Ischemic preconditioning: what else can it do ?

Ischemic preconditioning (IPC) can enhance maximal strength likely due to neural priming. Cruz et al. (Cruz R, Tramontin AF, Oliveira AS, Caputo F, Denadai BS, Greco CC. Scand J Med Sci Sports 34: e14591, 2024) examined the neurophysiological mechanisms responsible for the ergogenic effect. Although key neurophysiological measures remained largely unchanged, voluntary activation and maximal strength were greater following IPC than sham-IPC. Although the mechanistic evidence remains inconclusive, the greater maximal strength provides further evidence of the ergogenic benefit of IPC. Researchers should continue examining the broader functional implications of IPC.

Effects of acetazolamide combined with remote ischemic preconditioning on risk of acute mountain sickness: a randomized clinical trial.

BACKGROUND: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). METHODS: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. RESULTS: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. CONCLUSIONS: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05023941.

The Effect of Laparoscopic Gastric Ischemic Preconditioning Prior to Esophagectomy on Anastomotic Stricture Rate and Comparison with Esophagectomy-Alone Controls.

BACKGROUND: Benign anastomotic stricture is a recognized complication following esophagectomy. Laparoscopic gastric ischemic preconditioning (LGIP) prior to esophagectomy has been associated with decreased anastomotic leak rates; however, its effect on stricture and the need for subsequent endoscopic intervention is not well studied. METHODS: This was a case-control study at an academic medical center using consecutive patients undergoing oncologic esophagectomies (July 2012-July 2022). Our institution initiated an LGIP protocol on 1 January 2021. The primary outcome was the occurrence of stricture within 1 year of esophagectomy, while secondary outcomes were stricture severity and frequency of interventions within the 6 months following stricture. Bivariable comparisons were performed using Chi-square, Fisher's exact, or Mann-Whitney U tests. Multivariable regression controlling for confounders was performed to generate risk-adjust odds ratios and to identify the independent effect of LGIP. RESULTS: Of 253 esophagectomies, 42 (16.6%) underwent LGIP prior to esophagectomy. There were 45 (17.7%) anastomotic strictures requiring endoscopic intervention, including three patients who underwent LGIP and 42 who did not. Median time to stricture was 144 days. Those who underwent LGIP were significantly less likely to develop anastomotic stricture (7.1% vs. 19.9%; p = 0.048). After controlling for confounders, this difference was no longer significant (odds ratio 0.46, 95% confidence interval 0.14-1.82; p = 0.29). Of those who developed stricture, there was a trend toward less severe strictures and decreased need for endoscopic dilation in the LGIP group (all p < 0.20). CONCLUSION: LGIP may reduce the rate and severity of symptomatic anastomotic stricture following esophagectomy. A multi-institutional trial evaluating the effect of LGIP on stricture and other anastomotic complications is warranted.

Remote Ischemic Preconditioning Before Drug-Coated Balloon Implantation can Improve the Long-Term Prognosis of Patients with CAD.

Background: Drug-coated balloons (DCBs) have become increasingly vital to percutaneous coronary intervention, offering many advantages. However, a significant challenge is that many patients are intolerant to the myocardial ischemia caused by DCB dilation. Remote ischemic preconditioning (RIPC) is known to enhance heart's tolerance to ischemia and hypoxia. This study investigated whether preoperative RIPC could extend the tolerated DCB inflation time and improve the long-term prognosis of patients with coronary artery disease (CAD). Methods: A total of 653 patients with CAD were recruited and randomized into a RIPC group (n = 323) and a control (n = 330) group. The RIPC group underwent RIPC on the left upper limb twice daily, starting three days before the DCB implantation. The patients were followed up for one year after the operation, and 197 patients returned for coronary angiography (CAG) examination where the quantitative flow ratio (QFR) of the target vessels was measured. The primary endpoint of the study was the incidence of target lesion failure (TLF), which included target lesion revascularization (TLR), target vessel myocardial infarction, and cardiac death. The secondary endpoint was the rate of QFR loss in the target vessels. Results: The findings revealed a significantly lower incidence of TLR in the RIPC group compared to the control group. Additionally, at the one-year follow-up, the rate of QFR loss in target vessels was lower in the RIPC group than in the control group. Conclusions: The preoperative application of RIPC effectively extended the duration patients could tolerate DCB inflation. Furthermore, this approach positively impacted the long-term prognosis of CAD patients undergoing DCB treatment. Clinical Trial Registration Information: NCT04766749.

