- Email: [email protected]
Left ventricular function after coronary artery reperfusion
Left Ventricular Function After Coronary Artery Repemfusion John Ross, Jr., Leftvantrkulardysfunctknanddilatknafterreperbknrektetotheamountofkfarctedand dysfunctknal myocardkm and witl continue to be important determinants of morWtty and mottalttyi There is marked heterogeneity in the anatomk and pathophysklogk presentation of pa= Gents with acute myocardial kfarction prior to thromholysis, and many of these indlvkual sett@gs resembk those in animal specks wtth variousdegreesofcollateralfonnation.7hreamajor detemunantsofkfarctskearemspoMbkfor this heterogeneity and include the risk area, the dwatkn of the coronary occluskn, and the level oftheresidualcoronarybloodflowviacdlaterak or a part&My patent artery. All 3 of these determinants will influence the inttial and late resutts of reps&&m therapy on infarct s&e and ventrkular function. However, in addttkn to late or unsuccessfulthmmbu&is,thereareotherimportant factors determkring outcome inadequate reflow, reskual coronary steno&s, andcoronaryreocclusion, factors that can be aswckted WRhlateprOgresske left ventrkutar dtlation and dysfunctkn. lheriskfactorsforleftventrkulardysfunctkn anddtktionafterreper7usioncannowbeidsntttied,andsuchpatkntsshouldundergocoronary angkgraphy pmiorto hospbl discharge and, if revascutarizatkn of the Marct-rewwrop~e, lated artery (and perhaps othar vessels). In other pattents, Rserlal studks reveal pmgresske left ventrkular failure and dilatkn late after reperfusion, despitetherapywRh an angktensbconverting enzyme (ACE) inhibitor, and if repeat coronaryangkgraphyldenttftessigntfkantcoronary stewsesandareasofhibemattngorstunned myocardlum, revascutaftzatkn may knit pro-
From the Division of Cardiology, Department of Medicine, University of California, San Diego CA 92093, USA. Supported in part by an endowed chair awarded to Dr. Ross by the San Diego County Chapter of the American Heart Association, and by a Coronary Heart Disease SCOR grant HL-17682 awarded by the National Heart, Lung and Blood Institute, Bethesda, Maryland. Address for reprints: John Ross, Jr., MD, Department of Medicine (0613B), University of California, San Diego School of Medicine, La Jolla, CA 92093.
MD
gmsskn of dilatkn and improve teft ventrkutar function. Thus, many events occur during the evolution of myocardial Mar-don and after thrombotyskforwhkhtreatmentispossibk,andthsre is good reason to expect that left ventrkular functkn can be lmprovedwatl beyond the modest kcreasenowobservedwRhthwmbotytktherapy. This, in turn, coukl have a further signtRuant impactonmorbklRyandmortalRyafterreperb don. (Am J Cardkl1993;72~lG-G7G)
F
ollowing acute myocardial infarction, the major determinant of left ventricular (LV) function is the size of the damaged area, and the level of LV function, in turn, importantly affects prognosis. ly2In patients with acute myocardial infarction not treated with thrombolysis there is an inverse relation between the ejection fraction and mortality, and we have observed that an ejection fraction of I 45% is the most sensitive and specific discriminator of prognosis3 Heart failure and LV dysfunction remain key independent predictors of mortality in patients who have had thrombolysis.4 However, there are a number of events during the evolution of myocardial infarction, both before and after reperfusion therapy, for which further intervention is possible, and, if they were successful, LV function could be improved substantially more by reperfusion than is the case today. Before considering the effects of those factors, in addition to myocardial infarct size, that affect LV function after reperfusion, it will be useful to consider first the several determinants of myocardial infarct size and the early effects of reperfusion. Since there is a great heterogeneity of these influences in human subjects, we can usefully employ animal models, as well as examples from the clinical setting, to understand better such variables. DE7ERMINAR7S OF MYOCARDIAL INFARCT SIZE The 3 significant factors influencing the amount of ischemic damage are: (1) the risk area; (2) the A SYMPOSIUM:
UNRESOLVED
ISSUES IN THROMBOLYSIS
9ui
FIGURE l. Dhqframmatk represenMknofthe6sUmatdaveragetbnecollrseoflnyocarrnal neawdslnseveralspeder. Daslmdrlnelstbel@pae&d ~~~&-~~eTlreReaftandsy9##n.3
0 (30 min)
1
2
3
6
24
Hours
duration of complete coronary occlusion; and (3) the level of residual coronary blood flow (antegrade or collateral) during occlusion. The risk area, or vascular bed size, varies greatly in experimental animal models, as well as in humans. For example, using technetium-99m sestamibi perfusion scans to assess the risk area before reperfusion by thrombolysis or direct percutaneous transluminal coronary angioplasty (PTCA) in 89 patients with first acute myocardial infarction, Christian et al5 found a wide range of risk areas (2-73%) in the various vascular distributions, with an average risk area of 49% of the left ventricle in anterior, and 18% in inferior, infarctions. Similar variations (22% vs 10% of the left ventricle, respectively) were observed in residual
*O r 70 7 @ 3ifl
60 50 40 30
SHAM
naJRE2.Lertv~
REPERFUSION
PO
eJeotlon fraotkns(LVEF) ob
sIPotlp,dre 8-aftersbamoperatbn,operasonwltb~ occldonfor45mh -mmry ocduskn Pm, or COrOMCY UteewRllrepemhn.
tabned by quadtatfw
926
~-hW~hyin
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
infarct size following reperfusion in anterior and interior infarctions.5 The effect of the duration ofa complete coronary occlusion on the extent of myocardial infarction in the absence of coronary collaterals can best be seen in those species without significant collateral channels, such as the rat, the pig, or the baboon (Figure 1). In the rat, the bed size varies considerably, but permanent left coronary artery occlusion produces a transmural infarction that is often large (> 40% of the left ventricle) and causes LV failure.6 Recent quantitative left ventriculographic studies in rats in our laboratory7 show that the ejection fraction at 3 weeks after complete coronary occlusion averages 40% (Figure 2), and a large increase in LV end-diastolic volume also occurs.6’7In the rat, as in other species without coronary collaterals, the duration of coronary occlusion necessaryto produce a completed transmural infarction is relatively brief, averaging about 1 hour (Figure 1). In such animal models reperfusion after that time results in little or no myocardial salvage.8 Such rapid and complete infarction also undoubtedly occurs in some patients who have few or no coronary collaterals (many of whom may die outside the hospital). The presence of residual coronary flow via collateral channels or persistent antegrade flow around a coronary thrombus (as may occur with spontaneous thrombolysis) importantly affects the extent of necrosis, as well as regional and global function after acute myocardial infarction. In dogs, a specieswith native collateral channels, chronic survival of the epicardium usually occurs after complete coronary occlusion,9 and salvageof tissue is possible for 2-4 hours8 (Figure
DECEMBER 16, 1993
l), whereas in the guinea pig, which has extensive collaterals, infarction does not occur after coronary occlusion8J0 In the dog, the size of the damaged area is inversely proportional to the residual collateral blood flow after permanent coronary occlusion.” The wide variability of responses to coronary occlusion in humans depends not only on the risk area and the duration of complete coronary occlusion, but also importantly on residual blood flow, ranging from complete absence of collaterals to various levels of collateral or residual antegrade flow (sufficient in some instances to prevent infarction). This places the average time to irreversible necrosis somewhere in the midrange (3-4 hours), closer to that in dog than to that in rat or baboon8 (Figure 1). Supporting this view are studies by Rogers et all2 showing that following intracoronary thrombolysis after acute myocardial infarction relatively late after the onset of symptoms (average, 7 hours), regional wall motion improved following reperfusion only in those patients with coronary collaterals or residual antegrade flow. Also in the first Thrombolysis in Myocardial Infarction (TIMI-1) study, in which patients were admitted with chest pain lasting up to 7 hours, those with collaterals who failed reperfusion had a smaller infarct size (by enzymatic methods) and better LV function than patients without coronary collateral channels.13 EARLY EFFECTS OF REPERFUSION Experimental studies: Reperfusion does not
