thighs may improve anaerobic capacity.

Local and Remote Ischemic Preconditioning Improves Sprint Interval Exercise Performance in Team Sport Athletes.

The aim of this study was to investigate the effects of local (LIPC) and remote (RIPC) ischemic preconditioning on sprint interval exercise (SIE) performance. Fifteen male collegiate basketball players underwent a LIPC, RIPC, sham (SHAM), or control (CON) trial before conducting six sets of a 30-s Wingate-based SIE test. The oxygen uptake and heart rate were continuously measured during SIE test. The total work in the LIPC (+2.2%) and RIPC (+2.5%) conditions was significantly higher than that in the CON condition (p < 0.05). The mean power output (MPO) at the third and fourth sprint in the LIPC (+4.5%) and RIPC (+4.9%) conditions was significantly higher than that in the CON condition (p < 0.05). The percentage decrement score for MPO in the LIPC and RIPC condition was significantly lower than that in the CON condition (p < 0.05). No significant interaction effects were found in pH and blood lactate concentrations. There were no significant differences in the accumulated exercise time at ≥80%, 90%, and 100% of maximal oxygen uptake during SIE. Overall, both LIPC and RIPC could improve metabolic efficiency and performance during SIE in athletes.

Influence of strain, age, origin, and anesthesia on the cardioprotective efficacy by local and remote ischemic conditioning in an ex vivo rat model

BackgroundLocal ischemic preconditioning (IPC) and remote ischemic conditioning (RIC) induced by brief periods of ischemia and reperfusion protect against ischemia‐reperfusion injury.MethodsWe studied the sensitivity to IR‐injury and the influence of strain, age, supplier, and anesthesia upon the efficacy of IPC and RIC in 7‐ and 16‐weeks‐old Sprague‐Dawley and Wistar rats from three different suppliers. The influence of sedation with a hypnorm and midazolam mixture (rodent mixture) and pentobarbiturate was compared.ResultsIPC attenuated infarct size in both 7‐weeks‐old Sprague–Dawley (48.4 ± 17.7% vs. 20.3 ± 6.9, p < 0.001) and 7‐weeks‐old Wistar (55.6 ± 10.9% vs. 26.8 ± 5.0%, p < 0.001) rats. Infarct size was larger in 16‐weeks‐old Sprague–Dawley rats, however, IPC still lowered infarct size (78.8 ± 9.2% vs. 58.3 ± 12.3%, p < 0.01). RIC reduced infarct sizes in 7‐weeks‐old Sprague–Dawley (75.3 ± 11.8% vs. 58.6 ± 8.9%, p < 0.05), but not in 7‐weeks‐old Wistar rats (31.7 ± 17.6% and 24.0 ± 12.6%, p = 0.2). In 16‐weeks‐old Sprague–Dawley rats, RIC did not induce protection (76.4 ± 5.5% and 73.2 ± 14.7%, p = 0.6). However, RIC induced protection in 16‐weeks‐old Wistar rats (45.2 ± 8.5% vs. 14.7 ± 10.8%, p < 0.001). RIC did not reduce infarct size in 7‐weeks‐old Sprague–Dawley rats from Charles River (62.0 ± 13.5% and 69.4 ± 10.4% p = 0.3) or 16‐weeks‐old Wistar rats from Janvier (50.7 ± 11.3 and 49.2 ± 16.2, p = 0.8). There was no difference between sedation with rodent mixture or pentobarbiturate.ConclusionThe cardioprotective effect of IPC is consistent across rat strains independent of age, strain, and supplier. RIC seems to be less reproducible, but still yields protection across different rat strains. However, age, animal supplier, and anesthetics may modulate the sensitivity of IR‐injury and the response to RIC.

