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Ischaemic preconditioning (IPC), brief periods of ischaemia immediately followed by reperfusion applied to a vascular bed, has emerged as a method to improve exercise performance. There is, however, a lack of research exploring repeated episodes of IPC on anaerobic performance. The aim of this study was to determine if a 2-week repeated IPC intervention could enhance anaerobic performance in male academy football players. Eight male academy football players completed two, 2-week intervention trials: six IPC episodes (4 × 5 min at 220 mmHg per episode), and six SHAM episodes (4 × 5 min at 20 mmHg per episode). Prior to and following each intervention trial, the participants completed assessments of anaerobic performance (Running Anaerobic Sprint Test [RAST]), and superficial femoral artery endothelial function (flow-mediated dilation [FMD]). IPC significantly enhanced peak and mean power output by 12% (p = 0.026) and 11% (p = 0.019) and significantly improved superficial femoral artery FMD (p = 0.049). The increase in endothelial function suggests that this may be a mechanism contributing to this enhancement of anaerobic performance. The present study supports the use of repeated IPC prior to matches and training sessions to enhance anaerobic performance. [ABSTRACT FROM AUTHOR]

In recent years, ischemic preconditioning (IPC) has garnered significant attention in sports research. While IPC has demonstrated positive effects in high-intensity sports such as judo and swimming, its potential benefits for enhancing the performance of Taekwondo athletes have not been extensively studied. This study aimed to investigate the effects of IPC on taekwondo performance and to observe the metabolic characteristics associated with enhancing sports performance via LC‒MS/MS-based plasma metabolomics. Seventeen participants underwent the repeated frequency speed of kick test (FSKT) after IPC, along with pre- and post-exercise plasma metabolite analysis. Differential abundance metabolite analysis, enriched pathway analysis, and weighted gene coexpression network analysis (WGNCA) were employed to delve into metabolic characteristics. The findings highlighted a significant enhancement in FSKT performance in the experimental group. Metabolomic analysis revealed 109 differentially abundant metabolites, including Dl-lactate, hypoxanthine, acetylcarnitine, and acetylsalicylic acid. Enriched pathway analysis revealed pathways such as pentose and glucuronic acid interconversion, ascorbic acid and aldonic acid metabolism, the pentose phosphate pathway (PPP), and the Warburg effect. In conclusion, IPC can significantly increase the specific athletic abilities of Taekwondo athletes, with enhancements linked to anaerobic metabolism, PPP utilization, the Warburg effect for energy production, redox system stability, reduced muscle fatigue, and pain alleviation. [ABSTRACT FROM AUTHOR]

Abstract In recent years, ischemic preconditioning (IPC) has garnered significant attention in sports research. While IPC has demonstrated positive effects in high-intensity sports such as judo and swimming, its potential benefits for enhancing the performance of Taekwondo athletes have not been extensively studied. This study aimed to investigate the effects of IPC on taekwondo performance and to observe the metabolic characteristics associated with enhancing sports performance via LC‒MS/MS-based plasma metabolomics. Seventeen participants underwent the repeated frequency speed of kick test (FSKT) after IPC, along with pre- and post-exercise plasma metabolite analysis. Differential abundance metabolite analysis, enriched pathway analysis, and weighted gene coexpression network analysis (WGNCA) were employed to delve into metabolic characteristics. The findings highlighted a significant enhancement in FSKT performance in the experimental group. Metabolomic analysis revealed 109 differentially abundant metabolites, including Dl-lactate, hypoxanthine, acetylcarnitine, and acetylsalicylic acid. Enriched pathway analysis revealed pathways such as pentose and glucuronic acid interconversion, ascorbic acid and aldonic acid metabolism, the pentose phosphate pathway (PPP), and the Warburg effect. In conclusion, IPC can significantly increase the specific athletic abilities of Taekwondo athletes, with enhancements linked to anaerobic metabolism, PPP utilization, the Warburg effect for energy production, redox system stability, reduced muscle fatigue, and pain alleviation.

Off-pump coronary artery bypass grafting (OPCABG) surgery allows surgical revascularization of the heart whilst avoiding the inherent risks of cardiopulmonary bypass (CPB). Advances in technologies and techniques have improved operating conditions and have led to an increase in popularity of OPCABG. However, surgical manipulation of a beating heart and clamping of perfusing coronary arteries can cause significant haemodynamic consequences which must be anticipated and carefully managed. The anaesthetist must therefore assimilate information from multiple sources and remain vigilant to any changes intraoperatively. [ABSTRACT FROM AUTHOR]

Ischaemic preconditioning (IPC) involves the use of repeated occlusions and reperfusions of the peripheral muscle blood supply at a limb. This systematic literature review examines the typical responses in response to the method of application during an IPC applied at the lower limb. This review focuses on the physiological responses for VO2max, haemoglobin, metabolic and genetic responses to various IPC interventions. The literature search was performed using four databases and assessed using the PRISMA search strategy and COSMIN to assess the quality of the articles. Seventeen articles were included in the review, with a total of 237 participants. While there is variation in the method of application, the average occlusion pressure was 222 ± 34 mmHg, ranging from 170 to 300 mmHg typically for 3 or 4 occlusion cycles. The distribution of this pressure is influenced by cuff width, although 8 studies failed to report cuff width. The majority of studies applies IPC at the proximal thigh with 16/17 studies applying an occlusion below this location. The results highlighted the disparities and conflicting findings in response to various IPC methods. While there is some agreement in certain aspects of the IPC manoeuvre such as the location of the occlusion during lower limb IPC, there is a lack of consensus in the optimal protocol to elicit the desired responses. This offers the opportunity for future research to refine the protocols, associated responses, and mechanisms responsible for these changes during the application of IPC. [ABSTRACT FROM AUTHOR]

Ischaemic preconditioning (IPC) involves the use of repeated occlusions and reperfusions of the peripheral muscle blood supply at a limb. This systematic literature review examines the typical responses in response to the method of application during an IPC applied at the lower limb. This review focuses on the physiological responses for VO2max, haemoglobin, metabolic and genetic responses to various IPC interventions. The literature search was performed using four databases and assessed using the PRISMA search strategy and COSMIN to assess the quality of the articles. Seventeen articles were included in the review, with a total of 237 participants. While there is variation in the method of application, the average occlusion pressure was 222 ± 34 mmHg, ranging from 170 to 300 mmHg typically for 3 or 4 occlusion cycles. The distribution of this pressure is influenced by cuff width, although 8 studies failed to report cuff width. The majority of studies applies IPC at the proximal thigh with 16/17 studies applying an occlusion below this location. The results highlighted the disparities and conflicting findings in response to various IPC methods. While there is some agreement in certain aspects of the IPC manoeuvre such as the location of the occlusion during lower limb IPC, there is a lack of consensus in the optimal protocol to elicit the desired responses. This offers the opportunity for future research to refine the protocols, associated responses, and mechanisms responsible for these changes during the application of IPC.

