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Enhanced induction of ventricular arrhythmias during sympathetic stimulation before and during coronary artery occlusion
International Journal of Cardioiogy, 34 (1992) 75-83 0 1992 Elsevier Science Publishers B.V. All rights reserved
CARD10
75 0167-5273/92/$05.00
01373
Enhanced induction of ventricular arrhythmias during sympathetic stimulation before and during coronary artery occlusion Nicholas S. Gantenberg
* and Gilbert R. Hageman
Department of Physiology and Biophysics, Vniuersity of Alabama at Birmingham, Birmingham, Alabama, U.S.A. (Received
5 September
1990: revision
accepted
26 July 1991)
Gantenberg NS, Hageman GR. Enhanced induction of ventricular arrhythmias during sympathetic stimulation before and during coronary artery occlusion. Int J Cardiol 1992;34:75-83. We used programmed electrical stimulation to examine the arrhythmogenic influence of the sympathetic nervous system before and during coronary artery occlusion. In 29 anesthetized dogs the left and/or right stellate ganglia were stimulated at 2-g hertz. Program-induced ventricular arrhythmias included single premature ventricular depolarizations, doublets, triplets, ventricular tachycardia and ventricular fibrillation. Both the number of extrastimuli and the duration of coronary occlusion significantly influenced ventricular arrhythmia induction. After pooling the number of extrastimuli, type of artery occluded, and the duration of occlusion, the influences of unilateral and bilateral stellate stimulations were evaluated. The incidence of induced ventricular arrhythmias was 54% during control conditions (prior to sympathetic stimulation). Right stellate stimulation had no influence on arrhythmogenesis, causing ventricular arrhythmia induction in 52% (NS) of the trials. Left stellate stimulation resulted in increased ventricular arrhythmias (68%; P < 0.05) in response to programmed electrical stimulation. Bilateral stellate stimulation elevated program-induced ventricular arrhythmias (63%; P < 0.05). The effects of the stellate stimulations on arrhythmia induction were similar during and up to 180 minutes of coronary occlusion. Thus, the arrhythmogenic influence of sympathetic stimulation was present before and during coronary artery occlusion. Key words: Programmed electrical stimulation; Sympathetic nervous system; Acute myocardial ischemia: Myocardial infarction; Ventricular arrhythmia; Dog
Correspondence to: G.R. Hageman, Ph.D., Department of Physiology and Biophysics, Basic Health Science Building Room 844. University of Alabama at Birmingham, Birmingham, AL 35294-0005, U.S.A. * Present address; National Institute on Alcohol Abuse and Alcoholism, 12501 Washington Avenue. Rockville, MD 20852, U.S.A. Supported by National Institutes of Health Grant HL 37289.
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Methods
Introduction It is widely accepted that acute coronary artery occlusion can produce life-threatening arrhythmias and sudden death [l-3]. However, the influence of the autonomic nervous system on cardiac function during acute myocardial ischemia is not completely understood. Acute decreases in myocardial blood flow activate autonomic afferent nerves which elicit reflex changes in cardiac efferent activities [4-71. Increased sympathetic activity has been shown to be arrhythmogenic using a variety of techniques and in numerous animal preparations [S-141. Furthermore, heterogeneous or asymmetrical sympathetic neural activation is thought to be responsible in the generation and maintenance of ventricular arrhythmias known to cause sudden death [g-18]. Interactions between the sympathetic nervous system and myocardial ischemia/ infarction have also been described [5,12]. However, little is known about the arrhythmogenic influence(s) of sympathetic hyperactivity during the early period (less than 3 hours after occlusion) of acute myocardial infarction as evaluated using the technique of programmed electrical stimulation. Programmed stimulation of the heart, a standard test of susceptibility to lethal arrhythmias employed in clinical catheterization laboratories [19-211, was used to examine the arrhythmogenic influence of the sympathetic nervous system before and during acute myocardial ischemia. Programmed electrical stimulation was performed in the early stages of myocardial ischemia and infarction, which cannot be attempted in patients. In the dog model ventricular arrhythmia induction can be evaluated before and after selective damage to the myocardium. This model also controls the degree of autonomic nerve stimulation. Therefore, the objectives of the study were: (1) to determine the inducibility of ventricular arrhythmias in the neurally decentralized heart in the absence and presence of acute myocardial ischemia, and (2) to evaluate the induction of ventricular arrhythmias during unilateral and bilateral stellate ganglion stimulations prior to and in the presence of acute coronary occlusion.
General The use of animal experimentation in this study conformed to the “Position of the American Heart Association on Research Animal Use.” Animal care and experimentation was performed by qualified personnel and the animal facilities met the standards of the American Association for Accreditation of Laboratory Animal Care. Twenty nine adult mongrel dogs of either sex weighing 22 f 4 kg (SD) were anesthetized with sodium pentobarbital (30 mg/kg i.v.). Anesthesia was maintained throughout the experiment with additional amounts (lo-l.5 mg) of pentobarbital given each hour at a time when data were not sampled. A Harvard pump respirator ventilated the animals via a cuffed endotracheal tube with room air. Normal blood gases and blood pH were maintained by adjustment of the ventilator or with administration of sodium bicarbonate. Core temperature was maintained with a heating pad at 37 _t 1°C. The femoral vein was cannulated for fluid administration. Central aortic pressure was recorded via a femoral artery catheter. A standard limb lead electrocardiogram was recorded. A transsternal thoracotomy at the third or fourth intercostal space was performed to expose the heart and stellate ganglia. The pericardium was opened and retracted to cradle the heart. Multipolar plaque electrodes were sutured on the right atrium and the right ventricular outflow tract for local electrograms. Bipolar plunge electrodes were inserted in the anterior and posterior left ventricle for local electrograms. The multiple electrograms served to confirm the location .of the source of the arrhythmias. Strain gauge arches were sutured to the anterior and posterior left ventricle for regional force recordings. The force recordings were used to verify coronary occlusion via a decline in the regional force of contraction as well as to give evidence of the sympathetic stimulations. The left anterior descending coronary artery (n = 14) or the left circumflex coronary artery (n = 15) was carefully isolated and prepared with a silk, snare ligature. At the end of
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the experiment the percentage of ischemic/ infarcted ventricle was determined using the methylene blue technique [4,22]. Neural stimulations
A bilateral cervical vagotomy was performed and the right and left stellate ganglion were isolated and decentralized. Electrodes were inserted into each stellate ganglion for constant current stimulations at 2-8 hertz, 2 millisecond pulse duration, using a square wave stimulator (Grass S441, stimulus isolation unit (Grass SIU.5) and a constant current unit (Grass CCUl). Current was increased to determine the maximal cardiovascular response, that is, the greatest increase in heart rate, pulse pressure and force of contraction during sympathetic stimulation. All subsequent stimulations were adjusted to 70-80% of the maximal current. A return to steady state (3 to 10 minutes) was allowed between randomized stellate ganglia stimulations. Programmed electrical stimlulation trials were begun when the effects of stellate stimulation were evident from the recordings of heart rate, blood pressure, and force of contraction. Programmed