affect the risk area, of course, but it reduces the duration of coronary occlusion and, provided coronary blood flow after reperfusion remains adequate, eliminates residual ischemia and subsequent ischemia or necrosis. The magnitude of the effect on LV function of restoring coronary blood flow in a species without coronary collaterals, and with complete reflow achieved through a normal coronary artery, are well-illustrated in the rat. When a rat is subjected to 45 minutes of complete coronary occlusion (a period within the l-hour time period, when necrosis is incomplete) followed by reperfusion,14recent studies in our laboratory at 3 weeks after reperfusion in rats demonstrated an average ejection fraction of 52% (substantially and significantly higher than the ejection fraction of 40% after permanent coronary occlusion; Figure 2), and the LV end-diastolic volume was much smaller than after permanent occlusion7 Scatter within groups in these data probably largely reflects differences in risk area (vascular bed size) in
TABLE I Factors Adversely Affecting Left Ventriculae Function After Repetfusion l
Late thrombolysis in patients without effective residual flow
l
Coronary reocclusion and remfarction
individual animals. In these rats the LV ejection fraction was inversely related to the infarct size, and it was directly related to the size of the spared epicardial region. 7 The average improvement of ejection fraction after reperfusion in rats is larger than that seen following thrombolysis in patients with acute myocardial infarction, even in patients with anterior infarction who exhibit the greatest increases in LV ejection fraction.15 This observation may relate importantly to reperfusion through a normal coronary artery in the rat, whereas there is considerable influence of residual thrombosis, atherosclerotic disease, and reocclusion in the clinical setting, as discussedsubsequently. In the dog, a species with collaterals, reperfusion reduces infarct size provided reperfusion is carried out within 24 hours after coronary occlusion (Figure l), there is epicardial sparing,16J7and partial recovery of regional contractile function then occurs over about 2 weeks.l* Other studies in the dog show that after complete reperfusion following 2 hours of coronary occlusion, cellular hypertrophy (particularly marked in the spared epicardial region) is associated with the regional functional recovery.l9 In the rat, epicardial areas salvaged by reperfusion after 45 minutes of occlusion can undergo even further hypertrophy with exercise training. l4 Such hypertrophy could play a role in preventing ventricular dilation after reperfusion and may have significance in relation to the finding that inadequate reperfusion leads to unfavorable LV remodeling in some patients, as discussed subsequently. Clinkal studies: There is usually a favorable response of regional and global LV function to thrombolytic therapy in patients with acute myocardial infarction, but a number of factors are responsible for wide variability in such responses (Table I). Many studies have shown improved LV ejection fraction after thrombolysis compared with a placebo group as, for example, in the study by White et a120in patients with a first myocardial infarction treated at 4 hours in whom the average ejection fraction was 52% in treated, versus 46% in untreated, patients at 3 weeks after streptokinase therapy. Severalinvestigations have shown improveA SYMPOSIUM:
UNRESOLVED
ISSUES IN THROMBOLYSIS
9s
TABLE II Risk Factors After Thrombolysis Identified by Multivariate Analysis
Risk Factor
No LV Dilation (n = 38)
Llmited LV Dilation (n = 18)
Ventriculographic infarct 7 (5-l 1) size (%) Ejection fraction, 63 (54-64) day 4 (%) Infarct location 32% (% antenor) Stroke index, day 4 40 (35-43) (mL/m2) TIMI grade flow 2.2 (1.8-2.6) ‘Mean and95% confidence intervals. Modified from Circulation.32 LV = left ventricular; TIMI = Thrombolysis
Progressive LV Dilation (n = 14)
15 (7-24)
20 (14~27F
52 (47-60)
39 (34-46)
61%
57%
38 (32-39)
31 (25-36)
2.1 (1.7-2.6)
1.3 (0.6-1.9)
in Myocardial
Infarction
trial.13
ment in regional function or ejection fraction when thrombolysis is administered early, but there is lack of improvement if given later than 3-4 hours after symptom onset.21322 Large ongoing studies with very early reperfusion, not yet reported, aswell as a previous study by Koren et al23 suggest that the ejection fraction can be normal when reperfusion is achieved within 90 minutes after the onset of symptoms. Studies on LV function studied immediately before thrombolysis and again about 1 week later in the same patients sometimes have failed to show significant average changes in the ejection fraction,24>25although other reports show improvement, particularly when measured after several weeks.26 However, patients with unsuccessful thrombolysis or with small infarcts often have been included in such analyses, and also recovery of function may be incomplete by 1 week, as shown in laboratory studies.17J8 Additional factors can be involved when regional or global function fails to improve after reperfusion. Of particular importance appear to be an inadequate level of blood flow after reperfusion and coronary reocclusion, as discussed subsequently. IATE VENlRlCUl.AR REMODEUNG AND FUNCTION AFIER REPERFUSION
It is established in patients with a large first anterior myocardial infarction that, if the vessel is occluded at 3 weeks, progressive chamber dilation with LV dysfunction generally occurs over the following year, a change that does not result from initial infarct expansion.27If the artery is patent, less LV dilation occurs and it does not tend to be progressive.28,29Progressive late ventricular dilation after acute infarction often can be prevented by administration of an angiotensin-converting en940
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
zyme (ACE) inhibitor, both in the presence of anterior infarction, as shown by Pfeffer and Braunwald,29 or with inferior infarction as reported by Sharpe et aL30 Inadequate reflow or reddual stenosis: In patients who have undergone thrombolysis, several factors are important in the remodeling response, including the level of blood flow after reperfusion, the degree of residual coronary stenosis, and the occurrence of reocclusion (Table I). Recent studies after thrombolysis indicate that TIM1 flow grade 2 may be ineffective and not significantly different from TIM1 grade O-l flow in reducing infarct size.31In this regard, studies by Gaudron et aP2have further clarified the determinants of late unfavorable LV remodeling in patients receiving thrombolysis. In a study of 70 patients with a first myocardial infarction, cardiac catheterization and coronary angiography were performed at 3-5 weeks and the LV ejection fraction and diastolic volume were then studied serially over a 3-year period by radionuclide angiography. For analysis, patients were separated into groups without initial dilation of the left ventricle, with limited dilation (without progression), and with progressive dilation. The LV ejection fraction remained normal in the group without initial dilation; it was reduced but stable in those with limited dilation; however, it fell from an initially abnormal value (close to 40%) to <25% over the 3-year follow-up period in patients with progressive dilation. Deterioration of function occurred in the latter group only in those regions without initial dysfunction.32On multivariate analysis, predictors of progressive LV dilation, based on the initial postinfarction studies, were myocardial infarct size (ventriculography), ejection fraction, anterior infarct location, the stroke volume index, and TIM1 flow grade32(< 2.0 [average, 1.31in the progressive dilation group; Table II). Investigations by Leung and Lau33 in patients with first anterior myocardial infarction receiving thrombolysis have assessedthe effects of residual coronary stenosis present at 7-10 days on LV volume and function using serial echocardiography over a l-year period. As expected, in patients with total coronary occlusion there was progressive LV enlargement and a fall in ejection fraction, whereas in patients with a stenosis diameter > 1.5 mm the LV end-diastolic volume was initially smaller than that in those with an occluded artery and showed no further enlargement at 1 year. However, in patients with a residual minimal lumen diameter in the infarct-related artery of < 1.5 mm, at the end of 1 year the LV end-diastolic volume had signifi-
