 |
|
Organ Preconditioning
Christopher D. Raeburn, MD;
Joseph C. Cleveland, Jr, MD;
Michael A. Zimmerman, MD;
Alden H. Harken, MD
Arch Surg. 2001;136:1263-1266.
ABSTRACT
| |
The initial discovery of cardiac preconditioning has evolved into an exciting series of practical surgical applications. An enormous amount of evidence demonstrating both the safety and efficacy of ischemic preconditioning is available from animal studies. The challenging premise of intentionally subjecting patients and their organs to transient ischemia has acted as a formidable psychological and ethical impediment to the widespread clinical application of organ preconditioning. A more palatable alternative to ischemic preconditioning now involves approved medications designed to manipulate the cellular machinery mediating ischemic preconditioning. Pharmacologically induced preconditioning seems to confer equal organ protection. The relatively brief (but surgically relevant) window of protection provided by strategies such as ischemic preconditioning or adenosine agonists and potassium–adenosine triphosphate channel openers may, in the future, be extended. We have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes with subsequent protection against sepsis-induced dysfunction. Targeted strategies will ultimately broaden the therapeutic potential of organ preconditioning.
SO WHAT IS ORGAN PRECONDITIONING AND WHY DO YOU NEED TO KNOW ABOUT IT?
Organ preconditioning is a process whereby a brief antecedent event, be it transient ischemia, oxidative stress, temperature change, or drug administration, bestows on an organ a temporary tolerance to further insults by the same or similar stressors. Regardless of your surgical discipline, organ preconditioning is on the horizon and promises to reduce morbidity during coronary revascularization, to provide improved graft and patient survival after transplantation, to protect kidneys and intestines during vascular surgery, to improve skin and muscle flap survival, and perhaps even to protect the editors of this journal from the cerebrovascular ischemic ravages of old age. The purposes of this review are as follows: (1) to describe the evolution and mechanisms of organ preconditioning, (2) to examine the evidence that organ preconditioning is accessible and relevant to surgery, and (3) to discuss future implications for organ preconditioning.
EVOLUTION
Murry et al1 first recognized organ preconditioning. Paradoxically, while trying to create a larger myocardial infarction in a dog, they subjected animals to several brief episodes of myocardial ischemia and reperfusion prior to a protracted ischemic injury. To their surprise, the area of infarction in these stressed animals was reduced by up to 75% compared with animals not subjected to antecedent brief ischemia.1 In addition to limiting infarct size, ischemic preconditioning reduces myocardial functional "stunning,"2-3 post-ischemic arrhythmias,4-5 and accelerates the recovery of muscle function after ischemia.6 These counterintuitive findings have been challenged, but confirmed in multiple organs across many species.
MECHANISM
Though the mechanisms of preconditioning have been best studied in the heart, these cellular protective strategies have been identified in other organs.7-9 Ischemic preconditioning is psychologically repugnant to the active surgeon; we are reluctant to clamp a carotid artery even transiently prior to performing a carotid endarterectomy. Fortunately, ischemic preconditioning can be replicated by pharmacologic agonists to adenosine,  -adrenergic, opioid and/or bradykinin receptors, suggesting that tissues have evolved multiple parallel endogenous means of self-protection.6, 10-12 Intracellular signaling is a lot like the analog processing in a lap-top computer. In a computer, a fork in the network is transduced either yes/positive or no/negative. In a cell, kinases transmit the "yes" signal by phosphorylation, while phosphatases say "no" by cleaving a phosphate. A common theme among preconditioning receptors is that they are linked to protein kinase C,13 which is the first step in a complex cascade of phosphorylating (yes signal) kinases that activate the potassium–adenosine triphosphate (K-ATP) channel in the mitochondrial membrane (Figure 1). This K-ATP channel is the final common energy-producing pathway to organ preconditioning. We have reported that inhibition of this K-ATP channel completely abolishes the effects of ischemic preconditioning in the heart.14 Commonly prescribed drugs, such as oral hypoglycemic agents (inhibitors of the K-ATP channel) and L-type calcium channel blockers (inhibitors of the calcium "trigger"), compromise protective cardiac preconditioning and increase cardiac morbidity and mortality after an ischemic event.15-16 Conversely, the inhibition of bradykinin degradation in patients taking angiotensin-converting enzyme inhibitors may account for the reduced morbidity and mortality observed after a myocardial infarction.17
|
|
|
|
Cardiomyocyte preconditioning may occur via transient ischemia, oxidants, heat shock, osmolar stress, or by ligation of adenosine, -adrenergic, bradykinin, or opioid receptors. All of these signal through protein kinase C (PKC), which initiates a complex kinase cascade that ultimately opens mitochondrial potassium–adenosine triphosphatase channels (K-ATP), protecting the cell from subsequent injury. Gp indicates G-protein; PLC, phospholipase C; and Ca++, calcium.
