BRIEF REPORTS

Effects of Superoxide Dismutase on Reperfusion Arrhythmias and Left Ventricilar Function in Patients Undergoing Thrimbolysis for Anterior Wall Acute Myocardial Infarction Yoshiharu Murohara,

MD,

Yoshiki Yui,

MD,

Ryuichi Hattori,

MD,

and Chuichi Kawai,

MD

minutes’ but I mm in 12 contiguous anterior chest leads, age 200 mm Hg, or a history of a bleeding disorder. Patients with cardiogenic left ventricular function in the chronic phase. We studied 34 consecutive patients with AMI treated shock were also excluded. After recognition of the obstruction in the infarctby thrombolysis who fulfilled the inclusion criteria: no past history of myocardial infarction, chest pain of >20 related coronary artery, the patients were randomly allocated to SOD treatment or a control group. In SODtreated patients, human recombinant SOD (Nippon From the Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Kyoto 606, Japan. This work was supportKayaku Co.) was given as a 3,500-U/kg bolus, followed ed in part by a research grant for Cardiovascular Diseases from the by an infusion of 31,500 U/kgfor the subsequent 2 hours. Ministry of Health and Welfare, and by grants from the Ministry of Immediately after beginning the SOD infusion, the proEducation, Science and Culture, Tokyo, Japan. Manuscript received cedure of coronary thrombolysis by tissue plasminogen June 28, 1990; revised manuscript received and accepted January 1, activator or urokinase was begun. In the control group, 1991.

xygen-derived free radicals have been implicated as important factors involved in the genesisof reperfu0 sion injury. There is increasing evidencethat a free radi-

TABLE

I Patient

Profile

and Chronic

Left Ventricular

Function Regional Ejection Fraction (%)

Sex/Age

(yrs)

Time to Reperfusion (hr)

Anterolateral

Apex

Control patients F/68 M/74 M/35 F/72 M/41 F/74 M/69 M/M F/37 M/54 F/50 M/JO Mean fSD

55.2 f14.7

1.3 1.8 33.2

4.0 5.9 2.6 5.9 2.3 5.4 5.8 3.2 2.8 3.8 4.9 5.9

0.9 0.8 44.1

2.4

38.5 6.5 17.3 36.3 40.2 9.5 2.6 4.5

4.4 zk1.4

21.2 f20.3

16.4 f15.2

5.8 4.9 2.3 2.0 5.9 2.2 2.1 5.9 3.1 4.8 5.9

1.0 20.8 21.7 58.8 6.3 57 20.8 11.8 46.2 0.5 1.8

33.5 13.2 39.8 6.2 35.1 33.5 18.5 36.5 2.2 5.5

5.1

19.5 56.7

11.1 4.5 50.1 39.5 23.8

1.1

SOD patients M/72 F/71 M/69 F/57 F/49 M/50 M/64 M/58 M/52 M/46 F/50 Mean fSD There were no significant SD = standard deviation;

58.0

4.1

f9.1

rt1.7

differences between the 2 groups regarding SOD = superwde dismutase.

1.1

24.3

20.0

3~21.6

age. time to reperiusion.

f14.4

and regional ejection fraction.

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of VPCS

Vum

4ot

PcO.05 l--Yest)

m

Control

(n=12)

0

SOD (n=ll)

200

N.S. I

5 min

Prereperfusion

15 min

Postreperfusion

FIGURE 1. Total number of ventricular premature complexes (VPCs) during the period of 5 minutes More repewfusion (Prereperhrsion) and 15 minutes after reperfusion (Postreperfusion). NS = diffwence not significant; SOD = superoxide dis-

mutase.

thrombolysis was performed immediately after the study entry. As a rule, prophylactic use of antiarrhythmic drugs was prohibited before coronary reperfusion to analyze the effects of SOD on reperfusion arrhythmias. If necessary, 50 to 60 mg/hour of lidocaine was infused after thrombolysis (10 patients in the SOD group and 11 in the control group were treated with lidocaine infusion at doses of 52.0 f 7.9 mg/hour and 55.5 f 5.2 mglhour, respectively). Coronary recanalization was monitored by the abrupt occurrence of arrhythmias,3 the progressive resolution of ST-segment elevation or the abatement of chest pain, and was confirmed by subsequent angiography. A 2-channel continuous Holter recording was begun immediately after study entry and continued until 16 hours after reperfusion. Ventricular premature complexes were counted manually on a complete recording printout, and we counted ventricular premature beats separately from those occurring during the runs of ventricular tachycardia. The term ventricular tachycardia was used when 16 consecutive ventricular premature contractions occurred. Repeat cineangiography was performed 3 to 4 weeks after the onset of AMI. Regional ejection fractions were determined by the radial method4 from left ventriculography performed at the 30” right anterior oblique view. Data are expressed as mean f standard deviation. The differences for patient profiles and left ventricular function were evaluated by the unpaired t test for comparison between groups. Comparison of the frequency of ventricular premature complexes was analyzed by the U test, with Wilcoxon’s method. The occurrenceof ventricular tachycardia was compared by the chi-square method. Of the 34 consecutivepatients with anterior AMZ receiving thrombolytic agents, 25 (12, SOD: 13, control) had coronary recanalization of Thrombolysis in Myo-

