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Introduction to the role of oxygen radicals in myocardial ischemia and infarction
Free Radical Biology & Medicine, Vol.4, pp. 5-7, 1988
0891-5849/88 $3.00+ .00 © 1988PergamonJournalsLtd.
Printed in the USA. All fightsreserved.
Conference Proceedings INTRODUCTION TO MYOCARDIAL
THE ROLE OF OXYGEN RADICALS ISCHEMIA AND INFARCTION*
IN
ROBERT A. KLONER Department of Internal Medicine, Division of Cardiology, Harper-GraceHospital, Wayne State University, 3990 John R., Detroit, MI 48201, U.S,A. (Received 20 May 1987)
Abstract--There has been considerable interest over the past several years concerning the role of oxygen radicals in myocardial ischemia-reperfusion injury. The purpose of the following symposium will be to review recent advances in the understanding of oxygen free radical damage to the heart. Included in the symposium are descriptions of the biochemistry of free radicals and evidence of their direct toxic effects on the heart, as well as discussions concerning the effect of oxygen free radical scavengers on myocardial infarct size, the stunned myocardium, and cardiac preservation during surgery. Keywords--Oxygen radicals, Free radicals, Oxidants, Coronary repeffusion, Reperfusion injury, Myocardial ischemia, Myocardial infarction
Over the past 3 - 5 years there has been a growing interest in the concept that oxygen radicals play a role in the pathogenesis of myocardial ischemia and infarction. Up until about 5 years ago, it was generally held that the determinants of the degree of ischemic damage following a coronary occlusion were simply the oxygen supply versus the oxygen demand of the heart. Only recently has the concept emerged that oxygen radicals could be a determinant of the degree of ischemic damage in the heart. Much of the work in the field has dealt with coronary reperfusion models since with coronary reperfusion following myocardial ischemia, oxygen is reintroduced into the system. While the following papers concentrate on basic science studies, the concept that oxygen radicals may be deleterious has important clinical implications in situations of myocardial ischemia followed by reperfusion. First of all, it is clear that coronary reperfusion in the setting of acute myocardial infarction is feasible in man--interventions such as tissue plasminogen activator, streptokinase, and percutaneous transluminal
*This paper was presented at a symposiumentitled "The Role of Oxygen Free Radicals in Myocardial Ischemia." The symposium took place on March 30, 1987, in Washington, DC, U.S.A., as part of the 71st Annual Meeting of the Federation of AmericanSocieties for Experimental Biology (FASEB). The symposiumwas organized by Dr. Robert A. Kloner, under the auspices of the AmericanPhysiological Society (APS).
angioplasty have been shown to successfully reestablish coronary flow in humans during evolving myocardial infarction. ~-3 Coronary occlusion-reperfusion sequences also occur during coronary angioplasty and in patients with angina due to coronary vasospasm. In addition, ischemia-reperfusion sequences are relevant to thoracic patients undergoing cardiopulmonary bypass. Finally, oxygen radical scavengers are available to treat potential damage of oxygen-free radicals, such as superoxide dismutase and catalase.