Transformation of A1/A2 Astrocytes Participates in Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning via Inhibiting NDRG2.

Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia-reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10 min; (3) MCAO/R group: left middle cerebral artery was blocked for 90 min; (4) CIP + MCAO/R group: CIP was performed 72 h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24 h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10+/GFAP+ cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10+/GFAP+ cells yet increased C3d expression and the number of C3d+/GFAP+ cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d+/GFAP+ cells increased, while S100A10 expression and the number of S100A10+/GFAP+ cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.

Physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated in underlying of ischemia/reperfusion injury in different organs.

Ischemia-reperfusion (I/R) injury, as a pathological phenomenon, takes place when blood supply to an organ is disrupted and then aggravated during restoration of blood flow. Ischemic preconditioning (IPC) is a potent method for attenuating subsequent events of IR damage in numerous organs. IPC protocol is determined by a brief and sequential time periods of I/R before the main ischemia. MicroRNAs are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review introduces the physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated after I/R insult in different organs such as the liver, kidney, heart, brain, and intestine. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2023. Based on these literature studies, IPC/IR intervention can affect cellular mechanisms including oxidative stress, apoptosis, angiogenesis, and inflammation through up-regulation or down-regulation of multiple microRNAs and their target genes.

Remote ischemic preconditioning versus sham-control for prevention of anastomotic leakage after resection for rectal cancer (RIPAL trial): a pilot randomized controlled, triple-blinded monocenter trial.

PURPOSE: Remote ischemic preconditioning (RIPC) reportedly reduces ischemia‒reperfusion injury (IRI) in various organ systems. In addition to tension and technical factors, ischemia is a common cause of anastomotic leakage (AL) after rectal resection. The aim of this pilot study was to investigate the potentially protective effect of RIPC on anastomotic healing and to determine the effect size to facilitate the development of a subsequent confirmatory trial. MATERIALS AND METHODS: Fifty-four patients with rectal cancer (RC) who underwent anterior resection were enrolled in this prospectively registered (DRKS0001894) pilot randomized controlled triple-blinded monocenter trial at the Department of Surgery, University Medicine Mannheim, Mannheim, Germany, between 10/12/2019 and 19/06/2022. The primary endpoint was AL within 30 days after surgery. The secondary endpoints were perioperative morbidity and mortality, reintervention, hospital stay, readmission and biomarkers of ischemia‒reperfusion injury (vascular endothelial growth factor, VEGF) and cell death (high mobility group box 1 protein, HMGB1). RIPC was induced through three 10-min cycles of alternating ischemia and reperfusion to the upper extremity. RESULTS: Of the 207 patients assessed, 153 were excluded, leaving 54 patients to be randomized to the RIPC or the sham-RIPC arm (27 each per arm). The mean age was 61 years, and the majority of patients were male (37:17 (68.5:31.5%)). Most of the patients underwent surgery after neoadjuvant therapy (29/54 (53.7%)) for adenocarcinoma (52/54 (96.3%)). The primary endpoint, AL, occurred almost equally frequently in both arms (RIPC arm: 4/25 (16%), sham arm: 4/26 (15.4%), p = 1.000). The secondary outcomes were comparable except for a greater rate of reintervention in the sham arm (9 (6-12) vs. 3 (1-5), p = 0.034). The median duration of endoscopic vacuum therapy was shorter in the RIPC arm (10.5 (10-11) vs. 38 (24-39) days, p = 0.083), although the difference was not statistically significant. CONCLUSION: A clinically relevant protective effect of RIPC on anastomotic healing after rectal resection cannot be assumed on the basis of these data.

Amplification of Cardioprotective Response of Remote Ischemic Preconditioning in Rats by Quercetin: Potential Role of Activation of mTOR-dependent Autophagy and Nrf2.

