Pathophysiology of second degree atrioventricular block: A unified hypothesis

REVIEWS

Pathophysiology

of Second Degree Atrioventricular

Block:

A Unified Hypothesis

NABIL

EL-SHERIF,

MD

BENJAMIN J. SCHERLAG, RALPH LAZZARA, MD

PhD

Miami Beach, Florida

From the Division of Cardiology, Department of internal Medicine, Mount Sinai Medical Center, Miami Beach, Fla. This study was supported in part by Contract 72-2972-M from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Manuscript accepted July 17, 1974. Address for reprints: Nabil El-Sherif, MD, Mount Sinai Medical Center, 4300 Alton Rd., Miami Beach, Fla. 33140.

An in vivo and in vitro correlative study of second degree atrioventricutar (A-V) block in the canine proximal His-Purkinje system after iigation of the anterior septai artery is reported. Evidence is presented to suggest that Mobitz type ii and the Wenckebach type of conduction represent different degrees of the same disorder rather than two distinct eiectrophysiologic processes. The in vivo study showed that an increment of conduction delay almost always preceded the blocked impulse in second degree A-V block. The increment,as small as 1 or 2 msec at the early stage of block, often increased gradually up to 180 msec. The in vitro study consistently showed an increment of conduction delay preceding the blocked impulse. The same experiments revealed a greater increment in conduction delay early after excision that, on recovery during superfusion, gradually decreased to a few miiliseconds (the reverse order of the in vivo observation). Characteristic changes in duration and configuration of action potentials in the ischemit proximal His-Purkinje system were observed depending on the state of transmission and the temporal relation of the impaled ceil to areas of slow propagation and block. The study revealed a remarkable similarity between characteristics of conduction in the ischemic HisPurkinje system and conduction in both the normal A-V node and Purkinje fibers subjected to various pathophysioiogic interventions. it is suggested that in the pathologic situation-exemplified in this study by acute myocardial ischemiathe normal His-Purkinje system may gradually lose the characteristics of the fast response and start showing properties of the slow response. At an early stage of departure from normal, the proximal His-Purkinje system may show second degree A-V block with no perceptible to a few milliseconds’ increment of conduction delay (the equivalent of Mobitz type ii block). On further departure from normal, the His-Purkinje system resembles the A-V node in showing a significant increment of conduction delay prior to the blocked impulse (the equivalent of Wenckebach periodicity). Both the in vivo and in vitro observations demonstrated a clear propensity of the ischemic proximal His-Purkinje system to develop paroxysmal A-V block during the stage of second degree A-V block when there is no perceptible to a few milliseconds’ increment of conduction delay. A new classification of second degree A-V block is presented based on the suggested electrophysioiogic mechanism.

Two types of second degree atrioventricular (A-V) block were originally described by Wenckebach1T2 and Hay3 from analysis of the a-c interval of the jugular pulse. After the introduction of the electrocardiogram these were classified by Mobitz4 as types I and II. Type I A-V block. also known as Mobitz tvne I or the Wenckebach nhenomenon, is defined as intermittent faihrre of A-V conduction preceded by progressive lengthening of A-V conduction times. Type II A-V block, also known as Mobitz type II block, is characterized by inter-

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mittent failure of A-V conduction that occurs “suddenly” and in which the P-R intervals remain constant before the dropped beat. During three successive eras, beginning with deductive analysis of standard electrocardiograms, followed by electrophysiologic studies utilizing the microelectrode technique and the more recent catheter electrode technique, the classification of second degree A-V block into two types has been maintained. Emphasis was recently placed on specific localization of each type in the A-V conduction system with less attention directed to unraveling the basic electrophysiologic mechanisms involved. This is especially so for Mobitz type II A-V block, which is still considered by some an electrophysiologic curiosity. We recently produced an appropriate experimental model for study of A-V conduction disorders after ligation of the anterior septal artery in the dog.5-g Ligation of the artery gives rise to acute ischemic injury of the proximal His-Purkinje system. This model offers a unique opportunity to analyze the evolution of second degree A-V block. Evidence has been accumulated during these studies to suggest that Mobitz type II and the Wenckebach type of second degree A-V block represent different degrees of the same disorder rather than two different electrophysiologic processes. We conducted in vitro studies utilizing the same experimental model and obtained correlative evidence to the in vivo observations.le-l2 On the basis of both the in vivo and in vitro data, a unified hypothesis to explain second degree A-V block is presented.

ET AL.

Forty-five adult mongrel dogs weighing 10 to 20 kg were anesthetized with intravenously administered sodium pentobarbital (30 mg/kg body weight). The animals were intubated and placed on a mechanical respirator. Blood pressure in the femoral artery was monitored through a polyethylene catheter connected to a Statham transducer. A thoracotomy was performed through the fourth left intercostal space. The bifurcation of the left coronary artery was exposed by retracting the tip of the left atria1 appendage and incising the epicardium overlying the proximal portions of the anterior descending and left circumflex coronary arteries. The anterior septal artery was exposed by blunt dissection of the bifurcation and branches of the left coronary artery, and a silk ligature was placed around the vessel to be occluded after control records were taken. To increase the heart rate, atria1 pacing by means of a bipolar plunge wire electrode (diameter 0.003 inch) inserted at the left atria1 appendage was utilized. Pacing was performed with a Grass S-88 stimulator and SIU5 stimulus isolation unit. Vagal-induced slowing or cardiac arrest was accomplished by delivery of 0.05 msec square wave pulses of 1 to 20 volts intensity at a frequency of 20 hertz through silver electrodes (diameter 0.012 inch) inserted into the left or right cervical vagosympathetic trunk.13 Recordings from the specialized ventricular conducting tissue and regular ventricular muscle were obtained by electrode catheters inserted into peripheral arteries and veins14315; into the left or right common carotid artery to the aortic root for recording His bundle activation; into a

