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Experimental study on ventricular extrasystoles provoked by vagal stimulation
Experimental provoked
study by vagal
on ventricular
extrasystoles
stimulation
David Scherf, M.D. Serge Blumenfeld, M.D. Muhtar Yildiz, M.D. New York, N. Y.
C
arotid sinus pressure occasionally leads to the appearance of extrasystoles. They can be elicited and registered electrocardiographically in some patients during or shortly after carotid sinus pressure, thus confirming a clinical diagnosis. Both experimentally and clinically these ectopic beats are most often of ventricular origin. This is of interest since vagus fibers are said to be nonexistent in the ventricles, and vagal effects on the ventricles of the mammalian heart are generally absent. Investigations with the myocardiograph of Cushny3 and measurements of intraventricular pressure u showed no effect of vagal stimulation on cardiac contractility. An experimental study of the effect of vagal stimulation on ventricular extrasystoles was undertaken on dogs in 1929.“” A solution of aconitine in distilled water was injected intravenously. Before anychange in rate, rhythm, or form of the complexes was noticeable, vagal stimulation regularly elicited the appearance of a bigeminal ventricular rhythm. When the bigeminal rhythm was well established, stimulation of the vagus led to an increase in the number of ectopic beats after ;I normal complex. This effect was immediate ill1 d reproducible. However, it was not possible to generalize from these experiFrom the Department of Medicine, New York This study was supported in part by Grant Received for publication April 10, 1961.
670
ments, since aconitine extrasystoles showed “paradoxical” response to other measures. They disappeared promptly on sympathetic stimulation, and their number increased under the influence of choline or potassium. In view of these findings, we undertook the study of the effect of vagal stimulation on ventricular extrasystoles provoked by other substances. In experiments in which a 20 or 30 per cent solution of sodium chloride was applied focally to the ventricle of the exposed heart of the dog a paroxysmal ventricular tachycardia appeared, which originated in the treated area.rg The decision was made to study the effect of vagal stimulation on these extrasystoles. Method Dogs which weighed between 10 and 15 kilograms were anesthetized with intraperitoneal sodium pentobarbital (1X mg./Kg.) and morphine (8 mg./Kg.). The chest was opened after artificia1 respiration had been instituted, and the heart was exposed. The right vagus was attached to a shielded electrode. Injection of 0.01 c.c. of a 20 per cent solution of sodium chloride was made into a small area near the surface of the right or left ventricle. The ECG was registered in Lead II.
Medical College. New York. N. Y. H-230 from the National Heart Institute,
II. S. Public
Health
Service=.
Ventricular
extrasystoles
Results In most experiments there was an immediate ventricular tachycardia. This generally subsided within 1 or 2 minutes. To avoid the period during which chance recurrence of the tachycardia was likely, vagal stimulation was not applied during the first 2 or 3 minutes after injection of the salt solution. In some experiments no tachycardia developed after the application of sodium chloride, and in such cases the vagal stimulation elicited the arrhythmia. In most experiments the effects were reproducible. Thus, the effect of vagal stimulation seen in Fig. 1 could be elicited five additional times. About 8 to 10 minutes after the end of the tachycardia, vagal stimulation failed to provoke extrasystoles. Fig. 1 was obtained in an experiment in which an attempt was made to inject the solution of sodium chloride into the area of t-he atrioventricular node near the coronary sinus vein. This resulted at first in a ventricular tachycarclia which was caused by some of the sodium chloride reaching the base of the right ventricle (Fig. 1 ,A). After the tachycardia ended, an atrioveutricular rhythm without extrasystoles appeared. Vagal stimulation (Fig. 1,B) inhibited this rhythm and elicited groups of bigeminy and trigeminy with the same extraqstoles which caused the preceding ventricular tachycardia (Fig. l&D). After eleven such groups, atrioventricular rhythm and sinus rhythm reappeared. Renewed vagal stimulation had the same result. An important fact in these experiments is that the interval between the extrasystoles caused by vagal stimulation is very short (Fig. 2). In this experiment the interval measures 0.16 second, which corresponds to a heart rate of 375 beats per minute. Here, as in other experiments, the extrasystoles disappeared immediately after the end of the stimulation. These characteristics rule out the possibility that these extrasystoles could have been ectopic beats which escaped from the lower centers because of the slowing of the heart. The coupling in our experiments was so short that they could have appeared even if the heart rate had not decreased during vagal stimulation. Fig. 3, obtained in the course of another
provoked by vagal shulation.
