The CORONARY ARTERY DISEASE American

1 Journal 1 DECEMBER 1, 1990, VOL. 66, NO. 19

Usefulness of Late Coronary Thrombolysis (Recombinant Tissue-Type Plasminogen Activator) in Preserving Left Ventricular Function in Acute Myocardial Infarction

Bruno Villari, MD, Federico Piscione, MD, Domenico Bonaduce, MD, Paolo Golino, MD, Tonino Lanzillo, MD, Mario Condorelli, MD, and Massimo Chiariello, MD

This study assesses whether administration of re- combinant tissue-type plasminogen activator (rt- PA) up to 8 hours after onset of symptoms of acute myocardial infarction (AM) may result in a signifi- cant improvement in left ventricular function. Sixty patients were classified into 3 groups: group A (II = 21) received rt-PA within 4 hours from symptom onset; the remaining 39 patients, admitted between 4 and 8 hours, were randomized into 2 groups- group B (n = 19) received rt-PA, and group C (n = 21) was treated wlth conventional therapy. Coro- nary and left ventricular angiograms were recorded 8 to 10 days after r&PA administration. The paten- cy rate of the infarct-related artery was 76% in group A, and 63 and 35% in group B and C, re- spectively. The Thrombolysis in Myocardial Infarc- tion trial perfusion grade was higher in group A and 6 than in group C (A vs C: p <O.OOS; B vs C: p <O.Ol). Left ventricular ejection fraction was sig- nificantly higher in group A (60.2 f 10%) and B (54.7 f 12%) compared with group C (44.2 f 12%) (A vs C: p <O.Ol; B vs C: p <O.OS). Regional wall motion of the entire ischemic zone was better in group A and B than in group C (A vs 6: p <O.OOl; B vs C: p X0.01). In contrast, the kinesis of the central ischemic zone was significantly better in group A than in both group B and C (A vs B: p <O.O5;A vs C:p <O.OOl).

The number of hypokinetic, akinetic and dyski- netic segments were lower in group A and B than in group C (A vs B: p CO.01, B vs C: p <O.OS and A vs C: p <O.Ol and B vs C: p <O.Ol, respectively). Thus, these data confirm the efficacy of early thrombolysis and suggest that late reperfusion ma act beneficially in preserving left ventricular vol- umes and function.

(Am J Cardiol ~990;66~128~-~286)

From the Institute of Internal Medicine, Cardiology and Cardiac Sur- gery, Department of Cardiology, “Federico II” University of Naples, Second School of Medicine, Naples, Italy. Manuscript received May 14, 1990; revised manuscript received and accepted July 12, 1990.

Address for reprints: Massimo Chiariello, MD, Cattedra di Cardio- logia, II Policlinico, Via Sergio Pansini, 5, 80131, Naples, Italy.

coronary thrombolysis is considered the treat- t of choice for most patients with acute myo- ial infarction (AMI), because this procedure

may result in improvement in left ventricular function and reduction of in-hospital and long-term mortality.‘-” However, some controversy still exists with regard to the efficacy of thrombolytic therapy administered rela- tively late after the onset of symptoms.9 Several experi- mental studies have demonstrated that the extent of ischemic myocardium ultimately undergoing necrosis is dependent on the duration of the ischemic period and that reperfusion does not usually result in any apprecia- ble myocardial salvage after 3 to 4 hours.iO~il However, most patients sustaining AM1 may have developed col- lateral vessels that could have prolonged the time span before irreversible cellular damage occurred.7,12,13

Based on these considerations, the present study as- sessed whether coronary thrombolysis performed be- tween 4 and 8 hours from symptom onset would act beneficially on left ventricular function in patients with AMI. To accomplish this goal, we compared the effects of late thrombolysis on left ventricular function with those of conventional therapy in patients admitted 4 to 8 hours from the onset of chest pain. Furthermore, we compared these 2 groups with a third group of patients with AM1 treated with single chain recombinant tissue- type plasminogen activator (r&PA) earlier in the course of infarction (i.e., <4 hours from symptom onset).