CORONARY REPERFUSION FOR ACUTE MYOCARDIAL INFARCTION
It is known from both experimentaP '5 and clinical studies 6'7 that early coronary reperfusion reduces acute myocardial infarct size. Some clinical trials suggest that early coronary reperfusion (thrombolysis) reduces mortality. 1 While there is no question that overall, early coronary reperfusion is beneficial, there are some potentially negative aspects of reperfusion which have been documented, as shown in Table 1. There has been a fair amount of debate concerning the meaning of the term "reperfusion injury" in the setting of coronary reperfusion as a treatment for acute myocardial infarction. The term has had different meanings fork different investigators. In my opinion, the term "reperfusion injury" should be strictly de-
R. A. KLONER Table 1. Potential Negative Aspects of Coronary Reperfusion in Evolving Acute Myocardial Infarction 1) Explosive cell swelling: refers to marked cellular edema, increase in tissue H~O, Na, and Ca + - into irreversibly injured cells which are reperfused. 2) lntramyocardial hemorrhage (in our experience this is usually confined to zones of myocardium already irreversibly injured). 3) Arrhythmias: reperfusion arrhythmias are usually ventricular, including ventricular tachycardia, ventricular premature beats, accelerated idioventricular rhythm, ventricular fibrillation. 4) No-reflow phenomenon: refers to the inability to reperfuse zones of myocardium which were previously ischemic, following removal of epicardial coronary artery occlusion, resulting in severe reductions in flow in the post-ischemic tissue. 5) Low-reflow phenomenon: refers to mild to moderate reductions in flow to previously ischemic tissue following removal of epicardial coronary artery occlusion. 6) Stunned myocardium: refers to relatively prolonged functional derangement of post-ischemic myocardium salvaged by reperfusion. 7) Reperfusion injury: refers to myocardial cell death caused by the act of reperfusion per se.
fined as injury due to the act of reperfusion itself, in which cells reversibly injured at the end of ischemia become irreversibly injured upon reperfusion. There are a few studies utilizing in vivo models of myocardial ischemia and reperfusion that suggest that "reperfusion injury" exists and is amenable to treatment. Two of these studies by Jolly et al. 8 and Ambrosia et al. 9 showed that when oxygen radical scavengers were given during reperfusion alone, there was a reduction in myocardial infarct size, presumably by preventing "reperfusion injury." Therefore, it has been postulated that oxygen radicals are important mediators of so-called "reperfusion injury." However, not all studies assessing myocardial infarct size in occlusion-reperfusion models, in which oxygen radicals were given, have been positive.l°'~l Thus, several controversies exist regarding the role of oxygen-free radicals in mediating damage during ischemia-reperfusion in the heart. Do oxygen radical scavengers truly reduce myocardial infarct size? If they do, is this a permanent effect or merely a delay in the development of necrosis? Where are the oxygen radicals coming from--xanthine oxidase? neutrophils? mitochondria? Where are the free radical scavengers working--the endothelium? the interstitium? The following symposium manuscripts will address some of these issues as well as other recent advances regarding the role of oxygen radicals in myocardial ischemia and coronary reperfusion. The first manuscript, by Dr. Joe McCord, provides an overview of our current understanding of the biochemistry of free radicals in the setting of ischemia. Dr. Karen Burton then demonstrates direct evidence of toxic effects of oxygen radicals on myocardium, using an in vitro ventricular septal preparation. The effect of oxygen radical scavengers on myocardial infarct size and recent controversies concerning these studies are discussed by Dr. James Downey. Dr. Steven Werns presents data regarding oxygen radicals in relationship to the white blood cells. Oxygen radicals and the stunned myocar-
dium are discussed by Dr. Karin Przyklenk. The important role that oxygen radicals might have during cardiac surgery is presented by Dr. Timothy Gardner. As will become obvious upon reading the proceedings of this symposium, not all controversies regarding the role of oxygen radicals in the setting of myocardial ischemia and reperfusion have been resolved. It is likely that work in this field will continue for several years to come. Nevertheless, the proceedings of this symposium should provide a useful update on recent advances in this field.
