314
JACC Vol. 20, No. 2 August 1!392:314-6
tinued expansion of the infarct zone, expansion of the
ROBERT A. KLQNER, MD, PHD Los Angeles, Otliforniu
During the last 2 decades, the revolution in treating acute
myocardial infarction has largely originated from rhe concept that myocardial infarct size could be reduced by timely coronary artery reperfusion.Thrombolytic therapy has been shown (1) to reduce myocardialInfarct size and to improve left ventricular function and survival. In the late 1970sit became clear that postinfarction outcome is dependent on factors other than acute reduction of myocardiaiinfarct sine, an event that usually occurs within the 1st 24 h of coronary occlusion. Events occurring several days, weeks or perhaps even months after the initial coronary occlusion might ultimately determine patient outcome. Numerous studies (2-4) showed that topographic changes in the left ventricle after coronary occlusion could contribute to this outcome. Earlyinfarct expansionand left ventricular topographic changes. Within the 1st week of coronary artery occlusion the myocardialinfarct may exhibitthinningand stretchingof the necrotic myocytes (2,3)(Fig. 1).A recent study suggests (5)that early collagenbreakdownafter myocardialinfarction may contribute to the slippageof myocytes past each other. Early infarct expansion and left ventricular dilation occurring within the 1st week can be diagnosed by simple noninvasive techniques such as two-dimensional echocardiography (6). Patients with infarct expansion are prone to several deleterious clinicalcocsequences, includingcongestive heart failure, ventricular rupture, papillary muscle rupture, ventricular septal defect and death (3). Experimental studies (7,8) have shown that certain pharmacologicagents (steroids;some nonsteroid anti-inflammatoryagents, but not aspirin) can exacerbate myocardial infarct expansion. Beymd this early infarct expansion, continued topographic chadges may occur within the left ventricle (4). Smaller infarcts are likely to exhibit continued scar contraction. However, moderate-sizedto large infarcts may exhibit con*Editorialspublishedin Journalof /he AmericanCollegeof Cardiology reflectthe viewsof the authorsand do not necessarilyrepresentthe viewsof JACCor the AmericanCollegeof Cardioloa~. FmmTheHeartInstitute~Hospitalof the GoodSamaritanand Sectionof Cardiology,Universityof SouthernCalifornia,Los Angeles,California. BddressfolI. Robert A. Kloner, MD, PhD, The Heart Institite,ResearchDepartment, Hospitalof the GoodSara&m,616South
Witmer,LosAngeles,Califomia 90017.
01992by the AmericanCollegeof Cardiology
noninfarct zone with eccentric hypertropby, and regional and globalleft ventricular dilation (Fig. 1, A t ) (4,9,10).%+ ve~~~c~lar is now well accepted (IO) that the degree of dilation occurring after an acute myocardial infarction is an important predictor of death at 1 year. Those patients with dilated left ventricle are much more likely to die. The goo news is that this process of left ventricular remodeling does not occur instantly, can be diagnosed by noninvasive imaging (two-dimensionalechocardiography, radionuclide ventriculography, magnetic resonance imaging) and cam be treated. Unlike the decision to give thro which must be made rapidly and often u decision to try to reduce or prevent left ventricular remodeling can be made in a more systematic fashio appropriate noninvasive (or invasive) data have ered. Several studies (I l-15) have shown that lon apy with angiotensin-convertingenzyme inhibitors such as captopril, even when administered a few weeks after the initialmyocardialinfarction, can reduce the degree of postinfar&on left ventricular dilation (Fig. IG) (1l-15), improve exercise tolerance (12) and improve survival (13,14). Nitrates also have been shown to reduce infarct expansion (16). The mechanism by which these vasodilators are capable of preventing infarct expansion may be a reduction of wall stress by a reduction of preload or afterload, or both. We believe that the mechanism is unlikely to be a reduction in afterload alone, because calcium channel blockers do not seem to prevent infarct expansion in experimental models (17). In addition, it is conceivable that the tissue reninangiotensin system might be playing a role in modulating topographic alterations of the ventricle. The presentstudy. The study by Leung and Lau (18)in this issue of the Journal makes the important observation that in patients who received thrombolytic therapy, the degree of residual stenosis of the infarct-related artery before hospital discharge was a determinant of the degree of left ventriculardilation observed at 6 months and 1year after infarction. The study implies that another potential therapy for left ventricular dilation tier myocardial infarction may be angioplasty.The timing at which angioplasty would need to be performedin order to prevent or reduce left ventricular dilation is not clear. Obviously, early successful and sustained reperfusion by any means (thrombolysis or angioplasty) will lead to a smaller subendocardial infarct that is less likely to expand (Fig. 1E). However, even late reperfusiGn (too late to reduce infarct size) has been shown m experimental models to prevent infarct expansion and left ventricular dilation (Fig. 1F) (19,20).How late is too late remains to be determined. The mechanism wherety late reperfusion might reduce infmi expansion is uot known. Perhaps late reperfusion preserves a thin rim of epicardial myocardial cells or epicardial collagen that is enough to battle the infarct zone and prevent expansion. Another 0753097/92/$5.00
