J. ELECTROCARDIOLOGY, 10 (2) 1977, 179-188
Isorhythmic Dissociation A "Physiological" Arrhythmia BY ELIESER KAPLINSKY,* M.D., RAYMONDARONSON, M.D. AND HENRY N. NEUFELD, M.D.
neural mechanism by which cardiacc o n t r a c t i o n - d e p e n d e n t cyclical c h a n g e s in vagal discharge produce similar alterations in the sinus rate was also suggested. 3 Recently a physiological mechanism was demonstrated experimentally and strongly suggested clinically. 4,5 It was shown in these s t u d i e s t h a t t h e blood p r e s s u r e c h a n g e s dependent upon atrial contribution produce reflex alteration in sinus rhythm, and cons e q u e n t l y t h e sino-atrial nodal discharge tends to oscillate around the other independent ectopic mechanism. These oscillations in the rate of the sinus node discharge are classically observed in patients with complete h e a r t block ( u s u a l l y w i t h an a r t i f i c i a l l y pacemaker) in whom the v e n t r i c u l a r (and fixed) mechanism rate of discharge is close to t h e sinus. H o w e v e r , the s a m e oscillatory changes in P wave rate, resulting in migration of P wave in and out of the QRS complex, can be also observed in patients with preserved atrioventricular conductivity. In such a situation the ectopic (nodal or ventricular) mechanism fires slightly more rapidly than the pre-existing sinus rate. This produces cycles of acceleration-deceleration of the sinus node activity, resulting in migration of the P wave into the ectopic QRS complex (deceleration) and then back in front of it (acceleration). S u c h cyclic c h a n g e s in s i n u s r a t e produce for short periods atrio-ventricular dissociation although there is no heart block. We will hence term this group: temporary isorhythmic dissociation. During this period t h e s i n u s P w a v e b e c o m e s a c t u a l l y synchronized with the ectopic mechanism. Since the behavior of the sinus node was very similar in the two types of synchronization, we have included both types in our study. We have observed the oscillatory change in sinus rate described above in nine patients with acute myocardial infarction admitted to the coronary care unit, and produced it artificially, by t h e use of an e x t e r n a l d e m a n d pacemaker, in 12 others. Cuff blood pressure m e a s u r e m e n t and detailed analysis of the interrelationship between the sinus node and the other ectopic focus provided additional indirect support to the proposed physiological mechanism by which synchronization takes place.
SUMMARY The behavior of the sino-atrial mechanism in i s o r h y t h m i c d i s s o c i a t i o n ( I R D ) w a s studied in 21 patients, nine with spontaneous I R D and 12 w i t h a r t i f i c i a l l y p a c e m a k e r induced IRD following electrode placement for heart block. Successive P-P, R-R and P-R intervals and blood pressure ( B P ) fluctua t i o n s were d e t e r m i n e d and g r a p h i c a l l y i n t e r r e l a t e d at c o n t r o l and d u r i n g IRD. Several features were observed: a. IRD was present only when the independent ventricular rate was close to the atrial; b. P rate oscillations closely followed the P-R interval-dependent B P fluctuations (mean difference 30 m m H g ) during IRD. In cardiogenic shock and in severe hypertension IRD could not be achieved easily; c. While during complete dissociation or during 1:1 A-V conduction the sinus rate was remarkably constant (2-4 beats/min variations), it showed marked oscillations (differences of 6-19, mean 13, beats/min) during IRD. All the data and calculations support the theory that in most instances of IRD, the arrhythmia is sustained by the normal physiologically active baroreceptor reflex arc. The mechanism by which the two independent foci synchronize in isorhythmic dissociation (IRD) remained a fascinating enigma for m a n y years. The arrhythmia, in which synchronization can occur b e t w e e n the sinus node and an atrioventricular nodal or ventricular focus, had been attributed to several speculative mechanisms. It has been thus suggested that synchronization occurs as a result of a mechanism similar to the interaction of two electrical oscillators. 1 J a m e s proposed a mechanical explanation by which the arterial pulsations in the sino-atrial nodal artery affect the sino-atrial nodal discharge. 2 A
From the Heart Institute, Chaim Sheba Medical Center Tel-Hashomer and Tel-Aviv University Sackler Medical School, Israel. *Present address: Cardiology Department, Meir Hospital, Kfar-Saba, Israel. Reprint requests to: Elieser Kaplinsky, M.D., Meir Hospital, Kfar-Saba, Israel. 179
180
KAPLINSKY
ET AL
ing synchronization are s u m m a r i z e d in Table 2. Cuff blood p r e s s u r e m e a s u r e m e n t s were obtained by t h e following procedure: One observer monit o r e d the e l e c t r o c a r d i o g r a m d u r i n g the artificially induced IRD. A n o t h e r observer m e a s u r e d t h e blood p r e s s u r e upon instructions from t h e first one without a n y k n o w l e d g e as to the electrocardiographic s i t u a t i o n . M e a s u r e m e n t s were r e p e a t e d s e v e r a l t i m e s and by both observers. A l l studies in the pat i e n t s of group 2 were carried out in a t r a n q u i l atmosphere, u s u a l l y late in the evening. F i g u r e 2 is a n example of t e m p o r a r y IRD induced by an artificial p a c e m a k e r in a p a t i e n t with intact atriov e n t r i c u l a r conduction and F i g u r e 3 of a p a t i e n t in complete h e a r t block and IRD.
MATERIAL AND METHODS Clinical material
Group 1 - - Spontaneous t e m p o r a r y IRD: Tempora r y IRD was observed spontaneously in nine pat i e n t s a m o n g 180 consecutive p a t i e n t s w i t h acute m y o c a r d i a l i n f a r c t i o n a d m i t t e d to t h e coronary care unit. In seven p a t i e n t s t e m p o r a r y IRD was w i t h i n t a c t a t r i o v e n t r i c u l a r conduction a n d in two d u r i n g 2:1 h e a r t block. In the l a t t e r cases t h e synchronization d u r i n g t h e t e m p o r a r y IRD occurred b e t w e e n e v e r y second P w a v e a n d t h e ectopic mechanism. Clinical data, mode of atriov e n t r i c u l a r conduction, n a t u r e of ectopic activity ( j u n c t i o n a l or v e n t r i c u l a r ) a n d i t s r a t e of discharge, and m a x i m a l - m i n i m a l sinus r a t e d u r i n g s y n c h r o n i z a t i o n periods are s u m m a r i z e d in Table 1. Sinus P wave r a t e was d e t e r m i n e d in these pat i e n t s d u r i n g prolonged periods of n o r m a l sinus r h y t h m and d u r i n g periods of "synchronization." F i g u r e 1 is a n example of this t y p e of spontaneous t e m p o r a r y IRD in p a t i e n t s w i t h i n t a c t a t r i o v e n t r i c u l a r conduction.
