Methods for producing experimental complete atrioventricular block in dogs

REVIEW

ARTICLE

Methods for Producing Experimental Complete Atrioventricular Block in Dogs

M. BOUCHER AND P. DUCHENE-MARULLAZ

This paper reviews methods for producing experimental complete atrioventricular (A-V) block in dogs, with emphasis on those methods that enable chronic A-V block to be obtained. The dog with chronic complete A-V block, particularly when unanesthetized, is a useful experimental model, and the production of complete A-V block is an approach to the clinical treatment of certain supraventricular arrhythmias. Criteria for the choice of method are discussed, and the results obtained to date in the unanesthetized dog with chronic A-V block are briefly described to illustrate the usefulness of this experimental model. Complete A-V block; Dog; His bundle crushing; His bundle secKey Words: tion; His bundle ligature; His bundle necrotization; His bundle cauterization;

His bundle cryosurgical ablation INTRODUCTION

Ever since the discovery of the atrioventricular (A-V) conduction system by His Jr (1893-1895), who showed that severing the bundle that bears his name brought about a dissociation of atrial and ventricular rhythms in the rabbit, numerous research teams have studied ways of interrupting this conduction in order to achieve complete A-V block. Initially, the main aim was to determine whether the bundle of His really was solely responsible for A-V conduction. More recent research has been directed towards developing reliable methods for achieving complete chronic A-V block in experimental animals. The dog with chronic A-V block, particularly when unanesthetized, offers many useful possibilities as a model for physiological, physiopathological, and pharmacological studies. This review describes the various methods proposed for achieving chronic complete A-V block in the dog, and the specific aspects of each method. The results obtained are compared wherever sufficiently accurate data are available, particularly during the period immediately after surgery. On the other hand, methods developed on the heart perfused in situ or in vitro are only briefly mentioned, and those From the Department France.

of Pharmacology, U.195 INSERM, Faculty of Medicine,

Address reprint requests to: M. Boucher, Department of Pharmacology, Medicine, 63001 Clermont-Ferrand Cedex, France. Received August 1984; revised and accepted October 1984.

Clermont-Ferrand U.195 INSERM,

Cedex,

Faculty of

95 Journalof

Pharmacological Methods

6 1985 Elsevier Science Publishing

13, 95-107 (1985) Co., Inc., 52 Vanderbilt

0160-5402/85/$03.30 Avenue, New York, NY 10017

96

M. Boucher and P. Duchene-Marullaz

methods designed to produce acute complete A-V block are dealt with in detail only when they have also been used to achieve chronic A-V block after suitable modification. Criteria for the choice of method are discussed, and the results obtained to date in the unanesthetized dog with chronic A-V block are briefly described to illustrate the usefulness of this experimental model.

METHODS Production

FOR PRODUCING of Complete

COMPLETE

A-V BLOCK

A-V Block by Crushing

IN DOGS

the Bundle

of His

Fredericq (1904-1906) was the first to produce A-V dissociation by crushing the bundle of His. After thoracotomy, temporary occlusion of cavae, and atriotomy, a pair of forceps is introduced into the right atrium. The left forefinger is placed behind the root of the large arteries, and the forceps are manipulated with the right hand. The lower jaw of the forceps first grazes the floating edge of the septal leaflet of the tricuspid valve and is then pushed towards its septal edge. The forceps are then closed so that their upper jaw presses against the right endocardial side of the interatrial septum. Though initially meant for obtaining acute complete A-V block in the dog, this technique has, with modifications, been used to achieve chronic A-V block (Boucher et al., 1979; Boucher and Duchene-Marullaz, 1980; DucheneMarullaz et al., 1974). At about the same time, Erlanger (1906) and Erlanger and Hirschfelder (1906), who were mainly interested in obtaining a graduated compression of the bundle of His, developed a special clamp based on an L-shaped fish-hook. Its blunt end was fitted with a threaded brass bar along which a small brass block could travel. This block could be moved towards or away from the end of the hook by means of a threaded nut. After thoracotomy and opening of the pericardium, the point of the hook is introduced into the left ventricle through the wall of the aorta near its root and thence into the right ventricle through the ventricular septum 3-4 mm below the A-V junction. The brass block is then slid along its bar towards the end of the hook to compress the bundle of His. Erlanger and Blackman (1909), with this same clamp, In later experiments, achieved the first chronic A-V block in the dog using a modified procedure. After thoracotomy and opening of the pericardium, the point of the hook is first introduced into the right ventricle through the wall of the right atrium and then into the inter-ventricular septum below the bundle of His located by grasping the upper edge of the septum between thumb and forefinger. Then, as soon as tightening the clamp is felt to block A-V transmission, the tissue in the grasp of the clamp is thoroughly crushed. Meakins (1913), who also wanted to achieve graduated compression of the bundle of His, proposed another type of clamp. After thoracotomy, one arm of this clamp is introduced into the left carotid artery a few centimeters above its root and into the ventricle through the aortic valves, and the other arm enters through the right atrium. Complete A-V block is obtained by closing the arms after positioning using anatomical guidemarks.