SACC Vd. 20, No. 2 August 1992314-6
monihs, continued left ventricular dilation occurs. The noninfarct as well as the infarct zone lengthens. Eccentric hypertrophy (with dilation disproportionate to ~y~e~ro~by) develops ch occurs with volume ov show potential therapy. Early re~e~~s~o~ (er) (thrombolysis or duces myocardial infarct size. The infarct h) after coronary occlusio a) is subendocardial with salvage of tissue in the subepicardium of the risk Infarct expansion does not occur. F, Late reperfusion (Ir) (tbrombolysis 0th) may result in a large infarct but experimental studies suggest rbat less left ventricular dilation and expansion occur with this t~~era~y. T e lesl;lts of Leung and Lau ne!s E and F, the less the residual stenosis, the less the (IS) imply (hat, for the situations in uld reduce the degree of degree of left ventricular dilation. ence, angioplasty (wh residual stenosis) might have a treatment advanlage over t o!ysis alone. Hearts With residual stenosis of the infarct-related artery but with ~e~e~~sion might have ventricular dilatioo. Also implied is that if reoccluintermediate degrees of prote sion occurs in the situationsh ei E or F (and the previou
no longer patent), left ventric Finally, the situationshown I (acei)can prevent or reduce the degree of left ventricular dilation after coronary artery occlusion. Nitrates can also prevent this left ventricular dilation. These agents may be especially useful in cases of moderate to large infarction in which initial attempts at reperf;lsiou were unsuccessfulor reocclusionoccurred after initiallysuccessfulreperfusion. Preliminarydata from the Survival and Ventricular Enlargement trial presented by Pfeffer el al. at the 1992 ACC Scientific Session suggestedthat long-term captopril therapy after infarction improved survival, reduced heart failure and reduced reinfarctionrates.
theory is that the turgor within the reperfused vasculature acts as an epicardial b d Lau (18) also im The study of Leun quality of reperfusion after acute myocardial infarction is important. The more complete and permanent the reperfusion and the less the residual stenosis of the infarct-related artery, the less chance that left ventricular dihtim will develop after infarction. Thus, angioplasty, which will reduce the degree of resadual coronary artery stenosis due to atherosclerosis, may be a better therapy than thrombolysis alone (which will not do this) for preventing topographic changes to the left ventricle. Presumably the angioplasty would not need to be performed in the acute phase of infarction. Conchsims. There are several points in the natural history of myocardial infarction at which the clinician may improve outcome (Fig. 1). Acute early reperfusion will reduce infarct size (Fig. 1E) and improve left ventricular iu;,cZiCIna;rJ Slrrkk2d.S.al,2Ue;y, k dile~~iou3 ccnsequences of progressive left ventricular dilation may be prevented by other interventions including angiotensinconverting enzyme inhibitors (Fig. lG), nitrates and now, as suggested by Leung and Lau (lg), possibly angioplasty. Clinical trials are needed to determine whether angioplasty after infarction will reduce the degree of ultimate left ventricular dilation to a greater extent than thrombolysis alone,
and to determine the time after infarction tha,r an Wrgratefully acknowledge the excellent typing skills
oi Cathy Davisson, who
helped prepare the manuscript.
I. Tiefenbrunn AJ.Clinicalbenefits of thrombolytic therapy in 2.
3.
4.
5. 6.
7.
8.
acute myocardial infarction. Am I Cardiol 1992;6933A-1 IA. Hutchins GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am 3 Cardiol 1978;41:1127-32, Weisman HF. Healy B. Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts. Prog Cardiovasc Dis 1987; 30:73-l 10. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation 19%81:1161-72. Whittaker P, Boughner DR, Kloner RA. Role of collagen in acute myocardial infarct expansion. Circulation 1991;84:2123-34. Eaton EW, Weiss JL, Bulkley BH, Garrison JB, Weisfeldt ML. Regiona! cardiac dilatation after acute myocardial infarction: recognition by twodimensional echocardiog,raphy. N Engl J Med 1979;300:57-62. Brown EJ Jr, Kloner RA, Schoen FJ, Hammerman H, Hal@ S, Braunwasd E. Scar thinning due to ibuprofen administration fallowiflg experimental myocardial ;yfarction. Am 3 Cardiol 1983;5 I :877-83. Hammerman H, Kloner RA, Hale 8, Schoen FJ, Braunwald E. Dosedependent effects of short term methylprednisoidne on myocardial infarct
316
9.