Electrocardiographic
Group 2 - - Artificially induced IRD. Twelve pat i e n t s constitute this group: six with t h i r d degree heart block and six with preserved atriov e n t r i c u l a r conductivity (following recovery from t r a n s i e n t conduction d i s t u r b a n c e s ) . T e m p o r a r y I R D w a s p r o d u c e d in t h e l a t t e r p a t i e n t s b y s t i m u l a t i n g t h e ventricles at a r a t e s l i g h t l y h i g h e r than their normal sinus rate via a pervenous catheter-electrode. In t h e p a t i e n t s with complete h e a r t block, IRD was produced by p a c i n g at a r a t e close to t h e sinus (either lower or higher). The clinical a n d electrocardiographic d a t a before a n d dur-
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P-P, R-R a n d P-R i n t e r v a l s were d e t e r m i n e d duri n g IRD p e r i o d s . M e a s u r e m e n t s w e r e d o u b l e checked by two observers (E.K. A N D R.A.), and i f t h e r a t e per each R or P wave (determined as t h e reciprocal of t h e preceding R-R or P-P interval) differed in more t h a n two beats/min, m e a s u r e m e n t s were repeated. It was, however, r a r e l y necessary to do so. The r e s u l t a n t ectopic m e c h a n i s m r a t e and t h e m a x i m a l a n d m i n i m a l sinus r a t e s are depicted in Tables 1 and 2. Additional m e a s u r e m e n t s of t h e pre-IRD sinus P wave rates were carried out and t h e i r m a x i m a l a n d m i n i m a l levels a p p e a r in Tables 1 and 2. In t h e p a t i e n t s with t h i r d degree h e a r t block t h e pre-IRD rates were those m e a s u r e d d u r i n g complete dissociation. B e a t to b e a t i n t e r r e l a t i o n s h i p b e t w e e n t h e P-wave rate, v e n t r i c u l a r r a t e a n d t h e correspondi n g P-R i n t e r v a l s (positive when t h e P precedes t h e QRS and n e g a t i v e when it follows it) were plotted for each p a t i e n t for several IRD cycles.
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Fig. 1. Continuous monitor lead t r a c i n g of p a t i e n t 1, Table 1. Upon slowing of t h e sinus r a t e a high v e n t r i c u l a r (or j u n c t i o n a l with slight aberration) m e c h a n i s m t a k e s over (second line). Acceleration of the sinus r a t e soon r e s u l t s in r e s u m p t i o n of n o r m a l sinus r h y t h m . J. ELECTROCARDIOLOGY,
VOL.
10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
181
TABLE 1 Summary of Clinical and Electrocardiographic Data in 9 Patients with Spontaneous Isorhythmic Dissociation
Pt. No.
Patient's Initials
1
A.G.
M
73
Posterior
1:1
J
69
74
64
65
62
2
G.D.
M
65
Antermr
1:1
V
69
77
65
71
67
3
T.K.
IVI
69
Posterior
1:1
J
91
94
88
91
86
4
B.Y.
F
66
Anterior
1:1
V
75
85
70
76
74
5
M.K.
IVI
48
Antermr
1:1
V
89
99
83
86
80
6
I.A.
IVl
62
Anterior
1:1
V
75
83
72
79
74
7
IVI.S.
IVl
65
Undetermined
1:1
V
70
75
67
68
66
8
H.C.
F
59
Posterior
2:1
J
67
136
132
134
130
9
E.B.
F
60
Posterior
2:1
J
47
97
92
93
90
Sex Age
Location of infarction
A-V Conduction
Ectopic Mechanism Location Rate
IRD Sinus Rate Max. Min.
Control Sinus Rate Max. Min.
F - female, IVI - male, J - junctional mechanism, V - ventricular mechanism.
RESULTS Spontaneous temporary IRD. The patients with intact atrio-ventricular conduction, of course, were not in true dissociation. However, when an accelerated nodal or ventricular focus overtook the sinus at a slightly faster rate, oscillation of the P wave was observed (Fig. 1, Table 1). As a result of the appearance of the ectopic focus, most patients developed significant sinus arrhythmia (see "IRD sinus rate" in Table 1). Artificial production of IRD in patients with intact atrio-ventricular conduction. The first six patients in Table 2 represent this group. In t h e p r e - p a c i n g p e r i o d t h e i r s i n u s mechanism was stable and sinus arrhythmia was minimal (range 2-4 beats/min). Respiratory fluctuation in the blood pressure in all patients was below 10 mmHg. In contrast to the control state, marked fluctuations, both in systolic blood pressure and in the sinus rate, were observed upon t h e initiation of synchronization (Table 2, Fig. 2). Thus in contrast to 2-4 beats/min control oscillations in sinus rate, m a r k e d sinus a r r h y t h m i a developed during IRD (range 7-17 beats/min). The blood pressure fluctuations correlated with the position of the P wave, namely, it was high when the P was in front of the QRS and dropped upon the disappearance of the P in the QRS complex. J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
IRD in complete heart block. During periods of complete dissociation with no synchronization, the systolic blood pressure had signific a n t b e a t to b e a t f l u c t u a t i o n , as is well known to occur in complete heart block with complete dissociation between the atria and the ventricles. The sinus rate however was remarkably stable in all patients (range of change 2-3 beats/min). The stability of the sinus node was disrupted upon the production of isorhythmic dissociation. Thus, when the rate of the ectopic ventricular pacemaker was b r o u g h t to t h e vicinity of t h e sinus rate, marked sinus arrhythmia developed in patients 8, 11 and 12 and to a lesser degree in patients 7 and 10. The systolic blood pressure continued to fluctuate according to the position of the P wave in relation to the QRS complex. However, the fluctuations were now smoother and much slower. In patients 7 and 10, IRD was achieved with some difficulty and the sinus arrhythmia which developed during IRD was rather modest (6 beats/min). Both were hypertensive patients not well controlled at that time. It was impossible to produce IRD in patient 9, who was in cardiogenic shock. The changes in sinus rate of the patients in Table 2, depicted as percent of the lower rate, are represented in Fig. 4. Electrocardiographic analysis. Figures 5-7 a r e e x a m p l e s of t h e e l e c t r o c a r d i o g r a p h i c analysis described above.
182
KAPLINSKY ET AL
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F i g . 2. P r o d u c t i o n o f I R D b y v e n t r i c u l a r p a c i n g i n a p a t i e n t w i t h n o r m a l a t r i o - v e n t r i c u l a r conduction. The continuous monitor lead tracing shows the emergence of the demand pacemaker activity upon slowing of the sinus rate. Following a short period of pacing the sinus rate accelerates and the P wave reappears and therefore again captures the ventricles. This sequence is repeated two more times in this tracing.
