Determinants of improved left ventricular function after thrombolytic therapy in acute myocardial infarction

937

JACC Vol. 9. NO.4 April 1987:937-44

SEMINAR ON THROMBOLYSIS IN MYOCARDIAL INFARCTION-IV John H. K. Vogel, MD, FACC, Guest Editor

Determinants of Improved Left Ventricular Function After Thrombolytic Therapy in Acute Myocardial Infarction* FLORENCE H. SHEEHAN, MD Seattle. Washington

Many studies have been performed to evaluate the efficacy of thrombolytic therapy in achieving reperfusion, salvaging myocardium and enhancing survival. This review discusses the concordance between the results of these clinical studies and the observations made in experimental animals of the effect of reperfusion on the recovery of left ventricular function. The evaluation of functional recovery is affected by the timing of the measurement and the sensitivity of the method for detecting regional abnormalities. In addition, the underlying coronary anatomy also determines outcome, so that infarct location, collateral circulation and the degree of coronary obstruction merit consideration.

Since DeWood et al. (1) demonstrated the incidence of coronary thrombosis and the safety of performing cardiac catheterization in patients during acute myocardial infarction, there has been intense interest in thrombolytic therapy. Most studies have focused on measuring the coronary reperfusion rate achieved by various agents and dosage regimens. The underlying hypothesis is that reperfusion will salvage myocardium and thereby reduce mortality. This hypothesis is based on the observations made in studies of reperfusion and infarct size reduction in experimental animals, but has not yet been verified in humans. However, recent studies have demonstrated a beneficial effect of thrombolytic therapy and reperfusion on survival after myoParts I. II and III of this Seminar appeared in the November 1986 and January and March 1987 issues of the Journal. From the Cardiovascular Research and Training Center, University of Washington, Seattle, Washington. This study was supported in part by grants from the RJ. Reynolds Foundation, Winston-Salem, North Carolina and by Grants HL-27819 and HL-19451 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Baltimore, Maryland. Manuscript received June 17, 1986; revised manuscript received November 12, 1986, accepted November 20, 1986. Address for reprints: Florence H. Sheehan, MD, University of Washington, RG-22, Seattle, Washington 98195. © 1987 by the American College of Cardiology

Two factors are of paramount importance in determining the amount of myocardium salvaged, the recovery of left ventricular function and the reduction in mortality. These factors are: the time delay until reperfusion is achieved and the adequacy of the coronary reftow. The close agreement between studies measuring the effect of reperfusion on left ventricular function and studies with mortality as the end point provides indirect evidence that enhancement of survival in patients treated with thrombolytic agents is mediated by recovery of ventricular function. (J Am Coli Cardiol1987;9:937-44)

cardial infarction in certain patient subgroups. In retrospect, the identification of these subgroups was foreseen by certain experimental and clinical studies of the effect of reperfusion in salvaging myocardium. Therefore, the present report will review the experimental and clinical studies of myocardial salvage after reperfusion from the viewpoint of their concordance with the results of clinical trials testing survival after thrombolytic therapy. Because salvage of left ventricular function is the link between achievement of reperfusion and enhancement of survival, identification of the factors influencing recovery of ventricular function after thrombolytic therapy will form the framework for this discussion.

Measurement of Myocardial Salvage The term myocardial salvage refers to a reduction in infarct size from that anticipated if no intervention were applied (2). In experimental animals, it is possible to measure infarct size directly from the mass of infarcted tissue, with the assistance of tetrazolium stains of slices of the left ventricle, and compare it with the mass of myocardium at risk of infarction, determined by perfusing the beds of the occluded and nonoccluded arteries with differently colored 0735-1097/87/$3.50

lACC Vol. 9. No.4 April 1987:937-44

SHEEHAN LEFT VENTRICULAR FUNCTION AFTER THROMBOLYSIS

938

stains (3,4). In humans, measurements are much less precise, even using quantitative analysis of thallium-201 scintigrams (5,6). Estimation of infarct size from creatine kinase (CK) release (7) or changes on the electrocardiogram (8) is even more indirect. The term myocardial salvage is also applied to the recovery of left ventricular function after a therapeutic intervention in patients with infarction. Although the severity of left ventricular dysfunction correlates with infarct size, the relation is not close enough to permit an accurate assessment of the mass of the infarcted myocardium (9). This is partly because function may also be depressed in normally perfused myocardium adjacent to an acutely ischemic region (10). Also, the gradual resolution of wall motion abnormalities with time results in a constantly shifting relation with infarct size (II). Furthermore, ventricular function and infarct size are not linearly related (12,13). Finally, infarction may also cause asynchronous contraction, an abnormality that may be missed when evaluating function at endsystole alone (14,15). Thus measurement of left ventricular function provides only an approximation of the mass of infarcted myocardium. However, the appearance of clinical cardiac decompensation correlates with the level of left ventricular function and depends only indirectly on infarct size (16,17). Therefore, it is more clinically relevant to assess myocardial salvage by measuring the function of the viable myocardium than the mass of the infarct.