6il
experiment, showed the appearance of multiple extrasystoles during vagal stimulation. The extrasystoles caused by the application of sodium chloride without vagal stimulation never exhibited this rapid rate; they would beat at about 180 per minut-e, whereas after vagal stimulation the rate could become very much faster. In Fig. 3 the interval between the second and third extrasystoles is 0.12 second, corresponding to a rate of 500 beats per minute. In Fig. 4 the extrasystoles brought out by. vagal stimulation appeared in groups.‘k Pairs of ectopic beats are separated by. pauses of variable duration. After the end of vagal stimulation at the beginning of Fig. 4,B there are multiple extrasvstoles coupled to the sinus beats. Agairl in this instance the interectopic interval and the coupling are such that the abnormal beats could have appeared even if the heart hatI not been slowed by vagal stimulation. The same rapid rate of extrasystoles is again in evidence in Fig. 5 after vagal stinulation. In this experiment, we see left ventricular extrasystoles as the sodiunr chloride was applied to the left ventricle. This effect of vagal stimulation was observed in 11 out of 24 experiments. Discussion The results of these experiments show that extrasystoles caused by focal administration of hypertonic sodium chloride reappear during vagal stimulation, usually with a much faster rate. Whereas aconitine extrasystoles which were elicited in a similar manner persisted for a long time after cessation of the vagal stimulation, the extrasystoles in the present experiments disappeared immediately or within a few seconds, There is no doubt that we are dealing with true extrasystoles, that is, with beats elicited by the previous beat. Previous experimental studies on the effect of vagal stimulation and vagal reflexes on the appearance of extrasystoles are discussed elsewherez5 and will therefore not be analyzed here. We stress only the investigations of Hering, Heymans and SchottS6 on carotid sinus stimulation and extrasystoles in the rabbit. Ventricular extrasystoles may appear or disappear during vagal stimulation, and, in a previous
672
Scherf, Blumenfeld,
and E’ildiz
Fig. 1. A shows a ventricular tachycardia which appeared after the injection of 0.05 C.C. of a 20 per cent solution of sodium chloride into the posterior aspect of the right ventricle near the atrioventricular groove. The rate is 17.5 beats per minute. After the end of this tachycardia an atrioventricular rhythm appeared. figal stimulation slowed the rate, and sinus rhythm soon reappeared, with estrasystoles which followed the preceding sinus beat after a coupling of 0.36 to 0.40 second. The estrasystoles disappeared after a few seconds, but reappeared in the same manner during five consecutive stimulations.
Fig. 2. A and B are continuous tracings. *-I shows a sinus tachycardia of 166 beats per minute. Vagal stimulation leads immediately to the appearance of ventricular estrasystoles in the form of trigeminal groups. The extrasystoles disappear immediately after the end of the stimulation (last part of B). The first extrasystole appears after a coupling of 0.38 second. It varies in the other beats, and is only 0.16 second in A. The distance between two extrasystoles is as short as 0.16 second, which corresponds to a rate of 375 beats per minute.
report, we demonstrated the reappearance of a ventricular tachycardia upon such stimulation after the application of a 30 per cent solution of sodium chloride to the surface of the ventricle.‘” Vagal stimulation in the dog elicited similar rapid extrasystoles without premedication, at least in one experiment,13 and similar bursts of rapid extrasystoles have been seen in man during compression of the carotid sinus region2’
Textbooks generally state that carotid sinus pressure is of no effect in ventricular tachycardias. Although this is usually true, there is a well-documented observation reported by Wenckebach and Winterberg,“Y in which a ventricular tachycardia could be stopped by carotid pressure. In another study,20 mechanical irritation of the respiratorv tract caused the appearance of ventricular extrasystoles. Carotid pressure or eyeball pressure could pro-
Ventricular
extrasysloles
voke groups of rapid ventricular extrasystoles,g~*“~14 or abolish them if they were already present.’ Even such substances as calcium or potassium will cause or abolish extrasystoles, depending on the condition of the experiment. AA stimulating effect of the vagus on ventricular extrasystoles was observed in the dog after intravenous injection of digitalis and after administration of calcium chloride.ll IT7hen a solution of sodium
Fig. 3. There systoles with the preceding
provoked by zlugal stimuhtion
673
chloride is applied to the atria, vagal stimulation leads regularly to atria1 fibrillation.“” Vagal effects on ventricular impulse formation and ventricular conduction have been reported in several older observations. Erlanger observed a slight chronotropic effect of vagal stimulation during heart block, and this was confirmed.‘0~‘7 I8 In man, the injection of a choline ester, carbamylcholine chloride, was shown to slow the ectopic rhythm in parasystole,4 and
is a sinus tachycardia with a rate of 214. Vagal stimulation leads to a burst of ventricular extraa rate up to 500 per minute. After this burst, coupled beats appear, following after 0.20 second automatic beat. The first estrasystole follows the preceding sinus beat after 0.40 second.