10.
II. 12.
13.
14.
KLONER EDITORII(L
JACC Vol. 20, No. 2 COMMENT
extent, scar formation and ventricular function. Circulation 1983;68:44652. McKay RG. Pfeffer MA, Pasternak RC, et al. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation 1986;74:693-702. White HD, Norris RM. Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Let? ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987:76: 44-51. Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84-95. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF. Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80-6. Sweet CS, Emment SE, Stabilito II, Ribeiro LGT. Increased survival in rats with congestive heart failure treated with enalapril. J Cardiovasc Pharmacol 1987;10:636-42. Pfeffcr MA, PfeR’er JM. Steinberg C. Finn P. Survival after an experimental myocardial infarction: beneficial cfft’cts of loneterm therapy with captopril. Circulation 19A5;72:406-12.
august1992:314-G
15. Jugdutt BI, Schwarz-Michorowski BL, Khan MI. Effect of long-term captopril therapy on left ventricular remodeling and function during healing of canine myocardial infarction. J Am Coil Cardiol 1994;19:71321. 16. Jugdutt 91, Wamica JW. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion. and complications: effect of timing, dosage and infarct location. Circulation 1988;78:906-19. 17. Hagar JM, Newman LG. Kloner RA. EtTects of amlodipine on acme myocardial infarction, infarct expansion. and ventricdlar geometry (abstr). J Am Coil Cardiol 1992;19:45A. _. 18. Leung W-H, La,u C-P. Effects of severity of the residual stenosis of the infarct-related coronary artery on left ventricular dilation and function aftca acute myocardial infarction. J Am Coil Caediol 1992:20:3C7-13. 19. Hochmann JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation 1987:75:299306. 20. Halt SL, Kloner KA. Left ventricular topographic altentions in the compleiely healed rat infarct caused by early and late coronary artery reperfusion. Am Heart J 1988;116;15OB-13.
JACC Vol. 20, No. 2 August 1!392:314-6
tinued expansion of the infarct zone, expansion of the
ROBERT A. KLQNER, MD, PHD Los Angeles, Otliforniu
During the last 2 decades, the revolution in treating acute
myocardial infarction has largely originated from rhe concept that myocardial infarct size could be reduced by timely coronary artery reperfusion.Thrombolytic therapy has been shown (1) to reduce myocardialInfarct size and to improve left ventricular function and survival. In the late 1970sit became clear that postinfarction outcome is dependent on factors other than acute reduction of myocardiaiinfarct sine, an event that usually occurs within the 1st 24 h of coronary occlusion. Events occurring several days, weeks or perhaps even months after the initial coronary occlusion might ultimately determine patient outcome. Numerous studies (2-4) showed that topographic changes in the left ventricle after coronary occlusion could contribute to this outcome. Earlyinfarct expansionand left ventricular topographic changes. Within the 1st week of coronary artery occlusion the myocardialinfarct may exhibitthinningand stretchingof the necrotic myocytes (2,3)(Fig. 1).A recent study suggests (5)that early collagenbreakdownafter myocardialinfarction may contribute to the slippageof myocytes past each other. Early infarct expansion and left ventricular dilation occurring within the 1st week can be diagnosed by simple noninvasive techniques such as two-dimensional echocardiography (6). Patients with infarct expansion are prone to several deleterious clinicalcocsequences, includingcongestive heart failure, ventricular rupture, papillary muscle rupture, ventricular septal defect and death (3). Experimental studies (7,8) have shown that certain pharmacologicagents (steroids;some nonsteroid anti-inflammatoryagents, but not aspirin) can exacerbate myocardial infarct expansion. Beymd this early infarct expansion, continued topographic chadges may occur within the left ventricle (4). Smaller infarcts are likely to exhibit continued scar contraction. However, moderate-sizedto large infarcts may exhibit con*Editorialspublishedin Journalof /he AmericanCollegeof Cardiology reflectthe viewsof the authorsand do not necessarilyrepresentthe viewsof JACCor the AmericanCollegeof Cardioloa~. FmmTheHeartInstitute~Hospitalof the GoodSamaritanand Sectionof Cardiology,Universityof SouthernCalifornia,Los Angeles,California. BddressfolI. Robert A. Kloner, MD, PhD, The Heart Institite,ResearchDepartment, Hospitalof the GoodSara&m,616South
Witmer,LosAngeles,Califomia 90017.