Ischaemic preconditioning (IPC) applied locally and remotely has been shown to reduce pain which may underpin its ergogenic effect on exercise performance, however, it is unclear how many IPC cycles are needed to induce hypoalgesia. Therefore the purpose of this study was to examine the number of cycles of IPC on experimental pain perception. Sixteen healthy participants underwent four, randomised, experimental sessions where they either underwent a sham protocol (1 × 5 min at 20 mmHg), and 1, 2 or 3 cycles × 5 min of remote IPC at 105% of limb occlusion pressure. Ten minutes post-intervention, participants underwent a cold-pressor test where pain threshold, pain tolerance and pain intensity were examined and compared between conditions with a one-way repeated measure analysis of variance. Pain threshold was not different between conditions (P = 0.065); but pain tolerance was increased by ~30% in the 1 × 5 condition, 2 × 5 condition, and 3 × 5 condition compared to the sham condition. No differences in pain tolerance were seen between the different numbers of cycles (all P > 0.05). There was also no difference in the perception of pain 30 s into the cold pressor test (P = 0.279). Remote IPC appears to significantly improve tolerance to pain which may have significant implications for endurance performance and exercise rehabilitation, but this warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract Background Remote ischaemic preconditioning (RIPC) has been investigated as a simple intervention to potentially mitigate the ischaemic effect of the surgical insult and reduce postoperative morbidity. This review systematically evaluates the effect of RIPC on morbidity, including duration of hospital stay and parameters reflective of cardiac, renal, respiratory, and hepatic dysfunction following non-cardiac non-vascular (NCNV) surgery. Methods The electronic databases PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from their inception date to November 2021. Studies investigating the effect of local preconditioning or postconditioning were excluded. Methodological quality and risk of bias were determined according to the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). Calculation of the odds ratios and a random effects model was used for dichotomous outcomes and mean differences or standardised mean differences as appropriate were used for continuous outcomes. The primary outcomes of interest were cardiac and renal morbidity, and the secondary outcomes included other organ function parameters and hospital length of stay. Results A systematic review of the published literature identified 36 randomised controlled trials. There was no significant difference in postoperative troponin or acute kidney injury. RIPC was associated with lower postoperative serum creatinine (9 studies, 914 patients, mean difference (MD) - 3.81 µmol/L, 95% confidence interval (CI) - 6.79 to - 0.83, p = 0.01, I 2 = 5%) and lower renal stress biomarker (neutrophil gelatinase-associated lipocalin (NGAL), 5 studies, 379 patients, standardized mean difference (SMD) - 0.66, 95% CI - 1.27 to - 0.06, p = 0.03, I 2 = 86%). RIPC was also associated with improved oxygenation (higher PaO2/FiO2, 5 studies, 420 patients, MD 51.51 mmHg, 95% CI 27.32 to 75.69, p < 0.01, I 2 = 89%), lower biomarker of oxidative stress (malondialdehyde (MDA), 3 studies, 100 patients, MD - 1.24 µmol/L, 95% CI - 2.4 to - 0.07, p = 0.04, I 2 = 91%)) and shorter length of hospital stay (15 studies, 2110 patients, MD - 0.99 days, 95% CI - 1.75 to - 0.23, p = 0.01, I 2 = 88%). Conclusions This meta-analysis did not show an improvement in the primary outcomes of interest with the use of RIPC. RIPC was associated with a small improvement in certain surrogate parameters of organ function and small reduction in hospital length of stay. Our results should be interpreted with caution due to the limited number of studies addressing individual outcomes and the considerable heterogeneity identified. Trial registration PROSPERO CRD42019129503.

Reduction of blood flow to the limb using cuffs before or during exercise has become increasingly popular for training and rehabilitation. Our study tested the effects of cuff brand/width on pressures required to reach limb occlusion pressure (LOP) and developed, cross-validated, and compared accuracy of two LOP prediction equations to previously created methods. Supine LOP was determined in the distal popliteal artery using four different cuff brands/widths in 23 adult participants. Participants then had demographic and resting variables assessed, and two LOP prediction equations were developed from these variables and were compared to five previously developed models and a method using posterior tibial artery palpation for LOP assessment in an independent sample (n = 14 adult runners). For cuff comparison, the widest two cuffs had significantly lower LOP (mean ~149 mmHg) than the narrowest cuffs (mean ~176 mmHg), with the narrowest cuff unable to reach LOP. The eight methods used to predict LOP ranged in accuracy (mean absolute percent errors 3.9–23.0%), with highest accuracy in equations using mean arterial pressure (MAP) and BMI. Practitioners using blood flow reduction methods should be consistent with cuff use due to demonstrated differences across brands/widths. Equations using MAP and BMI appear best for prediction of leg LOP. [ABSTRACT FROM AUTHOR]

Ischaemic heart disease, which often manifests clinically as myocardial infarction (MI), remains a major cause of mortality worldwide. Despite the development of effective pre-clinical cardioprotective therapies, clinical translation has been disappointing. Nevertheless, the 'reperfusion injury salvage kinase' (RISK) pathway appears to be a promising target for cardioprotection. This pathway is crucial for the induction of cardioprotection by numerous pharmacological and non-pharmacological interventions, such as ischaemic conditioning. An important component of the cardioprotective effects of the RISK pathway involves the prevention of mitochondrial permeability transition pore (MPTP) opening and subsequent cardiac cell death. Here, we will review the historical perspective of the RISK pathway and focus on its interaction with mitochondria in the setting of cardioprotection. [ABSTRACT FROM AUTHOR]

Background: Remote ischaemic preconditioning (RIPC) has been investigated as a simple intervention to potentially mitigate the ischaemic effect of the surgical insult and reduce postoperative morbidity. This review systematically evaluates the effect of RIPC on morbidity, including duration of hospital stay and parameters reflective of cardiac, renal, respiratory, and hepatic dysfunction following non-cardiac non-vascular (NCNV) surgery. Methods: The electronic databases PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from their inception date to November 2021. Studies investigating the effect of local preconditioning or postconditioning were excluded. Methodological quality and risk of bias were determined according to the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). Calculation of the odds ratios and a random effects model was used for dichotomous outcomes and mean differences or standardised mean differences as appropriate were used for continuous outcomes. The primary outcomes of interest were cardiac and renal morbidity, and the secondary outcomes included other organ function parameters and hospital length of stay. Results: A systematic review of the published literature identified 36 randomised controlled trials. There was no significant difference in postoperative troponin or acute kidney injury. RIPC was associated with lower postoperative serum creatinine (9 studies, 914 patients, mean difference (MD) - 3.81 µmol/L, 95% confidence interval (CI) - 6.79 to - 0.83, p = 0.01, I2 = 5%) and lower renal stress biomarker (neutrophil gelatinase-associated lipocalin (NGAL), 5 studies, 379 patients, standardized mean difference (SMD) - 0.66, 95% CI - 1.27 to - 0.06, p = 0.03, I2 = 86%). RIPC was also associated with improved oxygenation (higher PaO2/FiO2, 5 studies, 420 patients, MD 51.51 mmHg, 95% CI 27.32 to 75.69, p < 0.01, I2 = 89%), lower biomarker of oxidative stress (malondialdehyde (MDA), 3 studies, 100 patients, MD - 1.24 µmol/L, 95% CI - 2.4 to - 0.07, p = 0.04, I2 = 91%)) and shorter length of hospital stay (15 studies, 2110 patients, MD - 0.99 days, 95% CI - 1.75 to - 0.23, p = 0.01, I2 = 88%). Conclusions: This meta-analysis did not show an improvement in the primary outcomes of interest with the use of RIPC. RIPC was associated with a small improvement in certain surrogate parameters of organ function and small reduction in hospital length of stay. Our results should be interpreted with caution due to the limited number of studies addressing individual outcomes and the considerable heterogeneity identified. Trial registration: PROSPERO CRD42019129503. [ABSTRACT FROM AUTHOR]