Fig. ?. \‘agal stimulation in this experiment caused the appearance of estrasystoles in groups. After the end of the vagal stimulation (lirst third of I?), coupled extrasystoles appear, followed by sinus rhythm with an occasional atrial extrasystole. The two tracings are continuous.
Fig. 5. In this experiment the solution of sodium chloride stimulation elicited left ventricular extrasystoles with rapid
had beeu rates.
applied
to the left
ventricle.
Here
vagal
674
Sckerf, Blumenfeld,
.4m. Hcavt 1. \~‘owmbcr, 1961
and E’ild iz
we have repeatedly observed the slowing of parasystolic ventricular centers by carotid pressure. The influence of carotid pressure on bundle branch block has been discussed by Dressier.” The mechanism of the appearance of ventricular extrasystoles during vagal stinulation is not clear. This same phenomenon in the aconitine experiments was explained by the release of acetylcholine in the atria, which led in a sensitized ventricle to an abnormal response to the minute amounts of acetylcholine reaching it.22 Acetylcholine reduces the resistance of membranes and increases their permeability for potassium.“q This may facilitate the appearance of afterpotentials and, therefore, of extrasystoles. It may be stated in objection to this that extrasystoles are related to changes in rate which result from vagal stimulation, but in Figs. 2 and 3, as well as in several other experiments, the change in rate, the duration of diastole preceding the first extrasystole, was so small that this mechanism is highly improbable. On the other hand, the extrasystoles appear so early after the onset of the vagal stimulation that the amount of acetylcholine reaching the ventricles from the atria can only be very small. The complete absence of vagal fibers in the mammalian heart has recently been denied.15J6 It is possible that such fibers, abundant in the lower classes of animals, do appear occasionally as an inherited anomaly. The extrasystoles in the present series of experiments are centainly not provoked by the stimulation of sympathetic fibers which are said to be found occasionally in the vagus nerve. Against this interpretation speaks their appearance without any latent period immediately after the onset of the vagal stimulation. The extrasystoles which appeared during vagal stimulation had, as the illustrations show, the same configuration as that of the extrasystoles which were provoked by the application of sodium chloride. They came from the same focus. Minor differences in form are caused by the differences in rate. The rapid rate of these extrasystoles is noteworthy. It was much higher than that observed in extrasystoles caused by focal application of digitalis, strophanthin, so-
dium chloride, sodium citrate, or oxalate and veratrine. The extrasystoles described in the present study follow each other so quickly that it seems possible that one extrasystole appearing during the vulnerable period may lead to ventricular fibrillation and sudden death. Summary
Ventricular extrasystolic tachycardias were provoked by focal application of a hypertonic solution of sodium chloride on the exposed heart of the dog. After these extrasystoles subsided, faradic stimulation of the right vagus nerve made them reappear. This effect was reproducible. The extrasystoles which were observed during vagal stimulation were identical with those which appeared after the application of sodium chloride. A characteristic feature of these extrasystoles was their unusu;dl?; high rate. 1.
2.
\1
4.
5.
6.
7.
8.
9.
10.
11.
Cope,R.