Cardioprotective effect of combination therapy by mild hypothermia and local or remote ischemic preconditioning in isolated rat hearts

A multitargeted strategy to treat the consequences of ischemia and reperfusion (IR) injury in acute myocardial infarction may add cardioprotection beyond reperfusion therapy alone. We investigated the cardioprotective effect of mild hypothermia combined with local ischemic preconditioning (IPC) or remote ischemic conditioning (RIC) on IR injury in isolated rat hearts. Moreover, we aimed to define the optimum timing of initiating hypothermia and evaluate underlying cardioprotective mechanisms. Compared to infarct size in normothermic controls (56 ± 4%), mild hypothermia during the entire or final 20 min of the ischemic period reduced infarct size (34 ± 2%, p < 0.01; 35 ± 5%, p < 0.01, respectively), while no reduction was seen when hypothermia was initiated at reperfusion (51 ± 4%, p = 0.90). In all groups with effect of mild hypothermia, IPC further reduced infarct size. In contrast, we found no additive effect on infarct size between hypothermic controls (20 ± 3%) and the combination of mild hypothermia and RIC (33 ± 4%, p = 0.09). Differences in temporal lactate dehydrogenase release patterns suggested an anti-ischemic effect by mild hypothermia, while IPC and RIC preferentially targeted reperfusion injury. In conclusion, additive underlying mechanisms seem to provide an additive effect of mild hypothermia and IPC, whereas the more clinically applicable RIC does not add cardioprotection beyond mild hypothermia.

Differences in intrinsic aerobic capacity alters sensitivity to ischemia-reperfusion injury but not cardioprotective capacity by ischemic preconditioning in rats.

IntroductionAerobic capacity is a strong predictor of cardiovascular mortality. Whether aerobic capacity influences myocardial ischemia and reperfusion (IR) injury is unknown.PurposeTo investigate the impact of intrinsic differences in aerobic capacity and the cardioprotective potential on IR injury.MethodsWe studied hearts from rats developed by selective breeding for high (HCR) or low (LCR) capacity for treadmill running. The rats were randomized to: (1) control, (2) local ischemic preconditioning (IPC) or (3) remote ischemic preconditioning (RIC) followed by 30 minutes of ischemia and 120 minutes of reperfusion in an isolated perfused heart model. The primary endpoint was infarct size. Secondary endpoints included uptake of labelled glucose, content of selected mitochondrial proteins in skeletal and cardiac muscle, and activation of AMP-activated kinase (AMPK).ResultsAt baseline, running distance was 203±7 m in LCR vs 1905±51 m in HCR rats (p<0.01). Infarct size was significantly lower in LCR than in HCR controls (49±5% vs 68±5%, p = 0.04). IPC reduced infarct size by 47% in LCR (p<0.01) and by 31% in HCR rats (p = 0.01). RIC did not modulate infarct size (LCR: 52±5, p>0.99; HCR: 69±6%, p>0.99, respectively). Phosphorylaion of AMPK did not differ between LCR and HCR controls. IPC did not modulate cardiac phosphorylation of AMPK. Glucose uptake during reperfusion was similar in LCR and HCR rats. IPC increased glucose uptake during reperfusion in LCR animals (p = 0.02). Mitochondrial protein content in skeletal muscle was lower in LCR than in HCR (0.77±0.10 arbitrary units (AU) vs 1.09±0.07 AU, p = 0.02), but not in cardiac muscle.ConclusionAerobic capacity is associated with altered myocardial sensitivity to IR injury, but the cardioprotective effect of IPC is not. Glucose uptake, AMPK activation immediately prior to ischemia and basal mitochondrial protein content in the heart seem to be of minor importance as underlying mechanisms for the cardioprotective effects.

Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges.

Stroke is one of the leading causes of morbidity and mortality worldwide, and it is increasing in prevalence. The limited therapeutic window and potential severe side effects prevent the widespread clinical application of the venous injection of thrombolytic tissue plasminogen activator and thrombectomy, which are regarded as the only approved treatments for acute ischemic stroke. Triggered by various types of mild stressors or stimuli, ischemic preconditioning (IPreC) induces adaptive endogenous tolerance to ischemia/reperfusion (I/R) injury by activating a multitude cascade of biomolecules, for example, proteins, enzymes, receptors, transcription factors, and others, which eventually lead to transcriptional regulation and epigenetic and genomic reprogramming. During the past 30 years, IPreC has been widely studied to confirm its neuroprotection against subsequent I/R injury, mainly including local ischemic preconditioning (LIPreC), remote ischemic preconditioning (RIPreC), and cross preconditioning. Although LIPreC has a strong neuroprotective effect, the clinical application of IPreC for subsequent cerebral ischemia is difficult. There are two main reasons for the above result: Cerebral ischemia is unpredictable, and LIPreC is also capable of inducing unexpected injury with only minor differences to durations or intensity. RIPreC and pharmacological preconditioning, an easy-to-use and non-invasive therapy, can be performed in a variety of clinical settings and appear to be more suitable for the clinical management of ischemic stroke. Hoping to advance our understanding of IPreC, this review mainly focuses on recent advances in IPreC in stroke management, its challenges, and the potential study directions.

