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Moving Preconditioning From Bench to Bedside*
Journal of the American College of Cardiology © 2006 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Moving Preconditioning From Bench to Bedside* Robert A. Kloner, MD, PHD, FACC Los Angeles, California Ischemic preconditioning is the one maneuver that has consistently been shown to reduce myocardial necrosis due to ischemia/reperfusion injury in experimental models (1). Brief coronary occlusions of a few minutes to 10 min followed by brief reperfusion periods markedly reduce the size of a subsequent myocardial infarction (MI) induced by a longer coronary artery occlusion followed by reperfusion. The ability of ischemic preconditioning to reduce myocardial infarct size has been observed in every species in which the phenomenon has been tested. Ischemic preconditioning also confers other benefits, including a reduction in lethal ventricular arrhythmias (2). There is now ample evidence that ischemic preconditioning can occur in the human heart (3). Studies of isolated cardiac myocytes and human cardiac muscle have shown that, in in vitro models that simulate ischemia/reperfusion, preconditioning protocols can protect the compromised heart tissue. During sequential percutaSee page 206 neous coronary artery angioplasty balloon inflations and deflations, the evidence for ischemia in humans (chest pain, ST-segment elevation, lactate production, and regional left ventricular dysfunction) are reduced during repeat inflation/ deflation sequences compared with a first balloon inflation. Induction of an ischemic preconditioning protocol by intermittent aortic cross clamping preserves myocardial adenosine triphosphate levels during coronary artery bypass graft surgery. Patients that experience pre-infarct angina pectoris, especially during the first 24 h before acute MI, demonstrate smaller myocardial infarcts, lower mortality, better left ventricular function, and less congestive heart failure (3–5). Second messenger pathways have been described to explain ischemic preconditioning, and release of adenosine with ischemia/reperfusion is one of the triggers of these pathways (6). Certain adenosine agonists were shown to mimic the protective effects of ischemic preconditioning (6,7). Conversely, adenosine antagonists have been shown to block the cardioprotective effects of ischemic preconditioning. There is evidence that pharmacologic agents that stimulate or mimic ischemic preconditioning pathways might do so in *Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Heart Institute, Good Samaritan Hospital, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Vol. 48, No. 1, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2006.04.045
humans. For example, in patients, adenosine was shown to lessen ischemia induced by percutaneous coronary artery balloon inflation (8), and adenosine administered before cardiac surgery lessened the need for high-dose inotropes and reduced the development of Q-wave MI (9,10). Adenosine infusion in high doses was shown to reduce myocardial infarct size in patients with anterior wall MIs in both the AMISTAD-I and -II (Acute Myocardial Infarction Study of Adenosine) studies (11,12). Of note, a recent preliminary report from the AMISTAD-II study showed that, when adenosine was given along with early reperfusion therapy (thrombolytic or percutaneous coronary intervention) within 3.2 h of onset of chest pain, 1-month and 6-month mortality and the combined end point of mortality at 6 months and heart failure were significantly reduced compared with patients receiving placebo (13). Because adenosine was administered after the onset of myocardial ischemia, however, it is unlikely that its mechanism was related to true preconditioning in these studies, although it could have been related to postconditioning (14). It has been 20 years since the initial description of ischemic preconditioning (1). Despite numerous studies verifying the phenomenon both in experimental studies and in human studies, no clinical therapy has emerged from the phenomenon that is routinely used in clinical practice. Neither brief episodes of ischemia nor pharmacologic agents that mimic ischemia are routinely used as therapy in patients. The study by Mangano et al. (15) in this issue of the Journal might change this. They investigated the use of acadesine, an adenosine-regulating agent known to increase adenosine levels within ischemic tissue. In this large, multicenter study of 2,698 patients undergoing coronary artery bypass graft surgery, patients were randomized in a doubleblinded fashion to receive a 7-h infusion of acadesine versus placebo starting 15 