A model of chronic ischemic arrhythmias: The relation between electrically inducible ventricular tachycardia, ventricular fibrillation threshold and myocardial infarct size

EXPERIMENTAL STUDIES

A Model of Chronic Ischemic Arrhythmias : The Relation Between Electrically Inducible Ventricular Tachycardia, Ventricular Fibrillation Threshold and Myocardial Infarct Size

ELI S . GANG, MD J . THOMAS BIGGER Jr ., MD FRANK D . LIVELLI Jr ., MD New York, New York

To study the relation between inducible ventricular tachycardia and ventricular vulnerability, myocardial infarction was created in 22 closed chest mongrel dogs by inflating a balloon catheter in the left anterior descending coronary artery for 2 hours . The presence of inducible ventricular tachycardia was determined by programmed electrical stimulation of the right ventricle in each dog before and 4 days after infarction, using a transvenous electrode catheter and a `clinical' stimulation protocol . In each dog the repetitive ventricular response threshold and the ventricular fibrillation threshold were measured before and 4 days after infarction . Ventricular tachycardia was not inducible in any dog before infarction . After Infarction, sustained ventricular tachycardia was inducible in 10 (45 percent) of 22 dogs and nonsustained tachycardia in an additional 4 dogs (18 percent) . Ventricular fibrillation threshold was greatly reduced 4 days after infarction in dogs with inducible sustained tachycardia (mean ± standard deviation 29 f 11 to 10 f 5 mA, p <0 .001) ; the mean threshold did not change significantly in dogs without inducible sustained tachycardia . Both the ventricular fibrillation threshold and mean ventricular repetitive response threshold were reduced in the dogs with sustained ventricular tachycardia ; neither was significantly altered in the dogs without sustained tachycardia . The magnitude of change in the two thresholds frequently differed ; hence, a correlation was weak between the control and postinfarction repetitive response/fibrillation threshold ratio (r = 0 .41) . Postmortem measurement of infarct size demonstrated an association between this measurement and the presence of inducible ventricular tachycardia . Sustained ventricular tachycardia was not inducible in the presence of a small infarct .

It is concluded that: (1) Inducible ventricular tachycardia on the 4th

From the Department of Medicine, Columbia University, New York, New York and the Arrhythmia Control Unit, Columbia-Presbyterian Medical Center, New York, New York . This study was supported in part by grants-in-aid from the Winthrop Foundation, New York, New York ; Merck Sharp and Dohme, West Point, Pennsylvania ; and by Grant HL-07406 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland . Manuscript received December 21, 1981 ; revised manuscript received March 16, 1982, accepted March 25, 1982 . Address for reprints : J . Thomas Bigger Jr ., MD, Department of Medicine, Columbia University, 630 West 168th Street, New York, New York 10032 .

day after myocardial infarction is associated with a considerable decrease in the ventricular fibrillation threshold ; (2) changes in the repetitive response and fibrillation thresholds after myocardial infarction may not be parallel, complicating the use of the repetitive ventricular response threshold as a substitute for the ventricular fibrillation threshold In the postinfarction state; (3) a large Infarct predisposes the heart to electrically inducible sustained ventricular tachycardia .

Sudden cardiac death in human beings is usually the result of ventricular

tachyarrhythmia 1 Recently, an electrophysiologic approach has been proposed to detect patients who are prone to have spontaneous ventricular tachycardia or ventricular fibrillation and to assess their treat-

ment with drugs or surgery. 2

5

Clinically, ventricular tachycardia induced

by constant strength, premature electrical stimuli has been used to assess

the risk of spontaneous ventricular tachycardia or fibrillation

.2 s

The

relation between ventricular tachycardia induced by programmed stimulation in the clinical laboratory and the ventricular fibrillation

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threshold is unknown at present . Since the time of Wiggers and Wegria,s ventricular vulnerability to fibrillation has been measured in animal models using the electrical ventricular fibrillation threshold ; that is, the minimal strength of a single current pulse that causes ventricular fibrillation . There have been no studies to relate sustained ventricular tachycardia induced by programmed stimulation using a stimulus that is twice diastolic threshold intensity (a "clinical" protocol) to the ventricular fibrillation threshold measured by increasing the amplitude of a single pulse in the vulnerable period (an "experimental" protocol) . In order to avoid repeated defibrillation of experimental animals, Matta et al . 7 recommended that the ventricular repetitive response threshold be substituted for the ventricular fibrillation threshold . The ventricular repetitive response threshold-the minimal current strength required to produce at least two ventricular responses to a single premature ventricular stimulus-was shown by these authors to be about two thirds of the value for the ventricular fibrillation threshold . Also, the ratio of repetitive ventricular response to ventricular fibrillation threshold remained constant during various experimental interventions, for example, stimulation of the cardiac sympathetic nerves . These findings encouraged the use of the ventricular repetitive response threshold rather than the ventricular fibrillation threshold itself, particularly for the study of awake dogs. To date, no studies have compared the ventricular repetitive response threshold to the ventricular fibrillation threshold during subacute or chronic myocardial ischemia or infarction.

