Reduce Ischemia-reperfusion Injury Research Articles

Effect of angelica polysaccharides on the hemorheology in flap ischemia reperfusion injury: an experimental study in rats

Objective To investigate the hemorheology changes in flap ischemia reperfusion injury and the protective effect of angelica polysaccharides (APS).Methods Fifty adult SD rats were divided into a sham group,a control group,a 2 mg/kg APS group,a 4 mg/kg APS group,and a 8 mg/kg APS group.After a 5 cm × 4 cm epigastric flap was elevated,flaps in the sham group were sutured back into its place without inducing any ischemia.Flaps in the control group and APS treatment groups were subject to a 6-hour ischemic period.Five minutes prior to the repeffusion,0.2 ml saline was injected via intraperitoneal route in the control group while 0.2 ml of corresponding doses of angelica polysaccharides were injected in the APS groups.Following a 12-hour reperfusion,the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the flap tissue were measured.Polymorphonuclear neutrophils (PMN) in the peripheral blood were counted.Flow cytometry was used to detect the expression of CD11a/CD18 and CD11b/CD18 on the polynorphonuclear neutrophils.Hemorheology parameters were detected in the rats of each group.Results Compared with the control group,8 mg/kg APS group showed significant decrease of MDA content and CD11a/CD18,CD11b/CD18 expression levels after 12-hour repeffusion (P ＜ 0.05).The level of SOD increased significantly (P ＜ 0.05).The PMN number,the low shear viscosity,the middle shear viscosity and high shear viscosity of the APS groups were significantly lower than those of the control group (P ＜ 0.05).Plasma viscosity,RBC aggregation index of the APS groups were not significantly different from the control group (P ＞ 0.05).Conclusion APS can reduce ischemia reperfusion injury of skin flaps in rats via reducing the number of neutrophils,down-regulating the expression of CD11a/CD18 and CD11b/CD18 on neutrophil surface,and decreasing blood viscosity,so as to improve blood supply of the flap. Key words: Angelica polysaccharides; Flaps; Ischemia reperfusion injury; Hemorheology

Effects of erythropoietin on ischemia, follicular survival, and ovarian function in ovarian grafts

Ovarian tissue transplantation is performed to preserve fertility in patients undergoing chemotherapy and radiotherapy. However, ischemia/reperfusion (IR) injury and free radical production occurring during the revascularization of the transplanted tissue are the major limitations of this procedure. The aim of this study was to investigate the effect of erythropoietin (EPO) as an antioxidant on oxidative stress and ovary survival following transplantation. The Naval Medical Research Institute (NMRI) mice (4-5 weeks old) were divided into three groups (six mice per group): control; autograft+saline, and autograft+EPO (500 IU/kg i.p.). After 28 days, ovary compartments were estimated stereologically. DNA fragmentation and plasma malondialdehyde (MDA), progesterone, and estradiol (E2) concentrations were also evaluated. The results were analyzed using one-way ANOVA and Tukey's test, and the means were significantly different at P<0.05. The mean total volume of ovary, cortex, and medulla and the number of follicles increased significantly in the autograft+EPO group (P<0.01). Apoptosis rate in the autograft+EPO group was lower than that in the autograft+saline group. The concentration of MDA decreased significantly in the autografted EPO-treated group than in the autografted saline-treated group (P<0.01). The concentration of E2 increased significantly in the autograft+EPO group than in the autograft+saline group (P<0.01). EPO reduced IR injury, increasing follicle survival and function in grafted ovaries. Free Persian abstract A Persian (Farsi) translation of the abstract is freely available online at http://www.reproduction-online.org/content/147/5/733/suppl/DC1.

