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To reperfuse or not to reperfuse, which is the question?
j Mol Cell Cardio120, 367-369 (1988)
EDITORIAL To R e p e r f u s e or n o t to R e p e r f u s e , W h i c h is t h e Q u e s t i o n ? (Received30 December 1987, acceptedin revisedform 11 January 1988)
The current revolution in the treatment of acute myocardial infarction by means of thrombolytic therapy has as its underlying strategy three aims: early restoration of the bloodflow in order to salvage jeopardized but still viable tissues, limitation of the ultimate infarct size, and preservation, as far as possible, of ventricular function. The hope is further that these three achievements will result in reduced short and long term mortality rates. The techniques employed in this overall strategy are still under investigation: three leading pharmacological compounds vie for supremacy; streptokinase as well as its anisoylated form (APSAC), recombinant technique tissue type, plasminogen activator (rt-PA) and urokinase (UK) with or without pro-urokinase (PUK). In addition the underlying anatomy may require early, or delayed, coronary angioplasty where needed, backed by coronary artery bypass grafting. Thus the tactics of the intervention may vary from case to case and indeed from center to center depending on experience and facilities, but the strategy is clearly the same : early reperfusion is a must if one wishes to save ischemic but viable tissue. Extensive theoretical work in the recent past by a number of highly competent investigators has pointed towards the potential damage that may he caused by attempts at reperfusion. This damage depends in its extent on the interval between the interruption of blood supply and the return of perfusion, on the extent of muscle involved, and on the functional state and requirements of the myocardium immediately preceding the occlusion of the involved coronary artery. Furthermore, in the various animal models which have been studied, quite varying condi0022-2828/88/040367 + 03 $03.00/0
tions have prevailed so that conclusions from the experimental laboratory cannot necessarily be extrapolated to the clinic (Fig. 1). Factors such as the availability of pre-existing collaterals, an assessment very difficult to make in the human heart under acute circumstances, variations in the anatomical layout of the coronary artery system, the degree of afterload and heart rate are all of major importance as to the ultimate outcome of the balance between non-perfusion and reperfusion. It is therefore readily understood why on the one hand authors such as Reimer et al. (1977) state the minimum period of interruption of blood supply to be less than 1 h before irrepairable damage has occurred, whilst clinical evidence from major trials such as The Netherlands Interuniversitary Institute Trial (Hugenholtz, 1987), G I S S I (1986) and I S I S - I I (1987) indicate that major benefit can accrue provided the restoration of the bloodflow takes place within the first 4 h of symptoms. Similar data have been reported from the USA, France, Germany and Israel, and each time the striking feature is that those patients who achieved effective recanalization within 2 h fared much better than those in whom the therapy was instituted between the second and the fourth hour or later (Fig. 2). Although experiments in the dog have earlier shown that beyond the critical period of 60 rain severe contraction band damage and other signs of irreversibility will occur, other experimental models demonstrated such damage to be significant in terms of loss of metabolic activity after the second to third hour (Bergmann et al., 1982). It is attractive therefore to postulate that the extent of reperfusion damage that might negate the benefi9 1988 Academic Press Limited
368
P.G. Hugenholtz I O0
-
9
.,.o
~o
/~f'~ 80
9 ~o]
II
Homosap/en,
Z l
.
0
2 5 4 5 Ourotion of occlusion followed by reperfusion (h)
6
F I G U R E 1. T h e interval between interruption of coronary flow and the extent of limitation of infarct size [modified from the data by Schaper (1983)]. Myocardial infarct size depends on the species studied. Note that h u m a n s have a declining yield when more than 2 h have elapsed since interruption of blood supply. If we were to suppose that thrombolysis would occur 30 min earlier when given at home or in the ambulance, the ultimate infarct size could be limited by a further 15%. A, Rabbit; O , p i g ; O , d o g ; ~ , c a t ; [],guinea-pig.
cial effects of early reperfusion need not be of major importance in the human heart, provided that reperfusion is achieved within the first 2 h. An interesting example of this may be the fact that reperfusion arrhythmias, frequently seen in animal models and cited as an example of the dangers of reperfusion, are significantly less often seen in those humans who are subjected to early reperfusion (Simoons et al., 1985). In contrast, when reperfusion is achieved between the second and fourth hour, all other circumstances being equal, it is possible that the extent of reperfusion damage is considerably increased, thereby negating part
of the benefits of the reperfusion strategy. This may explain the declining benefits in terms of infarct size and tissue salvage as time elapses (Fig. 2). Any later reperfusion efforts may actually be associated with so much reperfusiGn damage that the opposite of the desired intervention is achieved. In fact several trials such as G I S S I (1986) show an increased mortality when therapy is commenced late. In those patients in whom reperfusion is only possible after a prolonged coronary occlusive interval, additional tactics present themselves: the use of various agents that could bind the unwanted metabolites or at
~z
I
,
I I?