FIGURE 1 . Position of catheters in the dog heart . A left lateral view is displayed in this radiograph . Catheters shown are : (1) Judkins catheter positioned at the orifice of the left coronary artery, labeled "Sheath" ; (2) Fogarty catheter with balloon inflated in the proximal left anterior descending coronary artery ; (3) electrode catheter positioned in the right ventricular (RV) apex .

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The objectives of this study were : (1) to study the relation between electrically induced sustained ventricular tachycardia and the ventricular fibrillation threshold after myocardial infarction, (2) to study the changes in the ratio of the ventricular repetitive response threshold to ventricular fibrillation threshold that occur several days after myocardial infarction, and (3) to relate size of infarction to the response elicited with programmed ventricular stimulation . For these studies, we used a closed chest occlusion/reperfusion technique to produce myocardial infarction in the dog . We used traditional laboratory stimulation methods to measure ventricular repetitive response threshold and ventricular fibrillation threshold and a stimulation protocol of the type used in clinical electrophysiology laboratories to induce ventricular tachycardia . Methods

Study animals and experimental myocardial infarction : Twenty-two mongrel dogs (19 male, 3 female) ranging in weight from 13 to 29 kg were anesthetized with alphachloralose (100 mg/kg) . All animals were intubated with a cuffed endotracheal tube and ventilated with room air using a volume-cycled respirator . Arterial blood gases and esophageal temperature were monitored and maintained at physiologic levels . The dogs were placed on their right side and the left external jugular vein and carotid artery were isolated with use of a cutdown procedure . A 6 French quadripolar (USCI) transvenous catheter was inserted and positioned in the right ventricular apex under fluoroscopic control. The proximal two electrodes (5 and 8 cm from the tip) were used to record a ventricular electrogram while the distal two electrodes (located at the tip of the catheter, 1 .0 cm interelectrode distance) were used for bipolar stimulation ; the distal electrode was made the cathode . Standard limb leads were used to record the electrocardiogram . Data were displayed on an Electronics for Medicine VRI2 recorder and stored on FM magnetic tape (Honeywell, model 101) . The stimulation protocols (see later) were carried out in all dogs before creation of the infarction . Coronary occlusion was then performed using a modification of a closed chest balloon technique . 8 We modified an 8 French Judkins angiographic catheter by reducing its length to 43 cm and enlarging its distal opening to permit passage of a 2 French Fogarty embolectomy catheter . The Judkins catheter was inserted under fluoroscopic control by way of the left carotid artery into the orifice of the left coronary artery . The position of the catheter was confirmed by hand injection of contrast material (isothalamate meglumine) . A 2 French Fogarty embolectomy catheter was then passed through the Judkins catheter and positioned in the left anterior descending coronary artery (Fig . 1), 3 to 4 cm from the orifice of the angio. The position of the Fogarty catheter was graphic catheter confirmed with several fluoroscopic views . Occlusion of the coronary artery was achieved by inflation of the balloon at the tip of the Fogarty catheter, using diluted contrast material (isothalamate meglumine) . Inflation was maintained with a stopcock . Occlusion of the coronary artery was accompanied by characteristic S-T segment elevation in the surface leads in each dog (Fig. 2) . The occlusion was terminated in each dog 2 hours after inflation of the balloon . Five minutes before balloon deflation, an intravenous bolus injection of lidocaine (5 mg/kg) was administered . Ventricular fibrillation rarely occurred (two episodes) on release of the occlusion ; direct

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ECG CHANGES DURING BALLOON OCCLUSION LEAD I

CONTROL

15 MIN

1 .0

1 MV 30 MIN

120 MIN

FIGURE 2. Electrocardiographic (lead 1) evidence of ischemia caused by balloon occlusion of the left anterior descending coronary artery . Time elapsed (in minutes) from the onset of occlusion is indicated .

current cardioversion was effective in terminating both episodes . The catheters were subsequently removed, the cutdown site sutured and the dogs returned to the kennel . On the 4th day after occlusion/re perfusion, the dogs were brought back to the laboratory and anesthetized in the same manner and electrophysiologic testing was repeated (see later)In addition, an atrial electrogram was recorded in dogs with inducible ventricular tachycardia on the 4th day after infarction . Protocol for induction of ventricular tachycardia : Under a protocol similar to that being used by several clinical electrophysiology laboratories, including ours, programmed electric stimulation was performed using a direct current digital stimulator (Bloom Associates, Ltd .) . Stimulation of the right ventricular apex was performed before and 4 days after the experimental infarction . Both the basic pacing and the test stimuli were rectangular pulses 2 ms in duration and at a current setting of twice diastolic threshold . The basic pacing was always at a cycle length of 350 ms . Diastole was scanned using a single premature stimulus ((S 2 ) during every eighth pacing cycle . The S I--S, coupling interval was decreased by 10 ms until the effective refractory period of the ventricle was reached . The stimulation protocol also included the scanning of diastole with dual premature stimuli (5,-5 2 -53 ) as well as "burst" ventricular pacing (trains of 8 stimuli at decreasing cycle lengths until 1 :1 ventricular capture was no longer obtained) . Nonsustained ventricular tachyarrhythmia was defined as the reproducible induction of three or more consecutive ventricular complexes that terminated spontaneously . Sustained ventricular tachyarrhythmia was defined as a reproducibly induced tachyarrhythmia of ventricular origin that required programmed ventricular stimulation or direct current countershock for its termination . Measurement of ventricular repetitive response threshold and ventricular fibrillation threshold : We defined the ventricular repetitive response threshold as the minimal amplitude of current of S 2 required to produce 1 or more nonstimulated ventricular responses when stimulating in the ventricular vulnerable period (Fig-3) . The ventricular

