Right versus left ventricular stimulation: influence on induction of ventricular tachyarrhythmias in dogs

International Elsevier

CARD10

Journal of Cardiology,

317

28 (1990) 317-324

01116

Right versus left ventricular stimulation: influence on induction of ventricular tachyarrhythmias in dogs Geraldine Cardiology Unit, Department (Received

B. Hunt and David L. Ross

of Medicine,

9 January

Westmead

1990; revision

Hospital, New South Wales, Australia

accepted

28 March

Hunt GB, Ross DL. Right versus left ventricular stimulation: tachyarrhythmias in dogs. Int J Cardiol 1990;28:317-324.

1990)

influence

on induction

of ventricular

The contribution of left (versus right) ventricular stimulation to the induction of ventricular tachyarrhythmias was studied in 37 dogs with chronic experimental myocardial infarction, and 17 dogs with normal hearts. Programmed stimulation of the endocardium at both ventricular apices employed an aggressive protocol of up to 7 extrastimuli. The right ventricle was the most successful site for induction of ventricular tachycardia after myocardial infarction (74% of dogs with ventricular tachycardia). Ten of 11 animals with slow ventricular tachycardia (> 140 msec) were inducible from the right ventricle. In contrast, left ventricular stimulation was required to induce rapid ventricular tachycardia (cycle length -C 140 msec) in 5 of 10 dogs (P < 0.05). No animal required more than five extrastimuli from any site for induction of ventricular tachycardia. In the normal heart, ventricular fibrillation was induced most often from the right ventricle (77% of dogs) when compared with the left ventricle (47%, P < 0.05). Ventricular tachycardia was never induced in normal animals. These results show that the right ventricular apex is the most successful site for induction of “slow” ventricular tachycardia in this canine model when using five extrastimuli. Rapid ventricular tachycardia is frequently induced from the infarcted left ventricle, but this arrhythmia may not be clinically significant. The normal right ventricle is significantly more susceptible to ventricular fibrillation than is the left ventricle, but this does not interfere with induction of ventricular tachycardia in the infarcted heart. Key words: Stimulation

site; Ventricular

tachyarrhythmia;

Introduction Protocols for induction of ventricular tachyarrhythmias by programmed stimulation vary widely between laboratories. The protocol of Wellens et al. [l], first reported successfully to induce ventric-

Correspondence to: G.B. Hunt, Dept. of Veterinary Sciences, University of Sydney, NSW 2006, Australia.

0167-5273/90/$03.50

0 1990 Ekevier

Clinical

Science Publishers

Dog

ular tachycardia in 1972, has formed the basis for most electrophysiologic studies to date. Traditionally, stimulation is performed from the right ventricular apex at twice the intensity of the diastolic threshold current, and two extrastimuli follow a ventricular drive train of 8 beats. This protocol, nonetheless, may fail to induce ventricular tachycardia in up to half of the patients with clinical arrhythmias [2-41. Modifications to the basic protocol (in terms of the cycle length of the

B.V. (Biomedical

Division)

318

drive train and the stimulation current) were made in order to increase the sensitivity of the test [4-71. In recent years, greater versatility in design of stimulators has enabled the use of more extrastimuli, with a consequent improvement in the reliability of programmed stimulation [7-91. The use of large numbers of extrastimuli has also been shown to increase the yield of rapid ventricular tachycardia and ventricular fibrillation, considered to be non-specific responses [lo]. This may also be confusing in patients who are being routinely tested for susceptibility to ventricular tachyarrhythmias after myocardial infarction. As a result, some laboratories now use fewer extrastimuli, but deliver them from multiple pacing sites to reduce the likelihood of induction of ventricular fibrillation [ll-131. Unfortunately, it has been difficult thoroughly to compare different protocols of stimulation in humans. The use of aggressive protocols to determine the contribution of additional extrastimuli versus different pacing sites often leads to the induction of ventricular fibrillation, as well as to ventricular tachycardia. It is usually impossible to perform multiple inductions of arrhythmias in patients requiring cardioversion for termination of their arrhythmia and, therefore, the study cannot be completed. Most clinical trials have also failed to account for the contribution of repetition of programmed stimulation to the yield of arrhythmias [14]. Previous studies in animals have concentrated on the threshold for ventricular fibrillation [15,16] or have been performed in open-chest dogs using experimental rather than more clinically applicable pacing sites (epicardial versus endocardial). Furthermore, most reported studies have used only 3 extrastimuli [17-191. We have recently described a canine model of postinfarction ventricular tachycardia in which induction of arrhythmias is highly reproducible [20]. Furthermore, animals in which an inducible ventricular tachycardia had a cycle length of greater than 140 msec were shown to be at risk for the development of spontaneous ventricular tachycardia late after infarction. These animals are, therefore, similar to a sub-set of humans with slow inducible ventricular tachycardia who are at in-