Atorvastatin treatment attenuates renal injury in an experimental model of ischemia–reperfusion in rats

BackgroundRecent studies in animal models have shown that statins can protect against renal failure independent of their lipid-lowering actions, and there is also an association between statin use and improved renal function after suprarenal aortic clamping. We investigated the hypothesis that post-ischemic acute renal failure could be ameliorated with atorvastatin (ATO) treatment and the possible molecular mechanisms in a model of ischemia–reperfusion (IR) in rats.MethodsTwenty-four male Sprague–Dawley rats were divided into three groups: sham, IR, and IR + ATO. ATO was given by a single intraperitoneal injection (10 mg/kg) 30 min before reperfusion in the IR + ATO group. The IR group and sham group received saline vehicle via the intraperitoneal route.ResultsAfter 24 h of IR, serum creatinine levels were increased in the IR group compared with the sham group (p < 0.001). ATO treatment reduced the elevation of serum creatinine level by 18% (p < 0.05) and significantly increased the creatinine clearance rate (p < 0.001). Concentrations of advanced oxidation protein products and malondialdehyde were reduced in the ATO group, approaching levels observed in sham-group rats. ATO treatment alleviated pathological changes in renal tubular cells. Protein and mRNA levels of intercellular adhesion molecule-1 and monocyte chemotactic protein-1 were reduced significantly.ConclusionsThese data suggest that direct protection of injured kidneys by ATO was possible even though the drug was injected 30 min before reperfusion, and that ATO may reduce IR injury by anti-inflammatory effects and by reducing oxidation stress.

Induced hypothermia of 33°C does not affect host response compared with maintaining 36°C

Induced hypothermia is applied in the ICU and in the operating theater to reduce ischemia-reperfusion injury. It is thought that induced hypothermia may hamper the immune response and therefore carry the risk of acquiring or aggravating an infection. We investigated the effect of hypothermia on host response by comparing survivors of cardiac arrest in which body temperature was kept at either 33°C or 36°C.

Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials.

Discuss the recent progress on the clinical use of mesenchymal stromal (stem) cells (MSC) in solid organ transplantation (SOT). Tissue repair and immunomodulatory properties have been recognized for MSC obtained from different human tissues. MSC-based therapy has been proposed to reduce ischemia-reperfusion injury and to promote immune tolerance. The results of recent clinical trial support the safety and promising effects of autologous and allogeneic MSC in SOT. Collectively, the use of MSC in recipients of living donor kidney transplantation was associated with improved graft function, reduced rejection, ability to omit induction and/or lower maintenance immunosuppression regimen, as well as to treat rejection episodes. We are living in very exciting times with the implementation of novel clinical trials aimed at establishing safety, feasibility and efficacy of cellular therapies including MSC to improve SOT outcomes. The results of the initial clinical trials support the safety of MSC-based therapy and justifying cautious optimism for the immediate future.

Taurine attenuates lung ischemia–reperfusion injury after lung transplantation in rats

Taurine, the major intracellular free amino acid found in high concentrations in mammalian cells, is known to be an endogenous antioxidant and a membrane-stabilizing agent. It was hypothesized that taurine may be effective in reducing ischemia-reperfusion injury after lung transplantation and an experimental study was conducted in a rat model. The number of Sprague-Dawley rats used in the study was 35. Animals were randomized into five groups of 7 rats each, including control, donor I, donor II, ischemia-reperfusion injury, and treatment groups. All animals were exposed to the same experimental conditions in the preoperative period. Rats were fixed in a supine position after the induction. After the rats were shaved, a left pneumonectomy was performed following sternotomy in control, donor I, and donor II groups. The harvested grafts in donor I and donor II groups were transplanted to the rats of the ischemia-reperfusion group and treatment group, respectively. However, taurine was administered intraperitoneally for 3days before the harvesting procedure in donor II. All harvested lungs were kept in a Euro-Collins solution at +4°C for 24h in a half-inflated manner. After harvesting and transplantation, lungs were sampled for histopathological and biochemical analysis. Malondialdehyde and superoxide dismutase, glutathione peroxidase, and catalase levels were lower in the treatment group than the other groups (p<0.05). Histopathological findings were better in treatment group than the ischemia-reperfusion group (p<0.05). It was demonstrated that donor treatment with taurine resulted in preservation of transplanted lung tissue in respect to histopathological and biochemical findings.