Complete Atrioventricular Block in Dogs Taufic et al. (1955) later modified this method. After thoracotomy, temporary occlusion of the main arteries and veins (2 min, 30 set), and atriotomy, chronic A-V block is achieved by crushing with hemostatic forceps the portion of the ventricular septum that contains the two branches of the bundle of His and making a l-1.5cm-long incision just below the crushed zone. Production

of Complete

A-V Block by Sectioning the Bundle of His

Complete A-V block in the dog was first obtained by sectioning the bundle of His by Humblet (1904). After thoracotomy, temporary interruption of venous circulation, and atriotomy, Humblet performed an anterioposterior section from the lower perimeter of the Botal orifice towards the root of the coronary vein. However, after repeated failure in the intact animal, Humblet decided to use hearts perfused with Locke’s fluid and defibrinated blood. Hering (1905-1906) also obtained complete A-V block by sectioning the bundle of His using this same model. More recently, Starzl et al. (1955) and Starzl and Gaertner (1955) revived this method to obtain both acute and chronic A-V block. After thoracotomy, the bundle of His is sectioned through a right atrial myocardiotomy with temporary occlusion of cavae (60 set), aspiration of residual blood, and continuous drainage from the coronary sinus. Section is across the A-V junction 5-10 mm anterior to the coronary sinus starting at the posterior end of the base of the septal cusp and usually extending some way into the contiguous atrium and ventricle. Connolly et al. (1965) have used a modified version of this method. They have obtained chronic A-V block by sectioning the bundle of His and then cauterizing the incision. After thoracotomy, temporary occlusion of cavae (2-4 min), and atriotomy, the septal wall of the right atrium and related structures are visualized, and a vertical incision is made in the atrial septum just above the tricuspid valve about 1.75 cm anterior to the ostium of the coronary sinus. The incision is then cauterized by electrocautery. Production

of Complete

A-V Block by ligating the Bundle of His

Complete A-V block in perfused dog hearts by ligation of the bundle of His was first achieved by Humblet in 1905. He used a silk thread looped around the bundle where it runs parallel to the upper edge of the interventricular septum. Taufic et al. (1955) used this method, with modifications, to produce chronic A-V block in intact dogs. After thoracotomy, occlusion of main arteries and veins (2 min, 30 set), and atriotomy, a ligation is placed around the portion of the ventricular septum containing the His branches, and the myocardial tissue is sectioned by means of this ligature. This method is in fact more a sectioning method than a ligating method. Folkman and Watkins (1957) achieved acute and chronic A-V block using a method derived from that of Starzl and Gaertner (1955) in which a section of the bundle of His is replaced by ligation. A right atrial incision is made, and the bundle of His is encircled with a silk thread placed in the atrial septum 1 cm anterior to the coronary sinus. The suture runs at a 90” angle to the tricuspid valve annulus and includes a large portion of atrial septum and tricuspid valve annulus at the root of its septal leaflet.

97

98

M. Boucher and P. Duchene-Marullaz

Weirich et al. (1958), using the technique described by Taufic et al. (1955) which they accurately codified, achieved acute and chronic complete A-V block by placing, after thoracotomy, temporary occlusion of cavae (30-45 set), and atriotomy, a suture across the annulus of the tricuspid in a cephalocaudal direction l-l.5 cm anterior to the coronary sinus. The needle is inserted through the septal leaflet 3 mm below the annulus and emerges from the interatrial septum about 4 mm above the A-V junction. Cruze and Schiebler (1963) reported achieving chronic A-V block by a two-stage ligature method performed under only light general anesthesia. First, after thoracotomy, temporary occlusion of cavae (50-90 set), and atriotomy, a suture is passed around the bundle of His in a figure-eight configuration, drawn through the superior vena cava into a branch of the external jugular vein, and placed subcutaneously in the animal’s neck. In the second stage, once the dog is fully recovered, complete A-V block is induced under light general anesthesia by threading an instrument over and down the previously placed suture in the neck and tightening the suture around the bundle of His. Returning to the classical method of ligation, Leininger et al. (1970) achieved acute A-V block without prior atriotomy and so without temporary occlusion of cavae. After thoracotomy, the relevant cardiac structures are located by palpation, and a needle is passed through the anterior wall of the right atrium, through the edge of the medial leaflet of the tricuspid valve, back up through the interatrial septum, and then out through the anterior wall of the right atrium. Production