METHODS Patients: All patients admitted to our coronary care

unit between January 1989 and October 1989 with a diagnosis of AMI revealed within 8 hours were consid- ered for entry into this study. The diagnosis was estab- lished on the basis of typical chest pain and ST-segment elevation of 20.2 mV in a precordial lead or 0.1 mV in a limb lead. Exclusion criteria were: history of myocar- dial infarction, any major hemorrhage or stroke in the previous 6 months, major injury or surgery in the previ- ous 6 weeks, cardiopulmonary resuscitation performed on admission to the hospital, severe arterial hyperten- sion (systolic blood pressure >220 mm Hg), or active peptic ulcer. Sixty-nine patients entered this study but only 60 completed the study protocol. Nine patients

THE AMERICAN JOURNAL OF CARDIOLOGY DECEMBER I, 1990

TABLE I Patient Characteristics

Control rt-PA <4 hrs rt-PA 4-8 hrs Subjects

Patients (no.) 21 19 20

Age Ws) 51 i8 52f9 53&8 Peak creatine kinase 3,074f 1,764 2,749 f 1,678 2,890 & 1,651

(mu/liter) Time to peak 11*5 16*5* 21*7+

creatine kinase (hours)

Time of intervention 145 & 58 360 f 61 358 + 58

(min) (range) (30-220) (290-430) (250-430) Anterior AMI (no.) 12 10 11 Inferior AMI (no.) 9 9 9 Time to coronary 9.1 f0.7 9.1 f0.7 9.250.7

angiography

(days) l-vessel CAD (no). 9 8 10 TIMI grade 2.09 h .83* 1.78 4.845 0.85 f 0.93

” AvsB,p<O.O5;+A”sC. p<O.Ol;*A”sC. p <O.o05;S B”sCp<O.Ol AMI = acute myocardlal infarction; CAD = coronary artery disease; rt-PA = recom-

blnant tissue-type plasminogen: TIMI = Thrombolysis in Myocardial Infarction trial.

were excluded: 6 refused cardiac catheterization, 1 had a cerebral hemorrhage and underwent successful sur- gery, 1 patient had another AM1 during hospitalization and 1 died from cardiogenic shock. These latter events occurred before the time of catheterization.

All consecutive patients admitted to the coronary care unit within 4 hours from the onset of chest pain received rt-PA intravenously (10 mg bolus followed by an infusion of 50 mg over 1 hour and then 20 mg/hour over the next 2 hours) (group A, n = 21). Thirty-nine patients admitted to the coronary care unit between 4 and 8 hours from onset of chest pain were randomly assigned to a group treated with rt-PA’at the same dose as previously described (group B, n = 19) and to a group treated only with conventional therapy (intrave- nous nitroglycerin and oral nifedipine) (group C, n = 20) (Table I). All patients received conventional thera- py and a bolus of 10,000 U of heparin at the time of rt- PA administration, followed by an infusion of 1,000 U/ hour and adjusted thereafter to maintain the activated partial thromboplastin time between 1.5 and 2 times the upper limit of normal. Heparin therapy was continued

in the absence of serious hemorrhage, until coronary an- giography was performed. Blood was sampled for serum creatine kinase immediately after admission and then every 3 to 6 hours over the next 24 hours and every 12 to 24 hours up to 72 hours. Eight to 10 days after ad- mission, all patients underwent right- and left-sided car- diac catheterization and coronary angiography. The in- farct-related artery was localized by: (1) ST-segment elevation on the electrocardiogram; (2) hypokinetic wall motion on the ventriculograms; (3) residual stenosis or thrombotic material, or both, in the coronary artery,

Left ventriculography was performed in the 30° right anterior oblique projection using a powered injec- tion of 40 ml of nonionic contrast medium (iopamidol) through a pigtail catheter. The film speed was 50 frames/s. Calibration of the magnification factor was obtained by filming a square grid placed at the level of the left ventricle. Films were projected by a 35-mm film projector and converted into a video format with a video camera. The contours of the ventricle were traced on a working table by a blinded observer with the aid of a digitizing penlight. All contour data were coded and stored using a PDP 1 l/34 computer onto a RK-01 disk (Digital Equipment Co.). The intraobserver variability of the method was assessed in a previous study from our laboratory.14

Left ventricular chamber volumes and global ejec- tion fraction were calculated by the area-length meth- od.15 Regional wall motion was analyzed by a single observer in 2 different independent cycles free from ven- tricular ectopy, using a semiautomatic computer-aided system (Digital PDP 11/34) for analysis of ventricular wall motion (AVD Siemens). The left ventricle silhou- ettes were divided into 90 segments by the radial coordi- nate method.16 Regional left ventricular function was evaluated as follows: (1) Fractional shortening was ex- pressed as the mean shortening of segments in the worst 50% of the infarct zone. (2) Hypokinesia was expressed as the number of segments with a wall motion reduction exceeding 2 standard deviations of the normal value de- termined on left ventriculography in 21 age-matched normal subjects. These patients were suspected of hav- ing coronary heart disease, underwent diagnostic cardi- ac catheterization and were found to have normal cardi-

- rt-PA 4 4 h m d-PA 4-8 h ( Controls

150 p< .Ol 150 2 pr .os

3 120 $ g 120

E 90

PC .Ol

I 2 90 r”

2 PC .OI :

p 0 60 2 60 r Q 4 z

P 4J 30 30 I

i IL!