Background: Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts.Methods: Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified.Results: The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues.Conclusions: Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes. [ABSTRACT FROM AUTHOR]

The objective of our study was to elucidate the possible underlying mechanism for the protective effect of ischaemic preconditioning (IPC) against ischaemia-reperfusion (I/R) injury and to provide new research perspectives of long non-coding RNAs (lncRNAs). In this study, serum and liver tissue samples were collected to measure indexes of liver injury from a mouse liver model in sham, I/R injury and I/R + IPC groups. Furthermore, liver samples from 5 randomly selected mice per group were extracted and subjected to the microarray and subsequent bioinformatics analysis. IPC ameliorated liver damage by lowered liver transaminase levels and pro-inflammatory cytokines. A total of 167 lncRNAs and 108 messenger RNAs (mRNAs) were significantly differentially expressed genes (DEGs) between the I/R + IPC and I/R groups. Gene Ontology (GO) analysis revealed that these genes were mainly related to unfolded proteins, responses to topologically incorrect proteins, responses to temperature stimuli, protein folding and protein refolding. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated that the DEGs were enriched in the following pathways: protein processing in the endoplasmic reticulum; antigen processing and presentation; and fructose and mannose metabolism. Additionally, the 7 selected DEGs (Hspa1ab, Chka, Clec2h, Mvd, Adra1a, AK085737 and AK088966) were validated in modules of the lncRNA-mRNA weighted coexpression network, which agreed with the qRT–PCR and chip data. And the identified differentially expressed lncRNAs and mRNAs may provide new clues to understand the pivotal pathophysiological mechanism by which IPC alleviates I/R-caused liver damage. • Ischaemic preconditioning (IPC) attenuates the liver IR injury in mice. • The microarray identified markedly differentially expressed mRNAs and lncRNAs. • Functional analysis indicates lncRNAs participate in the effects of IPC. • A key gene cluster involves in IPC-mediated protection. • Some lncRNA-mRNA pairs relate to the protective effect of IPC. [ABSTRACT FROM AUTHOR]

There is limited evidence on the effect of remote ischaemic preconditioning (RIPC) following non-cardiac surgery. The aim of this study was to investigate the effect of RIPC on morbidity following intra-abdominal cancer surgery. We conducted a double blinded pilot randomised controlled trial that included 47 patients undergoing surgery for gynaecological, pancreatic and colorectal malignancies. The patients were randomized into an intervention (RIPC) or control group. RIPC was provided by intermittent inflations of an upper limb tourniquet. The primary outcome was feasibility of the study, and the main secondary outcome was postoperative morbidity including perioperative troponin change and the urinary biomarkers tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 (TIMP-2*IGFBP-7). The recruitment target was reached, and the protocol procedures were followed. The intervention group developed fewer surgical complications at 30 days (4.5% vs. 33%), 90 days (9.5% vs. 35%) and 6 months (11% vs. 41%) (adjusted p 0.033, 0.044 and 0.044, respectively). RIPC was a significant independent variable for lower overall postoperative morbidity survey (POMS) score, OR 0.79 (95% CI 0.63 to 0.99) and fewer complications at 6 months including pulmonary OR 0.2 (95% CI 0.03 to 0.92), surgical OR 0.12 (95% CI 0.007 to 0.89) and overall complications, OR 0.18 (95% CI 0.03 to 0.74). There was no difference in perioperative troponin change or TIMP2*IGFBP-7. Our pilot study suggests that RIPC may improve outcomes following intra-abdominal cancer surgery and that a larger trial would be feasible. [ABSTRACT FROM AUTHOR]

The translation of successful preclinical and clinical proof-of-concept studies on cardioprotection to the benefit of patients with reperfused acute myocardial infarction has been difficult so far. This difficulty has been attributed to confounders which patients with myocardial infarction typically have but experimental animals usually not have. The metabolic syndrome is a typical confounder. We hypothesised that there may also be a genuine non-responsiveness to cardioprotection and used Ossabaw minipigs which have the genetic predisposition to develop a diet-induced metabolic syndrome, but before they had developed the diseased phenotype. Using a prospective study design, a reperfused acute myocardial infarction was induced in 62 lean Ossabaw minipigs by 60 min coronary occlusion and 180 min reperfusion. Ischaemic preconditioning by 3 cycles of 5 min coronary occlusion and 10 min reperfusion was used as cardioprotective intervention. Ossabaw minipigs were stratified for their single nucleotide polymorphism as homozygous for valine (V/V) or isoleucine (I/I)) in the γ-subunit of adenosine monophosphate-activated protein kinase. Endpoints were infarct size and area of no-reflow. Infarct size (V/V: 54 ± 8, I/I: 54 ± 13% of area at risk, respectively) was not reduced by ischaemic preconditioning (V/V: 55 ± 11, I/I: 46 ± 11%) nor was the area of no-reflow (V/V: 57 ± 18, I/I: 49 ± 21 vs. V/V: 57 ± 21, I/I: 47 ± 21% of infarct size). Bioinformatic comparison of the Ossabaw genome to that of Sus scrofa and Göttingen minipigs identified differences in clusters of genes encoding mitochondrial and inflammatory proteins, including the janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway. The phosphorylation of STAT3 at early reperfusion was not increased by ischaemic preconditioning, different from the established STAT3 activation by cardioprotective interventions in other pig strains. Ossabaw pigs have not only the genetic predisposition to develop a metabolic syndrome but also are not amenable to cardioprotection by ischaemic preconditioning. [ABSTRACT FROM AUTHOR]