60
J2o
min
rain
~ I I ~ ~ / / O m V
~.'~ee~
fso
rain Dr
Time from onset of symptoms to admission F I G U R E 2. T h e predicted limitation of infarct size by a strategy designed to produce early thrombolysis will be the more favourable the earlier the strategy is initiated. This applies predominantly to the larger infarcts. HBDH ~ alfahydroxybutyrate dehydrogenase. Modified from the data by Vermeer et al. (1986).
The Reperfusion Dilemma least c o n t r o l t h e i r n e g a t i v e i n f l u e n c e on the s u r r o u n d i n g m a r g i n a l m y o c y t e . O t h e r substances are beta-blockers, or Ca 2 + antagonists which, provided they are " o n b o a r d " w h e n t h e i s c h e m i c e p i s o d e occurs, m i g h t e x e r t a p r o t e c t i v e a c t i o n o n the excess of a d r e n e r g i c substances or on the cell m e m b r a n e itself, a v o i d i n g c a l c i u m o v e r l o a d i n g . S u c h substances are n o w b e i n g tried in several centers in c o n j u n c t i o n w i t h t h r o m b o l y t i c t h e r a p y ; their a d m i n i s t r a t i o n will r e q u i r e v e r y careful t i m i n g in o r d e r to p r o v e their effectiveness, a m a t t e r difficult to a s c e r t a i n u n d e r clinical c i r c u m s t a n c e s . U n t i l these agents a r e p r o v e n to be o f use, it w o u l d seem t h a t o n l y r a r e l y a n i n d i c a t i o n exists w h e r e r e p e r f u s i o n s h o u l d be s t a r t e d b e y o n d the
369
f o u r t h to fifth h o u r , one c l e a r e x c e p t i o n b e i n g the p a t i e n t in w h o m a n o t h e r a r e a o f m y o c a r d i u m has m a n i f e s t l y b e c o m e a n e w risk. T h e q u e s t i o n posed in the title of this editorial t h e r e f o r e should be a n s w e r e d in the positive, p r o v i d e d the i n d i c a t e d i n t e r v a l s are meticulously observed. Reperfusion damage can be i g n o r e d p r o v i d e d r e p e r f u s i o n starts early enough.
P. G. H u g e n h o l t z
Professor of Cardiology, Thoraxcenter B D 408, University Hospital, Erasmus University Rotterdam P.O. Box 1738, 3000 D R Rotterdam, The Netherlands
References BERGMANNSR, LERCHRA, Fox, FAA, LUDBROOKPA, WELCHMJ, TER POGOSSIANMM, SOBELBE (1982) Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. AmJ Med 72 : 1 9. GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarcto myocardico) Tognoni F, Rovelli F, et al., (1986) Effectiveness of intravenous thromolytic therapy in acute myocardial infarction. Lancet 1 : 397 402. HUGENHOLTZ PG (1987) Acute coronary artery obstruction in myocardial infarction: overview of thrombolytic therapy. J Am Coll Cardiol 9 : 1375-84. HU6ENHOLTZPG, RENTROVP (1982) Thrombolytic therapy for acute myocardial infarction: quo vadis ? Eur Heart 3: 395-403. ISIS (International Studies of Infarct Survival) Pilot Study Investigator (1987) Randomized factorial trial of high-dose intravenous streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction. Eur Heart J 8: 634-642. REIMERKA, LowEJRE, RASMUSSENMM, et al. (1977) The wavefront phenomenon ofischemic cell death. Myocardial infarct size versus duration of coronary artery occlusion in dogs. Circulation56:786 794. SCHAPERW (1983) Natural defense mechanisms to ischemia. Eur HeartJ 4 [Suppl D] : 73-78. SIMOONSML, VAN DEN BRANDM, DE ZWAANC, VERHEUGTFWA, REMMEWJ, SERRUYSPW, BXR F, REs, J, KRAUSS XH, VERMEERF, LUBSENJ (1985) Improved survival after early thrombolysis in acute myocardial infarction. Lancet 1 : 578 82. VERMEERF, SIMOONSML, B.~R, FW, TmJSSENJGP, VAN DOMBURORT, SERRUYSPW, VERHEUGTFWA, REs j c j , DE ZWAANC, VAN r)ER LAARS~A, KRAUSSXH, LU~SENJ,HUOENHOLTZPG (1986) Which patients benefit most from early thrombolytic therapy with intracoronary streptokinase? Circulation 74: 137~1389.