When Should Left Ventricular Function Be Measured? After reperfusion of an occluded coronary artery in the dog, there is a delay before contractile function returns to normal (18). This delay occurs even after a 5 minute occlusion, which is too brief to induce necrosis (19). Recovery of function is more delayed after more prolonged occlusion

(18,20). Four to 7 days are required for recovery after a I hour coronary occlusion; up to 4 weeks are required for function to reach a plateau after 3 hour or permanent occlusions (20,21). Even after rest function has peaked, the ability of reperfused myocardium to respond to stress may not recover until weeks later (20). The dysfunction of this viable but' 'stunned" myocardium is attributed to disruption of oxidative metabolism (22,23). As a result, the salvage achieved by thrombolytic therapy may be underestimated if left ventricular function is measured early after myocardial infarction, before recovery is complete. Thus, no change in ejection fraction or regional wall motion is seen immediately after reperfusion in most (24-26) but not all (27) studies. Indeed, measurement of left ventricular function during the first 24 hours after acute infarction is so variable, as a result of I) the shifting hemodynamic status, or 2) changes in perfusion due to spontaneous reperfusion or opening of collateral channels, or both, that it would be difficult to demonstrate an improvement (28,29). Serial studies have not been performed in humans to determine when left ventricular function reaches maximal recovery after thrombolytic therapy. However, experimental data suggest that measurements made earlier than 2 weeks after infarction will overestimate dysfunction in patients who undergo reperfusion later than 2 hours after the onset of infarction or who fail to achieve reperfusion because their recovery occurs more slowly, if at all, than if reperfusion is achieved earlier.

Importance of Measuring Regional Left Ventricular Function In almost all experimental studies, the effect of coronary artery occlusion and reperfusion on ventricular function was evaluated within the ischemic region by measuring segment length changes using sonomicrometers or strain gauges. It

1.5 Q

Z

III

... f-

Z

o

o

I-

...J ...J

0

IL

Z

Z

It:

...

I-

Z ([

,W

o

e

0

I&J

:I:

0.5

([

([ :2

<>

Figure 1. Change in wall motionand ejection fraction after intracoronary streptokinase. Patientswith optimal reperfusion were sent for coronary artery bypass surgery (+CABG); although motion in the infarct region improved significantly, the ejection fraction change was small because hyperkinesia in the opposite wall decreased concurrently. Patients with partial reperfusion werenot sent to surgery (STREPTOKINASE ALONE); the ejection fraction reflected the marked decrease in hyperkinesia in the noninfarct region, rather than the small improvement in the infarct region. In patients without reperfusion or with rethrombosis, motion in both walls decreased. and so did the ejection fraction. (Adapted with permission from Sheehan FR et at

0

...

:E

...

*

-0.5

0 I&J

*p<.001

Q

Z

ex -1.5

i

*

WALL HOTION IN INFARCT SITE WALL MOTION HI NONINFARCT SITE EJECTION FRACTION

STREPTOKINASE +

CABG

STREPTOKINASE ALONE

PERMI=lNENT OCCLUSIONS. REINFARCTION5

[33].)

JACC Vol. 'I, NO.4 April 1'187:'137-44

has long been recognized (30) that dysfunction of noninvolved regions reduces the accuracy with which the ejection fraction indicates the severity of hypokinesia in the infarct site. This problem is heightened by the unpredictable severity and indeed the heterogeneity of the dysfunction in the noninfarct region, which has ranged from hyperkinesia to hypokinesia in experimental studies (31,32). Significance of changes in ejection fraction. Nevertheless, there has been a tendency in clinical studies to measure global ventricular performance from the ejection fraction, even though acute compensatory hyperkinesia in the noninfarcted region may develop in humans. Because of this acute hyperkinesia, which usually subsequently subsides, the ejection fraction has proved to be an unreliable and insensitive measure of either the severity of hypokinesia in the infarct region or the effect of therapeutic interventions in salvaging function (33-35). The ejection fraction change may not only underestimate recovery of regional function in the infarct site after reperfusion (Fig. I), but also overestimate recovery if reperfusion benefits function in both the infarct and noninfarct regions (36-38). Because of this variable response of the noninfarct region. measurement of the ejection fraction has usually yielded less significant, or even insignificant, responses to reperfusion compared with wall motion analysis (33,34.39). Thus. the inclusion of regional wall motion analysis in clinical trials of thrombolytic therapy or of other interventions in ischemic heart disease is useful for determining whether the observed ejection fraction changes accurately represent the effect of therapy on function in the region of interest.

How is Outcome Related to the Acute Severity of Ventricular Dysfunction? It was recognized very early (40) that contraction ceases within seconds after coronary artery occlusion and is often replaced by paradoxic motion due to passive bulging of the ischemic segment. Subsequent studies (41,42) demonstrated that such akinetic or dyskinetic segments can recover contractility even if reperfused as late as 3 hours after coronary occlusion. However Lavallee et al. (20) found that after 2 I hour of ischemia, regions of the myocardium with severe ventricular dysfunction were less likely to recover fully after reperfusion than were regions with mild hypokinesia. In patients with reperfusion, the greatest improvement in ejection fraction occurs in those who had a depressed ejection fraction «45%) acutely (39,43). Similarly, the change in wall motion after reperfusion correlates significantly with the acute severity of regional dysfunction such that the greatest improvement occurs among patients who had akinesia or dyskinesia acutely (44). These data can be interpreted on two levels. Simplistically. reperfusion results in recovery of normal function; therefore. only a small improvement will occur in patients with mild or moderate hypokinesia