FIGURE 1. Effects of the different treat- ments on left ventricular volumes: EDVI = end-diastolic volume index; ESVI = end- systolic volume index; &PA = recombi- nant tissue-type plasminogen activator.

1282 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66

ac anatomy, normal coronary arteries and normal ven- tricular function. (3) Akinesia-dyskinesia was defined as the number of segments with a shortening 10 (compar- ing both systolic and diastolic lengthening).

Artery territories were defined by the analysis of 74 patients with no history of thoracotomy or valvular or congenital heart disease, affected by isolated stenoses (>75%) of the left anterior descending or right coronary arteries studied in our laboratory between 1984 and 1988. The region of the left ventricle (segments 10 to 53), in which mean segment motion in the 39 patients with stenosis of the left anterior descending artery was significantly depressed compared with that of a control group without coronary artery disease, was defined as the left anterior descending territory. The territory of the right coronary artery was similarly defined as seg- ments 45 to 80 using the 35 patients with single stenosis of that vessel. The ischemic zone was defined as the segments of the zone supplied by the infarct-related ar- tery. The periinfarcted zone was defined as the 10 seg- ments before and after the ischemic zone. All remaining segments were considered as the noninfarcted zone. The shortening of the ischemic, periischemic and nonisch- emit zone was also evaluated.

Coronary perfusion was evaluated according to the Thrombolysis in Myocardial Infarction (TIMI) trial grading scale.2

Data are presented as mean f standard deviation. One-way analysis of variance was used for statistical evaluation. If a significant F test was found, Student’s t test for unpaired observation with the Bonferroni’s cor- rection was performed to obtain multiple comparisons.

RESULTS Patient characteristics are listed in Table I. Hemodynamics and coronary angiography: No sig-

nificant differences were found among the 3 groups of patients with regard to the hemodynamic variables (Ta- ble II). During coronary angiography, patency of the infarct-related vessel (TIM1 grade 2 or 3) was found in

LVSP = left ventricular systolic pressure; MAP = mean arterial pressure; MWP = mean wedge pressure; RAP = right atrial pressure: e-PA = recombinant tissue-type plasminogen activator.

I I

(63%) in group B and 7 of 20 patients (35%) in group C. The average TIMI grade was 2.1 f 0.8 in group A, 1.8 f 0.8 in group B and 0.9 f 0.9 in group C (A vs C = p <0.005; B vs C = p <O.Ol).

Left ventricular analysis: End-diastolic volume in- dex was significantly lower in group A (85 f 15 ml/ m2) and B (88 f 19 ml/m2) than in group C (103 f 19 ml/m*) (A vs C = p <O.Ol; B vs C = p <0.05) (Figure 1). End-systolic volume index was significantly lower in group A (33 f 15 ml/m2) and B (40 f 16 ml/m2) than ingroupC(56f15ml/m2)(AvsC=p<0.01;BvsC = p <O.OS) (Figure 1). Global ejection fraction was sig- nificantly higher in patients in group A (60 f 10%) and B (55 f 12%) than in group C patients (44 f 12%) (A vs C = p <O.Ol; B vs C = p cO.05) (Figure 2). The percent shortening of the ischemic zone was 23 f 8% in group A, 18 f 14% in group B and 5 f 9% in group C (A vs C = p <O.OOl; B vs C = p <O.Ol) (Figure 2); the percent shortening of the worst 50% of the infarct zone was significantly higher in group A (13 f 11%) than in group B (3 f 7%) and group C (-1 f 8%) (A vs B = p <0.05; A vs C = p <O.OOl) (Figure 2). No significant differences were found in shortening of the periischemic zone (21 f 7, 20 f 7, 16 f 7% in group A, B and C, respectively) and nonischemic zone (35 f 14, 35 f 9,

16 of 21 patients (76%) in group A, 12 of 19 patients 29 f 9 in group A, B and C, respectively),

FIGURE 2. Effects of different recombi- nant tissue-type plasminogen activator (rt- PA) administration on global and regional ejection fraction: the ejection fraction of the central ischemic zone was significantly higher in the early-treated group (black bars) than in the remaining groups.