of Complete

A-V Block by Injecting

Necrotizing

Solutions into the

Bundle of His Erlanger and Blackman (1909) first used this method by injecting a solution of iodine in alcohol into the bundle of His after thoracotomy but without atriotomy. However, this technique proved very uncertain for obtaining reproducible chronic A-V block and was soon abandoned by these workers. Guzman et al. (1959) subsequently improved this method and succeeded in achieving chronic A-V block by injecting, after thoracotomy, 2-4 ml of 10% formalin solution into the upper part of the interventricular septum by a direct right atrial needle puncture. The exact site of injection is the annulus of the septal leaflet of the tricuspid valve, l-l.5 cm below the coronary sinus. Williams and Lambert (1964) and Williams et al. (1969) were the first to produce acute and chronic A-V block without thoracotomy. A first step in this direction had been made by Cruze and Schiebler (1963). Complete A-V block is achieved with a rather complicated electrode-injection assembly which allows measurement of the pressure at the end of the injection catheter, injection of the necrotizing solution, and recording on an oscilloscope of the electrocardiogram (ECG) trace of the region being explored. This assembly is inserted percutaneously down the right external jugular vein and positioned near the A-V node using fluoroscopic and pressure monitoring. The A-V node deflection described by Pruitt and Essex (1960) is then sought by exploring the region with the outer needle of the assembly, which serves as an intracardiac electrode. As soon as it is detected, the inner needle is pushed

Complete Atrioventricular

Block in Dogs

through into the A-V node region to inject 0.2 ml of 10% formalin or absolute alcohol. Fisher et al. (1966) likewise achieved chronic A-V block by injection of formol without prior thoracotomy by a somewhat different technique. A curved-tip radiopaque catheter is inserted via the right femoral vein into the right ventricle in such a way that under fluoroscopic monitoring the curved portion describes an arc extending from the inferior caval orifice across the interatrial septum into the right ventricle. A straight radiopaque catheter is then inserted into the right atrium via the right external jugular vein. A curved-tip needle attached to a syringe containing 40% formalin is then pushed down the catheter. The arc made by the curve of the first catheter bounds the region of the interatrial septum containing the A-V node and bundle of His. With the curved tip of the needle facing the septum, the second catheter is advanced until the septal edge of the A-Vvalve annulus is felt. The needle is then pushed through into the underlying tissue, and 0.1-0.2 ml of formalin is injected. Steiner and Kovalik (1968) proposed a novel adaptation of this method to produce chronic A-V block. After thoracotomy, a traction suture is placed on the right atrial appendage which is retracted to expose the groove between the right atrium and the root of the aorta. A needle (1.5 cm long, bent at about 60”) is inserted into the atrial tissue at the groove and directed parallel to the aorta inferiorly and dorsally to a depth of 0.5-I cm, and 0.1 ml of 40% formalin is then injected. Turina et al. (1968) used an instrument somewhat similar in principle to that used by Williams and Lambert (1964) to produce acute and chronic A-V block. A cannula is introduced via the right external jugular vein into the right atrium with fluoroscopic monitoring. The tip of the cannula is bared of insulation so that it can act as an exploring electrode. The bundle of His is located by looking for characteristic potentials, and once found it is injected with 0.2-0.3 ml of 40% formalin by means of a needle-tipped catheter advanced through the cannula. Babotai and Brownlee (1971) proposed using an instrument similar in principle to that used by Williams and Lambert (1964) that enables acute and chronic A-V block to be produced by one person without either thoracotomy or fluoroscopy. A cannula is introduced into the right atrium via the right external jugular vein. The direction of its tip is controlled by means of a flange attached to the distal end of the instrument. As soon as the typical potential for the bundle of His is detected by the outer cannula, the inner cannula is inserted 3-4 mm into the myocardium overlying the bundle, and 0.4 ml of 40% formalin is injected. Baum et al. (1975) produced acute A-V block with thoracotomy using a novel multibarrel electrode. After posterior reflection of the right atrial appendage, the electrode assembly is introduced into the groove between the atrial wall and the root of the aorta. The central barrel acts as an exploring electrode to locate the bundle of His. Formalin (0.1 ml of 40%) is injected through another barrel by means of a plunger. Randall et al. (1981) have obtained acute and chronic A-V block using the method of Turina et al. (1968) and the instrument described by Babotai and Brownlee (1971), which is introduced into the right jugular vein and advanced into the right atrium

