Clinical applications of ischemic preconditioning: From head to toe

doi:10.1067/msy.2001.111192

Surgery

Volume 129, Issue 6, June 2001, Pages 664-667

https://doi.org/10.1067/msy.2001.111192 Get rights and content

Abstract

Surgery 2001;129:664-7.

Section snippets

What is ischemic preconditioning ?

Ischemic preconditioning describes the almost paradoxic phenomenon whereby short, repetitive, antecedent exposures of ischemia render an organ tolerant to a subsequent ischemia-reperfusion insult. Murry et al¹ initially described ischemic preconditioning in a canine model of myocardial ischemia. Ironically, they were originally attempting to induce a more severe infarction in dogs by exposing them to 4 sequential 5-minute periods of regional ischemia followed by 5 minutes of reperfusion before

Ischemic preconditioning: Basic mechanisms

Ischemia is a nonspecific stimulus that activates several redundant signaling pathways. At the cell surface receptor level, activation of adenosine,⁵ adrenergic,⁶ bradykinin,⁷ and opioid⁸ receptors can reproduce the protective effect of antecedent ischemia, and all of these substances are released during ischemia. The coupling of receptors to their specific intracellular effectors is certainly beyond the scope of this review, but the major intracellular mediators of ischemic preconditioning are

Coronary artery disease

Strategies to exploit the endogenous protective nature of ischemic preconditioning remain attractive during clinical myocardial revascularization. Observational studies in human beings suggest that pre-infarction angina may confer a survival advantage after myocardial infarction. Kloner et al examined in-hospital mortality and infarct size in the Thrombolysis in Myocardial Infarction (TIMI 4) trial. This large, multicenter study revealed that patients with angina occurring within the 48 hours

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Cited by (21)

Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: Impact on ischaemia-reperfusion injury and clinical relevance
2010, HPB
Citation Excerpt :
It has been shown to be protective in three clinical studies on liver resection.18–20 It has also been shown that a short period of warm ischaemia protects different organs including the heart, intestine, lung and kidney21,22 against subsequent cold ischaemia–reperfusion injury. Several studies in experimental models23–25 and humans26,27 suggest that IPC is suitable for use during liver transplantation.
Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT).
To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts.
Alternate patients were transplanted with right lobe grafts that were (n= 22; Group _Precond) or were not (n= 22; Group _Control) subjected to IPC in the living donor. Liver ischaemia–reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time.
Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P= 0.8) and alanine aminotransferase (ALT) peaks (P= 0.6) were similar in both groups (307 ± 189 and 437 ± 302 vs. 290 ± 146 and 496 ± 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P= 0.003) and pre-operative bilirubin concentration (P= 0.004) were significantly predictive of minimum prothrombin time post-transplantation.
Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain.
Remote Ischemic Preconditioning on Neovascularization and Follicle Viability on Ovary Autotransplantation in Rats
2008, Transplantation Proceedings
Verify the optimum remote vascular occlusion time to reduce ovarian injury in autologous transplants in rats.
Twenty-four adult female rats were assigned to four groups: GC (control group): bilateral oophorectomy followed by ovary transplant; GIPC (ischemic preconditioning group): remote ischemic preconditioning at the iliac artery for 5, 10, and 15 minutes (GIPC-5, GIPC-20, and GIPC-15) previous to bilateral oophorectomy and ovarian transplantation. The right ovary was fixed in the retroperitoneum. Euthanasia was performed 4 days after the surgical procedure. The follicles were counted and classified as developing versus atretic. The immunohistochemical assay identified vascular factor of endothelial growth (VEGF) in the ovarian stroma and assessed the proliferation capacity by means of the Ki-67 in the ovarian follicles.
Every group showed an inflammatory infiltrate, luteous body, and ovarian follicles in several phases of development. The ischemic preconditioning groups displayed greater amounts of viable ovarian follicles and increased vascularization and vasodilatation than the control group. GIPC-15 showed the highest amount of viable follicles compared to the others (P < .05 GIPC-15 vs GC; GIPC-15 vs GIPC-5). More VEGF-labeled cells were observed in GIPC-10 than the control group (P < .05, GIPC-10 vs GC). The proliferation index assessed by Ki-67 marking showed GC: 80%; GIPC-5: 76%; GIPC-10: 67%; and GIPC-15: 64% (P > .05).
The PCI-15 cohort seem to be the most adequate timing to achieve functional support and preservation of a greater number of viable ovarian follicles.
Preconditioning: Gender effects
2005, Journal of Surgical Research
Preconditioning is injury induced protection from subsequent injury. During preconditioning protective cellular responses to injury are up regulated resulting in acute and delayed defense against further damage. Several studies indicate that females experience a protective advantage after acute insult compared to males. Despite evidence of gender differences in acute injury, relatively few studies have evaluated whether there are sex differences in preconditioning. Variations in patients’ pre-morbid preconditioning status may explain outcome variations that are not apparent in small animal studies. This review discusses the differences in response to acute injury experienced by males and females, the basic mechanisms of preconditioning, and the sex differences in the mechanisms of preconditioning.
Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats
2004, Gastroenterology
Background & Aims: Hepatic ischemic preconditioning decreases sinusoidal endothelial cell injury and Kupffer cell activation after cold ischemia/reperfusion, leading to improved survival of liver transplant recipients in rats. Ischemic preconditioning also protects livers against warm ischemia/reperfusion injury, in which hepatocyte injury is remarkable. We aimed to determine whether ischemic preconditioning directly protects hepatocytes and to elucidate its mechanisms. Methods: Rats were injected with gadolinium chloride to deplete Kupffer cells or with N-acetyl-l-cysteine, superoxide dismutase, or catalase to scavenge reactive oxygen species. Livers were then preconditioned by 10 minutes of ischemia and 10 minutes of reperfusion. Subsequently, livers were subjected to 40 minutes of warm ischemia and 60 minutes of reperfusion in vivo or in a liver perfusion system. In other rats, livers were preconditioned by H₂O₂ perfusion instead of ischemia. In the other experiments, livers were perfused with nitro blue tetrazolium to detect reactive oxygen species formation. Results: Ischemic preconditioning decreased injury in hepatocytes, but not in sinusoidal endothelial cells. Kupffer cell depletion itself did not change hepatocyte injury after ischemia/reperfusion, indicating no contribution of Kupffer cells to ischemia/reperfusion injury. However, Kupffer cell depletion reversed hepatoprotection by ischemic preconditioning. Reactive oxygen species formation occurred in Kupffer cells after ischemic preconditioning. Scavenging of reactive oxygen species reversed the effect of ischemic preconditioning, and H₂O₂ preconditioning mimicked ischemic preconditioning. Conclusions: Ischemic preconditioning directly protected hepatocytes after warm ischemia/reperfusion, which is not via suppression of changes in sinusoidal cells as in cold ischemia/reperfusion injury. This hepatocyte protection was mediated by reactive oxygen species produced by Kupffer cells.
Causes of limited survival of microencapsulated pancreatic islet grafts
2004, Journal of Surgical Research
Successful transplantation of pancreatic tissue has been demonstrated to be an efficacious method of restoring glycemic control in type 1 diabetic patients. To establish graft acceptance patients require lifelong immunosuppression, which in turn is associated with severe deleterious side effects. Microencapsulation is a technique that enables the transplantation of pancreatic islets in the absence of immunosuppression by protecting the islet tissue through a mechanical barrier. This protection may even allow for the transplantation of animal tissue, which opens the perspective of using animal donors as a means to solve the problem of organ shortage. Microencapsulation is not yet applied in clinical practice, mainly because encapsulated islet graft survival is limited. In the present review we discuss the principal causes of microencapsulated islet graft failure, which are related to a lack of biocompatibility, limited immunoprotective properties, and hypoxia. Next to the causes of encapsulated islet graft failure we discuss possible improvements in the encapsulation technique and additional methods that could prolong encapsulated islet graft survival. Strategies that may well support encapsulated islet grafts include co-encapsulation of islets with Sertoli cells, the genetic modification of islet cells, the creation of an artificial implantation site, and the use of alternative donor sources. We conclude that encapsulation in combination with one or more of these additional strategies may well lead to a simple and safe transplantation therapy as a cure for diabetes.
Protecting the heart and other organs after cardiac surgery: Old problems, new solutions?
2004, Cardiology in the Young

View all citing articles on Scopus

^*: Reprint requests: Joseph C. Cleveland, Jr, MD, Department of Surgery and Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center, 4200 E. Ninth Ave, Campus Box C-310, Denver, CO 80262.

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Surgical Research ReviewsClinical applications of ischemic preconditioning: From head to toe*

Abstract

Section snippets

What is ischemic preconditioning ?

Ischemic preconditioning: Basic mechanisms

Coronary artery disease

J Surg Res

J Mol Cell Cardiol

FEBS Lett

Lancet

Am J Cardiol

Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium

Circulation

Ischemic preconditioning in human and rat ventricle

Am J Physiol

Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias

Am J Physiol

Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart

Circulation

Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha1-adrenergic mechanism

Circ Res

The role of bradykinin in cardiac functional protection after global ischemia-reperfusion in the rat heart

Am J Physiol

Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in rat heart

Circ Res

Preconditioning of isolated rat heart is mediated by protein kinase C

Circ Res

Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs

Circ Res

Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium

Circulation

Surgical Research Reviews
Clinical applications of ischemic preconditioning: From head to toe*

Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha₁-adrenergic mechanism