Vagal reflexes and survival during acute myocardial in conscious dogs with healed myocardial infarction GAETANO STEPHEN
ischemia
M. DE FERRARI, EMIL10 VANOLI, MARCO STRAMBA-BADIALE, S. HULL, JR., ROBERT D. FOREMAN, AND PETER J. SCHWARTZ
Department of Physiology and Biophysics, University of Oklahoma, Oklahoma City, Oklahoma 73190; Centro di Fisiologia Clinica e Ipertensione, Istituto di Clinica Medica II, Universita degli Studi di Milano, 20122 Milan; and Dipartimento di Medicina, Universita di Pavia, 27100 Pavia, Italy
DE FERRARI, GAETANO M., EMILIO VANOLI, MARCO 15, 32a, 34, 37). STRAMBA-BADIALE,~TEPHENS.HULL, JR., ROBERTD. FOREAlthough all these findings support the concept of a MAN, AND PETERJ. SCHWARTZ.Vagal reflexes and survival beneficial influence of vagal activity during myocardial
during
acute myocardial
ischemia
in conscious dogs with healed
myocczrdialinfarction. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H63-H69, 1991.- The role of vagal tone and reflexes in the genesisof life-threatening arrhythmias wasinvestigated in a clinically relevant animal model for sudden cardiac death. Forty-five dogswith a healedanterior myocardial infarction in which transient myocardial ischemia during exercise did not induce malignant arrhythmias were utilized for the study. They underwent a further exerciseand ischemiatest in which atropine (75 pg/kg) was injected before coronary artery occlusion. Novel occurrence of ventricular arrhythmia, or worsening of the type of arrhythmia present in the control test, occurred in 23 of 45 dogs(51%) and ventricular fibrillation occurred in 11 of 45 (24%, P = 0.001).Analysis of heart rate responseto acute ischemiain the control test indicates that these 11 animalshad powerful vagal reflexes during coronary artery occlusion, compared with the 34 survivors (-32 t 35 vs. +2 t 27 beats/min, P = 0.003). This study indicatesthat -75% of animalsresistant to ventricular fibrillation are characterized by weak sympathetic reflexes in responseto acute myocardial ischemia.In the remaining 25%powerful vagal reflexes counteract concomitant reflex sympathetic hyperactivity, decreaseheart rate, and are essentialfor survival. suddendeath; atropine; sympathetic reflexes
VAGAL TONE AND VAGAL REFLEXES may exert aprotec-
tive role against sudden cardiac death in the setting of ischemic heart disease (9, 31, 33). Depressed baroreflex sensitivity, largely a marker of reduced cardiac vagal efferent activity to the heart, is closely associated with risk of developing ventricular fibrillation during a transient episode of acute myocardial ischemia in dogs with a healed myocardial infarction (3, 32). Reduced heart rate variability, a marker of cardiac vagal tone, and depressed baroreflex sensitivity have been found to correlate with increased cardiac mortality in postmyocardial infarction patients. In these two clinical studies (16, 17) increased mortality was associated with signs of either reduced tonic vagal activity (16) or reduced capability to activate vagal reflexes (17). Conversely, vagal stimulation was found capable of preventing both ischemia- and reperfusion-induced life-threatening arrhythmias in anesthetized and in conscious animal preparations (6, 10,
ischemia, they do not provide direct evidence of the actual role of spontaneous vagal tone and reflexes. The objectives of the present study were to assess if they do indeed provide protection against ischemia-induced ventricular fibrillation and to investigate the parasympathetic reflex control of heart rate during acute myocardial ischemia in the conscious state. The experiments were conducted in a model for sudden cardiac death in which dogs with a healed myocardial infarction undergo a brief episode of myocardial ischemia while running on a treadmill (27). The high reproducibility of the outcome of this exercise and ischemia test, either ventricular fibrillation (susceptible animals) or survival (resistant animals), allows the use of each animal as its own control, thus avoiding the problem presented by group comparisons. In this study, the effects of muscarinic receptor blockade with atropine were investigated in a group of resistant dogs. METHODS
Mongrel study.
dogs weighing
15-25 kg were used for the
Surgical Preparation
Anesthesia was induced with thiopental sodium (Pentothal, Abbott Laboratories; 25 mg/kg iv) and was maintained by the inhalation of a halothane, nitrous oxide, and oxygen mixture. With aseptic procedures, a left thoracotomy was performed in the fourth intercostal space. The pericardium was opened, and the heart was suspended in a cradle. The left circumflex coronary artery was carefully dissected from surrounding epicardial fat, and both a 20 MHz continuous-wave Doppler flow transducer and hydraulic occluder were placed around the vessel. Insulated silver-coated copper wires were sutured to the epicardial surface of the right ventricle and atrium to record a bipolar electrogram and/or to pace the heart. A Tygon catheter was positioned in the aortic arch to record blood pressure. A Harris two-stage occlusion was performed on the left anterior descending coronary artery below the first
0363-6135/91 $1.50 Copyright 0 1991 the American Physiological Society
H63
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H64
VAGAL
REFLEXES
diagonal branch to produce a myocardial infarction. The vessel was partially occluded for 20 min and then tied completely. All lead wires were tunneled under the skin to exit from the dorsal surface of the neck. Pentazocine lactate (Talwin, Winthrop Laboratories, 30 mg im) was given approximately every 8 h for the first 24 h to control postoperative pain. We adhered to the guidelines of the American Heart Association on the care and treatment of experimental animals. Experimental Protocol
AND SURVIVAL
limb lead configuration. Baroreceptor reflex sensitivity was then assessed (32) and was expressed as the slope of the regression line relating R-R intervals to systolic arterial pressure changes. Infarct Size
Infarct size was assessed by a nitro blue enzymatic staining technique in 23 dogs (55%): 8 of the 11 dogs that developed ventricular fibrillation after atropine (73%) and 15 randomly chosen survivors. It was expressed in weight as a percentage of the left ventricle.
One month after production of myocardial infarction, the surviving animals performed a submaximal exercise stress test. The animals ran on a motor-driven treadmill for 12-M min while the work load increased every 3 min (4.8 km/h, 0% grade during the first 3 min; 6.4 km/h, 16% grade during the last 3-min period). At the beginning of the last minute of exercise, the left circumflex coronary artery was occluded; the treadmill was then stopped, and the occlusion was maintained for a second minute. Coronary occlusion was begun when either the animal completed 17 min of exercise or when heart rate had reached a level close to 210 beats/min. Completeness of occlusion was verified by the disappearance of the phasic blood flow velocity signal. Large steel plates were placed across the animal’s chest so that electrical defibrillation (American Optical, model 6217) could be performed with minimal delay. This exercise and ischemia test reproduces the protocol previously described (27). The timing was chosen to discriminate between arrhythmias related to exercise, to exercise combined with transient myocardial ischemia, to cessation of exercise, and to reperfusion. The dogs that did not show ventricular fibrillation during the control exercise and ischemia test represent the population of this study (n = 45). In these animals the exercise and ischemia test was repeated a few days later with the sole difference that atropine sulfate (75 pg/kg) was injected 2 min before coronary occlusion. The reproducibility of the arrhythmia pattern was assessed in a third exercise and ischemia test with no additional intervention, i.e., in a test identical to the control one. This was performed in all but one of the animals in which atropine had caused the appearance of malignant arrhythmias and in a randomly selected group of dogs (n = 20) in which no such effect had been noticed. In 7 of the 11 dogs in which atropine had caused the appearance of ventricular fibrillation, an additional exercise and ischemia test was repeated, keeping heart rate at the level reached during the atropine test by atria1 pacing.