SHEEHAN LEFT VENTRICULAR FUNCTION AFrER iHROMBOL YSIS

939

acutely because greater improvement would result in hyperkinesia. More importantly. the data suggest that patients with severely depressed ventricular function acutely have the potential to achieve near-normal contraction if reperfusion is achieved early. Reperfusion in cardiogenic shock and in anterior infarction. Indeed, clinical studies of the effect of thrombolytic therapy on survival support this conclusion, For example. data from the registry of the Society for Cardiac Angiography (45) showed that the in-hospital mortality rate among patients in cardiogenic shock was lower in those who achieved coronary reperfusion versus those who did not (42.1 versus 84.0%, n = 45. P < 0.001). Furthermore. although anterior infarcts are larger than inferior infarcts and produce more extensive left ventricular dysfunction, it is in patients with anterior infarction that reperfusion reduces in-hospital and long-term mortality (46). Thus, it is for the patient with the most severely compromised ventricular function that thrombolytic therapy offers the greatest potential benefit. The advisability of thrombolytic therapy for patients with inferior infarction needs to be evaluated in this light.

Influence of Pretreatment Coronary Anatomy on Recovery of Ventricular Function The status of the coronary circulation before thrombolytic therapy has been repeatedly shown to be an important determinant of the severity of ventricular dysfunction during the acute infarction and of the magnitude of functional recovery. Three factors are involved: the location of the infarct-related coronary lesion, the presence of collateral vessels and the presence of total or subtotal occlusion in the infarct-related artery. Left anterior descending versus right coronary artery occlusion. The left anterior descending coronary artery supplies more than half of the left ventricle in humans. the right coronary artery only 21 % (47). Therefore. the magnitude of left ventricular dysfunction is greater after anterior wall infarction, because of the larger infarct size (48). The location of the stenosis along the infarct artery is a significant determinant of left ventricular function in left anterior descending artery-related infarction with a more distal occlusion producing less severe hypokinesia. This is not true for right coronary artery-related infarction, perhaps because only the posterior descending branch of this artery supplies the left ventricle (49). Collateral circulation. Collateral circulation to the infarct artery can be induced in the dog by gradual coronary artery occlusion. The presence of collateral vessels reduces infarct size after complete coronary occlusion (4). However, in humans the incidence of collateral circulation at the time of acute infarction is generally small (6 to 16%). The estimates vary by I) whether all or only "well developed"

940

lACC Vol. 9. No. 4 April 1987:937- 44

SHEEHAN LEFr VENTRICULAR FUNCfION AFrER THROMBOLYSIS

collateral vessels are counted, and 2) when angiography was performed relative to the onset of infarction, because collateral vessels develop rapidly after infarction (50,51). When present, collateral vessels exert protective effect in relation to left ventricular function and prognosis (52,53). Total versus subtotal occlusion. Incomplete coronary occlusion is even mote protective; as indicated by the higher ejection fraction in patients with this finding than in patients with collateral vessels to a totally occluded artery. This suggests that retrograde flow by way of collateral vessels is less adequate than restricted anterogradeflow (54). Because the incidence of total coronary occlusion diminishes with time after Infarction (I), patients presentingwith incomplete coronary occlusion may have undergone spontaneous reperfusion of a previously occluded artery before the time of angiography. Alternatively, it is theoretically possible for infarction to occur under stressful conditions in the presence of a critieal coronary artery stenosis. This has been demonstrated in a dog model with an isoproterenol infusion as the stress and coronary constriction severe enough to prevent reactive hyperemia but allow normal flow at rest (55). The mechanism may be transient occlusion by platelet thrombi

'. o

r

a

(56) .

By either mechanism, the presence of incomplete coronary occlusion before treatment is a natural model of very early reperfusiori . This may explain the better baseline left ventricular function in such patients (44) and their spontaneous improvement even without thrombolytic therapy (57). The advantage of having incomplete or subtotal occlusion is further supported by the following indirect evidence: I) thallium perfusion defect size was most reduced after reperfusion achieved by intracoronary streptokinase in the subset of patients with either collateralcirculationor subtotal

... ...~

1

2

1II

1II

I

•••••• •••• ••• ••••• ••

...

o

o

o

Z

e • e

I

o

4

o

0

"

9•••••• .• ••••• •. .. . . . . .. . . . . . . . . . . . c.••

0

:0 :

e

~ "

:

o

~

l,

o

0

0

•

).i

:I:

0

o

0 0

(;

00

o

00 00

0

I .· :

e

e

I

0 . 2 0••

I

0.11

O.B

1.2

I .•

MINIMUM DIAMETER OF STENOSIS. MM Figure 3. Effect ofsevere residualcoronary stenosis onfunctional

recoveryafter thrombolytic therapy. Change inhypokinesia in the infarct site, measured using the centerline method and expressed in terms of SD from normal, is plotted on the y axis. Stenosis severity is plotted on the x axis in terms of the minimal diameter of the stenosis. Patients in whom the residual minimal diameter was ::;0.4 mm had significantly less functional recovery than patients with less severe residual stenosis. (Reproduced with permission from Sheehan FH . et al. [44].) occiusion of the infarct artery (58); 2) the ejection fraction decreased significantly in patients with unsuccessful reperfusion, except in those protected by collateral vessels or subtotal occlusion(59); and 3) the ejection fraction increased in patients in whomCK release peakedearly after infarction, presumably because of spontaneous reperfusion, but not in patients with slow release (60).