Abstract Background Vascular surgery patients have reduced tissues` blood supply, which may lead to mitochondrial dysfunction and accumulation of acylcarnitines (ACs). It has been suggested that remote ischaemic preconditioning (RIPC) has its organ protective effect via promoting mitochondrial function. The aim of this study was to evaluate the effect of RIPC on the profile of ACs in the vascular surgery patients. Methods This is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open surgical repair of abdominal aortic aneurysm, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 min of ischaemia, followed by 5 min of reperfusion, was applied. A blood pressure cuff was used for RIPC or a sham procedure. Blood was collected preoperatively and approximately 24 h postoperatively. The profile of ACs was analysed using the AbsoluteIDQp180 kit (Biocrates Life Sciences AG, Innsbruck, Austria). Results Ninety-eight patients were recruited and randomised into the study groups and 45 patients from the RIPC group and 47 patients from the sham group were included in final analysis. There was a statistically significant difference between the groups regarding the changes in C3-OH (p = 0.023)—there was a decrease (− 0.007 µmol/L, ± 0.020 µmol/L, p = 0.0233) in the RIPC group and increase (0.002 µmol/L, ± 0.015 µmol/L, p = 0.481) in the sham group. Additionally, a decrease from baseline to 24 h after surgery (p

Nitric oxide (NO) and protein S-nitrosylation (SNO) have been shown to play important roles in ischaemic preconditioning (IPC)-induced acute cardioprotection. The majority of proteins that show increased SNO following IPC are localized to the mitochondria, and our recent studies suggest that caveolae transduce acute NO/SNO cardioprotective signalling in IPC hearts. Due to the close association between subsarcolemmal mitochondria (SSM) and the sarcolemma/caveolae, we tested the hypothesis that SSM, rather than the interfibrillar mitochondria (IFM), are major targets for NO/SNO signalling derived from caveolae-associated eNOS. Following either control perfusion or IPC, SSM and IFM were isolated from Langendorff perfused mouse hearts, and SNO was analysed using a modified biotin switch method with fluorescent maleimide fluors. In perfusion control hearts, the SNO content was higher in SSM compared with IFM (1.33 ± 0.19, ratio of SNO content Perf-SSM vs. Perf-IFM), and following IPC SNO content significantly increased preferentially in SSM, but not in IFM (1.72 ± 0.17 and 1.07 ± 0.04, ratio of SNO content IPC-SSM vs. Perf-IFM, and IPC-IFM vs. Perf-IFM, respectively). Consistent with these findings, eNOS, caveolin-3, and connexin-43 were detected in SSM, but not in IFM, and IPC resulted in a further significant increase in eNOS/caveolin-3 levels in SSM. Interestingly, we did not observe an IPC-induced increase in SNO or eNOS/caveolin-3 in SSM isolated from caveolin-3(-/-) mouse hearts, which could not be protected with IPC. In conclusion, these results suggest that SSM may be the preferential target of sarcolemmal signalling-derived post-translational protein modification (caveolae-derived eNOS/NO/SNO), thus providing an important role in IPC-induced cardioprotection.

Achieving surgical revascularization of the heart, while avoiding the insult of cardiopulmonary bypass, is particularly desirable in specific high-risk patient groups. The relatively recent advances in surgical technique allowing high-quality grafting without mechanical arrest have led to an increase in popularity of off-pump coronary artery bypass surgery. Nonetheless, operating on the beating heart, manipulating it and purposely inducing ischaemia, invariably has significant haemodynamic consequences which must be carefully yet aggressively managed. To compound the situation, the intraoperative monitoring typically employed to evaluate cardiac function, such as electrocardiography and echocardiography, are of limited efficacy at crucial moments in the procedure. It is therefore essential that the anaesthetist is able to assimilate information from a multitude of sources in order to safely navigate the patient through a period of continually changing cardiovascular stress. [ABSTRACT FROM AUTHOR]

Introduction: Both ischaemic preconditioning (IPC) and muscle heat maintenance can be effective in enhancing repeated-sprint performance (RSA) when applied individually, acting mechanisms of these interventions, however, likely differ. It is unclear if, when combined, these interventions could further improve RSA. Methods: Eleven trained cyclists undertook experimental test sessions, whereby IPC (4 × 5-min at 220 mmHg) and SHAM (4 × 5-min at 20 mmHg) were each performed on two separate visits, each combined with either passive muscle heating or thermoneutral insulation prior to an "all-out" repeated-sprint task (10 × 6-s sprints with 24-s recovery). Primary outcome measures were peak and average power output (W), whist secondary measures were muscular activation and muscular oxygenation, measured via Electromyography (EMG) and Near-infrared spectroscopy (NIRS), respectively. Results: IPC did not enhance peak [6 (−14–26)W; P = 0.62] or average [12 (−7–31)W; P = 0.28] power output versus SHAM. Additionally, no performance benefits were observed when increasing muscle temperature in combination with IPC [5 (−14–19) watts; P = 0.67], or in isolation to IPC [9 (−9–28)W; P = 0.4] versus SHAM. No changes in EMG or microvascular changes were present (P > 0.05, respectively) between conditions. Conclusion: Overall, neither IPC, muscle heating, or a combination of both enhances RSA cycling performance in trained individuals. [ABSTRACT FROM AUTHOR]

We recently reported that non-preconditioned hearts from diet-induced obese rats showed, compared to controls, a significant reduction in infarct size after ischaemia/reperfusion, whilst ischaemic preconditioning was without effect. In view of the high circulating FFA concentration in diet rats, the aims of the present study were to: (i) compare the effect of palmitate on the preconditioning potential of hearts from age-matched controls and diet rats (ii) elucidate the effects of substrate manipulation on ischaemic preconditioning. Substrate manipulation was done with dichloroacetate (DCA), which enhances glucose oxidation and decreases fatty acid oxidation. Isolated hearts from diet rats, age-matched controls or young rats, were perfused in the working mode using the following substrates: glucose (10 mM); palmitate (1.2 mM)/3% albumin) + glucose (10 mM) (HiFA + G); palmitate (1.2 mM/3% albumin) (HiFA); palmitate (0.4 mM/3% albumin) + glucose(10 mM) (LoFA + G); palmitate (0.4 mM/3% albumin) (LoFA). Hearts were preconditioned with 3 × 5 min ischaemia/reperfusion, followed by 35 min coronary ligation and 60 min reperfusion for infarct size determination (tetrazolium method) or 20 min global ischaemia/10 or 30 min reperfusion for Western blotting (ERKp44/42, PKB/Akt). Preconditioning of glucose-perfused hearts from age-matched control (but not diet) rats reduced infarct size, activated ERKp44/42 and PKB/Akt and improved functional recovery during reperfusion (ii) perfusion with HiFA + G abolished preconditioning and activation of ERKp44/42 (iii) DCA pretreatment largely reversed the harmful effects of HiFA. Hearts from non-preconditioned diet rats exhibited smaller infarcts, but could not be preconditioned, regardless of the substrate. Similar results were obtained upon substrate manipulation of hearts from young rats. Abolishment of preconditioning in diet rats may be due to altered myocardial metabolic patterns resulting from changes in circulating FA. The harmful effects of HiFA were attenuated by stimulation of glycolysis and inhibition of FA oxidation. [ABSTRACT FROM AUTHOR]