femoral artery to the left ventricle to record from the proximal or distal left bundle branch; and into a femoral vein to the right heart to record from the His bundle at the A-V junction on the right side or the right bundle branch. In some cases after placement of the anterior septal ligature, the left thoracotomy was closed and the animal turned to expose the heart through a right thoracotomy. One to three pairs of plunge wire electrodes were placed in the His bundle areal and electrode catheters were inserted to record right and left bundle branch potentials. In addition to the electrograms two or more standard electrocardiographic leads were recorded, specifically leads II and aVR. To validate each of the catheter electrode and plunge wire recordings, pacing at various intensities, that is, just above threshold and two to three times threshold, was performed at various rates from each of the bipolar electrodes. In experiments in which an intra-His bundle lesion developed with the His bundle potential split into two deflections (Hi and Hz), validation of both His deflections was carried out as previously described.7 All records were obtained on a multichannel oscilloscopic photographic recorder (E for M DR-8) at paper speeds of 25 to 200 mm/set with filter frequencies of 0.1 to 200 hertz for electrocardiographic leads and 40 to 200 hertz for electrographic recordings. Calculations were accurate up to f3 msec at a paper speed of 200 mm/set. Some of the recordings were stored on a magnetic tape recorder (Honeywell 5600) and replayed so that selected sections could be registered on photographic paper for detailed analysis. Control records during sinus rhythm, vagal-induced cardiac slowing and atria1 pacing up to rates that produced A-V Wenckebath conduction were obtained in each experiment before the anterior septal artery was ligated. The recorded electrical activity was then monitored for intervals up to 8 hours after ligation. In all experiments postmortem dissection was performed to verify that the anterior septal artery had been completely occluded. In vitro studies were carried out in 15 hearts in which the anterior septal artery had been ligated and in vivo observations for 3 to 8 hours had shown the development of various degrees of conduction disorders in the proximal His-Purkinje system. In addition, 10 noninfarcted hearts were also studied as controls. A modified Elizari preparation17 was utilized to expose the proximal A-V conduction system. In both ischemic and control experiments, the heart was rapidly excised and immersed in cool, oxygenated Tyrode solutiqn. The right and left ventricles were opened from base to apex and most of the free walls was removed. The A-V valve leaflets and chordae tendineae were rapidly cut away close to their septal insertion on both the right and left sides. The atria were removed except for the basal portions containing the A-V node and His bundle. This atria1 and ventricular septal preparation was placed on a plastic plate with the left side down and, with use of a sharp no. 21 scalpel blade, one single straight-line incision was made from the mouth of the coronary sinus to just outside the origin of the right bundle branch. In this way the atria1 septum was transsected, exposing the penetrating and branching portions of the His bundle. The interventricular septum was then divided into right and left sides by splitting it down the center working from apex to base. This resulted in a flat relatively two-dimensional preparation of the top of the ventricular septum containing the His bundle and the right and left ventricular septum containing their respective proximal and distal bundle branches. The entire preparation was pinned in a lucite chamber with an approximate volume capacity of 60 ml and superfused

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with warmed (35 to 37’ C) and gassed (95 percent oxygen, 5 percent carbon dioxide) solution of the following millimolar composition: sodium ion 151.1; potassium ion 4.05; calcium ion 1.35; magnesium ion 0.5; chlorine ion 131.25; bicarbonate radical 24.0; dibasic phosphate radical 1.8, dextrose 5.5. Extracellular and intracellular potentials were recorded from the penetrating and branching portions of His as well as from the right and left bundle branches. The penetrating and branching portions of the bundle of His were identified grossly by anatomic landmarks.17 Extracellular potentials were recorded with bipolar electrodes of Tefloncoated stainless steel wires (diameter 0.003 inch) led into differential operational amplifiers. Intracellular potentials were recorded with machine-pulled microelectrodes with tip resistance of 10 to 40 megohms when filled by boiling with 3 molar potassium chloride. The microelectrodes were connected through a silver-silver chloride interface to the input of a high impedance (greater than 1Or2 ohms) amplifier of low gain (3X) and adjustable negative capacitance (Bioelectric NFl). The indifferent electrode in the chamber was an agar bridge of 3 molar potassium chloride with a silver-silver chloride interface. The outputs of the first stage amplifiers were led into a plug-in amplifier (Tektronix 3A74) in a dual beam oscilloscope (Tektronix 565). The preparation was stimulated by rectangular pulses delivered from wave form and pulse generators (Tektronix 160 series) through fine Teflon-coated bipolar silver wire electrodes. Voltage calibrations for intracellular recordings was accomplished by a calibrator voltage (100 mv) inserted across 100 ohms between the indifferent electrode and ground. The oscilloscopic tracings were photographed on 35 mm film (Grass C4N).

TABLE

OF SECOND DEGREE A-V BLOCK-EL

SHERIF ET AL.

I

Localization of Conduction Disorders in the Canine Proximal His-Purkinje System After Ligation of the Anterior Septal Artery in 38 Experiments Site of Conduction Disorder Experiments Group

(no.)

I II III IV V

Right Bundle

His Bundle

Left Bundle

2

-

10

+

+

-

-

12 4 8

+ + -

+ +

+ +

2

+

+

+

-

self nor the placement of plunge wire electrode was accompanied by significant trauma to the A-V conduction system, as shown in control experiments.7 All but 1 of the 39 dogs that survived the early arrhythmic period after ligation of the anterior septal artery subsequently manifested-within 1 to 2 I/2 hours of ligation-various degrees of conduction disorders at the level of the His bundle, right and left bundle branches or any combination thereof (Table I). Second degree A-V block in intra-His bundle lesion: The gradual evolution of second degree A-V block was more clearly illustrated when the conduction disorder was localized in the His bundle rather than in both bundle branches (bilateral bundle branch block). In case of an intra-His bundle lesion characteristic changes were observed in the recorded His bundle potential as well as the H-V interval.