!I!3

100

M. Boucher and P. Duchene-Marullaz under fluoroscopy. The His bundle is located with a quadripolar His catheter introduced into the left femoral vein under fluoroscopy, and with the blunt tip of the outer cannula, 0.2-0.4 ml of a solution made up of equal amounts of 40% formalin and radiopaque material is injected. The contrast material enables the myocardial position of the tip of the inner cannula to be confirmed. Ito and Feigl (1983) have proposed a new, improved instrument to produce acute and chronic A-V block by injecting a necrotizing agent into the area of the A-V node located by means of intracardiac landmarks identified with fluoroscopy. The cannula is inserted into the right external jugular vein and passed into the right atrium. Once the proper area is located, by inserting catheters into the sinus coronary ostium and into the sinus of Valsalva of the dorsal semilunar cusp of the aortic valve and by injecting radiopaque contrast media, the inner needle is extended into the tissue, and 0.1-0.3 ml of 37% formalin saturated with lead acetate is injected. Production

of Complete

A-V Block by Cauterizing

the Bundle of His

Eyster and Swarthout (1920) were the first to achieve acute complete A-V block by heating the A-V node region and upper part of the bundle of His with a thermode applied through the right atrial appendage after thoracotomy. Through a modification of the technique reported by Taufic et al. (1955), Warner and Toronto (1960) achieved chronic A-V block by electrocauterizing an area about 2 mm diameter on the interatrial septal surface just under the tricuspid valve through a right atrial incision made during 1.5-2-min venous inflow occlusion. Brutsaert (1965) and Wieberdink (1966) produced chronic A-V block by cauterization without interruption of the circulation. After thoracotomy, the electrode is introduced through a small incision, and a purse-string suture is made in the lateral wall of the right atrium opposite the A-V node. The area to be coagulated is roughly determined by the left forefinger, which is pushed downwards to the root of the aorta behind the right atrial appendage. The exact point to be coagulated is then located by directly watching the heart. Retardation of conduction in pressure tests indicates the correct point. The same year, Brutsaert (1966) proposed a technique for producing chronic AV block by electrocoagulation without thoracotomy. An electrode is introduced under fluoroscopic monitoring via the right external jugular vein into the right atrium. The uninsulated tip of the electrode is then pressed onto the area about 1.5 cm anterior to the junction of the inferior vena cava with the right atrium (readily seen fluoroscopically) or about 2 cm anterior to the coronary sinus (located by inserting a radiopaque catheter into its lumen). When pressure results in partial or complete A-V block, the underlying area is electrocauterized. MacDonald (1967) achieved chronic A-V block by a method pratically identical to that described by Wieberdink (1966), without attempting to locate the bundle of His by causing conduction delay. With this procedure, some ventricular fibrillation was observed immediately after creation of the A-V block. The fibrillation is reportedly readily corrected. Pruett and Woods (1967) report a method based on the technique of Starzl and Gaertner (1955) which they had modified by cauterizing the bundle of His instead

Complete Atrioventricular Block in Dogs of sectioning it. After incision of the right atrium, aspiration of residual blood, and continuous drainage of the coronary sinus, an area 2 x 7 mm, beginning near the center of the base of the septai leaflet of the tricuspid valve, is cauterized by a special cautery. Smyth and Magassy (1970) found that the methods of Wieberdink and MacDonald lacked accuracy in locating the A-V node and His bundle, and accordingly modified these techniques to achieve acute A-V block. They used a cautery which not only serves to perform the cauterization but also acts as an electrode for recording intracavital EC&. The region to be cauterized is thus located by its ECG characteristics. Beazell et al. (1976-1982) obtained acute and chronic A-V block without thoracotomy by an electrical discharge delivered via a needle connected to a directcurrent defibrillator. The needle is advanced through a catheter placed in the right atrium, the exposed tip is pushed into the atrial septum adjacent to the tricuspid valve, and a discharge is applied. In order to minimize ventricular fibrillation, Shiang et al. (1977) proposed a slight modification of the procedure used by MacDonald (1967). They used indirect cauterization of the bundle of His with a partially insulated wire and electric cautery forceps to produce acute and chronic A-V block. Gonzales et al. (1981) have proposed an improvement on the method of Beazell et al. (1976), which they judge insufficiently accurate to produce chronic A-V block. A modified quadripolar electrode catheter is inserted percutaneously into the right femoral vein and positioned under fluoroscopy across the tricuspid valve to record the His bundle potential and deliver an electrical discharge. As soon as His bundle potential is recorded, a direct-current discharge is delivered during the QRS complex between the electrode that shows the largest His bundle deflection, using a standard direct current-defibrillator, and a metal plate positioned over the dog’s back. Bardy et al. (1983) have used the same method as Gonzales et al. (1981) to produce chronic A-V block, but they use a standard tripolar intracardiac recording catheter without fluoroscopy. Production His

of Complete

A-V Block by Cryosurgically

Ablating the Bundle of

Harrison et al. (1977) proposed an original method for producing chronic complete A-V block in the dog by freezing the bundle of His. After thoracotomy, temporary occlusion of cavae (3 min at most), and atriotomy, a cryosurgical probe is placed in the floor of the right atrium just above the tricuspid valve in a line connecting the coronary sinus orifice with the atrial portion of the membranous septum. This area is then cooled to -55” to -60°C for 90-120 set by passing nitrous oxide under pressure down the inside of the hand-held probe. RESULTS AND DISCUSSION The results obtained with the various methods used to produce chronic complete A-V block are shown in Table 1. Despite the large number of techniques mentioned,