FIGURE 3 . Induction of repetitive responses (RVR) and ventricular fibrillation (VF). A single S 2 extrastimulus follows a train of 8 paced beats . A, at a current intensity of 16 mA (single) ventricular repetitive response is produced . B, an S 2 of 24 mA current intensity produces ventricular fibrillation .

fibrillation threshold was defined as the lowest current strength of S 2 required to produce ventricular fibrillation .6- 9 The repetitive response/fibrillation threshold ratio was determined for each dog before and 4 days after infarction . Stimulation was performed using the same electrode catheter used for the "clinical" protocol outlined earlier . A modification of our stimulator (Bloom Associates, Ltd .) enabled us to deliver an S 2 of up to 100 mA to the right ventricular endoeardial surface . Scanning of electrical diastole was performed using an S2 test pulse of 5 ms duration delivered in the eighth pacing cycle with pacing performed at a cycle length of 350 ms . Diastole was scanned in 3 ms decrements, starting 15 ms after the inscription of the T wave and ending at the effective refractory period of the right ventricle . During control (preinfarction) testing the initial current setting of the test pulse was 5 to 6 mA; the intensity of S2 was increased in 1 mA increments and scanning of diastole repeated until each of the thresholds was reached . After infarction, the initial amplitude of S 2 was set at 1 mA . Defibrillation was promptly performed using a direct current cardioverter (American Optical Co .) . Postmortem studies: After each experiment the dog was killed, the heart removed and infarct size measured . 1 D The left ventricle was sliced in 3 mm thick transverse sections ; these sections were incubated in a freshly prepared solution of triphenyl tetrazolium chloride for 15 to 20 minutes at 37° C. The border of the infarct was then directly traced on a transparent sheet and the cross-sectional area of infarct in each slice was measured with a computer-assisted planimeter . By summing the areas of infarction and areas of normal myocardium, the percent of infarcted left ventricle was obtained . Statistical methods: The results are summarized as mean values f standard deviation. We used the t test for paired

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Results A

Control Studies None of the 22 study animals manifested ventricular tachycardia (sustained or nonsustained) when the "clinical" stimulation protocol was performed before experimental myocardial infarction . `the current threshold for repetitive ventricular response and ventricular fibrillation was measured in each dog before coronary occlusion, using the variable amplitude S 2 technique . The mean control repetitive response threshold was 17 f 5 mA and the mean control ventricular fibrillation threshold was 27 ± 10 mA . The threshold current for repetitive responses was less than the ventricular fibrillation threshold in 19 (86 percent) of 22 animals . In 3 dogs (14 percent) ventricular fibrillation was not. preceded by repetitive responses .

I aVr RVA ,~

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I I1 S, S2 S 3

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. J V V 'I ~ ' l I~,I f~k RVA f t 0Vr

-1

S

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1 1 I( I I S, S, S, S

LO sec , ,

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FIGURE 4 . Induction and termination of ventricular tachycardia . A, two premature extrastimuli (S 2 and S 3) following a train of eight paced beats (S,) induce ventricular tachycardia at a cycle length of 300 ms . B, the tachycardia is terminated with an S 2 extrastimulus . Leads displayed are I and aVF and right ventricular apex (RVA). S = stimulus artifact .

samples to compare the ventricular fibrillation thresholds obtained before and after infarction in two groups of dogs : those with and those without inducible ventricular tachycardialt The coefficient of correlation was calculated betweenn the ventricular repetitive response/ventricular fibrillation threshold ratio obtained before and 4 days after infarction .' I When comparing infarct size with response to programmed stimulation, one-way analysis of variance as well as a t test for contrast between group means was performed in order to test for differences between three types of responses : no inducible ventricular tachycardia, inducible nonsustained ventricular tachycardia and inducible sustained ventricular tachycardia .