OBJECTIVES: Noninvasive remote ischemic preconditioning (RIPC) is a practical, acceptable, and feasible conditioning technique reported to provide cardioprotection in myocardial ischemia-reperfusion injury (MIRI). It has been well-reported that quercetin possesses antioxidant and anti-inflammatory properties. This study investigates the modification of the cardioprotective response of RIPC by quercetin. METHODS: Adult Wistar rats were randomized into 12 groups of six animals each. MIRI was induced by subjecting the isolated hearts of Wistar rats to global ischemia for 30 min, succeeded by reperfusion of 120 min after mounting on the Langendorff PowerLab apparatus. Hind limb RIPC was applied in four alternate cycles of ischemia and reperfusion of 5 min each by tying the pressure cuff before isolation of hearts. RESULTS: MIRI was reflected by significantly increased infarct size, LDH-1, and CK-MB, TNF-α, TBARS, and decreased GSH, catalase, and hemodynamic index, and modulated Nrf2. Pretreatment of quercetin (25 and 50 mg/kg; i.p.) significantly attenuated the MIRI-induced cardiac damage and potentiated the cardioprotective response of RIPC at the low dose. Pretreatment of ketamine (10 mg/kg; i.p.), an mTOR-dependent autophagy inhibitor, significantly abolished the cardioprotective effects of quercetin and RIPC. CONCLUSIONS: The findings highlight the modification of the cardioprotective effect of RIPC by quercetin and that quercetin protects the heart against MIRI through multiple mechanisms, including mTOR-dependent activation of autophagy and Nrf-2 activation.

Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis.

Ischemic preconditioning (IPC) has been considered as the most important mean to protect against ischemia/reperfusion (I/R) induced heart injury. It has been reported that cardiac myosin binding protein-C (cMyBP-C) phosphorylation plays an essential role in cardiac protection against I/R-induced heart injury. However, it is still obscured whether IPC-mediated cardiac protection is causally related to cMyBP-C phosphorylation and proteolysis and, if so, what the underlying mechanism is. In this study, IPC was found to increase the phosphorylation level of cMyBP-C, companying with the decreased calpain activity in the collected perfusate samples. Mechanistically, we confirmed that IPC promoted cMyBP-C phosphorylation and inhibited calpain-mediated cMyBP-C proteolysis. Moreover, inhibition of calpain activity significantly increased the phosphorylated cMyBP-C level by using calpain inhibitor (MG-101), and subsequently promoted stabilization and secretion of cMyBP-C. Functionally, adeno-associated virus (AAV)-mediated overexpression of mutated phosphorylation motif site of cMyBP-C exhibited impaired IPC-mediated cardiac protection via proteolysis of the full-length cMyBP-C protein. We concluded that IPC promoted cMyBP-C phosphorylation via inhibition of calpain-mediated proteolysis and participated in IPC-mediated protection against I/R induced heart injury.

The effect of short-term remote ischemic preconditioning on endothelial function of patients with chronic kidney disease: A randomized pilot study.

AIM: Patients with chronic kidney disease (CKD) are more susceptible to endothelial dysfunction and cardiovascular disease (CV). Remote ischemic preconditioning (rIPC) has been proven efficient in improving endothelial function and lowering the risk of CV. However, the safety and effect of rIPC on endothelial function in patients with CKD have not been effectively assessed. METHODS: 45 patients with CKD (average estimated glomerular filtration rate: 48.4 mL/min/1.73 m2) were randomly allocated to either 7-day daily upper-arm rIPC (4 × 5 min 200 mmHg, interspaced by 5-min reperfusion) or control (4 × 5 min 60 mmHg, interspaced by 5-min reperfusion). Vascular endothelial function was assessed by natural log-transformed reactive hyperemia index (LnRHI) before and after a 7-day intervention. Arterial elasticity was assessed by augmentation index (AI). RESULTS: The results showed that LnRHI could be improved by rIPC treatment (Pre = 0.57 ± 0.04 vs. Post = 0.67 ± 0.04, p = .001) with no changes relative to control (Pre = 0.68 ± 0.06 vs. Post = 0.64 ± 0.05, p = .470). Compared with the control group, the improvement of LnRHI was greater after rIPC treatment (rIPC vs. Control: 0.10 ± 0.03 vs. -0.04 ± 0.06, between-group mean difference, -0.15 [95% CI, -0.27 to -0.02], p = .027), while there was no significant difference in the change of AI@75 bpm (p = .312) between the two groups. CONCLUSION: RIPC is safe and well tolerated in patients with CKD. This pilot study suggests that rIPC seems to have the potential therapeutic effect to improve endothelial function. Of note, further larger trials are still warranted to confirm the efficacy of rIPC in improving endothelial function in CKD patients.