Adequacy of Reperfuslon Figure 2. Minimal Coronary cross-sectional areas inpatients with

coronary lesions that rethrombosed versus those with lesions that remained patent. Rethrotnbosis occurred in 7 of 12 patients with areas < 0.4 mm?versus0 of 12 with areas >0.4 mrrr' (p < 0.005). (Reprinted with permission from Harrison DG, et al. [641 .) o

-

2

III

I:

Hl s 1.11

8

0([

~li!

IP

~J
o ~

.

([ 1.2


i

t)

W

til 0• •

0

0

lib

0

fol

0 0

0

LESIONS R£IlAINING PATENT

LESIONS. RETHROMBDSED

Role of residual stenosis. Early investigators of thrombolytic therapy recognized that intracoronary streptokinase therapy leaves a significant residual stenosis in the infarct artery (61). Attempts to relate the severity of this residual stenosis to the patient's clinical outcome failed (62), probably because of the inaccuracy of visual estimates of stenosis severity (63). When quantitative analysis of the severity of the residual stenosis was perforrried, the risk of reocclusion could be shown to increase significantly when the minimal area of the lumen was less thim 0.4 mm? (Fig. 2) (64). Even in the absence of reocclusion, the recovery of regional ventricular function was precluded if the minimal diameter of the lumen was less than 0.4 mm (Fig. 3) (44). Because reflew occurs across a significant residual stenosis in most patients (61), thrombolysis is not strictly comparable with experimental studies of reperfusion in which the coronary occlusion was completely released. Instead, clinical thrombolysis is better resembled by an experimental model in which reflow is restricted to control levels and

lACC Vol. 9. No.4 April 1987:937-44

SHEEHAN LEFf VENTRICULAR FUNCTION AFfER THROMBOLYSIS

reactive hyperemia is prevented. Studies in such a model have demonstrated shunting of coronary blood flow to the subepicardium and persistent ischemia in the subendocardium (65). This may prevent or delay recovery of ventricular function (66). On the other hand, when postischemic myocardium is subjected to hyperperfusion at levels exceeding normal coronary flow it regains much of its function (67). Comparison with angioplasty. In concurrence with these experimental findings, recent studies indicate that by itself thrombolytic therapy results in less functional recovery than does combined therapy with percutaneous angioplasty (68,69) or acute revascularization with angioplasty alone (70,71). Although some of these are preliminary reports, the observations suggest that reducing the residual stenosis by mechanical means salvages more myocardium than does reperfusion by thrombolytic therapy alone. Partial reperfusion and survival. These studies of ventricular function are paralleled by the Western Washington trial (46) of survival after intracoronary streptokinase therapy; the adequacy of reperfusion, defined angiographically as complete, partial or no reperfusion, correlated significantly with I year survival after acute myocardial infarction (Fig. 4). The fact that survival in patients with partial reperfusion was nearly as poor as that of patients without reperfusion indicates that angiographically apparent slow anterograde flow or delayed washout of contrast medium is a marker of inadequate reperfusion.

Time Is an Important Determinant of Successful Outcome Experimental studies have clearly demonstrated that infarction progresses through the myocardial wall from subendocardium to subepicardium with increasing duration of coronary artery occlusion (19), and that reperfusion must take place within 2 to 3 hours after occlusion to salvage

l:l 0::

0

X

0

-,

.J

([

0

:E

0

a:

0

0

z 0

•

~

-I

([

....

*

III W

.... ~

0

Q.

X

Q.

::l I

::s

0 ...J ...J 0 u,

-2

1

80 >

64% 63%

~ 60 :::>

-'" c: u

40

0

*

•

rs>

o. 0 0

•

8

0 0

0

*

0

0

• *

*

0 0

o ANTERIOR INFARCTION

* INFERIOR

1Il

INFARCTION 2

3

Figure S. Relation between time from symptom onset to thrombolytic therapy and severity of residual hypokinesia in the infarct region (measured using thecenterline method andexpressed in SD from normal) at follow-up. Motion in the infarct region was significantly more hypokinetic in patients treated later than 2 hours after symptom onset. (Reproduced with permission from Mathey DG, et al. [78].)

myocardium (41). In clinical studies of thrombolytic therapy, patients who were treated by reperfusion early after the onset of symptoms of infarction had a significantly greater improvement in ventricular function. Schroder et al. (72) found a correlation between infarct size measured from the circumferential extent of hypokinesia and the time to treat-

Figure 6. The effectiveness of intravenous streptokinase in reducing hospital mortality after acute myocardial infarction. Patients are classified bytime from symptom onset to randomization. Patients treated within I hour are included among those treated :5:3 hours from symptom onset. (Adapted with permission from GISSI [771.) G. I.S.S. I. TRIAL· 11,712 PATIENTS P'.0001

-

w a:

<:1

C

15


U

ttl

"J

a:

10

,.

p •. 0005

r.