DECEMBER 16, 1993
cantly increased and was larger than that in the patients with a diameter > 1.5 mm.33In a recent preliminary report these same authors describe the use of PTCA at 1 week in patients after first anterior infarction with a minimum lumen diameter < 1.5 mm after thrombolysis compared with similar, randomized untreated patients; at 1 year, PTCA of the residual stenosis resulted in significantly less LV dilation and improved LV function compared with the group without PTCA.34 Coronary mocclusion: Another event potentially affecting LV function following the acute phase of infarction is described in studies by the Anthrombotics in Prevention of Reocclusion in Coronary Thrombolysis (APRICOT) investigators,35 demonstrating that the rate of coronary artery reocclusion is quite high (25-30%) by 3 months after conventional thrombolysis, even in the heparin or aspirin treatment groups. The reinfarction rate was 11% in the placebo group, and this was reduced by aspirin.35 Preliminary observations by these investigators using ventriculography at 3 months indicated that, compared with patients without reocclusion who showed improved LV ejection fraction, there was no improvement of function in patients with anterior infarction who had coronary reocclusion, although the degree of LV dilation was unaffected.36 THERAPEWIC CONSIDERATIONS
A number of the factors that importantly affect LV function during the evolution of myocardial infarction and after thrombolysis can only be influenced by measures discussed elsewhere in this symposium. Reduction of the time factor will require steps to increase the early use of thrombolytic agents within l-2 hours, but even late thrombolysis at 6-24 hours after symptom onset may benefit the left ventricle by limiting chamber dilation, without enhancing the ejection fraction.37Use of antithrombin agents such as hirudin38 may improve the rate and degree of thrombolysis, and these or other new agents are needed to improve the currently high early and late reocclusion rates and may enhance the level of residual myocardial blood flow after reperfusion. The use of primary PTCA in acute myocardial infarction has been reported to improve the LV ejection fraction from 52.6% immediately before angioplasty to 58.9% at 1 week39and undoubtedly would reduce the incidence of residual high-grade stenosisof the infarctrelated artery, but this approach will require further study with controlled trials. In the meantime, we are left with a subpopula-
tion within the group of patients treated by thrombolysis who will exhibit progressive unfavorable LV remodeling after reperfusion ending in cardiac failure. Compensatory hypertrophy and dilation occur initially in such patients, but despite these adaptations the cardiac index remains low and the systemic vascular resistance rises.32In some patients, residual coronary stenosis may prevent the development of compensatory hypertrophy in the reperfused zone, which occurs in animaIs after reperfusion when the artery is fully patent.14J9 Intermittent ischemia due to disease in other coronary vesselscould further contribute to unfavorable remodeling in some patients. When such events occur, the noninfarcted regions are subjected to increased systolic wall stress, with afterload mismatch,40resulting eventually in progressiveLV dilation and further depression of function, as wall thinning further contributes to elevated systolic and diastolic wall stress levels. Such events have been discussedbased on morphologic studies in the rat.41 Approaches to preventing or reversing left ventrkular dysfunction: Steps toward preventing
the above maladaptive sequence of events should be taken prior to hospital discharge. Patients at high risk for progressive LV dilation and dysfunction should be identified in the early convalescent phase. Such patients usually will have had a large infarction, more commonly anterior in location, and exhibit a significantly reduced LV ejection fraction by echocardiographic or radionuclide studies; they may have a prior infarction, and if other noninvasive studies are performed there may be an abnormal or equivocal response to exercise, or ineligibility to perform such testing. Whether or not exercise is attempted in such patients, coronary angiography in the early convalescent phase is indicated. On coronary angiography, such patients at high risk of progressive LV dilation often have TIM1 flow grade of I 2.0,31with residual coronary stenosis.32 Whether or not revascularization is immediately carried out, such patients should be treated with an ACE inhibitor,42 even if symptoms of cardiac failure are absent.43 Serial assessmentof LV size and ejection fraction by echocardiography or radionuclide studies for at least 2 years also seemsadvisable in patients who do not undergo revascularization, to search for evidenceof progressiveLV dilation and dysfunction. Should progressive LV dilation occur despite medical treatment, repeat angiography and consideration of revascularization of all vesselssupplying viable but dysfunctional regions may offer the best A SYMPOSIUM: UNRESOLVED ISSUES IN THROMBOLYSIS
950
possibility for reversing or halting the progression of LV dilation and dysfunction in this setting. It is known from laboratory experiments that during ischemia the level of regional contraction declines, or down-regulates, to match the available subendocardial blood flow per beat (perfusioncontraction matching), and this is reversible if the residual flow is sufficient to prevent infarction.44 Early investigations in patients with chronic stable angina pectoris after coronary artery bypass surgery demonstrated increased LV function in some patients, leading to the concept of chronic myocardial dysfunction, or “hibernation,” which is reversible.45Later, clinical studies showed that regional contractile dysfunction in which tissue viability could be demonstrated by positron emission tomography (preserved [18F]fluorodeoxyglucoseuptake) was at least partially reversible by myocardial revascularization.46T47Other, simpler techniques for detecting dysfunction in the presence of tissue viability are now available, including thallium-201 imaging with reinjection48 and echocardiography during dobutamine administration,49 as discussed by others in this symposium. Thus, in patients who show late cardiac enlargement with dysfunction following thrombolysis, despite medical treatment with an ACE inhibitor in addition to coronary angiography, a search should be undertaken to identify areas of hibernating or stunned myocardium, since appropriate revascularization in such patients may prevent further dilation or even partially reverse ventricular dysfunction. It is clear that many events occur during the evolution of myocardial infarction and after thrombolysis for which treatment is possible, and there is good reason to expect that LV function can be improved well beyond the modest increase now observed with thrombolytic therapy. This, in turn, could have a further significant impact on morbidity and mortality after reperfusion.
REFERENCES l. Multi-Center Post-Infarction Research Group. Risk stratification and survivaI after myocardial infarction. N Engl .I Med 1983;309:331-336. 2. Nicod P, Gilpin EA, Dittrich H, Chappuis F, EngIer R, Henning H, Ross J Jr. Influence on prognosis and morbidity of left ventricular ejection fraction with and without signsof let? ventricular failure after acute myocardial infamtion. Am f Cardio~1989;61:1165-1171. 3. Ahnve S, GiIpin E, Henning H, Maisel AA, Dittrich H, Carlisle J, Ross J Jr. Limitations and advantagesof the ejection fraction for defining high risk after acute myocardial infarction. Am J Cmfiol1986,58:872-878. 4. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G, and the Working Group of the GISSI-2 Data Base Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis.Circulafbn 1993;88:416429. 5. Christian TF, Schwartz RS, Gibbons RI. Determinams of infarct size in reperbrsion therapy for acute myocardial infarction. Ctiulnrion 1992,86:81-90.