electrical
stimulation
Programmed electrical stimulation trials consisted of ten paced heart cycles and one to four extrastimuli at twice diastolic threshold delivered to the right ventricular epicardial electrode. Programmed electrical stimulation was performed via a computer controlled stimulator. The computer controls the number of paced beats, the pacing cycle length, and the coupling intervals of each extrastimulus. The paced cycle length (315 343 milliseconds; 175-190 beats per minute) was chosen to exceed the positive chronotropic responses to sympathetic stimulations. Coupling intervals of the extrastimuli were chosen by positioning each successive extrastimulus 20 milliseconds beyond the shortest interval eliciting a captured beat. As a result of employing rapid drive cycles the intervals between extrastimuli were progressively shortened. Coupling intervals generally remained the same throughout the experi-
ment. Trials in which each extrastimulus failed to capture the ventricle were not included in the analysis. Programmed electrical stimulation trials were begun with one extrastimulus and subsequent extrastimuli were added to a maximum of four. There was at least a 20 second delay between trials, During each programmed electrical stimulation trial, the induction of any ventricular arrhythmia was considered a positive result. Program-induced ventricular arrhythmias included single premature ventricular depolarizations, doublets, triplets, ventricular tachycardia, and ventricular fibrillation. The data were analyzed with respect to positive occurrences divided by the total number of trials for that treatment or period. Programmed electrical stimulation with one to four extrastimuli was performed in the neurally decentralized preparation and in the presence of stellate stimulations. Each animal served as its own control. Rapid ventricular tachycardia and ventricular fibrillation were quickly cardioverted to sinus rhythm and several minutes of recovery to steady state were allowed. Experimental
protocol
The protocol consisted of multiple trials of programmed electrical stimulation in the absence and presence of unilateral and bilateral stellate ganglia stimulations before and during coronary artery occlusion lasting for a period of up to 180 minutes. The same coupling intervals between extrastimuli were generally used throughout the experiment. However, it was necessary to lengthen the coupling intervals on occasion to maintain capture of the ventricle. The result of each programmed electrical stimulation trial was tabulated throughout the experiment as a positive or negative event for up to four programmed electrical stimulation trials per treatment per extrastimulus. Hence, programmed electrical stimulation was performed up to four times for one extrastimulus, two, three, and four extrastimuli. This experimental format (lasting 4-8 minutes) was then repeated during right, left, and combined right and left stellate stimulations. In addition, this format was again repeated at 30, 60, 120, and 180 minutes following coronary occlusion in each
animal. In some animals, four repetitions could not always be performed due to the production of repeated episodes of ventricular fibrillation and subsequent defibrillations. In the first six preliminary dogs (included in the study), only the first 30 minutes of data were obtained following coronary occlusion. The results are expressed in terms of the incidence of program-induced ventricular arrhythmias. Control programmed electrical stimulation trials were then compared to intervention programmed electrical stimulation trials throughout the 30, 60, 120, 180 minute periods following the occlusion. Due to the varied numbers of programmed electrical stimulation trials for each animal in each treatment, the data were subjected to an arcsin transformation [23]. Arcsin or angular transformation of the raw data (relative frequencies) was used to ensure a normal distribution, uniform variance, and, additivity of the treatment effects prior to a general linear model least squares means weighted analysis of variance. Graphical data have been expressed as least squares means t_ standard error. A P value less than 0.05 was considered significant.
Results Analysis was performed to determine the effect of the number of extrastimuli, the duration of occlusion (no occlusion or control is included here and denoted as “Time 0” or “control”), the type of sympathetic stimulation and the location of the occlusion on the induction of ventricular arrhythmias. Subsequent to the analysis of variance for the large group of data, multiple comparisons were made on the pooled data sets. For instance, to determine the influence of the number of extrastimuli, the data were pooled with respect to time period, type of stellate stimulation, and the location of the coronary artery occluded. In a second analysis, the location of the occluded coronary artery was found to have a significant interaction with the duration of occlusion when only data pertaining to three extrastimuli were evaluated. In addition, an analysis of the trials which resulted in ventricular tachycardia or ventricular fibrillation (excluding premature ventricular complexes) exhibited the same pattern in
-i
351 1
2
3
4
EXTRASTIMULUS NUMBER Fig. 1. A graph illustrating the effect of increasing numbers of extrastimuli in the programmed electrical stimulation on the induction of ventricular arrhythmias. All effects (duration of occlusion, sympathetic stimulations and location of coronary artery occlusion) have been pooled (n = 1956). Least squares means+ standard error are graphed. The incidence of program-induced ventricular arrhythmias is on the ordinate and extrastimulus number is on the abscissa. * PI 0.05, versus one extrastimulus. PIVA = program-induced ventricular arrhythmias.
both groups. Therefore, the data were pooled and presented as foIlows. Fig. 1 illustrates the relationship between the number of extrastimuli and ventricular arrhythmia production. The data have been pooled with respect to the duration of occlusion (O-180 minutes), the type of sympathetic stimulation, and the location of the occluded coronary artery. The number of extrastimuli used in the programmed electrical stimulation had a significant influence on ventricular arrhythmia induction. Ventricular arrhythmia induction increased with increasing numbers of extrastimuli upto three (P < 0.05versus one extrastimulus). The addition of a fourth extrastimulus reduced the incidence of ventricular arrhythmia induction when compared to three extrastimuli (P < 0.051, yet remained above the incidence resulting from one extrastimulus. The ischemic/ infarct zones resulting from coronary occlusion were 16.4% f 1.1 (SEMI of the ventricular weight. Measurement of ischemic zones for each of the artery groups resulted in equivalent areas of damage: left anterior descending group, 16.3% and left circumflex group, 16.4%. As seen in Fig. 2, after any duration of occlusion there existed an increase in ventricular
80
s 2
-
70
I
*
-
*
79
T
*
LSS
RLSS
I
301 0
30
60
120
160
40
CONTROL
DURATION OF OCCLUSION (MINUTES) Fig. 2. A graph illustrating the effect of the duration of coronary occlusion on the induction of ventricular arrhyth-
mias. All treatments (extrastimuli number, sympathetic stimulations and coronary artery occlusion location) have been pooled (n = 1956). Least squares meansfstandard error are graphed. The incidence of program-induced ventricular arrhythmias is on the ordinate and the time of occlusion is on the abscissa. * P I 0.05, versus control. PIVA = programinduced ventricular arrhythmias.