REFERENCES
1. Patel, B.; Kloner, R. A. Analysis of reported randomized trials of streptokinase therapy for acute myocardial infarction in the 1980s. Am. J. Cardiol. 59:501-504; 1987. 2. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial: phase I findings. N. Engl. J. Med. 312:932-936; 1985. 3. O'Neill, W.; Timmis, G.; Bourdillon, P.; Lai, P.; Ganghadarhan, V.; Walton, J.; Ramos, R.; Laufer, N.; Gordon, S.; Schork, M. A.; Pitt, B. A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty therapy of acute myocardial infarction. N. Engl. J. Med. 314:812-828; 1986. 4. Reimer, K. A.; Lowe, J. E.; Rasmussen, M. M.; Jennings, R. B. The wavefront phenomenon of ischemic cell death. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 56:786-793; 1977. 5. Ellis, S. G.; Wynne, J.; Braunwald, E.; Henschke, C. I.; Sandor, T.; Kloner, R. A. Response of reperfusion salvaged stunned myocardium to inotropic stimulation. Am. Heart J. 107:13-19; 1984. 6. Markis, J. E.; Malagold, M.; Parker, J. A.; Silverman, K. J.; Barry, W. H.; Als, A. V.; Paulin, S.; Grossman, W.; Braunwald, E. Myocardial salvage after intracoronary thrombolysis with streptokinase in acute myocardial infarction. N. Engl. J. Med. 305:777-782; 1981. 7. Anderson, J. L.; Marshall, H. W.; Bray, B. E.; Lutz, J. R.; Frederick, P. R.; Yanowitz, F. G.; Datz, F. I.; Klausner, S. C.; Hagan, A. D. A randomized trial of intra-coronary streptokinase in the treatment of acute myocardial infarction. N. Eng. J. Med. 308:1312-1318; 1983. 8. Jolly, S. R.; Kane, W. J.; Baile, M. B.; Abrams, G. D.; Lucchesi, B. R. Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circ. Res. 54:277-285; 1984.
Oxygen radicals & myocardial ischemia/infarction 9. Ambrosio, G.; Becker, L. C.; Hutchins, G. M.; Weisman, H. E; Weisfeldt, M. L. Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of repeffusion injury. Circulation 74:14241433; 1986. 10. Reimer, K. A.; Jennings, R. B. Failure of xanthine oxidase
7
inhibitor allopurinol to limit infarct size after ischemia and repeffusion in dogs. Circulation 71:1069-1075; 1985. 11. Gallagher, K. P.; Buda, A. J.; Pace, D.; Gerren, R. A.; Shtafer, M. Failure of superoxide dismutase and catalase to alter size of infarction in conscious dogs after 3 hours of occlusion followed by repeffusion. Circulation 73:1065-1076; 1986.
0891-5849/88 $3.00+ .00 © 1988PergamonJournalsLtd.
Printed in the USA. All fightsreserved.
Conference Proceedings INTRODUCTION TO MYOCARDIAL
THE ROLE OF OXYGEN RADICALS ISCHEMIA AND INFARCTION*
IN
ROBERT A. KLONER Department of Internal Medicine, Division of Cardiology, Harper-GraceHospital, Wayne State University, 3990 John R., Detroit, MI 48201, U.S,A. (Received 20 May 1987)
Abstract--There has been considerable interest over the past several years concerning the role of oxygen radicals in myocardial ischemia-reperfusion injury. The purpose of the following symposium will be to review recent advances in the understanding of oxygen free radical damage to the heart. Included in the symposium are descriptions of the biochemistry of free radicals and evidence of their direct toxic effects on the heart, as well as discussions concerning the effect of oxygen free radical scavengers on myocardial infarct size, the stunned myocardium, and cardiac preservation during surgery. Keywords--Oxygen radicals, Free radicals, Oxidants, Coronary repeffusion, Reperfusion injury, Myocardial ischemia, Myocardial infarction
Over the past 3 - 5 years there has been a growing interest in the concept that oxygen radicals play a role in the pathogenesis of myocardial ischemia and infarction. Up until about 5 years ago, it was generally held that the determinants of the degree of ischemic damage following a coronary occlusion were simply the oxygen supply versus the oxygen demand of the heart. Only recently has the concept emerged that oxygen radicals could be a determinant of the degree of ischemic damage in the heart. Much of the work in the field has dealt with coronary reperfusion models since with coronary reperfusion following myocardial ischemia, oxygen is reintroduced into the system. While the following papers concentrate on basic science studies, the concept that oxygen radicals may be deleterious has important clinical implications in situations of myocardial ischemia followed by reperfusion. First of all, it is clear that coronary reperfusion in the setting of acute myocardial infarction is feasible in man--interventions such as tissue plasminogen activator, streptokinase, and percutaneous transluminal
*This paper was presented at a symposiumentitled "The Role of Oxygen Free Radicals in Myocardial Ischemia." The symposium took place on March 30, 1987, in Washington, DC, U.S.A., as part of the 71st Annual Meeting of the Federation of AmericanSocieties for Experimental Biology (FASEB). The symposiumwas organized by Dr. Robert A. Kloner, under the auspices of the AmericanPhysiological Society (APS).