|
|
|
CARDIOTHORACIC SURGERY
After the description by Murry et al1 of myocardial ischemic preconditioning, a myriad of publications corroborated this initial discovery. Although many laboratory studies have confirmed the existence of ischemic preconditioning in animals, care must be taken in extrapolating these findings to humans.18 In vitro studies using human atrial muscle strips exhibit preconditioning but an in vivo clinical strategy to investigate ischemic preconditioning is both logistically and ethically challenging.
Two important observational studies have provided strong evidence for the existence of ischemic preconditioning in human myocardium, and have thus paved the way for further clinical investigation of preconditioning as a therapeutic strategy. Patients undergoing coronary angioplasty experienced less pain and exhibited only mild S-T segment depression during sequential balloon inflation after an initial 90-second coronary artery occlusion.19 Similarly, patients experiencing preinfarction angina during the 24 hours preceding a myocardial infarction suffered smaller infarcts and enjoyed improved survival.20 Subsequent investigations revealed that adenosine antagonists and K-ATPase inhibition prevent protective preconditioning during angioplasty, confirming that the mechanisms of myocardial preconditioning are similar in animals and humans.21-22
Jenkins et al23 provided the first clinical evidence that ischemic preconditioning resulted in myocardial protection. During routine coronary artery bypass grafting (CABG), they applied two 3-minute periods of ischemia (aortic cross-clamping) followed by 3 minutes of reperfusion before the more extensive ischemia (10-15 minutes) obligatory for a coronary vascular anastomosis. Preconditioned patients released lower levels of serum troponin T at 72 hours postbypass.23
Despite these promising findings, the unnerving thought of intentionally inducing myocardial ischemia in patients is too difficult for many clinicians to bear, thus hindering the widespread clinical application of ischemic preconditioning. Fortunately, pharmacologic strategies have evolved that seem to mimic the mechanisms of ischemia while reaping the benefits of preconditioning without the actual ischemia (Figure 1). We and others have reported that adenosine administered prior to routine CABG decreases postoperative atrial arrhythmias,5 and a multi-institutional trial confirmed that adenosine administered immediately prior to cross-clamping the aorta improves ventricular function following CABG.24-25
TRANSPLANT SURGERY
Transplant surgery offers the perfect opportunity for preconditioning as it requires a scheduled, transient ischemic period during organ procurement and storage. Strong support for the application of organ preconditioning has been established in animals. In the rat, 2 short periods of ischemia and reperfusion, or administration of diazoxide (a K-ATP channel opener) prior to explantation and cold storage, improved postreperfusion left ventricular compliance and reduced creatine kinase leak.26
Yin et al27 have reported that rat livers subjected to ischemic preconditioning or adenosine administration prior to harvest prompted improved survival and reduced aspartate transaminase (AST) release after 16 hours of cold storage and transplantation. A clinical correlate to this study, again counterintuitively, reported that livers procured from donors suffering a brief cardiopulmonary arrest prior to procurement enjoyed similar graft function and host survival but lower posttransplant AST levels compared with the nonarrest group.28 Any rational surgeon would logically predict impaired posttransplantation hepatic function in the cardiopulmonary arrest donor group. Liver preconditioning, therefore, is the only plausible mode of protection.
Lung transplantation is associated with a 20% incidence of severe graft dysfunction in the early postoperative period.29 In animals, ischemic preconditioning of lungs prior to prolonged hypothermic storage is protective of both compliance30 and gas exchange.31
VASCULAR SURGERY
Elective vascular surgery also offers a unique opportunity for organ preconditioning, as it too involves an obligate period of transient ischemia. Preconditioning may improve functional recovery of skeletal muscle during peripheral vascular procedures8 and may also protect renal function during complex pararenal aortic aneurysm repair. Animal evidence has been overwhelming in showing that antecedent transient ischemia will protect the brain during carotid endarterectomy; however, the psychological hurdles for the surgeon who must intentionally clamp the carotid (of a university dean or even a trial lawyer) remain daunting.