96a
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
6. Pfeffer a Pfeffer JM, Fishbem M, Fletcher PJ, Spadaro J, KIoner RA, Bratmwald E. Myocardial infarct size and ventricular function in rats. Cti Res 1979;44:503-512. 7. Ono S, Bharghava V, Otto S, Mao L, Hagan G, Rockman HG Ross J. In ti assessmentof left ventricular remodeling after myocardiil infarction by digital video-contrast angiographyin the rat. CardiovasRe.s(in press). 8. Ross J Jr. Mechanical consequencesof regional myocardial ischemia. In: Fozzard HA, Haber A, JenningsRB, Katz AM, Morgan HE, eds. The Heart and Cardiovascular System:Scientific Foundations,vol. II, 2nd ed. New York: Raven Press,1992:1997-2020. 9. SasayamaS, Gallagher KP, Kemper WS, FrankIm D, Ross J Jr. Regional left ventricular waU thickness early and late after coronary occlusion in the consciousdog.Am J P&i01 1981;24&H293-H299. 10. SchaperW. Experimental infarcts and the micmcircuIation. In: Hearse DJ, YeIIon DM, eds. Therapeutic Approaches to Myocardiai Infarct Size Limitation. New York: Raven Press,1984z7990. iL Reimer KA, Jemrings RB, Cobb FR, Murdock RI-I, Greenfield JC Jr, Becker LC, BuIkIey BH, Hutchins GM, Schwartz RP Jr, Bailey KR. Animal modelsfor protecting ischemicmyocardium:results of the NHLBI Cooperative Study.Comparison of unconsciousand consciousdog models.Cim Res 1985,56: 651465. l2. Rogers WJ, Hood WP Jr, Mantle JA, Baxley WA, KirkIin JK, Zorn GL, Nath HP. Return of left ventricular function after reperfusion in patients with myocardiil infarction: importance of subtotal stenoses or intact CoUateraIs. Ckularion 1981;69338349. ia. Habib GB, Heibig J, Forman SA, Brown BG, Roberts R, Terrin ML, BoUi R. Influence of coronary collateral vesselson myocardial infarct size in humans. Results of phase I ThromboIysii in Myocardial Infarction (TIMI) trial. The TIM1 Investigators.CimuZadon1991;83:739-746. l4. Oh B-H, Ono S, Rockman w Ross J Jr. Myocardial hypertrophy in the ischemic zone induced by exercise in rats alter coronary reperfusion. Cirrularim 1993;87:598607. is. Martin GV, Sheehanm Stadius M, Maynard CM, Davis KB, Ritchie JL, Kennedy JW: Intravenous streptokinasefor acute myocardial infarction. Effects on global and regional systolic function. Circulation 1988;78:25%266. l6. Reimer KA, Lowe JE, RasmussenMM, Jennings RB. The wave front phenomenonof ischemiccell death. I. Myocardii infarct size versus duration of coronary occlusion in dogs,Cirnrlatin 1977;563786794. 17. Gii WR, Sybets HD, Maroko PR, CoveU JW, Sobel BE, Ross J Jr. Coronary artery reperfusion II: Reduction of myocardial infarct size at one week after the coronaty occlusion.J Clin Invest 1972;51:2717-2723. lB.Theroux P, Ross J Jr, Franklin D, Kemper WS, SasayamaS. Coronary arterial reperfusion. III. EarIy and late effects on regional myocardial function and dimensionsin consciousdogs.Am J CardioZ 1976;38:599606. 19. Kambayashi M, Miura T, Oh B-H, Murata K, Rockman I-& Parra G, Ross J Jr. Myocardial ceU hypertrophy with reperfusion in dogs. Cimhim 1992,86:1935-1944. 2O.White HD, Norris RM, Brown MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whidock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 198~317:85%355. 21 Serruys PW, SimoonsML, SutyapranataH, Vermeer F, Wijns W, van den Brand M, Bar F, Zwaan C, Krauss XII, Remme WJ. Preservation of global and regional left ventricular function after eady thromboIysisin acute myocardial infarction. JAm Co11Cardiol1986;7:729-742. 22. Schriider R, Neuhaus K-L, Leiirovicz A, Lmderer T, Tebbe U for the I.S.A.M. Study Group. A prospectivetrial of intravenous streptokinasein acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days.N Engr’JMed 1986;314:1465-1471. 25. Karen G, Weiss AT, Hasin Y, Appelbaum D, Welber S, Rozenman Y, Lotan C, Mosseri M, Sapoznikov D, Luria MH, Gotsman MS. Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase.N EnglJMed 1985;313:1384-1389. 2AChesebm JH, Knatterud G, Roberts R, Borer J, Cohen IS, Dalen J, Dodge HT, Francis CK, HiUis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, WilIerson JT, WiUiamsDCJ,Zaret BL, BraunwaId E. Thrombolysis in myocardial infarction (TIMI) trial, Phase I: a comparison between intravenous tissue plasminogenactivator and intravenous streptokinase. Circulation 1987;76:142154. 25. Marino P, Zanolla L, Zardii P on behalf of the Gruppo It&no per lo Studio deUaStreptochmasineU’Infarto Miocardico (GISSI). Effect of streptokinam on left ventricular modeling and function after myocardial infarction: The GISSI (Gruppo Italian0 per lo Studio della Streptochinasi neU’Infarto Miocardico) trial. JAm CoUCaniiof 1989;14:1149-1158.
DECEMBER 16, 1993
26.Anderson JL, Becker LC, Sorensen SG, Karagounis LG Browne KF, Shah PK, Morris DC, Fintel DJ, Mueller HS, Ross AM, Hall SM. Askins JC, Doorey AJ, Chines CL, Moreno % Marder VJ for the TEAM-3 Investigators. Antistreplase versus alteplase in acute myccardial infarction: comparative effects on left ventricular function, morbidity and l-day coronary artery patency. JAm Coil Cardioll9!?2;20:153-766.
27. Topol EI, CaIii RM, Vandotmael M, GrimesC, George B, Sam ML, Wall T, O’Brien M, Schwaiger M, Aguirre F, Young S, Popma JJ, Sigmon K, Lee a Ellis SG, and the TAMI- Study Group. A randomized trial of late reperfusion therapy for acute myocardial infarction. Circularion 1992;85:2@& 2099. 28. Pfeffer MA, Lamas GA, Vaughn DE, Parisi AF, Braunwald E. Effect of captopril on progressiveventricular dilatation after anterior myocardial infarction. N EngfI Med 1988;319:8&86. 29. Pfeffer h4A, BraunwaId E. Ventricular remodeling after myocardial infarction. Circularion 1990;81:1161-1172. 3O.Sharpe N, Smith H, Murphy J, Hannan S. Treatment of patients with symptomlessleft ventricular dysfunction after myocardial infarction. Lancef 1988;i:z5-259. 3l. Karagounis L, SorensenSG, Menlove RL, Moreno F, Anderson JL Does thrombolysis in myocardial infarction (TIMI) perfusion grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electmcardiographic evidencefrom the TEAM-2 study.JAm Coil Cardioi 1992;19:1-10. 32. Gaudron P, EiIIes C, Kugler I, Ertl G. Progressiveleft ventricular dysfunction and remodeling foIIowing myccardial infarction: potential mechanismsand early predictors. Cimulatin 1993;87:755-763. 33. Leung W-H, Lau C-P. Effects of severity of the residual stenosisof the infarct-related coronary artery on left ventricular dilation and function after acute myocardial infarction. JAm Coil Cardiol1992;20:307-313. 34. Leung W-H, Lau C-P. Beneficial effects of late angioplasty of the infarctrelated coronary artery on subsequentleft ventricular remodeling after acute myccardial infarction. JAm Co11Cardi 1993;21:44A. 36. Meijer A, Verheugt FWA, Wetter CJ, Lie KI, van der Pol JUT, van Eenige MJ. Aspirin versus coumadii in the prevention of reocchrsion and recurrent ischemia after successful thrombolysis: a prospective placebocontrolled angiographicstudy. Circukz?ion1993,87:1524-1530. 36. Meijer A Verheugt FWA, Wetter C for the APRICOT Investigators.Late reperfusion after thrombolysis: incidence and consequencesfor left ventricular recovery and dilatation. JAm Coil Canfiol1993;21:45A. 37. Top01 E, C?alitIRM, Vandormael M, Grines C, George B, Sam ML, WaII T, O’Brien M, Schwaiger M, Aguirre F, Young S, Popma J, Signron K, Lee
KL, Ellis S and the Thmmbolysis and Angioplasty in Myocardial Infarction-6 Study Group. A randomized trial of late reperfusion therapy for acute myocardial infarction. Circulation 1992$5:2090-2099. 38. Chescbro JH Webster MW, Zoldhelyi, Rcche PC, Badimon L, Badiion JJ. Antithrombolytic therapy and progressionof comnaty artery disease.Antiplatelet versusantithrombins. Cirnrlafion 1992;86(suppl):III-lC%III-110. 39. O’Keefe JH Jr, Rutherford BD, McConahay DR, Johnson WL Jr, Giorgi LV, Shimshak TM, Ligon RW, McAllister BD, HartzIer GO. Myocardial salvage with direct coronary angioplasty for acute infarction. Am Heart J 1992;123:1-6. 40. Ross J Jr. Afterload mismatch and preload reserve: a conceptual framework for the analysisof ventricular function, Prog Cardiovax Dis 1976;18:255264. 41. Olivetti G, CapassoJM, Meggs JM, Sonnenblick EH, Anvetsa P. CeIIuIar basisof chronic ventricular remodeling after myocardial infarction in rats. Cirr: Res 1991;68:856-869. 42. Pfeffer MA, Lamas GA, Vaughn DE, Parisi AF, BraunwaId E. Effect of captopril on progressiveventricular dilatation after anterior myocardial infarction. N Engl JMed 1988;319:8&86. 43. Pfeffer MA, BraunwaId E, Moye LA, Basta L Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect of captopril on mortality and morbidity in patientswith left ventrictdar dysfunctionafter myocardial infarction. Results of the sulvival and ventricular enlargement trial. The SAVE Investigators.N Engl J Med 1992,3276@-677. 44. Ross J Jr. Myocardial perfusion-contraction matching: implications for coronary heart diseaseand hibernation. Circuladon 1991;83:10761083. 45. Rahimtoola, SH. The hibernating myccardium.Am Heari J 1989;117:211221. 46. TiIIiih J, Brunken R, Marshall R, Schwaiger M, MandeIkem M, Phelps M, SchelbertH. Reversibility of cardiac waII motion abnormalities predicted by positron tomography.N Engf J Med 1986314884889. 47. de SiIva R, Yamamoto Y, Rhodes CG, Iida H, Nihoyannopoulos P, Davies GJ. Preoperative prediction of the outcome of coronary revascularization using positron emissiontomography.Cirwlation 1992;86:1738-1742. 48. Dilsiiian V, Rocco TP, Freedman NMT, Leon M, Borrow RO. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistributionimaging.N [email protected] Med 1990,323:141-146. 49. Maraullo P, Pamli 0, Reisenhofer B, SambucetiG, Picano E, D&ante A, Gimelli A, L’Abbate A. Value of rest thallium-ZWtechnetium-!39msestamibi scansand dobutamine echocardiographyfor detecting myocardial viability. Am J Cardiol 1993;71:166-172.