arrhythmia induction (P < 0.05 versus control or no ischemia). There existed an increase in ventricular arrhythmia induction after 30 minutes following the occlusion (P < 0.05). The decline in ventricular arrhythmia induction after 60 minutes of ischemia was significantly different from the 30, 120 and 180 minute periods, however, it remained increased above control conditions (P < 0.05). The increase at 120 and 180 minutes was not different from the 30 minute period. The effect of unilateral and bilateral sympathetic stimulation was evaluated in each animal before and following a coronary artery occlusion. Fig. 3 illustrates the effect of the individual and combined stellate stimulations. Ventricular arrhythmias were elicited in 54% of the trials during control condition, that is, in the absence of sympathetic stimulation. Trials during right stellate stimulation were not different from control (52%; NS). Left stellate stimulation alone increased (68%, P < 0.05) the occurrence of ventricular arrhythmias during control trials. Simultaneous right and left stellate stimulations elevated (63%, P < 0.05) the incidence of ventricular arrhythmias. There was a statistical difference between left stellate stimulation trials versus combined right and left stellate stimulation trials (P < 0.05).
RSS
Fig. 3. Graphical representation of the effect of unilateral and bilateral sympathetic stimulation on the induction of ventricular arrhythmias. Data have been pooled with respect to the duration of occlusion, coronary artery location, and the number of extrastimuli (n = 1956). Stellate stimulation is on the abscissa and the incidence of program-induced ventricular arrhythmias is on the ordinate. * P 5 0.05, versus control. * above bracket, P I 0.05, LSS versus RLSS. LSS = left stellate stimulation; PIVA = program-induced ventricular arrhythmias; RLSS = right and left stellate stimulation; RSS = right stellate stimulation.
Data resulting from the use of three extrastimuli during programmed electrical stimulation were analyzed separately. Fig. 4 illustrates that the location of the coronary artery occluded influ100 E
T
2 01’
0
30
60
160
120
DURATION OF OCCLUSION
(MINUTES)
Fig. 4. A graph illustrating the effect of the location of coronary artery occlusion on the induction of ventricular arrhythmias. Types of sympathetic (stellate) stimulations have been pooled. These data are the results following the use of three extrastimuli during programmed electrical stimulation (n = 491). The incidence of program-induced ventricular ar-
rhythmias is on the ordinate and the duration of occlusion is on the abscissa. Least squares meansfstandard error are graphed. n = left anterior descending coronary artery; q = left circumflex coronary artery. * P I 0.05, left anterior descending versus left circumflex coronary artery. PIVA = program-induced ventricular arrhythmias.
80
s
90
f
n--o
CONTROL
A--
LSS
v-.
RSS
m-m
RLSS
75 1
,Ot
K
304
/ 0
30
60
120
160
DURATION OF OCCLUSION(MINUTES) Fig. 5. A graph illustrating the effects of individual and combined stellate stimulations throughout the duration of coronary occlusion. These data are the results following the use of three extrastimuli during programmed electrical stimulation (n = 491). The incidence of program-induced ventricular arrhythmias is on the ordinate and the duration of occlusion is on the abscissa. Least squares means + standard error are graphed. LSS = left stellate stimulation; PIVA = program-induced ventricular arrhythmias; RLSS = right and left stellate stimulation; RSS = right stellate stimulation.
enced the outcome of ventricular arrhythmia production over the experimental period. For the left circumflex occlusion group the incidence of induced ventricular arrhythmias increased significantly after any duration of myocardial ischemia and a trend to increase further after each time period exists. In the left anterior descending coronary group, the ventricular arrhythmia incidence was elevated after 30 (78%; NS) and 120 (73%; NS) minutes of myocardial ischemia. The incidence of ventricular arrhythmia following 60 (61%; NS) and 180 (58%; NS) minutes of ischemia for animals subjected to left anterior descending occlusion did not differ from control (65%). During the control periods, that is, prior to coronary occlusion, the left anterior descending occlusion preparation had a higher occurrence of ventricular arrhythmia than that of the left circumflex occlusion group (65% versus 48%; P < 0.09.
Fig. 5 illustrates the effect of sympathetic stimulations throughout the experimental protocol in animals subject to three extrastimuli during programmed electrical stimulation. It illustrates the increased incidence of program-induced ventricular arrhythmias after any duration of coronary occlusion. This figure also shows the time
dependent changes occurring throughout the trials. Furthermore, it illustrates the influence of sympathetic stimulations before and during coronary occlusion. Note that right stellate stimulation did not further influence the incidence of induced arrhythmias. Left stellate stimulation, however, significantly elevated ventricular arrhythmia occurrence prior to and during myocardial ischemia and infarction. Combined right and left stellate stimulation results in arrhythmia occurrence that falls between that of the individual right and left stellate stimulations. Discussion The use of programmed electrical stimulation as an experimental challenge remains valuable in the study of ventricular arrhythmias [19-21,24,25]. The inducibility of ventricular arrhythmias in a normal heart is theoretically zero, however, a basal level of ventricular arrhythmia induction is a prerequisite to assess interventions which alter ventricular vulnerability. The data shows that this electrophysiological technique was sensitive to changes in the level of sympathetic neural activity as well as to ischemia-induced changes in excitability. For instance, in an animal which had only 2-3 premature ventricular complexes during control trials and then ‘9-10 premature ventricular complexes during the trials following a perturbation, we interpreted this as indicating that a change had taken place that had acted to enhance the likelihood of inducing a ventricular arrhythmia. Likewise, in an animal exhibiting few arrhythmias during control periods, but then developed arrhythmias given fewer extrastimuli, we also interpreted as there having been a change in the arrhythmia inducibility. Hence, in our model the increased incidence of program-induced ventricular arrhythmias during neural stimulations indicated the creation of a pathological condition. The production of ventricular fibrillation using multiple extrastimuli may be explained in part by the lowering of the ventricular fibrillation threshold following repetitive extrasystoles [26]. This interpretation supports the idea that, perhaps, one premature ventricular complex or multiple premature ventricular complexes do the same to