TABLE 2 Summary of Clinical and Electrocardiographic Data in 12 Patients with Artificially Induced Isorhythmic Dissociation Pt. Patient's Sex Age No. Initials
Clinical Diagnosis
A-V Pacing IRD Systolic BP Conduction Rate Max. Min.
IRD Sinus Rate Max. Min.
Control Sinus Rate Max. Min.
1
M.K.
IVl
44
Acute MI
1:1
92
112
98
96
86
87
85
2
D.B.
M
54
Acute IVll
1:1
87
106
88
96
79
84
80
3
F.K.
M
71
Acute MI
1:1
98
134
80
102
90
96
93
4
D.B.
IVl
45
Acute MI
1:1
86
136
94
94
75
87
83
5
A.K.
F
70
Cardiomyopathy
1:1
67
108
70
72
65
68
65
Y.S.
F
61
AdamsStokes
1:1
64
142
108
75
58
64
60
L.D.
F
66
AdamsStokes
3rd degree
74
210
180
76
70
73
71
8
M.E.
IVI
54
Acute MI
3rd degree
91
138
122
95
83
89
86
9
*F.K.
F
70
Acute MI
3rd degree
100
54
52
100
99
100
98
10
M.O.
F
81
AdamsStokes
3rd degree
86
190
165
88
82
88
86
11
0.K.
F
74
AdamsStokes
3rd degree
97
150
130
103
93
98
96
12
S.G.
M
69
AdamsStokes
3rd degree
94
138
118
100
87
100
97
* True I RD was not obtained except when pacing rate was exactly the same as sinus rate. J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
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Figure 5 represents the calculations performed on patient 6, Table 2. Similar graphic results were obtained from all patients with intact atrio-ventricular conduction in whom I R D w a s a r t i f i c i a l l y p r o d u c e d by t h e pacemaker. Prior to pacing, the sinus rate was relatively stable, as can be seen on the right hand side of the graph. The P-R interval remained unchanged. When the pacemaker was set at 64 (demand node), marked sinus a r r h y t h m i a resulted. At the beginning of the graph the P-R interval was '~negative" and t h e ventricles were being paced. Systolic blood pressure was at that point 108 mmHg. From the upper curve it is obvious that the sinus was accelerating. As a result the P-R became positive and long enough for the atria to capture the ventricles and normal conduction resumed. At t h a t point (as P-R became positive) systolic blood pressure rose to 142 mmHg. Several beats later the sinus began to slow and the P-R interval to shorten. Since this process dropped the sinus rate far below t h a t of the pre-set demand pacemaker, vent r i c u l a r pacing was r e s u m e d and systolic blood pressure fell again to 108 mmHg. As a r e s u l t of t h e s i n u s s l o w i n g t h e P waves ~marched" beyond the QRS and P-R became negative. At t h a t point the cycle began all over again, namely, fall in pressure, sinus tachycardia, positive P-R interval, rise in J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
pressure, sinus bradycardia, negative P-R, fall in pressure, etc. Figure 6 represents graphically the results of the calculations (same as performed in Fig. 30,
z 20' z z < T U
I0-
F-
Z ,.J
r~
CONTROL
I R D
Fig. 4. Sinus rate oscillations in the patients listed in Table 2. Fluctuations are presented as percent of the lower rate. Control: during 1:1 conduction or complete dissociation. IRD: measurements during periods of IRD,
184
KAPLINSKY ET AL
?O
A[RIA .....
RATE
VENTRICULAR RATE
74
72 :0 Z 08
| t
06 .< 04
nl
62
60 58
56
IRD
NO IRD
Fig. 5. Graphic representation of the electrocardiographic calculations in patient 6 from Table 2. Upper curves: beat to beat calculations of atrial and ventricular rates. Lower curves: P-R interval of the corresponding beats. IRD: during periods of isorhythmic dissociation. No IRD: during 1:1 conduction. See discussion in text.
200
5
150 I00
E
,50
o -50 Z
-100 -150
i
-200
-250
k,, 10 BEATS
5) in patient 12, who was in complete heart block. At the left h a n d side of the graph the ventricles were paced at 87 beats/min. The dissociation was complete, sinus rate stable (97-100 beats/min) and no synchronization occurred. This is well seen in the lower graph, as the P-R interval shows no cyclical changes. Pacing at 91 beats/min still produced no IRD. However, since the rates of the two foci were somewhat closer, the slope of the P-R interval curves became less steep (but with no synchronization at all). In contrast to the left hand and middle graphs, classical synchronization with atrio-ventricular dissociation occurred when the ventricles were paced at 94 beats/min. As a result, m a r k e d sinus arr h y t h m i a ensued, and following a long period
of positive P-R interval the sinus rate dropped to 86 beats/min. The synchronization is classically demonstrated by the oscillation of the P-R interval. Again, as in Fig. 5, the positive P-R intervals were associated with a systolic blood pressure of 138 while the negative P-R intervals were associated with a systolic pressure of 118 mmHg. Figure 7 represents the failure to achieve IRD in the patient in cardiogenic shock (Table 2, patient 9). It can be seen t h a t the sinus rate r e m a i n e d u n c h a n g e d even though by manipulating the pacemaker rate (as seen by the course of the interrupted line in the upper portion) we were able to produce prolonged periods of positive P-R interval. There was no change in the blood pressure or in the sinus J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
185
~INU$ R/t'l'E - - .
92
U
86
Fig. 6. Graphic representation of electrocardiographic calculations in patient 12 from Table 2. Upper and lower tracings are as in Fig. 5. CD: calculations made during complete dissociation. IRD: Calculations made during IRD. See discussion in text.
CD
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e~
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rate. Blood pressure was 52-53 m m H g regardless of the position of the P wave in relation to the QRS complex.
DISCUSSION The synchronization of two seemingly independent electrophysiological foci presented an intriguing problem for m a n y years. It was shown by Segers 8 that frog hearts beating in vitro tend to synchronize if they come close together and if their initial rates are not too far apart. While the phenomenon was clear, its explanation remains an enigma even today. Only two forms of transmission from cell to cell are possible: synaptic and electrotonic. J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
Except for the tight junction of the cardiac intercalated disc, electrotonic intercellular spread of excitation is impossible. 7 In fact, it had been shown in tissue cultures t h a t h e a r t cells beat independently until intercellular bridges are formed, thus enabling synchronization, s Subthreshold electrotonic intercellul a r e f f e c t s a r e k n o w n to e x i s t b e t w e e n a d j a c e n t n e r v e fibers (axons), t h u s synchronizing the transmission of the action potential which was started simultaneously at one end of both axons. 9 Phenomena of synchronization are readily observed in t h e h u m a n h e a r t , a n d m a n y theories were put forward to explain it, as outlined in the introduction.~'5 Following the extensive studies of Levy et al 4'5 it became
186
KAPLINSKY ET AL
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. . . . . . . .