A SYMPOSIUM: UNRESOLVED ISSUES IN THROMBOLYSIS
970
From the Division of Cardiology, Department of Medicine, University of California, San Diego CA 92093, USA. Supported in part by an endowed chair awarded to Dr. Ross by the San Diego County Chapter of the American Heart Association, and by a Coronary Heart Disease SCOR grant HL-17682 awarded by the National Heart, Lung and Blood Institute, Bethesda, Maryland. Address for reprints: John Ross, Jr., MD, Department of Medicine (0613B), University of California, San Diego School of Medicine, La Jolla, CA 92093.
MD
gmsskn of dilatkn and improve teft ventrkutar function. Thus, many events occur during the evolution of myocardial Mar-don and after thrombotyskforwhkhtreatmentispossibk,andthsre is good reason to expect that left ventrkular functkn can be lmprovedwatl beyond the modest kcreasenowobservedwRhthwmbotytktherapy. This, in turn, coukl have a further signtRuant impactonmorbklRyandmortalRyafterreperb don. (Am J Cardkl1993;72~lG-G7G)
F
ollowing acute myocardial infarction, the major determinant of left ventricular (LV) function is the size of the damaged area, and the level of LV function, in turn, importantly affects prognosis. ly2In patients with acute myocardial infarction not treated with thrombolysis there is an inverse relation between the ejection fraction and mortality, and we have observed that an ejection fraction of I 45% is the most sensitive and specific discriminator of prognosis3 Heart failure and LV dysfunction remain key independent predictors of mortality in patients who have had thrombolysis.4 However, there are a number of events during the evolution of myocardial infarction, both before and after reperfusion therapy, for which further intervention is possible, and, if they were successful, LV function could be improved substantially more by reperfusion than is the case today. Before considering the effects of those factors, in addition to myocardial infarct size, that affect LV function after reperfusion, it will be useful to consider first the several determinants of myocardial infarct size and the early effects of reperfusion. Since there is a great heterogeneity of these influences in human subjects, we can usefully employ animal models, as well as examples from the clinical setting, to understand better such variables. DE7ERMINAR7S OF MYOCARDIAL INFARCT SIZE The 3 significant factors influencing the amount of ischemic damage are: (1) the risk area; (2) the A SYMPOSIUM:
UNRESOLVED
ISSUES IN THROMBOLYSIS
9ui
FIGURE l. Dhqframmatk represenMknofthe6sUmatdaveragetbnecollrseoflnyocarrnal neawdslnseveralspeder. Daslmdrlnelstbel@pae&d ~~~&-~~eTlreReaftandsy9##n.3
0 (30 min)
1
2
3
6
24
Hours
duration of complete coronary occlusion; and (3) the level of residual coronary blood flow (antegrade or collateral) during occlusion. The risk area, or vascular bed size, varies greatly in experimental animal models, as well as in humans. For example, using technetium-99m sestamibi perfusion scans to assess the risk area before reperfusion by thrombolysis or direct percutaneous transluminal coronary angioplasty (PTCA) in 89 patients with first acute myocardial infarction, Christian et al5 found a wide range of risk areas (2-73%) in the various vascular distributions, with an average risk area of 49% of the left ventricle in anterior, and 18% in inferior, infarctions. Similar variations (22% vs 10% of the left ventricle, respectively) were observed in residual
*O r 70 7 @ 3ifl
60 50 40 30
SHAM
naJRE2.Lertv~
REPERFUSION
PO
eJeotlon fraotkns(LVEF) ob
sIPotlp,dre 8-aftersbamoperatbn,operasonwltb~ occldonfor45mh -mmry ocduskn Pm, or COrOMCY UteewRllrepemhn.
tabned by quadtatfw
926
~-hW~hyin
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
infarct size following reperfusion in anterior and interior infarctions.5 The effect of the duration ofa complete coronary occlusion on the extent of myocardial infarction in the absence of coronary collaterals can best be seen in those species without significant collateral channels, such as the rat, the pig, or the baboon (Figure 1). In the rat, the bed size varies considerably, but permanent left coronary artery occlusion produces a transmural infarction that is often large (> 40% of the left ventricle) and causes LV failure.6 Recent quantitative left ventriculographic studies in rats in our laboratory7 show that the ejection fraction at 3 weeks after complete coronary occlusion averages 40% (Figure 2), and a large increase in LV end-diastolic volume also occurs.6’7In the rat, as in other species without coronary collaterals, the duration of coronary occlusion necessaryto produce a completed transmural infarction is relatively brief, averaging about 1 hour (Figure 1). In such animal models reperfusion after that time results in little or no myocardial salvage.8 Such rapid and complete infarction also undoubtedly occurs in some patients who have few or no coronary collaterals (many of whom may die outside the hospital). The presence of residual coronary flow via collateral channels or persistent antegrade flow around a coronary thrombus (as may occur with spontaneous thrombolysis) importantly affects the extent of necrosis, as well as regional and global function after acute myocardial infarction. In dogs, a specieswith native collateral channels, chronic survival of the epicardium usually occurs after complete coronary occlusion,9 and salvageof tissue is possible for 2-4 hours8 (Figure
DECEMBER 16, 1993
l), whereas in the guinea pig, which has extensive collaterals, infarction does not occur after coronary occlusion8J0 In the dog, the size of the damaged area is inversely proportional to the residual collateral blood flow after permanent coronary occlusion.” The wide variability of responses to coronary occlusion in humans depends not only on the risk area and the duration of complete coronary occlusion, but also importantly on residual blood flow, ranging from complete absence of collaterals to various levels of collateral or residual antegrade flow (sufficient in some instances to prevent infarction). This places the average time to irreversible necrosis somewhere in the midrange (3-4 hours), closer to that in dog than to that in rat or baboon8 (Figure 1). Supporting this view are studies by Rogers et all2 showing that following intracoronary thrombolysis after acute myocardial infarction relatively late after the onset of symptoms (average, 7 hours), regional wall motion improved following reperfusion only in those patients with coronary collaterals or residual antegrade flow. Also in the first Thrombolysis in Myocardial Infarction (TIMI-1) study, in which patients were admitted with chest pain lasting up to 7 hours, those with collaterals who failed reperfusion had a smaller infarct size (by enzymatic methods) and better LV function than patients without coronary collateral channels.13 EARLY EFFECTS OF REPERFUSION Experimental studies: Reperfusion does not
affect the risk area, of course, but it reduces the duration of coronary occlusion and, provided coronary blood flow after reperfusion remains adequate, eliminates residual ischemia and subsequent ischemia or necrosis. The magnitude of the effect on LV function of restoring coronary blood flow in a species without coronary collaterals, and with complete reflow achieved through a normal coronary artery, are well-illustrated in the rat. When a rat is subjected to 45 minutes of complete coronary occlusion (a period within the l-hour time period, when necrosis is incomplete) followed by reperfusion,14recent studies in our laboratory at 3 weeks after reperfusion in rats demonstrated an average ejection fraction of 52% (substantially and significantly higher than the ejection fraction of 40% after permanent coronary occlusion; Figure 2), and the LV end-diastolic volume was much smaller than after permanent occlusion7 Scatter within groups in these data probably largely reflects differences in risk area (vascular bed size) in
TABLE I Factors Adversely Affecting Left Ventriculae Function After Repetfusion l
Late thrombolysis in patients without effective residual flow
l
Coronary reocclusion and remfarction
individual animals. In these rats the LV ejection fraction was inversely related to the infarct size, and it was directly related to the size of the spared epicardial region. 7 The average improvement of ejection fraction after reperfusion in rats is larger than that seen following thrombolysis in patients with acute myocardial infarction, even in patients with anterior infarction who exhibit the greatest increases in LV ejection fraction.15 This observation may relate importantly to reperfusion through a normal coronary artery in the rat, whereas there is considerable influence of residual thrombosis, atherosclerotic disease, and reocclusion in the clinical setting, as discussedsubsequently. In the dog, a species with collaterals, reperfusion reduces infarct size provided reperfusion is carried out within 24 hours after coronary occlusion (Figure l), there is epicardial sparing,16J7and partial recovery of regional contractile function then occurs over about 2 weeks.l* Other studies in the dog show that after complete reperfusion following 2 hours of coronary occlusion, cellular hypertrophy (particularly marked in the spared epicardial region) is associated with the regional functional recovery.l9 In the rat, epicardial areas salvaged by reperfusion after 45 minutes of occlusion can undergo even further hypertrophy with exercise training. l4 Such hypertrophy could play a role in preventing ventricular dilation after reperfusion and may have significance in relation to the finding that inadequate reperfusion leads to unfavorable LV remodeling in some patients, as discussed subsequently. Clinkal studies: There is usually a favorable response of regional and global LV function to thrombolytic therapy in patients with acute myocardial infarction, but a number of factors are responsible for wide variability in such responses (Table I). Many studies have shown improved LV ejection fraction after thrombolysis compared with a placebo group as, for example, in the study by White et a120in patients with a first myocardial infarction treated at 4 hours in whom the average ejection fraction was 52% in treated, versus 46% in untreated, patients at 3 weeks after streptokinase therapy. Severalinvestigations have shown improveA SYMPOSIUM:
UNRESOLVED
ISSUES IN THROMBOLYSIS
9s
TABLE II Risk Factors After Thrombolysis Identified by Multivariate Analysis
Risk Factor
No LV Dilation (n = 38)
Llmited LV Dilation (n = 18)
Ventriculographic infarct 7 (5-l 1) size (%) Ejection fraction, 63 (54-64) day 4 (%) Infarct location 32% (% antenor) Stroke index, day 4 40 (35-43) (mL/m2) TIMI grade flow 2.2 (1.8-2.6) ‘Mean and95% confidence intervals. Modified from Circulation.32 LV = left ventricular; TIMI = Thrombolysis
Progressive LV Dilation (n = 14)
15 (7-24)
20 (14~27F
52 (47-60)
39 (34-46)
61%
57%
38 (32-39)
31 (25-36)
2.1 (1.7-2.6)
1.3 (0.6-1.9)
in Myocardial
Infarction
trial.13
ment in regional function or ejection fraction when thrombolysis is administered early, but there is lack of improvement if given later than 3-4 hours after symptom onset.21322 Large ongoing studies with very early reperfusion, not yet reported, aswell as a previous study by Koren et al23 suggest that the ejection fraction can be normal when reperfusion is achieved within 90 minutes after the onset of symptoms. Studies on LV function studied immediately before thrombolysis and again about 1 week later in the same patients sometimes have failed to show significant average changes in the ejection fraction,24>25although other reports show improvement, particularly when measured after several weeks.26 However, patients with unsuccessful thrombolysis or with small infarcts often have been included in such analyses, and also recovery of function may be incomplete by 1 week, as shown in laboratory studies.17J8 Additional factors can be involved when regional or global function fails to improve after reperfusion. Of particular importance appear to be an inadequate level of blood flow after reperfusion and coronary reocclusion, as discussed subsequently. IATE VENlRlCUl.AR REMODEUNG AND FUNCTION AFIER REPERFUSION
It is established in patients with a large first anterior myocardial infarction that, if the vessel is occluded at 3 weeks, progressive chamber dilation with LV dysfunction generally occurs over the following year, a change that does not result from initial infarct expansion.27If the artery is patent, less LV dilation occurs and it does not tend to be progressive.28,29Progressive late ventricular dilation after acute infarction often can be prevented by administration of an angiotensin-converting en940
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
zyme (ACE) inhibitor, both in the presence of anterior infarction, as shown by Pfeffer and Braunwald,29 or with inferior infarction as reported by Sharpe et aL30 Inadequate reflow or reddual stenosis: In patients who have undergone thrombolysis, several factors are important in the remodeling response, including the level of blood flow after reperfusion, the degree of residual coronary stenosis, and the occurrence of reocclusion (Table I). Recent studies after thrombolysis indicate that TIM1 flow grade 2 may be ineffective and not significantly different from TIM1 grade O-l flow in reducing infarct size.31In this regard, studies by Gaudron et aP2have further clarified the determinants of late unfavorable LV remodeling in patients receiving thrombolysis. In a study of 70 patients with a first myocardial infarction, cardiac catheterization and coronary angiography were performed at 3-5 weeks and the LV ejection fraction and diastolic volume were then studied serially over a 3-year period by radionuclide angiography. For analysis, patients were separated into groups without initial dilation of the left ventricle, with limited dilation (without progression), and with progressive dilation. The LV ejection fraction remained normal in the group without initial dilation; it was reduced but stable in those with limited dilation; however, it fell from an initially abnormal value (close to 40%) to <25% over the 3-year follow-up period in patients with progressive dilation. Deterioration of function occurred in the latter group only in those regions without initial dysfunction.32On multivariate analysis, predictors of progressive LV dilation, based on the initial postinfarction studies, were myocardial infarct size (ventriculography), ejection fraction, anterior infarct location, the stroke volume index, and TIM1 flow grade32(< 2.0 [average, 1.31in the progressive dilation group; Table II). Investigations by Leung and Lau33 in patients with first anterior myocardial infarction receiving thrombolysis have assessedthe effects of residual coronary stenosis present at 7-10 days on LV volume and function using serial echocardiography over a l-year period. As expected, in patients with total coronary occlusion there was progressive LV enlargement and a fall in ejection fraction, whereas in patients with a stenosis diameter > 1.5 mm the LV end-diastolic volume was initially smaller than that in those with an occluded artery and showed no further enlargement at 1 year. However, in patients with a residual minimal lumen diameter in the infarct-related artery of < 1.5 mm, at the end of 1 year the LV end-diastolic volume had signifi-
DECEMBER 16, 1993
cantly increased and was larger than that in the patients with a diameter > 1.5 mm.33In a recent preliminary report these same authors describe the use of PTCA at 1 week in patients after first anterior infarction with a minimum lumen diameter < 1.5 mm after thrombolysis compared with similar, randomized untreated patients; at 1 year, PTCA of the residual stenosis resulted in significantly less LV dilation and improved LV function compared with the group without PTCA.34 Coronary mocclusion: Another event potentially affecting LV function following the acute phase of infarction is described in studies by the Anthrombotics in Prevention of Reocclusion in Coronary Thrombolysis (APRICOT) investigators,35 demonstrating that the rate of coronary artery reocclusion is quite high (25-30%) by 3 months after conventional thrombolysis, even in the heparin or aspirin treatment groups. The reinfarction rate was 11% in the placebo group, and this was reduced by aspirin.35 Preliminary observations by these investigators using ventriculography at 3 months indicated that, compared with patients without reocclusion who showed improved LV ejection fraction, there was no improvement of function in patients with anterior infarction who had coronary reocclusion, although the degree of LV dilation was unaffected.36 THERAPEWIC CONSIDERATIONS
A number of the factors that importantly affect LV function during the evolution of myocardial infarction and after thrombolysis can only be influenced by measures discussed elsewhere in this symposium. Reduction of the time factor will require steps to increase the early use of thrombolytic agents within l-2 hours, but even late thrombolysis at 6-24 hours after symptom onset may benefit the left ventricle by limiting chamber dilation, without enhancing the ejection fraction.37Use of antithrombin agents such as hirudin38 may improve the rate and degree of thrombolysis, and these or other new agents are needed to improve the currently high early and late reocclusion rates and may enhance the level of residual myocardial blood flow after reperfusion. The use of primary PTCA in acute myocardial infarction has been reported to improve the LV ejection fraction from 52.6% immediately before angioplasty to 58.9% at 1 week39and undoubtedly would reduce the incidence of residual high-grade stenosisof the infarctrelated artery, but this approach will require further study with controlled trials. In the meantime, we are left with a subpopula-
tion within the group of patients treated by thrombolysis who will exhibit progressive unfavorable LV remodeling after reperfusion ending in cardiac failure. Compensatory hypertrophy and dilation occur initially in such patients, but despite these adaptations the cardiac index remains low and the systemic vascular resistance rises.32In some patients, residual coronary stenosis may prevent the development of compensatory hypertrophy in the reperfused zone, which occurs in animaIs after reperfusion when the artery is fully patent.14J9 Intermittent ischemia due to disease in other coronary vesselscould further contribute to unfavorable remodeling in some patients. When such events occur, the noninfarcted regions are subjected to increased systolic wall stress, with afterload mismatch,40resulting eventually in progressiveLV dilation and further depression of function, as wall thinning further contributes to elevated systolic and diastolic wall stress levels. Such events have been discussedbased on morphologic studies in the rat.41 Approaches to preventing or reversing left ventrkular dysfunction: Steps toward preventing
