Post extra-systolic potentiation during coupled stimulation of the heart

j . ELECTROCARDIOLOGY, 4 (4) 341-346, 1971

Post Extra-Systolic Potentiation During Coupled Stimulation of the Heart* BY A. M. CHEVALIER-CHOLAT~, J. TORRESANI++, A. SAADJIAN, M.D.w G. HEUILLET, M.D., AND A. JOUVE, M.D. *~ With the Technical Assistance of M. Garcia

SUMMARY Coupled stimulation was performed in acute experiments on 60 dogs under pentobarbital anesthesia. Stimuli were delivered successively on right a n d / o r left ventricle with progressively increasing coupling delays. Post extra-systolic potentiation assessed by the increase in peak ventricular pressure and d p / d t max was studied in both ventricles. Selective effects were obtained depending on the site of stimulation. The maximal potentiation was always obtained in the stimulated ventricle because of the shorter delay of coupling. Cardiac output measurements made by the thermodilution technique, for coupling delays corresponding to the maximal potentiation, failed to show any statistically significant difference. INTRODUCTION It has long been known that, following a premature beat, the force of cardiac contraction is increased. This phenomenon, initially described by LangendoW in the heart of the frog, was considered to be the result of a compensatory pause leading to a better dias~*From the Experimental Cardiology Laboratoiv, University of Marseilles, J. Cantini Cardio-Vascular Center, Av. Vedrines, 13 Marseilles IX, France. This project was supported by: General Delegation for Scientific and Technical Research - 67/00/656. tAttachge de recherche, I.N.S.E.R.M. ~Ma~tre de Conference Agr~g6. w de recherche, I.N.S.E.R.M. **Professeur Clinique Cardiologique. Reprint requests: A. M. Chevalier-Cholat, Centre J. Cantini, Av. Vedrines, 13-Marseilles IX, France.

tolic ventricular filling. A few years later, Woodworth is presented a more detailed analysis, pointing out the fact that the increase in cardiac contraction is due to specific changes in contractility rather than to simple hemodynamic changes. These results were subsequently confirmed in experiments on isolated myocardial preparations (Siebens 14) (Wallon17). Paired and coupled cardiac stimulation allowed numerous investigators to study post extra-systolic potentiation (HoffmannS, s) (Lopezl~ (Chardack ~) (Braunwald 2) (Torresani15). Besides their potential clinical applications, these techniques may result in an interesting approach to myocardial function. However, it can be questioned whether post extra-systolic potentiation can affect the whole myocardium in the same way and whether dissociated responses can be elicited when varying the site of stimulation. The present experiments were designed in order to study the various degrees of potentiation obtained by right a n d / o r left ventricular stimulation. Coupled ventricular stimulation was thought to be better adapted to this study than paired stimulation because it allowed more accurate measurements throughout the cardiac cycle. In addition, cardiac output measurements were done to check whether different levels of potentiation in each ventricle resulted in subsequent changes in cardiac output. M A T E R I A L S AND M E T H O D S Experiments were conducted on 60 unselected mongrel dogs, weighing 8 to 17 kg. Anesthesia was obtained by sodium pentobarbital. Respiration was maintained by a Palmer Pump through a cuffed endo-tracheal