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the otherwise unsuspecting heart. That is, single premature ventricular complexes may be precursors to more serious arrhythmias. The occurrence of premature ventricular complexes may indicate a risk for sudden cardiac death 13,271. Therefore, it is possible that a life-threatening arrhythmia could be initiated by an otherwise innocuous premature ventricular contraction should the proper coupling interval be achieved. Increased sympathetic activity has a permissive action during programmed electrical stimulation. Both the number and complexity (coupling intervals and occurrence time within a cycle) of arrhythmias are increased during sympathetic stimulation. Furthermore, as the frequency and complexity of the arrhythmias increases, so does the likelihood of a life-threatening arrhythmia. The relevance of the effects of sympathetic stimulation to the clinical setting is strengthened by reports demonstrating asymmetric responses in humans upon removal of left-sided versus rightsided sympathetic nerves [8,171. Surgical or pharmacological ablation of the left stellate ganglion provides dramatic results in the treatment of long QT syndrome patients [8]. In addition, the extent of infarct damage and irreversible cellular injury is reduced in stellectomized animals [281. This effect appears to be due to increased collateral flow and lower myocardial oxygen demand after stellectomy 1281. Puddu et al. [14] investigated the effects of stellectomy upon arrhythmogenesis. It was found that a sympathectomy eight weeks prior to a left circumflex occlusion decreased the incidence of spontaneous ventricular arrhythmias. Their data corroborates the strong arrhythmogenic influence of the left stellate ganglion during coronary occlusion. In addition, the authors also reported similar effects upon right stellate ganglionectomy, although to a much lesser degree. In contrast, our data demonstrates that arrhythmia induction is not significantly influenced by stimulation of the right stellate ganglion. In addition, Schwartz et al. [S] and others [183 have shown that during short bouts of ischemia (less than 2 minutes), extirpation of the right stellate ganglion resulted in increased ventricular ectopy, while left stellate ganglionectomy resulted in fewer episodes of ven-
tricular ectopy. These observations are in agreement with the concept that the left stellate has a greater role in arrhythmogenesis. Randall et al. [29] demonstrated that heterogeneous sympathetic stimulation to the heart in an exercising conscious dog resulted in multiform premature ventricular complexes and/or ventricular tachycardia. They provide direct evidence of the arrhythmogenic impact of activation of a single cardiac nerve in a model of autonomic imbalance. The left-sided sympathetic fibers play a greater role in the autonomic regulation of the ventricle, especially, the inferoposterior ventricle [30]. In contrast, the right-sided sympathetic fibers, while shown to innervate the anterolateral ventricle, play a greater role in controlling sinus rate 2301. The effect of activation of right-sided sympathetic nerves on heart rate may serve to overdrive ventricular arrhythmias that might otherwise result in sudden death. Our data suggest, however, that even in the face of homogeneous sympathetic stimulation (i.e., combined right and left stellate stimulation), that a proarrhythmic factor still exists. There appears to be a trend for the right stellate stimulation to reduce the influence of the left stellate stimulation during the combined stimulations, both, before and during acute myocardial ischemia and infarction. Using the measurement of early afterdepolarizations in anesthetized, open-chested dogs, Ben-David and Zipes [31] observed greater effects of left ansae subclaviae stimulation and bilateral subclaviae stimulation than that of right ansae subclaviae stimulation. They believe quantitative differences in neurotransmitter output exist for stellate ganglia stimulations, right versus left side. Our results agree with their report; however, our interpretation is that the differential effects are due to the varied innervation patterns of the sympathetic ganglia. Assessment of the ischemic insult was limited to a post hoc analysis of the ischemic zone using the methylene blue technique [22]. Placement of the ligature was chosen so as to produce a relatively large infarct, but hopefully without producing ventricular fibrillation or heart failure during the early period of the occlusion. Sympathetic activation can induce post-stenotic myocardial is-
82
chemia [6] and, thereby, act to increase the area of damage. Thus, it is possible that the size of ischemic zones was made larger by the subsequent sympathetic stimulations. There are no obvious explanations for the decline in the induction of ventricular arrhythmias at the 60-minute occlusion period. Other physiological variables that were measured failed to indicate possible changes in the arrhythmia substrate. It is likely that the changes responsible for the difference in ventricular arrhythmia induction are cellular in nature and go undetected by standard measurements made during our experiments. The differences noted for the two arterial occlusion groups are not clear. A left circumflex coronary occlusion may activate different receptors but these reflexes should not influence the results in our decentralized preparations. In conclusion, this study has shown that the clinical technique of programmed electrical stimulation of the heart is reliable for the induction of ventricular arrhythmias during acute myocardial ischemia and infarction in our canine model. The results demonstrate that right stellate stimulation is not arrhythmogenic before or during myocardial ischemia. Sympathetic imbalance due to left stellate stimulation, however, is arrhythmogenie both before and during myocardial ischemia. Homogeneous sympathetic efferent activity during combined right and left stellate stimulation produced arrhythmias before and during myocardial ischemia and infarction. A possible protective role of the right stellate ganglion in the face of enhanced left sympathetic activity was suggested by the observation that the incidence of ventricular arrhythmias was reduced by combined right and left stellate stimulation before and during myocardial ischemia. Thus, our findings are consistent with the hypothesis that a sympathetic imbalance is arrhythmogenic and, that the arrhythmogenic influence of the sympathetic nervous system is present before and during acute myocardial ischemia. Acknowledgements The authors wish to acknowledge the constructive criticism and helpful comments of Drs. Fer-
dinand Urthaler and Brett H. Neely. Special thanks go to Dr. Katharine Kirk for her statistical expertise. References 1 Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989;69:1049-1169. 2 Myerburg RJ, Kessler KM, Bassett AL, Castellanos A. A biological approach to sudden cardiac death: Structure, function and cause. Am J Cardiol 1989;63:1512-1516. 3 Rosen MR. Janse MJ, Myerburg RJ. Arrhythmias induced by coronary artery occlusion: what are the electrophysiological mechanisms? In: Hearse D, Manning A, Janse M, eds. Life-threatening arrhythmias during ischemia and infarction. New York: Raven Press, 1987;11-47. 4 Neely BH, Hageman GR. Differential cardiac sympathetic activity during acute myocardial ischemia. Am J Physiol 1990;258:H1534-1541. 5 Corr PB, Yamada KA, Witkowski FX. Mechanisms controlling cardiac autonomic function and their relation to arrhythmogenesis. In: Fozzard HA, et al., eds. The heart and cardiovascular system. New York: Raven Press. 1986;1343-1404. 6 Heusch G, Deussen A, Thamer V. Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Autonom Nerv Sys 1985;13:311-326. 7 Malliani A, Schwartz PJ, Ranchetti A. A sympathetic reflex elicited by experimental coronary occlusion. Am J Physiol 1969;217:703-709. 8 Schwartz PJ. Sympathetic imbalance and cardiac arrhythmias. In: Randall WC., ed. Nervous control of cardiovascular function. New York: Oxford University Press, 1984: 225-252. Kliks RK, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol 1975; 36~45-49. Lombardi F, Verrier RL, Lown B. Relationship between sympathetic activity, coronary dynamics, and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion. Am Heart J 1983;105:958-965. Abildskov JA. Neural mechanisms involved in the regulation of ventricular repolarization. Eur Heart J 1985;6(Suppl D);31-39. Euler DE, Nattel S, Spear JF, Moore EN, Scanlon PJ. Effect of sympathetic tone on ventricular arrhythmias during circumflex coronary occlusion. Am J Physiol 1985; 249:H1045-1050. Herre JM, Wetstein L, Yuh-Lin L, Mills AS, Dae M, Thames MD. Effect of transmural versus nontransmural myocardial infarction on inducibility of ventricular arrhythmias during sympathetic stimulation in dogs. J Am Coll Cardiol 1988;11:414-421.