01992by the AmericanCollegeof Cardiology
noninfarct zone with eccentric hypertropby, and regional and globalleft ventricular dilation (Fig. 1, A t ) (4,9,10).%+ ve~~~c~lar is now well accepted (IO) that the degree of dilation occurring after an acute myocardial infarction is an important predictor of death at 1 year. Those patients with dilated left ventricle are much more likely to die. The goo news is that this process of left ventricular remodeling does not occur instantly, can be diagnosed by noninvasive imaging (two-dimensionalechocardiography, radionuclide ventriculography, magnetic resonance imaging) and cam be treated. Unlike the decision to give thro which must be made rapidly and often u decision to try to reduce or prevent left ventricular remodeling can be made in a more systematic fashio appropriate noninvasive (or invasive) data have ered. Several studies (I l-15) have shown that lon apy with angiotensin-convertingenzyme inhibitors such as captopril, even when administered a few weeks after the initialmyocardialinfarction, can reduce the degree of postinfar&on left ventricular dilation (Fig. IG) (1l-15), improve exercise tolerance (12) and improve survival (13,14). Nitrates also have been shown to reduce infarct expansion (16). The mechanism by which these vasodilators are capable of preventing infarct expansion may be a reduction of wall stress by a reduction of preload or afterload, or both. We believe that the mechanism is unlikely to be a reduction in afterload alone, because calcium channel blockers do not seem to prevent infarct expansion in experimental models (17). In addition, it is conceivable that the tissue reninangiotensin system might be playing a role in modulating topographic alterations of the ventricle. The presentstudy. The study by Leung and Lau (18)in this issue of the Journal makes the important observation that in patients who received thrombolytic therapy, the degree of residual stenosis of the infarct-related artery before hospital discharge was a determinant of the degree of left ventriculardilation observed at 6 months and 1year after infarction. The study implies that another potential therapy for left ventricular dilation tier myocardial infarction may be angioplasty.The timing at which angioplasty would need to be performedin order to prevent or reduce left ventricular dilation is not clear. Obviously, early successful and sustained reperfusion by any means (thrombolysis or angioplasty) will lead to a smaller subendocardial infarct that is less likely to expand (Fig. 1E). However, even late reperfusiGn (too late to reduce infarct size) has been shown m experimental models to prevent infarct expansion and left ventricular dilation (Fig. 1F) (19,20).How late is too late remains to be determined. The mechanism wherety late reperfusion might reduce infmi expansion is uot known. Perhaps late reperfusion preserves a thin rim of epicardial myocardial cells or epicardial collagen that is enough to battle the infarct zone and prevent expansion. Another 0753097/92/$5.00
SACC Vd. 20, No. 2 August 1992314-6
monihs, continued left ventricular dilation occurs. The noninfarct as well as the infarct zone lengthens. Eccentric hypertrophy (with dilation disproportionate to ~y~e~ro~by) develops ch occurs with volume ov show potential therapy. Early re~e~~s~o~ (er) (thrombolysis or duces myocardial infarct size. The infarct h) after coronary occlusio a) is subendocardial with salvage of tissue in the subepicardium of the risk Infarct expansion does not occur. F, Late reperfusion (Ir) (tbrombolysis 0th) may result in a large infarct but experimental studies suggest rbat less left ventricular dilation and expansion occur with this t~~era~y. T e lesl;lts of Leung and Lau ne!s E and F, the less the residual stenosis, the less the (IS) imply (hat, for the situations in uld reduce the degree of degree of left ventricular dilation. ence, angioplasty (wh residual stenosis) might have a treatment advanlage over t o!ysis alone. Hearts With residual stenosis of the infarct-related artery but with ~e~e~~sion might have ventricular dilatioo. Also implied is that if reoccluintermediate degrees of prote sion occurs in the situationsh ei E or F (and the previou
no longer patent), left ventric Finally, the situationshown I (acei)can prevent or reduce the degree of left ventricular dilation after coronary artery occlusion. Nitrates can also prevent this left ventricular dilation. These agents may be especially useful in cases of moderate to large infarction in which initial attempts at reperf;lsiou were unsuccessfulor reocclusionoccurred after initiallysuccessfulreperfusion. Preliminarydata from the Survival and Ventricular Enlargement trial presented by Pfeffer el al. at the 1992 ACC Scientific Session suggestedthat long-term captopril therapy after infarction improved survival, reduced heart failure and reduced reinfarctionrates.