angioplasty have been shown to successfully reestablish coronary flow in humans during evolving myocardial infarction. ~-3 Coronary occlusion-reperfusion sequences also occur during coronary angioplasty and in patients with angina due to coronary vasospasm. In addition, ischemia-reperfusion sequences are relevant to thoracic patients undergoing cardiopulmonary bypass. Finally, oxygen radical scavengers are available to treat potential damage of oxygen-free radicals, such as superoxide dismutase and catalase.
CORONARY REPERFUSION FOR ACUTE MYOCARDIAL INFARCTION
It is known from both experimentaP '5 and clinical studies 6'7 that early coronary reperfusion reduces acute myocardial infarct size. Some clinical trials suggest that early coronary reperfusion (thrombolysis) reduces mortality. 1 While there is no question that overall, early coronary reperfusion is beneficial, there are some potentially negative aspects of reperfusion which have been documented, as shown in Table 1. There has been a fair amount of debate concerning the meaning of the term "reperfusion injury" in the setting of coronary reperfusion as a treatment for acute myocardial infarction. The term has had different meanings fork different investigators. In my opinion, the term "reperfusion injury" should be strictly de-
R. A. KLONER Table 1. Potential Negative Aspects of Coronary Reperfusion in Evolving Acute Myocardial Infarction 1) Explosive cell swelling: refers to marked cellular edema, increase in tissue H~O, Na, and Ca + - into irreversibly injured cells which are reperfused. 2) lntramyocardial hemorrhage (in our experience this is usually confined to zones of myocardium already irreversibly injured). 3) Arrhythmias: reperfusion arrhythmias are usually ventricular, including ventricular tachycardia, ventricular premature beats, accelerated idioventricular rhythm, ventricular fibrillation. 4) No-reflow phenomenon: refers to the inability to reperfuse zones of myocardium which were previously ischemic, following removal of epicardial coronary artery occlusion, resulting in severe reductions in flow in the post-ischemic tissue. 5) Low-reflow phenomenon: refers to mild to moderate reductions in flow to previously ischemic tissue following removal of epicardial coronary artery occlusion. 6) Stunned myocardium: refers to relatively prolonged functional derangement of post-ischemic myocardium salvaged by reperfusion. 7) Reperfusion injury: refers to myocardial cell death caused by the act of reperfusion per se.
