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.

Cardioprotective Effects of Sodium-Glucose Cotransporter Subtype Inhibition on Ischemic and Pharmacological Preconditioning.

BACKGROUND: Sodium-glucose cotransporter (SGLT) 2 inhibitors partially inhibit SGLT1 expression; however, whether a clinical dose of SGLT2 inhibitor abrogates ischemic preconditioning (IPC) is unknown, and the pharmacological cardioprotective effect under SGLT1 inhibition has not been examined. In this study, we investigated whether a clinical dose of tofogliflozin abrogates IPC and whether pharmacological preconditioning with olprinone has cardioprotective effects under SGLT1 inhibition. METHODS: Male Wistar rats were divided into seven groups (seven rats per group) and subjected to the following treatments before inducing ischemia/reperfusion (I/R; 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion): saline infusion control treatment (Con); ischemic preconditioning (IPC); IPC after phlorizin infusion (IPC+Phl); IPC after low-dose tofogliflozin infusion (IPC+L-Tof); IPC after high-dose tofogliflozin infusion (IPC+H-Tof); olprinone infusion (Olp); and Olp infusion after phlorizin infusion (Olp+Phl). RESULTS: The infarct size was significantly decreased in the IPC group, but not in the IPC+Phl group. In contrast, the infarct size decreased in the IPC+L-Tof and IPC+H-Tof groups. Additionally, Olp reduced the infarct size, and the effect was preserved in Olp+Phl groups. Phosphorylated AMP-activated protein kinase (AMPK) expression was lower in the IPC+Phl group compared to that in the IPC group. CONCLUSION: The cardioprotective effect of IPC was attenuated by strong SGLT1 inhibition, but the effect was preserved under a clinical dose of highly selective SGLT2 inhibitor. Olprinone exerts a cardioprotective effect even under strong SGLT1 inhibition.

Inhibition of the protective effects of preconditioning in ischemia-reperfusion injury by chronic methadone: the role of pAkt and pSTAT3.

Cardiac ischemic preconditioning (Pre) reduces cardiac ischemia-reperfusion injury (IRI) by stimulating opioid receptors. Chronic use of opioids can alter the signaling pathways. We investigated the effects of chronic methadone use on IRI and Pre. The experiments were performed on isolated hearts of male Wistar rats in four groups: IRI, Methadone + IRI (M-IRI), Pre + IRI (Pre-IRI), Methadone + Pre + IRI (M-Pre-IRI). The infarct size (IS) in the Pre-IRI group was smaller than the IRI group (26.8% vs. 47.8%, P < 0.05). In the M-IRI and M-Pre-IRI groups, the infarct size was similar to the IRI group. Akt (Ak strain transforming) phosphorylation in the Pre-IRI, M-IRI, and M-Pre-IRI groups was significantly higher than in the IRI group (0.56 ± 0.15, 0.63 ± 0.20, and 0.93 ± 0.18 vs 0.28 ± 0.17 respectively). STAT3 (signal transducer and activator of transcription 3) phosphorylation in the Pre-IRI and M-Pre-IRI groups (1.38 ± 0.14 and 1.46 ± 0.33) was significantly higher than the IRI and M-IRI groups (0.99 ± 0.1 and 0.98 ± 0.2). Thus, chronic use of methadone not only has no protective effect against IRI but also destroys the protective effects of ischemic preconditioning. This may be due to the hyperactivation of Akt and changes in signaling pathways.

Does remote ischemic preconditioning affect the systemic inflammatory response by modulating presepsin levels?

OBJECTIVE: We investigated the effect of Remote Ischemic Preconditioning (RIPC) on the inflammatory response during CPB by means of serum presepsin levels at preoperative and postoperative 1st and 24th h. METHODS: In this prospective, randomized, cross-sectional study we included 81 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass (CPB). Patients were randomized and RIPC was applied to 40 patients in the study group before anesthesia. The remaining 41 patients were determined as the control group. The relationships between RIPC and factors such as presepsin, C-reactive protein (CRP), and leukocyte levels were investigated. RESULTS: There was no significant difference between the groups in postoperative leukocyte and CRP values (p = 0.52, p = 0.13, respectively). When the preoperative and postoperative first hour presepsin values of the patients were compared, no significant difference was found in the control group (p = 0.17), but a significant difference was found in the study group (p < 0.05). When the presepsin values were compared between the groups, a significant difference was found only in the postoperative first hour value (p < 0.05). CONCLUSIONS: It was observed that RIPC application caused to increase the presepsin levels in the postoperative first hour significantly in the study group (p < 0.05).