L.: Suppressive effect of carotid sinus stimulation on premature ventricular beats in c.crtain instances, Am. J. Cardiol. 4:314, 1959. Dressier, W. : Transient bundle branch block occurring during slowing of the heart beat and following gagging, AM. HEART J. 58:760, 1959. Drur)-, A. S.: The influence of vagal stimulation upon the force of contraction and the refractory period of ventricular muscle in the dog’s heart, Heart 10:405, 1923. Eckey, P.: ITntersuchungen zur Frage der Extrasystolenentstehung durch Interferenz zweier Rhythmen, -Deutsches Arch. klin. Med. 181:229. 1937. Erlanger, J.: i;ber den Grad der Vaguswirkung auf die Kammern des Hundeherzens, Pfliigers Arch. ges. Physiol. 127:77, 1909. Golbey, M., Ladopoulos, C. P., Roth, F. H., and Scherf, D.: Changes of ventricular impulse formation during carotid sinus pressure in man, Circulation 10:735, 1954. Hering, H. E.: iiber das Alusloesen oder Beseitigen heterotoper Herzschl%ge beim Karotisdruckversuch, Wien. Arch. inn. Med. 10:497, 1925. Heymans, C., Bouckaert, and Regniers, P.: Le sinus carotidien et la zone homologue cardioaortique, Paris, 1933, Doin et Cie. Hollander, W., and Entwistle, G.: Transient ventricular tachycardia following the Valsalva maneuver in a patient with paroxysmal atria1 tachycardia, AM. HEART J. 52:799, 19.56. Jourdan, F., and Froment, K.: Le rythme idio-ventriculaire experimental, tchappe-t-i1 Q tout controles de nerfs vagues? Compt. rend. Sot. Biol. 125:915, 1937. Kobacker, J. L., and Scherf,D.: \‘ersucheiiber
~~‘ohtme
b.!
Ntcmber
5
12.
13. l-1.
1.5.
16.
17.
18.
19.
20.
T’entriculur
extrasystolcs
die Entstehung der Digitalis Extrasystolen, Ztschr. ges. exper. Med. 67:372, 1929. Landman, M. E., and Ehrenfeld, I.: \,.entricular fibrillation following eyeball pressure in a case of paroxysmal ventricular tachycardia, AM. HEART J. 43:791, 1952. Lewis, T.: The effect of vagal stimulation upon atrioventricular rhythm, Heart S:247, 1914. Meredith. H. C.. and Beckwith. I. R.: Devrelopment of ventricular tachycardia following carotid sinus stimulation in supraventricular tachycardia, AM. HEART J. 39:604, 1950. Mitchell, G. A. G.: Cardiovascular innervation, Edinburgh and London, 1956, Livingstone, Ltd. Mitchell, G. A. G., Brown, R., and Cookson, F. B.: Ventricular nerve cells in mammals, Nature 172:812, 19.53. Pekar, M., and Lelkes, Z.: Einfluss der Vagusreizung auf den idioventricularen Rhythmus, Pfliigers Arch. ges. Physiol. 238:66, 1936. Puddu, V.: Beitrage zur Kenntnis der Herz nervenwirkung, Pfliigers Arch. ges Physiol. 238:467, 1936. Piccione, F. V., and Scherf, D.: The rhythmic formation of coupled beats and paroxysmal tachycardias in the outer layers of the myocardium, Bull. New York M. Coll. 3:83, 1940. Reid, C. C., and Brace. D. E.: Irritation of the respiratory tract and its reflex effect upon the heart, Surg. Gynec. & Obst. 70:157, 1940. I
provoked by eqnl
21.
stimulatio~z
67.5
Rothberger, C. J., and Scherf, D.: \Virkt der Vagus auf die Kontraktionsstaerke der Kammerns des Saugetierherzens, Ztschr. ges. exper. Med. 71:274, 1930. 22. Scherf, D.: Zur Entstehungsweise der Extrasystolen und der extrasystolischen Allorhythmien, Ztschr.. ges. exper. Med. 51:816, 1929. 23. Scherf. D.. Blumenfeld. S.. Yildiz. M.. anti Duplessy, M. T.: Focal application of hypertonic solutions of sodium chloride on impulse formation in the heart of the dog, AM. HICARY J. 57:383, 1959. 24. Scherf, D., and Romano, F. J.: Extrasystoles in groups, -4~. HEART J. 35:81, 1948. 2.5. Scherf, D., and Schott, A.: Extrasystoles and allied arrhythmias, New York, 1953, Grune & Stratton, Inc. 26. Scott, A.: Zur Frage der heterotopen =Irrhythmien durch Carotidenabklemmung, Pfliigers Arch. ges. Physiol. 23451, 1934. 27. Schott. A.: Behandlung von Vorhofflattern und-flimmern, Verhandl. Deutsch. Ges. Kreislaufforsch. 26:224, 1960. 28. ‘l‘rautwein, W., and Dudel, J.: Zum Mechanism der Membranwirkung des Acetylcholins an der Herzmuskelfaser. Pfliirrers Arch. ., pes. I’hvsiol. 266:324, 1958. 29. Wenckebach, K. F., and VVinterberg, H.: Die unregelmassige Herztatigkeit, Leipzig, 1927, Engelmann. I
study by vagal
on ventricular
extrasystoles
stimulation
David Scherf, M.D. Serge Blumenfeld, M.D. Muhtar Yildiz, M.D. New York, N. Y.