Results In Vivo Observations

In all animals the control records showed a Wenckebach type second degree A-V block localized between recording sites of the atria1 and His bundle deflections at pacing rates between 240 and 3lO/min. Neither the dissection of the anterior septal artery it-

Figure 1 illustrates a catheter electrode recording of the His bundle from the right side (Hb-R). The control recording (panel A) reveals a sharp His bundle spike with an H-V interval of 30 msec. Panels B to D, obtained 60, 75, and 90

A II

Control A-*=3% mrec

1” 4.A

aVR

6

1 hr.

C

1 hr. 15 min.

D

1 hr. 3Omin.

FIGURE 1. Catheter electrode recording of the His bundle from the right side (Hb-R) recorded simultaneously with leads II and aVR, showing evolution of intra-His bundle block. See text for details.

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-J_

OF SECOND DEGREE A-V BLOCK-EL-SHERIF

I

A*A 590

msec

/ 590

AbA

A_-

Characteristic pattern of second degree intraHis bundle block: In most of the experiments showing an intra-His bundle lesion, the His bundle potential was usually split into two deflections (H, and HZ), and an increase of the H-V interval of 10 to 20 msec was observed before intermittent block of the impulse developed either spontaneously or in response to atria1 pacing. A characteristic pattern was observed for the evolution of second degree intra-pis bundle block. At early stages of the experiment, intra-His bundle block occurred with no perceptible increment of conduction delay. The P-R, HI-V and HI-HZ intervals remained “constant” in the first conducted beat subsequent to and the last conducted beat prior to the blocked atria1 impulse. This corresponded to the Mob&z type II block. Later in the experiments, the HI-V interval lengthened gradually and the HI-HZ intervals showed a gradual increment before the blocked P wave. The increment, which is at first only a few milliseconds, may gradually increase up to 180 msec giving rise to an obvious Wenckebach periodic&y in the electrocardiographic

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590

590

minutes, respectively, after ligation of the anterior septal artery, illustrate the gradual fractionation of the ,His bundle potential that later split into three distinct deflections (HI, Hz and Ha) in panel D. This process was associated with a gradual increase in duration of the His bundle deflection and the H-V interval and represents first degree intra-His bundle block. Figure 1, panel D, shows the development of A-V block localized between the HI deflection on one side and the Hz-Hz deflections on the other side.

424

ET AL.

FIGURE 2. Record obtained from the same experiment as in Figure 1 showing characteristic evolution of second degree intra-His bundle block. See text for details. In this and subsequent figures, Hb-R and Hb-L represent catheter electrode recordings of the His bundle from the right and left sides of the heart, respectively. Time lines in this and subsequent figures are set at 1 second intervals.

leads. The sequence of second degree intra-His bundle block is shown in Figure 2, which was obtained from the same experiment as Figure 1. Figure 2, panel A, was recorded 100 minutes after ligation of the anterior septal artery and illustrates catheter electrode recordings of the His bundle potential from the right and left sides of the heart (Hb-R and Hb-L, respectively). The Hb-R recording illustrates a split His bundle deflection whereas the Hb-L recording depicts only the HI deflection.7 The record shows second degree intra-His bundle block with essentially constant HI-V and HI-H2 intervals in the last conducted beat prior to and in the first conducted beat subsequent to the blocked impulse. Panel B was obtained 60 minutes later and illustrates a gradual increment of the HI-V interval of 30 msec before failure of ventricular response to the fourth atria1 impulse. The gradual increment of conduction delay is mainly localized between the Hl-Hs deflections where the final block of the impulse takes place. However, there are additional conduction delays at the site of recording of the Hz deflection and between the Hz and V deflections, as revealed by the decrease in amplitude and increase in the duration of the Hz deflection as well as the increase in the Hz-V interval. Panel C, obtained 60 minutes after panel B, illustrates an obvious Wenckebach peri;dicity in the electrocardiographic leads. An increment of 143 msec in the HI-V intervals is observed before block of the atria1 impulse.

Wenckebach phenomenon: Typical Wenckebach periodicity18 was not a common observation in the study. Several variations of the Wenckebach phenomenon were commonly observed. Two of these variations are shown in Figure 3.

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ET AL.

II A

aVR

II aVR

FIGURE 3. Records A and B were obtained from two different experiments and illustrate two variants of the periodicity. See text for details.

typical

intra-His

bundle

Wen&&a&

1

A,

II aVR

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FIGURE 4. Record illustrating another variation of the typical Wenckebach periodicity. See text for details.

Figure 3, panel A, illustrates the last part of a long Wenckebach period. There are continual increments of the Hi-V interval of 15 msec; a larger increment of 50 msec is seen in the last conducted beat. These changes resulted in a gradual increase of the R-R intervals before the pause. Panel B, obtained from another experiment, illustrates catheter electrode recordings of the His bundle from the right and left sides of the heart (Hb-R and Hb-L, respectively). The record shows that the increment of the Hi-V interval was greatest in the second conducted beat of the Wenckebach cycle (from 75 to 100 msec). Shortening of the Hi-V interval of the third conducted beat to 75 msec then occurred, followed by a gradual increase of the Hi-V interval of the fourth and fifth conducted beats to 95 and 98 msec before the block. Figure 4 shows another variation of the typical Wenckebath periodicity. The record illustrates an apparent Mobitz type II block when the criterion used is only the presence of constant P-R intervals prior to the blocked impulse rather than a constant P-R interval of the beats immediately preceding and immediately following the pause. The record shows constant prolonged Hi-V intervals of 155 msec with sudden intra-His bundle block of the fifth atria1 impulse.

The first conducted beat after the pause shows marked shortening of the Hi-V interval to 90 msec. This arrangement was occasionally seen in long Wenckebach periods in which the last conducted beats showed a prolonged and almost constant conduction time. The sudden block of the impulse sometimes coincided with minimal shortening of the P-P cycles. Figure 4 demonstrates that the intra-His bundle block of the fifth atria1 impulse coincided with a sudden shortening of the A-A cycle by 40 msec. In these cases the P-R interval of the first conducted beat after the pause was always shorter than the P-R interval of the last conducted beat in the Wenckebach period.

