Reduction of Infarct Size-A
Rational Aim?
R. R. Hope*, 8 . J. Scherlagt and R. Lazzara' From the Section of Cardiology, Veterans Administration Hospital and Department of Medicine, University of Miami School of Medicine, Miami, Florida
Keduction of myocardial infarction s i x has become an area of increasing involvement for both expcrimcntal and clinical cardiologists. The obvious aim of such studies is to salvage as much viable, and thereby potentially functional. myocardium as possible after acute myocardial infarction. It is known with reasonable certainty that critical amounts of left ventricular muscle involved in acute infarction result in left ventricular failure (20-251?,) and in cardiogenic shock (40",J. Amsterdam' has summarized recent studies in this field. Reduction of infarct size by various manoeuvres in both experimental and clinical situations attests in general to improved left ventricular haemodynamic function.' Nevertheless, it should be remembered that ventricular arrhythmias are the major cause by far of death following acute myocardial i n f a r ~ t i o n . ~ ,Heart failure and cardiogenic shock form a considerably smaller- and perhaps decreasin&proportion of the complications of myocardial infarction. Techniques aimed at reduction of infarct si7e attempt to prevent "jeopardized" myocardium from becoming "blighted" myocardium.6 From the point of view of arrhythmias however, dead tissue may be safer than ischaemic tissue.' In those patients successfully resuscitated from primary ventricular fibrillation, a favourable prognosis is closely associated with the presence of a recent myocardial infarction. Patients showing no evidence of recent infarction are at high risk of further episodes of ventricular fibrillation and sudden ~ l e a t h . It~ .has ~ been proposed that an arrhythSupported in part by NIH Grant Number 1 R01 HL-18139 'Associate Professor of Medicine :Prolessor of Medicine Correspondence Dr R Hope University of Oklahoma Health Science Center P 0 BOX26901 Oklahoma City, Oklahoma 73 190 USA Accepted lor publication 16 October, 1978
mogcnic focus has been killed in those w i t h myocardial infarction but remains viable, irritable and potentially lethal in the non-infarciion patient.' This problem may be further illustrated by examining the differences between transmural and subendocardial infarction. It is widely accepted that transmural infarction almost always occurs in the prcscncc of arterial obstruction whereas subendocardial infarction usually occurs in the presence ofdiseased, though patent. In addition, this high coronary arteries.") frequency of occlusive coronary artery thrombosis (90",,) in association with transmural infarction is much less prominent (one-third of cases) in autopsies of patients after sudden cardiac death.13 If we arc to sustain the belief that reduction of infarct size is beneficial, it would seem wise to further investigate the apparent discrepancy between increased mortality and arrhythmias in subendocardial (smaller) versus transmural (larger) infarction. Prcvious workers have postulated that survivors of non-transmural infarction are prone to fatal arrhythmias and sudden death."-" Scheinman and Abbott when comparing transmural with subendocardial infarction found that overall mortality was related to the magnitude of enzyme changes." However, closer inspection of their data indicates that their patients (Group I ) with subendocardial infarction and enzyme levels comparable to those with transmural infarction (Group III), had exactly double the mortality of the transinural infarction patients. Even when transmural and subendocardial infarction are not separately discussed, the relationship of infarct size with subsequent ventricular arrhythmias is controversial.'"2' More recently, Cannom C t al. have clearly indicated the guarded prognosis of patients with non-transmural myocardial infarction.2h A
statistically significant greater than two-fold incidence of sudden death was seen in survivors of subendocardial versus transmural infarction over a 36 month follow-up period. In this study. high serum enzyme levels were associated with the transmural infarction patients and were not correlated with a poorer course after hospital discharge. It is unfortunate that some studies purporting to demonstrate a direct rclationship between infarct size and ventricular arrhythmia have completcly excluded subendocardial myocardial infarction paticnts". or have omitted this information."' 2 3 24 It is possible therefore that measures designed to reduce infarct size may prevent transmural infxrction but result in varying degrees of non-transmural infarction. Hacmodynainic complications of such infarction may be less than with transmural infarctions but the risks of arrhythmias and sudden death relatcd Lo ischacniia and electrophysiologic instability2' may be increased. An ischacmic area which fails to infarct may retain a triggcr zone for ventricular fibrillation.27 The recent experimental and clinical literature has been replete with studies whosc aim ~ v a sto reduce infarct size. The tacit assumption has been made but not well tested that by reducing infarct size, heart function (electrical and haemodynamic) must improve and that the converse rclation also holds true. To measure or quantify infarct size has thus become an end unto itself, viz.. S-T segment mapping, MB-CPK detei-mination and scintigraphic techniques. A critical factor for which it is difficult to account is the influence of infarcted (blighted) and ischacmic (jeopardized) tissues on cardiac arrhythmias. Othcr important determinants of arrhythmia incidence may also bc examined, such as s i x of the ischaemic area and degree of elcctrophysiological dysfunction ofjeopardized cells. Since the most frequent clinical effects of myocardial infarction involve arrhythmias, studies should provide a means to test the relationship between reduced or increased size of infarct or ischaemic zones on frequcncy and severity of cardiac rhythm disturbances. Specifically, it behooves
those who would reduce infarct size to determine whether or not interventions directed towards reducing infarct size may decrease or even increase the incidence of lethal ventricular arrh! thmias. References 7
3. 4.