min before induction of anesthesia. Use of acadesine in this pre-ischemia fashion thus mimics the timing of preconditioning. The primary outcome measured in this Acadesine 1024 Trial was a 4-day assessment of cardiac death, MI, or stroke, and this outcome was negative, although there was a nonsignificant trend with a 22% reduction in the primary combined end point favoring acadesine. The present study assessed long-term (2-year) survival in patients who developed a perioperative MI. Two-year mortality among patients who developed a perioperative MI was significantly lower in the acadesinetreated group, 6.52% (3 of 46 patients), versus the placebotreated patients, 27.78% (15 of 54 patients). The incidence of perioperative MI was 22% lower in the acadesine-treated group, although this did not reach statistical significance. Thus, the present study suggests that pretreatment with acadesine—a potentially preconditioning mimetic agent— improves long-term survival in patients who develop a perioperative MI. The exact mechanism by which acadesine had this benefit remains to be determined. The fact that there was a trend
216
Kloner Editorial Comment
for acadesine to reduce the incidence of perioperative MI suggests that it might have an anti-necrosis effect possibly by stimulating preconditioning pathways via adenosine. Whether myocardial infarct size was truly reduced by acadesine remains to be determined from this study. Other issues that remain to be resolved is whether acadesine imparted some anti-arrhythmic effect in these patients or whether it improved long-term global and regional left ventricular function. In summary, the present study by Mangano et al. (15) provides original data that suggest that a preconditioning mimetic agent can be used to improve survival of patients who develop a perioperative MI associated with a coronary artery bypass surgery. The adenosine-regulating agent acadesine reduced mortality by 4.3-fold in these patients, and the benefit was long-lasting. This study successfully moves forward the concept of preconditioning as a therapy from bench to bedside. Reprint requests and correspondence: Dr. Robert A. Kloner, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, California 90017. E-mail: rkloner@goodsam. org.
REFERENCES 1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124 –36. 2. Hagar JM, Hale SL, Kloner RA. Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat. Circ Res 1991;68:61– 8. 3. Przyklenk K, Kloner RA. Ischemic preconditioning: exploring the paradox. Prog Cardiovasc Dis 1998;40:517– 47.
JACC Vol. 48, No. 1, 2006 July 4, 2006:215–6 4. Kloner RA, Yellon D. Does ischemic preconditioning occur in patients? J Am Coll Cardiol 1994;24:1133– 42. 5. Kloner RA, Shook T, Antman EM , et al. A prospective temporal analysis of the onset of preinfarct angina versus outcome: a prospective ancillary study in TIMI 9B. Circulation 1998;97:1042–5. 6. Thornton JD, Liu GS, Olsson RA, et al. Intravenous pretreatment with A1-selective adenosine analogue protects the heart against infarction. Circulation 1992;85:659 – 65. 7. Hale SL, Bellows SD, Hammerman H, Kloner RA. An adenosine A1 receptor agonist, R (-)-N-E2-Phenylisopropyl-Adenosine (PIA), but not adenosine itself, acts as a therapeutic preconditioning-mimetic agent in rabbits. Cardiovasc Res 1993;27:2140 –5. 8. Leesar MA, Stoddard M, Ahmed M, et al. Preconditioning of human myocardium with adenosine during coronary angioplasty. Circulation 1997;95:2500 –7. 9. Mentzer RM Jr., Birjiniuk V, Khuri S, et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann Surg 1999;229:643–9. 10. Lasley RD, Mentzer RM Jr. Preconditioning and its potential role in myocardial protection during cardiac surgery. J Card Surg 1995;10: 349 –53. 11. Mahaffey KW, Puma JA, Barbagelata A, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction. Results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol 1999;34:1711–20. 12. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 2005;45: 1775– 80. 13. Kloner RA, Gibbons RJ, Ross AM, Alexander RW, Forman MB, Stone GW. Impact of time to presentation and reperfusion modality on the efficacy of adenosine during reperfusion therapy for acute myocardial infarction: the AMISTAD-2 trial. J Am Coll Cardiol 2006;47 Suppl A:175A. 14. Vinten-Johansen J, Yellon DM, Opie LH. Postconditioning. A simple, clinically applicable procedure to improve revascularization in acute myocardial infarction. Circulation 2005;112:2085– 8. 15. Mangano DT, Miao Y, Tudor IC, Dietzel C, for the McSPI Research Group and the IREF. Post-reperfusion myocardial infarction: longterm survival improvement using adenosine regulation with acadesine. J Am Coll Cardiol 2006;48:206 –14.