83 14 Puddu PE, Joure R, Langlet F, Guillen JC, Lanti M, Reale A. Prevention of postischemic ventricular fibrillation late after right or left ganglionectomy in dogs. Circulation 1988;77:935-946. 15 Corr PB, Pitt B, Natelson BH, Reis DJ, Shine KI, Skinner JE. Sudden cardiac death: Neural-chemical interactions. Circulation 1987;76(Suppl 0208-214. 16 Verrier RL, Hohnloser SH. How is the nervous system implicated in the genesis of cardiac arrhythmias? In: Hearse D, Manning A, Janse M, eds. Life-threatening arrhythmias’ during ischemia and infarction. New York: Raven Press, 1987;153-168. 17 Cinca J, Evangelista A, Montoyo J, et al. Electrophysiologic effects of unilateral right and left stellate ganglion block on the human heart. Am Heart J 1985;109:46-54. 18 Janse MJ, Schwartz PJ, Wilms-Schopman F, Peters RJG, Durrer D. Effects of unilateral stellate ganglion stimulation and ablation on electrophysiologic changes induced by acute myocardial ischemia in dogs. Circulation 1985; 72585-595. 19 Denniss AR, Richards DA, Cody DV, et al. Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction. Circulation 1986; 741731-745. 20 Wellens HJJ, Brugada P, Stevenson WG. Programmed electrical stimulation: its role in the management of ventricular arrhythmias in coronary heart disease. Prog Cardiovasc Dis 1986;29:165-180. 21 Prystowsky EN, Miles WM, Evans JJ, et al. Induction of ventricular tachycardia during programmed electrical stimulation: Analysis of pacing methods. Circulation 1986; 73(Suppl II):II32-1138. 22 Kloner RA, Ganote CE, Reimer KA, Jennings RA. Distri-
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CARD10
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01373
Enhanced induction of ventricular arrhythmias during sympathetic stimulation before and during coronary artery occlusion Nicholas S. Gantenberg
* and Gilbert R. Hageman
Department of Physiology and Biophysics, Vniuersity of Alabama at Birmingham, Birmingham, Alabama, U.S.A. (Received
5 September
1990: revision
accepted
26 July 1991)
Gantenberg NS, Hageman GR. Enhanced induction of ventricular arrhythmias during sympathetic stimulation before and during coronary artery occlusion. Int J Cardiol 1992;34:75-83. We used programmed electrical stimulation to examine the arrhythmogenic influence of the sympathetic nervous system before and during coronary artery occlusion. In 29 anesthetized dogs the left and/or right stellate ganglia were stimulated at 2-g hertz. Program-induced ventricular arrhythmias included single premature ventricular depolarizations, doublets, triplets, ventricular tachycardia and ventricular fibrillation. Both the number of extrastimuli and the duration of coronary occlusion significantly influenced ventricular arrhythmia induction. After pooling the number of extrastimuli, type of artery occluded, and the duration of occlusion, the influences of unilateral and bilateral stellate stimulations were evaluated. The incidence of induced ventricular arrhythmias was 54% during control conditions (prior to sympathetic stimulation). Right stellate stimulation had no influence on arrhythmogenesis, causing ventricular arrhythmia induction in 52% (NS) of the trials. Left stellate stimulation resulted in increased ventricular arrhythmias (68%; P < 0.05) in response to programmed electrical stimulation. Bilateral stellate stimulation elevated program-induced ventricular arrhythmias (63%; P < 0.05). The effects of the stellate stimulations on arrhythmia induction were similar during and up to 180 minutes of coronary occlusion. Thus, the arrhythmogenic influence of sympathetic stimulation was present before and during coronary artery occlusion. Key words: Programmed electrical stimulation; Sympathetic nervous system; Acute myocardial ischemia: Myocardial infarction; Ventricular arrhythmia; Dog
Correspondence to: G.R. Hageman, Ph.D., Department of Physiology and Biophysics, Basic Health Science Building Room 844. University of Alabama at Birmingham, Birmingham, AL 35294-0005, U.S.A. * Present address; National Institute on Alcohol Abuse and Alcoholism, 12501 Washington Avenue. Rockville, MD 20852, U.S.A. Supported by National Institutes of Health Grant HL 37289.
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Methods
Introduction It is widely accepted that acute coronary artery occlusion can produce life-threatening arrhythmias and sudden death [l-3]. However, the influence of the autonomic nervous system on cardiac function during acute myocardial ischemia is not completely understood. Acute decreases in myocardial blood flow activate autonomic afferent nerves which elicit reflex changes in cardiac efferent activities [4-71. Increased sympathetic activity has been shown to be arrhythmogenic using a variety of techniques and in numerous animal preparations [S-141. Furthermore, heterogeneous or asymmetrical sympathetic neural activation is thought to be responsible in the generation and maintenance of ventricular arrhythmias known to cause sudden death [g-18]. Interactions between the sympathetic nervous system and myocardial ischemia/ infarction have also been described [5,12]. However, little is known about the arrhythmogenic influence(s) of sympathetic hyperactivity during the early period (less than 3 hours after occlusion) of acute myocardial infarction as evaluated using the technique of programmed electrical stimulation. Programmed stimulation of the heart, a standard test of susceptibility to lethal arrhythmias employed in clinical catheterization laboratories [19-211, was used to examine the arrhythmogenic influence of the sympathetic nervous system before and during acute myocardial ischemia. Programmed electrical stimulation was performed in the early stages of myocardial ischemia and infarction, which cannot be attempted in patients. In the dog model ventricular arrhythmia induction can be evaluated before and after selective damage to the myocardium. This model also controls the degree of autonomic nerve stimulation. Therefore, the objectives of the study were: (1) to determine the inducibility of ventricular arrhythmias in the neurally decentralized heart in the absence and presence of acute myocardial ischemia, and (2) to evaluate the induction of ventricular arrhythmias during unilateral and bilateral stellate ganglion stimulations prior to and in the presence of acute coronary occlusion.