P·.03

p •• 0002

~

~

STK

f-

.J


f-

a:

5

z

Complete Reperfusion n- 41 A PortioI Reperfusion ne 8 No Reperfusion n= 14 p= 0.005

0

~ 20

,.,

0

:I:

•

TIME TO THROMBOLYTIC THERRPY, HRS.

o

(J)

*

~ -3

0


"0

R~

0

**

,..'" ...a: -4 ... :> ...

0

0 0

1Il

o

I

95%

*

•

s

Cl

10

0

0

u

20

Figure4. One year survival curves forthe63patients with anterior infarction who received streptokinase, grouped according to reperfusion status. Patients with an angiographically normal coronary flow rate survived better than those without reperfusion or with perceptibly slow flow in the infarct artery. (Reproduced with permission from Kennedy JW, et al. [46].)

•

0

Z

0

0

l:l III

:r

941

• 0

2

4

6 Months

e

8

10

12

<1

0-3

3-6

6-51

TIME FROM ONSET OF S¥MPTOMS TO TREATMENT, HRS

Att

942

SHEEHAN LEFT VENTRICULAR FUNCTION AFTER THROMBOLYSIS

ment with intravenous streptokinase. Schwartz et al. (73) observed that the infarct size measured from peak CK activity was smaller and the ejection fraction at follow-up was higher in patients whose coronary arteries were reperfused <4 hours versus >4 hours after symptom onset. Mathey et al. (74,75) found that improvement in wall motion at the infarct site was significantlygreater if reperfusion was achieved <2 '12 hours after symptom onset (Fig. 5), or if thrombolytic therapy using either intracoronary streptokinase or intravenous urokinase was begun <2 hours after symptom onset, compared with later reperfusion or treatment. Serruys et al. (37) reported significantly greater recovery of regional wall motion in patients treated with intracoronary or intravenous streptokinase within 3 hours after symptom onset than in those treated later. Few or no patients treated <2 hours after symptom onset were enrolled in studies that failed to demonstrate a significant relation between time to treatment and left ventricular function (24,59,76). The importance of early treatment was confirmed in the recently completed Italian large scale controlled study of intravenous streptokinase (77). Not only was significant reduction in in-hospital mortality limited to patients treated early «6 hours) after symptom onset, but the magnitude and significance of the reduction increased with progressively earlier treatment (Fig. 6). Conclusions. The evaluation of thrombolytic therapy has been a three stage process. First, the success with which the various thrombolytic agents achieved sustained reperfusion was determined. Because the underlying hypothesis attributes enhanced survival to salvage of left ventricular function, ventricular function was the second end point measured in studies of thrombolytic therapy. The final stage is demonstration that thrombolysis improves survival after acute myocardial infarction. The recent decline in postinfarction mortality, however, has made assessment of this end point more difficult and expensive by necessitating enrollment and treatment of hundreds or even thousands of patients in clinical trials seeking to demonstrate a significant benefit of treatment on survival. This has focused attention on using nonfatal end points such as ventricular function. Measurements of regional ventricular function in the infarct site are sensitive indicators of the perfusion status of the infarct artery and the degree of myocardial salvage. The use of quantitative methods has facilitated analysis of the factors that influence recovery of ventricular function after thrombolysis and enabled the demonstration of significant correlations even in small study populations. The selection of left ventricular function as the end point has proved to be particularly appropriate for assessing the value of thrombolytic therapy. Studies of reperfusion as a means of salvaging jeopardized myocardium have been characterized by a strong concordance between the experimental studies of the effect of reperfusion on ventricular

JACC Vol. 9. No.4 April 1987:937-44

function and infarct size, clinical studies measuring the effect of reperfusion on left ventricular function and clinical trials testing the effect of thrombolytic therapy on survival. Just as seen after reperfusion in the dog, thrombolytic therapy in humans results in recovery of ventricular function if I) reperfusion is adequate, and 2) if reperfusion is achieved in the early hours after the onset of acute infarction. Under these conditions, even patients with severe acute dysfunction may benefit. The same factors also determine the efficacy of thrombolytic therapy in reducing mortality. These results provide indirect confirmation for the hypothesis that enhancement of survival in patients treated with thrombolytic agents is mediated by recovery of ventricular function.