Data Recording
Baroreceptor Reflex Testing
TABLE
Before baroreceptor reflex testing, the dogs were allowed to adapt to the laboratory for a few days to minimize any orienting response elicited by the new environment. A bipolar right atria1 electrogram and the surface electrocardiogram were recorded from the epicardial leads and from needle electrodes placed in the standard
During each exercise and ischemia test, recordings of flow velocity in the left circumflex coronary artery, arterial blood pressure, electrocardiograms, and heart rate were made on an eight-channel R 612 Beckman polygraph recorder. The signals were also recorded on a magnetic tape (Ampex FR-1300) for later analysis. Statistical Analysis
Statistical analysis was performed using two-way analysis of variance for repeated measures followed by t test, with Bonferroni correction when appropriate. A P < 0.05 was considered significant for the differences tested. Data are reported as means t SD. RESULTS
The study was performed in 45 dogs that had survived an exercise and ischemia test and were therefore defined as “resistant.” This group originates from an initial number of 157 dogs that underwent a myocardial infarction and were chronically instrumented. Of them, 61 (39%) either died in the first week after surgery or had a malfunction of the implanted instrumentation; of the 96 dogs that performed the exercise and ischemia test 51 developed ventricular fibrillation and were defined as “susceptible” and were assigned to other protocols. The remaining 45 resistant animals constitute the group under study. Heart Rate
Heart rate at different steps of the test is shown in Table 1. In the trials performed in control conditions, heart rate did not change significantly during the first 30 and 60 s of acute myocardial ischemia. After 2 min of ischemia, i.e., 1 min after cessation of exercise, heart rate had significantly decreased, as expected. In the trials performed with atropine, heart rate was similar to that of control condition both at rest and at 2 1. Heart rate Before Exercise
Before Atropine
Peak Exercise
60-s Occlusion
120-s Occlusion
Control 108t24 210t22 203k34 158t31 Atropine 107t24 207t24 230*21* 241+26t 214+34t Values are means t SD in beats/min; n, 45 dogs. * P < 0.01 vs. before atropine; t P < 0.01 vs. control.
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VAGAL
REFLEXES
AND
CONTROL
min before coronary artery occlusion, just before atropine injection. One min after atropine administration, heart rate rose significantly and was higher (P < 0.01) than in the control condition both after 30 and 60 s of coronary artery occlusion. Also, at the end of the coronary occlusion, i.e., 1 min after cessation of exercise, heart rate was higher than in the control trials. Analysis of these data indicates that atropine reversed the heart rate response to coronary occlusion; indeed, after 1 min of ischemia heart rate had increased by 10 t 19 beats/min compared with a decrease of 7 t 31 beats/ min observed in control condition (P c 0.05, Fig. 1).
H65
SURVIVAL
rk45
ATROPINE
Arrhythmias In the control trials, 39 animals (87%) were completely free of arrhythmia, 5 (11%) had few (40) isolated premature ventricular contractions, and just one had a single episode of three consecutive ventricular beats. In the atropine trials, 19 animals (42%) had no arrhythmia (P c 0.001 vs. control trial), 12 (27%) had isolated premature ventricular contractions, 3 (7%) had runs of ventricular tachycardia (range 6-30 beats), and 11 dogs (24%) had ventricular fibrillation. This latter arrhythmia occurred 75 t 19 s after the beginning of the occlusion (range 50-98 s), in four dogs shortly before the cessation of exercise, and in the remaining seven after stopping the treadmill. The arrhythmia exacerbation induced by atropine is clearly evident in Fig. 2, which shows the pattern observed in each individual dog. No change was present in one-half of the animals (22 of 45, 49%), whereas there was a worsening in 23 of 45 (51%). The overall survival (percent of animals not suffering ventricular fibrillation) decreased from 100 to 76% (P < 0.001, Fisher exact test). To confirm the reproducibility of the outcome, an additional test was nerformed in 30 animals in control +20
7 NO
ARR.
2. Effect of atropine on incidence of arrhythmias during exercise and ischemia test. In control conditions 1 animal had single episode of 3 consecutive premature ventricular beats and is assigned to ventricular tachycardia group (VT), 5 had scattered isolated premature ventricular contractions (40, PVC’s), and remaining had no arrhythmia (NO ARR). Atropine caused worsening in 23 of 45 dogs (51%). VF, ventricular fibrillation. FIG.
conditions (i.e., without atropine), as detailed in METHODS. In none of these 30 dogs did ventricular fibrillation or tachycardia occur. Thus the occurrence of arrhythmias after atropine administration cannot be ascribed to spontaneous increase in susceptibility. Pacing In 7 of the 11 dogs that had ventricular fibrillation in the atropine trial, another exercise and ischemia test was performed while heart rate was maintained, by atria1 pacing, at the same level attained during the atropine test. In five of these seven animals (71%) ventricular fibrillation developed again, as shown in Fig. 3, whereas no arrhythmias were observed in two dogs (29%).
* 10
A HR
NO ARR.
0
b/min
Survival and Ventricular Fibrillation
10
-20 Before
CA0
lmin
CA0
FIG. 1. Heart rate (HR) response to coronary artery occlusion (CAO) performed during exercise and ischemia test. In the test with atropine administration, slight but significant heart rate increase is observed, compared with modest decrease in control condition. Open circle, 210 k 3 beats/min; closed circle, 230 t 3 beats/min. Data are expressed as means k SE; n, 45 dogs. * P < 0.05.
The 11 animals in which atropine caused the occurrence of ventricular fibrillation will be called hereafter “VF group,” and the 34 dogs that, despite atropine, survived also the second exercise and ischemia test will be called “survivors.” The VF group and the survivors represent two different subgroups and were analyzed separately. When the VF group and the survivors were compared in the second exercise and ischemia test during which atropine was administered before coronary occlusion, heart rate was found to be similar at rest (108 t 23 vs. 109 t 26 beats/min), at peak exercise (205 t 22 vs. 208 t 20 beat s/ min), and after atropine administration (225 t 19 vs. 233 t 23 beats/min). Also, there was no
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H66
VAGAL
REFLEXES
AND
SURVIVAL
CONTROL HR
157
b/min
t ATROPINE
\
HR 248
A
\\ \
HR
\
\
PACING HR
\
246
\
t 60 soc
CA0
- and
of
OX-
\ \
18OC
3. Electrocardiographic tracings of 1 dog during subsequent exercise and ischemia tests. Arrow indicates end of first minute of coronary artery occlusion when treadmill is stopped. During atropine test (middle) rapid ventricular tachycardia that degenerates into ventricular fibrillation occurs. Further exercise and ischemia test was then performed (bottom) without atropine, keeping heart rate at same level reached with atropine by means of atria1 pacing. In this condition ventricular tachycardia and fibrillation occurred again.