The depletion of donor macrophages reduces ischaemia-reperfusion injury after mouse lung transplantation

Macrophages (M) are one of the most important cells of the innate immune system for first line defense. Upon transplantation (Tx), M play a prominent role during lung ischaemia reperfusion (I/R) injury. Here, we hypothesize that the depletion of donor M ameliorates the post-transplant lung I/R injury. Orthotopic single-lung Tx was performed between syngeneic BALB/c mice after a cold ischaemic time of 8 h and a reperfusion time of 10 h. Prior to graft implantation, alveolar macrophages of donor lungs were selectively depleted applying the 'suicide technique' by intratracheal application of clodronate liposomes (experimental, n = 6) vs the application of empty liposomes (control, n = 6). Cell count (number of F4/80(+)-macrophages) and graft injury were evaluated by histology and immunohistochemistry, and levels of lactat dehydrogenase (LDH) (apoptosis assay), enzyme linked immunosorbent assay for nuclear protein high-mobility-group-protein B1 (HMGB1), tumor necrosis factor alpha (TNF-α) and transforming growth factor beta1 (TGF-β1) in plasma were analysed. Clodronate liposomes successfully reduced 70% of M from donor lungs when compared with grafts treated with empty liposome only. M-depleted transplants showed improved histology and revealed considerably less graft damage when compared with control recipients (LDH, P = 0.03; HMGB1, P = 0.3). Oxygenation capacity was ameliorated in M-depleted transplants, if not significant (P = 0.114); however, wet/dry ratio did not differ between groups (P = 0.629). The inflammatory response was significantly reduced in M-depleted mice when compared with control recipients (TNF-α, P = 0.042; TGF-β1, P = 0.039). The selective depletion of M in donor lung transplants can be successfully performed and results in a sustained anti-inflammatory response upon I/R-injury. The beneficial effect of this preconditioning method should be further evaluated as a promising tool for the attenuation of I/R prior to graft implantation in clinical Tx.

The role of remote ischemic preconditioning in the treatment of atherosclerotic diseases

BackgroundRemote ischemic preconditioning (RIPC) is the application of a transient and brief ischemic stimulus to a distant site from the organ or tissue that is afterward exposed to injury ischemia, and has been found to reduce ischemia–reperfusion injury (IRI) in various animal models. RIPC appears to offer two distinct phases of endothelial IRI protection, which are presumably mediated through neuronal and humoral pathways.MethodsWe conducted a comprehensive literature review on the available published data about the potential effect of RIPC in patients undergoing IRI in one or more vital organs.ResultsOur search highlighted 24 randomized clinical trials about the effect of RIPC on variable clinical settings (abdominal aortic aneurysm repair, open heart surgery, percutaneous coronary intervention, living donor renal transplantation, coronary angiography, elective decompression surgery, carotid endarterectomy, recent stroke, or transient ischemic attack combined with intracranial carotid artery stenosis). Most of the trials focused on postoperative cardiac or renal function after RIPC with conflicting results. Preconditioning protocols, age limits, comorbidities, and concomitant drug use varied significantly across trials, and therefore no firm conclusions can be drawn using the available data. However, no severe local adverse events were observed in any patient undergoing limb or arm preconditioning.ConclusionsRIPC is a safe and well-tolerated procedure that may constitute a potentially promising innovative treatment in atherosclerotic diseases. Large, multicenter, randomized clinical trials are required to determine an optimal protocol for the RIPC procedure, and to evaluate further the potential benefits of RIPC in human ischemic injury.