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_ 284
obvious t h a t the clinical type of synchronization is totally different from the early observation on small hearts and nerve axons. It was shown in these studies t h a t in m a n (and in the dog) the synchronization of the atria a n d ventricles in most of the cases of complete heart block are the result of a negative feedback mechanism involving t h e baroreceptor a n d the autonomous .nervous system. The arterial blood-pressure fluctuations, caused by variations in the P-R interval, produced the cyclical changes in the sinus rate. As a result the P wave migrated and oscillated around the fixed QRS complex. .The behavior of a system governed by a negative feedback control is dependent upon the gain of the sensor and its frequency response (FR), the sensitivity and FR of the coordinating center and of its messengers and upon the sensitivity and FR of the responsive t a r g e t organ. T h e b a r o r e c e p t o r s are ex-
tremely fast in their reaction to blood pressure changes and thus have a very high FR. 1~ On t h e other hand, both the coordinating center and the target organs (of which the sino-atrial node is the fastest) have a much slower FR and thus tend to "average" blood pressure fluctuations. 1~Therefore, patients in complete heart block in whom beat to beat c h a n g e s in blood p r e s s u r e m a y r e a c h 50 m m H g and more still have a very stable autonomic nervous activity. This stability is demonstrated by the narrow range of sinus a r r h y t h m i a at rest (Table 2, Fig. 6). The pressure fluctuations (produced by the rapidly varying P-R interval) are too rapid to produce an effect and the central nervous system averages them. However, when t h e basic rates of the dissociated atria and ventricles vary less t h a n 10 beats/min, the "movement" of the P wave across the ventricular QRS complex cycle is slower. As a result the P wave stays in J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
front of the QRS complex (although the P-R changes) for several beats. Now the elevation (or reduction, when the P stays in the ventricular systole for several beats) of the blood pressure is longer and the vasomotor center responds accordingly by changing the sinus r a t e , p r o d u c i n g a fine d e m o n s t r a t i o n of Marey's law. The result of all the above is that when the atria and the ventricles are completely dissociated (as in complete heart block), both independent foci are extremely stable (Table 2, Fig. 6). In contrast, as was shown in this study, when the ventricular rate was brought to the vicinity of the sinus rate, the latter, rather than synchronize exactly to the ventricular rate, became markedly u n s t a b l e and marked fluctuations appeared. Figure 6 demonstrates it beautifully. As long as the atria and ventricles were truly dissociated, the atrial rate was relatively fixed (97-100 beats/min). Upon a p p r o x i m a t i n g t h e ventricular rate to the atrial, the latter became markedly unstable and fluctuated from 86 to 101 beats/min. These fluctuations behaved as a typical part of a negative feedback control system. Acceleration appeared always a few beats after a period of a few seconds of low blood pressure (no P in front of the QRS complex). As the acceleration brought the P wave in front of the QRS complex for several consecutive beats, the sustained elevation of the blood pressure was long enough for the relatively slow responding centers to reduce the sinus rate. This in turn "moved" the P back into the QRS, causing a drop in blood pressure, and the cycle was repeated. The same p h e n o m e n a could be produced in patients with n o r m a l a t r i o - v e n t r i c u l a r conduction (Fig. 5). When the artificial pacemaker was only slightly faster than the basal rate, again P-R interval changes were slow enough for the central nervous system to take notice and respond. The only difference from the patients with complete A-V block was, of course, the ability of the ventricles to follow the accelerated sinus rate. The rise in pressure as a result was augmented not only by a "positive" P-R interval but also by the normal activation of the ventricles. Since the change was long enough, the negative feedback loop responded and marked slowing occurred, whereupon the ventricular demand pacemaker took over to start it all over again. Another feature in Fig. 6 deserves notice. Pacing at 87 and at 91 beats/min had no effect on the sinus node activity and there was no tendency to synchronize whatsoever (straight lines in the P-R interval graph). However, when the ventricular rate was elevated to 94 beats/min, a rate very close to the original sinus rate, the sinus node started oscillating J. ELECTROCARDIOLOGY, VOL, 10, NO. 2, 1977
187
and reached levels as low as 86. There was therefore no actual synchronization except, of course, that the m e a n rates were equal. Figure 4 summarizes the marked unstabilizing effect on sinus rate caused by the productior/ of isorhythmic dissociation. The dependency of these sinus rate oscillations on the baroreceptor reflex loop is further demonstrated in cases 7, 9 and 10 of Table 2. Case 9 represents a patient in terminal cardiogenic shock (Fig. 7). No IRD could b e produced despite repeated trials. The failure is explained by the almost total absence of any activity of the baroreceptors when the blood pressure falls to below 50 m m H g (systolic pressure in this patient was 54 mmHg). Patients 7 to 10 were hypertensive at the time of study and IRD was produced with difficulty. Furthermore, during the short periods of synchronization the range of sinus node rate fluctuations was narrow (6 beats/min in both patients), even though the blood pressure did fluctuate as expected. This again demonstrates the dependency of IRD on active and sensitive baroreceptors. At high blood pressure the carotid sinus approaches its maximal activity, and thus loses its high s e n s i t i v i t y . 1~ L o w e r e d s e n s i t i v i t y of baroreceptor reflex arch prevents the production of IRD, as shown by Levy and Edelstein 4 in their study on animals and in the study on computer models by Levy and Zieske. 1~ The reflex becomes insensitive at both ends of the clinical blood pressure scale and its effect on the ability to produce IRD is clearly demonstrated by these three patients. While in rare instances atria and ventricles are virtually "locked" together even though no atrio-ventricular conduction exists, most cases of isorhythmic dissociation show t h e classical oscillation of the P wave around the QRS complex. We have again shown in this clinical study the physiological dependence of these oscillations on an active baroreceptor reflex arch. I s o r h y t h m i c dissociation can therefore be viewed as a unique example of a negative feedback controlled physiological arrhythmia.