FIGURE 2. Total number of ventricular premature complexes (VPCs) per hew after coronary reperbton. Pre-Rep = before reperiusion. SOD = superoxide disnlutase.

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cardial Infarction’ grade 22. One patient in the control group had reocclusion of the infarct-related artery and 1 patient in the SOD group did not undergo repeat cineangiography because of cerebral infarction. The remaining 23 patients were analyzed. Baseline characteristics of the SOD-treated and control groups were similar (Table I). No adverse reaction to SOD occurred. During the3rst 15 minutes after coronary reperfusion, the incidence of ventricular tachycardia tended to be lower in the SOD group than in the control group (27 us 58%,p = 0.14 by chi-square). The number of ventricular premature complexes during 15 minutes after reperfusion was significantly smaller in the SOD group than in the control group, although there was no difference in the counts of ventricular premature complexes during the 5 minutes before reperfusion (Figure I). Ventricular fibrillation occurred in I control patient, and was converted to sinus rhythm with a dejibrillator. The number of ventricular premature complexes per hour after reperfusion tended to be lower in the SOD group than in the control group. The difference was significant between 2 and 3, 7 and 8,9 and 10 and 10 and 11 hours after reperfusion (Figure 2). There was no difference in regional ejection fraction (anterolateral and apex) determined 3 to 4 weeks after the onset of AMI (Table I).

The present study supports the view of Nejima et al2 that an intravenousadministration of SOD had beneficial effectson reperfusion arrhythmias but not on left ventricular function. The reduction of arrhythmias by SOD also suggestsan important role of superoxide anions in the genesisof reperfusion arrhythmias. Failure to improve left ventricular function by treatment with SOD raises 2 possibilities. First, myocardial

cell injury during coronary reperfusion may be mediated not by super-oxideanion but by other radical species, including hydrogen peroxide or hydroxyl radicaL6 Second, it is possiblethat during the period before reperfusion, the infused SOD is not sufficiently delivered to the jeopardized myocardium becauseof a lack of adequate blood flow to that area. Our present study provides the basisfor future randomizedstudiesto establishthe role of SOD as the therapeutic agent in patients undergoing thrombolysis. However, this is a pilot study to assessthe hemodynamiceffectsand the overall feasibility of giving SOD in the human population. Further studiesare needed to confirm the beneficial effectsof SOD and to explore the possibleadverseeffects, if any.

1. Ambrosia G, BeckerLC, Hutchins GM, WeismanHF, Weisfeldt ML. Reduction in experimental infarct size by recombinant human superoxidedismutase: insight into the pathophysiologyof reperfusioninjury. Circulation 1986;74: 14241433. 2. Nejima J, Knight DR, Fallon JT, Uemura N, Manders T, Canfield DR, Cohen MV, Vatner SF. Superoxidedismutasereducesreperfusionarrhythmias but fails to salvageregional function or myocardiumat risk in consciousdogs.Circulation 1989;79:143-153.

3. Goldberg S, GreensponAJ, Urban PC, Mum B, Gerger B, Walinsky P, Maroko P. Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysisfor acute myocardial infarction. Am Heart J 1983;105:26-32. 4. SheehanFH, Mathely DG, Schafer J, Krebber HJ, Dodge HT. Effect of interventionsin salvagingleft ventricular function in acute myocardial infarction: a study of intracoronary streptokinase.Am J Cardiol 1983;52:431-438. 5. ChesebroJH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, PassamaniER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in Mywardial Infarction (TIMI) trial. PhaseI: a comparisonbetweenintravenousplasminogenactivator and intravenous streptokinase.Circulation 1987;76:142-154. 6. Kelvin JAD. Protein damageand degradationby oxygenradicals.JBiol Chem 1987;262:9895-9901.

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