theory is that the turgor within the reperfused vasculature acts as an epicardial b d Lau (18) also im The study of Leun quality of reperfusion after acute myocardial infarction is important. The more complete and permanent the reperfusion and the less the residual stenosis of the infarct-related artery, the less chance that left ventricular dihtim will develop after infarction. Thus, angioplasty, which will reduce the degree of resadual coronary artery stenosis due to atherosclerosis, may be a better therapy than thrombolysis alone (which will not do this) for preventing topographic changes to the left ventricle. Presumably the angioplasty would not need to be performed in the acute phase of infarction. Conchsims. There are several points in the natural history of myocardial infarction at which the clinician may improve outcome (Fig. 1). Acute early reperfusion will reduce infarct size (Fig. 1E) and improve left ventricular iu;,cZiCIna;rJ Slrrkk2d.S.al,2Ue;y, k dile~~iou3 ccnsequences of progressive left ventricular dilation may be prevented by other interventions including angiotensinconverting enzyme inhibitors (Fig. lG), nitrates and now, as suggested by Leung and Lau (lg), possibly angioplasty. Clinical trials are needed to determine whether angioplasty after infarction will reduce the degree of ultimate left ventricular dilation to a greater extent than thrombolysis alone,
and to determine the time after infarction tha,r an Wrgratefully acknowledge the excellent typing skills
oi Cathy Davisson, who
helped prepare the manuscript.
I. Tiefenbrunn AJ.Clinicalbenefits of thrombolytic therapy in 2.
3.
4.
5. 6.
7.
8.
acute myocardial infarction. Am I Cardiol 1992;6933A-1 IA. Hutchins GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am 3 Cardiol 1978;41:1127-32, Weisman HF. Healy B. Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts. Prog Cardiovasc Dis 1987; 30:73-l 10. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation 19%81:1161-72. Whittaker P, Boughner DR, Kloner RA. Role of collagen in acute myocardial infarct expansion. Circulation 1991;84:2123-34. Eaton EW, Weiss JL, Bulkley BH, Garrison JB, Weisfeldt ML. Regiona! cardiac dilatation after acute myocardial infarction: recognition by twodimensional echocardiog,raphy. N Engl J Med 1979;300:57-62. Brown EJ Jr, Kloner RA, Schoen FJ, Hammerman H, Hal@ S, Braunwasd E. Scar thinning due to ibuprofen administration fallowiflg experimental myocardial ;yfarction. Am 3 Cardiol 1983;5 I :877-83. Hammerman H, Kloner RA, Hale 8, Schoen FJ, Braunwald E. Dosedependent effects of short term methylprednisoidne on myocardial infarct
316
9.
10.
II. 12.
13.
14.
KLONER EDITORII(L
JACC Vol. 20, No. 2 COMMENT
extent, scar formation and ventricular function. Circulation 1983;68:44652. McKay RG. Pfeffer MA, Pasternak RC, et al. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation 1986;74:693-702. White HD, Norris RM. Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Let? ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987:76: 44-51. Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84-95. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF. Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80-6. Sweet CS, Emment SE, Stabilito II, Ribeiro LGT. Increased survival in rats with congestive heart failure treated with enalapril. J Cardiovasc Pharmacol 1987;10:636-42. Pfeffcr MA, PfeR’er JM. Steinberg C. Finn P. Survival after an experimental myocardial infarction: beneficial cfft’cts of loneterm therapy with captopril. Circulation 19A5;72:406-12.
august1992:314-G
15. Jugdutt BI, Schwarz-Michorowski BL, Khan MI. Effect of long-term captopril therapy on left ventricular remodeling and function during healing of canine myocardial infarction. J Am Coil Cardiol 1994;19:71321. 16. Jugdutt 91, Wamica JW. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion. and complications: effect of timing, dosage and infarct location. Circulation 1988;78:906-19. 17. Hagar JM, Newman LG. Kloner RA. EtTects of amlodipine on acme myocardial infarction, infarct expansion. and ventricdlar geometry (abstr). J Am Coil Cardiol 1992;19:45A. _. 18. Leung W-H, La,u C-P. Effects of severity of the residual stenosis of the infarct-related coronary artery on left ventricular dilation and function aftca acute myocardial infarction. J Am Coil Caediol 1992:20:3C7-13. 19. Hochmann JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation 1987:75:299306. 20. Halt SL, Kloner KA. Left ventricular topographic altentions in the compleiely healed rat infarct caused by early and late coronary artery reperfusion. Am Heart J 1988;116;15OB-13.