--cl
\
\ t
T
-a--
-e--
- ----
O-'-c
75 Mg/Kg
\
difference in the response to myocardial ischemia: heart rate increased 17 t 21 beats/min after 60 s in the VF group vs. 8 t 18 beats/min in the survivors. By contrast, analysis of the exercise and ischemia test in control conditions, i.e., without atropine, revealed an unexpected and interesting difference. Heart rate was similar at rest (107 t 21 and 110 t 25 beats/min) and at peak of exercise (208 t 12 and 210 t 23 beats/min) but had a strikingly different response to coronary occlusion. Indeed, the VF group, after onset of ischemia and despite continuation of exercise, showed a significant heart rate reduction that was absent among survivors (-32 t 35 vs. +2 t 27, P = 0.003; Fig. 4). Baroreflex
Sensitivity
To ascertain whether this pattern of more powerful vagal reflexes observed in the VF group characterized these animals also at rest and without myocardial ischemia, we analyzed their baroreceptive reflex sensitivity. The one-sided hypothesis was tested that these dogs would have greater baroreceptor sensitivity slopes. This proved to be correct; indeed, within these 45 resistant dogs, the animals that developed ventricular fibrillation after atropine had a higher baroreceptor sensitivity compared with the survivors (19.6 t 9.4 vs. 14.4 t 6.3 ms/ mmHg, P = 0.027).
Before
4. Heart rate (CAO) during control ventricular fibrillation heart rate that was not min; triangle, 208 t 4
CA0
VF with Atropine n=ll
\
FIG.
FIG.
No VF with Atropine k34
lmin
\
CA0
(HR) response to coronary artery occlusion exercise and ischemia test. Dogs that develop (VF) in atropine test show marked decrease in observed in other dogs. Square, 210 * 4 beats/ beats/min. Data are expressed as means & SE.
* P = 0.003. TABLE
2. Mean blood pressure
Control Atropine
Before Exercise
Before Atropine
Peak Exercise
60-s Occlusion
120-s Occlusion
98t12 98t13
109t15
112t14* 111&18*
76t18t 81-r-22-f
83t20t 102&20?$
Values are means t SD in mmHg; exercise; t P < 0.01 vs. peak exercise;
n, 45 dogs. * P < 0.05 vs. before $ P c 0.05 vs. control test.
mia test it declined significantly 1 and 2 min after ischemia. Blood pressure values were not influenced by atropine during exercise; during myocardial ischemia, blood pressure did not differ at 60 s but was higher in the atropine trial after 120 s of ischemia. Mean blood pressure values were similar comparing the VF group and the survivors, before and after coronary artery occlusion. Just before coronary occlusion, blood pressure tended to be higher in the survivors [113 t 20 vs. 102 t 9 mmHg; not significant (NS)], but the mean blood pressure decrease after 60 s of ischemia was comparable in the two groups (-24 t 21 in the survivors vs. -32 + 18 mmHg in the VF group; NS). In the trials with pacing at the heart rate levels attained in the atropine tests, blood pressure did not differ. DISCUSSION
Infarct
Size
Infarct size was 12.0 t 4.1% of the left ventricle and was similar in the VF group and in the survivors (12.6 t 4.5 vs. 11.7 t 4.0%). Blood Pressure
Mean blood pressure at different steps of the test is shown in Table 2. During the control exercise and ische-
The main goal of this study was to assess whether vagal tone and reflexes do provide protection against ischemia-induced ventricular fibrillation in a clinically relevant animal model. The results show that, among dogs resistant to sudden death, muscarinic blockade caused a worsening in the arrhythmia in 51% of the animals and the occurrence of ventricular fibrillation in 24%. Therefore, the ability to activate vagal reflexes was
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VAGAL
REFLEXES
found to be essential for the survival of -25% of animals. Analysis of the effect of atropine on heart rate during exercise and ischemia disclosed an unexpected finding on the autonomic balance and reflexes in the animals that survived and in those that did not; namely, the animals that developed ventricular fibrillation were those with the more pronounced vagal reflexes in control conditions. Atropine
and Lethal Arrhythmias
AND
SURVIVAL
H67
with that (71%) of the present study. These combined data indicate that -50% of the protective effect is independent of a heart rate change. Similar conclusions can be drawn from a different experimental model that also combines acute ischemia and sympathetic hyperactivity as triggers for malignant arrhythmias (ll), in which the antiarrhythmic efficacy of the muscarinic agonist oxotremorine was only partially mediated by the heart rate effects. Electrophysiological effects. Parasympathetic activity may influence the electrophysiological properties at ventricular level (1, 5, 9, 33, 34). This influence may counteract both automatic and reentrant arrhythmia mechanisms (31), and its removal by atropine has presumably contributed to the results of this study. Vagal effects on ventricular electrophysiology are largely mediated by an antiadrenergic mechanism (1, 9, 34). Nonetheless, data exist at experimental (24) and at clinical levels (25) that suggest direct electrophysiological effects, possibly more marked at the epicardial level (19).
At variance with the wide acceptance of the detrimental effects of sympathetic activation during acute myocardial ischemia (9, 20, 21, 28, 30) the effects of either surgical or pharmacological parasympathetic blockade are unclear. The available data suggest differences according to species and site of coronary artery occlusion. Vagotomy increases the incidence of ventricular fibrillation during acute anterior myocardial ischemia in the cat (7) but not in the dog (12). Atropine is detrimental after occlusion of the left anterior descending (7, 14) but not of the circumflex coronary artery (8, 18). In the Survival vs. Ventricular Fibrillation present study, arrhythmia worsening and novel occurThe effect of atropine on the occurrence of arrhythrence of life-threatening arrhythmia after atropine indimias, although present in 51% of the animals, was quite cate that the presence of adequate vagal tone and reflexes deleterious in 24% as manifested by the development of has an important role in reducing the incidence of sudden ventricular fibrillation. Possible causes of distinction death during acute myocardial ischemia. This worsening between the VF group and the survival group include occurred during circumflex coronary occlusion at variof the previous myocardial infarction, degree of ance with the previous studies. This discrepancy may be extent acute myocardial ischemia, and a different neural redue to three characteristics unique to our experimental sponse to coronary occlusion. model: conscious state, high sympathetic background, Infarct size did not differ in the two groups. The size and presence of a previous anterior myocardial infarcof the acutely ischemic area after circumflex coronary tion. artery occlusion during exercise was not measured. It is The mechanism of the deleterious influence of atropine entirely possible that the different effect of atropine in depends primarily on its heart rate effect and on the the two groups of animals may have resulted from a electrophysiological effect at the ventricular level. larger ischemic area in the VF group. It is conceivable Heart rate. The detrimental effect of elevated heart that among the survivors, those more dependent for rate is supported by several lines of evidence. First, heart protection on vagal hyperactivity would be the ones with rate is a major determinant of myocardial oxygen de- a larger ischemic area and an increased tendency to left mand. In fact, higher heart rates are accompanied by ventricular dysfunction during coronary artery occlusion. greater degrees of myocardial ischemia during acute cor- They would be more vulnerable to muscarinic blockade onary artery occlusion in anesthetized (22) and conscious and to the increase in myocardial oxygen demand caused (26) dogs. Second, both triggered (36) and reentrant (13) by the attendant increase in heart rate. arrhythmias are facilitated by elevated heart rates. InThe reflex heart rate response during the control exdeed, during acute myocardial ischemia in anesthetized ercise and ischemia test was markedly different between dogs, both ventricular fibrillation threshold (15) and the VF group and the survivors. This was an unexpected actual occurrence of ventricular tachycardia and fibriland critical finding of the present study. In the first lation (4) are worsened by heart rate increases. minute of ischemia the VF group had a more powerful The occurrence of ventricular fibrillation in 71% of parasympathetic activation directed to the sinus node the animals during pacing indicated that the increase in (-32 + 35 vs. +2 t 27 beats/min). This tendency for heart rate as well as the abolition of the reflex decrease strong vagal reflexes in these animals was not confined during myocardial ischemia played a major role in the to myocardial ischemia. Indeed, they also had higher deleterious effect of atropine. values of baroreflex sensitivity, suggesting accentuated Two recent sets of observations suggest that the an- vagal responses to different pathophysiological stimuli. tiarrhythmic effect of vagal activation is not exclusively Atropine interfered with these prominent vagal reflexes dependent on the reduction in heart rate. In this same and unmasked the electrical vulnerability of this group experimental model, electrical stimulation of the vagus during myocardial ischemia. has a striking antifibrillatory effect in susceptible animals (10, 32a); moreover, the data with atria1 pacing Susceptible and Resistant: Animal Model indicate that protection from ventricular fibrillation was These experiments were performed in a conscious andependent on heart rate decrease in four of nine animals imal model for sudden cardiac death, developed in our (44%), a percentage not significantly smaller compared Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 6, 2018. Copyright © 1991 American Physiological Society. All rights reserved.