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tube. In ten experiments where cardiac output was determined, sodium pentobarbital was used as a starter (20 m g / k g ) , anesthesia being maintained by an intravenous continuous infusion of Diazepam, with the animal breathing spontaneously. Zucker catheters allowing pressure measurements, intracardiac ECG recording, or bipolar stimulation, were introduced into the left and fight ventricles, using, respectively, femoral or carotid arterial retrograde catheterization, and a femoral venous approach. Pressures were recorded using Elema E M T 35 electromanometers or Sanborn P 23 DB gauges. The first derivative of these pressures ( d p / d t ) was obtained through a ThomsonTelco differentiator. These parameters, continuously monitored on an oscilloscope, were registered on an Elema Mingograph or Sanborn Recorder. Cardiac output was determined by the thermodilution technique. For this purpose, a thermistor (Y.S.I. 140 12A) was introduced into the pulmonary artery. A 5 ml saline bolus, at room temperature (18 to 23 ~ centigrade), was injected into the right atrium by means of a Reynolds pneumatic syringe. Thermodilution, using a short lasting indicator, allowed numerous determinations over a short period of time. Each figure used in the calculations was the mean value of ten determinations obtained in 10 minutes. In these experimental conditions, statistical studies indicated that standard error never exceeded 6%. Stimulation was performed using a Medtronic 5837 R wave coupled pulse generator. In the coupled mode, this device can be triggered by potentials from 0.5 to 10 mV, allowing good synchronization on intracardiac ECG. The refractory period cannot be reduced to less than 300 msec, so continuous coupled stimulation could be obtained only when the cardiac period exceed 300 reset, when a 100 to 150 msec coupling delay was used. The response to coupled stimulation was systematically studied using supra liminal impulses, delivered with the delay from the R

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Fig. 1. Exploration of the entire cardiac cycle by coupled stimuli. wave progressively increased by increments of ten msec. In this way, the entire cardiac cycle was explored from the end of the refractory period of the synchronizing systole (S1) to the beginning of the refractory period of the third systole ($3) (Fig. 1). Coupled stimulation was successively performed on each ventricle, the impulse being triggered by the intracardiac ECG of the opposite ventricle. The experiments were completed by bilateral simultaneous coupled stimulations and right atrial stimulation. Post extra-systolic potentiation was assessed using peak systolic ventricular pressures and d p / d t max. RESULTS 1. Onset of post extra-systolic potentiation. Classical features of post extra-systolic potentiation were registered. As shown by the increase in ventricular peak pressure and d p / d t max values, post extra-systolic potentiation appears after two or three coupled extrasystoles and reaches its maximal level for a given coupling delay after the 5th extrasystole. It lasts as long as coupled pacing is maintained. Its magnitude is related to the prematurity of the extra-systole, being maximal when the electrically induced beat does not result in a mechanical response. When coupled stimulation is stopped, a depression occurs. The greater the potentiation, the more marked the depression. Besides these well known features, the resuits indicate that the site of application of J. ELE~TROCARDIOLOGY, VOL. 4. NO. 4. 1971

POST E X T R A - S Y S T O L I C

34 3

POTENTIATION

When both ventricles were simultaneously submitted to coupled stimulation, potentiation occurred in a similar manner in each and evolved in the same way when coupling delay was progressively changed (Fig. 4). 2. Influence of selective coupled stimulation on cardiac output.

Fig. 2. From top to bottom left ventricular pressure, ECG, right ventricular pressure. A = Basal B = Stimulation A stimulus delivered to the right ventricle 140 msec after the R wave results in an important potentiating effect on right ventricular pressure. Coupled extrasystole appears to be delayed in the left ventricle where no potentiation occurs. the coupled stimulus plays an important role in the onset of post extra-systolic potentiation, allowing selective action on each ventricle. In Fig. 2, right ventricular coupled stimulation (delay = 14-0 msec) results in a significant potentiating effect, as shown by the increase in peak ventricular pressure, while the induced extra-systole is without mechanical effect; at the same time, this same extra-systole appears to be mechanically effective in the left ventricle, and no potentiation occurs. Fig. 3 shows the evolution of potentiation in both ventricles (as shown by ventricular peak pressures) for increasing values o f coupling delay during left ventricular coupled pacing. In this experiment, potentiation is present in the left ventricle for delays ranging from 200 to 410 msec. At the right ventricle, potentiation occurs 20 msec later. This difference is due to the propagation of excitation from the stimulated ventricle. Such findings were consistently registered throughout the experiments. It was possible in this way to get a potentiation effect selectively on one ventricle without affecting the other one. Maximum potentiation was always obtained in the stimulated ventricle because of the shorter delay of coupling. J, ELE~CTROCARDIOLOGY, V O L . 4, N O . 4, 1971