Paroxysmal A-V block: During temporal currence

the study a close association was observed between the ocof early stages of second degree A-V block in

the proximal His-Purkinje system and the induction or spontaneous onset of intermittent complete A-V block (paroxysmal A-V block). Paroxysmal A-V block was clearly tachycardia-dependent since block could be induced by atria1 pacing at a critical heart rate

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II aVR

FIGURE 5. Record illustrating tachycardiadependent

(180 to 300/min in different shown in Figure 5.

paroxysmal intra-His bundle block induced by rapid atrial pacing (PI). See text for details.

experiments).

This is

Figure 5, panel A, was obtained 2 hours after ligation of

the anterior septal artery and shows catheter electrode recordings from the left and right sides of the heart. The record illustrates a spontaneous Mobitz type II intra-His bundle block. Panel B shows distal His bundle pacing from the catheter electrode in the aortic root. Panel C was obtained 5 minutes later. The first two beats represent 1:l A-V conduction at a rate of 153/min. Atria1 pacing started at the third P wave (PI) with gradual increase of the pacing rate. A 21 intra-His bundle block developed and was followed by complete intra-His bundle block at a critical shortening of the atria1cycle length to 290 msec (rate 207/min).

lb0m& FIGURE 6. Action potential of a Purkinje cell from the penetrating portion of the His bundle in a normal preparation (A) and an ischemic preparation (B) recorded at different time intervals after excision. Note gradual recovery during superfusion in B. See text for details.

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In Vitro Observations Noninfarcted hearts: In 10 preparations from noninfarcted hearts, the action potentials recorded from the penetrating and the branching portions of the His bundle as well as from the proximal bundle branches were normal. In some preparations there was a slight increase in resting potential, upstroke velocity, amplitude and overshoot in time during superfusion (Fig. 6, panel A). This change probably indicated recovery of the cells from any slight damage suffered during the dissection. The mean resting potential of a His bundle Purkinje cell in 10 normal preparations was 72 mv (standard deviation f 4), the mean action potential amplitude was 85 f 9 mv, and the mean action potential duration at a driving cycle length of 800 to 1,000 msec was 220 f20 msec. The mean conduction time from a proximal His bundle position to a proximal right or left bundle position was 16 f 4 msec. His bundle cells were usually able to follow rapid driving at rates of 300/min or more. Infarcted hearts: All the preparations from infarcted hearts manifested deviations from the electrophysiologic properties described above. Most of the altered cells were localized quite proximally in the His-Purkinje system. Intracellular recordings from Purkinje cells in the bundle of His and very proximal bundle branches revealed diminished resting and action potentials, reduced upstroke velocity and depressed excitability. In time, during superfusion, these cells underwent a process of recovery characterized by gain in amplitude of resting and action

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A

B

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OF SECOND

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7. Recordings from the proximal His-Purkinje system in an ischemic preparation showing different patterns of second degree block. See text for details. The sketch in A shows the arrangement of the stimulating and recording electrodes. The preparation was stimulated from a proximal His bundle position (S) with an intracellular recording electrode in the penetrating portion of the His bundle (Hb) and extracellular bipolar electrodes from the proximal right (Rb) and left (Lb) bundles (marked by arrows). CL = cycle length; M = muscle potential. FIGURE

potentials

and augmentation of maximal upstroke velocity. The rate of recovery varied among preparations and within different portions of the His bundle and proximal bundle branches. However, during superfusion of up to 4 hours no preparation recovered

to a state that might he described as normal, that is, similar to the state of nonischemic control preparations. Figure 6, panel B, shows resting and action potentials of a Purkinje cell from the branching portion of the His bundle in various states of recovery.

Conduction disorders and effect on action potentials in ischemic His-Purkinje system: An obvious correlate of the changes seen in the action potentials recorded from the ischemic proximal HisPurkinje system was the demonstration of slow conduction. An increase in the degree of conduction delay between the His bundle and proximal bundle branches together with intermittent failure of transmission could be demonstrated by increasing the driving rate. This is shown in Figure 7. Figure 7, panel A, shows the arrangement of the stimulating and recording electrodes. Panel B shows a recording obtained 30 minutes after excision at a driving rate of 1321 min. There is 1:l conduction between the His bundle and proximal bundle branches. Recording of the transmembrane action potential from the His bundle shows diminished resting and action potentials with reduced upstroke velocity. These changes are reflected in the delayed inscription of the electrograms from the proximal right and left bundles (both are inscribed simultaneously) with an Hb-Lb conduction time of 45 msec. Panel C shows that increasing the driving rate resulted in Wenckebach periodicity. The action potential recorded from the His bundle is strikingly changed in both duration and configuration in relation to changes in the state of transmission, The opening action

potential of the Wenckebach cycle (the first and seventh action potentials) has a normal-looking plateau. The second and subsequent action potentials have a hump-like inflection on the plateau. The inscription of the notch on the plateau coincides almost exactly with the bipolar electrograms recorded from the proximal right and left bundles. Starting from the third action potential the notch is gradually inscribed later on the plateau while the bundle branch electrograms are inscribed at an equal pace with a resultant increase in the transmission time between the His bundle and bundle branch recordings. Finally, impulse transmission fails and the bundle branch electrograms are not recorded. The action potential recorded from the His bundle that corresponds to a dropped beat (the sixth action potential) has no hump-like prolongation of the plateau and is significantly shortened. Critical analysis of the Hb-Lb conduction times during the Wenckebach period in Figure 7, panel C, reveals an interesting arrangement. The Hb-Lb conduction time of the opening beat of the Wenckebach period is the shortest (45 msec). The second Hb-Lb interval is significantly prolonged to 76 msec. However, the third Hb-Lb conduction time is again shortened to 68 msec then gradually increases to 76 msec and 102 msec before the final failure of transmission. This variation of the typical Wenckebach periodicity represents the in vitro correlation to the in vivo observation shown in Figure 3, panel B. Analysis of the action potential duration of the first two beats of the Wenckebach cycle provides an explanation for this arrangement. The duration of the second action potential in the Wenckebach period measured at 50 percent of its peak amplitude is about 10 msec shorter than the opening action potential. The action potential duration then becomes gradually longer with the longest action potential being the one inscribed immediately before the dropped beat and associated with the longest Hb-Lb conduction delay. Figure 7, panel D, was recorded 2 hours after excision.

