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Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase–myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] −0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI −0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. Trial registration: ClinicalTrials.gov, no. NCT01071265.

Purpose: To report a randomized clinical trial designed to determine if remote ischemic preconditioning (IP) has the ability to reduce renal and cardiac damage following endovascular aneurysm repair (EVAR). Methods: Forty patients (all men; mean age 76±7 years) with abdominal aortic aneurysms averaging 6.3±0.8 cm in diameter were enrolled in the trial from November 2006 to January 2008. Eighteen patients (mean age 74 years, range 72–81) were randomized to preconditioning and completed the full remote IP protocol; there were no withdrawals. Twenty-two patients (mean age 76 years, range 66–80) were assigned to the control group. Remote IP was induced using sequential lower limb ischemia. Serum and urinary markers of renal and cardiac injury were compared between the groups. Results: Urinary retinol binding protein (RBP) levels increased 10-fold from a median of 235 µmol/L to 2356 µmol/L at 24 hours (p=0.0001). There was a lower increase in the preconditioned group, from 167 µmol/L to 413 µmol/L at 24 hours (p=0.04). The median urinary albumin:creatinine ratio was significantly lower in the preconditioned group at 24 hours (5 versus 8.8, p=0.06). There were no differences in the rates of renal impairment or major adverse cardiac events. Conclusion: Remote preconditioning reduces urinary biomarkers of renal injury in patients undergoing elective EVAR. This small pilot trial was unable to detect an effect on clinical endpoints; further trials are warranted.

Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69 ± 5.8 % ( n  = 11) to 40 ± 6.5 % ( n  = 12), P  = 0.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62 ± 7.6 % controls, n  = 10, versus 61 ± 6.9 % rIPC after cyanamide, n  = 10, P  > 0.05). (ii) In a forearm plethysmography model of endothelial ischaemia–reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia–reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine ( P  = 0.9), but rIPC failed to protect carriers of Glu504Lys polymorphism ( P  = 0.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600 mg od or placebo for 48 h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18 ± 1.03 % and 4.76 ± 0.93 % P  = 0.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87 ± 1.27 % and 3.05 ± 0.53 %, P  = 0.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.

BackgroundThe benefit of ischemic postconditioning (IPostC) might be the throttled inflow following cold ischemia. The current study investigated advantage and mechanisms of IPostC in healthy and fatty rat livers.MethodsMale SD rats received a high-fat diet to induce fatty livers. Isolated liver perfusion was performed after 24 h ischemia at 4 °C as well as in vivo experiments after 90 min warm ischemia. The so-called follow-up perfusions served to investigate the hypothesis that medium from IPostC experiments is less harmful. Lactate dehydrogenase (LDH), transaminases, different cytokines, and gene expressions, respectively, were measured.ResultsFatty livers showed histologically mild inflammation and moderate to severe fat storage. IPostC reduced LDH and TXB2 in healthy and fatty livers and increased bile flow. LDH, TNF-α, and IL-6 levels in serum decreased after warm ischemia + IPostC. The gene expressions of Tnf, IL-6, Ccl2, and Ripk3 were downregulated in vivo after IPostC.ConclusionsIPostC showed protective effects after ischemia in situ and in vivo in healthy and fatty livers. Restricted cyclic inflow was an important mechanism and further suggested involvement of necroptosis. IPostC represents a promising and easy intervention to improve outcomes after transplantation.

In a multicenter, controlled trial, patients undergoing transplantation of a liver from a donor after circulatory death were randomly assigned to receive the liver after hypothermic oxygenated machine perfusion or conventional static cold storage. Hypothermic perfusion led to a lower risk of post-transplantation nonanastomotic biliary strictures.