In each type of coupled ventricular stimulation (right, left), cardiac output determinations were obtained for coupling delays corresponding to the maximal potentiating effect. In order to minimize spontaneous variations, the values for normal sinus rhythm were obtained at the beginning of the experiments, and then between randomized episodes of stimulation. The difference was established between every stimulation run and the last control period. In general, coupled stimula-

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Fig. 3. Left ventricular coupled stimulation. The values of peak systolic pressure of the systole (S) and the extrasystole (ES) are plotted for increasing coupling delay. The onset (~f) and the offset ( * ) of potentiation are indicated by arrows. Potentiation occurs earlier at the level of left ventricle.

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C HEVALIER C HOLAT ET AL -

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Fig. 4. Left and right simultaneous ventricular coupled stimulation. From top to bottom ECG, first derivative of left ventricular pressure, right ventricular pressure (RV), left ventricular pressure (LV). The amplitude of systole and extra-systole evolves in a parallel manner in both ventricles for increasing coupling delays.

T~LEI Effect o f right and left ventricular coupled stimulation u p o n cardiac output measured by the t h e r m o d i l u t i o n method.

Mean value 1 / m i n Basal Right ventricular stimulation

Basal Left ventricular stimulation

3,23

F 0,176

N o t significant

0,292

N o t significant

2,86

3,26 2,78

Table I - - Effect of right and left ventricular coupled stimulation upon cardiac output measured by the thermodilution method. J. EL~CTROCARDIOLOGY, VOL. 4. NO. 4. 1971

POST EXTRA-SYSTOLIC POTENTIATION

tion resulted in a slight, statistically insignificant decrease in cardiac output (Table 1).

DISCUSSION From these experiments, it is evident that selective effects can be obtained by coupled stimulation. Since we want to compare the increase in myocardial contractile force that can be obtained in various situations, it seems necessary to make a critical analysis of the criteria of post extra-systolic potentiation. The simplest among them are the increase in peak ventricular systolic pressure and the decrease in ventricular end diastolic pressure. The former was used in these experiments to show the evolution of post extra-systolic potentiation (Fig. 3). The first derivative of ventricular pressure d p / d t max appeared to be a more accurate index of myocardial contractile force. But, as pointed out by Mason z2, d p / d t max is affected by changes in pre-load and after-load as well as by alterations in heart rate. Wallace 16, using auricular pacing, demonstrated a linear correlation between d p / d t max and heart rate. Mason stated that "by the use of peak d p / d t alone, it is not possible to assess precisely the direct positive or negative inotropic effects of an intervention when that intervention also produces chronotropic effects." Correct assessment of such changes in contractility requires the study of more complex indexes in which ventricular and diastolic volumes and integrated systolic volumetric tension are taken into account. Aortic velocity measurements are of restricted interest in comparative studies, because they cannot yield information when potentiation is induced in the right ventricIe. As far as cardiac output is concerned, most authors agree that paired stimulation does not lead to significant variations in normal hearts (Braunwald a, Chardack 4, Ross 1~, Lluch 9, Bassett 1 and LaurentS). Our results are in agreement with these findings. They indicate that the lack of stimulation induced changes in cardiac output are not related to th~ Tocation t . ELBCTROCARDIOLOGY, VOL. 4. NO. 4, 1971

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of the stimulus on the right or left ventricle. An increase in cardiac output cannot be considered as a criterion for post extra-systolic potentiation in the absence of heart failure.

CONCLUSIONS Post extra-systolic potentiation elicited by coupled stimulation cannot be considered as a global phenomenon affecting in an equal manner the whole myocardium. According to the site of stimulation (right or left ventricle), a selective right or left effect can be obtained for given delays of coupling. Maximal potentiation effect is produced upon the stimulated ventricle. These dissociated effects, which are not described in previous literature, are not accompanied by significant changes in cardiac output. Further studies are necessary to control the possible action of selective potentiation upon right and left sided cardiac failure. It is possible that the inconsistent results obtained by coupled pacing in human heart failure are related to inaccurate ventricular coupling.