creased risk of spontaneous arrhythmias [21]. In the present study, endocardial catheters, and an aggressive protocol similar to that used by our group in humans [14], was used to determine the importance of the site of stimulation in induction of arrhythmias in this canine model, as well as in normal dogs. Reproducibility of induction of arrhythmias was established by repetition of the protocol for stimulation at least once from each site, combined with the use of up to 7 extrastimuli.

Methods This experiment was approved by the Westmead Hospital Research and Animal Care Committees.

Normal dogs Seventeen normal dogs were anesthetized with intravenous pentobarbital (30 mg/kg). Pentobarbital was used as it is a standard anesthetic agent for experimental studies of this type. A quadripolar catheter was positioned at the right ventricular apex via percutaneous puncture of an external jugular vein. In addition, the left common carotid artery was exposed using a sterile technique via a small lateral neck incision. The carotid artery was ligated distally and an endocardial electrode catheter was positioned at the left ventricular apex using fluoroscopy. A bipolar catheter was used at this site to facilitate crossing of the aortic valve. The catheters were sutured to the skin to reduce movement. The catheter tips were one to two cm apart, separated by the interventricular septum. One to three surface electrocardiographic leads were recorded simultaneously with a right ventricular electrogram on paper using an ink-jet recorder (Siemens Mingograf) at paper speeds of 25 to 100 mm/set. Bipolar pacing was performed through the distal electrode pair of each catheter, the protocol for programmed stimulation consisting of a drive train of 8 ventricular paced beats delivered at a cycle length sufficiently fast to ensure stable capture during sinus rhythm (300350 msec), using a current intensity of twice diastolic threshold. Stimuli were delivered by a battery powered impulse generator (WPI Model 520).

379

The first extrastimulus was delivered in mid-diastole, commencing with a coupling interval of 200 msec. The coupling interval was reduced in 10 msec steps until ventricular refractoriness was encountered. It was then placed 10 msec above the refractory period and the following extrastimuli were introduced in the same fashion until sustained ventricular tachycardia, or ventricular fibrillation, was induced, or else a minimum of 7 extrastimuli had been delivered. Ventricular tachycardia was defined as a wide complex rhythm with a cycle length of 110 msec or greater, showing sustained organised surface and intracardiac electrograms. Ventricular fibrillation was defined as any rhythm of cycle length less than 110 msec with disorganised surface and intracardiac electrograms. Ventricular arrhythmias lasting 10 seconds were considered to be sustained, and usually continued until terminated by overdrive pacing or direct current shock. The electrode through which induction of arrhythmias was first attempted was varied, and programmed stimulation was performed at least twice from each ventricle. A period of recovery sufficient to allow return of spontaneous heart rate to baseline (at least 10 minutes) was allowed between inductions of arrhythmias.

At least two weeks after infarction (36 f 7 days), the dogs were anesthetized with pentobarbital, and programmed stimulation was performed as described above. Statistical analysis Electrophysiologic variables, and the results of programmed stimulation, were compared between the right and left ventricle in normal and infarcted dogs. In addition, cycle length and ease of inducibility were compared between arrhythmias inducible from both ventricles versus arrhythmias inducible from only one ventricle. Student’s paired t-test was used to compare data from the same dogs. Student’s t-test for unpaired data, was used to compare results between different dogs. McNemars test for correlated proportions was used to compare proportions after left and right ventricular stimulation in the same dogs and the Chi square test was used to compare proportions between different groups of dogs. P values less than 0.05 were considered significant. All values are expressed as mean + standard error of the mean. Results

Postinfarct dogs Normal dogs Thirty seven dogs were anesthetized with intravenous thiopental (20 mg/kg). They were then intubated and anesthesia maintained with halothane (l-2%) delivered by a Fluotec Mk 3 out-ofcircuit vaporizer in a 1: 2 oxygen to nitrous oxide mixture. Ventilation was commenced using a Harvard 613A respirator and a thoracotomy was performed in the left fourth intercostal space using a sterile technique. Lidocaine (2 mg/kg) was administered intravenously and the left anterior descending coronary artery was ligated at the tip of the left atrial appendage and 2 cm distally. Any intervening diagonal branches were also ligated. Bupivicaine, a long acting local anesthetic was infiltrated around the 3rd to 5th intercostal nerves to provide postoperative analgesia. The incision was repaired and the dogs allowed to recover. Prophylactic quinidine bisulphate (15 mg/kg) was administered orally twice daily for two days.