Stimulation Studies 4 Days After Infarction Induction of ventricular tachycardia using the "clinical" protocol : On the 4th postinf'arction day we were able to induce sustained ventricular tachyarrhythmia reproducibly in 10 (45 percent) of 22 dogs (Fig . 4 and 5) . The stimulation mode most frequently successful in inducing the ventricular tachycardia was Sl-S2-S 3 (9 of 10 dogs) . "Burst" ventricular pacing induced ventricular tachyarrhythmia in 4 of 10 dogs and was the only successful mode in 1 dog . The rate of the ventricular tachycardia was relatively slow (200 to 220 beats/min) in 3 of the 10 dogs . In these 3 dogs, ventricular tachycardia was terminated readily with programmed stimulation . The rate of tachycardia was greater than 250 beats/min in the other 7 dogs ; direct current countershock was required to terminate the tachycardia in each of these 7 dogs . Figure 4 shows an example of the initiation and termination of ventricular tachycardia and Figure 5 an example of the initiation of a rapid ventricular tachycardia . The induced yen-

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FIGURE 5 . Induction of rapid, sustained ventricular tachycardia . The atrial electrogram The remaining leads are the same as in Figure 4 . 472

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displays A-V dissociation during the ventricular tachycardia .



VENTRICULAR TACHYCARDIA, VENTRICULAR FIBRILLATION THRESHOLD AND MYOCARDIAL INFARCT SIZE- GANG ET AL .

SUSTAINED VT

tricular tachyarrhythmia had morphologic features that resembled "torsade de pointes" in two of the seven dogs with rapid ventricular tachycardia . Four dogs (18 percent) had only self-terminating, nonsustained ventricular tachycardia during stimulation . All episodes of nonsustained ventricular tachycardia contained fewer than 10 QRS complexes, In eight dogs (36 percent), ventricular tachycardia could not be induced with programmed electrical stimulation .

NO VT

50

40

a

3

E LJ

Ventricular fibrillation thresholds in the postinfarction dog : The average ventricular fibrillation threshold for all 22 dogs on the 4th day after infarction was 18 ± 10 mA, a33 percent decrease . When compared

20

IO

10

o

0CONTROL

DAY 4

CONTROL

DAY 4

FIGURE 6 . Ventricular fibrillation threshold (VFT) before and after myocardial infarction in the 2 groups of dogs . In the first group (n = 10) sustained ventricular tachycardia (VT) was inducible ; substantial changes in the ventricular fibrillation threshold can be seen between the control (pre-infarction) and the post-infarction (day 4) values . In the second group (n = 12, no sustained ventricular tachycardia), no appreciable changes in the ventricular fibrillation threshold were measured . Results expressed in mA .

to the preinfarction ventricular fibrillation threshold (27 f 10 mA), the difference was highly significant (p <0.001) . The decrease in the ventricular fibrillation threshold in these postinfarction dogs is entirely confined to the group of 10 dogs with inducible sustained ventricular tachycardia (Fig . 6) . That is, in the group with ventricular tachycardia a highly significant decrease in ventricular fibrillation threshold occurred between the control day and the 4th day (29 ± 11 to 10 ± 5 mA, a 62 ± 20 percent decrease, p <0 .001), while the average ventricular fibrillation threshold did not change

TABLE I Effect of Experimental Myocardial Infarction on Repetitive Ventricular Response Threshold (RVRT) and Ventricular Fibrillation Threshold (VFT) ---- -------RVRT (mA) VFT (mA) RVRT/VFT Dog

% IS

Before

After

Before

After

Before

After

0.93 0 .36 0 .35 0 .88

0 .89 0 .75 0 .04 -

0 .78 0 .50 0 .33

0 .14

0 .59 ±27

0 .34 +38

0 .71 0 .94 0 .84 0 .79 0 .95 0 .94 0,79 0 .63 0 .89 0 .75 0 .67 0 .70 0 .80 + 11

0 .82 041 067 0 .05 093 094 0 .10 0 .75 0 .89 0 .92 0 .75 0 .41 0 .64 +32

Group I :Inducible Sustained Ventricular Tachycardia 6 a 12 13* 14* 15 16* 17 19' 20' Mean ±SD

30 26 21 38 17 33 31 38 55 21 31 +11

26 10 12 7 14 22 10 -

1 2r 3 4t 5t 7 9t 10 11 18 21 22 Mean +SD

10 9 0 10 26 3 27 3 13 11 23 2 11 19

20 17 16 22 23 15 11 19 16 18 16 34 19 +6

18 9 14 1 27 16 1 18 16 24 18 18 15 18

Mean ±SD

20 ±14

17 ±5

12 t9

14 ±7

16 9 1 1 1 1 5 +6

28 28 34 8 24 18 44 30 42 38 29 ±11

18 12 14 5 1

7 13 17 6 10 10 ±5

0 .06 0 .17

Group II : No Inducible Sustained Ventricular Tachycardia 28 18 19 28 24 16 14 30 18 24 24 48 24 +9

22 22 21 29 29 17 12 24 18 26 24 44 24 ±8

Groups I and II 27 ±10

18 ±10

0 .72 0 .54 ±20 +36 * The ventricular fibrillation threshold was not preceded by a repetitive ventricular response threshold in these dogs (see text) . T Dogs with inducible nonsustained ventricular tachycardia only . IS = infarct size, expressed as percent of infarcted left ventricle .