the above maladaptive sequence of events should be taken prior to hospital discharge. Patients at high risk for progressive LV dilation and dysfunction should be identified in the early convalescent phase. Such patients usually will have had a large infarction, more commonly anterior in location, and exhibit a significantly reduced LV ejection fraction by echocardiographic or radionuclide studies; they may have a prior infarction, and if other noninvasive studies are performed there may be an abnormal or equivocal response to exercise, or ineligibility to perform such testing. Whether or not exercise is attempted in such patients, coronary angiography in the early convalescent phase is indicated. On coronary angiography, such patients at high risk of progressive LV dilation often have TIM1 flow grade of I 2.0,31with residual coronary stenosis.32 Whether or not revascularization is immediately carried out, such patients should be treated with an ACE inhibitor,42 even if symptoms of cardiac failure are absent.43 Serial assessmentof LV size and ejection fraction by echocardiography or radionuclide studies for at least 2 years also seemsadvisable in patients who do not undergo revascularization, to search for evidenceof progressiveLV dilation and dysfunction. Should progressive LV dilation occur despite medical treatment, repeat angiography and consideration of revascularization of all vesselssupplying viable but dysfunctional regions may offer the best A SYMPOSIUM: UNRESOLVED ISSUES IN THROMBOLYSIS
950
possibility for reversing or halting the progression of LV dilation and dysfunction in this setting. It is known from laboratory experiments that during ischemia the level of regional contraction declines, or down-regulates, to match the available subendocardial blood flow per beat (perfusioncontraction matching), and this is reversible if the residual flow is sufficient to prevent infarction.44 Early investigations in patients with chronic stable angina pectoris after coronary artery bypass surgery demonstrated increased LV function in some patients, leading to the concept of chronic myocardial dysfunction, or “hibernation,” which is reversible.45Later, clinical studies showed that regional contractile dysfunction in which tissue viability could be demonstrated by positron emission tomography (preserved [18F]fluorodeoxyglucoseuptake) was at least partially reversible by myocardial revascularization.46T47Other, simpler techniques for detecting dysfunction in the presence of tissue viability are now available, including thallium-201 imaging with reinjection48 and echocardiography during dobutamine administration,49 as discussed by others in this symposium. Thus, in patients who show late cardiac enlargement with dysfunction following thrombolysis, despite medical treatment with an ACE inhibitor in addition to coronary angiography, a search should be undertaken to identify areas of hibernating or stunned myocardium, since appropriate revascularization in such patients may prevent further dilation or even partially reverse ventricular dysfunction. It is clear that many events occur during the evolution of myocardial infarction and after thrombolysis for which treatment is possible, and there is good reason to expect that LV function can be improved well beyond the modest increase now observed with thrombolytic therapy. This, in turn, could have a further significant impact on morbidity and mortality after reperfusion.
REFERENCES l. Multi-Center Post-Infarction Research Group. Risk stratification and survivaI after myocardial infarction. N Engl .I Med 1983;309:331-336. 2. Nicod P, Gilpin EA, Dittrich H, Chappuis F, EngIer R, Henning H, Ross J Jr. Influence on prognosis and morbidity of left ventricular ejection fraction with and without signsof let? ventricular failure after acute myocardial infamtion. Am f Cardio~1989;61:1165-1171. 3. Ahnve S, GiIpin E, Henning H, Maisel AA, Dittrich H, Carlisle J, Ross J Jr. Limitations and advantagesof the ejection fraction for defining high risk after acute myocardial infarction. Am J Cmfiol1986,58:872-878. 4. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G, and the Working Group of the GISSI-2 Data Base Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis.Circulafbn 1993;88:416429. 5. Christian TF, Schwartz RS, Gibbons RI. Determinams of infarct size in reperbrsion therapy for acute myocardial infarction. Ctiulnrion 1992,86:81-90.
96a
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
6. Pfeffer a Pfeffer JM, Fishbem M, Fletcher PJ, Spadaro J, KIoner RA, Bratmwald E. Myocardial infarct size and ventricular function in rats. Cti Res 1979;44:503-512. 7. Ono S, Bharghava V, Otto S, Mao L, Hagan G, Rockman HG Ross J. In ti assessmentof left ventricular remodeling after myocardiil infarction by digital video-contrast angiographyin the rat. CardiovasRe.s(in press). 8. Ross J Jr. Mechanical consequencesof regional myocardial ischemia. In: Fozzard HA, Haber A, JenningsRB, Katz AM, Morgan HE, eds. The Heart and Cardiovascular System:Scientific Foundations,vol. II, 2nd ed. New York: Raven Press,1992:1997-2020. 9. SasayamaS, Gallagher KP, Kemper WS, FrankIm D, Ross J Jr. Regional left ventricular waU thickness early and late after coronary occlusion in the consciousdog.Am J P&i01 1981;24&H293-H299. 10. SchaperW. Experimental infarcts and the micmcircuIation. In: Hearse DJ, YeIIon DM, eds. Therapeutic Approaches to Myocardiai Infarct Size Limitation. New York: Raven Press,1984z7990. iL Reimer KA, Jemrings RB, Cobb FR, Murdock RI-I, Greenfield JC Jr, Becker LC, BuIkIey BH, Hutchins GM, Schwartz RP Jr, Bailey KR. Animal modelsfor protecting ischemicmyocardium:results of the NHLBI Cooperative Study.Comparison of unconsciousand consciousdog models.Cim Res 1985,56: 651465. l2. Rogers WJ, Hood WP Jr, Mantle JA, Baxley WA, KirkIin JK, Zorn GL, Nath HP. Return of left ventricular function after reperfusion in patients with myocardiil infarction: importance of subtotal stenoses or intact CoUateraIs. Ckularion 1981;69338349. ia. Habib GB, Heibig J, Forman SA, Brown BG, Roberts R, Terrin ML, BoUi R. Influence of coronary collateral vesselson myocardial infarct size in humans. Results of phase I ThromboIysii in Myocardial Infarction (TIMI) trial. The TIM1 Investigators.CimuZadon1991;83:739-746. l4. Oh B-H, Ono S, Rockman w Ross J Jr. Myocardial hypertrophy in the ischemic zone induced by exercise in rats alter coronary reperfusion. Cirrularim 1993;87:598607. is. Martin GV, Sheehanm Stadius M, Maynard CM, Davis KB, Ritchie JL, Kennedy JW: Intravenous streptokinasefor acute myocardial infarction. Effects on global and regional systolic function. Circulation 1988;78:25%266. l6. Reimer KA, Lowe JE, RasmussenMM, Jennings RB. The wave front phenomenonof ischemiccell death. I. Myocardii infarct size versus duration of coronary occlusion in dogs,Cirnrlatin 1977;563786794. 17. Gii WR, Sybets HD, Maroko PR, CoveU JW, Sobel BE, Ross J Jr. Coronary artery reperfusion II: Reduction of myocardial infarct size at one week after the coronaty occlusion.J Clin Invest 1972;51:2717-2723. lB.Theroux P, Ross J Jr, Franklin D, Kemper WS, SasayamaS. Coronary arterial reperfusion. III. EarIy and late effects on regional myocardial function and dimensionsin consciousdogs.Am J CardioZ 1976;38:599606. 19. Kambayashi M, Miura T, Oh B-H, Murata K, Rockman I-& Parra G, Ross J Jr. Myocardial ceU hypertrophy with reperfusion in dogs. Cimhim 1992,86:1935-1944. 2O.White HD, Norris RM, Brown MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whidock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 198~317:85%355. 21 Serruys PW, SimoonsML, SutyapranataH, Vermeer F, Wijns W, van den Brand M, Bar F, Zwaan C, Krauss XII, Remme WJ. Preservation of global and regional left ventricular function after eady thromboIysisin acute myocardial infarction. JAm Co11Cardiol1986;7:729-742. 22. Schriider R, Neuhaus K-L, Leiirovicz A, Lmderer T, Tebbe U for the I.S.A.M. Study Group. A prospectivetrial of intravenous streptokinasein acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days.N Engr’JMed 1986;314:1465-1471. 25. Karen G, Weiss AT, Hasin Y, Appelbaum D, Welber S, Rozenman Y, Lotan C, Mosseri M, Sapoznikov D, Luria MH, Gotsman MS. Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase.N EnglJMed 1985;313:1384-1389. 2AChesebm JH, Knatterud G, Roberts R, Borer J, Cohen IS, Dalen J, Dodge HT, Francis CK, HiUis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, WilIerson JT, WiUiamsDCJ,Zaret BL, BraunwaId E. Thrombolysis in myocardial infarction (TIMI) trial, Phase I: a comparison between intravenous tissue plasminogenactivator and intravenous streptokinase. Circulation 1987;76:142154. 25. Marino P, Zanolla L, Zardii P on behalf of the Gruppo It&no per lo Studio deUaStreptochmasineU’Infarto Miocardico (GISSI). Effect of streptokinam on left ventricular modeling and function after myocardial infarction: The GISSI (Gruppo Italian0 per lo Studio della Streptochinasi neU’Infarto Miocardico) trial. JAm CoUCaniiof 1989;14:1149-1158.