Role of STAT3 signal transduction pathway in diazoxide cardioplegic solution-induced reduction of ischemia-reperfusion injury in isolated rat hearts

Objective To evaluate the role of signal transducer and activator of transcription 3 (STAT3) signal transduction pathway in diazoxide cardioplegic solution-induced reduction of ischemia-reperfusion (I/R) injury in isolated rat hearts.Methods Sixty adult male Sprague-Dawley rats,aged 2-3 months,weighing 240-260 g,were used in this study.Their hearts were excised and perfused in a Langendorff apparatus and then randomly divided into 5 groups (n=12 each):control group (group C),group I/R,cardioplegic solution group (group P),diazoxide cardioplegic solution group (group DZX),and STAT3 signal transduction pathway blocker Stattic group (group Stattic).The hearts were continuously perfused for 90 min after 15 min of equilibration in group C.Perfusion was stopped after 15 min of equilibration and restored 30 min later in I/R,P,DZX and Stattic groups.In P and DZX groups,the hearts were perfused with the cardioplegic solution containing 0.4％ dimethyl sulfoxide and 50μmol/L diazoxide,respectively,before perfusion was stopped.In group Stattic,the hearts were perfused with 10μmol/L Stattic for 5 min before perfusion with diazoxide.At 60 min of reperfusion,the hearts were sliced and stained for determination of myocardial infarct size (IS) as a percentage of area at risk (AAR) (IS/AAR),cell apoptosis and expression of phosphorylated STAT3 (p-STAT3) protein (by Western blot) and STAT3 mRNA (using RT-PCR).Apoptotic index (AI) was calculated.Results Compared with group C,the IS/AAR and AI were significantly increased in the other four groups,the expression of p-STAT3 and STAT3 mRNA was down-regulated in I/R and Stattic groups,and the expression of p-STAT3 was down-regulated and STAT3 mRNA was up-regulated in P and DZX groups (P ＜ 0.05).Compared with group I/R,the IS/AAR and AI were significantly decreased,and the expression of p-STAT3 and STAT3 mRNA was up-regulated in P and DZX groups (P ＜ 0.05),and no significant changes were found in the parameters mentioned above in Stattic group (P ＞ 0.05).The IS/AAR and AI were significantly lower,and the expression of p-STAT3 and STAT3 mRNA was higher in DZX group than in P group (P ＜ 0.05).Conclusion STAT3 signal transduction pathway is involved in diazoxide cardioplegic solution-induced reduction of I/R injury in isolated rat hearts. Key words: STAT3 transcription factor; Diazoxide; Myocardial reperfusion injury

GW24-e3157 Possible mechanism of liver X receptors attenuate ischaemia reperfusion injury in isolated rat hearts

ObjectivesThe present study was designed to investigate the effect of liver X receptors (LXRs) on ischaemia reperfusion induced injury in isolated rat heart and to explore the mechanism whether attenuate...

Evaluation effects of allopurinol and FSH on reduction of ischemia-reperfusion injury and on preservation of follicle after heterotopic auto-transplantation of ovarian tissue in mouse.

Allopurinol and FSH injection are applied to reduce ischemia-reperfusion injury and to increase survival rate for ovarian follicles after ovarian heterotopic autotransplantation in mice. Ovarian tissues from 6-week-old mice were grafted into back muscle then collected after 3 weeks. A total of five groups were included in this experiment as follows: control group (n = 5), sham-operated group (n = 5), allopurinol treatment group (AP) (n = 5), follicle stimulating hormone (FSH) treatment group (n = 5), as well as, allopurinol and FSH treatment group (APF) (n = 5). We investigated survival, number and development of follicles, vaginal cytology along with plasma malondialdehyde (MDA) concentration in grafted ovary. Total follicles count significantly increased in APF group compared with other treatment groups (p < 0.05). MDA concentration significantly decreased in AP group and APF treatment group compared with sham-operated group. In AP group, vaginal smears showed presence of cornified epithelial cells three-five day after surgery. We demonstrated that allopurinol, as a XO inhibitor, plays an important role in order to decrease ischemia injury and to increase survival rate for follicles. Also, FSH, as a folliculogenesis and angiogenesis factor, increases development of follicles. It seems that allopurinol can cause re-establishing hypothalamus-pituitary axis and finally can restore estrous cycle earlier than for the sham operated group, so it explains the increasing survival rate for follicles.