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.

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

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

Dynamics in Redox-Active Molecules Following Ischemic Preconditioning in the Brain.

It is well known that the brain is quite vulnerable to oxidative stress, initiating neuronal loss after ischemia-reperfusion (IR) injury. A potent protective mechanism is ischemic preconditioning (IPC), where proteins are among the primary targets. This study explores redox-active proteins' role in preserving energy supply. Adult rats were divided into the control, IR, and IPC groups. Protein profiling was conducted to identify modified proteins and then verified through activity assays, immunoblot, and immunohistochemical analyses. IPC protected cortex mitochondria, as evidenced by a 2.26-fold increase in superoxide dismutase (SOD) activity. Additionally, stable core subunits of respiratory chain complexes ensured sufficient energy production, supported by a 16.6% increase in ATP synthase activity. In hippocampal cells, IPC led to the downregulation of energy-related dehydrogenases, while a significantly higher level of peroxiredoxin 6 (PRX6) was observed. Notably, IPC significantly enhanced glutathione reductase activity to provide sufficient glutathione to maintain PRX6 function. Astrocytes may mobilize PRX6 to protect neurons during initial ischemic events, by decreased PRX6 positivity in astrocytes, accompanied by an increase in neurons following both IR injury and IPC. Maintained redox signaling via astrocyte-neuron communication triggers IPC's protective state. The partnership among PRX6, SOD, and glutathione reductase appears essential in safeguarding and stabilizing the hippocampus.

Effect of remote ischemic preconditioning intervention on serum levels of microRNA-582-5p/HMGB1 in patients with acute cerebral infarction.

OBJECTIVE: Acute cerebral infarction (ACI) contributes to disability and death accross the globe. Remote ischemic preconditioning (RIPC) reduces cerebral infarct size and improves neurological function in ACI. We conducted this research to reveal the effects of RIPC intervention on serum levels of microRNA-582-5p (miR-582-5p)/high mobility group box-1 protein (HMGB1), inflammation, oxidative stress and neurological function in patients with ACI. METHODS: In this study, 158 patients with ACI were prospectively selected and randomized into the control (administered symptomatic medication alone) and the RIPC (underwent RIPC of the limbs based on medication) groups, with their clinical baseline data documented. Serum levels of miR-582-5p, and HMGB1 and inflammatory factors [tumor necrosis factor alpha (TNF-α)/interleukin-1beta (IL-1ß)/IL-10] were assessed by RT-qPCR/ELISA, followed by comparisons of oxidative stress indices [glutathione-peroxidase (GSH-Px)/catalase (CAT)/superoxide dismutase (SOD)] using a fully automatic biochemical analyzer. Correlations between serum miR-582-5p with serum HMGB1, and between their levels with TNF-α/IL-1ß/IL-10 were analyzed by Pearson analysis. The NIHSS score/Barthel Index scale were used to assess neurological function/daily living ability. Intervention safety for ACI patients was evaluated. RESULTS: RIPC intervention increased serum miR-582-5p levels and decreased serum HMGB1 levels in ACI patients. RIPC intervention significantly reduced inflammation (diminished TNF-α/IL-1ß levels, increased IL-10 level) and oxidative stress (elevated GSH-Px/CAT/SOD levels) in ACI patients. Serum miR-582-5p was negatively correlated with TNF-α and IL-1ß levels, while positively correlated with IL-10 level, while HMGB1 was positively correlated with TNF-α and IL-1ß levels, while negatively correlated with IL-10 level. miR-582-5p was negatively correlated with HMGB1. RIPC intervention improved neurological function (reduced NIHSS, increased Barthel scores) in ACI patients to some extent. RIPC had certain effectiveness and safety in the treatment of ACI. CONCLUSION: After RIPC intervention, serum miR-582-5p levels were increased, HMGB1 levels were decreased, and inflammation and oxidative stress were reduced in ACI patients, which mitigated neurological deficits, improved patients' ability to perform life activities, and exerted neuroprotective effects to some extent.