The main aim of this study was to evaluate the effect of remote ischaemic preconditioning (RIPC) on preventing the leakage of cardiac damage biomarkers in patients undergoing vascular surgery. This is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open abdominal aortic aneurysm repair, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 minutes of ischaemia, followed by 5 minutes of reperfusion, was applied. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia. High sensitivity troponin T level was measured preoperatively and 2, 8 and 24 hours after surgery and pro b-type natriuretic peptide was measured preoperatively and 24 hours after surgery. There was significantly higher leakage of high sensitivity troponin T (peak change median 2 ng/L, IQR 0.9–6.2 ng/L vs 0.6 ng/L, IQR 0.7–2.1 ng/L, p =.0002) and pro b-type natriuretic peptide (change median 144 pg/mL, IQR 17–318 pg/mL vs 51 pg/mL, IQR 12–196 pg/mL, p =.02) in the sham group compared to the RIPC group. RIPC reduces the leakage of high sensitivity troponin T and pro b-type natriuretic peptide. Therefore, it may offer cardioprotection in patients undergoing non-cardiac vascular surgery. The clinical significance of RIPC has to be evaluated in larger studies excluding the factors known to influence its effect. [ABSTRACT FROM AUTHOR]

Coronary heart disease (CHD) is the leading cause of death world-wide. Since 1990, more people in the world have diedfrom CHD than from any other disease (World Health Organisation, WHO). “Conditioning” the heart to render it more resistant to the detrimental effects of acute ischaemia-reperfusion injury harnesses the endogenous ability of the heart to protect itself. This can be achieved using various mechanical strategies including the application of brief episodes of ischaemia and reperfusion to either the heart itself (ischaemic preconditioning) or an organ/tissue remote from the heart (remote ischaemic preconditioning) prior to the sustained ischaemic insult. Importantly, this form of protection can be mimicked by pharmacological agents capable of recapitulating the protective effect of IPC(pharmacological preconditioning). Preconditioning-induced cardioprotection is clearly restricted to patients undergoing an anticipated ischaemic insult such as in patients undergoing cardiac surgery. In contrast, the other major form of “conditioning” termed postconditioning can be implemented in patients presenting with an acute myocardial infarction after the onset of the sustained ischaemic insult. In this setting, myocardial reperfusion is interrupted with intermittent short-lived episodes of myocardial ischaemia applied to the heart itself (ischaemic postconditioning) or an organ or tissue remote from the heart (remote ischaemic postconditioning) – an effect which can again be mimicked by pharmacological agents (pharmacological postconditioning).This article will briefly review these various forms of “conditioning” examining the underlying mechanistic pathways and their clinical application.

Introduction: Tumour Necrosis Factor alpha (TNFα) contributes to cardiac dysfunction following ischaemia-reperfusion. Nonetheless, brief exposure to exogenous low doses of TNFα can mimic ischaemic preconditioning and thus be cardio-protective. The extracellular signal-regulated kinase (Erk) has been implicated in the protection against ischaemia-reperfusion and is known to be activated by TNFα. However, whether Erk activation contributes to TNFα-induced cardio-protection remains unknown. Methods: PD 98059 (10μM), an Erk inhibitor, was used to evaluate the role of this prosurvival kinase with respect to infarct size (expressed as a percentage of the area at risk) in isolated rat hearts subjected to ischaemic preconditioning (IPC) or TNFα preconditioning (TNFαP). Western blot analyses were used to determine the degree of Erk phosphorylation after the application of the preconditioning stimulus. Results: Pre-treatment of the hearts with 0.5ng/ml of TNFα (for 7min) or 2 cycles of 5min ischaemia-reperfusion prior to 30min regional index ischaemia and 2h of reperfusion reduced the infarct size by 76% and 88%, respectively, versus control. Western blot analysis of isolated rat hearts revealed that IPC but not TNFαP activated phosphorylation of Erk (+54% for IPC vs. control). Coadministration of PD 98059 during the preconditioning stimulus did not influence the infarct size. Conclusion: These findings confirm that activation of TNFα may be considered as a novel therapeutic approach against ischaemic heart disease and that its effect is independent of the activation of the classic prosurvival factor Erk.

New Findings: •What is the central question of this study?What is the impact of chronic adult‐onset diabetes on cardiac ischaemic outcomes and preconditioning?•What is the main finding and its importance?Chronic adult‐onset type 2 but not type 1 diabetes significantly impairs myocardial ischaemic tolerance and ischaemic preconditioning. Preconditioning may be detrimental in type 2 diabetes, exaggerating nitrosative stress and apoptotic protein expression. Effects of diabetes on myocardial responses to ischaemia–reperfusion (I–R) and cardioprotective stimuli remain contentious, potentially reflecting influences of disease duration and time of onset. Chronic adult‐onset type 1 diabetes (T1D) and type 2 diabetes (T2D) were modelled non‐genetically in male C57Bl/6 mice via 5 × 50 mg kg−1 daily streptozotocin (STZ) injections + 12 weeks' standard chow or 1 × 75 mg kg−1 STZ injection + 12 weeks' obesogenic diet (32% calories as fat, 57% carbohydrate, 11% protein), respectively. Systemic outcomes were assessed and myocardial responses to I–R ± ischaemic preconditioning (IPC; 3 × 5 min I–R) determined in Langendorff perfused hearts. Uncontrolled T1D was characterised by pronounced hyperglycaemia (25 mm fasting glucose), glucose intolerance and ∼10% body weight loss, whereas T2D mice exhibited moderate hyperglycaemia (15 mm), hyperinsulinaemia, glucose intolerance and 17% weight gain. Circulating ghrelin, resistin and noradrenaline were unchanged with T1D, while leptin increased and noradrenaline declined in T2D mice. Ischaemic tolerance and IPC were preserved in T1D hearts. In contrast, T2D worsened post‐ischaemic function (∼40% greater diastolic and contractile dysfunction) and cell death (100% higher troponin efflux), and abolished IPC protection. Whereas IPC reduced post‐ischaemic nitrotyrosine and pro‐apoptotic Bak and Bax levels in non‐diabetic hearts, these effects were reduced in T1D and IPC augmented Bax and nitrosylation in T2D hearts. The data demonstrate chronic T1D does not inhibit myocardial I–R tolerance or IPC, whereas metabolic and endocrine disruption in T2D is associated with ischaemic intolerance and inhibition of IPC. Indeed, normally protective IPC may exaggerate damage mechanisms in T2D hearts. [ABSTRACT FROM AUTHOR]