H68
VAGAL
REFLEXES
laboratory (27). The protocol includes three factors known to be important in the genesis of life-threatening arrhythmias: a healed myocardial infarction, an episode of acute myocardial ischemia, and sympathetic activity physiologically elevated by exercise. We suggested (3) and then confirmed in 192 dogs (32) that vagal refle xes are predominant, among resistant ani mals, during acute ischemia and in response to a blood pressure increase, whereas sympathetic reflexes predominate among susceptible animals. Resistant animals had a baroreflex sensitivity of 17.8 t 6.6 vs. 9.1 t 6.0 ms/mmHg in susceptible. Previous studies have suggested absence of hemodynamic differences between these two groups at rest, but a tendency toward a greater systolic dysfunction during exercise in the susceptible group (2). The present study further explores the autonomic balance at the level of the sinus node in resistant dogs. Muscarinic blockade allows two principal considerations. First, vagal tone still contributes to heart rate control during submaximal exercise, as shown by the significant heart rate increase after atropine. Second, atropine unmasks a significant sympathetic activation in response to ischemia. This is indicated by the reversal in heart rate response to coronary artery occlusion (a mean of +lO vs. -7 beats/min in control condition). Thus the heart rate response in the entire group results from activation of moderate and contrasting autonomic reflexes. The parasympathetic component is slightly dominant.
AND SURVIVAL K. D., V. S. BANKA, AND R. H. HELFANT. Rate dependent ventricular ectopia following acute coronary occlusion. Circulation
4. CHADDA,
49: 654-659, 1974. 5. CHANDRASEKARAN, K., B. J. SCHERLAG, E. J. BERBARI, HARRISON, K. FRIDAY, W. M. JACKMAN, AND R. LAZZARA.
L. A. Cholinergic effects on electrophysiology of ischemic myocardium and arrhythmias (Abstract). J. Am. CoZZ.Cardiol. 3: 476, 1984. CORR, P. B., AND R. A. GILLIS. Effect of autonomic neural influences on the cardiovascular changes induced by coronary occlusion. Am. Heart J. 89: 766-774, 1975. CORR, P. B., AND R. A. GILLIS. Role of the vagus nerves in the cardiovascular changes induced by coronary occlusion. Circulation 49: 86-97, 1974. CORR, P. B., D.
10.
11.
12.
13.
14.
Conclusions
In this clinically relevant animal model for sudden cardiac death, vagal tone and reflexes contribute significantly to the protection from ventricular fibrillation. Whereas for -75% of the animals resistant to sudden death the key factor is represented by the absence of major sympathetic activation, in 25% of them myocardial ischemia activates powerful vagal reflexes that decrease heart rate and myocardial oxygen demand, counteract concomitant sympathetic hyperactivity, and are essential for survival. We are grateful to G. Stout and R. Fitts for technical assistance, to Dr. G. E. Billman for help in performing some of the initial experiments, to C. Zanchetti and R. Sarri for assistance in preparing the figures, and to G. De Tomasi for secretarial support. This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-33727. Address for reprint requests: P. J. Schwartz, Istituto di Clinica Medica II, Via F. Sforza 35, 20122 Milan, Italy. Received 7 May 1990; accepted in final form 1 March 1991.
16.
256-262,1987. 17. LA ROVERE, SCHWARTZ.
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G. E., P. J. SCHWARTZ, J. P. GAGNOL, AND H. L. STONE. Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death. J. Appl. Physiol. 59: 890-897, 1985. 3. BILLMAN, G. E., P. J. SCHWARTZ, AND H. L. STONE. Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death. Circulation 66: 874-880, 1982.
217: 703-709, 1969. 22. MAROKO, P. R., J. K. KJEKSHUS, B. E. SOBEL, T. WATANABE, J. W. COVELL, J. Ross, JR., AND E. BRAUNWALD. Factors influencing
infarct size following experimental coronary artery occlusions. Circulation 43: 67-74, 1971. 23. MYERS, R. W., A. S. PEARLMAN, R. M. HYMAN, R. A. GOLDSTEIN, K. M. KENT, R. E. GOLDSTEIN, AND S. E. EPSTEIN. Beneficial effects of vagal stimulation and bradycardia during experimental acute myocardial ischemia. Circulation 49: 943-947, 1974. 24. PAPPANO, A. J., AND D. INOUE. Development of different electrophysiological mechanisms for muscarinic inhibition of atria and
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VAGAL
REFLEXES
ventricles. Federation Proc. 43: 2607-2612,
1984. R. L. RINKENBERGER,
J. J. HEGER, AND 11. P. ZIPES. Effect of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans. Evidence supporting a direct cholinergic action on ventricular muscle refractoriness. Circ. Res. 49: 511-518, 1981. 26. REDWOOD, D. R., E. R. SMITH, AND S. E. EPSTEIN. Coronary artery occlusion in the conscious dog: effects of alterations in heart rate and arterial pressure on the degree of myocardial ischemia. 25. PRISTOWSKY,
Circulation 27. SCHWARTZ,
E. N., W. M. JACKMAN,
46: 323-329, 1972. P. J., G. E. BILLMAN,
AND H. L. STONE. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation
69: 790-800, 1984. 28. SCHWARTZ, P. J., Neural Mechanisms
A. M.
BROWN,
in Cardiac
A.
MALLIANI,
Arrhythmias.
A. ZANCHETTI. New York: Raven,
AND
1978. 29.