Ischemia reperfusion injury and the immune system

Intestinal transplantation represents one of those crossroads in which ischemia–reperfusion (IR) injury and the actions of the immune system appear to intersect. Despite being the treatment of choice for a great number of people with irreversible intestinal failure who cannot be sustained with total parenteral nutrition, and despite improved early 1-y survival at around 90%, the main problems of bacterial infection and acute cellular rejection remain [ 1 Ueno T. Fukuzawa M. Current status of intestinal transplantation. Surg Today. 2010; 40: 1112 Crossref PubMed Scopus (44) Google Scholar , 2 Selvaggi G. Gaynor J.J. Moon J. et al. Analysis of acute cellular rejection episodes in recipients of primary intestinal transplantation: a single center, 11-year experience. Am J Transplant. 2007; 7: 1249 Crossref PubMed Scopus (56) Google Scholar ]. The main mechanism appears to be that of bacterial translocation through a graft–intestinal barrier that has been weakened by IR and preservation injury [ 3 Koudstaal L.G. Hart N.A. van den Berg A. et al. Brain death causes structural and inflammatory changes in donor intestine. Transplant Proc. 2005; 37: 448 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar , 4 Thuijls G. de Haan J.J. Derikx J.P. et al. Intestinal cytoskeleton degradation precedes tight junction loss following hemorrhagic shock. Shock. 2009; 31: 164 Crossref PubMed Scopus (61) Google Scholar , 5 Wang M. Li Q. Wang J. et al. Intestinal tight junction in allograft after small bowel transplantation. Transplant Proc. 2007; 39: 289 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar ]. The epithelial enterocytes and tight junction proteins, which are an essential part of the intestinal mucosa, are very vulnerable to the ischemia that is an unavoidable component of the donation process [ [6] Ito A. Higashiguchi T. Kitagawa M. Yokoi H. Noguchi T. Kawarada Y. Effect of luminal administration of glutamine to suppress preservation graft injury in small bowel transplants. Transplant Proc. 1995; 27: 780 PubMed Google Scholar ]. This leads to an inflammatory activation of the innate immune response, which, in turn, can cause increased immunogenicity. Given the apparent importance of the intestinal barrier and the threat that IR injury represents, overcoming these obstacles becomes critical. Polyethylene glycol (PEG), a nontoxic, water-soluble polymer, has been proposed as a possible answer, given its reputation of limiting the negative effects of edema by its oncotic nature and by stabilizing membrane lipids and enhancing the immune protection of the graft [ 7 Itasaka H. Wicomb W.N. Burns W. et al. Effect of polyethylene glycol on rat small bowel rejection. Transplant Proc. 1992; 24: 1179 PubMed Google Scholar , 8 Hauet T. Eugene M. A new approach in organ preservation: potential role of new polymers. Kidney Int. 2008; 74: 998 Crossref PubMed Scopus (70) Google Scholar ]. Additionally, there is the process of PEGylation, which involves attaching a drug of choice to different sizes of the PEG molecule and, thus, affecting the half-life and metabolism of the drug [ [9] Harris J.M. Chess R.B. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003; 2: 214 Crossref PubMed Scopus (2662) Google Scholar ]. This can be combined with the anti-inflammatory actions of PEG, such as in the case of conjugating PEG with nitric oxide in an effort to control the level of nitric oxide and reduce IR injury [ [10] Bertuglia S. Veronese F.M. Pasut G. Polyethylene glycol and a novel developed polyethylene glycol-nitric oxide normalize arteriolar response and oxidative stress in ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2006; 291: H1536 Crossref PubMed Scopus (28) Google Scholar ].