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A

OF SECOND DEGREE A-V BLOCK-EL-SHERIF

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The preparation showed partial recovery during superfusion with an increase in the resting and action potentials and an increased upstroke velocity of the His bundle cell. These changes were also reflected in improvement of conduction between the His bundle and bundle branches with 1:l transmission sustained up to a cycle length of 330 msec. At a shorter cycle length of 310 msec a regular repetition of the alternation between a 3:2 Wenckebach cycle and 2:l block was seen. The alternation is explained by a slightly shorter action potential duration of the opening beat of the 3:2 Wenckebach cycle compared with that of the conducted beat during the 2:l block. This observation represents the in vitro correlation of the frequent in vivo finding of 2:l block after the blocked impulse in second degree A-V block (Fig. 2).

Recovery of conduction in His-Purkinje tem: The process of recovery during superfusion

sys-

with improvement of conduction frequently allowed the demonstration in the same preparation of two phenomena: (1) Early after the excision, pacing resulted in failure of transmission preceded by significant increment of conduction delay equivalent to the Wenckebach conduction; and (2) later in the experiment, failure of transmission could occur with only a few milliseconds’ increment of conduction delay that simulated Mobitz type II block. This is shown in Figure 8. In Figure 8, the arrangement of the stimulating and recording electrodes is the same as in Figure 7, panel A. The record in panel A was obtained 45 minutes after excision and shows the last part of a long Wenckebach cycle during pacing at a rate of 120/min. There was a gradual increase of the Hb-Rb conduction time from 26 msec (not shown in the figure) to 55 msec before failure of impulse transmission. The action potential recorded from the His bundle shows very characteristic alterations in relation to changes in the state of transmission. The first action potential in the record has a notch between the spike and plateau that gradually widens with the inscription of a double component action potential. The initial component (the spike) shows gradual loss of amplitude in spite of a constant rapid slope of the initial depolarization. The second component is a dome-shaped depolarization with an amplitude much greater than that of the initial spike, resulting in an overshoot whereas its maximal slope is considerably slower. The bipolar electrograms of the right and left bundles, which are more or less simultaneously inscribed, show a temporal relation to the second depolarization and are re-

428

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ET AL.

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The American Journal of CARDIOLOGY

\27 I

\

FIGURE 8. Recordings from the proximal HisPurkinje system in an ischemic preparation showing change from a Wenckebach type of conduction (record A) to a Mobitz type II block (record B) on recovery during superfusion. See text for details. The arrangement of the stimulating (S) and recording electrodes is the same as in Figure 7.

corded correspondingly later, resulting in a gradual increase of the Hb-Rb and Hb-Lb conduction times. The action potential corresponding to the dropped beat shows disappearance of the second depolarization with the inscription of a low amplitude spike with a markedly shorter duration. Panel B was recorded 90 minutes after excision. Pacing applied at a faster rate of 150/min resulted in intermittent failure of transmission. A constant Hb-Rb conduction time precedes the blocked beat, but after the block there is a 7 msec. shortening of the Hb-Rb conduction time together with a noticeable increase in the amplitude of the action potential recorded from the His bundle. Thus, in spite of the constant conduction time before the blocked beat, this arrangement actually represents a long Wenckebach periodicity with only a few milliseconds’ increment of conduction delay.

Wenckebach periodicity: As in the in vivo study, typical Wenckebach periodicity was not common. Several variations of the Wenckebach phenomenon were seen. One of these variations is shown in Figure 7, panel C. Another variation is shown in Figure 9. In Figure 9, the sketch at the lower right corner illustrates the arrangement of the stimulating and recording electrodes. The figure shows a 6:5 Wenckebach cycle. The action potential recorded from the His bundle has a characteristic configuration. There is a slow initial step followed by a more rapid but still abnormally slow upstroke. The His bundle electrogram (recorded within a 1 mm distance) reveals a very diminutive deflection that coincides with the beginning of the initial slow step. The electrogram recorded from the right bundle coincides almost exactly with the inscription of the rapid upstroke and is inscribed simultaneously with it during the Wenckebach cycle. In the last beat of the Wenckebach cycle the rapid upstroke fails and only a long slow step is inscribed. Correspondingly, conduction to the right bundle fails, as shown by absence of the right bundle electrogram. The conduction time between the Hb and Rb electrograms during the Wenckebach cycle reveals an interesting arrangement. There is a clear alternation of Hb-Rb conduction time with an overall gradual increase in conduction delay. The alternation of Hb-Rb conduction time is explained by a peculiar relation between the time of takeoff of the rapid upstroke from the slow initial step and the duration of the ensuing action potential. Thus, the earlier the takeoff of the rapid upstroke, the longer the duration of the action potential. The long action potential duration results

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lib-Rb

\

58 I

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ET AL.

L

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58 I

FIGURE 9. Recording from the proximal His-Purkinje system in an ischemic preparation showing a variant type of Wenckebach conduction and evidence of longitudinal dissociation in the ischemic His bundle. See text for details. The preparation was stimulated from the proximal His bundle (S), and both an intracellular microelectrode (Hb-me) and an extracellular bipolar electrode (Hb) were applied within a 1 mm distance to the penetrating portion of the His bundle. In addition, a bipolar electrogram was recorded from the proximal right and left bundles (Rb and Lb, respectively). The arrows point to the Hb, Rb and Lb electrograms.

lation of the in vivo observation of tachycardia-dependent paroxysmai A-V block (Fig. 5) could be demonstrated by a critical increase of the driving rate. This is shown in Figure 10.

in the inscription of the next foot potential before the completion of repolarization of the previous impulse. This leads to a delayed takeoff of the next rapid upstroke and a shorter action potential. This process regularly alternates with an overall increase of conduction delay until the last beat of the Wenckebach cycle when the fast potential starts from a relatively lower diastolic potential and fails to conduct. The record in Figure 9 also shows that while this peculiar Wenckebach cycle is taking place between the sites of His bundle and right bundle branch recordings, there is a 19 response with delayed transmission at the left bundle branch recording. Thus, the right and left bundles are showing two different conduction patterns to stimulatian from the proximal His bundle. The presence of a close temporal relation between the His bundle recording and conduction to the right bundle and the absence of such a relation between it and conduction to the left bundle strongly suggest that longitudinal dissociation and asynchronous conduction are taking place in the His bundle itself.