[Effect of distal ischemic preconditioning on cardiovascular events in adult patients with hip fracture one year after operation].

OBJECTIVE: To investigate the effect of remote ischemic preconditioning (RIPC) on major adverse cardiovascular events (MACE) in elderly patients with hip fracture 1 year after operation. METHODS: Total of 314 elderly patients with hip fracture of gradeⅡand Ⅲ for American Society of Anesthesiologists (ASA) were treated by surgical operation from April 2015 to May 2020 including 116 males and 198 females, the age ranged from 60 to 76 years old. The subjects were divided into intervention group and control group according to whether received RIPC. Among them, 157 cases in intervention group included 56 males and 101 females with an average age of (68.12±7.13) years old and 157 cases in control group included 60 males and 97 females with an average age of (68.24±7.05) years old. Both groups were given routine anesthesia. The intervention group was treated with RIPC on the basis of routine anesthesia. The MACE events 1 year after operation in two groups were compared and analyzed. RESULTS: The OR values of RIPC for myocardial infarction, heart failure, stroke, nonfatal cardiac arrest, coronary revascularization, severe arrhythmia, peripheral artery thrombosis, readmission of cardiovascular disease, and all-cause death in patients with hip fracture one year after operation were 1.269, 1.304, 0.977, 1.089, 1.315, 1.335, 0.896, 0.774, 1.191, respectively, but there was no significant difference (P>0.05). CONCLUSION: RIPC did not significantly affect and change the occurrence of major cardiovascular adverse events within 1 year after hip fracture surgery. The long term impact of RIPC on clinical cardiovascular outcomes in non cardiac surgery needs to be confirmed in appropriate randomized clinical trials.

Potential effect of the non-neuronal cardiac cholinergic system on hepatic glucose and energy metabolism.

The vagus nerve belongs to the parasympathetic nervous system, which is involved in the regulation of organs throughout the body. Since the discovery of the non-neuronal cardiac cholinergic system (NNCCS), several studies have provided evidence for the positive role of acetylcholine (ACh) released from cardiomyocytes against cardiovascular diseases, such as sympathetic hyperreactivity-induced cardiac remodeling and dysfunction as well as myocardial infarction. Non-neuronal ACh released from cardiomyocytes is believed to regulate key physiological functions of the heart, such as attenuating heart rate, offsetting hypertrophic signals, maintaining action potential propagation, and modulating cardiac energy metabolism through the muscarinic ACh receptor in an auto/paracrine manner. Moreover, the NNCCS may also affect peripheral remote organs (e.g., liver) through the vagus nerve. Remote ischemic preconditioning (RIPC) and NNCCS activate the central nervous system and afferent vagus nerve. RIPC affects hepatic glucose and energy metabolism through the central nervous system and vagus nerve. In this review, we discuss the mechanisms and potential factors responsible for NNCCS in glucose and energy metabolism in the liver.

Bilateral remote ischemic conditioning in children: A two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery.

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis. Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants. Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 µg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 µg/L/h, n = 58) (mean difference, 13.2 µg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups. Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery.

Remote ischaemic preconditioning for transcatheter aortic valve replacement: a protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) has become an important treatment in patients with aortic valve disease with the continuous advancement of technology and the improvement of outcomes. However, TAVR-related complications still increase patient morbidity and mortality. Remote ischaemic preconditioning (RIPC) is a simple procedure that provides perioperative protection for many vital organs. However, the efficiency of RIPC on TAVR remains unclear based on inconsistent conclusions from different clinical studies. Therefore, we will perform a protocol for a systematic review and meta-analysis to identify the efficiency of RIPC on TAVR. METHODS AND ANALYSIS: English databases (PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library), Chinese electronic databases (Wanfang Database, VIP Database and China National Knowledge Infrastructure) and trial registry databases will be searched from inception to December 2023 to identify randomised controlled trials of RIPC on TAVR. We will calculate mean differences or standardised mean differences with 95% CIs for continuous data, and the risk ratio (RR) with 95% CIs for dichotomous data by Review Manager version 5.4. Fixed-effects model or random-effects model will be used according to the degree of statistical heterogeneity assessed by the I-square test. We will evaluate the risk of bias using the Cochrane risk-of-bias tool 2 and assess the evidence quality of each outcome by the Grading of Recommendations Assessment, Development and Evaluation. The robustness of outcomes will be evaluated by trial sequential analysis. In addition, we will evaluate the publication bias of outcomes by Funnel plots and Egger's regression test. ETHICS AND DISSEMINATION: Ethical approval was not required for this systematic review protocol. The results will be disseminated through peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42023462926.