P. J., AND H. L. STONE. The analysis and modulation of autonomic reflexes in the prediction and prevention of sudden death. In: Cardiac Arrhythmias: Mechanisms and Management, edited by D. P. Zipes and J. Jalife. New York: Grune and Stratton, 1985, p. 165-176. 30. SCHWARTZ, P. J., AND H. L. STONE. The role of the autonomic nervous system in sudden coronary death. Ann. NY Acad. Sci. 382: SCHWARTZ,
162-181,1982. 31. SCHWARTZ,
P. J.,
AND
M.
STRAMBA-BADIALE.
Parasympathetic
AND SURVIVAL
H69
nervous system and malignant arrhythmias. In: Neurocardiology, edited by H. E. Kulbertus and G. Frank. Mount Kisco, NY: Futura, 1988, p. 179-200. 32. SCHWARTZ, P. J., E. VANOLI, M. STRAMBA-BADIALE, G. M. DE FERRARI, G. E. BILLMAN, AND R. D. FOREMAN. Autonomic mechanisms and sudden death. New insights from the analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation 78: 969-979, 1988. 32a.VANOL1, E., G. M. DE FERRARI, M. STRAMBA-BADIALE, S. S. HULL, JR., R. D. FOREMAN, AND P. J. SCHWARTZ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ. Res. 68: 1471-1481, 1991. 33. VERRIER, R. L. Neurochemical approaches to the prevention of ventricular fibrillation. Federation Proc. 45, Suppl. 8: 2191-2198, 1986. 34. VERRIER, In: Sudden
R. L. Neural factors and ventricular electrical instability. Death, edited by H. E. Kulbertus and H. J. J. Wellens. The Hague: Nijhoff, 1980, p. 137-155. 35. VERRIER, R. L., AND B. LOWN. Behavioral stress and cardiac arrhythmias. Annu. Rev. Physiol. 46: 155-176, 1984. 36. WIT, A. L., AND M. R. ROSEN. Afterdepolarizations and triggered activity. In: The Heart and Cardiovascular System, edited by H. A. Fozzard, E. Haber, R. B. Jennings, A. N. Katz, and H. E. Morgan. New York: Raven, 1986, p. 1449-1490. 37. ZUANETTI, G., G. M. DE FERRARI, S. G. PRIORI, AND P. J. SCHWARTZ. Protective effect of vagal stimulation on reperfusion arrhythmias in cats. Circ. Res. 61: 429-435, 1987.
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ischemia
M. DE FERRARI, EMIL10 VANOLI, MARCO STRAMBA-BADIALE, S. HULL, JR., ROBERT D. FOREMAN, AND PETER J. SCHWARTZ
Department of Physiology and Biophysics, University of Oklahoma, Oklahoma City, Oklahoma 73190; Centro di Fisiologia Clinica e Ipertensione, Istituto di Clinica Medica II, Universita degli Studi di Milano, 20122 Milan; and Dipartimento di Medicina, Universita di Pavia, 27100 Pavia, Italy
DE FERRARI, GAETANO M., EMILIO VANOLI, MARCO 15, 32a, 34, 37). STRAMBA-BADIALE,~TEPHENS.HULL, JR., ROBERTD. FOREAlthough all these findings support the concept of a MAN, AND PETERJ. SCHWARTZ.Vagal reflexes and survival beneficial influence of vagal activity during myocardial
during
acute myocardial
ischemia
in conscious dogs with healed
myocczrdialinfarction. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H63-H69, 1991.- The role of vagal tone and reflexes in the genesisof life-threatening arrhythmias wasinvestigated in a clinically relevant animal model for sudden cardiac death. Forty-five dogswith a healedanterior myocardial infarction in which transient myocardial ischemia during exercise did not induce malignant arrhythmias were utilized for the study. They underwent a further exerciseand ischemiatest in which atropine (75 pg/kg) was injected before coronary artery occlusion. Novel occurrence of ventricular arrhythmia, or worsening of the type of arrhythmia present in the control test, occurred in 23 of 45 dogs(51%) and ventricular fibrillation occurred in 11 of 45 (24%, P = 0.001).Analysis of heart rate responseto acute ischemiain the control test indicates that these 11 animalshad powerful vagal reflexes during coronary artery occlusion, compared with the 34 survivors (-32 t 35 vs. +2 t 27 beats/min, P = 0.003). This study indicatesthat -75% of animalsresistant to ventricular fibrillation are characterized by weak sympathetic reflexes in responseto acute myocardial ischemia.In the remaining 25%powerful vagal reflexes counteract concomitant reflex sympathetic hyperactivity, decreaseheart rate, and are essentialfor survival. suddendeath; atropine; sympathetic reflexes
VAGAL TONE AND VAGAL REFLEXES may exert aprotec-
tive role against sudden cardiac death in the setting of ischemic heart disease (9, 31, 33). Depressed baroreflex sensitivity, largely a marker of reduced cardiac vagal efferent activity to the heart, is closely associated with risk of developing ventricular fibrillation during a transient episode of acute myocardial ischemia in dogs with a healed myocardial infarction (3, 32). Reduced heart rate variability, a marker of cardiac vagal tone, and depressed baroreflex sensitivity have been found to correlate with increased cardiac mortality in postmyocardial infarction patients. In these two clinical studies (16, 17) increased mortality was associated with signs of either reduced tonic vagal activity (16) or reduced capability to activate vagal reflexes (17). Conversely, vagal stimulation was found capable of preventing both ischemia- and reperfusion-induced life-threatening arrhythmias in anesthetized and in conscious animal preparations (6, 10,
ischemia, they do not provide direct evidence of the actual role of spontaneous vagal tone and reflexes. The objectives of the present study were to assess if they do indeed provide protection against ischemia-induced ventricular fibrillation and to investigate the parasympathetic reflex control of heart rate during acute myocardial ischemia in the conscious state. The experiments were conducted in a model for sudden cardiac death in which dogs with a healed myocardial infarction undergo a brief episode of myocardial ischemia while running on a treadmill (27). The high reproducibility of the outcome of this exercise and ischemia test, either ventricular fibrillation (susceptible animals) or survival (resistant animals), allows the use of each animal as its own control, thus avoiding the problem presented by group comparisons. In this study, the effects of muscarinic receptor blockade with atropine were investigated in a group of resistant dogs. METHODS
Mongrel study.
dogs weighing
15-25 kg were used for the
Surgical Preparation
Anesthesia was induced with thiopental sodium (Pentothal, Abbott Laboratories; 25 mg/kg iv) and was maintained by the inhalation of a halothane, nitrous oxide, and oxygen mixture. With aseptic procedures, a left thoracotomy was performed in the fourth intercostal space. The pericardium was opened, and the heart was suspended in a cradle. The left circumflex coronary artery was carefully dissected from surrounding epicardial fat, and both a 20 MHz continuous-wave Doppler flow transducer and hydraulic occluder were placed around the vessel. Insulated silver-coated copper wires were sutured to the epicardial surface of the right ventricle and atrium to record a bipolar electrogram and/or to pace the heart. A Tygon catheter was positioned in the aortic arch to record blood pressure. A Harris two-stage occlusion was performed on the left anterior descending coronary artery below the first
0363-6135/91 $1.50 Copyright 0 1991 the American Physiological Society
H63
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H64
VAGAL
REFLEXES
diagonal branch to produce a myocardial infarction. The vessel was partially occluded for 20 min and then tied completely. All lead wires were tunneled under the skin to exit from the dorsal surface of the neck. Pentazocine lactate (Talwin, Winthrop Laboratories, 30 mg im) was given approximately every 8 h for the first 24 h to control postoperative pain. We adhered to the guidelines of the American Heart Association on the care and treatment of experimental animals. Experimental Protocol
AND SURVIVAL
limb lead configuration. Baroreceptor reflex sensitivity was then assessed (32) and was expressed as the slope of the regression line relating R-R intervals to systolic arterial pressure changes. Infarct Size
Infarct size was assessed by a nitro blue enzymatic staining technique in 23 dogs (55%): 8 of the 11 dogs that developed ventricular fibrillation after atropine (73%) and 15 randomly chosen survivors. It was expressed in weight as a percentage of the left ventricle.