References I. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897-902. 2. Reimer KA. Myocardial infarct size. Arch Pathol Lab Med 1980;104: 225-30. 3. Lie JT, Paierolero PC, Holley KE, Titus SL. Macroscopic enzymemapping verification of large, homogeneous, experimental myocardial infarcts of predictable size and location in dogs. J Thorac Cardiovasc Surg 1975;69:599-604. 4. Schaper W. Remijsen P. Xhonneux R. The size of myocardial infarction after experimental coronary artery ligation. Zeitschrift fur Kreislaufforschung 1969;58:904. 5. Wachers FJT, Becker AE. Samson G, et al. Location and size of acute transmural myocardial infarction estimated from thallium-201 scintiscans. A clinicopathological study. Circulation 1977;72:72-8. 6. Niess GS, Logic JR, Russell RO Jr. Rackley CE, Rogers WJ. Usefullness and limitations of thallium-201 myocardial scintigraphy in delineating location and size of prior myocardial infarction. Circulation 1979;59:1010-19. 7. Sobel BE. Bresnahan OF, Shell WE, Yoder RD. Estimation of infarct size in man and its relation to prognosis. Circulation 1972;46:640-8. 8. Ideker RE. Wagner GS, Ruth WK, et al. Evaluation of a QRS scoring system for estimating myocardial infarct size. II. Correlation with quantitativeanatomic findingsfor anterior infarcts. Am J Cardiol 1982;49: 1604-14. 9. Falsetti HL. Marcus ML, Kerber RE, Skorton OJ. Quantification of myocardial ischemia and infarction by left ventricular imaging. Circulation 1981;63:747-51. 10. Homans DC, Asinger R, Elsperger KJ, et al. Regional function and perfusion at the lateral border of ischemic myocardium. Circulation 1985;71:1038-47. II. Gibbons EF. Hogan RD, Franklin TO, Nolting M, Weyman AE. The natural history of regional dysfunction in a canine preparation of chronic infarction. Circulation 1985;71:394-402. 12. Lieberman AN, Weiss JL, Jugdutt BI, et al. Two-dimensional echocardiography and infarct size: relationship of regional wall motion and thickening to the extent of myocardial infarction in the dog. Circulation 1981;63:739-46. 13. Sheehan FH, Bolson EL, Dodge HT, Mathey DG. Schofer J, WOO HW. Advantages and applications of the centerline method for characterizing regional ventricularfunction. Circulation 1986;74:293-305. 14. Herman MV, Gorlin R. Implications of left ventricular asynergy. Am J Cardiol 1969;23:538-47. 15. Kaul S, Pandian NG, Gillam LD. et al. Contrast echocardiography in acute myocardial ischemia. III. An in vivo comparison of the extent

lACC Vol. 9. No.4

April 1987:937-44

of abnormal wall motion with the area at risk for necrosis. J Am Coli Cardiol 1986;7:383-92.

SHEEHAN LEFT VENTRICULAR FUNCTION AFTER THROMBOLYSIS

943

16. Klein MD. Herman MV. Gorlin R. A hemodynamic study of left ventricular aneurysm. Circulation 1967;35:614-30.

36. Hooghoudt TEH. Serruys PW. ReiberJHC, Slager CJ. Vanden Brand M. Hugenholtz PG. The effect of recanalization of the occluded coronary artery in acute myocardial infarctionon left ventricularfunction. Eur Heart J 1982;3:416-21.

17. Page DL. Caulfield JB. Kastor JA, DeSanctis RW. Sanders CA. Myocardial changes associatedwith cardiogenic shock. N Engl J Med 1971 ;285:133-37.

37. Serruys PW, Simoons ML, Suryapranata H, et al. Preservation of global and regional left ventricular function after early thrombolysis in acute myocardial infarction. J Am Coli Cardiol 1986;7:729-42.

18. Heyndrickx GR. Millard RW. McRitchie RJ. Maroko PRo VatnerSF. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest 1975 ;56:978-85.

38. Wynne J. Sayres M. Maddox DE, et al. Regional left ventricular function in acute myocardial infarction: evaluation with quantitative radionuclide ventriculography. Am J Cardiol 1980;45:203-9.

19. Reimer KA. Lowe JE. Jennings RB. Effect of the calcium antagonist verapamil on necrosis following temporary coronary artery occlusion in dogs. Circulation 1977;55:581-7. 20. Lavallee M. Cox D. Patrick TA. Vatner SF. Salvage of myocardial function by coronary artery reperfusion I. 2. and 3 hours after occlusion in conscious dogs. Circ Res 1983;53:235-47. 21. Pairolero P. Hallermann FJ. Ellis F Jr. Left ventriculogram in experimental myocardial infarction. Radiology 1970;95:311-16. 22. BraunwaldE. Kloner RA. The stunned myocardium: prolonged. postischemic ventricular dysfunction. Circulation 1982;66: 1146-9. 23. Jennings RB. Steenbergen Jr. Nucleotide metabolism and cellular damage in myocardial ischemia. Annu Rev Physiol 1985:47:727-49. 24. Reduto LA. Smalling RW. Freund GC Gould KL. Intracoronary infusion of streptokinase in patients with acute myocardial infarction: effects of reperfusion on left ventricular performance. Am J Cardiol 1981 :48:403-9. 25. Khaja F. Walton JA Jr. Brymer JF, et al. Intracoronary fibrinolytic therapy in acutemyocardial infarction. N EnglJ Med 1983:308: 1306-11. 26. Charuzi Y, Beeder C Marshall LA. et al. Improvement in regional and global left ventricular function after intracoronary thrombolysis: assessment with two-dimensional echocardiography. Am J Cardiol 1984;53:662-5.