C
arotid sinus pressure occasionally leads to the appearance of extrasystoles. They can be elicited and registered electrocardiographically in some patients during or shortly after carotid sinus pressure, thus confirming a clinical diagnosis. Both experimentally and clinically these ectopic beats are most often of ventricular origin. This is of interest since vagus fibers are said to be nonexistent in the ventricles, and vagal effects on the ventricles of the mammalian heart are generally absent. Investigations with the myocardiograph of Cushny3 and measurements of intraventricular pressure u showed no effect of vagal stimulation on cardiac contractility. An experimental study of the effect of vagal stimulation on ventricular extrasystoles was undertaken on dogs in 1929.“” A solution of aconitine in distilled water was injected intravenously. Before anychange in rate, rhythm, or form of the complexes was noticeable, vagal stimulation regularly elicited the appearance of a bigeminal ventricular rhythm. When the bigeminal rhythm was well established, stimulation of the vagus led to an increase in the number of ectopic beats after ;I normal complex. This effect was immediate ill1 d reproducible. However, it was not possible to generalize from these experiFrom the Department of Medicine, New York This study was supported in part by Grant Received for publication April 10, 1961.
670
ments, since aconitine extrasystoles showed “paradoxical” response to other measures. They disappeared promptly on sympathetic stimulation, and their number increased under the influence of choline or potassium. In view of these findings, we undertook the study of the effect of vagal stimulation on ventricular extrasystoles provoked by other substances. In experiments in which a 20 or 30 per cent solution of sodium chloride was applied focally to the ventricle of the exposed heart of the dog a paroxysmal ventricular tachycardia appeared, which originated in the treated area.rg The decision was made to study the effect of vagal stimulation on these extrasystoles. Method Dogs which weighed between 10 and 15 kilograms were anesthetized with intraperitoneal sodium pentobarbital (1X mg./Kg.) and morphine (8 mg./Kg.). The chest was opened after artificia1 respiration had been instituted, and the heart was exposed. The right vagus was attached to a shielded electrode. Injection of 0.01 c.c. of a 20 per cent solution of sodium chloride was made into a small area near the surface of the right or left ventricle. The ECG was registered in Lead II.
Medical College. New York. N. Y. H-230 from the National Heart Institute,
II. S. Public
Health
Service=.
Ventricular
extrasystoles
Results In most experiments there was an immediate ventricular tachycardia. This generally subsided within 1 or 2 minutes. To avoid the period during which chance recurrence of the tachycardia was likely, vagal stimulation was not applied during the first 2 or 3 minutes after injection of the salt solution. In some experiments no tachycardia developed after the application of sodium chloride, and in such cases the vagal stimulation elicited the arrhythmia. In most experiments the effects were reproducible. Thus, the effect of vagal stimulation seen in Fig. 1 could be elicited five additional times. About 8 to 10 minutes after the end of the tachycardia, vagal stimulation failed to provoke extrasystoles. Fig. 1 was obtained in an experiment in which an attempt was made to inject the solution of sodium chloride into the area of t-he atrioventricular node near the coronary sinus vein. This resulted at first in a ventricular tachycarclia which was caused by some of the sodium chloride reaching the base of the right ventricle (Fig. 1 ,A). After the tachycardia ended, an atrioveutricular rhythm without extrasystoles appeared. Vagal stimulation (Fig. 1,B) inhibited this rhythm and elicited groups of bigeminy and trigeminy with the same extraqstoles which caused the preceding ventricular tachycardia (Fig. l&D). After eleven such groups, atrioventricular rhythm and sinus rhythm reappeared. Renewed vagal stimulation had the same result. An important fact in these experiments is that the interval between the extrasystoles caused by vagal stimulation is very short (Fig. 2). In this experiment the interval measures 0.16 second, which corresponds to a heart rate of 375 beats per minute. Here, as in other experiments, the extrasystoles disappeared immediately after the end of the stimulation. These characteristics rule out the possibility that these extrasystoles could have been ectopic beats which escaped from the lower centers because of the slowing of the heart. The coupling in our experiments was so short that they could have appeared even if the heart rate had not decreased during vagal stimulation. Fig. 3, obtained in the course of another
provoked by vagal shulation.