One month after production of myocardial infarction, the surviving animals performed a submaximal exercise stress test. The animals ran on a motor-driven treadmill for 12-M min while the work load increased every 3 min (4.8 km/h, 0% grade during the first 3 min; 6.4 km/h, 16% grade during the last 3-min period). At the beginning of the last minute of exercise, the left circumflex coronary artery was occluded; the treadmill was then stopped, and the occlusion was maintained for a second minute. Coronary occlusion was begun when either the animal completed 17 min of exercise or when heart rate had reached a level close to 210 beats/min. Completeness of occlusion was verified by the disappearance of the phasic blood flow velocity signal. Large steel plates were placed across the animal’s chest so that electrical defibrillation (American Optical, model 6217) could be performed with minimal delay. This exercise and ischemia test reproduces the protocol previously described (27). The timing was chosen to discriminate between arrhythmias related to exercise, to exercise combined with transient myocardial ischemia, to cessation of exercise, and to reperfusion. The dogs that did not show ventricular fibrillation during the control exercise and ischemia test represent the population of this study (n = 45). In these animals the exercise and ischemia test was repeated a few days later with the sole difference that atropine sulfate (75 pg/kg) was injected 2 min before coronary occlusion. The reproducibility of the arrhythmia pattern was assessed in a third exercise and ischemia test with no additional intervention, i.e., in a test identical to the control one. This was performed in all but one of the animals in which atropine had caused the appearance of malignant arrhythmias and in a randomly selected group of dogs (n = 20) in which no such effect had been noticed. In 7 of the 11 dogs in which atropine had caused the appearance of ventricular fibrillation, an additional exercise and ischemia test was repeated, keeping heart rate at the level reached during the atropine test by atria1 pacing.
Data Recording
Baroreceptor Reflex Testing
TABLE
Before baroreceptor reflex testing, the dogs were allowed to adapt to the laboratory for a few days to minimize any orienting response elicited by the new environment. A bipolar right atria1 electrogram and the surface electrocardiogram were recorded from the epicardial leads and from needle electrodes placed in the standard
During each exercise and ischemia test, recordings of flow velocity in the left circumflex coronary artery, arterial blood pressure, electrocardiograms, and heart rate were made on an eight-channel R 612 Beckman polygraph recorder. The signals were also recorded on a magnetic tape (Ampex FR-1300) for later analysis. Statistical Analysis
Statistical analysis was performed using two-way analysis of variance for repeated measures followed by t test, with Bonferroni correction when appropriate. A P < 0.05 was considered significant for the differences tested. Data are reported as means t SD. RESULTS
The study was performed in 45 dogs that had survived an exercise and ischemia test and were therefore defined as “resistant.” This group originates from an initial number of 157 dogs that underwent a myocardial infarction and were chronically instrumented. Of them, 61 (39%) either died in the first week after surgery or had a malfunction of the implanted instrumentation; of the 96 dogs that performed the exercise and ischemia test 51 developed ventricular fibrillation and were defined as “susceptible” and were assigned to other protocols. The remaining 45 resistant animals constitute the group under study. Heart Rate
Heart rate at different steps of the test is shown in Table 1. In the trials performed in control conditions, heart rate did not change significantly during the first 30 and 60 s of acute myocardial ischemia. After 2 min of ischemia, i.e., 1 min after cessation of exercise, heart rate had significantly decreased, as expected. In the trials performed with atropine, heart rate was similar to that of control condition both at rest and at 2 1. Heart rate Before Exercise
Before Atropine
Peak Exercise
60-s Occlusion
120-s Occlusion
Control 108t24 210t22 203k34 158t31 Atropine 107t24 207t24 230*21* 241+26t 214+34t Values are means t SD in beats/min; n, 45 dogs. * P < 0.01 vs. before atropine; t P < 0.01 vs. control.
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VAGAL
REFLEXES
AND
CONTROL
min before coronary artery occlusion, just before atropine injection. One min after atropine administration, heart rate rose significantly and was higher (P < 0.01) than in the control condition both after 30 and 60 s of coronary artery occlusion. Also, at the end of the coronary occlusion, i.e., 1 min after cessation of exercise, heart rate was higher than in the control trials. Analysis of these data indicates that atropine reversed the heart rate response to coronary occlusion; indeed, after 1 min of ischemia heart rate had increased by 10 t 19 beats/min compared with a decrease of 7 t 31 beats/ min observed in control condition (P c 0.05, Fig. 1).
H65
SURVIVAL
rk45
ATROPINE
Arrhythmias In the control trials, 39 animals (87%) were completely free of arrhythmia, 5 (11%) had few (40) isolated premature ventricular contractions, and just one had a single episode of three consecutive ventricular beats. In the atropine trials, 19 animals (42%) had no arrhythmia (P c 0.001 vs. control trial), 12 (27%) had isolated premature ventricular contractions, 3 (7%) had runs of ventricular tachycardia (range 6-30 beats), and 11 dogs (24%) had ventricular fibrillation. This latter arrhythmia occurred 75 t 19 s after the beginning of the occlusion (range 50-98 s), in four dogs shortly before the cessation of exercise, and in the remaining seven after stopping the treadmill. The arrhythmia exacerbation induced by atropine is clearly evident in Fig. 2, which shows the pattern observed in each individual dog. No change was present in one-half of the animals (22 of 45, 49%), whereas there was a worsening in 23 of 45 (51%). The overall survival (percent of animals not suffering ventricular fibrillation) decreased from 100 to 76% (P < 0.001, Fisher exact test). To confirm the reproducibility of the outcome, an additional test was nerformed in 30 animals in control +20
7 NO
ARR.
2. Effect of atropine on incidence of arrhythmias during exercise and ischemia test. In control conditions 1 animal had single episode of 3 consecutive premature ventricular beats and is assigned to ventricular tachycardia group (VT), 5 had scattered isolated premature ventricular contractions (40, PVC’s), and remaining had no arrhythmia (NO ARR). Atropine caused worsening in 23 of 45 dogs (51%). VF, ventricular fibrillation. FIG.
conditions (i.e., without atropine), as detailed in METHODS. In none of these 30 dogs did ventricular fibrillation or tachycardia occur. Thus the occurrence of arrhythmias after atropine administration cannot be ascribed to spontaneous increase in susceptibility. Pacing In 7 of the 11 dogs that had ventricular fibrillation in the atropine trial, another exercise and ischemia test was performed while heart rate was maintained, by atria1 pacing, at the same level attained during the atropine test. In five of these seven animals (71%) ventricular fibrillation developed again, as shown in Fig. 3, whereas no arrhythmias were observed in two dogs (29%).