EDITORIAL COMMENT
Moving Preconditioning From Bench to Bedside* Robert A. Kloner, MD, PHD, FACC Los Angeles, California Ischemic preconditioning is the one maneuver that has consistently been shown to reduce myocardial necrosis due to ischemia/reperfusion injury in experimental models (1). Brief coronary occlusions of a few minutes to 10 min followed by brief reperfusion periods markedly reduce the size of a subsequent myocardial infarction (MI) induced by a longer coronary artery occlusion followed by reperfusion. The ability of ischemic preconditioning to reduce myocardial infarct size has been observed in every species in which the phenomenon has been tested. Ischemic preconditioning also confers other benefits, including a reduction in lethal ventricular arrhythmias (2). There is now ample evidence that ischemic preconditioning can occur in the human heart (3). Studies of isolated cardiac myocytes and human cardiac muscle have shown that, in in vitro models that simulate ischemia/reperfusion, preconditioning protocols can protect the compromised heart tissue. During sequential percutaSee page 206 neous coronary artery angioplasty balloon inflations and deflations, the evidence for ischemia in humans (chest pain, ST-segment elevation, lactate production, and regional left ventricular dysfunction) are reduced during repeat inflation/ deflation sequences compared with a first balloon inflation. Induction of an ischemic preconditioning protocol by intermittent aortic cross clamping preserves myocardial adenosine triphosphate levels during coronary artery bypass graft surgery. Patients that experience pre-infarct angina pectoris, especially during the first 24 h before acute MI, demonstrate smaller myocardial infarcts, lower mortality, better left ventricular function, and less congestive heart failure (3–5). Second messenger pathways have been described to explain ischemic preconditioning, and release of adenosine with ischemia/reperfusion is one of the triggers of these pathways (6). Certain adenosine agonists were shown to mimic the protective effects of ischemic preconditioning (6,7). Conversely, adenosine antagonists have been shown to block the cardioprotective effects of ischemic preconditioning. There is evidence that pharmacologic agents that stimulate or mimic ischemic preconditioning pathways might do so in *Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Heart Institute, Good Samaritan Hospital, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Vol. 48, No. 1, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2006.04.045
humans. For example, in patients, adenosine was shown to lessen ischemia induced by percutaneous coronary artery balloon inflation (8), and adenosine administered before cardiac surgery lessened the need for high-dose inotropes and reduced the development of Q-wave MI (9,10). Adenosine infusion in high doses was shown to reduce myocardial infarct size in patients with anterior wall MIs in both the AMISTAD-I and -II (Acute Myocardial Infarction Study of Adenosine) studies (11,12). Of note, a recent preliminary report from the AMISTAD-II study showed that, when adenosine was given along with early reperfusion therapy (thrombolytic or percutaneous coronary intervention) within 3.2 h of onset of chest pain, 1-month and 6-month mortality and the combined end point of mortality at 6 months and heart failure were significantly reduced compared with patients receiving placebo (13). Because adenosine was administered after the onset of myocardial ischemia, however, it is unlikely that its mechanism was related to true preconditioning in these studies, although it could have been related to postconditioning (14). It has been 20 years since the initial description of ischemic preconditioning (1). Despite numerous studies verifying the phenomenon both in experimental studies and in human studies, no clinical therapy has emerged from the phenomenon that is routinely used in clinical practice. Neither brief episodes of ischemia nor pharmacologic agents that mimic ischemia are routinely used as therapy in patients. The study by Mangano et al. (15) in this issue of the Journal might change this. They investigated the use of acadesine, an adenosine-regulating agent known to increase adenosine levels within ischemic tissue. In this large, multicenter study of 2,698 patients undergoing coronary artery bypass graft surgery, patients were randomized in a doubleblinded fashion to receive a 7-h infusion of acadesine versus placebo starting 15 min before induction of anesthesia. Use of acadesine in this pre-ischemia fashion thus mimics