REFERENCES 1. GRANT,R P: Mechanism of A-V arrhythmias, with an electronic analogue of the human A-V node. Am J Med 20:334, 1956 2. JAMES, T N: Pulse and impulse in the sinus node. Henry Ford Hosp Med J 15:275, 1967 3. LEVY,M N, MARTIN, P J, IANO, T AND ZIESKE, H: Paradoxical effect of vagus nerve stimulation on heart rate in dogs. Circ Res 25:303, 1969
188
KAPLINSKY ET AL
4. LEVY, M N AND ZIESKE, H: Mechanism of synchronization in isorhythmic dissociation: I. Experiments on dogs. Circ Res 27:429, 1970 5. LEVY, M N AND EDELSTEIN, J: Mechanism of synchronization in isorhythmic A-V dissociation: II. Clinical studies. Circulation 42:689, 1970 6. SEGERS, M: Les ph~nomenes de synchronisation au niveau du coeur. Arch Int Physiol 54:87, 1946 7. NOBLE, D: Applications of Hodgkin & Huxley equations to excitable tissues. Physiol Rev 46:1, 1966
8. HARARY, I AND FARLEY, B: In vitro studies of single isolated beating heart cells. Science 131:1674, 1960 9. KATZ, B AND SCHMITT, O H: Electric interaction between two adjacent nerve fibers. J Physiol 97:471, 1940 10. KORNER, P I: N e u r a l circulatory control. Physiol Rev 51:312, 1971 11. LEVYM N AND ZIESKE, H: Mechanism of synchronization in isorhythmic A-V dissociation. III. Computer model. Circ Res 28:253, 1971
J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
Isorhythmic Dissociation A "Physiological" Arrhythmia BY ELIESER KAPLINSKY,* M.D., RAYMONDARONSON, M.D. AND HENRY N. NEUFELD, M.D.
neural mechanism by which cardiacc o n t r a c t i o n - d e p e n d e n t cyclical c h a n g e s in vagal discharge produce similar alterations in the sinus rate was also suggested. 3 Recently a physiological mechanism was demonstrated experimentally and strongly suggested clinically. 4,5 It was shown in these s t u d i e s t h a t t h e blood p r e s s u r e c h a n g e s dependent upon atrial contribution produce reflex alteration in sinus rhythm, and cons e q u e n t l y t h e sino-atrial nodal discharge tends to oscillate around the other independent ectopic mechanism. These oscillations in the rate of the sinus node discharge are classically observed in patients with complete h e a r t block ( u s u a l l y w i t h an a r t i f i c i a l l y pacemaker) in whom the v e n t r i c u l a r (and fixed) mechanism rate of discharge is close to t h e sinus. H o w e v e r , the s a m e oscillatory changes in P wave rate, resulting in migration of P wave in and out of the QRS complex, can be also observed in patients with preserved atrioventricular conductivity. In such a situation the ectopic (nodal or ventricular) mechanism fires slightly more rapidly than the pre-existing sinus rate. This produces cycles of acceleration-deceleration of the sinus node activity, resulting in migration of the P wave into the ectopic QRS complex (deceleration) and then back in front of it (acceleration). S u c h cyclic c h a n g e s in s i n u s r a t e produce for short periods atrio-ventricular dissociation although there is no heart block. We will hence term this group: temporary isorhythmic dissociation. During this period t h e s i n u s P w a v e b e c o m e s a c t u a l l y synchronized with the ectopic mechanism. Since the behavior of the sinus node was very similar in the two types of synchronization, we have included both types in our study. We have observed the oscillatory change in sinus rate described above in nine patients with acute myocardial infarction admitted to the coronary care unit, and produced it artificially, by t h e use of an e x t e r n a l d e m a n d pacemaker, in 12 others. Cuff blood pressure m e a s u r e m e n t and detailed analysis of the interrelationship between the sinus node and the other ectopic focus provided additional indirect support to the proposed physiological mechanism by which synchronization takes place.
SUMMARY The behavior of the sino-atrial mechanism in i s o r h y t h m i c d i s s o c i a t i o n ( I R D ) w a s studied in 21 patients, nine with spontaneous I R D and 12 w i t h a r t i f i c i a l l y p a c e m a k e r induced IRD following electrode placement for heart block. Successive P-P, R-R and P-R intervals and blood pressure ( B P ) fluctua t i o n s were d e t e r m i n e d and g r a p h i c a l l y i n t e r r e l a t e d at c o n t r o l and d u r i n g IRD. Several features were observed: a. IRD was present only when the independent ventricular rate was close to the atrial; b. P rate oscillations closely followed the P-R interval-dependent B P fluctuations (mean difference 30 m m H g ) during IRD. In cardiogenic shock and in severe hypertension IRD could not be achieved easily; c. While during complete dissociation or during 1:1 A-V conduction the sinus rate was remarkably constant (2-4 beats/min variations), it showed marked oscillations (differences of 6-19, mean 13, beats/min) during IRD. All the data and calculations support the theory that in most instances of IRD, the arrhythmia is sustained by the normal physiologically active baroreceptor reflex arc. The mechanism by which the two independent foci synchronize in isorhythmic dissociation (IRD) remained a fascinating enigma for m a n y years. The arrhythmia, in which synchronization can occur b e t w e e n the sinus node and an atrioventricular nodal or ventricular focus, had been attributed to several speculative mechanisms. It has been thus suggested that synchronization occurs as a result of a mechanism similar to the interaction of two electrical oscillators. 1 J a m e s proposed a mechanical explanation by which the arterial pulsations in the sino-atrial nodal artery affect the sino-atrial nodal discharge. 2 A
From the Heart Institute, Chaim Sheba Medical Center Tel-Hashomer and Tel-Aviv University Sackler Medical School, Israel. *Present address: Cardiology Department, Meir Hospital, Kfar-Saba, Israel. Reprint requests to: Elieser Kaplinsky, M.D., Meir Hospital, Kfar-Saba, Israel. 179
180
KAPLINSKY
ET AL
ing synchronization are s u m m a r i z e d in Table 2. Cuff blood p r e s s u r e m e a s u r e m e n t s were obtained by t h e following procedure: One observer monit o r e d the e l e c t r o c a r d i o g r a m d u r i n g the artificially induced IRD. A n o t h e r observer m e a s u r e d t h e blood p r e s s u r e upon instructions from t h e first one without a n y k n o w l e d g e as to the electrocardiographic s i t u a t i o n . M e a s u r e m e n t s were r e p e a t e d s e v e r a l t i m e s and by both observers. A l l studies in the pat i e n t s of group 2 were carried out in a t r a n q u i l atmosphere, u s u a l l y late in the evening. F i g u r e 2 is a n example of t e m p o r a r y IRD induced by an artificial p a c e m a k e r in a p a t i e n t with intact atriov e n t r i c u l a r conduction and F i g u r e 3 of a p a t i e n t in complete h e a r t block and IRD.