. (i.. C'IIRISIII:. 1). and PrSSISCiTOX. C. (1977). Changing patterns ofmortalily of acute myocardial inlirction in a coronary c a n unit. B'if. nrrd. J. I . 795. SOMI..B. E. and SIIIXI.. W. I< (1973): Jeopardized. hlightrvl and nccrntic myocardium. Circirhrbn 47, 215. W.%RRES. J. V. (1974): Di si dolce mortc. It may be safer 10 he dead than alive. Circir/urion 50, 41 5 . HKV. R. S.. AI.VM~Y. 111. A . end Cons; c'. A. (1974): Sxv:ral at!cr resuscitalinn from out-or-hwpital ventricular librillation. Circululirirr 50. 1231. CCIHH. C. A,. HA~:M. R. S.. AIVAREZ. 111. S . and SCHAi;iTR. W. A. (197.5): Resuscitation from out-of-hospital ventricular fibrillation: Four years follow-up. Cirrwlurbn 51, 52 Suppl. 111. 113. MII.I.~:R. R. I).. Ik:a~~iiti.i.. H. 8. and EIIWAKIIS. J. E. (1951): Myixardial infarction s,ith and without acutecoronary occlusion, .4rrh. i r m m . M d .88, 597 __..
II
I2 13
14 15 16
17 18 19
20.
21.
22.
23. 24.
25. 26.
17.
BAROI.I)I, G (1971): Function;il morphology of the martomatic circulation in human cardiac p d t h o l o ~ .In: . Wincliuiml M o r p h o b , ~u~f rhu tkfirr. Methods and Achievements in Expcrimenral Pathology. Bajusz. E. and Jasmn G. (edr.). Bawl. Karpr. pp. 4311 473. M. W. R. (1975): Diseases of the coronary lh~it.~ . J. and RI)IWRTXOS. Hrorr. A. Porncrance and IM. Davics.(eds.), artcrics. In: l%r I'ir/liulug)~y~rhr Blackwell Scientific Publications. Oxford, London. 1:dinburgh. Yelhournc. SCI~WART~...C. I. and GERRITY, R. A. (1975): Analomical palhology ol' sudden unexpecrcd cardiac death. Circzrlufim 51. 52 Suppl. 111, I R . SAI.ISHI:KY, P.I:., CROSS. C. E. and RIMS, P. A. (19631:Acutu ivchcmia or inncr layers of ventricular wall. Arnrr. I h r 1 J. 66, 650. Ei.ioi. R. S and H m S i h w R . 1. W. (IY72): A unilicd concspl of thc pathophywlogy oi myocardial infarcrion and sudden death, Clic.vr 62,469. STIYLII:~.. B., Knrz, A. Y. and UOSOWI. E. (1973): Q-wave development in acute aubendwdrdial infarction, Ardr. inrern. .Med 131, 676. S r t l e n m s . M. Y. and AIIIUWT. J. A. (IY73). Clinical sigriilicancc of transmural versus nontransmural electrocardiographic changes in patients with actit? myocardial infarction. A m v . J. ,Wed. IS. 6n2. VISMARA,I.. A,, AltulaRllAM. E. A. and MASIOS. D. T. (1975): Relation of wntricular arrhythmias in the late hospital phase or acute myocardial inlhrclion to sudden dcalh aftcr hospital divchargc, Amrr. J. Mrd 59, 6. LAWRE. I). M.. Hit;ol?;s. M. R..GOI>M.nS..M. J.. 01.1Vl1:R. Y. I:..JI:I.IAY, D. A. and LXIEAI.II. R. W. ( 1968): \'mlricular fibrillation complicating acute myocardial Infarction. Lancer 2. 523. SIIGAI.~.. 1'. H.. Masr1.E. J. A., RWERS.W. J., MCDAEIEI..H. G., RCSSKLI., R. 0. JNR. and RA(XILY.C. E. (1977): Chmprison of ventricular arrhythmias to cnrymatic. hcmodynamic and angiopraphic estimation of myocardial infarct sizc. (.'/in. Nus. 25, 8A. Soiiiii. H. E.. ROIII:RTS. R., AYHLR. 11. I).. OI.IVI:R. A. C. and Cox, I. R . (19741: The influence or infarct size 011 wntricular dysrhythmia. Circslafiun 49, M suppi. 111. I in. ROBERTS,R., HUSAIE.A, AHME. H. U.,OLIVER, A. C.. COX. J. R. and Soni:i.. B. E. (1975): Relation betwcen infarct si7e and ventricular arrhythmia. Brir. tiporr J. 37, 1169. Cox. J. R.. ROFIERTS,R., AYHW. 11. D..OI.IVI:K. G. C. and SOHM., B. E. (1976): Relations between enzymatically estimated myocardial infarct size and early ventricular dysrhylhmia. Ciriululiuii 50 Suppl. 1, 150. RWSQVISI.N.and SJWRES.A. (1976):Vcntricular arrhythmiasthrcc weeks and one year allcr acuk mycrardial inParction. Brit. Hem/ J. 38. 532. . R. A R a n C A S ~J.. Rwo. P.. BOWERS.S.. STRAI'SS. ti, W .and En.B. (1975): Vcnlricular arrhythmias in the Idtc ].,ospiralpkdx ol'acutc myocardial inkction. Circii/rrtion 52, 1006. CAESOY. 1). S.. Llivu. W.and COHEK.I.. S. (1976):The short and long lerm prognnsis of paticnts with transmural and nontransmural myocardial infarction. Ammar. J . M P ~61, . 452. RAPAIWRT. E. (1974): Prchovpildl ventricular defihrillation. Niw EngL J . Y r d . 291, 3.58.