the timing of preconditioning. The primary outcome measured in this Acadesine 1024 Trial was a 4-day assessment of cardiac death, MI, or stroke, and this outcome was negative, although there was a nonsignificant trend with a 22% reduction in the primary combined end point favoring acadesine. The present study assessed long-term (2-year) survival in patients who developed a perioperative MI. Two-year mortality among patients who developed a perioperative MI was significantly lower in the acadesinetreated group, 6.52% (3 of 46 patients), versus the placebotreated patients, 27.78% (15 of 54 patients). The incidence of perioperative MI was 22% lower in the acadesine-treated group, although this did not reach statistical significance. Thus, the present study suggests that pretreatment with acadesine—a potentially preconditioning mimetic agent— improves long-term survival in patients who develop a perioperative MI. The exact mechanism by which acadesine had this benefit remains to be determined. The fact that there was a trend
216
Kloner Editorial Comment
for acadesine to reduce the incidence of perioperative MI suggests that it might have an anti-necrosis effect possibly by stimulating preconditioning pathways via adenosine. Whether myocardial infarct size was truly reduced by acadesine remains to be determined from this study. Other issues that remain to be resolved is whether acadesine imparted some anti-arrhythmic effect in these patients or whether it improved long-term global and regional left ventricular function. In summary, the present study by Mangano et al. (15) provides original data that suggest that a preconditioning mimetic agent can be used to improve survival of patients who develop a perioperative MI associated with a coronary artery bypass surgery. The adenosine-regulating agent acadesine reduced mortality by 4.3-fold in these patients, and the benefit was long-lasting. This study successfully moves forward the concept of preconditioning as a therapy from bench to bedside. Reprint requests and correspondence: Dr. Robert A. Kloner, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, California 90017. E-mail: rkloner@goodsam. org.
REFERENCES 1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124 –36. 2. Hagar JM, Hale SL, Kloner RA. Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat. Circ Res 1991;68:61– 8. 3. Przyklenk K, Kloner RA. Ischemic preconditioning: exploring the paradox. Prog Cardiovasc Dis 1998;40:517– 47.
JACC Vol. 48, No. 1, 2006 July 4, 2006:215–6 4. Kloner RA, Yellon D. Does ischemic preconditioning occur in patients? J Am Coll Cardiol 1994;24:1133– 42. 5. Kloner RA, Shook T, Antman EM , et al. A prospective temporal analysis of the onset of preinfarct angina versus outcome: a prospective ancillary study in TIMI 9B. Circulation 1998;97:1042–5. 6. Thornton JD, Liu GS, Olsson RA, et al. Intravenous pretreatment with A1-selective adenosine analogue protects the heart against infarction. Circulation 1992;85:659 – 65. 7. Hale SL, Bellows SD, Hammerman H, Kloner RA. An adenosine A1 receptor agonist, R (-)-N-E2-Phenylisopropyl-Adenosine (PIA), but not adenosine itself, acts as a therapeutic preconditioning-mimetic agent in rabbits. Cardiovasc Res 1993;27:2140 –5. 8. Leesar MA, Stoddard M, Ahmed M, et al. Preconditioning of human myocardium with adenosine during coronary angioplasty. Circulation 1997;95:2500 –7. 9. Mentzer RM Jr., Birjiniuk V, Khuri S, et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann Surg 1999;229:643–9. 10. Lasley RD, Mentzer RM Jr. Preconditioning and its potential role in myocardial protection during cardiac surgery. J Card Surg 1995;10: 349 –53. 11. Mahaffey KW, Puma JA, Barbagelata A, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction. Results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol 1999;34:1711–20. 12. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 2005;45: 1775– 80. 13. Kloner RA, Gibbons RJ, Ross AM, Alexander RW, Forman MB, Stone GW. Impact of time to presentation and reperfusion modality on the efficacy of adenosine during reperfusion therapy for acute myocardial infarction: the AMISTAD-2 trial. J Am Coll Cardiol 2006;47 Suppl A:175A. 14. Vinten-Johansen J, Yellon DM, Opie LH. Postconditioning. A simple, clinically applicable procedure to improve revascularization in acute myocardial infarction. Circulation 2005;112:2085– 8. 15. Mangano DT, Miao Y, Tudor IC, Dietzel C, for the McSPI Research Group and the IREF. Post-reperfusion myocardial infarction: longterm survival improvement using adenosine regulation with acadesine. J Am Coll Cardiol 2006;48:206 –14.