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significantly in the group without sustained ventricular tachyarrhythmia (24 ± 9 to 24 18 mA) . Repetitive ventricular response threshold/ventricular fibrillation threshold ratio : In 17 dogs we were able to compare the ratio of ventricular repetitive response threshold to the ventricular fibrillation threshold before and after the infarction period . The other five dogs did not have repetitive responses before fibrillation on control testing (three dogs) or after occlusion/reperfusion (two dogs) ; that is, in five dogs the first response produced during threshold testing was ventricular fibrillation rather than repetitive responses . Table I lists the ventricular repetitive response thresholds and ventricular fibrillation thresholds measured before and 4 days after infarction . In the group with sustained ventricular tachycardia both the ventricular repetitive response threshold and the ventricular fibrillation threshold decreased significantly after infarction ; in the group without sustained ventricular tachycardia neither threshold was significantly changed from the control value . Table I lists the ratio of repetitive response threshold to fibrillation threshold measured before and 4 days after infarction . Correlation between the control and postinfarction ratio of the repetitive response threshold to the fibrillation threshold was weak (n = 17, r = 0 .41) . The discordance between the pre- and postinfarction threshold ratios (Fig . 7) was most pronounced in four dogs with sustained and three dogs with nonsustained ventricular tachycardia. Therefore, while changes in the ventricular repetitive response threshold gave a valid indication of the direction of change in the ventricular fibrillation threshold, after infarction the repetitive response threshold frequently manifested more pronounced changes than the ventricular fibrillation threshold, particularly in dogs with inducible sustained and nonsustained ventricular tachycardia . Myocardial infarct size : Infarct size was measured in each of the 22 dogs (Table I) . Tetrazolium staining revealed the presence of myocardial infarction in all but Dog 3 . The relation between the size of the myocardial infarction (percent. of left ventricle infarcted) and the

INFARCT

SIZE-GANG ET

AL .

response to programmed ventricular stimulation is displayed in Figure 8 . Mean infarct size was small (8 f 7 percent) in the 8 dogs without inducible ventricular tachycardia; it was intermediate (18 ± 10 percent) in the 4 dogs with nonsustained ventricular tachycardia and greatest (31 + 11 percent) in the 10 with inducible sustained ventricular tachycardia . The difference between the group without inducible tachycardia and the group with inducible sustained tachycardia was highly significant (p <0 .001) . Discussion A closed chest model for reperfusion infarction and inducible ventricular tachycardia : In this study we used an animal model that simulates the clinical findings of inducible ventricular tachycardia in the patient with previous myocardial infarction . Utilizing this model we sought to answer two questions : (1) Is the ventricular fibrillation threshold lower in animals that have inducible ventricular tachycardia than in animals that do not? (2) Is repetitive response threshold a useful index of ventricular fibrillation threshold after myocardial infarction? To avoid complications of thoracotomy, myocardial infarction was produced by closed chest balloon occlusion and reperfusion of the left anterior descending coronary artery . To simulate clinical electrophysiologic testing, the programmed stimulation protocol was performed in the intact, closed chest dog using an electrode catheter introduced via a peripheral vein .

• 50

40

w LU ~

T

'0

20 J a$ 10

0

0

0

NO RESPONSE

05

RVR/VF THRESHOLD

0 CONTROL

FIGURE 7 . Relationship between control and postinfarction (MI) repetitive ventricular response/ventricular fibrillation (RVR/VF) threshold ratios in 17 dogs .

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NON-SUSTAINED VT

SUSTAINED VT

FIGURE 8 . Scatter diagram relating percent infarcted left ventricle (LV) to inducibility of ventricular tachycardia (VT) 4 days after myocardial infarction . The difference between the first and third group is highly significant (p <0 .001) .