101

15 5 9 IO

15 5 10 10

Cauterization

12

9

11 13

3 24

5

38

immediately

--

FIRST

of A-V block.

s

14E 5 9

12

9

2 lgc

7

28

7-56 90

?

a-64

14-56

90 2-14

150-578

42-280

II

8-3870

7-343

(DAYS)

PERIODa

-

WEEK

OBSERVATION

0

80

4

POSTOP

A-V BLOCKBEYOND

after production

0

0" 0 0

I= 0 0 5

0

0

2=

lb

1

0

0

0 3=

0

a

Section icauterization Ligature Injection of formol Injection of formal Injection of formal Cauterization Cauterization Cauterization

IO

1

0

12

4

16

WEEK

DIED FIRSTPOSTOP

IN CHRONIC

Chronic A-V Block in Dogs

0

23

1

RHMHM

12

SINUS

RETURNED TO

Dacs

This table does not include results involving dogs fitted with a ventricular pacemaker Abbreviatian: postop = postoperative. a End of observation period corresponds to death or sacrifice of animal. * Dog killed (reason unknown). c Evolution over first postoperative week not accurately known.

MacDonald (1967) Shiang et al. (1977) Gonzales et al. (1981) Bardy et al. I19831

(I 968) Turina et al. (1968)

Steiner and Kovalik

(19651 Taufic et al. (1955) Fisher et al. (1966)

Starzl and Caertner (1955) Connolly et al.

4

a

Crushing + section Section

119

133

Crushing

6

POSTOP

13

OPERATED ON

3COCK

Crushing

METHODS

A-V

IMMEDIATELY

iN

NUMBER OF

Results Obtained with Various Methods for Producing Experimental Complete

Erlanger and Blackman (1909) 3oucher et al, (unpublished results} Taufic et al. (1955)

AUTHORS

TABLE 1

Complete

Atrioventricular

Block in Dogs

only a few results are known with sufficient accuracy to warrant inclusion. These results also show considerable variability, apparently owing more to experimental than methodological factors. Of course, it may be that not all results have been reported. Which method, then, is the best? Among all those described, no single method stands out as being evidently more efficient than the others. With a few exceptions, all authors consider that, in their hands, the method they have chosen gives good results on the whole. This is hardly surprising since creation of A-V block is always a fairly complex operation in which success depends to a great extent on the skill and experience of the experimenter. Thus, provided they are carried out by experimenters who are used to them, most of the procedures described seem to be capable of giving good results. Indeed, proper choice of a particular method for achieving chronic A-V block would seem to depend more on the previous experience of the experimenters, the availability of materials and instrumentation, and on the use to which the dogs are to be put, than on any objective appraisal of the method itself. Thus although need for thoracotomy might a priori be considered a major disadvantage, if subsequent experimentation requires placement of myocardial electrodes or intrathoracic probes, a method that involves thoracotomy may well be preferable. Choice may also be limited by the availability of costly equipment such as a fluoroscopy instrument, oscilloscope, or cryosurgical unit. Employment of unfamiliar instruments such as a special clamp, electrode-injection assembly, or cannula may be disadvantageous. Finally, in methods that involve two techniques, e.g., crushing and sectioning, any likelihood of improving results does not seem to outweigh the extra risks incurred. Whatever the method employed, the production of chronic A-V block in the dog offers interesting possibilities for physiological and pharmacological studies, particularly in the unanesthetized animal, as shown by reported results. Under these experimental conditions, a number of studies (Boucher and Duchene-Marullaz, 1980; Duchene-Marullaz et al., 1975; Reynolds and Di Salvo, 1978; Robinson et al., 1973; Ruttenberg et al., 1970) have evidenced very marked sensitivity of the ventricular automaticity, unlike the sinus automaticity, to beta-blocking agents, ascribed to the existence of high adrenergic cardioaccelerator tone in the ventricles. Similarly, Duchene-Marullaz et al. (1974b) and Boucher et al. (1982a) have shown that the ventricles are also very sensitive to clonidine; the observed marked ventricular bradycardiac effects are attributable to the stimulation of alpha-adrenoceptors by clonidine. Other work (Boucher et al., 1979; Duchene-Marullaz et al., 1973; Robinson et al., 1973) has evidenced the low level of cholinergic cardiomoderator tone in the ventricles; however, Boucher et al. (1979-1984) have demonstrated the possible existence of enhanced stimulation of the ventricular vagal cardiomoderator fibers under certain experimental conditions involving an increase in basal ventricular rate. This model has also been used in other studies dealing with the autonomic nervous control of the atrial rate (Boucher et al., 1982b; Chassaing et al., 1976; Duchene-Marullaz et al., 1974a; Fisher et al., 1984; Robinson et al., 19731, the comparison of atrial and ventricular beta-adrenoceptors (Boucher et al., 1981), and the existence of chronotropic alpha-adrenoceptors in the ventricles (Boucher and