.
Rational Aim?
R. R. Hope*, 8 . J. Scherlagt and R. Lazzara' From the Section of Cardiology, Veterans Administration Hospital and Department of Medicine, University of Miami School of Medicine, Miami, Florida
Keduction of myocardial infarction s i x has become an area of increasing involvement for both expcrimcntal and clinical cardiologists. The obvious aim of such studies is to salvage as much viable, and thereby potentially functional. myocardium as possible after acute myocardial infarction. It is known with reasonable certainty that critical amounts of left ventricular muscle involved in acute infarction result in left ventricular failure (20-251?,) and in cardiogenic shock (40",J. Amsterdam' has summarized recent studies in this field. Reduction of infarct size by various manoeuvres in both experimental and clinical situations attests in general to improved left ventricular haemodynamic function.' Nevertheless, it should be remembered that ventricular arrhythmias are the major cause by far of death following acute myocardial i n f a r ~ t i o n . ~ ,Heart failure and cardiogenic shock form a considerably smaller- and perhaps decreasin&proportion of the complications of myocardial infarction. Techniques aimed at reduction of infarct si7e attempt to prevent "jeopardized" myocardium from becoming "blighted" myocardium.6 From the point of view of arrhythmias however, dead tissue may be safer than ischaemic tissue.' In those patients successfully resuscitated from primary ventricular fibrillation, a favourable prognosis is closely associated with the presence of a recent myocardial infarction. Patients showing no evidence of recent infarction are at high risk of further episodes of ventricular fibrillation and sudden ~ l e a t h . It~ .has ~ been proposed that an arrhythSupported in part by NIH Grant Number 1 R01 HL-18139 'Associate Professor of Medicine :Prolessor of Medicine Correspondence Dr R Hope University of Oklahoma Health Science Center P 0 BOX26901 Oklahoma City, Oklahoma 73 190 USA Accepted lor publication 16 October, 1978
mogcnic focus has been killed in those w i t h myocardial infarction but remains viable, irritable and potentially lethal in the non-infarciion patient.' This problem may be further illustrated by examining the differences between transmural and subendocardial infarction. It is widely accepted that transmural infarction almost always occurs in the prcscncc of arterial obstruction whereas subendocardial infarction usually occurs in the presence ofdiseased, though patent. In addition, this high coronary arteries.") frequency of occlusive coronary artery thrombosis (90",,) in association with transmural infarction is much less prominent (one-third of cases) in autopsies of patients after sudden cardiac death.13 If we arc to sustain the belief that reduction of infarct size is beneficial, it would seem wise to further investigate the apparent discrepancy between increased mortality and arrhythmias in subendocardial (smaller) versus transmural (larger) infarction. Prcvious workers have postulated that survivors of non-transmural infarction are prone to fatal arrhythmias and sudden death."-" Scheinman and Abbott when comparing transmural with subendocardial infarction found that overall mortality was related to the magnitude of enzyme changes." However, closer inspection of their data indicates that their patients (Group I ) with subendocardial infarction and enzyme levels comparable to those with transmural infarction (Group III), had exactly double the mortality of the transinural infarction patients. Even when transmural and subendocardial infarction are not separately discussed, the relationship of infarct size with subsequent ventricular arrhythmias is controversial.'"2' More recently, Cannom C t al. have clearly indicated the guarded prognosis of patients with non-transmural myocardial infarction.2h A