Targeted effect of ischemic preconditioning on the gas exchange threshold in healthy males and females.

Ischemic preconditioning (IPC) appears to improve exercise performance although there is uncertainty about the intensity dependence of this effect. The present study sought to clarify effects of IPC on physiological responses at and below peak oxygen uptake, including the gas exchange threshold (GET). Ten male and female participants completed five cycling ramp tests (10 W/min) to failure, with the final two tests preceded by either IPC (4 × 5 min 220 mmHg bilateral leg occlusions) or SHAM (20 mmHg), in a randomised crossover design. The rates of O2 uptake ( V ˙ O2), carbon dioxide output ( V ˙ CO2), and expired ventilation ( V ˙ E) were measured at rest and throughout exercise. Exercise data were fitted using several functions to identify GET, two ventilatory thresholds and peak V ˙ O2. IPC increased V ˙ O2 at GET by ~ 9% (IPC: 1.89 ± 0.51 L/min, SHAM: 1.73 ± 0.56 L/min; p = 0.055) and power output at GET by ~ 11% (IPC: 133 ± 36 W, SHAM: 120 ± 39 W; p = 0.022). In addition, peak power output increased by 2.4% following IPC (IPC: 217 ± 50 W, SHAM: 212 ± 51 W; p = 0.052), but there was no significant effect of IPC on peak V ˙ O2 (IPC: 2.87 ± 0.68 L/min, SHAM: 2.84 ± 0.73 L/min; p = 0.60) or the ventilatory thresholds. The present results suggest that IPC improves GET and peak power output but not peak V ˙ O2 during a maximal graded test.

Effects of ischemic pre-conditioning on electrically stimulated contractions.

PURPOSE: Ischemic pre-conditioning (IPC) offers protection against future ischemic events and may improve sports performance due to several mechanisms at local and systemic levels. This study investigates the local effects on muscle contractility in electrically induced muscle contractions, thus effectively excluding any uncontrolled change in the motor drive. METHODS: Twenty-one subjects were divided into two groups: 12 subjects in the IPC group (3 × 5/5 min right arm ischemia/reperfusion; cuff pressure 250 mmHg) and 9 subjects in the SHAM group (same treatment at 20 mmHg). The adductor pollicis was contracted by supramaximal stimulation of the ulnar nerve with single pulses, trains of stimuli (5, 8, 10 and 12 Hz, 1-s duration) and bursts (4 pulses, 25 Hz), all separated by 5-s intervals. The stimulation sequence was delivered before and 15 and 30 min after IPC/SHAM treatment. The isometric contraction force, the superficial electromyographic signal, and tissue oxygenation were continuously monitored. RESULTS: A significant force decrease in time was observed at 8, 10 (p < 0.01) and 12 Hz (p < 0.05) along with a decrease in half-relaxation time in single twitches and bursts (p = 0.01), regardless of treatment. This general time-related weakening was more marked in IPC than SHAM at 5-Hz stimulation. No effects were observed on the magnitude of the superficial electromyographic signal. CONCLUSION: Data indicate that IPC does not increase muscle force during electrically stimulated contractions, supporting the idea that IPC's ergogenic effects are not due to increased muscle contractility.

Effects of remote ischemic preconditioning in hepatectomy: a systematic review and meta-analysis.