CIBER-CLAP (CIBERCV Cardioprotection Large Animal Platform): A multicenter preclinical network for testing reproducibility in cardiovascular interventions

Despite many cardioprotective interventions have shown to protect the heart against ischemia/reperfusion injury in the experimental setting, only few of them have succeeded in translating their findings into positive proof-of-concept clinical trials. Controversial and inconsistent experimental and clinical evidence supports the urgency of a disruptive paradigm shift for testing cardioprotective therapies. There is a need to evaluate experimental reproducibility before stepping into the clinical arena. The CIBERCV (acronym for Spanish network-center for cardiovascular biomedical research) has set up the “Cardioprotection Large Animal Platform” (CIBER-CLAP) to perform experimental studies testing the efficacy and reproducibility of promising cardioprotective interventions based on a pre-specified design and protocols, randomization, blinding assessment and other robust methodological features. Our first randomized, control-group, open-label blinded endpoint experimental trial assessing local ischemic preconditioning (IPC) in a pig model of acute myocardial infarction (n = 87) will be carried out in three separate sets of experiments performed in parallel by three laboratories. Each set aims to assess: (A) CMR-based outcomes; (B) histopathological-based outcomes; and (C) protein-based outcomes. Three core labs will assess outcomes in a blinded fashion (CMR imaging, histopathology and proteomics) and 2 methodological core labs will conduct the randomization and statistical analysis.

Attenuation of ST‐segment elevation reflects infarct size reduction by ischemic conditioning in pigs

Cardioprotection by ischemic conditioning maneuvers, either locally in the heart or remotely from the heart, reduces infarct size. However, infarct size reduction is seen only hours to days after the acute event. To study the potential of ST‐segment elevation (STE) and its attenuation to reflect infarct size reduction already during ongoing coronary occlusion or early during reperfusion, pigs were subjected to 1 h LAD occlusion and 3 h reperfusion. Cardioprotection was recruited prior to the index ischemia by local ischemic preconditioning (IPC; n=14; 2x3 min LAD occlusion, interspersed by 2 min reperfusion, 15 min prior to ischemia) or remote ischemic preconditioning (RIPC; n=20; 4x5 min / 5 min hindlimb ischemia/reperfusion, 90 min prior to ischemia), during the index ischemia by remote ischemic perconditioning1 (RPER; n=18; 4x5 min / 5 min hindlimb ischemia/reperfusion, starting 20 min after the onset of ischemia), or at the onset of reperfusion by ischemic postconditioning (PoCo; n=9; 4x1 min / 1 min coronary reocclusion/reperfusion at 1 min reperfusion). Pigs without ischemic conditioning served as controls (PLA; n=29). Transmural myocardial blood flow (microspheres), area at risk (blue dye), and infarct size (TTC) were measured. STE amplitude was defined as the voltage difference in a V2‐like ECG lead between a point 30 ms before the P‐wave and one 20 ms after the J‐point.Area at risk and transmural myocardial blood flow during ischemia were similar among groups, and the cardioprotective maneuvers robustly reduced infarct size (PLA 42±11% of area at risk; mean±SD; IPC 19±10%; RIPC 23±12%; RPER 23±12%; PoCo 22±11%; all p&lt;0.05 vs. PLA). With PLA, STE was markedly increased at 5 min ischemia and this elevation was sustained throughout ischemia. At 10 min reperfusion, STE increased even further, possibly reflecting additional reperfusion injury, followed by a gradual, but incomplete STE recovery over 120 min reperfusion. RIPC and IPC did not impact on STE at 5 min ischemia, but STE was attenuated at 55 min ischemia. With RPER, STE was attenuated immediately after completion of the maneuver at 55 min ischemia. PoCo abolished the further increase of STE at 10 min reperfusion. (see figure)The infarct size reduction by IPC, RIPC, RPER, or PoCo is robustly reflected in an attenuation of STE. Whereas PoCo and RPER attenuate STE within minutes after completion of the maneuver, the two cardioprotective maneuvers which were performed prior to myocardial ischemia, i.e. IPC and RIPC, did not attenuate STE immediately at 5 min ischemia, but did so at 55 min ischemia. A speculative explanation for such discrepancy is that STE attenuation only reflects protection from irreversible ischemic or reperfusion injury. In any event, STE analysis provides an on‐line estimate of cardioprotection much earlier than a measurement of infarct size.Support or Funding InformationSupported by: DFG (SFB 1116 B08)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comparison of hepatoprotective effect from ischemia-reperfusion injury of remote ischemic preconditioning of the liver vs local ischemic preconditioning of the liver during human liver resections