statistically significant greater than two-fold incidence of sudden death was seen in survivors of subendocardial versus transmural infarction over a 36 month follow-up period. In this study. high serum enzyme levels were associated with the transmural infarction patients and were not correlated with a poorer course after hospital discharge. It is unfortunate that some studies purporting to demonstrate a direct rclationship between infarct size and ventricular arrhythmia have completcly excluded subendocardial myocardial infarction paticnts". or have omitted this information."' 2 3 24 It is possible therefore that measures designed to reduce infarct size may prevent transmural infxrction but result in varying degrees of non-transmural infarction. Hacmodynainic complications of such infarction may be less than with transmural infarctions but the risks of arrhythmias and sudden death relatcd Lo ischacniia and electrophysiologic instability2' may be increased. An ischacmic area which fails to infarct may retain a triggcr zone for ventricular fibrillation.27 The recent experimental and clinical literature has been replete with studies whosc aim ~ v a sto reduce infarct size. The tacit assumption has been made but not well tested that by reducing infarct size, heart function (electrical and haemodynamic) must improve and that the converse rclation also holds true. To measure or quantify infarct size has thus become an end unto itself, viz.. S-T segment mapping, MB-CPK detei-mination and scintigraphic techniques. A critical factor for which it is difficult to account is the influence of infarcted (blighted) and ischacmic (jeopardized) tissues on cardiac arrhythmias. Othcr important determinants of arrhythmia incidence may also bc examined, such as s i x of the ischaemic area and degree of elcctrophysiological dysfunction ofjeopardized cells. Since the most frequent clinical effects of myocardial infarction involve arrhythmias, studies should provide a means to test the relationship between reduced or increased size of infarct or ischaemic zones on frequcncy and severity of cardiac rhythm disturbances. Specifically, it behooves
those who would reduce infarct size to determine whether or not interventions directed towards reducing infarct size may decrease or even increase the incidence of lethal ventricular arrh! thmias. References 7
3. 4.
. (i.. C'IIRISIII:. 1). and PrSSISCiTOX. C. (1977). Changing patterns ofmortalily of acute myocardial inlirction in a coronary c a n unit. B'if. nrrd. J. I . 795. SOMI..B. E. and SIIIXI.. W. I< (1973): Jeopardized. hlightrvl and nccrntic myocardium. Circirhrbn 47, 215. W.%RRES. J. V. (1974): Di si dolce mortc. It may be safer 10 he dead than alive. Circir/urion 50, 41 5 . HKV. R. S.. AI.VM~Y. 111. A . end Cons; c'. A. (1974): Sxv:ral at!cr resuscitalinn from out-or-hwpital ventricular librillation. Circululirirr 50. 1231. CCIHH. C. A,. HA~:M. R. S.. AIVAREZ. 111. S . and SCHAi;iTR. W. A. (197.5): Resuscitation from out-of-hospital ventricular fibrillation: Four years follow-up. Cirrwlurbn 51, 52 Suppl. 111. 113. MII.I.~:R. R. I).. Ik:a~~iiti.i.. H. 8. and EIIWAKIIS. J. E. (1951): Myixardial infarction s,ith and without acutecoronary occlusion, .4rrh. i r m m . M d .88, 597 __..