BACKGROUND: Animal experiments have confirmed that remote ischemic preconditioning (RIPC) can reduce hepatic ischemia-reperfusion injuries (HIRIs), significantly improving early tissue perfusion and oxygenation of the residual liver after resections, accelerating surgical prognoses, and improving survival rates. However, there is still controversy over the role of RIPC in relieving HIRI in clinical studies, which warrants clarification. This study aimed to evaluate the beneficial effects and applicability of RIPC in hepatectomy and to provide evidence-based information for clinical decision-making. METHODS: Randomized controlled trials (RCTs) evaluating the efficacy and safety of RIPC interventions were collected, comparing RIPC to no preconditioning in patients undergoing hepatectomies. This search spanned from database inception to January 2024. Data were extracted independently by two researchers according to the PRISMA guidelines. The primary outcomes assessed were postoperative alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), and albumin (ALB) levels. The secondary outcomes assessed included duration of surgery and Pringle, length of postoperative hospital stay, intraoperative blood loss and transfusion, indocyanine green (ICG) clearance, hepatocyte apoptosis index, postoperative complications, and others. RESULTS: Ten RCTs were included in this meta-analysis, with a total of 865 patients (428 in the RIPC group and 437 in the control group). ALT levels in the RIPC group were lower than those in the control group on postoperative day (POD) 1 (WMD = - 59.24, 95% CI: - 115.04 to - 3.45; P = 0.04) and POD 3 (WMD = - 27.47, 95% CI: - 52.26 to - 2.68; P = 0.03). However, heterogeneities were significant (I2 = 89% and I2 = 78%), and ALT levels on POD 3 were unstable based on a sensitivity analysis. AST levels on POD 1 in the RIPC group were lower than those in the control group (WMD = - 50.03, 95% CI: - 94.35 to - 5.71; P = 0.03), but heterogeneity was also significant (I2 = 81%). A subgroup analysis showed no significant differences in ALT and AST levels on POD 1 between groups, regardless of whether the Pringle maneuver or propofol was used for anesthesia (induction only or induction and maintenance, P > 0.05). The remaining outcome indicators were not statistically significant or could not be analyzed due to lack of sufficient data. CONCLUSION: RIPC has some short-term liver protective effects on HIRIs during hepatectomies. However, there is still insufficient evidence to encourage its routine use to improve clinical outcomes. TRIAL REGISTRATION: The protocol of this study was registered with PROSPERO (CRD42022333383).

Endothelial Cell Apoptosis but Not Necrosis Is Inhibited by Ischemic Preconditioning.

This study aimed to assess the influence of ischemic preconditioning (IP) on hypoxia/reoxygenation (HR)-induced endothelial cell (EC) death. Human umbilical vein endothelial cells (HUVECs) were subjected to 2 or 6 h hypoxia with subsequent reoxygenation. IP was induced by 20 min of hypoxia followed by 20 min of reoxygenation. Necrosis was assessed by the release of lactate dehydrogenase (LDH) and apoptosis by double staining with propidium iodide/annexin V (PI/AV), using TUNEL test, and Bcl-2 and Bax gene expression measured using RT-PCR. In PI/AV staining, after 24 h of reoxygenation, 30-33% of EC were necrotic and 16-21% were apoptotic. In comparison to HR cells, IP reduced membrane apoptosis after 24 h of reoxygenation by 50% but did not influence EC necrosis. Nuclear EC apoptosis affected about 15-17% of EC after 24 h of reoxygenation and was reduced with IP by 55-60%. IP was associated with a significantly higher Bcl-2/Bax ratio, at 8 h 2-4 times and at 24 h 2-3 times as compared to HR. Longer hypoxia was associated with lower values of Bcl-2/Bax ratio in EC subjected to HR or IP. IP delays, without reducing, the extent of HR-induced EC necrosis but significantly inhibits their multi-level evaluated apoptosis.

[Cytosteatonecrosis after breast reconstruction by fat flap with or without ischemic preconditioning]. / Cytostéatonécrose après reconstruction mammaire par lambeau graisseux avec ou sans préconditionnement ischémique.

INTRODUCTION: Cytosteatonecrosis (CTN) is a frequent postoperative complication after breast autologous reconstruction using DIEP (deep inferior epigastric perforator) flap. CTN radiological diagnostic reveals different types of lesions, as nodes or extended fat necrosis, which become in some cases infected, or pass for tumor recurrence after breast cancer treatment. CTN is caused by intraoperative ischemia of the flap, and no current method can prevent postoperative CTN development after DIEP breast reconstruction. Mechanical ischemic preconditioning, consisting in intraoperative briefs consecutive cycles of ischemia reperfusion using vascular clamp upon the graft pedicle, is used in transplantation surgery. This procedure improves the graft tolerance towards ischemic surgical lesions. The aim of this retrospective observational study was to assess PCIM effects on CTN development after DIEP surgery, comparing CTN occurrence after breast reconstruction using DIEP flap with or without intraoperative PCIM. MATERIAL AND METHODS: All patients breats reconstructed using DIEP flap between novembre 2020 and may 2022, presenting 6 months postoperative breast echography were retrospectively included. Primary outcome was the ultrasonic existence of CTN, according to the Wagner classification. Clinical data, postoperative outcomes such as infection, hematoma or surgical revision, and length of stay in hospital were also recorded. RESULTS: Twenty nine patients among which 8 PCIM were included. CTN occurrence rate after PCIM (25%) was quite lower than CTN rate without PCIM (71,4%), although the difference was not significant (P=0,088). Other postoperative complications rates were not significantly different with or without PCIM. CONCLUSION: PCIM seems to improve CTN occurrence after DIEP breast reconstruction, improving fat flap tolerance to ischemic perioperative lesions. Those preliminary results need to be confirmed with clinical prospective study.