6il
experiment, showed the appearance of multiple extrasystoles during vagal stimulation. The extrasystoles caused by the application of sodium chloride without vagal stimulation never exhibited this rapid rate; they would beat at about 180 per minut-e, whereas after vagal stimulation the rate could become very much faster. In Fig. 3 the interval between the second and third extrasystoles is 0.12 second, corresponding to a rate of 500 beats per minute. In Fig. 4 the extrasystoles brought out by. vagal stimulation appeared in groups.‘k Pairs of ectopic beats are separated by. pauses of variable duration. After the end of vagal stimulation at the beginning of Fig. 4,B there are multiple extrasvstoles coupled to the sinus beats. Agairl in this instance the interectopic interval and the coupling are such that the abnormal beats could have appeared even if the heart hatI not been slowed by vagal stimulation. The same rapid rate of extrasystoles is again in evidence in Fig. 5 after vagal stinulation. In this experiment, we see left ventricular extrasystoles as the sodiunr chloride was applied to the left ventricle. This effect of vagal stimulation was observed in 11 out of 24 experiments. Discussion The results of these experiments show that extrasystoles caused by focal administration of hypertonic sodium chloride reappear during vagal stimulation, usually with a much faster rate. Whereas aconitine extrasystoles which were elicited in a similar manner persisted for a long time after cessation of the vagal stimulation, the extrasystoles in the present experiments disappeared immediately or within a few seconds, There is no doubt that we are dealing with true extrasystoles, that is, with beats elicited by the previous beat. Previous experimental studies on the effect of vagal stimulation and vagal reflexes on the appearance of extrasystoles are discussed elsewherez5 and will therefore not be analyzed here. We stress only the investigations of Hering, Heymans and SchottS6 on carotid sinus stimulation and extrasystoles in the rabbit. Ventricular extrasystoles may appear or disappear during vagal stimulation, and, in a previous
672
Scherf, Blumenfeld,
and E’ildiz
Fig. 1. A shows a ventricular tachycardia which appeared after the injection of 0.05 C.C. of a 20 per cent solution of sodium chloride into the posterior aspect of the right ventricle near the atrioventricular groove. The rate is 17.5 beats per minute. After the end of this tachycardia an atrioventricular rhythm appeared. figal stimulation slowed the rate, and sinus rhythm soon reappeared, with estrasystoles which followed the preceding sinus beat after a coupling of 0.36 to 0.40 second. The estrasystoles disappeared after a few seconds, but reappeared in the same manner during five consecutive stimulations.
Fig. 2. A and B are continuous tracings. *-I shows a sinus tachycardia of 166 beats per minute. Vagal stimulation leads immediately to the appearance of ventricular estrasystoles in the form of trigeminal groups. The extrasystoles disappear immediately after the end of the stimulation (last part of B). The first extrasystole appears after a coupling of 0.38 second. It varies in the other beats, and is only 0.16 second in A. The distance between two extrasystoles is as short as 0.16 second, which corresponds to a rate of 375 beats per minute.
report, we demonstrated the reappearance of a ventricular tachycardia upon such stimulation after the application of a 30 per cent solution of sodium chloride to the surface of the ventricle.‘” Vagal stimulation in the dog elicited similar rapid extrasystoles without premedication, at least in one experiment,13 and similar bursts of rapid extrasystoles have been seen in man during compression of the carotid sinus region2’
Textbooks generally state that carotid sinus pressure is of no effect in ventricular tachycardias. Although this is usually true, there is a well-documented observation reported by Wenckebach and Winterberg,“Y in which a ventricular tachycardia could be stopped by carotid pressure. In another study,20 mechanical irritation of the respiratorv tract caused the appearance of ventricular extrasystoles. Carotid pressure or eyeball pressure could pro-
Ventricular
extrasysloles
voke groups of rapid ventricular extrasystoles,g~*“~14 or abolish them if they were already present.’ Even such substances as calcium or potassium will cause or abolish extrasystoles, depending on the condition of the experiment. AA stimulating effect of the vagus on ventricular extrasystoles was observed in the dog after intravenous injection of digitalis and after administration of calcium chloride.ll IT7hen a solution of sodium
Fig. 3. There systoles with the preceding
provoked by zlugal stimuhtion
673
chloride is applied to the atria, vagal stimulation leads regularly to atria1 fibrillation.“” Vagal effects on ventricular impulse formation and ventricular conduction have been reported in several older observations. Erlanger observed a slight chronotropic effect of vagal stimulation during heart block, and this was confirmed.‘0~‘7 I8 In man, the injection of a choline ester, carbamylcholine chloride, was shown to slow the ectopic rhythm in parasystole,4 and
is a sinus tachycardia with a rate of 214. Vagal stimulation leads to a burst of ventricular extraa rate up to 500 per minute. After this burst, coupled beats appear, following after 0.20 second automatic beat. The first estrasystole follows the preceding sinus beat after 0.40 second.