Remote ischaemic preconditioning (RIPC) is a phenomenon that promotes protection of tissues and organs against ischaemia reperfusion injury. RIPC has been shown to reduce myocardial and renal injury but its effect on arterial stiffness in patients undergoing lower limb digital subtraction angiography (DSA) is unknown. The aim of this study was to evaluate the effect of RIPC on arterial stiffness in patients with peripheral arterial disease (PAD) undergoing lower limb DSA. In the RIPC intervention, the blood pressure cuff on the arm was inflated to 200 mmHg or to 20 mmHg above systolic pressure, and in the sham intervention to 20 mmHg. For both, the procedure was repeated for four five minute cycles at five minute intervals between the cycles. Changes in heart rate corrected augmentation index (AIx@75), augmentation index (AIx), carotid femoral pulse wave velocity (PWV), and haemodynamic parameters were measured before and 24 h after DSA. 111 (RIPC 54, sham 57) patients with symptomatic lower limb PAD scheduled for DSA were randomised. 102 patients (RIPC 47, sham 55) were included in final analysis. RIPC significantly improved AIx (−5.46% in RIPC and −1.45% in sham group; p =.05), but not AIx@75 (−4.88% in RIPC and −1.38% in sham group; p =.07) or PWV (−0.41 m/s in RIPC and −0.27 m/s in sham group; p =.74). In the RIPC group a significant reduction in AIx (p =.002) and AIx@75 (p =.003) was noted after stenting when compared with the sham intervention. AIx (p =.001), AIx@75 (p =.002), mean arterial (p =.01), peripheral (p =.02), and central systolic blood pressure (p =.006) were significantly reduced only in the RIPC group 24 h after DSA. This study evaluates for the first time the effects of RIPC on arterial stiffness parameters in patients with symptomatic PAD following DSA. RIPC may modulate arterial stiffness following a DSA procedure and is more pronounced in patients after stent placement. [ABSTRACT FROM AUTHOR]

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n  =  10) and the control group (n  =  10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA. [ABSTRACT FROM AUTHOR]

Background: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress.Methods: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range).Results: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7].Conclusions: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest.Clinical Trial Registration: NCT02602977. [ABSTRACT FROM AUTHOR]

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n  =  10) and the control group (n  =  10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA. [ABSTRACT FROM AUTHOR]

The main aim of this study was to evaluate the effect of remote ischaemic preconditioning (RIPC) on arterial stiffness in patients undergoing vascular surgery. This was a randomised, sham controlled, double blind, single centre study. Patients undergoing open abdominal aortic aneurysm repair, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited. A RIPC or a sham procedure was performed, using a blood pressure cuff, along with preparation for anaesthesia. The RIPC protocol consisting of four cycles of 5 min of ischaemia, followed by 5 min of reperfusion was applied. Arterial stiffness and haemodynamic parameters were measured pre-operatively and 20–28 h after surgery. Two primary outcomes were selected: augmentation index and pulse wave velocity. Ninety-eight patients were randomised. After dropouts 44 and 46 patients were included in the RIPC and sham groups, respectively. Both groups were comparable. There were no statistically significant differences in augmentation index (p =.8), augmentation index corrected for heart rate of 75 beats per minute (p =.8), pulse wave velocity (p =.7), large artery elasticity indices (p =.8), small artery elasticity indices (p =.6), or mean arterial pressure (p =.7) changes between the RIPC and sham groups. There occurred statistically significant (p ≤.01) improvement in augmentation index (−5.8% vs. −5.5%), augmentation index corrected for a heart rate of 75 beats per minute (−2.5% vs. −2%), small artery elasticity indices (0.7 mL/mmHg × 100 vs. 0.9 mL/mmHg × 100), and mean arterial pressure post-operatively in both the RIPC and the sham groups (change median values in RIPC and sham groups, respectively). RIPC had no significant effect on arterial stiffness, but there was significant improvement in arterial stiffness after surgery in both groups. Arterial stiffness and haemodynamics may be influenced by surgery or anaesthesia or oxidative stress or all factors combined. Further studies are needed to clarify these findings. NCT02689414 [ABSTRACT FROM AUTHOR]

Purpose: Cardiovascular disease (CVD) is the leading cause of death worldwide. Many risk factors for CVD can be modified pharmacologically; however, uptake of medications is low, especially in asymptomatic people. Exercise is also effective at reducing CVD risk, but adoption is poor with time-commitment and cost cited as key reasons for this. Repeated remote ischaemic preconditioning (RIPC) and isometric handgrip (IHG) training are both inexpensive, time-efficient interventions which have shown some promise in reducing blood pressure (BP) and improving markers of cardiovascular health and fitness. However, few studies have investigated the effectiveness of these interventions in premenopausal women.Method: Thirty healthy females were recruited to twelve supervised sessions of either RIPC or IHG over 4 weeks, or acted as non-intervention controls (CON). BP measurements, flow-mediated dilatation (FMD) and cardiopulmonary exercise tests (CPET) were performed at baseline and after the intervention period.Results: IHG and RIPC were both well-tolerated with 100% adherence to all sessions. A statistically significant reduction in both systolic (- 7.2 mmHg) and diastolic (- 6 mmHg) BP was demonstrated following IHG, with no change following RIPC. No statistically significant improvements were observed in FMD or CPET parameters in any group.Conclusions: IHG is an inexpensive and well-tolerated intervention which may improve BP; a key risk factor for CVD. Conversely, our single arm RIPC protocol, despite being similarly well-tolerated, did not elicit improvements in any cardiorespiratory parameters in our chosen population. [ABSTRACT FROM AUTHOR]

Achieving surgical revascularization of the heart, while avoiding the insult of cardiopulmonary bypass, is particularly desirable in specific high-risk patient groups. The relatively recent advances in surgical technique allowing high-quality grafting without mechanical arrest have led to an increase in popularity of off-pump coronary artery bypass surgery. Nonetheless, operating on the beating heart, manipulating it and purposely inducing ischaemia, invariably has significant haemodynamic consequences which must be carefully yet aggressively managed. To compound the situation, the intraoperative monitoring typically employed to evaluate cardiac function, such as electrocardiography and echocardiography, are of limited efficacy at crucial moments in the procedure. It is therefore essential that the anaesthetist is able to assimilate information from a multitude of sources in order to safely navigate the patient through a period of continually changing cardiovascular stress. [ABSTRACT FROM AUTHOR]

Objective: The present study was been designed to investigate the role and pharmacological potential of hedgehog in oestrogen-deficient rat heart. Methods: Oestrogen deficiency was produced in female Wistar rats by the surgical removal of both ovaries and these animals were used four weeks later. Isolated rat heart was subjected to 30 min ischaemia followed by 120 min of reperfusion (I/R). The heart was subjected to pharmacological preconditioning with the hedgehog agonist purmorphamine (1μM) and GDC-0449, a hedgehog antagonist, in the last episode of reperfusion before I/R. Myocardial infarction was assessed in terms of the increase in lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), myeloperoxidase (MPO) level and infarct size (triphenyltetrazolium chloride staining). Immunohistochemistry analysis was done for the assessment of tumour necrosis factor (TNF)-α level in cardiac tissue. eNOS expression was estimated by rt-PCR. Results: Pharmacological preconditioning with purmorphamine significantly attenuated I/R-induced myocardial infarction, TNF-α, MPO level and release of LDH and CK-MB compared to the I/R control group. However, GDC-0449 prevented the ameliorative preconditioning effect of estradiol. Conclusion: It may be concluded that the hedgehog agonist purmorphamine prevents the ovariectomised heart from ischaemic reperfusion injury. [ABSTRACT FROM AUTHOR]