AimTo compare and evaluate the hepatoprotective effect of remote ischemic preconditioning (RIPC) with local ischemic preconditioning (LIPC) of the liver during human liver resections. MethodsA prospective, single-centre, randomised control trial was conducted in the Clinical Hospital “***” from April 2017 to January 2018. A total of 60 patients, who underwent liver resection due to colorectal cancer liver metastasis, were randomised to one of three study arms: 1) a RIPC group, 2) an LIPC group and 3) a control group (CG) in which no ischemic preconditioning was done before liver resection. The hepatoprotective effect was evaluated by comparing serum transaminase levels, bilirubin levels, albumin, and protein levels, coagulograms and through pathohistological analysis. The trial was registered on ClinicalTrials.gov (NCT****). ResultsSignificant differences were found in serum levels of liver transaminases and bilirubin levels between thegroups, the highest level in the CG and the lowest level in the LIPC group. Levels of cholinesterase were also significantly higher in the LIPC group. Pathohistological findings graded by the Rodriguez score showed favourable changes in the LIPC and RIPC groups versus the CG. ConclusionStrong evidence supports the hepatoprotective effect of RIPC and LIPC preconditioning from an ischemia-reperfusion injury of the liver. Better synthetic liver function preservation in these two groups supports this conclusion.

Effects of local versus remote ischemic preconditioning on repeated sprint running performance.

The aim of this study was to compare the effect of local and remote ischemic preconditioning (IPC) on repeated sprint exercise. Twelve males (age 22±2 years; stature 1.79±0.07 m; body mass 77.8±8.4 kg; mean±SD) completed four trials consisting of remote (arm) and local (leg) IPC and SHAM interventions prior to repeated sprint exercise (3x[6x15+15-m] shuttle sprints), in a double-blind, randomized, crossover designed study. These tests were immediately preceded by IPC (4x5-minute intervals at 220 mmHg bilateral occlusion) or SHAM treatment (4x5-minute intervals at 20 mmHg bilateral occlusion). Sprint performance and percentage decrement score alongside measurement of Tissue Saturation Index, blood lactate and RPE were measured throughout the intervention. During the IPC/SHAM intervention there was a large decrease in TSI for IPC-arm in comparison to IPC-leg (P<0.05), however IPC-legs resulted in greater soreness compared with the other three conditions (P<0.05). There was no main effects or interaction effects for sprint performance. There was a significant effect of condition (P=0.047, r=0.56) on percentage decrement score across all 18 sprints with IPC demonstrating less fatigue than SHAM. There were no other effects of IPC during the sprint trials for any other physiological measure. In conclusion local IPC resulted in more pain/soreness during the IPC/SHAM intervention but both remote and local IPC reduced the fatigue associated with repeated sprint exercise.

Conduit Artery Diameter During Exercise Is Enhanced After Local, but Not Remote, Ischemic Preconditioning.