103

104

M. Bouchet and P. Duchene-Marull~

Duch$ne-Marullaz, 1981, 1982; Hordof et al., 1982). Recently, Dubray et al. (1983) have also shown that this model can be useful in the determination of atrial effective refractory period for various experimental purposes, both physiological and pharmacological. Finally, the production of complete A-V block also represents a useful approach to the clinical treatment of some supraventricular arrhythmias that fail to respond to classical treatment (Gallagher et al., 1982; Giannelli et al., 1967; Klein et al., 1980; Sealy et al., 1977; Slama et al., 1967). The authors wish to express thanks to Mrs. Hosmalin for her assistance in the preparation manuscript.

of this

REFERENCES Babotai I, Brownlee R (1971) Experimental atrioventricular block without thoracotomy. A new instrument. Cardiovasc Res 5:416-4X% Bardy Cl-l, ldeker RE, Kasell J, Worley SJ, Smith WM, German LD, Gallagher JJ (1983) Transvenous ablation of the atrioventricular conduction system in dogs: Electrophysiologic and histologic observations. Am J Cardio/51:1775-1782. Baum T, Peters JR, Butz F, Much DR (1975) A method for the placement of His bundle electrodes and production of atrioventricular block in dogs. ] Appl Physiol38:932-933. Beazell JW, Adomian GE, Furmanski M, Tan KS (1982) Experimental production of complete heart block by electrocoagulation in the closed chest dog. Am Heartf 104:1328-1334. Beazell J, Tan K, Criley j, Schulman J (1976) The electrosurgical production of heart block without thoracotomy. Clin Res 24~137. Boucher M, Dubray C, Duch$ne-Marullaz P (1981) Comparison des effets bloquants de I’alpr~nolol, de I’ acebutolol et du metoprolol vis-a-vis des actions chronotropes auriculaire et ventriculaire de I’isoprenaline chez le chient non narcose en bloc auriculo-ven~riculaire chronique. Unicite ou pluralite des recepteurs chronotropes bCta*adrCnergiques?. / Pharmacol12:323-324. Boucher M, Dubray C, Duch&ne-Marullaz P (1982a) MBcanismes de I’action bradycardisante de la clonidine chez le chien non narcosC en bloc auriculo-ventriculaire chronique. 1 Pharmacol 13:459. Boucher M, Dubray C, Duch&ne-Marullaz P (198213) Long-term observation of atrial and ventricular rates in the unanestheti~ed dog with complete

atrioventricular block. Pfluegers Arch EurJ Physiol395 : 341-343. Boucher M, Dubray C, Duch~ne-Marull~ P (1984) Dopamine in the conscious dog with chronic heart-block. Mechanisms of chronotropic cardiac effects. ~aunyn-Schmiedebergs Arch Pharmakol326:148-154. Boucher M, Duch&ne-Marullaz P (1980) Acebutolo], metoprolol and propranolol in conscious dogs with chronic heart-block: Chronotropic effects and relation between depression of ventricular activity and beta-adrenoceptor blocking potency. Brit J Pharmacol70:335-340. Boucher M, Duchene-Marullaz P (1981) Negativechronotropic ventricular alpha-adrenoceptors in the conscious dog in chronic A-V block. Villth lnt Congress Pharmacoi, Tokyo. No. 960. Boucher M, Duchene-Maruflaz P (1982) Effets chronotropes nbgatifs de la noradr~naline et de la dopamine chez le chien non narcosC en bloc auriculo-ventriculaire chronique. / Pharmacol 13:100-101. Boucher M, ~uch~ne-Marull~ P, Lavarenne J 11979) Catecholamines and cardiac rhythms in the unanesthetized dog with chronic A-V block. Am J Physiol237:10-17. Brutsaert DL (1965) Influence of different stimulation frequencies on the cardiac output at rest and during moderate exercise in dogs with chronic atrioventricular heart block. Acta Cardiof20:469498. Brutsaert DL (1966) Comparison of singled and paired electrical heart stimulation on cardiac hemodynamics at rest and during exercise in dogs with atrioventricular heart block. Arch Int Physiol Biocbim 74: 9-20.