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Stimulation was limited to the left ventricle, a site from which most (80 to 90 percent) ventricular tachycardias can be induced in the clinical setting of a previous myocardial infarction .5 Several dog models for inducible ventricular tachyarrhythmias after infarction have previously been described . L2-16 Important differences may exist between our model and those heretofore used . First, both stimulation and infarction were performed without any major surgical intervention, avoiding any problems that may arise as a result of the open chest approach)? Second, ours is the first animal model for inducible ventricular tachycardia in which electrical stimulation data are available both in the control state and several days after infarction. W e were therefore able to observe the changes in cardiac electrical properties that occurred as a consequence of the occlusion/reperfusion procedure, whereas previous studies obtained data only after infarction . Third, the use of transvenous electrode catheter stimulation techniques identical to those used in our clinical electrophysiology laboratory for provoking ventricular tachycardia makes this model suitable for future multiday pharmacologic studies . Relation between inducible ventricular tachycardia and the ventricular fibrillation threshold : In the 10 dogs that had sustained ventricular tachycardia induced by programmed electrical stimulation, the fibrillation threshold was greatly reduced from the preinfarction level . In the 12 dogs that did not have ventricular tachycardia induced, there was no significant mean change in the ventricular fibrillation threshold. The time course of changes in the ventricular fibrillation threshold that occur immediately after acute coronary arterial ligation has been extensively studied . IS-21 Similarly, changes in the ventricular fibrillation threshold of the chronically ischemic heart also have been explored.222,23 However, no previous studies have related the ventricular fibrillation threshold to inducible ventricular tachycardia in the subacute and chronic postinfarction state . In fact, the physiologic relevance of the ventricular fibrillation threshold has recently been questioned . 24 Our finding of a striking reduction in fibrillation threshold in postinfarction dogs with inducible sustained ventricular tachycardia provides the first, link between traditional measures of ventricular vulnerability to fibrillation and the inducibility of ventricular tachycardia during programmed electrical stimulation . Despite their obvious morphologic differences in the surface electrocardiogram, ventricular fibrillation and tachycardia share certain similarities . First, epicardial

maps obtained during reperfusion-induced ventricular fibrillation in the dog have demonstrated the presence of organized epicardial activation sequences occurring during the early phases of ventricular fibrillation, while a simultaneous body surface electrocardiogram may show a chaotic electrical pattern,"" Hence, the electrocardiographic distinction between rapid ventricular tachyarrhythmia and ventricular fibrillation is not always precise . Second, both ventricular tachycardia and ventricular fibrillation are thought to be reentrant rhythms . Ventricular fibrillation is likely to occur when

sufficient dispersion in recovery of excitability takes place among adjacent regions of the myocardium,2G- 29 and can be induced even in the normal ventricle by a properly timed electrical stimulus of sufficient strength and duration .9 A premature impulse encountering tissue in which some fibers are excitable and others are not may produce multiple reentrant circuits and thereby initiate ventricular fibrillation . The term `random reentry' has therefore been applied to describe ventricular fibrillation .29 Electrically induced ventricular tachyarrhythmia in the postinfarction experimental animalls';e as well as in the clinical setting of chronic ischemic heart disease in patients 4.5 also is likely to be due to reentry . If both ventricular tachycardia and fibrillation are reentrant arrhythmias and dependent on heterogeneity of excitability for their initiation, then the need for a stimulus of significantly lesser intensity to provoke ventricular fibrillation in our dogs with inducible ventricular tachycardia suggests that a substrate of increased heterogeneity of excitability must exist in the ventricles of these dogs . Such heterogeneity was shown in another long-term dog model of scar-related ventricular tachyarrhythmia. 15 The close association between reduced ventricular fibrillation threshold and inducible ventricular tachycardia in our dog model permits us to entertain the following hypotheses . First, even allowing for

known differences between the experimental dog model and the postinfarction patient, it may be that the presence of inducible ventricular tachycardia in the patient recuperating from an acute myocardial infarction may reflect a profoundly reduced fibrillation threshold and a greater susceptibility to spontaneously occurring lethal ventricular tachyarrhythmias. Second, the extent to which an antiarrhythmic drug is capable of raising the ventricular fibrillation threshold may also be closely linked to its efficacy in abolishing inducible ventricular tachycardia in the subacute postinfarction state . Repetitive response threshold/ventricular fibrillation threshold ratio : On the assumption that the ratio of the ventricular repetitive response threshold to ventricular fibrillation threshold remains constant, investigators have measured the ventricular repetitive response threshold during various experimental conditions such as acute ischernia, ;' manipulation of autonomic tone, 7. 34,35 pharmacologic intervention' and psychologic stress . -96 The validity of this assumption has recently been questioned .;' Our dog model allowed us to study the relation between the ventricular repetitive response threshold and the ventricular fibrillation threshold before and after myocardial infarction . In the control state our values for the repetitive response/ fibrillation threshold ratio (72 ± 20 percent) were similar to those obtained by Matta et al .,7 who employed a single extrastimulus delivered to the endocardium and found a value of 66 t 26 percent, and to those of Jaillon et al .,37 who measured the fibrillation threshold by delivering a train of rectangular pulses to the epicardium of the right ventricle and obtained a repetitive response/fibrillation threshold ratio of 54 ± 13 percent .