Introduction: The ability of ischemic preconditioning (IPC) to enhance exercise capacity may be mediated through altering exercise-induced blood flow and/or vascular function. This study investigated the hypothesis that (local) IPC enhances exercise-induced blood flow responses and prevents decreases in vascular function following exercise.Methods: Eighteen healthy, recreationally trained, male participants (mean ±SD: age 32 ± 8 years; BMI 24.2 ± 2.3; blood pressure 122 ± 10/72 ± 8 mmHg; resting HR 58 ± 9 beats min-1) received IPC (220 mmHg; 4 × 5-min bilateral arms), REMOTE IPC (220 mmHg; 4 × 5-min bilateral legs), or SHAM (20 mmHg; 4 × 5-min bilateral arms) in a counterbalanced order prior to 30-min of submaximal (25% maximal voluntary contraction) unilateral rhythmic handgrip exercise. Brachial artery diameter and blood flow were assessed every 5-min throughout the 30-min submaximal exercise using high resolution ultrasonography. Pre- and post-exercise vascular function was measured using flow-mediated dilation (FMD).Results: IPC resulted in enlarged brachial artery diameter during exercise [0.016 cm (0.003–0.03 cm), P = 0.015] compared to REMOTE IPC, but blood flow during exercise was similar between conditions (P > 0.05). Blood flow (l/min) increased throughout exercise (time: P < 0.005), but there was no main effect of condition (P = 0.29) or condition ∗ time interaction (P = 0.83). Post-exercise FMD was similar between conditions (P > 0.05).Conclusion: Our data show that local (but not remote) IPC, performed as a strategy prior to exercise, enhanced exercise-induced conduit artery diameter dilation, but these changes do not translate into increased blood flow during exercise nor impact post-exercise vascular function.

The effects of local ischemic preconditioning and topical hypothermia in renal ischemia/reperfusion injury in rats.

Topical hypothermia and local ischemic preconditioning have been shown to reduce renal ischemia-reperfusion (I/R) injury individually. We examined whether combination of both strategies lessens renal I/R injury. Post right nephrectomy, 40 male Wistar rats were randomly assigned to five experimental protocols performed in the left kidney: topical hypothermia without ischemia (TH), warm ischemia (IR), ischemic preconditioning followed by warm ischemia (IPC+IR), cold ischemia (TH+IR), and ischemic preconditioning followed by cold ischemia (IPC+TH+IR). Eight randomly assigned right kidneys constituted the control group. After 240 min of reperfusion, the left kidney was retrieved to evaluate histological changes, lipid peroxidation and antioxidant enzymes activity. Serum was collected to evaluate urea and creatinine. IPC+TH+IR group revealed no difference to any other group subjected to ischemia in relation to histological changes, lipid peroxidation and antioxidant enzymes activity. Creatinine was lower in IPC+TH+IR group compared with IPC+IR, but showed no difference compared to TH+IR group. Combination of local ischemic preconditioning (IPC) and topical hypothermia conferred no protection in renal I/R injury. Moreover, local IPC solely followed by warm ischemia impaired renal function more than warm ischemia alone.

Is There an Optimal Ischemic-Preconditioning Dose to Improve Cycling Performance?

Ischemic preconditioning (IPC) may enhance endurance performance. No previous study has directly compared distinct IPC protocols for optimal benefit. To determine whether a specific IPC protocol (ie, number of cycles, amount of muscle tissue, and local vs remote occlusion) elicits greater performance outcomes. Twelve cyclists performed 5 different IPC protocols 30min before a blinded 375-kJ cycling time trial (TT) in a laboratory. Responses to traditional IPC (4 × 5-min legs) were compared with those to 8 × 5-min legs and sham (dose cycles), 4 × 5-min unilateral legs (dose tissue), and 4 × 5-min arms (remote). Rating of perceived exertion and blood lactate were recorded at each 25% TT completion. Power (W), heart rate (beats/min), and oxygen uptake ([Formula: see text]) (mL · kg-1 · min-1) were measured continuously throughout TTs. Magnitude-based-inference statistics were employed to compare variable differences to the minimal practically important difference. Traditional IPC was associated with a 17-s (0, 34) faster TT time than sham. Applying more dose cycles (8 × 5min) had no impact on performance. Traditional IPC was associated with likely trivial higher blood lactate and possibly beneficial lower [Formula: see text] responses vs sham. Unilateral IPC was associated with 18-s (-11, 48) slower performance than bilateral (dose tissue). TT times after remote and local IPC were not different (0 [-16, 16] s). The traditional 4 × 5-min (local or remote) IPC stimulus resulted in the fastest TT time compared with sham; there was no benefit of applying a greater number of cycles or employing unilateral IPC.