* 10
A HR
NO ARR.
0
b/min
Survival and Ventricular Fibrillation
10
-20 Before
CA0
lmin
CA0
FIG. 1. Heart rate (HR) response to coronary artery occlusion (CAO) performed during exercise and ischemia test. In the test with atropine administration, slight but significant heart rate increase is observed, compared with modest decrease in control condition. Open circle, 210 k 3 beats/min; closed circle, 230 t 3 beats/min. Data are expressed as means k SE; n, 45 dogs. * P < 0.05.
The 11 animals in which atropine caused the occurrence of ventricular fibrillation will be called hereafter “VF group,” and the 34 dogs that, despite atropine, survived also the second exercise and ischemia test will be called “survivors.” The VF group and the survivors represent two different subgroups and were analyzed separately. When the VF group and the survivors were compared in the second exercise and ischemia test during which atropine was administered before coronary occlusion, heart rate was found to be similar at rest (108 t 23 vs. 109 t 26 beats/min), at peak exercise (205 t 22 vs. 208 t 20 beat s/ min), and after atropine administration (225 t 19 vs. 233 t 23 beats/min). Also, there was no
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H66
VAGAL
REFLEXES
AND
SURVIVAL
CONTROL HR
157
b/min
t ATROPINE
\
HR 248
A
\\ \
HR
\
\
PACING HR
\
246
\
t 60 soc
CA0
- and
of
OX-
\ \
18OC
3. Electrocardiographic tracings of 1 dog during subsequent exercise and ischemia tests. Arrow indicates end of first minute of coronary artery occlusion when treadmill is stopped. During atropine test (middle) rapid ventricular tachycardia that degenerates into ventricular fibrillation occurs. Further exercise and ischemia test was then performed (bottom) without atropine, keeping heart rate at same level reached with atropine by means of atria1 pacing. In this condition ventricular tachycardia and fibrillation occurred again.
--cl
\
\ t
T
-a--
-e--
- ----
O-'-c
75 Mg/Kg
\
difference in the response to myocardial ischemia: heart rate increased 17 t 21 beats/min after 60 s in the VF group vs. 8 t 18 beats/min in the survivors. By contrast, analysis of the exercise and ischemia test in control conditions, i.e., without atropine, revealed an unexpected and interesting difference. Heart rate was similar at rest (107 t 21 and 110 t 25 beats/min) and at peak of exercise (208 t 12 and 210 t 23 beats/min) but had a strikingly different response to coronary occlusion. Indeed, the VF group, after onset of ischemia and despite continuation of exercise, showed a significant heart rate reduction that was absent among survivors (-32 t 35 vs. +2 t 27, P = 0.003; Fig. 4). Baroreflex
Sensitivity
To ascertain whether this pattern of more powerful vagal reflexes observed in the VF group characterized these animals also at rest and without myocardial ischemia, we analyzed their baroreceptive reflex sensitivity. The one-sided hypothesis was tested that these dogs would have greater baroreceptor sensitivity slopes. This proved to be correct; indeed, within these 45 resistant dogs, the animals that developed ventricular fibrillation after atropine had a higher baroreceptor sensitivity compared with the survivors (19.6 t 9.4 vs. 14.4 t 6.3 ms/ mmHg, P = 0.027).
Before
4. Heart rate (CAO) during control ventricular fibrillation heart rate that was not min; triangle, 208 t 4
CA0
VF with Atropine n=ll
\
FIG.
FIG.
No VF with Atropine k34
lmin
\
CA0
(HR) response to coronary artery occlusion exercise and ischemia test. Dogs that develop (VF) in atropine test show marked decrease in observed in other dogs. Square, 210 * 4 beats/ beats/min. Data are expressed as means & SE.
* P = 0.003. TABLE
2. Mean blood pressure
Control Atropine
Before Exercise
Before Atropine
Peak Exercise
60-s Occlusion
120-s Occlusion
98t12 98t13
109t15
112t14* 111&18*
76t18t 81-r-22-f
83t20t 102&20?$
Values are means t SD in mmHg; exercise; t P < 0.01 vs. peak exercise;
n, 45 dogs. * P < 0.05 vs. before $ P c 0.05 vs. control test.
mia test it declined significantly 1 and 2 min after ischemia. Blood pressure values were not influenced by atropine during exercise; during myocardial ischemia, blood pressure did not differ at 60 s but was higher in the atropine trial after 120 s of ischemia. Mean blood pressure values were similar comparing the VF group and the survivors, before and after coronary artery occlusion. Just before coronary occlusion, blood pressure tended to be higher in the survivors [113 t 20 vs. 102 t 9 mmHg; not significant (NS)], but the mean blood pressure decrease after 60 s of ischemia was comparable in the two groups (-24 t 21 in the survivors vs. -32 + 18 mmHg in the VF group; NS). In the trials with pacing at the heart rate levels attained in the atropine tests, blood pressure did not differ. DISCUSSION
Infarct
Size
Infarct size was 12.0 t 4.1% of the left ventricle and was similar in the VF group and in the survivors (12.6 t 4.5 vs. 11.7 t 4.0%). Blood Pressure
Mean blood pressure at different steps of the test is shown in Table 2. During the control exercise and ische-
The main goal of this study was to assess whether vagal tone and reflexes do provide protection against ischemia-induced ventricular fibrillation in a clinically relevant animal model. The results show that, among dogs resistant to sudden death, muscarinic blockade caused a worsening in the arrhythmia in 51% of the animals and the occurrence of ventricular fibrillation in 24%. Therefore, the ability to activate vagal reflexes was
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VAGAL
REFLEXES
found to be essential for the survival of -25% of animals. Analysis of the effect of atropine on heart rate during exercise and ischemia disclosed an unexpected finding on the autonomic balance and reflexes in the animals that survived and in those that did not; namely, the animals that developed ventricular fibrillation were those with the more pronounced vagal reflexes in control conditions. Atropine
and Lethal Arrhythmias
AND
SURVIVAL
H67
with that (71%) of the present study. These combined data indicate that -50% of the protective effect is independent of a heart rate change. Similar conclusions can be drawn from a different experimental model that also combines acute ischemia and sympathetic hyperactivity as triggers for malignant arrhythmias (ll), in which the antiarrhythmic efficacy of the muscarinic agonist oxotremorine was only partially mediated by the heart rate effects. Electrophysiological effects. Parasympathetic activity may influence the electrophysiological properties at ventricular level (1, 5, 9, 33, 34). This influence may counteract both automatic and reentrant arrhythmia mechanisms (31), and its removal by atropine has presumably contributed to the results of this study. Vagal effects on ventricular electrophysiology are largely mediated by an antiadrenergic mechanism (1, 9, 34). Nonetheless, data exist at experimental (24) and at clinical levels (25) that suggest direct electrophysiological effects, possibly more marked at the epicardial level (19).