Ischemic preconditioning affects phosphosites and accentuates myocardial stunning while reducing infarction size in rats.

Background and aims: Ischemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. This study aimed primarily to examine the effects of IPC on the relationship between ischemia duration, stunning, and infarct size in an ischemia-reperfusion injury model. Secondarily, this study aimed to examine to which extent the phosphoproteomic changes induced by IPC relate to myocardial contractile function. Methods and results: Rats were subjected to different durations of left anterior descending artery (LAD) occlusion, with or without preceding IPC. Echocardiograms were acquired to assess cardiac contraction in the affected myocardial segment. Infarction size was evaluated using triphenyl tetrazolium chloride staining. Phosphoproteomic analysis was performed in heart tissue from preconditioned and non-preconditioned animals. In contrast to rats without IPC, reversible akinesia was observed in a majority of the rats that were subjected to IPC and subsequently exposed to ischemia of 13.5 or 15 min of ischemia. Phosphoproteomic analysis revealed significant differential regulation of 786 phosphopeptides between IPC and non-IPC groups, with significant associations with the sarcomere, Z-disc, and actin binding. Conclusion: IPC induces changes in phosphosites of proteins involved in myocardial contraction; and both accentuates post-ischemic myocardial stunning and reduces infarct size.

Remote ischemic preconditioning and cognitive dysfunction following coronary artery bypass grafting: A systematic review and meta-analysis of randomized controlled trials.

Introduction: Postoperative cognitive dysfunction (POCD) is a common neurological issue following cardiopulmonary bypass (CPB)-assisted heart surgery. Remote ischemic preconditioning (RIPC) increases the tolerance of vital organs to ischemia/reperfusion injury, leading to reduced brain injury biomarkers and improved cognitive control. However, the exact mechanisms underlying RIPC's neuroprotective effects remain unclear. This systematic review aimed to explore the hypothesis that RIPC lowers neurocognitive dysfunction in patients undergoing CPB surgery. Method: All relevant studies were searched in PubMed, ScienceDirect, EBSCOhost, Google Scholar, Semantic Scholar, Scopus, and Cochrane Library database. Assessment of study quality was carried out by two independent reviewers individually using the Cochrane Risk of Bias (RoB-2) tool. Meta-analysis was performed using a fixed-effect model due to low heterogeneity among studies, except for those with substantial heterogeneity. Results: A total of five studies with 1,843 participants were included in the meta-analysis. RIPC was not associated with reduced incidence of postoperative cognitive dysfunction (five RCTs, odds ratio [OR:] 0.79, 95% confidence interval [CI]: 0.56-1.11) nor its improvement (three RCTs, OR: 0.80, 95% CI: 0.50-1.27). In addition, the analysis of the effect of RIPC on specific cognitive function tests found that pooled SMD for RAVLT 1-3 and RAVLT LT were -0.07 (95% CI: -0.25,012) and -0.04 (95% CI: -0.25-0.12), respectively, and for VFT semantic and phonetic were -0.15 (95% CI: -0.33-0.04) and 0.11 (95% CI: -0.40-0.62), respectively. Conclusion: The effect of RIPC on cognitive performance in CABG patients remained insignificant. Results from previous studies were unable to justify the use of RIPC as a neuroprotective agent in CABG 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.

Ischemic preconditioning modulates the DNA methylation process of the rat heart to provide tolerance to withstand ischemia reperfusion injury and its associated mitochondrial dysfunction.