= d-PA < 4 h m rt-PA 4-8 h m Controls

p* .ot

PI .oe

T T--

lschetnic orse 50% Ischemic

THE AMERICAPI JOURNAL OF CARDIOLOGY DECEMBER 1, 1990 8283

The number of hypokinetic segments was signifi- cantly lower in group A (14 f 11 segments) and group B (20 f 15 segments) than in group C (36 f 14 seg- ments) (A vs C = p <O.Ol; B vs C = p <0.05) (Figure 3).

The number of akinetic-dyskinetic segments was sig- nificantly lower in group A (1 f 4) and B (4 f 6) with respect to group C (14 f 4) (A vs C = p <O.Ol; B vs C = p <O.Ol) (Figure 3). Akinetic-dyskinetic segments were found in 4 of 21 patients (19%) in group A, in 6 of 19 patients (28%) in group B and in 11 of 20 patients (55%) in group C.

DISCUSSION Our study supports the hypothesis that late throm-

bolysis may exert a beneficial effect on left ventricular function and reduce end-systolic and end-diastolic vol- umes.

In both early and late rt-PA-treated groups, we have found a significantly higher ejection fraction with respect to the control group. This was mainly due to an improved motion of the ischemic zone (Figure 2), whereas shortening of the peri- and nonischemic zones was not significantly affected by treatment. The central ischemic zone has shown a higher shortening in group A than in both group B and C, confirming the concept that the earlier reperfusion is achieved, the bigger sal- vage of ischemic myocardium is obtained. We have also found a lesser extension of hypokinetic and a-dyskinetic segments in groups A and B than in group C, suggest- ing the continued beneficial effects of thrombolysis per- formed within 8 hours. The mechanisms leading to these positive effects of thrombolysis, performed both early (<4 hours) and late (4 to 8 hours), are through a better perfusion of the ischemic zone.17 In fact, we found a significantly higher TIM1 grade and a higher

Y 60 z E

% 40

z

* 20

m rt-PA + 4 h m rt-PA 4-8 h I Controls

p< .Ol

t

pc .Ol

p* .Ol

i

HYPOKINETIC A-DYSKINETIC

Influence of perfusion on hypokinesia

P< .00!5

P4 .Ol -1

PC .Ol I

P< .05 , 0

TIMI GRADE

FIGURE 3. In the early-treated group (re- combinant tissue-type plasmbrogen activa- tor @t-PA) <4 hours) and In the late-treat- ed group &t-PA 4 to 8 hours), the number of hypohinetic and aldnetic-dyshinetic seg- ments (a-dysldnetic) was significantly low- er with respect to the control group.

FIGURE 4. Influence of the perfusion grade on the extension of hypoldnesia: The higher the Thrombolysis in Myocardi- al Infarction trial perfusion grade, the few- er the number of hypoldnetic segments.

1284 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66

patency rate of the infarct-related artery at 8 to 10 days after myocardial infarction in our rt-PA-treated pa- tients (groups A and B) than in group C patients (Table I). It has been suggested that residual flow through a subtotal lesion extends the time window for myocardial salvage by thrombolytic therapy in a similar way as does residual flow through collateral channels.7,12,13 Thus, a better perfusion of the ischemic territories oc- curring in our group A and B patients compared with group C patients led to the reduction of the extension of hypokinesia and a-dyskinesia with a consequent higher ejection fraction. The importance of the perfusion grade in preserving wall motion of the ischemic zone in our patients is shown in Figure 4, where this effect on the extension of hypokinesia is evident regardless of the treatment arm. Conversely, infarct vessel patency at 8 to 10 days after infarction is not necessarily representa- tive of infarct vessel patency noted immediately after thrombolytic therapy. There is a substantial potential for spontaneous thrombolysis and reocclusion to occur in the interim. One should consider that, as suggested by others,18-22 an increased wall stiffness might have improved ejection fraction by minimizing dyskinesia, as demonstrated by the lower extent of the a-dyskinetic zone in our rt-PA-treated patients (Figure 3). A better global and regional ejection fraction and a reduction in hypokinesia in early rt-PA-treated patients 8 to 10 days from myocardial infarction has also been found in other studies.2,3,23,24 The TIMI- trial2 demonstrated at 8 to 10 days after infarction a reduction in the extent of hy- pokinesia and an improvement in the kinesis of the in- farct zone in patients treated within 7 hours from pain onset. Furthermore, in a subgroup analysis, the same study showed a small but significant increase in ejection fraction in patients who achieved sustained reperfusion. This finding was not observed in patients who had no reperfusion, late reperfusion, or reocclusion.2