EDITORIAL To R e p e r f u s e or n o t to R e p e r f u s e , W h i c h is t h e Q u e s t i o n ? (Received30 December 1987, acceptedin revisedform 11 January 1988)
The current revolution in the treatment of acute myocardial infarction by means of thrombolytic therapy has as its underlying strategy three aims: early restoration of the bloodflow in order to salvage jeopardized but still viable tissues, limitation of the ultimate infarct size, and preservation, as far as possible, of ventricular function. The hope is further that these three achievements will result in reduced short and long term mortality rates. The techniques employed in this overall strategy are still under investigation: three leading pharmacological compounds vie for supremacy; streptokinase as well as its anisoylated form (APSAC), recombinant technique tissue type, plasminogen activator (rt-PA) and urokinase (UK) with or without pro-urokinase (PUK). In addition the underlying anatomy may require early, or delayed, coronary angioplasty where needed, backed by coronary artery bypass grafting. Thus the tactics of the intervention may vary from case to case and indeed from center to center depending on experience and facilities, but the strategy is clearly the same : early reperfusion is a must if one wishes to save ischemic but viable tissue. Extensive theoretical work in the recent past by a number of highly competent investigators has pointed towards the potential damage that may he caused by attempts at reperfusion. This damage depends in its extent on the interval between the interruption of blood supply and the return of perfusion, on the extent of muscle involved, and on the functional state and requirements of the myocardium immediately preceding the occlusion of the involved coronary artery. Furthermore, in the various animal models which have been studied, quite varying condi0022-2828/88/040367 + 03 $03.00/0
tions have prevailed so that conclusions from the experimental laboratory cannot necessarily be extrapolated to the clinic (Fig. 1). Factors such as the availability of pre-existing collaterals, an assessment very difficult to make in the human heart under acute circumstances, variations in the anatomical layout of the coronary artery system, the degree of afterload and heart rate are all of major importance as to the ultimate outcome of the balance between non-perfusion and reperfusion. It is therefore readily understood why on the one hand authors such as Reimer et al. (1977) state the minimum period of interruption of blood supply to be less than 1 h before irrepairable damage has occurred, whilst clinical evidence from major trials such as The Netherlands Interuniversitary Institute Trial (Hugenholtz, 1987), G I S S I (1986) and I S I S - I I (1987) indicate that major benefit can accrue provided the restoration of the bloodflow takes place within the first 4 h of symptoms. Similar data have been reported from the USA, France, Germany and Israel, and each time the striking feature is that those patients who achieved effective recanalization within 2 h fared much better than those in whom the therapy was instituted between the second and the fourth hour or later (Fig. 2). Although experiments in the dog have earlier shown that beyond the critical period of 60 rain severe contraction band damage and other signs of irreversibility will occur, other experimental models demonstrated such damage to be significant in terms of loss of metabolic activity after the second to third hour (Bergmann et al., 1982). It is attractive therefore to postulate that the extent of reperfusion damage that might negate the benefi9 1988 Academic Press Limited
368
P.G. Hugenholtz I O0
-
9
.,.o
~o
/~f'~ 80
9 ~o]
II
Homosap/en,
Z l
.
0
2 5 4 5 Ourotion of occlusion followed by reperfusion (h)
6
F I G U R E 1. T h e interval between interruption of coronary flow and the extent of limitation of infarct size [modified from the data by Schaper (1983)]. Myocardial infarct size depends on the species studied. Note that h u m a n s have a declining yield when more than 2 h have elapsed since interruption of blood supply. If we were to suppose that thrombolysis would occur 30 min earlier when given at home or in the ambulance, the ultimate infarct size could be limited by a further 15%. A, Rabbit; O , p i g ; O , d o g ; ~ , c a t ; [],guinea-pig.
cial effects of early reperfusion need not be of major importance in the human heart, provided that reperfusion is achieved within the first 2 h. An interesting example of this may be the fact that reperfusion arrhythmias, frequently seen in animal models and cited as an example of the dangers of reperfusion, are significantly less often seen in those humans who are subjected to early reperfusion (Simoons et al., 1985). In contrast, when reperfusion is achieved between the second and fourth hour, all other circumstances being equal, it is possible that the extent of reperfusion damage is considerably increased, thereby negating part
of the benefits of the reperfusion strategy. This may explain the declining benefits in terms of infarct size and tissue salvage as time elapses (Fig. 2). Any later reperfusion efforts may actually be associated with so much reperfusiGn damage that the opposite of the desired intervention is achieved. In fact several trials such as G I S S I (1986) show an increased mortality when therapy is commenced late. In those patients in whom reperfusion is only possible after a prolonged coronary occlusive interval, additional tactics present themselves: the use of various agents that could bind the unwanted metabolites or at
~z
I
,
I I?