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H₂ is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H₂ (2%), or NO + H₂, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H₂ alone. NO inhalation plus H₂ reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H₂ with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H₂. In conclusion, breathing NO + H₂ during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H₂ gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

Atrial natriuretic peptide reduces hepatic ischemia–reperfusion injury in rabbits

Atrial natriuretic peptide (ANP) has been known to be protective against hepatic ischemia/reperfusion injury. The purpose of this study was to verify the hypothesis that ANP conserves microvascular circulation and reduces ischemia-reperfusion injury in the in vivo rabbit model. With IRB approval, 30 male Japanese white rabbits under pentobarbital anesthesia were studied. These animals were randomly assigned to the following three groups (n = 10 each): control, ANP, and sham group. Animals in the ANP group received continuous infusion of ANP at 0.1 μg/kg/min throughout the study period. Animals in control and ANP groups underwent 90 min of partial hepatic ischemia by clamping the right hepatic artery and portal vein. Descending aortic blood flow (AoF) was monitored with a transit-time ultrasound flowmeter. Hepatic tissue microvascular blood flow (HTBF) at both right (ischemic) and left (nonischemic) lobe was intermittently evaluated with the hydrogen clearance method. After 180 min of reperfusion, hepatic injury was determined with serum AST and ALT. Galactose clearance of reperfused right lobe was also measured as an indicator of hepatic metabolic function. Histopathological change and the number of apoptotic hepatocytes were also evaluated. Systemic hemodynamic data including mean arterial pressure, heart rate, and AoF did not differ among the three groups during the study period. ANP attenuated ischemia-induced right HTBF decrease. ANP also suppressed histopathological degeneration, apoptosis, and decline in galactose clearance after reperfusion. ANP attenuated hepatic microvascular dysfunction and hepatocyte injury after reperfusion without significant hemodynamic change.

Protocol: does sodium nitrite administration reduce ischaemia-reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites in acute myocardial infarction (NIAMI)

BackgroundWhilst advances in reperfusion therapies have reduced early mortality from acute myocardial infarction, heart failure remains a common complication, and may develop very early or long after the acute event. Reperfusion itself leads to further tissue damage, a process described as ischaemia-reperfusion-injury (IRI), which contributes up to 50% of the final infarct size. In experimental models nitrite administration potently protects against IRI in several organs, including the heart. In the current study we investigate whether intravenous sodium nitrite administration immediately prior to percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction will reduce myocardial infarct size. This is a phase II, randomised, placebo-controlled, double-blinded and multicentre trial.Methods and outcomesThe aim of this trial is to determine whether a 5 minute systemic injection of sodium nitrite, administered immediately before opening of the infarct related artery, results in significant reduction of IRI in patients with first acute ST elevation myocardial infarction (MI). The primary clinical end point is the difference in infarct size between sodium nitrite and placebo groups measured using cardiovascular magnetic resonance imaging (CMR) performed at 6–8 days following the AMI and corrected for area at risk (AAR) using the endocardial surface area technique. Secondary end points include (i) plasma creatine kinase and Troponin I measured in blood samples taken pre-injection of the study medication and over the following 72 hours; (ii) infarct size at six months; (iii) Infarct size corrected for AAR measured at 6–8 days using T2 weighted triple inversion recovery (T2-W SPAIR or STIR) CMR imaging; (iv) Left ventricular (LV) ejection fraction measured by CMR at 6–8 days and six months following injection of the study medication; and (v) LV end systolic volume index at 6–8 days and six months.Funding, ethics and regulatory approvalsThis study is funded by a grant from the UK Medical Research Council. This protocol is approved by the Scotland A Research Ethics Committee and has also received clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) (EudraCT number: 2010-023571-26).Trial registrationClinicalTrials.gov: NCT01388504 and Current Controlled Trials: ISRCTN57596739

Electroacupuncture reduces myocardial infarct size and improves post-ischemic recovery by invoking release of humoral, dialyzable, cardioprotective factors

Previous studies have shown that electroacupuncture (EA) can induce cardioprotection against ischemia-reperfusion (IR) injury, but its mechanisms are incompletely understood. We have previously shown that several other forms of remote preconditioning of the heart work, at least in part, via the release of circulating cardioprotective factors into the bloodstream, that can be dialyzed and subsequently shown to reduce IR injury in isolated hearts. We used the same methods to assess whether EA leads to similar humoral cardioprotection. EA rabbits were subjected to 60 min of bilateral stimulation at the Neiguan point, following which their blood was drawn, dialyzed, and used to perfuse hearts in Langendorff preparation and subsequently subjected to 60 min of global ischemia and 120 min of reperfusion. Compared to controls, dialysate from EA animals led to significant reduction in infarct size and improved functional recovery. The degree of cardioprotection was no different to that seen in animals randomized to receive remote preconditioning using transient limb ischemia (4 cycles of 5 min ischemia/5 min reperfusion). These results suggest that EA recapitulates the cardioprotection achieved by remote preconditioning, by similarly leading to release of circulating cardioprotective factors.