Lee and Emala7 have reported that ischemic preconditioning prior to a 45-minute ischemic event resulted in improved renal function and morphological structure in rats. Moreover, these investigators found that A-1 adenosine agonists and A-3 adenosine antagonists reproduced the benefits of ischemic preconditioning.7 This study delineates and confirms the role of the various adenosine receptors in organ preconditioning.
NEUROSURGERY
Analogous to the study by Ottani et al20 correlating preinfarction angina with reduced morbidity after a myocardial infarction, several groups have reported that patients suffering transient ischemic attacks (TIA) experience a more favorable outcome after a subsequent ischemic stroke.32-33 Animal investigations have confirmed similar benefits with protective ischemic preconditioning in reducing neuronal damage after subsequent prolonged ischemia.34
PLASTIC OR RECONSTRUCTIVE SURGERY
Despite a better understanding of vascular anatomy and improved flap design, the devastating complication of partial or complete myocutaneous flap necrosis following reconstructive surgery still occurs.35 Zahir et al36 have reported that ischemic preconditioning reduces the incidence of skin and free-muscle flap necrosis in rats.36 Preliminary clinical trials using ischemic preconditioning have shown improved survival rates of both transverse rectus abdominis flaps and groin flaps.37-38
FUTURE IMPLICATIONS
Despite the enormous amount of evidence demonstrating the safety and efficacy of ischemic preconditioning in animal studies, the challenge of intentionally subjecting patients to transient ischemia has acted as a formidable impediment to its widespread clinical application. The development of approved medications designed to replicate the cellular machinery involved in preconditioning offers a more palatable alternative to ischemic preconditioning. Moreover, the relatively brief window of protection provided by strategies such as ischemic preconditioning, adenosine agonists, and K-ATP channel openers may, in the future, be extended. For instance, we have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes, with subsequent protection against sepsis-induced cardiac dysfunction.39 Strategies such as this may ultimately broaden the therapeutic potential of organ preconditioning even further.
AUTHOR INFORMATION
Corresponding author: Christopher D. Raeburn, MD, Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Campus Box C-320, Denver, CO 80262 (e-mail: christopher.raeburn{at}uchsc.edu).
From the Department of Surgery and the Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center, Denver.
REFERENCES
| |
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136.
FREE FULL TEXT
2. Cleveland JC Jr, Wollmering MM, Meldrum DR, et al. Ischemic preconditioning in human and rat ventricle. Am J Physiol. 1996;271:H1786-H1794.
3. Sun JZ, Tang XL, Knowlton AA, Park SW, Qiu Y, Bolli R. Late preconditioning against myocardial stunning: an endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J Clin Invest. 1995;95:388-403.
4. Shiki K, Hearse DJ. Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. Am J Physiol. 1987;253:H1470-H1476.
5. Pomerantz BJ, Joo K, Shames BD, Cleveland JC Jr, Banerjee A, Harken AH. Adenosine preconditioning reduces both pre and postischemic arrhythmias in human myocardium. J Surg Res. 2000;90:191-196.
FULL TEXT
|
ISI
| PUBMED
6. Banerjee A, Locke-Winter C, Rogers KB, et al. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res. 1993;73:656-670.
FREE FULL TEXT
7. Lee HT, Emala CW. Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A(1) and A(3) receptors. Am J Physiol Renal Physiol. 2000;278:F380-F387.
8. Hopper RA, Forrest CR, Xu H, et al. Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction. Am J Physiol Regul Integr Comp Physiol. 2000;279:R666-R676.
9. Reshef A, Sperling O, Zoref-Shani E. Opening of K(ATP) channels is mandatory for acquisition of ischemic tolerance by adenosine. Neuroreport. 2000;11:463-465.
ISI
| PUBMED
10. Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation. 1991;84:350-356.
FREE FULL TEXT
11. Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res. 1996;78:1100-1104.
FREE FULL TEXT
12. Brew EC, Mitchell MB, Rehring TF, et al. Role of bradykinin in cardiac functional protection after global ischemia-reperfusion in rat heart. Am J Physiol. 1995;269(pt2):H1370-H1378.
13. Mitchell MB, Meng X, Ao L, Brown JM, Harken AH, Banerjee A. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res. 1995;76:73-81.