General The use of animal experimentation in this study conformed to the “Position of the American Heart Association on Research Animal Use.” Animal care and experimentation was performed by qualified personnel and the animal facilities met the standards of the American Association for Accreditation of Laboratory Animal Care. Twenty nine adult mongrel dogs of either sex weighing 22 f 4 kg (SD) were anesthetized with sodium pentobarbital (30 mg/kg i.v.). Anesthesia was maintained throughout the experiment with additional amounts (lo-l.5 mg) of pentobarbital given each hour at a time when data were not sampled. A Harvard pump respirator ventilated the animals via a cuffed endotracheal tube with room air. Normal blood gases and blood pH were maintained by adjustment of the ventilator or with administration of sodium bicarbonate. Core temperature was maintained with a heating pad at 37 _t 1°C. The femoral vein was cannulated for fluid administration. Central aortic pressure was recorded via a femoral artery catheter. A standard limb lead electrocardiogram was recorded. A transsternal thoracotomy at the third or fourth intercostal space was performed to expose the heart and stellate ganglia. The pericardium was opened and retracted to cradle the heart. Multipolar plaque electrodes were sutured on the right atrium and the right ventricular outflow tract for local electrograms. Bipolar plunge electrodes were inserted in the anterior and posterior left ventricle for local electrograms. The multiple electrograms served to confirm the location .of the source of the arrhythmias. Strain gauge arches were sutured to the anterior and posterior left ventricle for regional force recordings. The force recordings were used to verify coronary occlusion via a decline in the regional force of contraction as well as to give evidence of the sympathetic stimulations. The left anterior descending coronary artery (n = 14) or the left circumflex coronary artery (n = 15) was carefully isolated and prepared with a silk, snare ligature. At the end of
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the experiment the percentage of ischemic/ infarcted ventricle was determined using the methylene blue technique [4,22]. Neural stimulations
A bilateral cervical vagotomy was performed and the right and left stellate ganglion were isolated and decentralized. Electrodes were inserted into each stellate ganglion for constant current stimulations at 2-8 hertz, 2 millisecond pulse duration, using a square wave stimulator (Grass S441, stimulus isolation unit (Grass SIU.5) and a constant current unit (Grass CCUl). Current was increased to determine the maximal cardiovascular response, that is, the greatest increase in heart rate, pulse pressure and force of contraction during sympathetic stimulation. All subsequent stimulations were adjusted to 70-80% of the maximal current. A return to steady state (3 to 10 minutes) was allowed between randomized stellate ganglia stimulations. Programmed electrical stimlulation trials were begun when the effects of stellate stimulation were evident from the recordings of heart rate, blood pressure, and force of contraction. Programmed
electrical
stimulation
Programmed electrical stimulation trials consisted of ten paced heart cycles and one to four extrastimuli at twice diastolic threshold delivered to the right ventricular epicardial electrode. Programmed electrical stimulation was performed via a computer controlled stimulator. The computer controls the number of paced beats, the pacing cycle length, and the coupling intervals of each extrastimulus. The paced cycle length (315 343 milliseconds; 175-190 beats per minute) was chosen to exceed the positive chronotropic responses to sympathetic stimulations. Coupling intervals of the extrastimuli were chosen by positioning each successive extrastimulus 20 milliseconds beyond the shortest interval eliciting a captured beat. As a result of employing rapid drive cycles the intervals between extrastimuli were progressively shortened. Coupling intervals generally remained the same throughout the experi-
ment. Trials in which each extrastimulus failed to capture the ventricle were not included in the analysis. Programmed electrical stimulation trials were begun with one extrastimulus and subsequent extrastimuli were added to a maximum of four. There was at least a 20 second delay between trials, During each programmed electrical stimulation trial, the induction of any ventricular arrhythmia was considered a positive result. Program-induced ventricular arrhythmias included single premature ventricular depolarizations, doublets, triplets, ventricular tachycardia, and ventricular fibrillation. The data were analyzed with respect to positive occurrences divided by the total number of trials for that treatment or period. Programmed electrical stimulation with one to four extrastimuli was performed in the neurally decentralized preparation and in the presence of stellate stimulations. Each animal served as its own control. Rapid ventricular tachycardia and ventricular fibrillation were quickly cardioverted to sinus rhythm and several minutes of recovery to steady state were allowed. Experimental
protocol
The protocol consisted of multiple trials of programmed electrical stimulation in the absence and presence of unilateral and bilateral stellate ganglia stimulations before and during coronary artery occlusion lasting for a period of up to 180 minutes. The same coupling intervals between extrastimuli were generally used throughout the experiment. However, it was necessary to lengthen the coupling intervals on occasion to maintain capture of the ventricle. The result of each programmed electrical stimulation trial was tabulated throughout the experiment as a positive or negative event for up to four programmed electrical stimulation trials per treatment per extrastimulus. Hence, programmed electrical stimulation was performed up to four times for one extrastimulus, two, three, and four extrastimuli. This experimental format (lasting 4-8 minutes) was then repeated during right, left, and combined right and left stellate stimulations. In addition, this format was again repeated at 30, 60, 120, and 180 minutes following coronary occlusion in each
animal. In some animals, four repetitions could not always be performed due to the production of repeated episodes of ventricular fibrillation and subsequent defibrillations. In the first six preliminary dogs (included in the study), only the first 30 minutes of data were obtained following coronary occlusion. The results are expressed in terms of the incidence of program-induced ventricular arrhythmias. Control programmed electrical stimulation trials were then compared to intervention programmed electrical stimulation trials throughout the 30, 60, 120, 180 minute periods following the occlusion. Due to the varied numbers of programmed electrical stimulation trials for each animal in each treatment, the data were subjected to an arcsin transformation [23]. Arcsin or angular transformation of the raw data (relative frequencies) was used to ensure a normal distribution, uniform variance, and, additivity of the treatment effects prior to a general linear model least squares means weighted analysis of variance. Graphical data have been expressed as least squares means t_ standard error. A P value less than 0.05 was considered significant.