Seventeen normal dogs underwent programmed stimulation from the right and left ventricular apices under pentobarbital anesthesia. Electrophysiologic data for these animals is shown in Table 1. Both the diastolic threshold and the effective refractory period were significantly higher in the left versus the right ventricle. Ventricular fibrillation was induced from the right ventricular apex in 13 animals (77%), but from the left ventricular apex in only 8 (47%; P < 0.05). In the 8 animals with ventricular fibrillation induced from both ventricles, the number of extrastimuli required was 3.3 f 0.1 and 3.8 + 0.3 from the right and left ventricles respectively (P = 0.14). All animals with ventricular fibrillation induced from the left ventricle also had ventricular fibrillation induced from the right ventricle. Five animals had ventric-

320 TABLE

1

TABLE

Electrophysiologic data from programmed stimulation of the right and left ventricle in 17 normal dogs (mean + SEM).

Electrophysiologic data from programmed stimulation of the right and left ventricle in 37 postinfarct dogs (mean * SEM).

P

Ventricle

Right Baseline sinus cycle length (msec) Diastolic threshold (mA) Drive train cycle length (msec) Ventricular refractory period (msec)

2

Right Baseline

435 + 32

429 + 28

0.38

0.84 + 0.03

0.92 rf: 0.04

0.006

threshold Drive train

0.17

cycle length (msec) Ventricular refractory

318 f

11

(mA)

period (msec) 149 f 3

161 + 4

Left

sinus

cycle length (msec) Diastolic

324 f 12

P

Ventricle

Left

432 f

14

429 f 11

0.13

0.66 f 0.1

0.77 + 0.1

-C 0.001

340 + 5

339 + 6

0.3

144 + 3

152 f 3

0.002

0.002

resulted in a significantly greater yield of ventricular fibrillation than did left. ular fibrillation induced from the right ventricle only. There was no significant difference in the number of extrastimuli required to induce ventricular fibrillation when the group of dogs inducible from the right ventricle only was compared with those inducible from both the right and left ventricles (3.8 f 0.3 versus 3.3 f 0.1 extrastimuli; P = 0.13). Ventricular tachycardia was not induced in any normal heart. Four animals (23%) had no arrhythmia induced with the maximum of 7 extrastimuli. Thus, left ventricular stimulation did not increase the yield of induced ventricular fibrillation in the normal heart. Right ventricular stimulation

TABLE

3

Number

of animals

in which ventricular Bight ventricle

Induced rhythm

VT ( < 140 msec)

VT (a 140 msec) VF No inducible arrhythmia VF = ventricular

tachycardia

fibrillation;

or ventricular

Dogs with myocardial infarction

Thirty-seven dogs underwent programmed stimulation from both the right and left ventricular apices under pentobarbital anesthesia at least 14 days after infarction. Electrophysiologic data for these animals are shown in Table 2. In accordance with the findings for the normal heart, ventricular refractory periods and diastolic threshold were significantly greater in the left versus the right ventricle. The number of animals with inducible ventricular tachycardia or ventricular fibrillation from the right and/or left ventricles is shown in Table 3.

fibrillation

was inducible Left ventricle only

only

Bight and left ventricles

3 5 6

1 5 4

4 1 3

4

9

10

VT = ventricular

tachycardia.

from the right and/or Additional contribution left ventricle

left ventricle.

of

100% (P < 0.05) 10% 30% 77% (P < 0.05)

321

z

3 + 0.2 versus 3.4 * 0.2 extrastimuli; P = 0.12). It should be noted that, although 7 extrastimuli were available, no animal required more than 5 extrastimuli for induction of ventricular tachycardia from any site. Ventricular fibrillation, rather than ventricular tachycardia was induced by left ventricular stimulation in one animal with 5 extrastimuli (versus 3 for ventricular tachycardia from the right ventricle). The remaining 7 animals with ventricular tachycardia inducible from the right ventricle had no inducible arrhythmia when programmed stimulation was performed from the left ventricle using the maximum of 7 extrastimuli.