Purpose: To accurately estimate the effect size of both local or classic ischaemic preconditioning (IPC) and remote ischaemic preconditioning (RIPC) using a pooling data set of 91 animals.Methods: We combined all the available mouse data collected from our Institute over the last 3 years regarding (i) local IPC (4 cycles of 5 min of global ischaemia/reperfusion injury, IRI, followed by 35-min ischaemia and 2-h reperfusion) in the Langendorff-isolated perfused mouse heart model and (ii) RIPC (3 cycles of 5 min of limb occlusion followed by 40-min ischaemia and 2-h reperfusion) in the in vivo mouse model.Results: Five independent experiments containing 27 control and 29 IPC mice were used to estimate the overall (i) local IPC effect, which reduced infarct size in the ex-vivo setting by a mean difference of 24.1% (95% CI 19.5, 28.6%) when compared to untreated controls (P < 0.001) and for (ii) RIPC, three independent experiments including data for 16 control and 19 RIPC mice were used to estimate that RIPC diminished infarct size in the in-vivo setting by a mean difference of 20.8% (95% CI 14.7, 26.9%) when compared to controls (P < 0.001).Conclusions: Using a significant animal dataset, we found that local IPC reduces myocardial infarct size by 24.1% and RIPC by 20.8% in the ex vivo and in vivo mouse models of IRI, respectively. These differences may be used as reference values to either establish positive controls or to determine by how much myocardial infarct size can be reduced by novel cardioprotective interventions following an IRI insult. [ABSTRACT FROM AUTHOR]

Abstract: The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro‐survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K‐Akt, its negative regulator PTEN and other pro‐survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3β and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3β was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K‐dependent during the IPC phase. In conclusion, PI3K‐Akt plays a major role in IPC‐induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K‐independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade. [ABSTRACT FROM AUTHOR]

Angiotensin II-preconditioning ( APC) has been shown to reproduce the cardioprotective effects of ischaemic preconditioning ( IPC), however, the molecular mechanisms mediating the effects of APC remain unknown. In this study, Langendorff-perfused rat hearts were subjected to IPC, APC or both ( IPC/ APC) followed by ischaemia-reperfusion ( IR), to determine translocation of PKCε, PKCδ, Akt, Erk1/2, JNK, p38 MAPK and GSK-3β to mitochondria as an indicator of activation of the protein kinases. In agreement with previous observations, IPC, APC and IPC/ APC increased the recovery of left ventricular developed pressure ( LVDP), reduced infarct size ( IS) and lactate dehydrogenase ( LDH) release, compared to controls. These effects were associated with increased mitochondrial PKCε/ PKCδ ratio, Akt, Erk1/2, JNK, and inhibition of permeability transition pore ( mPTP) opening. Chelerythrine, a pan- PKC inhibitor, abolished the enhancements of PKCε but increased PKCδ expression, and inhibited Akt, Erk1/2, and JNK protein levels. The drug had no effect on the APC- and IPC/ APC-induced cardioprotection as previously reported, but enhanced the post-ischaemic LVDP in controls. Losartan, an angiotensin II type 1 receptor ( AT1-R) blocker, abolished the APC-stimulated increase of LVDP and reduced PKCε, Akt, Erk1/2, JNK, and p38. Both drugs reduced ischaemic contracture and LDH release, and abolished the inhibition of mPTP by the preconditioning. Chelerythrine also prevented the reduction of IS by APC and IPC/ APC. These results suggest that the cardioprotection induced by APC and IPC/ APC involves an AT1-R-dependent translocation of PKCε and survival kinases to the mitochondria leading to mPTP inhibition. In chelerythrine-treated hearts, however, alternate mechanisms appear to maintain cardiac function. [ABSTRACT FROM AUTHOR]

Ischaemic preconditioning (IPC) phenomenon has been known for thirty years. During that time several studies showed that IPC provided by brief ischaemic and reperfusion episodes prior to longer ischaemia can bestow a protective effect to both preconditioned and also remote organs. IPC affecting remote organs is called remote ischaemic preconditioning. Initially, most IPC studies were focused on enhancing myocardial resistance to subsequent ischaemia and reperfusion injury. However, preconditioning was found to be a universal phenomenon and was observed in various organs and tissues including the heart, liver, brain, retina, kidney, skeletal muscles and intestine. Currently, there are a lot of simultaneous studies are underway aiming at finding out whether IPC can be helpful in protecting these organs. The mechanism of local and remote IPC is complex and not well known. Several triggers, intracellular pathways and effectors, humoral, neural and induced by genetic changes may be considered potential pathways in the protective activity of local and remote IPC. Local and remote IPC mechanism may potentially serve as heart protection during cardiac surgery and may limit the infarct size of the myocardium, can be a strategy for preventing the development of acute kidney injury development and liver damage during transplantation, may protect the brain against ischaemic injury. In addition, the method is safe, non-invasive, cheap and easily applicable. The main purpose of this review article is to present new advances which would help to understand the potential mechanism of IPC. It also discusses both its potential applications and utility in clinical settings. [ABSTRACT FROM AUTHOR]

Ischaemic preconditioning (IPC) provides myocardial resistance to ischaemia/reperfusion (I/R) injuries. The protection afforded by IPC is not limited to the target tissue but extends to remote tissues, suggesting a mechanism mediated by humoral factors. The aim of the present study was to identify the humoral factors that are responsible for the cardioprotection induced by the coronary effluent transferred from IPC to naïve hearts. Isolated rat hearts were submitted to IPC (three cycles of 5 min I/R) before 30-min global ischaemia and 60-min reperfusion. The coronary effluent (Efl_IPC) collected during IPC was fractionated by ultrafiltration in different molecular weight ranges (<3, 3-5, 5-10, 10-30, 30-50, and >50 kDa) and evaluated for cardioprotective effects by perfusion before I/R in naïve hearts. Only the <3, 5-10 and <10 kDa fractions of hydrophobic eluate reduced I/R injuries. The cardioprotective effect of the 5-10 fraction was blocked by K channel blockers and a PKC inhibitor. An Efl_IPC proteomic analysis revealed 14 cytoprotection-related proteins in 4-12 kDa peptides. HSP10 perfusion protected the heart against I/R injuries. These data provide insights into the mechanisms of cardioprotection in humoral factors released by IPC. Cardioprotection is afforded by hydrophobic peptides in the 4-12 kDa size range, which activate pathways that are dependent on PKC and K. Fourteen 4-12 kDa peptides were identified, suggesting a potential therapeutic role for these molecules in ischaemic diseases. One of these, HSP10, identified by mass spectrometry, reduced I/R injuries and may be a potential candidate as a therapeutic target. [ABSTRACT FROM AUTHOR]

Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and L-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field. [ABSTRACT FROM AUTHOR]