Results Analysis was performed to determine the effect of the number of extrastimuli, the duration of occlusion (no occlusion or control is included here and denoted as “Time 0” or “control”), the type of sympathetic stimulation and the location of the occlusion on the induction of ventricular arrhythmias. Subsequent to the analysis of variance for the large group of data, multiple comparisons were made on the pooled data sets. For instance, to determine the influence of the number of extrastimuli, the data were pooled with respect to time period, type of stellate stimulation, and the location of the coronary artery occluded. In a second analysis, the location of the occluded coronary artery was found to have a significant interaction with the duration of occlusion when only data pertaining to three extrastimuli were evaluated. In addition, an analysis of the trials which resulted in ventricular tachycardia or ventricular fibrillation (excluding premature ventricular complexes) exhibited the same pattern in
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EXTRASTIMULUS NUMBER Fig. 1. A graph illustrating the effect of increasing numbers of extrastimuli in the programmed electrical stimulation on the induction of ventricular arrhythmias. All effects (duration of occlusion, sympathetic stimulations and location of coronary artery occlusion) have been pooled (n = 1956). Least squares means+ standard error are graphed. The incidence of program-induced ventricular arrhythmias is on the ordinate and extrastimulus number is on the abscissa. * PI 0.05, versus one extrastimulus. PIVA = program-induced ventricular arrhythmias.
both groups. Therefore, the data were pooled and presented as foIlows. Fig. 1 illustrates the relationship between the number of extrastimuli and ventricular arrhythmia production. The data have been pooled with respect to the duration of occlusion (O-180 minutes), the type of sympathetic stimulation, and the location of the occluded coronary artery. The number of extrastimuli used in the programmed electrical stimulation had a significant influence on ventricular arrhythmia induction. Ventricular arrhythmia induction increased with increasing numbers of extrastimuli upto three (P < 0.05versus one extrastimulus). The addition of a fourth extrastimulus reduced the incidence of ventricular arrhythmia induction when compared to three extrastimuli (P < 0.051, yet remained above the incidence resulting from one extrastimulus. The ischemic/ infarct zones resulting from coronary occlusion were 16.4% f 1.1 (SEMI of the ventricular weight. Measurement of ischemic zones for each of the artery groups resulted in equivalent areas of damage: left anterior descending group, 16.3% and left circumflex group, 16.4%. As seen in Fig. 2, after any duration of occlusion there existed an increase in ventricular
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RLSS
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120
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CONTROL
DURATION OF OCCLUSION (MINUTES) Fig. 2. A graph illustrating the effect of the duration of coronary occlusion on the induction of ventricular arrhyth-
mias. All treatments (extrastimuli number, sympathetic stimulations and coronary artery occlusion location) have been pooled (n = 1956). Least squares meansfstandard error are graphed. The incidence of program-induced ventricular arrhythmias is on the ordinate and the time of occlusion is on the abscissa. * P I 0.05, versus control. PIVA = programinduced ventricular arrhythmias.
arrhythmia induction (P < 0.05 versus control or no ischemia). There existed an increase in ventricular arrhythmia induction after 30 minutes following the occlusion (P < 0.05). The decline in ventricular arrhythmia induction after 60 minutes of ischemia was significantly different from the 30, 120 and 180 minute periods, however, it remained increased above control conditions (P < 0.05). The increase at 120 and 180 minutes was not different from the 30 minute period. The effect of unilateral and bilateral sympathetic stimulation was evaluated in each animal before and following a coronary artery occlusion. Fig. 3 illustrates the effect of the individual and combined stellate stimulations. Ventricular arrhythmias were elicited in 54% of the trials during control condition, that is, in the absence of sympathetic stimulation. Trials during right stellate stimulation were not different from control (52%; NS). Left stellate stimulation alone increased (68%, P < 0.05) the occurrence of ventricular arrhythmias during control trials. Simultaneous right and left stellate stimulations elevated (63%, P < 0.05) the incidence of ventricular arrhythmias. There was a statistical difference between left stellate stimulation trials versus combined right and left stellate stimulation trials (P < 0.05).
RSS
Fig. 3. Graphical representation of the effect of unilateral and bilateral sympathetic stimulation on the induction of ventricular arrhythmias. Data have been pooled with respect to the duration of occlusion, coronary artery location, and the number of extrastimuli (n = 1956). Stellate stimulation is on the abscissa and the incidence of program-induced ventricular arrhythmias is on the ordinate. * P 5 0.05, versus control. * above bracket, P I 0.05, LSS versus RLSS. LSS = left stellate stimulation; PIVA = program-induced ventricular arrhythmias; RLSS = right and left stellate stimulation; RSS = right stellate stimulation.
Data resulting from the use of three extrastimuli during programmed electrical stimulation were analyzed separately. Fig. 4 illustrates that the location of the coronary artery occluded influ100 E
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0
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60
160
120
DURATION OF OCCLUSION
(MINUTES)
Fig. 4. A graph illustrating the effect of the location of coronary artery occlusion on the induction of ventricular arrhythmias. Types of sympathetic (stellate) stimulations have been pooled. These data are the results following the use of three extrastimuli during programmed electrical stimulation (n = 491). The incidence of program-induced ventricular ar-
rhythmias is on the ordinate and the duration of occlusion is on the abscissa. Least squares meansfstandard error are graphed. n = left anterior descending coronary artery; q = left circumflex coronary artery. * P I 0.05, left anterior descending versus left circumflex coronary artery. PIVA = program-induced ventricular arrhythmias.
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s
90
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n--o
CONTROL
A--
LSS
v-.
RSS
m-m
RLSS
75 1
,Ot
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304
/ 0
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60
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DURATION OF OCCLUSION(MINUTES) Fig. 5. A graph illustrating the effects of individual and combined stellate stimulations throughout the duration of coronary occlusion. These data are the results following the use of three extrastimuli during programmed electrical stimulation (n = 491). The incidence of program-induced ventricular arrhythmias is on the ordinate and the duration of occlusion is on the abscissa. Least squares means + standard error are graphed. LSS = left stellate stimulation; PIVA = program-induced ventricular arrhythmias; RLSS = right and left stellate stimulation; RSS = right stellate stimulation.
enced the outcome of ventricular arrhythmia production over the experimental period. For the left circumflex occlusion group the incidence of induced ventricular arrhythmias increased significantly after any duration of myocardial ischemia and a trend to increase further after each time period exists. In the left anterior descending coronary group, the ventricular arrhythmia incidence was elevated after 30 (78%; NS) and 120 (73%; NS) minutes of myocardial ischemia. The incidence of ventricular arrhythmia following 60 (61%; NS) and 180 (58%; NS) minutes of ischemia for animals subjected to left anterior descending occlusion did not differ from control (65%). During the control periods, that is, prior to coronary occlusion, the left anterior descending occlusion preparation had a higher occurrence of ventricular arrhythmia than that of the left circumflex occlusion group (65% versus 48%; P < 0.09.