FREE FULL TEXT
14. Cleveland JC Jr, Meldrum DR, Rowland RT, Banerjee A, Harken AH. Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. J Mol Cell Cardiol. 1997;29:175-182.
FULL TEXT
|
ISI
| PUBMED
15. Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited [comments]. Circulation. 1997;96:29-32.
FREE FULL TEXT
16. Cain BS, Meldrum DR, Cleveland JC Jr, Meng X, Banerjee A, Harken AH. Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of human myocardium [comments]. J Mol Cell Cardiol. 1999;31:2191-2197.
FULL TEXT
|
ISI
| PUBMED
17. Morris SD, Yellon DM. Angiotensin-converting enzyme inhibitors potentiate preconditioning through bradykinin B2 receptor activation in human heart. J Am Coll Cardiol. 1997;29:1599-1606.
ABSTRACT
18. Tomai F, Crea F, Chiariello L, Gioffre PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation. 1999;100:559-563.
FREE FULL TEXT
19. Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW Jr, Herrmann HC, Laskey WK. Adaptation to ischemia during percutaneous transluminal coronary angioplasty: clinical, hemodynamic, and metabolic features. Circulation. 1990;82:2044-2051.
FREE FULL TEXT
20. Ottani F, Galvani M, Ferrini D, et al. Prodromal angina limits infarct size: a role for ischemic preconditioning [comments]. Circulation. 1995;91:291-297.
FREE FULL TEXT
21. Tomai F, Crea F, Gaspardone A, et al. Effects of A1 adenosine receptor blockade by bamiphylline on ischaemic preconditioning during coronary angioplasty [comments]. Eur Heart J. 1996;17:846-853.
FREE FULL TEXT
22. Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994;90:700-705.
FREE FULL TEXT
23. Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart. 1997;77:314-318.
FREE FULL TEXT
24. Mentzer RM Jr, Birjiniuk V, Khuri S, et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial [discussion]. Ann Surg. 1999;229:643-649.
FULL TEXT
|
ISI
| PUBMED
25. Lee HT, LaFaro RJ, Reed GE. Pretreatment of human myocardium with adenosine during open heart surgery. J Card Surg. 1995;10:665-676.
ISI
| PUBMED
26. Kevelaitis E, Oubenaissa A, Peynet J, Mouas C, Menasche P. Preconditioning by mitochondrial ATP-sensitive potassium channel openers: an effective approach for improving the preservation of heart transplants. Circulation. 1999;100:II345-II350.
27. Yin DP, Sankary HN, Chong AS, et al. Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats. Transplantation. 1998;66:152-157.
ISI
| PUBMED
28. Totsuka E, Fung JJ, Urakami A, et al. Influence of donor cardiopulmonary arrest in human liver transplantation: possible role of ischemic preconditioning. Hepatology. 2000;31:577-580.
FULL TEXT
|
ISI
| PUBMED
29. Novick RJ, Gehman KE, Ali IS, Lee J. Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg. 1996;62:302-314.
FREE FULL TEXT
30. Featherstone RL, Chambers DJ, Kelly FJ. Ischemic preconditioning enhances recovery of isolated rat lungs after hypothermic preservation. Ann Thorac Surg. 2000;69:237-242.
FREE FULL TEXT
31. Du ZY, Hicks M, Winlaw D, Spratt P, Macdonald P. Ischemic preconditioning enhances donor lung preservation in the rat. J Heart Lung Transplant. 1996;15:1258-1267.
ISI
| PUBMED
32. Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? Neurology. 2000;54:2089-2094.
FREE FULL TEXT
33. Weih M, Kallenberg K, Bergk A, et al. Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke. 1999;30:1851-1854.
FREE FULL TEXT
34. Liu Y, Kato H, Nakata N, Kogure K. Protection of rat hippocampus against ischemic neuronal damage by pretreatment with sublethal ischemia. Brain Res. 1992;586:121-124.
FULL TEXT
|
ISI
| PUBMED
35. Banic A, Boeckx W, Greulich M, et al. Late results of breast reconstruction with free TRAM flaps: a prospective multicentric study [discussion]. Plast Reconstr Surg. 1995;95:1195-1204.
ISI
| PUBMED
36. Zahir KS, Syed SA, Zink JR, Restifo RJ, Thomson JG. Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model [discussion]. Plast Reconstr Surg. 1998;102:140-150.
ISI
| |