In our study 8 to 10 days after AMI, both early and late rt-PA-treated patients had lower end-systolic and end-diastolic volumes with respect to group C patients (Figure 1). This could be the consequence of a reduc- tion in infarct size (lower number of hypokinetic and akinetic-dyskinetic segments) and of an improved left ventricular function due to a better perfusion of the ischemic zone (higher TIMI perfusion grade and paten- cy rate). In fact, early mechanical expansion of the in- farcted myocardial segments are, together with the de- pressed systolic function and impaired diastolic relaxa- tion, the causes of volume overload in AMI.25,26 Jeremy et all7 recently demonstrated that perfusion of the in- farct zone during the healing phase is important in pre- venting continuing infarct expansion and subsequent left ventricular dilation. These findings of smaller ven- tricular volumes and contained myocardial expansion in patients treated with thrombolytic therapy early in the time course of myocardial infarction are in agreement with other studies.4,21,26,27 Furthermore, the analysis of the Italian Group for the Study of Streptokinase in Myocardial Infarction-l trial, including patients treated within 12 hours from symptom onset with regard to left ventricular volumes and function,27 has shown a con-

-I

tained myocardial expansion and lower ventricular vol- umes in patients receiving intravenous streptokinase with respect to the control group.

Study limitations: The major limitation of this study was the small number of patients. However, the patients were consecutively considered for entry into the study and, for those admitted between 4 to 8 hours, randomly assigned to receive rt-PA or conventional therapy. Thus, our groups should be general with regard to demo- graphic study. Furthermore, the results are in agree- ment with experimental data dealing with assessment of postinfarction function and infarct expansion. Because coronary angiography was not performed before rt-PA infusion, we do not know the baseline variables or whether spontaneous thrombolysis had occurred.

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18. Hochman JS, Choo H. Limitation of myocardial expansion by reperfusion independent of myocardial salvage. Circulation 1987;75:299-306. 19. Hood WB, Bianco J, Kumar R, Whiting RB. Experimental myocardial infarction, IV. Reduction of left ventricular compliance in the healing phase. J Clin Itwest 1970;49:1316-1323. 20. Kurnik PB, Courtois MR, Ludbrook PA. Diastolic stiffening induced by acute myocardial infarction is reduced by early reperfusion. J Am Coil Cardiol 1988;12:1029-1036. 21. Pasipoularides A. On mechanism of improved ejection fraction by early reperfusion in acute myocardial infarction: myocardial salvage or infarct stiffen- ing? J Am Co11 Cardiol 1988;12:1037-1038. 22. Mirsky I. Elastic properties of the myocardium: a quantitative approach with physiological application. In: Berne R, Sperelakis N, eds. Handbook of Physiolo- gy. Section 2. The Cardiovascular System. vol. 1. Baltimore: Williams & Wilkins, 1979:497-531. 23. Armstrong PW, Baigrie RS, Daly PA, Haq A, Gent M, Roberts RS, Free- man MR, Burns R, Liu P, Morgan CD. Tissue plasminogen activator: Toronto (TPAT) placebo-controlled randomized trial in acute myocardial infarction. J Am Co11 Cardiol 1989;13:1469-1476.

24. Guerci AD, Gerstenblith G, Brinker JA, Chandra NC, Gottlieb 0, Bahr RD, Weiss JL, Shapiro EP, Flaherty JT, Bush DE, Chew PH, Gottlieb SH, Halperin HR, Ouyang P, Walford GD, Bell WR, Fatterpaker AK, Llewellyn RN, Top01 EJ, Healy B, Siu CO, Becker LC, Weisfeldt ML. A randomized trial of intrave- nous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective angioplasty. N Engl J A4ed 1987;317:1613-1618. 25. Erlebacher JA, Weiss JL, Weisfeldt ML, Bulkley BH. Early dilation of the infarcted segment in acute trammural myocardial infarction: Role of infarct expansion in acute left ventricular enlargement. J Am Coil Cardiol 1984;4:201- 208. 26. McKay RG, Pfeffer MA, Pasternak RC, Markis JE, Come PC, Nakao S, Alderman JD, Ferguson JJ, Safian RD, Grossman W. Left ventricular remodel- ing after myocardial infarction: a corollary to infarct expansion. Cimdation 1986;74:693-702. 27. Marino P, Zanolla L, Zardini P, on behalf of the Gruppo Italian0 per lo Studio della Streptochinasi nell’Infarto Miocardico. Effects of streptokinase on left ventricular modeling and function after myocardial infarction: the GISSI (Gruppo Italian0 per lo Studio della Streptochinasi dell’Infarto Miocardico) trial. J Am Coil Cardiol 1989;14:1149-1158.

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