Ischaemia-induced tissue injury has wide-ranging clinical implications including myocardial infarction, stroke, compartment syndrome, ischaemic renal failure and replantation and revascularization. However, the restoration of blood flow produces a 'second hit' phenomenon, the effect of which is greater than the initial ischaemic event and characterizes ischaemia-reperfusion (IR) injury. Some examples of potential settings of IR injury include: following thrombolytic therapy for stroke, invasive cardiovascular procedures, solid organ transplantation, and major trauma resuscitation. Pathophysiological events of IR injury are the result of reactive oxygen species (ROS) production, microvascular vasoconstriction, and ultimately endothelial cell-neutrophil adhesion with subsequent neutrophil infiltration of the affected tissue. Initially thought to increase the amount of free radical oxygen in the system, hyperbaric oxygen (HBO) has demonstrated a protective effect on tissues by influencing the same mechanisms responsible for IR injury. Consequently, HBO has tremendous therapeutic value. We review the biochemical mechanisms of ischaemia-reperfusion injury and the effects of HBO following ischaemia-reperfusion. [ABSTRACT FROM AUTHOR]

Aim: Upregulation of miR-21 in renal ischaemic preconditioning (IPC)was associated with increased hypoxia inducible factor (HIF)-1α expression. Hypoxic induction of HIF-1α is mediated by inhibition of prolyl hydroxylase domain protein 2 (PHD2). We hypothesized thatmiR-21 regulated HIF-1α by targeting PHD2 in the renal IPC. Methods: Luciferase reporter assay examined if miR-21 target the 3'-untranslated region of PHD2. In vitro, human proximal tubular cell line (HK-2) was incubated in hypoxia or hypoxia/reoxygenation condition. Kidneys of Mice were respectively subjected to ischaemia/reperfusion injury (IRI) and IPC. Locked nucleic acid (LNA) modified anti-miR-21 was used to knockdown miR-21. Serum creatinine and histological changes estimated the renal injury. Levels of HIF-1α, PHD2, VEGF and miR-21 were examined by western blot or real-time PCR. Result: miR-21 targeting of PHD2was confirmed by 3'-untranslated region reporter assay. miR-21 was significantly upregulated by hypoxia/reoxygenation in HK-2 cell, while PHD2 protein level decreased significantly. LNA anti-miR-21 significantly repressed miR-21 levels and increased the abundance of PHD2. In vivo, IPC upregulated miR-21 expression 24h after the second ischaemia, while PHD2 expression decreased significantly with upregulation of HIF-1α protein and VEGF mRNA. MiR-21 induced by delayed IPC was effectively inhibited by the LNA anti-miR-21. With downregulation of miR-21, the protection of delayed IPC was attenuated and PHD2 protein was increased. Furthermore, upregulation of HIF-1α and VEGF were abolished after the LNA anti-miR-21 treatment. Conclusion: miR-21 could protect kidney against IRI via HIF-1α by inhibiting its target PHD2.The study suggested a new relationship between miR-21 and HIF-1α. [ABSTRACT FROM AUTHOR]

Background: Reports on the effect of age and obesity on myocardial ischaemia/reperfusion (I/R) injury and ischaemic preconditioning are contradictory. The aim of this study was to re-evaluate the effects of age and diet-induced obesity (DIO) on myocardial I/R injury and preconditioning potential. Methods: Four groups of Wistar male rats were used: age-matched controls (AMC) receiving standard rat chow for (i) 16 weeks and (ii) 16 months respectively; DIO rats receiving a sucrose-supplemented diet for (iii) 16 weeks and (iv) 16 months respectively. The ages of groups (i) and (iii) were 22 weeks ("young") and groups (ii) and (iv) 17 months ("middle-aged") at time of experimentation. Isolated perfused working hearts were subjected to 35 min regional ischaemia/1 h reperfusion. Endpoints were infarct size (tetrazolium staining) and functional recovery. Hearts were preconditioned by 3 × 5 min ischaemia/5 min reperfusion. Results were processed using GraphPad Prism statistical software. Results: Age did not affect baseline heart function before induction of ischaemia and I/R damage as indicated by infarct size and similar values were obtained in hearts from both age groups. Age also had no effect on functional recovery of hearts during reperfusion after regional ischaemia in AMC rats, but cardiac output during reperfusion was better in hearts from middle-aged than young DIO rats. The diet reduced infarct size in hearts from young rats (% of area at risk: AMC: 32.4 ± 3.6; DIO: 20.7 ± 2.9, p < 0.05), with no differences in hearts from middle-aged rats (AMC: 24.6 ± 4.6; DIO: 28.3 ± 13.5, p = NS). Compared to their respective AMC, diet-induced obesity had no significant effect on functional recovery of hearts from both age groups after exposure to regional ischaemia. When exposed to the more severe stress of global ischaemia, the functional recovery potential of middle-aged DIO rats appeared to be impeded compared to hearts of young DIO rats, while age had no effect on the functional recovery of AMC hearts. Preconditioning reduced infarct size in hearts from young control rats and both middle-aged groups, but not from young DIO rats. Age had a significant effect on functional recovery in preconditioning: it was improved in hearts from young control and DIO rats, but depressed in both middle-aged groups. Conclusions: The data showed that middle-age and obesity had no effect on baseline myocardial function and did not increase susceptibility to I/R damage upon exposure to regional ischaemia. On the contrary, obesity reduced I/R damage in young rats. Preconditioned aging hearts showed a decreased infarct size, but a reduction in functional recovery. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 μM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPC = 0.36 ± 0.03 μM vs C = 0.04 ± 0.04 μM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning (IPC) may enhance exercise performance. Cardioprotective effects of IPC are known to re-occur 24h after the stimulus. Whether the delayed effect of IPC has similar effects as IPC on exercise performance is unknown.Objectives: Examine whether IPC applied 24h (24-IPC) before exercise is equally effective as IPC in improving exercise performance.Design: Randomized, cross-over study METHODS: 12 healthy participants were randomly exposed to SHAM-session, IPC or 24-IPC before a self-paced 5km running trial on a treadmill. Subjects were blinded for time, speed and heart rate. Furthermore, heart rate, BORG, and the local tissue saturation index were measured during exercise, while lactate levels were determined after running. Using a regression model, we explored whether these parameters predicted the change in running time after IPC and 24-IPC.Results: We found no differences in finish time after IPC (SHAM: 1400±105s, IPC: 1381±112s, 24-IPC: 1385±113s; p=0.30). However, we observed a significant positive relation between the change in finish time after IPC and 24-IPC (p=0.016; r=0.677). Using stepwise linear regression, a lower post-exercise blood lactate level after IPC or 24-IPC was significantly related to an improvement in finish time (R2=0.47, β=-0.687, p=0.007).Conclusions: Although no significant effect of IPC or 24-IPC on exercise performance was found, individual finish time after IPC and 24-IPC were strongly correlated. Therefore, our data suggest that, at the individual level, the effects of 24-IPC are closely related to the effects of IPC. [ABSTRACT FROM AUTHOR]