Complete Atrioventricular Chassaing C, Duchene-Marullaz P, Moins N, Combre A (1976) Effets paradoxaux du propran0101 et de I’atropine sur la frequence cardiaque du chien non narcose. / Pharmacol7:609-618. Connolly CJ, Hannon DW, Edwards JE (1965) Experimental induction of chronic complete heart block. / Thorac Cardiovasc Surg 49:313-316. Cruze K, Schiebler CL (1963) Production of complete atrioventricular dissociation. A new experimental technique. Arch Surg 86:331-333. Dubray C, Boucher M, Paire M, Duchene-Marullaz P (1983) A method for determining the atrial effective refractory period in the unanesthetized dog. 1 fharmacol Methods 9:157-164. Duchene-Marullaz P, Combre A, Chassaing C, Delort P (1974a) Observation telemetrique de la frequence auriculaire du Chien en dissociation auriculoventriculaire chronique. C R Sot Biol 168:300-303. Duchene-Marullaz P, Combre A, Lavarenne J, Boucher M, Lapalus P (1973) Le tonus cardiomoderateur s’exerce-t-il sur la frequence idioventriculaire? C R Sot Bio/167:279-282. Duchene-Marullaz P, Combre A, Lavarenne J, Lapalus P, Schaff G (1975) Comparaison des effets du propranolol, de I’alprenolol, du pindolol et du practolol sur les rythmes cardiaques de chiens non narcoses en dissociation auriculo-ventriculaire chronique / fharmaco/6:441-452. Duchene-Marullaz P, Lavarenne J, Lapalus P, Boucher M, Mongheal Y (1974b) Effect of clonidine on heart rate in dogs with acute or chronic heart block. fur / fharmacol28:76-80. Erlanger J (1906) in mammals causation of physiology of 8:8-58.

On the physiology of heart block with special reference to the Stokes-Adams disease. On the heart block in the dog. / Exp Med

Erlanger J, Blackman JR (1909) Further studies in the physiology of heart block in mammals. Chronic auriculo-ventricular block in the dog. Heart 1:177-229. Erlanger J, Hirschfelder AD (1906) Further studies on the physiology of heart block in mammals. Am / Physiol15:153-206. Eyster JAE, Swarthout EC (1920) Experimental determination of the influence of abnormal cardiac rhythms on the mechanical efficiency of the heart Arch intern Med 25:317-324. Fisher VJ, Lee RJ, Christianson LC, Kavaler F (1966)

Block in Dogs

Production of chronic atrioventricular block in dogs without thoracotomy. / Appl Physiol 21:1119-1121. Fisher SJ, Scher AM, Wyss CR (1984) Long-term responses of atrial rate and peripheral resistance to changes in ventricular pacing rate in awake dogs with atrioventricular block. Circ Res 54 : 196-203. Folkman MJ, Watkins E (1957) An artificial conduction system for the management of experimental complete heart block. Surg Forum 8:331-334. Fredericq L (1904) L’atriotomie temporaire, procede nouveau d’exploration des fonctions du coeur. Arch Int Physiol Biochim 1:83-85. Fredericq L (1906) La pulsation du coeur du chien. Arch Int Physiol Biochim 4157-75. Gallagher JJ, Svenson RH, Kasell JH, German LD, Bardy GH, Broughton A, Critelli G (1982) Catheter technique for closed-chest ablation of the atrioventricular conduction system. A therapeutic alternative for the treatment of refractory supraventricular tachycardia. N Engl / Med 306 : 194-200. GiannelJi S, Ayres SM, Gomprecht RF, Conklin EF, Kennedy RI (1967) Therapeutic surgical division of the human conduction system.IAMA 199:155160. Gonzales R, Scheinman M, Margaretten W, Rubinstein M (1981) Closed-chest electrode-catheter technique for His bundle ablation in dogs. Am 1 Physiol241:283-287. Guzman SV, De Leon AC, West JW, Bellet S (1959) Cardiac effects of isoproterenol, norepinephrine and epinephrine in complete A-V heart block during experimental acidosis and hyperkaliemia. Circ Res 7:666-672. Harrison L, Gallagher JJ, Kasell J, Anderson RH, Mikat E, Hackel DB, Wallace AC (1977) Cryosurgical ablation of the A-V node-His bundle. A new method for producing A-V block. Circulation 55 :463-470. Hering HE (1905) Nachweis dass das His’sche Uebergangsbiindel Vorhof und Kammer des Saugetierherzens functionell verbindet. Zweite Mitteilung. Pfluegers Arch Gesamte Physiol Menschen Tiere 108:267-286. Hering HE (1906) Die Durchschneidung des Uebergangsbundels beim Saugetierherzen. Dritte Mitteilung. Pfluegers Arch Gesamte Physiol Menschen Tiere 111:298-299.

105

106

M. Boucher and P. Duchene-Marullaz His Jr W (1893) Die Tatigkeit des embryonalen Herzens und deren Bedeutung fur die Lehre von der Herzbewegung beim Erwachsenen. Arb MedKlin Lpz 14-18.-

Ruttenberg H, Hurwitz R, Blesa M, Pappelbaum S

His Jr W (1895) Bericht des dritten internationalen Physiologenkongress in Bern. Zbl Physiol9:469. Hordof Al, Rose E, Danilo P Jr, Rosen MR (1982) Alpha- and beta-adrenergic effects of epinephrine on ventricular pacemakers in dogs. Am 1 Physio1242

~677-682.