Remote Ischemic Conditioning: Challenges and Opportunities.

Remote ischemic conditioning (RIC) has been investigated as a promising, safe, and well-tolerated nonpharmacological therapy for cardio-cerebrovascular disease over the past 3 decades; variable results have been found when it is used in cerebrovascular versus cardiovascular disease. For patients with cardiovascular disease, milestone studies suggest that the roles of RIC may be limited. Recently, however, 2 large trials investigating RIC in patients with cerebrovascular disease found promising results, which may reignite the field's research prospects after its setbacks in the cardiovascular field. This perspectives article highlights several important clinical trials of RIC in the cardio-cerebrovascular disease and describes the many challenges of RIC in clinical translation. Finally, based on the available evidence, several promising research directions such as chronic RIC, early initiation in target population, improvement of compliance, better understanding of dosing, and identification of specific biomarkers are proposed and should be investigated before RIC can become applied into clinical practice for patient benefit.

Identification of serum exosomal metabolomic and proteomic profiles for remote ischemic preconditioning.

BACKGROUND: Remote ischemic preconditioning (RIPC) refers to a brief episode of exposure to potential adverse stimulation and prevents injury during subsequent exposure. RIPC has been shown to increase tolerance to ischemic injury and improve cerebral perfusion status. Exosomes have a variety of activities, such as remodeling the extracellular matrix and transmitting signals to other cells. This study aimed to investigate the potential molecular mechanism of RIPC-mediated neuroprotection. METHODS: Sixty adult male military personnel participants were divided into the control group (n = 30) and the RIPC group (n = 30). We analyzed the differential metabolites and proteins in the serum exosomes of RIPC participants and control subjects. RESULTS: Eighty-seven differentially expressed serum exosomal metabolites were found between the RIPC and control groups, which were enriched in pathways related to tyrosine metabolism, sphingolipid metabolism, serotonergic synapses, and multiple neurodegeneration diseases. In addition, there were 75 differentially expressed exosomal proteins between RIPC participants and controls, which involved the regulation of insulin-like growth factor (IGF) transport, neutrophil degranulation, vesicle-mediated transport, etc. Furthermore, we found differentially expressed theobromine, cyclo gly-pro, hemopexin (HPX), and apolipoprotein A1 (ApoA1), which are associated with neuroprotective benefits in ischemia/reperfusion injury. In addition, five potential metabolite biomarkers, including ethyl salicylate, ethionamide, piperic acid, 2, 6-di-tert-butyl-4-hydroxymethylphenol and zerumbone, that separated RIPC from control individuals were identified. CONCLUSION: Our data suggest that serum exosomal metabolites are promising biomarkers for RIPC, and our results provide a rich dataset and framework for future analyses of cerebral ischemia‒reperfusion injury under ischemia/reperfusion conditions.

Impact of handgrip exercise and ischemic preconditioning on local and remote protection against endothelial reperfusion injury in young men.