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In our experiments, 4 days after occlusion/reperfusion the dogs with a large reduction in the ventricular fibrillation threshold (and with inducible sustained ventricular tachycardia) also manifested a large reduction in the repetitive response threshold, while the dogs without a lowered fibrillation threshold had no significant change in the repetitive response threshold. These results extend the observations of Matta et al . to the postinfarction state and indicate that in a large group of postinfarction dogs, mean changes in the repetitive response threshold are likely to be indicative of similar changes in the ventricular fibrillation threshold . A few words of caution are in order regarding the use of the ventricular repetitive response threshold as a reliable index of the fibrillation threshold . First, values for the ventricular repetitive response/ventricular fibrillation threshold ratio after infarction vary widely, and discordance between the pre- and postinfarction ratios is common, particularly in dogs with inducible ventricular tachycardia (sustained or nonsustained) . The most frequent cause for this discordance in threshold ratios is a marked reduction in the ventricular repetitive response threshold without a corresponding change of similar magnitude in the ventricular fibrillation threshold after occlusion/reperfusion infarction . Another potential drawback to using the repetitive response as an index of the ventricular fibrillation threshold is the lack of repetitive responses before attainment of ventricular fibrillation in some dogs . The 14 percent of our control dogs without a repetitive response is also in agreement with the findings of others .,, 7 Testing on the 4th day produced two additional dogs that failed to show a ventricular repetitive response before ventricular fibrillation . Larger sample sizes are required when the experimental design requires the use of the repetitive response threshold rather than the ventricular fibrillation threshold, in awake dogs, for example . Relation between infarct size and ventricular tachycardia : We found a strong association between myocardial infarct size and the inducibility of ventricular tachycardia . These findings are in agreement with the results reported in several previous animal studies . 14' 16 However, other postinfarction canine models

have not shown a close association between infarct size and inducible ventricular tachyarrhythmias)' "' Differences in experimental design may account for these differences in results . Specifically, in the latter studies, 73"L 5 electrical stimulation was performed in the open chest animal utilizing multiple pacing sites, whereas our closed chest stimulation protocol was performed from one endocardial site in the right ventricular apex . Our finding of a large infarct in dogs with inducible sustained ventricular tachycardia is also in agreement with clinical studies that demonstrated an association between ventricular arrhythmias in the postinfarction patient and the extent of myocardial injury . 3 8' is It is probable that interventions designed to limit infarct size would also prevent. postinfarction ventricular instability, both in animal models and in patients . Implications : Several conclusions may be drawn from our studies . First, the ability to induce sustained ventricular tachycardia with programmed electrical stimulation after infarction is associated with a markedly reduced fibrillation threshold . Further studies are required to determine whether this finding is applicable to the human patient during the in-hospital phase of recovery from an acute myocardial infarction . Also, further studies are required to determine whether fibrillation threshold changes and inducible ventricular tachycardia remain linked during drug treatment . Second, we conclude that after infarction the repetitive response threshold tends to change in the same direction as the ventricular fibrillation threshold . However, because nonparallel changes in these thresholds are common after infarction, the use of the ventricular repetitive response threshold as an indicator of the ventricular fibrillation threshold in models of chronic ischemia will require increased sample sizes and, therefore, will increase the cost . Finally, we conclude that electrical instability of the ventricle is much more likely to occur after a large myocardial infarct, whereas a small infarct is unlikely to permit the induction of sustained ventricular tachycardia .

Acknowledgment We thank Elizabeth W . IJhl for expert technical assistance with the animal experiments and Linda M . Rolnitzky for her consultation on design and statistical analysis of the results.

References 1. 2.

3.

Lown B. Sudden cardiac death : the major challenge confronting contemporary cardiology . Am J Cardiol 1979 ;43 :313-28 . Wellens HJJ, Lie KI, Durrer D . Further observations on ventricular tachycardia as studied by electrical stimulation of the heart . Chronic recurrent ventricular tachycardia and ventricular tachycardia during acute myocardial infarction . Circulation 1974;49:647-53 . Josephson ME, Horowitz LN, Farshidi A, Kastor JA . Recurrent sustained ventricular tachycardia . 1 . Mechanisms . Circulation

6.

7.

1469-73 . 8.

1978 ;57 :431-9 . 4.

5.

476

Ruskin JN, DiMarco JP, Garen H . Out-of-hospital cardiac arrest . Electrophysiologic observations and selection of long-term antiarrhythmic therapy N EnglJ Med 1980 ;303 :607-13 . Mason JW, Winkle RA . Accuracy of the ventricular tachycardiainduction study for predicting long-term efficacy and inefficacy of