fined as injury due to the act of reperfusion itself, in which cells reversibly injured at the end of ischemia become irreversibly injured upon reperfusion. There are a few studies utilizing in vivo models of myocardial ischemia and reperfusion that suggest that "reperfusion injury" exists and is amenable to treatment. Two of these studies by Jolly et al. 8 and Ambrosia et al. 9 showed that when oxygen radical scavengers were given during reperfusion alone, there was a reduction in myocardial infarct size, presumably by preventing "reperfusion injury." Therefore, it has been postulated that oxygen radicals are important mediators of so-called "reperfusion injury." However, not all studies assessing myocardial infarct size in occlusion-reperfusion models, in which oxygen radicals were given, have been positive.l°'~l Thus, several controversies exist regarding the role of oxygen-free radicals in mediating damage during ischemia-reperfusion in the heart. Do oxygen radical scavengers truly reduce myocardial infarct size? If they do, is this a permanent effect or merely a delay in the development of necrosis? Where are the oxygen radicals coming from--xanthine oxidase? neutrophils? mitochondria? Where are the free radical scavengers working--the endothelium? the interstitium? The following symposium manuscripts will address some of these issues as well as other recent advances regarding the role of oxygen radicals in myocardial ischemia and coronary reperfusion. The first manuscript, by Dr. Joe McCord, provides an overview of our current understanding of the biochemistry of free radicals in the setting of ischemia. Dr. Karen Burton then demonstrates direct evidence of toxic effects of oxygen radicals on myocardium, using an in vitro ventricular septal preparation. The effect of oxygen radical scavengers on myocardial infarct size and recent controversies concerning these studies are discussed by Dr. James Downey. Dr. Steven Werns presents data regarding oxygen radicals in relationship to the white blood cells. Oxygen radicals and the stunned myocar-
dium are discussed by Dr. Karin Przyklenk. The important role that oxygen radicals might have during cardiac surgery is presented by Dr. Timothy Gardner. As will become obvious upon reading the proceedings of this symposium, not all controversies regarding the role of oxygen radicals in the setting of myocardial ischemia and reperfusion have been resolved. It is likely that work in this field will continue for several years to come. Nevertheless, the proceedings of this symposium should provide a useful update on recent advances in this field.
REFERENCES
1. Patel, B.; Kloner, R. A. Analysis of reported randomized trials of streptokinase therapy for acute myocardial infarction in the 1980s. Am. J. Cardiol. 59:501-504; 1987. 2. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial: phase I findings. N. Engl. J. Med. 312:932-936; 1985. 3. O'Neill, W.; Timmis, G.; Bourdillon, P.; Lai, P.; Ganghadarhan, V.; Walton, J.; Ramos, R.; Laufer, N.; Gordon, S.; Schork, M. A.; Pitt, B. A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty therapy of acute myocardial infarction. N. Engl. J. Med. 314:812-828; 1986. 4. Reimer, K. A.; Lowe, J. E.; Rasmussen, M. M.; Jennings, R. B. The wavefront phenomenon of ischemic cell death. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 56:786-793; 1977. 5. Ellis, S. G.; Wynne, J.; Braunwald, E.; Henschke, C. I.; Sandor, T.; Kloner, R. A. Response of reperfusion salvaged stunned myocardium to inotropic stimulation. Am. Heart J. 107:13-19; 1984. 6. Markis, J. E.; Malagold, M.; Parker, J. A.; Silverman, K. J.; Barry, W. H.; Als, A. V.; Paulin, S.; Grossman, W.; Braunwald, E. Myocardial salvage after intracoronary thrombolysis with streptokinase in acute myocardial infarction. N. Engl. J. Med. 305:777-782; 1981. 7. Anderson, J. L.; Marshall, H. W.; Bray, B. E.; Lutz, J. R.; Frederick, P. R.; Yanowitz, F. G.; Datz, F. I.; Klausner, S. C.; Hagan, A. D. A randomized trial of intra-coronary streptokinase in the treatment of acute myocardial infarction. N. Eng. J. Med. 308:1312-1318; 1983. 8. Jolly, S. R.; Kane, W. J.; Baile, M. B.; Abrams, G. D.; Lucchesi, B. R. Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circ. Res. 54:277-285; 1984.
Oxygen radicals & myocardial ischemia/infarction 9. Ambrosio, G.; Becker, L. C.; Hutchins, G. M.; Weisman, H. E; Weisfeldt, M. L. Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of repeffusion injury. Circulation 74:14241433; 1986. 10. Reimer, K. A.; Jennings, R. B. Failure of xanthine oxidase
7
inhibitor allopurinol to limit infarct size after ischemia and repeffusion in dogs. Circulation 71:1069-1075; 1985. 11. Gallagher, K. P.; Buda, A. J.; Pace, D.; Gerren, R. A.; Shtafer, M. Failure of superoxide dismutase and catalase to alter size of infarction in conscious dogs after 3 hours of occlusion followed by repeffusion. Circulation 73:1065-1076; 1986.