DECEMBER 16, 1993
26.Anderson JL, Becker LC, Sorensen SG, Karagounis LG Browne KF, Shah PK, Morris DC, Fintel DJ, Mueller HS, Ross AM, Hall SM. Askins JC, Doorey AJ, Chines CL, Moreno % Marder VJ for the TEAM-3 Investigators. Antistreplase versus alteplase in acute myccardial infarction: comparative effects on left ventricular function, morbidity and l-day coronary artery patency. JAm Coil Cardioll9!?2;20:153-766.
27. Topol EI, CaIii RM, Vandotmael M, GrimesC, George B, Sam ML, Wall T, O’Brien M, Schwaiger M, Aguirre F, Young S, Popma JJ, Sigmon K, Lee a Ellis SG, and the TAMI- Study Group. A randomized trial of late reperfusion therapy for acute myocardial infarction. Circularion 1992;85:2@& 2099. 28. Pfeffer MA, Lamas GA, Vaughn DE, Parisi AF, Braunwald E. Effect of captopril on progressiveventricular dilatation after anterior myocardial infarction. N EngfI Med 1988;319:8&86. 29. Pfeffer h4A, BraunwaId E. Ventricular remodeling after myocardial infarction. Circularion 1990;81:1161-1172. 3O.Sharpe N, Smith H, Murphy J, Hannan S. Treatment of patients with symptomlessleft ventricular dysfunction after myocardial infarction. Lancef 1988;i:z5-259. 3l. Karagounis L, SorensenSG, Menlove RL, Moreno F, Anderson JL Does thrombolysis in myocardial infarction (TIMI) perfusion grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electmcardiographic evidencefrom the TEAM-2 study.JAm Coil Cardioi 1992;19:1-10. 32. Gaudron P, EiIIes C, Kugler I, Ertl G. Progressiveleft ventricular dysfunction and remodeling foIIowing myccardial infarction: potential mechanismsand early predictors. Cimulatin 1993;87:755-763. 33. Leung W-H, Lau C-P. Effects of severity of the residual stenosisof the infarct-related coronary artery on left ventricular dilation and function after acute myocardial infarction. JAm Coil Cardiol1992;20:307-313. 34. Leung W-H, Lau C-P. Beneficial effects of late angioplasty of the infarctrelated coronary artery on subsequentleft ventricular remodeling after acute myccardial infarction. JAm Co11Cardi 1993;21:44A. 36. Meijer A, Verheugt FWA, Wetter CJ, Lie KI, van der Pol JUT, van Eenige MJ. Aspirin versus coumadii in the prevention of reocchrsion and recurrent ischemia after successful thrombolysis: a prospective placebocontrolled angiographicstudy. Circukz?ion1993,87:1524-1530. 36. Meijer A Verheugt FWA, Wetter C for the APRICOT Investigators.Late reperfusion after thrombolysis: incidence and consequencesfor left ventricular recovery and dilatation. JAm Coil Canfiol1993;21:45A. 37. Top01 E, C?alitIRM, Vandormael M, Grines C, George B, Sam ML, WaII T, O’Brien M, Schwaiger M, Aguirre F, Young S, Popma J, Signron K, Lee
KL, Ellis S and the Thmmbolysis and Angioplasty in Myocardial Infarction-6 Study Group. A randomized trial of late reperfusion therapy for acute myocardial infarction. Circulation 1992$5:2090-2099. 38. Chescbro JH Webster MW, Zoldhelyi, Rcche PC, Badimon L, Badiion JJ. Antithrombolytic therapy and progressionof comnaty artery disease.Antiplatelet versusantithrombins. Cirnrlafion 1992;86(suppl):III-lC%III-110. 39. O’Keefe JH Jr, Rutherford BD, McConahay DR, Johnson WL Jr, Giorgi LV, Shimshak TM, Ligon RW, McAllister BD, HartzIer GO. Myocardial salvage with direct coronary angioplasty for acute infarction. Am Heart J 1992;123:1-6. 40. Ross J Jr. Afterload mismatch and preload reserve: a conceptual framework for the analysisof ventricular function, Prog Cardiovax Dis 1976;18:255264. 41. Olivetti G, CapassoJM, Meggs JM, Sonnenblick EH, Anvetsa P. CeIIuIar basisof chronic ventricular remodeling after myocardial infarction in rats. Cirr: Res 1991;68:856-869. 42. Pfeffer MA, Lamas GA, Vaughn DE, Parisi AF, BraunwaId E. Effect of captopril on progressiveventricular dilatation after anterior myocardial infarction. N Engl JMed 1988;319:8&86. 43. Pfeffer MA, BraunwaId E, Moye LA, Basta L Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect of captopril on mortality and morbidity in patientswith left ventrictdar dysfunctionafter myocardial infarction. Results of the sulvival and ventricular enlargement trial. The SAVE Investigators.N Engl J Med 1992,3276@-677. 44. Ross J Jr. Myocardial perfusion-contraction matching: implications for coronary heart diseaseand hibernation. Circuladon 1991;83:10761083. 45. Rahimtoola, SH. The hibernating myccardium.Am Heari J 1989;117:211221. 46. TiIIiih J, Brunken R, Marshall R, Schwaiger M, MandeIkem M, Phelps M, SchelbertH. Reversibility of cardiac waII motion abnormalities predicted by positron tomography.N Engf J Med 1986314884889. 47. de SiIva R, Yamamoto Y, Rhodes CG, Iida H, Nihoyannopoulos P, Davies GJ. Preoperative prediction of the outcome of coronary revascularization using positron emissiontomography.Cirwlation 1992;86:1738-1742. 48. Dilsiiian V, Rocco TP, Freedman NMT, Leon M, Borrow RO. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistributionimaging.N [email protected] Med 1990,323:141-146. 49. Maraullo P, Pamli 0, Reisenhofer B, SambucetiG, Picano E, D&ante A, Gimelli A, L’Abbate A. Value of rest thallium-ZWtechnetium-!39msestamibi scansand dobutamine echocardiographyfor detecting myocardial viability. Am J Cardiol 1993;71:166-172.
A SYMPOSIUM: UNRESOLVED ISSUES IN THROMBOLYSIS
970