MATERIAL AND METHODS Clinical material
Group 1 - - Spontaneous t e m p o r a r y IRD: Tempora r y IRD was observed spontaneously in nine pat i e n t s a m o n g 180 consecutive p a t i e n t s w i t h acute m y o c a r d i a l i n f a r c t i o n a d m i t t e d to t h e coronary care unit. In seven p a t i e n t s t e m p o r a r y IRD was w i t h i n t a c t a t r i o v e n t r i c u l a r conduction a n d in two d u r i n g 2:1 h e a r t block. In the l a t t e r cases t h e synchronization d u r i n g t h e t e m p o r a r y IRD occurred b e t w e e n e v e r y second P w a v e a n d t h e ectopic mechanism. Clinical data, mode of atriov e n t r i c u l a r conduction, n a t u r e of ectopic activity ( j u n c t i o n a l or v e n t r i c u l a r ) a n d i t s r a t e of discharge, and m a x i m a l - m i n i m a l sinus r a t e d u r i n g s y n c h r o n i z a t i o n periods are s u m m a r i z e d in Table 1. Sinus P wave r a t e was d e t e r m i n e d in these pat i e n t s d u r i n g prolonged periods of n o r m a l sinus r h y t h m and d u r i n g periods of "synchronization." F i g u r e 1 is a n example of this t y p e of spontaneous t e m p o r a r y IRD in p a t i e n t s w i t h i n t a c t a t r i o v e n t r i c u l a r conduction.
Electrocardiographic
Group 2 - - Artificially induced IRD. Twelve pat i e n t s constitute this group: six with t h i r d degree heart block and six with preserved atriov e n t r i c u l a r conductivity (following recovery from t r a n s i e n t conduction d i s t u r b a n c e s ) . T e m p o r a r y I R D w a s p r o d u c e d in t h e l a t t e r p a t i e n t s b y s t i m u l a t i n g t h e ventricles at a r a t e s l i g h t l y h i g h e r than their normal sinus rate via a pervenous catheter-electrode. In t h e p a t i e n t s with complete h e a r t block, IRD was produced by p a c i n g at a r a t e close to t h e sinus (either lower or higher). The clinical a n d electrocardiographic d a t a before a n d dur-
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P-P, R-R a n d P-R i n t e r v a l s were d e t e r m i n e d duri n g IRD p e r i o d s . M e a s u r e m e n t s w e r e d o u b l e checked by two observers (E.K. A N D R.A.), and i f t h e r a t e per each R or P wave (determined as t h e reciprocal of t h e preceding R-R or P-P interval) differed in more t h a n two beats/min, m e a s u r e m e n t s were repeated. It was, however, r a r e l y necessary to do so. The r e s u l t a n t ectopic m e c h a n i s m r a t e and t h e m a x i m a l a n d m i n i m a l sinus r a t e s are depicted in Tables 1 and 2. Additional m e a s u r e m e n t s of t h e pre-IRD sinus P wave rates were carried out and t h e i r m a x i m a l a n d m i n i m a l levels a p p e a r in Tables 1 and 2. In t h e p a t i e n t s with t h i r d degree h e a r t block t h e pre-IRD rates were those m e a s u r e d d u r i n g complete dissociation. B e a t to b e a t i n t e r r e l a t i o n s h i p b e t w e e n t h e P-wave rate, v e n t r i c u l a r r a t e a n d t h e correspondi n g P-R i n t e r v a l s (positive when t h e P precedes t h e QRS and n e g a t i v e when it follows it) were plotted for each p a t i e n t for several IRD cycles.
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VOL.
10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
181
TABLE 1 Summary of Clinical and Electrocardiographic Data in 9 Patients with Spontaneous Isorhythmic Dissociation
Pt. No.
Patient's Initials
1
A.G.
M
73
Posterior
1:1
J
69
74
64
65
62
2
G.D.
M
65
Antermr
1:1
V
69
77
65
71
67
3
T.K.
IVI
69
Posterior
1:1
J
91
94
88
91
86
4
B.Y.
F
66
Anterior
1:1
V
75
85
70
76
74
5
M.K.
IVI
48
Antermr
1:1
V
89
99
83
86
80
6
I.A.
IVl
62
Anterior
1:1
V
75
83
72
79
74
7
IVI.S.
IVl
65
Undetermined
1:1
V
70
75
67
68
66
8
H.C.
F
59
Posterior
2:1
J
67
136
132
134
130
9
E.B.
F
60
Posterior
2:1
J
47
97
92
93
90
Sex Age
Location of infarction
A-V Conduction
Ectopic Mechanism Location Rate
IRD Sinus Rate Max. Min.
Control Sinus Rate Max. Min.
F - female, IVI - male, J - junctional mechanism, V - ventricular mechanism.
RESULTS Spontaneous temporary IRD. The patients with intact atrio-ventricular conduction, of course, were not in true dissociation. However, when an accelerated nodal or ventricular focus overtook the sinus at a slightly faster rate, oscillation of the P wave was observed (Fig. 1, Table 1). As a result of the appearance of the ectopic focus, most patients developed significant sinus arrhythmia (see "IRD sinus rate" in Table 1). Artificial production of IRD in patients with intact atrio-ventricular conduction. The first six patients in Table 2 represent this group. In t h e p r e - p a c i n g p e r i o d t h e i r s i n u s mechanism was stable and sinus arrhythmia was minimal (range 2-4 beats/min). Respiratory fluctuation in the blood pressure in all patients was below 10 mmHg. In contrast to the control state, marked fluctuations, both in systolic blood pressure and in the sinus rate, were observed upon t h e initiation of synchronization (Table 2, Fig. 2). Thus in contrast to 2-4 beats/min control oscillations in sinus rate, m a r k e d sinus a r r h y t h m i a developed during IRD (range 7-17 beats/min). The blood pressure fluctuations correlated with the position of the P wave, namely, it was high when the P was in front of the QRS and dropped upon the disappearance of the P in the QRS complex. J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
IRD in complete heart block. During periods of complete dissociation with no synchronization, the systolic blood pressure had signific a n t b e a t to b e a t f l u c t u a t i o n , as is well known to occur in complete heart block with complete dissociation between the atria and the ventricles. The sinus rate however was remarkably stable in all patients (range of change 2-3 beats/min). The stability of the sinus node was disrupted upon the production of isorhythmic dissociation. Thus, when the rate of the ectopic ventricular pacemaker was b r o u g h t to t h e vicinity of t h e sinus rate, marked sinus arrhythmia developed in patients 8, 11 and 12 and to a lesser degree in patients 7 and 10. The systolic blood pressure continued to fluctuate according to the position of the P wave in relation to the QRS complex. However, the fluctuations were now smoother and much slower. In patients 7 and 10, IRD was achieved with some difficulty and the sinus arrhythmia which developed during IRD was rather modest (6 beats/min). Both were hypertensive patients not well controlled at that time. It was impossible to produce IRD in patient 9, who was in cardiogenic shock. The changes in sinus rate of the patients in Table 2, depicted as percent of the lower rate, are represented in Fig. 4. Electrocardiographic analysis. Figures 5-7 a r e e x a m p l e s of t h e e l e c t r o c a r d i o g r a p h i c analysis described above.
182
KAPLINSKY ET AL
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TABLE 2 Summary of Clinical and Electrocardiographic Data in 12 Patients with Artificially Induced Isorhythmic Dissociation Pt. Patient's Sex Age No. Initials
Clinical Diagnosis
A-V Pacing IRD Systolic BP Conduction Rate Max. Min.