39. Raimer AE, Tortoledo FA. Verani MS. et al. Intracoronary thromboytic therapy in acute myocardial infarction: a prospective, randomized. controlled trial. Am J Cardiol 1985;55:301-8. 40. Tennant R, Wiggers CJ. Effect of coronary occlusion on myocardial contraction. Am J Physiol 1935;112:351-61. 41. Maroko PR, Libby P, Ginks WR, et al. Coronary artery reperfusion. I. Early effects on local myocardial function and the extent of myocardial necrosis. J Clin Invest 1972;51 :2710-16. 42. Costantini C, Corday E. Lang T-W. et al. Revascularization after 3 hours of coronary arterial occlusion: effects on regional cardiac metabolic function and infarct size. Am J Cardiol 1975;36:368-84. 43. Smalling RW. Fuentes F, Freund GC, et al. Beneficial effects of intracoronary thrombolysis up to eighteen hours after onset of pain in evolving myocardial infarction. Am Heart J 1982;104:912-20. 44. Sheehan FH. Mathey DG. Schofer J. Dodge HT. Bolson EL. Factors determining recovery of left ventricularfunction following thrombolysis in acute myocardial infarction. Circulation 1985;71:1121-8. 45. Kennedy JW, GensiniGG, TimmisGC. Maynard C Acutemyocardial infarction treated with intracoronary streptokinase: a report of the Society for Cardiac Angiography. Am J Cardiol 1985;55:871-7. 46. Kennedy JW. Ritchie JL, Davis KB. Stadius ML. Maynard C. Fritz JK. Western Washington Randomized Trial of Intracoronary Streptokinase in Acute Myocardial Infarction: a 12-month follow-upreport. N Engl J Med 1985;312: 1073-8.

27. Rentrop P. BlankeH. Karsch KR. Changes in left ventricular function after intracoronary streptokinase infusion in clinically evolving myocardial infarction. Am Heart J 1981;102:1188-93.

47. Kalbfleisch H, Hort W. Quantitative study on the size of coronary artery supplying areas postmortem. Am Heart J 1977;94: 183-8.

28. Wackers FJ. BergerHJ. Weinberg MA, Zaret BL. Spontaneous changes in left ventricular function over the first 24 hours of acute myocardial infarction: implications for evaluating early therapeutic interventions. Circulation 1982;66:748-54.

48. Miller RR. Olson HG, Vismara LA, Bogren HG, Amsterdam EA. Mason DT. Pump dysfunction after myocardial infarction: importance of location. extent and pattern of abnormal left ventricular segmental contraction. Am J Cardiol 1976;37:340-4.

29. Nemerovaski M, Shah PK. Pichler M. BermanOS. ShellockF. Swan HJC Radionuclide assessment of sequential changes in left and right ventricular function following first acute transmural myocardial infarction. Am Heart J 1982:104:709-17.

49. Kumpuris AG. Quinones MA, Kanon D. Miller RR. Isolatedstenosis of left anterior descending or right coronary artery: relation between site of stenosis and ventricular dysfunction and therapeutic implications. Am J Cardiol 1980;46:13-20.

30. Feild BJ. Russel 0, DowlingJT. RackleyCEo Regional left ventricular performance in the year following myocardial infarction. Circulation 1972:46:679-89.

50. Stadius ML. Maynard C. Fritz JK. et al. Coronary anatomy and left ventricularfunction in the first 12 hoursof acute myocardialinfarction: the Western Washington Randomized Intracoronary Streptokinase Trial. Circulation 1985;72:292-301.

31. Corday E. Kaplan L. Meerbaum S. et al. Consequences of coronary arterial occlusion 'on remote myocardium: effects of occlusion and reperfusion. Am J Cardiol 1975;36:385-94. 32. Theroux P, Franklin 0, Ross J Jr, Kemper WS. Regional myocardial function during acute coronary artery occlusion and its modification by pharmacologic agents in the dog. Circ Res 1974;35:896-907. 33. Sheehan FH. Mathey DG. Schofer J. Krebber HJ. Dodge HT. Effect of interventions in salvaging left ventricular function in acute myocardial infarction: a studyof intracoronary streptokinase. Am J Cardiol 1983;52:431-8. 34. Stack RS. PhillipsHR III. GriersonOS. et al. Functional improvement of jeopardized myocardium following intracoronary streptokinase infusion in acute myocardial infarction. J Clin Invest 1983;72:34-95. 35. Sheehan FH. Szente A. Mathey DG. Dodge HT. Assessment of left ventricular function in acute myocardial infarction: the relationship between global ejection fraction and regional wall motion. Eur Heart J 1985;6(suppl E):117-25.

51. Schwartz H, Leiboff RH. Bren GB. et al. Temporal evolution of the human coronary collateral circulation after myocardial infarction. J Am Coil Cardiol 1984;4: 1088-93. 52. Williams DO. Amsterdam EA. Miller RR. Mason DT. Functional significance of coronary collateral vessels in patients with acute myocardial infarction: relation to pump performance. cardiogenic shock and survival. Am J Cardiol 1976;37:345-51. 53. Cortina A. Ambrose JA. Prieto-Granada J. Left ventricular function after myocardial infarction: clinical and angiographic correlations. J Am Coli Cardiol 1985;5:619-24. 54. Blanke H. Cohen M. Karsch KR. Fagerstrom R, Rentrop KP. Prevalence and significance of residual flow to the infarct zone during the acutephase of myocardial infarction. J Am CoilCardiol 1985;5:827-31. 55. Schwarz F. Wagner HO. Hofmann M. Schaper W. Determinants of myocardial infarction in critical coronary stenosis. In: Mason DT. Neri Serneri GG, Oliver MF, eds. Proceedings of the Florence Inter-

944

SHEEHAN LEFr VENTRICULAR FUNCTION AFrER THROMBOLYSIS

JACC Vol. 9. No.4 April 1987:937-44

national Meeting on Myocardial Infarction. Amsterdam: Excerpta Medica, 1979;7399-741.

tion of stunned myocardium by increased flow. Circulation 1986;74: 843- 51.