Fig. ?. \‘agal stimulation in this experiment caused the appearance of estrasystoles in groups. After the end of the vagal stimulation (lirst third of I?), coupled extrasystoles appear, followed by sinus rhythm with an occasional atrial extrasystole. The two tracings are continuous.
Fig. 5. In this experiment the solution of sodium chloride stimulation elicited left ventricular extrasystoles with rapid
had beeu rates.
applied
to the left
ventricle.
Here
vagal
674
Sckerf, Blumenfeld,
.4m. Hcavt 1. \~‘owmbcr, 1961
and E’ild iz
we have repeatedly observed the slowing of parasystolic ventricular centers by carotid pressure. The influence of carotid pressure on bundle branch block has been discussed by Dressier.” The mechanism of the appearance of ventricular extrasystoles during vagal stinulation is not clear. This same phenomenon in the aconitine experiments was explained by the release of acetylcholine in the atria, which led in a sensitized ventricle to an abnormal response to the minute amounts of acetylcholine reaching it.22 Acetylcholine reduces the resistance of membranes and increases their permeability for potassium.“q This may facilitate the appearance of afterpotentials and, therefore, of extrasystoles. It may be stated in objection to this that extrasystoles are related to changes in rate which result from vagal stimulation, but in Figs. 2 and 3, as well as in several other experiments, the change in rate, the duration of diastole preceding the first extrasystole, was so small that this mechanism is highly improbable. On the other hand, the extrasystoles appear so early after the onset of the vagal stimulation that the amount of acetylcholine reaching the ventricles from the atria can only be very small. The complete absence of vagal fibers in the mammalian heart has recently been denied.15J6 It is possible that such fibers, abundant in the lower classes of animals, do appear occasionally as an inherited anomaly. The extrasystoles in the present series of experiments are centainly not provoked by the stimulation of sympathetic fibers which are said to be found occasionally in the vagus nerve. Against this interpretation speaks their appearance without any latent period immediately after the onset of the vagal stimulation. The extrasystoles which appeared during vagal stimulation had, as the illustrations show, the same configuration as that of the extrasystoles which were provoked by the application of sodium chloride. They came from the same focus. Minor differences in form are caused by the differences in rate. The rapid rate of these extrasystoles is noteworthy. It was much higher than that observed in extrasystoles caused by focal application of digitalis, strophanthin, so-
dium chloride, sodium citrate, or oxalate and veratrine. The extrasystoles described in the present study follow each other so quickly that it seems possible that one extrasystole appearing during the vulnerable period may lead to ventricular fibrillation and sudden death. Summary
Ventricular extrasystolic tachycardias were provoked by focal application of a hypertonic solution of sodium chloride on the exposed heart of the dog. After these extrasystoles subsided, faradic stimulation of the right vagus nerve made them reappear. This effect was reproducible. The extrasystoles which were observed during vagal stimulation were identical with those which appeared after the application of sodium chloride. A characteristic feature of these extrasystoles was their unusu;dl?; high rate. 1.
2.
\1
4.
5.
6.
7.
8.
9.
10.
11.
Cope,R.