In Figure 10, the arrangement of the stimulating and recording electrodes is the same as in Figure 7. Panel A shows 1:l conduction between the His bundle and both bundle branches at a slow driving rate of 40/min. Panel B shows that increasing the driving rate to 75/min resulted in a 3:2 response. There is a slight increment of the Hb-Lb conduction time before the blocked beat. The His bundle recording shows only a local potential during failure of transmission. Panel C shows a further increase of the driving rate to lll/min, which resulted in complete failure of transmission. The His bundle recording shows repetitive local potentials with failure of inscription of a regenerative action potential. Both the intermittent failure of transmission in panel B and the complete failure in panel C occurred at driving cycle lengths that far exceeded the action potential duration so that stimuli applied quite late in diastole failed to conduct.

paroxysmal A-V Tachycardia-dependent block: In some of the experiments, the in vitro corre-

A Hb Lb Rb

B

2 -

CL I500

msec

I -

...

S-S Hb.Lb

FIGURE 10. Recordings from the proximal HisPurkinje system in an ischemic preparation showing tachycardiadependent paroxysmal block. The arrangement of the stimulating (S) and recording electrodes is the same as in Figure 7. See text for details.

I

79J

I

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Discussion Correlation of In Vivo and In Vitro Observations Second Degree A-V Block

on

The occurrence of similar phenomena in vivo and in vitro argues for the relevance of the data obtained in these studies. Exposure of the His bundle entailed more mechanical trauma than is usually employed in studies of the conduction system in vitro. However, comparison of the data obtained from control and infarcted preparations strongly suggests that the disturbances observed in the infarcted specimens were due to ischemia rather than to mechanical trauma.ls In the present study several correlations between the in vivo and in vitro observations have been cited. By far the most significant correlative evidence concerns the presence and magnitude of increment of conduction delay in second degree A-V block in the proximal His-Purkinje system. Our in vivo observations have shown that an increment of conduction delay almost always precedes the blocked impulse. This increment may be as small as 1 or 2 msec at the early stages of second degree A-V block and may gradually increase up to 180 msec. Although an increment of 1 or 2 msec is within the measurement error in our in vivo study, it is possible that at a more rapid recording speed an increment of a fraction of a millisecond may have been detected. In vitro observations recorded at more rapid recording speeds have consistently shown some increment of conduction time prior to the blocked impulse. The process of recovery of conduction during superfusion allowed a unique opportunity to observe the correlate of the in vivo pattern of evolution of second degree A-V block in the reverse order. Thus, early after excision, one can observe a greater degree of increment of conduction delay during second degree block that on recovery during superfusion may gradually decrease to only a few milliseconds. Both the in vivo and in vitro observations strongly suggest that Mobitz type II block and the Wenckebath type of conduction are not two distinct electrophysiologic processes but represent different degrees of the same process. Mobitz type II A-V block probably represents an early stage of departure from the normal His-Purkinje system conduction characteristics and is associated with a minimal increment of conduction delay that may not be detected at relatively slow recording speeds. Action Potential Changes

in the lschemic

His Bundle

The evidence obtained in this study shows characteristic changes in both the duration and configuration of action potentials in the ischemic His bundle depending on the state of transmission and the temporal relation of the impaled cell to areas of slow propagation and block. We have shown that greatly slowed propagation may lengthen the action potential and that failure of propagation may shorten it. At least two characteristic changes in action potential configuration were observed. The first pattern is a

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hump-like slurring of the plateau that can sometimes result in significant prolongation of the action potential. In the second pattern, the depolarization limb takes off from a very distinct step or foot potential and on failure of propagation only the step is recorded. Similar changes in action potential were described in the A-V node1g,20 and in Purkinje fibers superfused with high concentrations of potassium’ ion21 and were ascribed to interaction between regions proximal and distal to areas of slow propagation. The hump-like inflections on the repolarization limb and the steps on the depolarization limb represent electrotonic spread to cells upstream and downstream, respectively, to areas of slow propagation.20,21 We have seen a third characteristic pattern of action potential configuration that we believe may represent recording in a region closely bordering the depressed area (Fig. 8). It is likely that the split action potential in Figure 8, panel A, could be explained on the basis of a single cell activity with dissociation between a rapid sodium ion current and a slow calcium ion current. However the gradual decrease in the amplitude of the initial spike without a change in the rapid slope of the initial depolarization may suggest an alternative explanation. Thus the spike may be attributed to electrotonic spread from a normal His bundle fiber characterized by a large spike, whereas the large dome-like second component may represent the activity of the cell impaled by the microelectrode that may be showing the slow response. Similar action potential configurations have been reported in human atria1 strips and have been attributed to nonhomogeneous excitation of the preparation.22 The very brief action potential recorded in Figure 8 during conduction block resembles the spike-like responses observed by Churney and Oshima.23 Nature of Slow Conduction System

in lschemic

His-Purkinje

Slow conduction in cardiac muscle, best exemplified in the region of the A-V node, has been attributed to several factors including variations in geometry and changes in membrane properties or intercellular connections.24 Recently, however, several lines of evidence have been reported to suggest that the cardiac action potential might be composed of a fast component and a slow component.25m31 The fast component, which gives r.ise to the initial spike in normal cardiac muscle, is linked to the rapid sodium channe1.32 The slow component seems to be related to the slow inward channel which may be used by either sodium ion or calcium ion. It has been suggested that both the action potential and conduction characteristics of the A-V node might represent properties’of the slow response.33 The slow response has also been described in several experimental preparations including Purkinje strands exposed to increased potassium ion or increased potassium ion plus epinephrine.28J1 An extensive review of the characteristics of the slow response has recently been published.34 This study has shown a remarkable similarity be-