56. Haft JI , Fani K. Stress and the induction of intravascular platelet aggregation in the heart. Circulation 1973;63:164-9.

68. Topol EJ, Weiss JL, Brinker JA, er al. Regional wall motion improvement after coronary thrombolysis with recombinant tissue plasminogen activator: importance of coronary angioplasty. J Am Coll Cardiol 1985;6:426- 33.

57. Leiboff RH, Katz RJ, Wasserman AG, et a!. A randomized, angiographically controlled trialof intracoronary streptokinase inacute myocardial infarction. Am J Cardiol 1984:53:404-7 . 58. Schuler G, Schwarz F, Hofmann M, et al. Thrombolysis in acute myocardial infarction using intracoronary streptokinase: assessment by thallium-201 scintigraphy. Circulation 1982;66:658-64.

69. Raizner AE, Tadro S, Minor ST, Davis MJ. Coronary reperfusion using intracoronary streptokinase alone or combined with angioplasty in acute myocardial infarction (abstr.) Circulation 1985;72(suppl III): I1I-309.

59. Rogers WJ, Hood WP Jr. Mantle JA, et al. Return of left ventricular function after reperfusion in patients with myocardial infarction: importance of subtotal stenoses or intact collaterals. Circulation 1984;69: 338- 49.

70. Bourdillon PD, Timmis G, Terris S, et a!. Improved regional left ventricular function after coronary angioplasty in acute myocardial infarction: comparison with intracoronary streptokinase (abstr). Circulation 1985;72(suppl I1I):I1I-309.

60. Ong L, Reister P, CoromilasJ, Scherr L, Morrison J. Left ventricular function and rapid release of creatine kinase MB in acute myocardial infarction. N Engl J Med 1983;309:1-6.

71. Timmis oc, O'Neill W, Bakalyar D, Lai PY, Gordon S. Effect of reperfusion adequacy on ventricular function versus infarction size (abstr). Circulation 1985;72(suppl 111):111-308.

61. Merx W, BethgeC, Effert S, von Essen R, Dorr R, Schrnid-Schonbein H. Supraselective fibrinolysis in acute myocardial infarction. Bibl HaematoI1 981;47:205-12.

72. Schroder R, Biamino G, Leitner ERV, et al. Intravenous short-term infusion of streptokinase in acute myocardial infarction . Circulation 1983;67:536-48 .

62. Smalling RW, Fuentes F, Matthews MW, et al. Sustained improvement in left ventricular function and mortality by intracoronary streptokinase administration during evolving myocardial infarction. Circulation 1983;68:131-8.

73. Schwarz F, Schuler G. Katus H. et al. Intracoronary thrombolysis in acute myocardial infarction: duration of ischemia as a major determinant of late results after recanalization. Am J Cardiol 1982'50' 933- 7. ' .

63. Koh D. Mitten S, Stewart D, Bolson E. Dodge HT. Comparison between computerized quantitative coronary angiography and clinical interpretation (abstr). Circulation 1979;60(suppl 11):11-1 60.

74. Mathey DG, Schofer J, Sheehan FH. Becker H, Tilsner V, Dodge HT. Intravenous urokinase in acute myocardial infarction. Am J Cardiol 1985;55:878-82.

64. Harrison DG. Ferguson DW, Collins SM. et al. Rethrombosis after reperfusion with streptokinase: importance of geometry of residual lesions. Circulation 1984;69:991- 9.

75. Mathey DG, Sheehan FH. Schofer J. Dodge HT. Time from onset of symptoms to thrombolytic therapy: a major determinant of myocardial salvage in patients with acute transmural infarction. J Am Coil Cardiol 1985;6:518-25 . 76. Ferguson DW, White CWo Schwartz, et a!. Influence of baseline ejection fraction and success of thrombolysis on mortality and ventricular function after acute myocardial infarction. AmJ Cardiol 1984;54: 705- 11. 77. Gruppo Italiano per 10 Studio della Streptochinasi nell ' Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402.

65. Bache RJ, McHale PA. Greenfield JC Jr. Transmural myocardial perfusion during restricted coronary inflow in the awake dog. Am J Physiol 1977;232:H645-H651. 66. Akaishi M. Weintraub WS. Schneider RM. Klein LW. Agarwal lB , Helfant RH. Coronary reserve affects myocardial blood flow distribution after reperfusion (abstr). J Am Coli Cardiol 1986;7:206A. 67. Stahl LD, Aversano TR, Becker LC. Selective enhancement of func-