L.: Suppressive effect of carotid sinus stimulation on premature ventricular beats in c.crtain instances, Am. J. Cardiol. 4:314, 1959. Dressier, W. : Transient bundle branch block occurring during slowing of the heart beat and following gagging, AM. HEART J. 58:760, 1959. Drur)-, A. S.: The influence of vagal stimulation upon the force of contraction and the refractory period of ventricular muscle in the dog’s heart, Heart 10:405, 1923. Eckey, P.: ITntersuchungen zur Frage der Extrasystolenentstehung durch Interferenz zweier Rhythmen, -Deutsches Arch. klin. Med. 181:229. 1937. Erlanger, J.: i;ber den Grad der Vaguswirkung auf die Kammern des Hundeherzens, Pfliigers Arch. ges. Physiol. 127:77, 1909. Golbey, M., Ladopoulos, C. P., Roth, F. H., and Scherf, D.: Changes of ventricular impulse formation during carotid sinus pressure in man, Circulation 10:735, 1954. Hering, H. E.: iiber das Alusloesen oder Beseitigen heterotoper Herzschl%ge beim Karotisdruckversuch, Wien. Arch. inn. Med. 10:497, 1925. Heymans, C., Bouckaert, and Regniers, P.: Le sinus carotidien et la zone homologue cardioaortique, Paris, 1933, Doin et Cie. Hollander, W., and Entwistle, G.: Transient ventricular tachycardia following the Valsalva maneuver in a patient with paroxysmal atria1 tachycardia, AM. HEART J. 52:799, 19.56. Jourdan, F., and Froment, K.: Le rythme idio-ventriculaire experimental, tchappe-t-i1 Q tout controles de nerfs vagues? Compt. rend. Sot. Biol. 125:915, 1937. Kobacker, J. L., and Scherf,D.: \‘ersucheiiber
~~‘ohtme
b.!
Ntcmber
5
12.
13. l-1.
1.5.
16.
17.
18.
19.
20.
T’entriculur
extrasystolcs
die Entstehung der Digitalis Extrasystolen, Ztschr. ges. exper. Med. 67:372, 1929. Landman, M. E., and Ehrenfeld, I.: \,.entricular fibrillation following eyeball pressure in a case of paroxysmal ventricular tachycardia, AM. HEART J. 43:791, 1952. Lewis, T.: The effect of vagal stimulation upon atrioventricular rhythm, Heart S:247, 1914. Meredith. H. C.. and Beckwith. I. R.: Devrelopment of ventricular tachycardia following carotid sinus stimulation in supraventricular tachycardia, AM. HEART J. 39:604, 1950. Mitchell, G. A. G.: Cardiovascular innervation, Edinburgh and London, 1956, Livingstone, Ltd. Mitchell, G. A. G., Brown, R., and Cookson, F. B.: Ventricular nerve cells in mammals, Nature 172:812, 19.53. Pekar, M., and Lelkes, Z.: Einfluss der Vagusreizung auf den idioventricularen Rhythmus, Pfliigers Arch. ges. Physiol. 238:66, 1936. Puddu, V.: Beitrage zur Kenntnis der Herz nervenwirkung, Pfliigers Arch. ges Physiol. 238:467, 1936. Piccione, F. V., and Scherf, D.: The rhythmic formation of coupled beats and paroxysmal tachycardias in the outer layers of the myocardium, Bull. New York M. Coll. 3:83, 1940. Reid, C. C., and Brace. D. E.: Irritation of the respiratory tract and its reflex effect upon the heart, Surg. Gynec. & Obst. 70:157, 1940. I
provoked by eqnl
21.
stimulatio~z
67.5
Rothberger, C. J., and Scherf, D.: \Virkt der Vagus auf die Kontraktionsstaerke der Kammerns des Saugetierherzens, Ztschr. ges. exper. Med. 71:274, 1930. 22. Scherf, D.: Zur Entstehungsweise der Extrasystolen und der extrasystolischen Allorhythmien, Ztschr.. ges. exper. Med. 51:816, 1929. 23. Scherf. D.. Blumenfeld. S.. Yildiz. M.. anti Duplessy, M. T.: Focal application of hypertonic solutions of sodium chloride on impulse formation in the heart of the dog, AM. HICARY J. 57:383, 1959. 24. Scherf, D., and Romano, F. J.: Extrasystoles in groups, -4~. HEART J. 35:81, 1948. 2.5. Scherf, D., and Schott, A.: Extrasystoles and allied arrhythmias, New York, 1953, Grune & Stratton, Inc. 26. Scott, A.: Zur Frage der heterotopen =Irrhythmien durch Carotidenabklemmung, Pfliigers Arch. ges. Physiol. 23451, 1934. 27. Schott. A.: Behandlung von Vorhofflattern und-flimmern, Verhandl. Deutsch. Ges. Kreislaufforsch. 26:224, 1960. 28. ‘l‘rautwein, W., and Dudel, J.: Zum Mechanism der Membranwirkung des Acetylcholins an der Herzmuskelfaser. Pfliirrers Arch. ., pes. I’hvsiol. 266:324, 1958. 29. Wenckebach, K. F., and VVinterberg, H.: Die unregelmassige Herztatigkeit, Leipzig, 1927, Engelmann. I