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tween action potential changes and characteristics of conduction in the ischemic His-Purkinje system and conduction in both the normal A-V node and Purkinje fibers subjected to a variety of pathophysiologic interventions. Most of our observations could be explained by suggesting that the ischemic His-Purkinje system shows the characteristics of the slow response. We have to account, however, for the observed evolution from second degree A-V block with no perceptible or minimal increment of conduction delay to one that shows a greater degree of increment; both are considered in this study to represent various degrees of the same electrophysiologic mechanism. Two factors may be implicated: The first suggests a greater degree of deterioration of the membrane responses of ischemic Purkinje cells; the second postulates a larger population of Purkinje cells with an abnormal response. Thus, second degree A-V block with a minimal increment of conduction delay may represent a lesser degree of derangement of the membrane responses or involvement of a relatively small but strategically positioned area of the His-Purkinje system, or both. Further studies including histopathologic correlations may define the role played by either factor. On the other hand, this study may suggest that the characteristic low safety factor of conduction of the slow response,34 which can result in single or repetitive failure of transmission, should not be temporally related to slow conduction. The latter is probably more linked to the size of the Purkinje population showing the slow response, and very slow conduction may be accounted for by summation of a series of slow or even discontinuous propagations.21J5 Thus, the low safety factor of conduction may be operative in the early stages of second degree A-V block when there is a relatively lesser degree of slow conduction. Meanwhile, there is some evidence to indicate that with the development of a greater degree of increment of conduction delay, there is less chance for the occurrence of intermittent complete failure of transmission (paroxysmal A-V block). The relation of acute ischemia to the characteristic changes of conduction in the proximal His-Purkinje system that follow ligation of the anterior septal artery is far from simple. In a recent study from this laboratory,35 we discussed evidence suggesting that factors other than hypoxia alone might be instrumental in the production of acute ischemic disorders in the conduction system. The latter probably result from prolonged exposure to a pathologic environment in vivo that may alter the ionic currents that flow during the generation of the action potential. The leak of large amounts of potassium ion from the intracellular to the extracellular space,37 the increased release of catecholamines3s and other factors may be implicated. These factors are known to favor the occurrence of the slow response.34 On the other hand, the recovery of Purkinje fibers in vitro can be ascribed to the washout of these deleterious factors.36

OF SECOND DEGREE A-V BLOCK-EL-SHERIF

Refractoriness in the lschemic His-Purkinje and Tachycardia-Dependent Block

ET AL.

System

The electrophysiologic properties of normal and diseased Purkinje fibers are distinctly different. The refractory period in normal Purkinje fibers depends on a normal voltage-time course of the sodium pump and the end of repolarization usually signals full recovery of excitability. 32 On the other hand, the excitatory response of diseased Purkinje fibers depends on flow of current through channels whose time- and voltage-dependent conductance are different, and full recovery of excitability may extend late in diastole after completion of repolarization.21T34 We have shown severe impairment of conduction, single and repetitive block, at cycle lengths that far exceed the action potential duration. However, a close relation still exists between the action potential duration and refractoriness in ischemic His-Purkinje cells. We have illustrated that the well known effect of rate and rhythm on the duration of the action potential can explain the common occurrence of 2:l block after the dropped beat in second degree A-V block. It can also explain the Ashman phenomenon during the Wenckebach periodicity shown in Figures 3B and 7C. Similar conduction patterns were described in Purkinje fibers superfused with high levels of potassium ion and were explained on the same basis.21 Thus, it seems that although refractoriness in ischemic Purkinje cells still maintains a proportional relation to the action potential, the duration of the two is not equal. The concept of refractoriness that outlasts the action potential duration is of vital significance in understanding tachycardia-dependent block. Several authors3g,40 have attempted to interpret the situation in the pathologic His-Purkinje system by extrapolating from electrophysiologic data in normal His-Purkinje systems, in which impairment of conduction of a premature stimulus or during rapid rates can be ascribed to stimulation in phase 3. In a recent report by Rosenbaum et a1.3g an inordinate lengthening of the action potential has to be assumed to account for the so-called phase 3 block in some clinical records of tachycardia-dependent block. On the other hand, the clinical relevance of the recently popularized “gate” concept,40 which was again based on studies of the normal His-Purkinje system, may be questioned. Thus, severe impairment of conduction in the ischemit His-Purkinje system can occur at cycle lengths that far exceed the longest action potential that could be recorded at any “gate” in the normal heart. This underscores the need for more electrophysiologic studies in the pathologic situation. Unified Hypothesis

for Second Degree

A-V Block

According to current concepts,41,42 the first type of second degree A-V block is considered to represent primarily A-V nodal block whereas the second type indicates block below the A-V node. However, recent clinical43 and experimental observations7s,JQs in addition to the findings in the present study show the

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A

A

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vc A

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FIGURE 11. Diagrammatic illustration of second degree A-V block based on the suggested electrophysiologic mechanism. See text for details. The diagrams depict only the beat immediately preceding and the one immediately following the blocked impulse. A, A-V and V represent activation of the atria, A-V junction and ventricles, respectively. All values are in milliseconds.