IRD Sinus Rate Max. Min.
Control Sinus Rate Max. Min.
1
M.K.
IVl
44
Acute MI
1:1
92
112
98
96
86
87
85
2
D.B.
M
54
Acute IVll
1:1
87
106
88
96
79
84
80
3
F.K.
M
71
Acute MI
1:1
98
134
80
102
90
96
93
4
D.B.
IVl
45
Acute MI
1:1
86
136
94
94
75
87
83
5
A.K.
F
70
Cardiomyopathy
1:1
67
108
70
72
65
68
65
Y.S.
F
61
AdamsStokes
1:1
64
142
108
75
58
64
60
L.D.
F
66
AdamsStokes
3rd degree
74
210
180
76
70
73
71
8
M.E.
IVI
54
Acute MI
3rd degree
91
138
122
95
83
89
86
9
*F.K.
F
70
Acute MI
3rd degree
100
54
52
100
99
100
98
10
M.O.
F
81
AdamsStokes
3rd degree
86
190
165
88
82
88
86
11
0.K.
F
74
AdamsStokes
3rd degree
97
150
130
103
93
98
96
12
S.G.
M
69
AdamsStokes
3rd degree
94
138
118
100
87
100
97
* True I RD was not obtained except when pacing rate was exactly the same as sinus rate. J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
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Figure 5 represents the calculations performed on patient 6, Table 2. Similar graphic results were obtained from all patients with intact atrio-ventricular conduction in whom I R D w a s a r t i f i c i a l l y p r o d u c e d by t h e pacemaker. Prior to pacing, the sinus rate was relatively stable, as can be seen on the right hand side of the graph. The P-R interval remained unchanged. When the pacemaker was set at 64 (demand node), marked sinus a r r h y t h m i a resulted. At the beginning of the graph the P-R interval was '~negative" and t h e ventricles were being paced. Systolic blood pressure was at that point 108 mmHg. From the upper curve it is obvious that the sinus was accelerating. As a result the P-R became positive and long enough for the atria to capture the ventricles and normal conduction resumed. At t h a t point (as P-R became positive) systolic blood pressure rose to 142 mmHg. Several beats later the sinus began to slow and the P-R interval to shorten. Since this process dropped the sinus rate far below t h a t of the pre-set demand pacemaker, vent r i c u l a r pacing was r e s u m e d and systolic blood pressure fell again to 108 mmHg. As a r e s u l t of t h e s i n u s s l o w i n g t h e P waves ~marched" beyond the QRS and P-R became negative. At t h a t point the cycle began all over again, namely, fall in pressure, sinus tachycardia, positive P-R interval, rise in J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
pressure, sinus bradycardia, negative P-R, fall in pressure, etc. Figure 6 represents graphically the results of the calculations (same as performed in Fig. 30,
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Fig. 4. Sinus rate oscillations in the patients listed in Table 2. Fluctuations are presented as percent of the lower rate. Control: during 1:1 conduction or complete dissociation. IRD: measurements during periods of IRD,
184
KAPLINSKY ET AL
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5) in patient 12, who was in complete heart block. At the left h a n d side of the graph the ventricles were paced at 87 beats/min. The dissociation was complete, sinus rate stable (97-100 beats/min) and no synchronization occurred. This is well seen in the lower graph, as the P-R interval shows no cyclical changes. Pacing at 91 beats/min still produced no IRD. However, since the rates of the two foci were somewhat closer, the slope of the P-R interval curves became less steep (but with no synchronization at all). In contrast to the left hand and middle graphs, classical synchronization with atrio-ventricular dissociation occurred when the ventricles were paced at 94 beats/min. As a result, m a r k e d sinus arr h y t h m i a ensued, and following a long period
of positive P-R interval the sinus rate dropped to 86 beats/min. The synchronization is classically demonstrated by the oscillation of the P-R interval. Again, as in Fig. 5, the positive P-R intervals were associated with a systolic blood pressure of 138 while the negative P-R intervals were associated with a systolic pressure of 118 mmHg. Figure 7 represents the failure to achieve IRD in the patient in cardiogenic shock (Table 2, patient 9). It can be seen t h a t the sinus rate r e m a i n e d u n c h a n g e d even though by manipulating the pacemaker rate (as seen by the course of the interrupted line in the upper portion) we were able to produce prolonged periods of positive P-R interval. There was no change in the blood pressure or in the sinus J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
185
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92
U
86
Fig. 6. Graphic representation of electrocardiographic calculations in patient 12 from Table 2. Upper and lower tracings are as in Fig. 5. CD: calculations made during complete dissociation. IRD: Calculations made during IRD. See discussion in text.
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rate. Blood pressure was 52-53 m m H g regardless of the position of the P wave in relation to the QRS complex.
DISCUSSION The synchronization of two seemingly independent electrophysiological foci presented an intriguing problem for m a n y years. It was shown by Segers 8 that frog hearts beating in vitro tend to synchronize if they come close together and if their initial rates are not too far apart. While the phenomenon was clear, its explanation remains an enigma even today. Only two forms of transmission from cell to cell are possible: synaptic and electrotonic. J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
Except for the tight junction of the cardiac intercalated disc, electrotonic intercellular spread of excitation is impossible. 7 In fact, it had been shown in tissue cultures t h a t h e a r t cells beat independently until intercellular bridges are formed, thus enabling synchronization, s Subthreshold electrotonic intercellul a r e f f e c t s a r e k n o w n to e x i s t b e t w e e n a d j a c e n t n e r v e fibers (axons), t h u s synchronizing the transmission of the action potential which was started simultaneously at one end of both axons. 9 Phenomena of synchronization are readily observed in t h e h u m a n h e a r t , a n d m a n y theories were put forward to explain it, as outlined in the introduction.~'5 Following the extensive studies of Levy et al 4'5 it became
186
KAPLINSKY ET AL
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. . . . . . . .