Key Points Currently, no treatment has been proven to be effective for preventing 'myocardial reperfusion injury' — the death of cardiomyocytes that paradoxically occurs when reperfusing ischaemic myocardium One or more brief cycles of ischaemia and reperfusion can protect the heart from acute myocardial infarction and myocardial reperfusion injury — a phenomenon termed 'ischaemic conditioning' Ischaemic conditioning can be applied either directly to the heart or from afar; that is, to a remote organ or tissue (such as an arm or a leg) Investigation of signalling pathways underlying ischaemic conditioning has identified molecular targets for pharmacological manipulation — a therapeutic strategy termed 'pharmacological cardioprotection' Proof-of-concept clinical studies have shown mixed results of ischaemic conditioning in cardiac surgery and percutaneous coronary intervention; more consistently positive results have been observed in acute myocardial infarction The results of large, multicentre, randomized, controlled clinical trials of ischaemic conditioning on clinical outcomes after cardiac surgery have highlighted the challenges in translating cardioprotection into clinical practice Ischaemic conditioning is an endogenous cardioprotective strategy that involves the application of brief cycles of ischaemia and reperfusion either directly to the heart, or to a remote organ or tissue, and which has been shown to reduce infarct size. In this Review, Hausenloy and Yellon summarize the various forms of ischaemic conditioning and pharmacological cardioprotection, and highlight the challenges of translating these methods into the clinical setting. The 30-year anniversary of the discovery of 'ischaemic preconditioning' is in 2016. This endogenous phenomenon can paradoxically protect the heart from acute myocardial infarction by subjecting it to one or more brief cycles of ischaemia and reperfusion. Apart from complete reperfusion, this method is the most powerful intervention known for reducing infarct size. The concept of ischaemic preconditioning has evolved into 'ischaemic conditioning', a term that encompasses a number of related endogenous cardioprotective strategies, applied either directly to the heart (ischaemic preconditioning or postconditioning) or from afar, for example a limb (remote ischaemic preconditioning, perconditioning, or postconditioning). Investigations of signalling pathways underlying ischaemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. Over the past 3 decades, a number of ischaemic and pharmacological cardioprotection strategies, discovered in experimental studies, have been examined in the clinical setting of acute myocardial infarction and CABG surgery. The results from many of the studies have been disappointing, and no effective cardioprotective therapy is currently used in clinical practice. Several large, multicentre, randomized, controlled clinical trials on cardioprotection have highlighted the challenges of translating ischaemic conditioning and pharmacological cardioprotection strategies into patient benefit. However, a number of cardioprotective therapies have shown promising results in reducing infarct size and improving clinical outcomes in patients with ischaemic heart disease.

Myocardial ischemia‐reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK‐MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex‐treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI. Dex reduces lactate levels and downregulates MDH2 lactylation to enhance mitochondrial function and prevent ferroptosis, ultimately alleviating myocardial ischemia‐reperfusion injury. This mechanism involves through Dex facilitating the phosphorylation and nuclear export of NR3C1, leading to the suppression of PDK4 and influencing metabolic reprogramming.

BackgroundSmall studies suggest that postconditioning reperfusion interrupted by brief repetitive cycles of reocclusions, may protect the myocardium in the clinical setting.ObjectiveTo test the hypothesis that postconditioning limits infarct size in relation to the area at risk in patients with ST elevation myocardial infarction (STEMI).Methods76 patients (aged 37–87 years) eligible for primary percutaneous coronary intervention due to STEMI were randomised to standard percutaneous coronary intervention (n=38) or postconditioning, consisting of four cycles of 60 s reperfusion and 60 s of reocclusion before permanent reperfusion (n=38).ResultsThe area at risk was determined from angiographic abnormally contracting segments. Infarct size was quantified from delayed enhancement MRI on days 6–9. Infarct size, expressed in relation to the area at risk, did not differ between the control group (44%; 30, 56) (median and quartiles) and the post-conditioned group (47%; 23, 63). The slope of the regression lines relating infarct size to the area at risk differed between the two groups. Infarct size was significantly (p=0.001) reduced by postconditioning in patients with large areas at risk. The area under the curve and peak troponin T release and CKMB during 48 h did not differ between patients in the control and postconditioning groups.ConclusionsThis prospective, randomised trial suggests that postconditioning does not reduce infarct size in patients with STEMI in the overall study group. The data indicate that postconditioning may be of value in patients with large areas at risk.Clinical trial registration informationKarolinska Clinical Trial Registration (http://www.kctr.se). Unique identifier: CT20080014.

ObjectiveTo examine whether endogenous bradykinin mediates the endothelium-dependent vasomotor dysfunction induced by ischaemia-reperfusion injury, or the protection afforded by remote ischaemic preconditioning in vivo in man.DesignRandomised double-blind, cross-over study.SettingsRoyal Infirmary of Edinburgh, Wellcome Trust Clinical Research Facility.PatientsTwenty healthy male volunteers.InterventionsSubjects were randomised to intravenous infusion of the bradykinin B2 receptor antagonist, HOE-140 (100 μg/kg), or saline placebo in a double-blind, crossover trial. Ischaemia-reperfusion injury was induced in the non-dominant arm by inflating a cuff to 200 mm Hg for 20 min in all subjects. Ischaemia-reperfusion injury was preceded by three cycles of remote ischaemic preconditioning in the dominant arm in 10 subjects.Main outcome measuresBilateral forearm blood flow was assessed using venous occlusion plethysmography during intra-arterial infusion of acetylcholine (5–20 μg/min).ResultsAcetylcholine caused vasodilatation in all studies (p<0.05) that was attenuated by ischaemia-reperfusion injury, both in the presence (p=0.0002) and absence (p=0.04) of HOE-140. Remote ischaemic preconditioning abolished the impairment of endothelium-dependent vasomotor function induced by ischaemia-reperfusion injury. HOE-140 had no effect on the protection afforded by remote ischaemic preconditioning.ConclusionsThese findings do not support a major role for endogenous bradykinin, acting via the B2 kinin receptor, in the mechanism of ischaemia-reperfusion injury or the protective effects of remote ischaemic preconditioning in man.Clinical Trial Registration InformationNCT00965120 and NCT00965393.

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.