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mapping verification of large, homogeneous experimental myocardial infarcts of predictable size and location in dogs . J Thorac Cardiovasc Surg 1975 ;69 :599-605 . 11 . Snedecor GW, Cochran WG . Statistical Methods . Ames, IA : Iowa State University Press, 1980 :83-102 . 12 . EI-Sheriff N, Scherlag BJ, Lazzara R, Hope R . Re-entrant ventricular arrhythmia in the late myocardial infarction period . 1 . Conduction characteristics in the infarction zone . Circulation 1977 :55 :686-702 . 13 . Garan H, Fallon JT, Ruskin JN . Sustained ventricular tachycardia in recent canine myocardial infarction . Circulation 1980 ;62 : 980-7 . 14 . Karagueuzian HS, Fenogllo JJ, Weiss MB, Wit AL . Protracted ventricular tachycardia induced by premature stimulation of the canine heart after coronary artery occlusion and reperfusion . Circ Res 1979 ;44 :833-46 . 15 . Michelson EL, Spear JF, Moore EN . Electrophysiologic and anatomic correlates of sustained ventricular tachyarrhythmias in a model of chronic myocardial infarction . Am J Cardiol 1980 ;45 : 583-90 . 16 . Jones-Collins BA, Patterson RE. QuantItatIve measurement of electrical instability as a function of myocardial infarct size in the dog . Am J Cardiol 1981 ;48 :858-63 . 17 . Ferguson TB, Shadle OW, Gregg DW . Effect of blood and saline infusion on ventricular end-diastolic pressure, stroke work volume and cardiac output in the open and closed chest dog . Circ Res 1953 ;1 :62-73 . 18 . Battle WE, Naiml S, AvItall B, et al . Distinctive time course of ventricular vulnerability to fibrillation during and after release of coronary ligation . Am J Cardiol 1974 ;34 :42-7 . 19 . Burgess MJ, Abildskov JA, Miller K, Geddes JS, Green LS . Time course of vulnerability to fibrillation after experimental coronary occlusion. Am J Cardiol 1971 ;27 :817-21 . 20 . Axelrod PJ, Verrier RL, Lown B . Vulnerability to ventricular fibrillation during acute coronary arterial occlusion and release, Am J Cardiol 1975 :36 :776-8221 . Suzukl S, Kato T, Kambe T, Sakamoto N, Suglyama S, Ozawa T. An experimental study of release arrhythmia : occlusion timedependent changes in ventricular fibrillation threshold . Am Heart J 1979 ;98 :727-31 . 22 . MacLean LD, Phlbbs CM . Relative effect of chronic ischemia and a myocardial revascularization procedure on the ventricular fibrillation threshold . Circ Res 1960 ;8 :473-80 . 23 . Horowitz LN, Spear JF, Josephson ME, Kastor JA, Moore EN . The effects of coronary artery disease on the ventricular fibrillation

threshold in man . Circulation 1979 ;40 :792 . 7 . 24 . Elharrar V, Zipes DP . Cardiac electrophysiologic alterations during myocardial ischemia . Am J Physiol 1977 ;233 :H329-45 . 25 . Ideker RE, Klein GJ, Harrison L, et al . The transition of ventricular fibrillation induced by reperfusion after acute ischemia in the dog : a period of organized epicardial activation . Circulation 1981 ;63 : 1371-9 . 26 . Moore EN, Spear JF . Ventricular fibrillation threshold : its physiological and pharmacological importance . Arch Intern Med 1975; 135 :446-53 . 27 . Surawicz B . Ventricular fibrillation . Am J Cardiol 1971 :28:26887 . 28 . Cranefield PF . Ventricular fibrillation . N Engl J Med 1973 ;289 : 732-6. 29 . Hoffman BF, Rosen MR . Cellular mechanisms for cardiac arrhythmias . Circ Res 1981 ;49 :1-15 . 30 . EI-Sherif N, Hope R, Scherlag BJ, Lazzara R . Re-entrant ventricular arrhythmia in the late myocardial period . 2 . Patterns of initiation and termination of re-entry . Circulation 1977 ;55 :70219 . 31 . Han J. Ventricular vulnerability during acute coronary occlusion . Am J Cardiol 1969 ;24 :857-64 . 32 . Logic JR . Rapid assessment of ventricular fibrillation thresholds during experimental infarction in the canine heart . Free Soc Exp Siol Med 1975;149 :968-71 . 33 . Kowey PR, Verrier RL, Lown B . The repetitive extrasystole as an index of vulnerability to ventricular fibrillation during myocardial ischemia (abstr) . Am J Cardiol 1981 ;47 :391 . 34 . Han J, de Jalon PG, Moe GK . Adrenergic effects on ventricular vulnerability . Circ Res 1964 :15 :516-24 . 35 . Rabinowitz SH, Verrier RL, Lown B . Muscarinic effects of vagosympathetic trunk stimulation on the repetitive extrasystole (RE) threshold . Circulation 1976 ;53 :622-727 . 36 . Lown B, Verrier RL, Corbalan R . Psychologic stress and threshold for repetitive ventricular responses . Science 1973 ;182 :834-6 . 37 . Jaillon P, Schnittger I, Griffin JC, Winkle RA . The relationship between the repetitive extrasystole threshold and the ventricular fibrillation threshold in the dog . Circ Res 1980 ;46:599-605 . 38 . Roberts R, Husain A, Ambos HD, Oliver GC, Cox JR, Sobel BE. Relation between infarct size and ventricular arrhythmia . Br Heart J 1975 ;37 :1169-75 . 39 . Calif RM, Burks JM, Behar VS, Margolis JR, Wagner GS . Relationships among ventricular arrhythmias, coronary artery disease and angiographic and electrocardiographic indicators of myocardial fibrosis . Circulation 1978 ;57 :725-32 .

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