~
_ 284
obvious t h a t the clinical type of synchronization is totally different from the early observation on small hearts and nerve axons. It was shown in these studies t h a t in m a n (and in the dog) the synchronization of the atria a n d ventricles in most of the cases of complete heart block are the result of a negative feedback mechanism involving t h e baroreceptor a n d the autonomous .nervous system. The arterial blood-pressure fluctuations, caused by variations in the P-R interval, produced the cyclical changes in the sinus rate. As a result the P wave migrated and oscillated around the fixed QRS complex. .The behavior of a system governed by a negative feedback control is dependent upon the gain of the sensor and its frequency response (FR), the sensitivity and FR of the coordinating center and of its messengers and upon the sensitivity and FR of the responsive t a r g e t organ. T h e b a r o r e c e p t o r s are ex-
tremely fast in their reaction to blood pressure changes and thus have a very high FR. 1~ On t h e other hand, both the coordinating center and the target organs (of which the sino-atrial node is the fastest) have a much slower FR and thus tend to "average" blood pressure fluctuations. 1~Therefore, patients in complete heart block in whom beat to beat c h a n g e s in blood p r e s s u r e m a y r e a c h 50 m m H g and more still have a very stable autonomic nervous activity. This stability is demonstrated by the narrow range of sinus a r r h y t h m i a at rest (Table 2, Fig. 6). The pressure fluctuations (produced by the rapidly varying P-R interval) are too rapid to produce an effect and the central nervous system averages them. However, when t h e basic rates of the dissociated atria and ventricles vary less t h a n 10 beats/min, the "movement" of the P wave across the ventricular QRS complex cycle is slower. As a result the P wave stays in J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
ISORHYTHMIC DISSOCIATION
front of the QRS complex (although the P-R changes) for several beats. Now the elevation (or reduction, when the P stays in the ventricular systole for several beats) of the blood pressure is longer and the vasomotor center responds accordingly by changing the sinus r a t e , p r o d u c i n g a fine d e m o n s t r a t i o n of Marey's law. The result of all the above is that when the atria and the ventricles are completely dissociated (as in complete heart block), both independent foci are extremely stable (Table 2, Fig. 6). In contrast, as was shown in this study, when the ventricular rate was brought to the vicinity of the sinus rate, the latter, rather than synchronize exactly to the ventricular rate, became markedly u n s t a b l e and marked fluctuations appeared. Figure 6 demonstrates it beautifully. As long as the atria and ventricles were truly dissociated, the atrial rate was relatively fixed (97-100 beats/min). Upon a p p r o x i m a t i n g t h e ventricular rate to the atrial, the latter became markedly unstable and fluctuated from 86 to 101 beats/min. These fluctuations behaved as a typical part of a negative feedback control system. Acceleration appeared always a few beats after a period of a few seconds of low blood pressure (no P in front of the QRS complex). As the acceleration brought the P wave in front of the QRS complex for several consecutive beats, the sustained elevation of the blood pressure was long enough for the relatively slow responding centers to reduce the sinus rate. This in turn "moved" the P back into the QRS, causing a drop in blood pressure, and the cycle was repeated. The same p h e n o m e n a could be produced in patients with n o r m a l a t r i o - v e n t r i c u l a r conduction (Fig. 5). When the artificial pacemaker was only slightly faster than the basal rate, again P-R interval changes were slow enough for the central nervous system to take notice and respond. The only difference from the patients with complete A-V block was, of course, the ability of the ventricles to follow the accelerated sinus rate. The rise in pressure as a result was augmented not only by a "positive" P-R interval but also by the normal activation of the ventricles. Since the change was long enough, the negative feedback loop responded and marked slowing occurred, whereupon the ventricular demand pacemaker took over to start it all over again. Another feature in Fig. 6 deserves notice. Pacing at 87 and at 91 beats/min had no effect on the sinus node activity and there was no tendency to synchronize whatsoever (straight lines in the P-R interval graph). However, when the ventricular rate was elevated to 94 beats/min, a rate very close to the original sinus rate, the sinus node started oscillating J. ELECTROCARDIOLOGY, VOL, 10, NO. 2, 1977
187
and reached levels as low as 86. There was therefore no actual synchronization except, of course, that the m e a n rates were equal. Figure 4 summarizes the marked unstabilizing effect on sinus rate caused by the productior/ of isorhythmic dissociation. The dependency of these sinus rate oscillations on the baroreceptor reflex loop is further demonstrated in cases 7, 9 and 10 of Table 2. Case 9 represents a patient in terminal cardiogenic shock (Fig. 7). No IRD could b e produced despite repeated trials. The failure is explained by the almost total absence of any activity of the baroreceptors when the blood pressure falls to below 50 m m H g (systolic pressure in this patient was 54 mmHg). Patients 7 to 10 were hypertensive at the time of study and IRD was produced with difficulty. Furthermore, during the short periods of synchronization the range of sinus node rate fluctuations was narrow (6 beats/min in both patients), even though the blood pressure did fluctuate as expected. This again demonstrates the dependency of IRD on active and sensitive baroreceptors. At high blood pressure the carotid sinus approaches its maximal activity, and thus loses its high s e n s i t i v i t y . 1~ L o w e r e d s e n s i t i v i t y of baroreceptor reflex arch prevents the production of IRD, as shown by Levy and Edelstein 4 in their study on animals and in the study on computer models by Levy and Zieske. 1~ The reflex becomes insensitive at both ends of the clinical blood pressure scale and its effect on the ability to produce IRD is clearly demonstrated by these three patients. While in rare instances atria and ventricles are virtually "locked" together even though no atrio-ventricular conduction exists, most cases of isorhythmic dissociation show t h e classical oscillation of the P wave around the QRS complex. We have again shown in this clinical study the physiological dependence of these oscillations on an active baroreceptor reflex arch. I s o r h y t h m i c dissociation can therefore be viewed as a unique example of a negative feedback controlled physiological arrhythmia.
REFERENCES 1. GRANT,R P: Mechanism of A-V arrhythmias, with an electronic analogue of the human A-V node. Am J Med 20:334, 1956 2. JAMES, T N: Pulse and impulse in the sinus node. Henry Ford Hosp Med J 15:275, 1967 3. LEVY,M N, MARTIN, P J, IANO, T AND ZIESKE, H: Paradoxical effect of vagus nerve stimulation on heart rate in dogs. Circ Res 25:303, 1969
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KAPLINSKY ET AL
4. LEVY, M N AND ZIESKE, H: Mechanism of synchronization in isorhythmic dissociation: I. Experiments on dogs. Circ Res 27:429, 1970 5. LEVY, M N AND EDELSTEIN, J: Mechanism of synchronization in isorhythmic A-V dissociation: II. Clinical studies. Circulation 42:689, 1970 6. SEGERS, M: Les ph~nomenes de synchronisation au niveau du coeur. Arch Int Physiol 54:87, 1946 7. NOBLE, D: Applications of Hodgkin & Huxley equations to excitable tissues. Physiol Rev 46:1, 1966
8. HARARY, I AND FARLEY, B: In vitro studies of single isolated beating heart cells. Science 131:1674, 1960 9. KATZ, B AND SCHMITT, O H: Electric interaction between two adjacent nerve fibers. J Physiol 97:471, 1940 10. KORNER, P I: N e u r a l circulatory control. Physiol Rev 51:312, 1971 11. LEVYM N AND ZIESKE, H: Mechanism of synchronization in isorhythmic A-V dissociation. III. Computer model. Circ Res 28:253, 1971
J. ELECTROCARDIOLOGY, VOL. 10, NO. 2, 1977