180

(3 a

160

-I

140

”5

120

t;

100

Fig. 1. Top: proportion of dogs whose ventricular tachycardia was inducible from the right ventricle only, the right and left ventricle or the left ventricle only (right ventricle = crosshatched area, left ventricle = stippled area). Bottom: cycle length of ventricular tachycardia induced from the right ventricle only, the right and left ventricle when both were successful, and the left ventricle only. Note that ventricular tachycardia which was inducible from the right or left ventricle only was more rapid than that induced from both sites.

Dogs with ventricular the right ventricle

arrhythmias

inducible from

Ventricular tuchycurdia. Fourteen animals had ventricular tachycardia induced from the right ventricle (cycle length: 144 * 6 msec) with 3.2 * 0.2 extrastimuli. Of these animals, only 6 (46%) also had ventricular tachycardia induced by left ventricular stimulation (P < 0.05; see Table 3). Fig. 1 demonstrates the contribution of the right and left ventricles to yield of ventricular tachycardia. In animals with ventricular tachycardia induced from both ventricles, there was no significant difference in cycle length (153 L- 6 versus 148 + 10 msec; P = 0.28) or the number of extrastimuli required (3.0 f 0.2 versus 2.7 + 0.5; P = 0.06) between the right and left ventricle respectively. Furthermore, there was no significant difference between the cycle length of ventricular tachycardia or number of extrastimuli required in animals which were inducible from both ventricles versus those inducible from the right ventricle alone (153 f 6 versus 138 f 10 msec; P = 0.15;

Ventricular fibrillation. Ten animals had ventricular fibrillation induced from the right ventricular apex with 3.6 of:0.2 extrastimuli. Three of these animals had sustained, monomorphic ventricular tachycardia rather than ventricular fibrillation induced from the left ventricle. This ventricular tachycardia was very rapid (cycle length 117 &-3 msec) and it was induced with a similar number of extrastimuli to that required to induce ventricular fibrillation from the right ventricle (3.0 f 0 versus 3.0 + 0.6 extrastimuli; left and right ventricle respectively). Four animals had ventricular fibrillation induced from the left in addition to the right ventricle with a similar number of extrastimuli (3.8 k 0.3 right ventricle versus 3.2 + 0.6 left ventricle; P = 0.26). The remaining 3 animals had no arrhythmia induced from the left ventricle. No inducible arrhythmia. Thirteen animals had no arrhythmia induced from the right ventricle. Of these animals, 2 had ventricular tachycardia induced by left ventricular stimulation (cycle lengths 110 and 150 msec) with 4 and 5 extrastimuli, respectively. Two animals had ventricular fibrillation induced from the left ventricle with 4 and 5 extrastimuli. The remaining 9 animals had no arrhythmia induced. Additional contribution tion

of left ventricular stimula-

Ventricular tachycardia was induced in an additional 5 animals (23% of all dogs with ventricu-

322

lar tachycardia) when left ventricular stimulation was employed. Ventricular tachycardia which could only be induced from the left ventricle was rapid in 4 animals. Left ventricular stimulation increased the yield of ventricular tachycardia with a cycle length less than 140 msec by 100% whereas it increased the yield of slow ventricular tachycardia by only 10% (P c 0.02: see Table 3). Comparison of ventricular arrhythmias from both sites versus one site

induced

Dogs with inducible ventricular tachycardia after myocardial infarction were divided into two subgroups, those in which ventricular tachycardia could be induced from only one site (right or left ventricle; n = 13) and those in which ventricular tachycardia could be induced from both the right and left ventricles (n = 6). Ventricular tachycardia inducible from only one site tended to be more rapid than that induced from both ventricles (134 I~I7 versus 151 f 8 ms, P = 0.09) and required significantly more extrastimuli (3.5 * 0.2 versus 2.9 k 0.2, P = 0.03). Ventricular fibrillation which was inducible from only one site also required significantly more extrastimuli than that which was inducible from both ventricles (4.2 f 0.2 versus 3.5 * 0.2, P = 0.03). Discussion Ventricular tachycardia The present study demonstrates the marked influence of the site of stimulation on the inducibility of ventricular tachyarrhythmias in both the normal and infarcted heart. Programmed stimulation was most successful when performed from the right ventricle (74% of ventricular tachycardia and 77% of ventricular fibrillation in infarcted hearts, 100% of ventricular fibrillation in normal hearts). Left ventricular stimulation was required, nonetheless, to induce ventricular tachycardia in 26% of postinfarct dogs. Interestingly, ventricular tachycardia induced from the left, but not the right ventricle, was usually rapid (cycle length less than 140 msec, 4 of