Abstract 13510: No-reflow in Reperfused Myocardium Does Not Contribute to Final Infarct Size in Pigs

The no-reflow phenomenon is a frequent complication in patients with reperfused acute myocardial infarction and associated with a worse prognosis. It is unclear whether cardioprotection, apart from infarct size (IS) reduction, has also a beneficial impact on the extent of no-reflow. In an anesthetized pig model of myocardial ischemia/reperfusion, we have now used established conditioning maneuvers as a tool to distinguish damage and protection from it in the myocardium, expressed as final IS, and in the coronary microcirculation, expressed as area of no-reflow (ANR). Myocardial ischemia was induced by transient occlusion of the left anterior descending coronary artery (LAD). Myocardial blood flow was measured with microspheres. Cardioprotection was induced by local ischemic preconditioning (IPC; n=10; 2 x 3 min LAD occlusion/2 min reperfusion 15 min prior to 60 min LAD occlusion), remote ischemic preconditioning (RIPC; n=10; 4x5 min hindlimb occlusion/reperfusion 90 min prior to 60 min LAD occlusion), or ischemic postconditioning (POCO; n=6; 4x1 min LAD re-occlusion/reperfusion at 1 min reperfusion after 60 min LAD occlusion). Pigs without protection (PLA; n=10) served as controls. After 180 min reperfusion, the ANR (intra-atrial injection of thioflavin S) and the area at risk (AAR; intra-atrial injection of blue dye with re-occluded LAD) were demarcated. IS was determined by post-mortem triphenyl-tretrazolium chloride (TTC) staining. The AAR and myocardial blood flow during ischemia were not different among groups. IS reduction was similar with IPC, RIPC, and POCO (PLA: 37±3% of AAR; IPC*: 21±3%; RIPC*: 17±2; POCO*: 24±5%; mean±SEM; *p&lt;0.05 vs. PLA). Only IPC and RIPC reduced the ANR (PLA: 28±4% of AAR; IPC*: 4±3%; RIPC* 9±2%), whereas POCO did not (24±5%). All conditioning maneuvers protected the myocardium, but the microcirculation was only protected by conditioning maneuvers applied prior to LAD occlusion. POCO’s protection of myocardium, but not coronary microcirculation might be related to different time frames or to different underlying mechanisms of injury and/or protection in the two compartments. Nevertheless, the remaining no-reflow observed with POCO did not result in greater infarction.

Cardiomyocyte mitochondria as targets of humoral factors released by remote ischemic preconditioning.

IntroductionRemote ischemic preconditioning (RIPC) reduces myocardial infarct size, and protection can be transferred with plasma to other individuals, even across species. Mitochondria are the end-effectors of cardioprotection by local ischemic conditioning maneuvers. We have now analyzed mitochondrial function in response to RIPC.Material and methodsPlasma from pigs undergoing placebo or RIPC (infarct size reduction by 67% in RIPC pigs compared to placebo) was transferred to isolated perfused rat hearts subjected to 30 min global ischemia followed by 120 min reperfusion for infarct size measurement. Additional experiments were terminated at 10 min reperfusion to isolate mitochondria for functional measurements. Effects of RIPC pig plasma were compared to local ischemic preconditioning (IPC) or to infusion of tumor necrosis factor α (TNF-α).ResultsIschemia/reperfusion (I/R) induced an infarct of 41 ±2% of total ventricular mass. Placebo pig plasma did not affect infarct size (38 ±1, p = 0.13). The RIPC pig plasma reduced infarct size (27 ±2, p < 0.001), as did IPC (20 ±1, p < 0.001) and TNF-α (28 ±2, p < 0.001). Associated with cardioprotection, reductions of mitochondrial adenosine diphosphate (ADP)-stimulated respiration, adenosine triphosphate (ATP) production and calcium retention capacity (CRC) by I/R and placebo pig plasma were prevented by RIPC pig plasma, as they were by IPC and TNF-α. Mitochondrial reactive oxygen species production (nmol H2O2/100 µg protein) induced by I/R (272 ±34) was comparable in response to placebo pig plasma (234 ±28, p = 0.37) and was reduced by RIPC pig plasma (83 ±15, p < 0.001) as well as by IPC (78 ±21, p < 0.001) and TNF-α (125 ±42, p = 0.002).ConclusionsIn rat myocardium, mitochondria are an intracellular target of protection induced by humoral factors retrieved from pigs undergoing RIPC.