60
J2o
min
rain
~ I I ~ ~ / / O m V
~.'~ee~
fso
rain Dr
Time from onset of symptoms to admission F I G U R E 2. T h e predicted limitation of infarct size by a strategy designed to produce early thrombolysis will be the more favourable the earlier the strategy is initiated. This applies predominantly to the larger infarcts. HBDH ~ alfahydroxybutyrate dehydrogenase. Modified from the data by Vermeer et al. (1986).
The Reperfusion Dilemma least c o n t r o l t h e i r n e g a t i v e i n f l u e n c e on the s u r r o u n d i n g m a r g i n a l m y o c y t e . O t h e r substances are beta-blockers, or Ca 2 + antagonists which, provided they are " o n b o a r d " w h e n t h e i s c h e m i c e p i s o d e occurs, m i g h t e x e r t a p r o t e c t i v e a c t i o n o n the excess of a d r e n e r g i c substances or on the cell m e m b r a n e itself, a v o i d i n g c a l c i u m o v e r l o a d i n g . S u c h substances are n o w b e i n g tried in several centers in c o n j u n c t i o n w i t h t h r o m b o l y t i c t h e r a p y ; their a d m i n i s t r a t i o n will r e q u i r e v e r y careful t i m i n g in o r d e r to p r o v e their effectiveness, a m a t t e r difficult to a s c e r t a i n u n d e r clinical c i r c u m s t a n c e s . U n t i l these agents a r e p r o v e n to be o f use, it w o u l d seem t h a t o n l y r a r e l y a n i n d i c a t i o n exists w h e r e r e p e r f u s i o n s h o u l d be s t a r t e d b e y o n d the
369
f o u r t h to fifth h o u r , one c l e a r e x c e p t i o n b e i n g the p a t i e n t in w h o m a n o t h e r a r e a o f m y o c a r d i u m has m a n i f e s t l y b e c o m e a n e w risk. T h e q u e s t i o n posed in the title of this editorial t h e r e f o r e should be a n s w e r e d in the positive, p r o v i d e d the i n d i c a t e d i n t e r v a l s are meticulously observed. Reperfusion damage can be i g n o r e d p r o v i d e d r e p e r f u s i o n starts early enough.
P. G. H u g e n h o l t z
Professor of Cardiology, Thoraxcenter B D 408, University Hospital, Erasmus University Rotterdam P.O. Box 1738, 3000 D R Rotterdam, The Netherlands
References BERGMANNSR, LERCHRA, Fox, FAA, LUDBROOKPA, WELCHMJ, TER POGOSSIANMM, SOBELBE (1982) Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. AmJ Med 72 : 1 9. GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarcto myocardico) Tognoni F, Rovelli F, et al., (1986) Effectiveness of intravenous thromolytic therapy in acute myocardial infarction. Lancet 1 : 397 402. HUGENHOLTZ PG (1987) Acute coronary artery obstruction in myocardial infarction: overview of thrombolytic therapy. J Am Coll Cardiol 9 : 1375-84. HU6ENHOLTZPG, RENTROVP (1982) Thrombolytic therapy for acute myocardial infarction: quo vadis ? Eur Heart 3: 395-403. ISIS (International Studies of Infarct Survival) Pilot Study Investigator (1987) Randomized factorial trial of high-dose intravenous streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction. Eur Heart J 8: 634-642. REIMERKA, LowEJRE, RASMUSSENMM, et al. (1977) The wavefront phenomenon ofischemic cell death. Myocardial infarct size versus duration of coronary artery occlusion in dogs. Circulation56:786 794. SCHAPERW (1983) Natural defense mechanisms to ischemia. Eur HeartJ 4 [Suppl D] : 73-78. SIMOONSML, VAN DEN BRANDM, DE ZWAANC, VERHEUGTFWA, REMMEWJ, SERRUYSPW, BXR F, REs, J, KRAUSS XH, VERMEERF, LUBSENJ (1985) Improved survival after early thrombolysis in acute myocardial infarction. Lancet 1 : 578 82. VERMEERF, SIMOONSML, B.~R, FW, TmJSSENJGP, VAN DOMBURORT, SERRUYSPW, VERHEUGTFWA, REs j c j , DE ZWAANC, VAN r)ER LAARS~A, KRAUSSXH, LU~SENJ,HUOENHOLTZPG (1986) Which patients benefit most from early thrombolytic therapy with intracoronary streptokinase? Circulation 74: 137~1389.