REFERENCES 1. Bassett, A. L., and Kao, F. F.: Effects of paired stimulation on cardiac output in dogs at rest and during exercise. Am. J. Physiol. 216:63, 1969.

2. Braunwald, N. S., Gay, W. A., Morrow, A. G., and Braunwald, E. : Sustained, paired electrical stimuli. Slowing of the ventricular rate and augmentation of contractile force. Am. J. Cardiol. 14:385, 1964. 3. Braunwald, E., Ross, J., Frommer, P. L., Williams, J. F., Sonnenblick, E. H. : Clinical observations on paired electrical stimulation of the heart. Amer. J. Med. 37:701, 1964.

4. Chardack, W. M., Gage, A. A., and Dean, P. C.: Slowing of the heart by paired pulse pacemaking. Am. J, Cardiol. 14:374, 1964. 5. Hoffman, B. F., Bindler, E., and Suckling, E. : Post extra-systolic potentiation of contraction in cardiac muscle. Am. J. Physiol. 185:95, 1956. 6. Hoffman, B. F., and Cranefield, P. F.: Paired pulse stimulation of the heart. Am. Heart J.

71:143, 1956. 7. Langendorf, O.: Ueber Elektrische Reizung

des Herzens. Arch. Physiol. 8:284, 1885. 8. Laurent, D., and Gourgon, R.: Potentialisation post extrasystolique et consommation

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10.

11. 12.

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myocardique d'oxyg~ne. J. Physiologie $9:252, 1967. Lluch, S., Hirsch, L. J., and Katz, L. N.: Influence of site and driving frequency of paired pacing on its hemodynamies effects. Am. J. Physiol. 213:1131, 1967. Lopez, F. J., Edelist, A., and Katz, L. N.: Slowing of the heart rate by artificial electrical stimulation with pulses of long duration. Abstract Circulation 28:759, 1963. Lopez, J. F., Edelist, A., and Katz, L. N.: Reducing heart rate of the dog by electrical ~timulation. Circulation Res. l 5:414, 1964. Mason, D. T.: Usefulness arid limitations of the rate of rise of intraventricular pressure (dp/dt) in the evaluation of myocardial contractility in man. Am. J. Cardiol. 23:516, 1969. Ross, Jr., J., Sonnenblick, E. H., Kaiser, G. A., Frommer, P. L., and Braunwald, E.: Electroaugmentation of ventricular performance and oxygen consumption by repetitive application of paired electrical stimuli. Cir. Res. 16:332, 1965.

14. Siebens, A. A., Hoffman, B. F., Cranefield, P. F., and Brooks, C. McC.: Regulation of contractile force during ventricular arrhythmias. Am. J. Physiol. 197:968, 1959. 15. Torresani, J., Arnoux, M., Jobin, A., Giraud, M., Henry, E., and Jouve, A. : Ralentissement cardiaque par stimulation ~lectrlque. Arch. Mal. Coeur. $8:1669, 1965. 16. Wallace, A. G., Sheldon, Jr., S. N., and Mitchell, J. H. : Hemodynamic determinants of the maximal rate of rise of left ventricular pressure. Am. J. Physiol. 205:30, 1963. 17. Wallon, G., Coraboeuf, E., and Gargouil, Y. M. : Relation entre m~canogramme localis~ et ~lectrocardiogramrue cardiaque intra-cellulaire sur le coeur de mammif~re isol~. Effet inotrope positif des contractions pr~alables. C. R. Soc. Biol. 153:1451, 1959. 18. Woodworth, R. S.: Maximal contraction, "staircase" contraction, refractory period, and compensatory pause of the heart. Am. J. Physiol. 8:213, 1903.

J. ELECTROCARDIOLOGY, VOL. 4, NO. 4, 1971