At variance with the wide acceptance of the detrimental effects of sympathetic activation during acute myocardial ischemia (9, 20, 21, 28, 30) the effects of either surgical or pharmacological parasympathetic blockade are unclear. The available data suggest differences according to species and site of coronary artery occlusion. Vagotomy increases the incidence of ventricular fibrillation during acute anterior myocardial ischemia in the cat (7) but not in the dog (12). Atropine is detrimental after occlusion of the left anterior descending (7, 14) but not of the circumflex coronary artery (8, 18). In the Survival vs. Ventricular Fibrillation present study, arrhythmia worsening and novel occurThe effect of atropine on the occurrence of arrhythrence of life-threatening arrhythmia after atropine indimias, although present in 51% of the animals, was quite cate that the presence of adequate vagal tone and reflexes deleterious in 24% as manifested by the development of has an important role in reducing the incidence of sudden ventricular fibrillation. Possible causes of distinction death during acute myocardial ischemia. This worsening between the VF group and the survival group include occurred during circumflex coronary occlusion at variof the previous myocardial infarction, degree of ance with the previous studies. This discrepancy may be extent acute myocardial ischemia, and a different neural redue to three characteristics unique to our experimental sponse to coronary occlusion. model: conscious state, high sympathetic background, Infarct size did not differ in the two groups. The size and presence of a previous anterior myocardial infarcof the acutely ischemic area after circumflex coronary tion. artery occlusion during exercise was not measured. It is The mechanism of the deleterious influence of atropine entirely possible that the different effect of atropine in depends primarily on its heart rate effect and on the the two groups of animals may have resulted from a electrophysiological effect at the ventricular level. larger ischemic area in the VF group. It is conceivable Heart rate. The detrimental effect of elevated heart that among the survivors, those more dependent for rate is supported by several lines of evidence. First, heart protection on vagal hyperactivity would be the ones with rate is a major determinant of myocardial oxygen de- a larger ischemic area and an increased tendency to left mand. In fact, higher heart rates are accompanied by ventricular dysfunction during coronary artery occlusion. greater degrees of myocardial ischemia during acute cor- They would be more vulnerable to muscarinic blockade onary artery occlusion in anesthetized (22) and conscious and to the increase in myocardial oxygen demand caused (26) dogs. Second, both triggered (36) and reentrant (13) by the attendant increase in heart rate. arrhythmias are facilitated by elevated heart rates. InThe reflex heart rate response during the control exdeed, during acute myocardial ischemia in anesthetized ercise and ischemia test was markedly different between dogs, both ventricular fibrillation threshold (15) and the VF group and the survivors. This was an unexpected actual occurrence of ventricular tachycardia and fibriland critical finding of the present study. In the first lation (4) are worsened by heart rate increases. minute of ischemia the VF group had a more powerful The occurrence of ventricular fibrillation in 71% of parasympathetic activation directed to the sinus node the animals during pacing indicated that the increase in (-32 + 35 vs. +2 t 27 beats/min). This tendency for heart rate as well as the abolition of the reflex decrease strong vagal reflexes in these animals was not confined during myocardial ischemia played a major role in the to myocardial ischemia. Indeed, they also had higher deleterious effect of atropine. values of baroreflex sensitivity, suggesting accentuated Two recent sets of observations suggest that the an- vagal responses to different pathophysiological stimuli. tiarrhythmic effect of vagal activation is not exclusively Atropine interfered with these prominent vagal reflexes dependent on the reduction in heart rate. In this same and unmasked the electrical vulnerability of this group experimental model, electrical stimulation of the vagus during myocardial ischemia. has a striking antifibrillatory effect in susceptible animals (10, 32a); moreover, the data with atria1 pacing Susceptible and Resistant: Animal Model indicate that protection from ventricular fibrillation was These experiments were performed in a conscious andependent on heart rate decrease in four of nine animals imal model for sudden cardiac death, developed in our (44%), a percentage not significantly smaller compared Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 6, 2018. Copyright © 1991 American Physiological Society. All rights reserved.
H68
VAGAL
REFLEXES
laboratory (27). The protocol includes three factors known to be important in the genesis of life-threatening arrhythmias: a healed myocardial infarction, an episode of acute myocardial ischemia, and sympathetic activity physiologically elevated by exercise. We suggested (3) and then confirmed in 192 dogs (32) that vagal refle xes are predominant, among resistant ani mals, during acute ischemia and in response to a blood pressure increase, whereas sympathetic reflexes predominate among susceptible animals. Resistant animals had a baroreflex sensitivity of 17.8 t 6.6 vs. 9.1 t 6.0 ms/mmHg in susceptible. Previous studies have suggested absence of hemodynamic differences between these two groups at rest, but a tendency toward a greater systolic dysfunction during exercise in the susceptible group (2). The present study further explores the autonomic balance at the level of the sinus node in resistant dogs. Muscarinic blockade allows two principal considerations. First, vagal tone still contributes to heart rate control during submaximal exercise, as shown by the significant heart rate increase after atropine. Second, atropine unmasks a significant sympathetic activation in response to ischemia. This is indicated by the reversal in heart rate response to coronary artery occlusion (a mean of +lO vs. -7 beats/min in control condition). Thus the heart rate response in the entire group results from activation of moderate and contrasting autonomic reflexes. The parasympathetic component is slightly dominant.
AND SURVIVAL K. D., V. S. BANKA, AND R. H. HELFANT. Rate dependent ventricular ectopia following acute coronary occlusion. Circulation
4. CHADDA,
49: 654-659, 1974. 5. CHANDRASEKARAN, K., B. J. SCHERLAG, E. J. BERBARI, HARRISON, K. FRIDAY, W. M. JACKMAN, AND R. LAZZARA.
L. A. Cholinergic effects on electrophysiology of ischemic myocardium and arrhythmias (Abstract). J. Am. CoZZ.Cardiol. 3: 476, 1984. CORR, P. B., AND R. A. GILLIS. Effect of autonomic neural influences on the cardiovascular changes induced by coronary occlusion. Am. Heart J. 89: 766-774, 1975. CORR, P. B., AND R. A. GILLIS. Role of the vagus nerves in the cardiovascular changes induced by coronary occlusion. Circulation 49: 86-97, 1974. CORR, P. B., D.
10.
11.
12.
13.
14.
Conclusions
In this clinically relevant animal model for sudden cardiac death, vagal tone and reflexes contribute significantly to the protection from ventricular fibrillation. Whereas for -75% of the animals resistant to sudden death the key factor is represented by the absence of major sympathetic activation, in 25% of them myocardial ischemia activates powerful vagal reflexes that decrease heart rate and myocardial oxygen demand, counteract concomitant sympathetic hyperactivity, and are essential for survival. We are grateful to G. Stout and R. Fitts for technical assistance, to Dr. G. E. Billman for help in performing some of the initial experiments, to C. Zanchetti and R. Sarri for assistance in preparing the figures, and to G. De Tomasi for secretarial support. This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-33727. Address for reprint requests: P. J. Schwartz, Istituto di Clinica Medica II, Via F. Sforza 35, 20122 Milan, Italy. Received 7 May 1990; accepted in final form 1 March 1991.
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