Ischemic preconditioning (IPC), cyclical bouts of nonlethal ischemia, provides immediate protection against ischemic injury, which is evident both locally and remotely. Given the similarities in protective effects of exercise with ischemic preconditioning, we examined whether handgrip exercise also offers protection against endothelial ischemia-reperfusion (IR) injury and whether this protection is equally present in the local (exercised) and remote (contralateral, nonexercised) arm. Fifteen healthy males (age, 24 ± 3 yr; body mass index, 25 ± 2 kg/m2) attended the laboratory on three occasions. Bilateral brachial artery flow-mediated dilation (FMD) was examined at rest and after a temporary IR injury in the upper arm. Before the IR injury, in the dominant (local) arm, participants performed (randomized, counterbalanced): 1) 4 × 5 min unilateral handgrip exercise (50% maximal voluntary contraction), 2) 4 × 5 min unilateral IPC (220 mmHg), or 3) 4 × 5 min rest (control). Data were analyzed using repeated-measures general linear models. Allometrically scaled FMD declined after IR in the control condition (4.6 ± 1.3% to 2.2 ± 1.7%, P < 0.001), as well as following handgrip exercise (4.6 ± 1.6% to 3.4 ± 1.9%, P = 0.01), however, was significantly attenuated with IPC (4.5 ± 1.4% to 3.8 ± 3.5%, P = 0.14). There were no differences between the local and remote arm. Our findings reinforce the established protective effects of IPC in young, healthy males and also highlight a novel strategy to protect against IR injury with handgrip exercise, which warrants further study.

Klotho Upregulation via PPARγ Contributes to the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning in Rats.

Cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance protects neurons from subsequent lethal ischemic insult. However, the specific mechanisms underlying CIP remain unclear. In the present study, we explored the hypothesis that peroxisome proliferator-activated receptor gamma (PPARγ) participates in the upregulation of Klotho during the induction of brain ischemic tolerance by CIP. First we investigated the expression of Klotho during the brain ischemic tolerance induced by CIP. Lethal ischemia significantly decreased Klotho expression from 6 h to 7 days, while CIP significantly increased Klotho expression from 12 h to 7 days in the hippocampal CA1 region. Inhibition of Klotho expression by its shRNA blocked the neuroprotection induced by CIP. These results indicate that Klotho participates in brain ischemic tolerance by CIP. Furthermore, we tested the role of PPARγ in regulating Klotho expression after CIP. CIP caused PPARγ protein translocation to the nucleus in neurons in the CA1 region of the hippocampus. Pretreatment with GW9962, a PPARγ inhibitor, significantly attenuated the upregulation of Klotho protein and blocked the brain ischemic tolerance induced by CIP. Taken together, it can be concluded that Klotho upregulation via PPARγ contributes to the induction of brain ischemic tolerance by CIP.

Effect of remote ischemic preconditioning in patients undergoing laparoscopic colorectal cancer surgery: a randomized controlled trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) is reported to reduce ischemia-reperfusion injury (IRI) in many vital organs by inhibiting a systemic inflammatory response. Inflammation also plays an essential role in the pathophysiology of prolonged post-operative ileus (PPOI) in patients undergoing colorectal cancer (CRC) surgery. However, the role of RIPC is unclear in reducing the incidence of PPOI in patients undergoing CRC surgery. METHODS: This was a prospective, randomized trial of RIPC vs. placebo-controlled in patients undergoing elective laparoscopic CRC surgery. Eighty patients were randomized to either a RIPC group or a control group (40 per arm), with computer-generated randomization. The aim was to determine whether RIPC improved the recovery of gut function. The primary outcomes assessed were time to gastrointestinal tolerance and incidence of PPOI. RESULTS: Median time to stool of the RIPC group was significantly lower than that of the control group [RIPC vs. control, 4.0 (3.0, 6.0) vs. 5.0 (4.0, 7.8) days, p = 0.027]. Median time to gastrointestinal tolerance and incidence of PPOI in the RIPC group were lower than the control group; however, there were no statistical differences between the two groups [RIPC vs. control: 5.0 (3.0, 7.0) vs. 6.0 (4.0, 8.8) days, p = 0.178; 15 vs. 30%, p = 0.108]. CONCLUSION: RIPC could shorten the median time to stool in patients undergoing laparoscopic CRC surgery, but did not improve the overall recovery time of gut function or reduce the incidence of PPOI. REGISTRATION NUMBER: ChiCTR2100043313 (http://www.chictr.org.cn).Key pointsQuestion: In patients undergoing laparoscopic CRC surgery, does RIPC improve time to the overall recovery of gut function and reduce the incidence of PPOI?Findings: In this randomized clinical trial that included 80 patients undergoing elective laparoscopic CRC surgery, no significant difference was found between the RIPC group and the control group concerning median time to gastrointestinal tolerance and incidence of PPOI.Meaning: RIPC did not improve the time for overall recovery of gut function or reduce the incidence of PPOI in patients undergoing laparoscopic CRC surgery.