Humblet M (1904) Le faisceau inter-auriculo-ventriculaire constitue le lien physiologique entre les oreillettes et les ventricules du coeur de chien. Arch Int Physiol Biochim 1~278-285. Humblet M (1905) Allorythmie cardiaque par section du faisceau de His. Arch Int Physiol Biochim 3:330-337.

Ito BR, Feigl EO (1983) Technique for producing heart block in closed-chest dogs without electrical recording. Pfluegers Arch Eur / Physiol 397:160-163.

Klein GJ, Sealy WC, Pritchett ELC, Harrison L, Hackel DB, Davis D, Kasell J, Wallace AC, Gallagher JJ (1980) Cryosurgical ablation of the atrioventricular node-His bundle: Long-term followup and properties of the junctional pacemaker. Circulation

61:8-15.

Leininger BJ, Raghunath TK, Neville WE (1970) A simplified method of producing experimental heart block. Ann Thorac Surg 10:560-562. MacDonald IB (1967) A simple method of producing experimental heart block in dogs. / Thorac Cardiovasc

Robinson JL, Farr WC, Grupp G (1973) Atrial rate response to ventricular pacing in the unanesthetized A-V blocked dog. Am J Physio/224:40-45.

Surg 53:695-697.

Meakins J (1913) Experimental heart block with atrio-ventricular rhythm. Heart 5:281-288. Pruett JK, Woods EF (1967) Technique for experimental complete heart block. 1 Appl Physiol 22 : 830-831.

(1970) Effects of propranolol on myocardial automaticity in conscious dogs with chronic complete heart block. UCLA Forum Med Sci 13:6974.

Sealy WC, Anderson RW, Gallagher JJ (1977) Surgical treatment of supraventricular arrhythmias. 1 Thorac Cardiovasc Surg 73:511-522. Shiang HH, Kupersmith J, Wiemann GF, Rhee CY, Litwak RS (1977) Creating permanent complete heart block by indirect cauterization without atriotomy. Am / Physiol233:723-726. Slama R, Blondeau PH, Aigueperse J, Cachera J, Degorges M, Abbou E (1967) Creation chirurgitale d’un bloc auriculo-ventriculaire et implantation d’un stimulateur dans deuxcas de troubles du rythme irreductibles. Arch Ma/ Coeur Vaiss 60:406-422. Smyth NPD, Magassy CL (1970) Experimental heart block in the dog. An improved method. / Thorac Cardiovasc

Surg 59:201-205.

Starzl TE, Gaertner RA (1955) Chronic heart block in dogs. A method for producing experimental heart failure. Circulation 12:259-270. Starzl TE, Gaertner RA, Baker RR (1955) Acute complete heart block in dogs. Circulation 12:82-89. Steiner C, Kovalik AT (1968) A simple technique for the production of chronic complete heart block in dogs. I Appl Physiol25:631-632. Taufic M, Bashour FA, Lewis FJ (1955) Production of heart block in dogs under direct vision. Surg Forum 5 : 96-101.

Pruitt RD, Essex HE (1960) Potential changes attending the excitation process in the atrioventricular conduction system of bovine and canine hearts. Circ Res 8:149-174.

Turina M, Babotai I, Wegmann W (1968) Production of chronic atrioventricular block in dogs without thoracotomy. Cardiovasc Res 4:389-393.

Randall OS, Westerhof N, Van Den Bos CC, Sipkema P (1981) Production of chronic heart block in closed-chest dogs: An improved technique.

Warner HR, Toronto AF (1960) Regulation of cardiac output through stroke volume Circ Res 8:549552.

Am J Physiol241:279-282.

Reynolds RD, Di Salvo J (1978) Effects of dl-propranolol on atrial and ventricular rates in unanesthetized atrio-ventricular blocked dogs. I Pharmacol

fxp

Ther 205 :374-381.

Weirich WL, Paneth M, Gott VL, Lillehei CW (1958) Control of complete heart block by use of an artificial pacemaker and a myocardial electrode. Circ Res 6:410-415.

Complete Wieberdink J (1966) Experimental production of permanent heart block (total or bundle-branch block) without circulatory arrest or extracorporeal circulation. Thorax 21:401-404. Williams

JCP, Lambert

EH (1964) Production

of

Atrioventricular

heart block in dogs without

Block in Dogs

thoracotomy.

Fed

Proc 23:413.

Williams JCP, Lambert EH, Titus JL (1969) Use of intracardiac A-V nodal potentials in producing complete heart block in dogs. / Appl Physiol 27: 740-744.

107