Fig. 5 illustrates the effect of sympathetic stimulations throughout the experimental protocol in animals subject to three extrastimuli during programmed electrical stimulation. It illustrates the increased incidence of program-induced ventricular arrhythmias after any duration of coronary occlusion. This figure also shows the time
dependent changes occurring throughout the trials. Furthermore, it illustrates the influence of sympathetic stimulations before and during coronary occlusion. Note that right stellate stimulation did not further influence the incidence of induced arrhythmias. Left stellate stimulation, however, significantly elevated ventricular arrhythmia occurrence prior to and during myocardial ischemia and infarction. Combined right and left stellate stimulation results in arrhythmia occurrence that falls between that of the individual right and left stellate stimulations. Discussion The use of programmed electrical stimulation as an experimental challenge remains valuable in the study of ventricular arrhythmias [19-21,24,25]. The inducibility of ventricular arrhythmias in a normal heart is theoretically zero, however, a basal level of ventricular arrhythmia induction is a prerequisite to assess interventions which alter ventricular vulnerability. The data shows that this electrophysiological technique was sensitive to changes in the level of sympathetic neural activity as well as to ischemia-induced changes in excitability. For instance, in an animal which had only 2-3 premature ventricular complexes during control trials and then ‘9-10 premature ventricular complexes during the trials following a perturbation, we interpreted this as indicating that a change had taken place that had acted to enhance the likelihood of inducing a ventricular arrhythmia. Likewise, in an animal exhibiting few arrhythmias during control periods, but then developed arrhythmias given fewer extrastimuli, we also interpreted as there having been a change in the arrhythmia inducibility. Hence, in our model the increased incidence of program-induced ventricular arrhythmias during neural stimulations indicated the creation of a pathological condition. The production of ventricular fibrillation using multiple extrastimuli may be explained in part by the lowering of the ventricular fibrillation threshold following repetitive extrasystoles [26]. This interpretation supports the idea that, perhaps, one premature ventricular complex or multiple premature ventricular complexes do the same to
81
the otherwise unsuspecting heart. That is, single premature ventricular complexes may be precursors to more serious arrhythmias. The occurrence of premature ventricular complexes may indicate a risk for sudden cardiac death 13,271. Therefore, it is possible that a life-threatening arrhythmia could be initiated by an otherwise innocuous premature ventricular contraction should the proper coupling interval be achieved. Increased sympathetic activity has a permissive action during programmed electrical stimulation. Both the number and complexity (coupling intervals and occurrence time within a cycle) of arrhythmias are increased during sympathetic stimulation. Furthermore, as the frequency and complexity of the arrhythmias increases, so does the likelihood of a life-threatening arrhythmia. The relevance of the effects of sympathetic stimulation to the clinical setting is strengthened by reports demonstrating asymmetric responses in humans upon removal of left-sided versus rightsided sympathetic nerves [8,171. Surgical or pharmacological ablation of the left stellate ganglion provides dramatic results in the treatment of long QT syndrome patients [8]. In addition, the extent of infarct damage and irreversible cellular injury is reduced in stellectomized animals [281. This effect appears to be due to increased collateral flow and lower myocardial oxygen demand after stellectomy 1281. Puddu et al. [14] investigated the effects of stellectomy upon arrhythmogenesis. It was found that a sympathectomy eight weeks prior to a left circumflex occlusion decreased the incidence of spontaneous ventricular arrhythmias. Their data corroborates the strong arrhythmogenic influence of the left stellate ganglion during coronary occlusion. In addition, the authors also reported similar effects upon right stellate ganglionectomy, although to a much lesser degree. In contrast, our data demonstrates that arrhythmia induction is not significantly influenced by stimulation of the right stellate ganglion. In addition, Schwartz et al. [S] and others [183 have shown that during short bouts of ischemia (less than 2 minutes), extirpation of the right stellate ganglion resulted in increased ventricular ectopy, while left stellate ganglionectomy resulted in fewer episodes of ven-
tricular ectopy. These observations are in agreement with the concept that the left stellate has a greater role in arrhythmogenesis. Randall et al. [29] demonstrated that heterogeneous sympathetic stimulation to the heart in an exercising conscious dog resulted in multiform premature ventricular complexes and/or ventricular tachycardia. They provide direct evidence of the arrhythmogenic impact of activation of a single cardiac nerve in a model of autonomic imbalance. The left-sided sympathetic fibers play a greater role in the autonomic regulation of the ventricle, especially, the inferoposterior ventricle [30]. In contrast, the right-sided sympathetic fibers, while shown to innervate the anterolateral ventricle, play a greater role in controlling sinus rate 2301. The effect of activation of right-sided sympathetic nerves on heart rate may serve to overdrive ventricular arrhythmias that might otherwise result in sudden death. Our data suggest, however, that even in the face of homogeneous sympathetic stimulation (i.e., combined right and left stellate stimulation), that a proarrhythmic factor still exists. There appears to be a trend for the right stellate stimulation to reduce the influence of the left stellate stimulation during the combined stimulations, both, before and during acute myocardial ischemia and infarction. Using the measurement of early afterdepolarizations in anesthetized, open-chested dogs, Ben-David and Zipes [31] observed greater effects of left ansae subclaviae stimulation and bilateral subclaviae stimulation than that of right ansae subclaviae stimulation. They believe quantitative differences in neurotransmitter output exist for stellate ganglia stimulations, right versus left side. Our results agree with their report; however, our interpretation is that the differential effects are due to the varied innervation patterns of the sympathetic ganglia. Assessment of the ischemic insult was limited to a post hoc analysis of the ischemic zone using the methylene blue technique [22]. Placement of the ligature was chosen so as to produce a relatively large infarct, but hopefully without producing ventricular fibrillation or heart failure during the early period of the occlusion. Sympathetic activation can induce post-stenotic myocardial is-
82
chemia [6] and, thereby, act to increase the area of damage. Thus, it is possible that the size of ischemic zones was made larger by the subsequent sympathetic stimulations. There are no obvious explanations for the decline in the induction of ventricular arrhythmias at the 60-minute occlusion period. Other physiological variables that were measured failed to indicate possible changes in the arrhythmia substrate. It is likely that the changes responsible for the difference in ventricular arrhythmia induction are cellular in nature and go undetected by standard measurements made during our experiments. The differences noted for the two arterial occlusion groups are not clear. A left circumflex coronary occlusion may activate different receptors but these reflexes should not influence the results in our decentralized preparations. In conclusion, this study has shown that the clinical technique of programmed electrical stimulation of the heart is reliable for the induction of ventricular arrhythmias during acute myocardial ischemia and infarction in our canine model. The results demonstrate that right stellate stimulation is not arrhythmogenic before or during myocardial ischemia. Sympathetic imbalance due to left stellate stimulation, however, is arrhythmogenie both before and during myocardial ischemia. Homogeneous sympathetic efferent activity during combined right and left stellate stimulation produced arrhythmias before and during myocardial ischemia and infarction. A possible protective role of the right stellate ganglion in the face of enhanced left sympathetic activity was suggested by the observation that the incidence of ventricular arrhythmias was reduced by combined right and left stellate stimulation before and during myocardial ischemia. Thus, our findings are consistent with the hypothesis that a sympathetic imbalance is arrhythmogenic and, that the arrhythmogenic influence of the sympathetic nervous system is present before and during acute myocardial ischemia. Acknowledgements The authors wish to acknowledge the constructive criticism and helpful comments of Drs. Fer-
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