DNA methylation plays a crucial role in the pathogenesis of myocardial ischemia reperfusion injury(I/R) and the I/R injury can be combated effectively by ischemia preconditioning (IPC), but the role is DNA methylation in this process is unknown. In this study, we uncovered the role of ischemic preconditioning (IPC)- mediated cardioprotection of rat myocardium by using a Langendorff rat heart model with 30 min of ischemia followed by 60 min of reperfusion. Heart conditioned with short cycles of ischemia and reperfusion (IPC procedure) prior to I/R protocol significantly reduced the I/R-induced global DNA hypermethylation level by 32% and the DNMT activity by 33% while rendering cardioprotection. Blocking the PI3K pathway via wortmannin not only negates the cardio-protection by IPC, but also increases the methylation of DNA by 75%. Besides, the correlation analysis showed a negative relationship between PI3K gene expression and the global DNA methylation level (r = - 0.8690, p = 0.0419) in IPC-treated rat hearts. Moreover, the global level DNA hypomethylation induced by IPC exhibited a regulatory effect on the genes involved in I/R pathology mediators like apoptosis (Caspase3), mitochondrial function (PGC 1α, TFAM, ND1) and oxidative stress (CuZnSOD, SOD2), and their corresponding function. The present study results provide novel evidence for the involvement of DNA methylation in the IPC procedure, and suggest DNA methylation as one of the potential therapeutic targets regulated by ischemic preconditioning in rat hearts subjected to ischemia reperfusion. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03965-0.

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.

A Comparative Study: Cardioprotective Effects of High-Intensity Interval Training Versus Ischaemic Preconditioning in Rat Myocardial Ischaemia-Reperfusion.

(1) Background: Years of research have identified ischemic preconditioning (IPC) as a crucial endogenous protective mechanism against myocardial ischemia-reperfusion injury, enhancing the myocardial cell's tolerance to subsequent ischemic damage. High-intensity interval training (HIIT) is promoted by athletes because it reduces exercise duration and improves metabolic response and cardiopulmonary function. Our objective was to evaluate and compare whether HIIT and IPC could reduce myocardial ischemia and reperfusion injury in rats. (2) Methods: Male Sprague-Dawley rats were divided into four groups: sham surgery, coronary artery occlusion (CAO), high-intensity interval training (HIIT), and ischemic preconditioning (IPC). The CAO, HIIT, and IPC groups experienced 40 min of coronary artery occlusion followed by 3 h of reperfusion to induce myocardial ischemia-reperfusion injury. Subsequently, the rats were sacrificed, and blood samples along with cardiac tissues were examined. The HIIT group received 4 weeks of training before surgery, and the IPC group underwent preconditioning before the ischemia-reperfusion procedure. (3) Results: The HIIT and IPC interventions significantly reduced the extent of the myocardial infarction size and the levels of serum troponin I and lactate dehydrogenase. Through these two interventions, serum pro-inflammatory cytokines, including TNF-α, IL-1ß, and IL-6, were significantly decreased, while the anti-inflammatory cytokine IL-10 was increased. Furthermore, the expression of pro-apoptotic proteins PTEN, caspase-3, TNF-α, and Bax in the myocardium was reduced, and the expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) was increased, ultimately reducing cellular apoptosis in the myocardium. In conclusion, both HIIT and IPC demonstrated effective strategies with potential for mitigating myocardial ischemia-reperfusion injury for the heart.

The New Orientation of Postoperative Analgesia: Remote Ischemic Preconditioning.

Purpose of Review: Postoperative analgesia is currently a significant topic in anesthesiology. Currently, the predominant approach for achieving multimodal analgesia involves the utilization of pharmacotherapy and regional anesthesia procedures. The primary objectives of this approach are to mitigate postoperative pain, enhance patient satisfaction, and diminish overall opioid usage. Nevertheless, there is a scarcity of research on the use of remote ischemia preconditioning aimed at mitigating postoperative pain. Recent Findings: Transient stoppage of blood flow to an organ has been found to elicit remote ischemia preconditioning (RIPC), which serves as a potent intrinsic mechanism for protecting numerous organs. In addition to its established role in protecting against reperfusion injury, RIPC has recently been identified as having potential benefits in the context of postoperative analgesia. Summary: In addition to traditional perioperative analgesia, RIPC provides perioperative analgesia and organ protection.