Management of the no-reflow phenomenon

Cardiologia CROATICA Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for treating acute ST-segment elevation myocardial infarction (STEMI). The main goals are to restore epicardial infarct-related artery (IRA) patency and achieve microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Unfortunately, in many patients myocardial perfusion remains poor despite the successful restoration of IRA patency. The lack of adequate myocardial perfusion of a given coronary segment after prolonged ischemia without angiographic evidence of mechanical vessel obstruction is termed. It is clinically important as it is independently associated with increased occurrence of malignant arrhythmias, heart failure, in-hospital and long-term mortality. After the onset of STEMI an efficient emergency system that reduces ischaemic time is crucial for no-reflow prevention in patients undergoing PPCI. The risk of distal embolization is related to thrombus burden, which may be reduced by the use of glycoprotein IIb/IIIa inhibitors. The most potent endogenous mechanism to limit infarction is ischaemic preconditioning. Among patients undergoing PPCI thrombus aspiration has an emerging role. Other pharmacological agents (calcium channel blockers, sodium nitroprusside, adenosine, nicorandil) show promise for reduction of no reflow but require validation in larger, randomized trials. In conclusion, to improve clinical outcomes of STEMI we need to focus on increasing microvascular flow to ischaemic (but not infarcted) myocardium and reducing ischaemiareperfusion injury. No reflow is a multifactorial process, so it is unlikely that one treatment will prevent or cure the process. Thus, prophylactic vasodilator therapy, mechanical devices, ischaemic preconditioning and potent platelet inhibitors in combination are more likely to be effective than any of these alone.

Does chronic metformin therapy offer cardiomyoprotection in coronary artery bypass grafting surgery patients? A case-control study

Metformin, widely used as an antidiabetic drug, activates the AMP activated protein kinase, a key regulator of the metabolism providing protection under fuel deficiency. Chronic metformin therapy has been shown in long-term follow-up clinical studies to reduce cardiovascular mortality [1]. In animal experiments, acute metformin pretreatment has been shown to reduce ischemia-reperfusion injury on cardiomyocytes [2]. We want to evaluate whether outcomes are affected in coronary artery bypass grafting (CABG) surgery.

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivotacrolimus perfusion

BackgroundCritical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.Methods/DesignThe TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients.DiscussionTacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage.Trial registerEudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095

The science and clinical translation of remote postconditioning

The treatment of reperfusion injury requires measures beyond timely reperfusion. Conventional postconditioning (PostC) of ischemic tissues offers a strategy to reduce reperfusion injury, but its adoption is challenged by requiring access and imposing additional ischemia to the ischemic organ. Generating protective signals by PostC in a tissue remote from the target organ such as the limb, i.e. remote PostC (rPostC), may present an alternative approach to exerting endogenous tissue protection. Because rPostC is only recently reported, the fundamental biology of rPostC is not well understood, and studies to date are largely observational. rPostC has been observed to reduce ischemia-reperfusion injury experimentally in heart, kidney, brain and skeletal muscle in multiple species, including rat, rabbit and pig. Both necrosis and apoptosis are reduced. As in remote ischemic preconditioning, rPostC requires a transfer or communication of protective factors or signals through humoral and/or neural pathways. Triggers of target organ protection include G-protein-coupled receptor ligands, metabolites of ischemia, or small thermolabile molecules. Some evidence suggests that reperfusion injury salvage kinases may be involved in rPostC, in agreement with both preconditioning and conventional PostC. Clinical studies investigating improvements in clinical outcomes or biomarkers with rPostC are encouraging.