5 dogs). In contrast, slower ventricular tachycardia (cycle length greater than 140 msec) was almost invariably inducible from the right ventricular apex (10 of 11 dogs, see Table 3). Ventricular tachycardia induced in dogs is usually faster than that seen in man, probably due to shorter canine refractory periods and smaller heart size. It is, however, well tolerated hemodynamically. In this canine model, the behavior of ventricular tachycardia with a cycle length greater than 140 msec is similar to ventricular tachycardia with a cycle length of 220 msec or greater (termed “slow” ventricular tachycardia) induced in man [20,21]. The use of 5 extrastimuli from the right ventricle alone is adequate to identify the great majority of animals with “slow” ventricular tachycardia, which we have previously shown to be at risk of spontaneous arrhythmias after infarction [20]. We suspect, therefore, that ventricular tachycardia which requires left ventricular stimulation for induction is likely to be clinically insignificant. The present study also shows that arrhythmias that are inducible from one site only tend to be faster and require more extrastimuli than those inducible from multiple sites, suggesting that it is harder to achieve the critical degree of conduction delay and block within the abnormal tissue from which rapid ventricular tachycardia arises. Factors such as the direction of approach of a premature impulse, or the extrastimulus coupling intervals achieved at the site of reentry may play an important role in determining the optimal site for arrhythmia induction when the reentrant circuit is short. A previous study in dogs has shown stimulation sites in normal myocardium within 2 cm of the infarct border to be twice as successful as other sites for arrhythmia induction of ventricular tachyarrhythmias when only 3 extrastimuli are used [17]. In the present study, all infarcts were situated in the left anterior wall and anterior septum, therefore both stimulation electrodes were in close proximity to the infarct border. This is somewhat different to humans, in whom the extent of infarction and its location is variable. It is likely, nonetheless, that the same principle will apply, with the site of stimulation being less important for slower, more clinically important ventricular tachycardia.

323

Ventricular fibrillation Ventricular fibrillation was induced more frequently from the right ventricle than the left in both normal and infarcted hearts. The right ventricular effective refractory period was significantly shorter than the left, resulting in extrastimuli delivered at the right ventricular apex falling within the refractory period of the left ventricle. Such marked variation in myocardial excitability would predispose to establishment of disorganised electrical activity and fibrillation. In contrast, because of the relatively long left ventricular refractory period, the right ventricle was more fully recovered prior to delivery of a left ventricular extrastimulus. Similar differences in refractory period between the right and left ventricles have also been observed by others [22]. Left ventricular stimulation resulted in ventricular tachycardia being induced in only two animals with ventricular fibrillation from the right ventricle. In one of these dogs, ventricular tachycardia was rapid, and likely to be clinically insignificant. The predisposition of the right ventricle to ventricular fibrillation, therefore, does not significantly interfere with induction of ventricular tachycardia in the infarcted heart. Pentobarbital, the anesthetic agent used in the present study, is an extensively used experimental anesthetic. It has been shown by us to increase the likelihood of induction of ventricular fibrillation [23]. This may account for the high incidence of ventricular fibrillation seen in normal dogs. Even if this factor is important, it should not interfere with evaluation of differences between the right and left ventricles in the same animal.

Conclusion The present study shows that the right ventricle is the most successful site for induction of slow ventricular tachycardia (similar to ventricular tachycardia observed clinically) by programmed stimulation in dogs with infarction of the anterior left ventricle and septum [20,21]. Left ventricular stimulation only increases the yield of rapid, less clinically significant ventricular tachycardia and, therefore, offers little advantage. Despite the in-

herent limitations in extrapolating mental animal studies to man, we the use of multiple sites of stimulation to be important for identification risk of ventricular tachycardia when stimuli are used.

from expericonclude that is not likely of patients at up to 5 extra-

Acknowledgements We would like to acknowledge the valuable technical assistance of Miss Denise Ramsey and Miss Erica Eves in performing this experiment. This project was funded by a grant from the National Health and Medical Research Council of Australia, Canberra, ACT, Australia.

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