II
I2 13
14 15 16
17 18 19
20.
21.
22.
23. 24.
25. 26.
17.
BAROI.I)I, G (1971): Function;il morphology of the martomatic circulation in human cardiac p d t h o l o ~ .In: . Wincliuiml M o r p h o b , ~u~f rhu tkfirr. Methods and Achievements in Expcrimenral Pathology. Bajusz. E. and Jasmn G. (edr.). Bawl. Karpr. pp. 4311 473. M. W. R. (1975): Diseases of the coronary lh~it.~ . J. and RI)IWRTXOS. Hrorr. A. Porncrance and IM. Davics.(eds.), artcrics. In: l%r I'ir/liulug)~y~rhr Blackwell Scientific Publications. Oxford, London. 1:dinburgh. Yelhournc. SCI~WART~...C. I. and GERRITY, R. A. (1975): Analomical palhology ol' sudden unexpecrcd cardiac death. Circzrlufim 51. 52 Suppl. 111, I R . SAI.ISHI:KY, P.I:., CROSS. C. E. and RIMS, P. A. (19631:Acutu ivchcmia or inncr layers of ventricular wall. Arnrr. I h r 1 J. 66, 650. Ei.ioi. R. S and H m S i h w R . 1. W. (IY72): A unilicd concspl of thc pathophywlogy oi myocardial infarcrion and sudden death, Clic.vr 62,469. STIYLII:~.. B., Knrz, A. Y. and UOSOWI. E. (1973): Q-wave development in acute aubendwdrdial infarction, Ardr. inrern. .Med 131, 676. S r t l e n m s . M. Y. and AIIIUWT. J. A. (IY73). Clinical sigriilicancc of transmural versus nontransmural electrocardiographic changes in patients with actit? myocardial infarction. A m v . J. ,Wed. IS. 6n2. VISMARA,I.. A,, AltulaRllAM. E. A. and MASIOS. D. T. (1975): Relation of wntricular arrhythmias in the late hospital phase or acute myocardial inlhrclion to sudden dcalh aftcr hospital divchargc, Amrr. J. Mrd 59, 6. LAWRE. I). M.. Hit;ol?;s. M. R..GOI>M.nS..M. J.. 01.1Vl1:R. Y. I:..JI:I.IAY, D. A. and LXIEAI.II. R. W. ( 1968): \'mlricular fibrillation complicating acute myocardial Infarction. Lancer 2. 523. SIIGAI.~.. 1'. H.. Masr1.E. J. A., RWERS.W. J., MCDAEIEI..H. G., RCSSKLI., R. 0. JNR. and RA(XILY.C. E. (1977): Chmprison of ventricular arrhythmias to cnrymatic. hcmodynamic and angiopraphic estimation of myocardial infarct sizc. (.'/in. Nus. 25, 8A. Soiiiii. H. E.. ROIII:RTS. R., AYHLR. 11. I).. OI.IVI:R. A. C. and Cox, I. R . (19741: The influence or infarct size 011 wntricular dysrhythmia. Circslafiun 49, M suppi. 111. I in. ROBERTS,R., HUSAIE.A, AHME. H. U.,OLIVER, A. C.. COX. J. R. and Soni:i.. B. E. (1975): Relation betwcen infarct si7e and ventricular arrhythmia. Brir. tiporr J. 37, 1169. Cox. J. R.. ROFIERTS,R., AYHW. 11. D..OI.IVI:K. G. C. and SOHM., B. E. (1976): Relations between enzymatically estimated myocardial infarct size and early ventricular dysrhylhmia. Ciriululiuii 50 Suppl. 1, 150. RWSQVISI.N.and SJWRES.A. (1976):Vcntricular arrhythmiasthrcc weeks and one year allcr acuk mycrardial inParction. Brit. Hem/ J. 38. 532. . R. A R a n C A S ~J.. Rwo. P.. BOWERS.S.. STRAI'SS. ti, W .and En.B. (1975): Vcnlricular arrhythmias in the Idtc ].,ospiralpkdx ol'acutc myocardial inkction. Circii/rrtion 52, 1006. CAESOY. 1). S.. Llivu. W.and COHEK.I.. S. (1976):The short and long lerm prognnsis of paticnts with transmural and nontransmural myocardial infarction. Ammar. J . M P ~61, . 452. RAPAIWRT. E. (1974): Prchovpildl ventricular defihrillation. Niw EngL J . Y r d . 291, 3.58.
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