Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke.

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Aims: Donation after circulatory death (DCD) could improve cardiac graft availability, which is currently insufficient to meet transplant demand. However, DCD organs undergo an inevitable period of warm ischemia and most cardioprotective approaches can only be applied at reperfusion (procurement) for ethical reasons. We investigated whether modifying physical conditions at reperfusion, using four different strategies, effectively improves hemodynamic recovery after warm ischemia.Methods and Results: Isolated hearts of male Wistar rats were perfused in working-mode for 20 min, subjected to 27 min global ischemia (37°C), and 60 min reperfusion (n = 43). Mild hypothermia (30°C, 10 min), mechanical postconditioning (MPC; 2x 30 s reperfusion/30 s ischemia), hypoxia (no O2, 2 min), or low pH (pH 6.8–7.4, 3 min) was applied at reperfusion and compared with controls (i.e., no strategy). After 60 min reperfusion, recovery of left ventricular work (developed pressure*heart rate; expressed as percent of pre-ischemic value) was significantly greater for mild hypothermia (62 ± 7%), MPC (65 ± 8%) and hypoxia (61 ± 11%; p < 0.05 for all), but not for low pH (45 ± 13%), vs. controls (44 ± 7%). Increased hemodynamic recovery was associated with greater oxygen consumption (mild hypothermia, MPC) and coronary perfusion (mild hypothermia, MPC, hypoxia), and with reduced markers of necrosis (mild hypothermia, MPC, hypoxia) and mitochondrial damage (mild hypothermia, hypoxia).Conclusions: Brief modifications in physical conditions at reperfusion, such as hypothermia, mechanical postconditioning, and hypoxia, improve post-ischemic hemodynamic function in our model of DCD. Cardioprotective reperfusion strategies applied at graft procurement could improve DCD graft recovery and limit further injury; however, optimal clinical approaches remain to be characterized.

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Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that 3 reperfusion strategies-mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset-provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all 3 strategies improve oxygen-consumption-cardiac-work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator-activated receptor-gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial-based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation.

Heart transplantation remains the treatment of reference for patients experiencing end‐stage heart failure; unfortunately, graft availability through conventional donation after brain death is insufficient to meet the demand. Use of extended‐criteria donors or donation after circulatory death has emerged to increase organ availability; however, clinical protocols require optimization to limit or prevent damage in hearts possessing greater susceptibility to injury than conventional grafts. The emergence of cardiac ex situ machine perfusion not only facilitates the use of extended‐criteria donor and donation after circulatory death hearts through the avoidance of potentially damaging ischemia during graft storage and transport, it also opens the door to multiple opportunities for more sensitive monitoring of graft quality. With this review, we aim to bring together the current knowledge of biomarkers that hold particular promise for cardiac graft evaluation to improve precision and reliability in the identification of hearts for transplantation, thereby facilitating the safe increase in graft availability. Information about the utility of potential biomarkers was categorized into 5 themes: (1) functional, (2) metabolic, (3) hormone/prohormone, (4) cellular damage/death, and (5) inflammatory markers. Several promising biomarkers are identified, and recommendations for potential improvements to current clinical protocols are provided.

Introduction: Donation after circulatory death (DCD) could substantially improve donor heart availability. However, warm ischemia prior to procurement is of particular concern for cardiac graft quality. We describe a rat model of DCD with in-situ ischemia in order to characterize the physiologic changes during the withdrawal period before graft procurement, to determine effects of cardioplegic graft storage, and to evaluate the post-ischemic cardiac recovery in comparison with an established ex-situ ischemia model.Methods: Following general anesthesia in male, Wistar rats (404 ± 24 g, n = 25), withdrawal of life-sustaining therapy was simulated by diaphragm transection. Hearts underwent no ischemia or 27 min in-situ ischemia and were explanted. Ex situ, hearts were subjected to a cardioplegic flush and 15 min cold storage or not, and 60 min reperfusion. Cardiac recovery was determined and compared to published results of an entirely ex-situ ischemia model (n = 18).Results: In donors, hearts were subjected to hypoxia and hemodynamic changes, as well as increased levels of circulating catecholamines and free fatty acids prior to circulatory arrest. Post-ischemic contractile recovery was significantly lower in the in-situ ischemia model compared to the ex-situ model, and the addition of cardioplegic storage improved developed pressure-heart rate product, but not cardiac output.Conclusion: The in-situ model provides insight into conditions to which the heart is exposed before procurement. Compared to an entirely ex-situ ischemia model, hearts of the in-situ model demonstrated a lower post-ischemic functional recovery, potentially due to systemic changes prior to ischemia, which are partially abrogated by cardioplegic graft storage.