common occurrence of Wenckebach conduction in the His-Purkinje system. Moreover, within the limitations of the available technique of His bundle recordings in man, it is possible that an intra-His bundle Mobitz type II (Fig. 5) or Wenckebach conduction (Fig. 3B) may be mistaken for A-V nodal Mobitz type II block or Wenckebach conduction.7 In fact, in light of the long-standing misconception in the diagnosis of Mobitz type II block-which undoubtedly stemmed from limited insight into the underlying electrophysiologic mechanism-several records designated classic Mobitz type II may turn out to be examples of Wenckebach conduction. The diagnosis of Mobitz type II was originally based on the presence of constant P-R intervals before the dropped beat without emphasis on the necessity for a constant P-R in the beats immediately preceding and immediately following the block. Thus, several records of long Wenckebach cycles in which the last conducted beats before the blocked impulse showed no perceptible or a few milliseconds’ increment of conduction delay were diagnosed as Mobitz type II block. Some of these records have recently been reported as examples of Mobitz type II in the A-V node,46-48 and the blocked impulse occasionally coincided with slight shortening of the P-P interval.46 A similar conduction pattern was shown to occur in the proximal HisPurkinje system in this study (Fig. 4). Some authors42 have expressed the idea that slight shortening of the P-R interval (not exceeding 20 msec) in the beat after the intermittence is acceptable in records otherwise characteristic of Mobitz type II block. It is clear, however, that a 20 msec difference in A-V conduction time between the beat immediately preceding and the one immediately following the block can occur only if there is an overall increment of conduction delay of 20 msec whether

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the increment is equally distributed in all beats of the Wenckebach period or inscribed in only one or two beats. Not only clinical records designated as Mobitz type II block actually represented Wenckebath conduction, but also some in vitro records previously published as examples of Mobitz type II block revealed the presence of a few milliseconds’ increment of conduction delay.4g A similar conclusion was emphasized in a recent study in which 98 percent of intracellular records of second degree block showed various degrees of increment of conduction delay when tracings were obtained at more rapid sweep speeds.45 Conduction in A-V node vs. His-Purkinje system: An understanding of the mechanisms of conduction in the A-V node can help to emphasize that second degree A-V block with no perceptible increment of conduction delay (the equivalent of Mobitz type II) is not expected to occur in the A-V node. All available reports indicate that conduction in the A-V node is normally slow. As mentioned, several authors entertain the possibility that normal A-V nodal cells show characteristics of the slow response. Thus, the A-V conduction system can be viewed as consisting of a proximal portion normally showing the characteristics of the slow response (the A-V node) and a distal portion normally showing the properties of the fast response (the His-Purkinje system). Under the influence of a variety of pathophysiologic interventionsexemplified in this study by acute myocardial ischemia-the His-Purkinje system gradually loses the characteristics of the fast response and begins to show properties of the slow response. At an early stage of departure from normal, the His-Purkinje system may show second degree A-V block with no perceptible to a few milliseconds’ increment of conduction delay. On further departure from normal, the His-Purkinje system resembles the A-V node in showing a significant increment of conduction delay before the blocked impulse. To reiterate, the A-V node, since it cannot normally show the fast response of normal His-Purkinje system, is not expected to illustrate the earlier stages of departure from the fast response. Classification of second degree A-V block: On the basis of this study, coupled with current understanding of the electrophysiology of A-V nodal conduction, it is suggested that second degree A-V block should be classified according to the degree of increment of conduction time as calculated in the beat immediately preceding and the one immediately following the blocked impulse (Fig. 11).The classification does not primarily consider the behavior of the P-R interval preceding the blocked impulse nor the duration of the QRS complexes in the conventional leadsso According to this classification, second degree A-V block can occur with no perceptible increment of conduction delay or can show an increment of 1 up to several hundred milliseconds. When second degree A-V block occurs with no perceptible increment of conduction delay (Fig. llA), the lesion is

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probably localized in the His-Purkinje system. In accordance with the hypothesis presented in this study, it also seems logical to assume that when second degree A-V block occurs with only a few milliseconds’ increment of conduction delay (Fig. llB), the disorder is probably localized in the His-Purkinje syst,em rather than in the A-V node, which usually shows more significant increments of conduction delay. Second degree A-V block with significant increments of conduction delay (Fig. 11 C) could be localized in either the A-V node or His-Purkinje system. This classification has one obvious limitation in the occasional case in which the shortened P-R interval after the block is caused by a fortuitous A-V junctional escape beat and does not reflect the genuine A-V conduction time. However, this does not weaken the general concept since it holds only for the few exceptional cases in which no perceptible increment of conduction delay precedes the block. The recording of a long rhythm strip and spontaneous or induced change in the atria1 rate may help to unravel these cases. Clinical implications: This study has presented sufficient evidence to justify abandoning the term Mobitz type II block, at least when describing electrophysiologic mechanisms. The term does not represent an electrophysiologic entity but probably an imaginary line of departure from the characteristics of the fast response to those of the slow response.

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There also seems to be little advantage in the term Wenckebach type of conduction. Originally the term was used to refer to a characteristic arrangement in which a gradual beat to beat increment of conduction delay precedes the blocked impulse. That this is not necessarily the case is shown in the present study and others.lT4s Our study seems to indicate that the overall increment of conduction delay is more important than the behavior of the P-R intervals before the blocked impulse. The empirical classification of second degree A-V block into types I and II is still very useful clinically because the relatively small increment often seen with infranodal lesions cannot be measured on the conventional electrocardiogram. However, this study is primarily a plea to discard the old classification of second degree A-V block, and in particular the term Mobitz type II block, when describing electrophysiologic phenomena. On the other hand, this classification may still be applicable in clinical practice and in routine clinical electrocardiograms. Acknowledgment We thank Mr. Jorge Rodriguez, Mr. Israel Dingle, Mr. David Young, Jr., Mr. Edward J. Berbari and Dr. Joseph Herb&man for their surgical and technical assistance, and Mrs. Marie Ellis for her aid in preparation of the manuscript.

References 1. Wenckebach 2. 3.

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KF: Zur Analyse des unregelmassigen Pulses. Z Klin Med 371475-488, 1899 Wenckebach KF: Beitrlge zur Kenntnis der menschlichen Herztatigkeit. Arch Anat Physiol (Physiol Abtheilung) 297-354, 1906 Hay J: Bradycardia and cardiac arrhythmia produced by depression of certain of the functions of the heart. Lancet 1:139-143, 1906 Mobitz W: Gber die unfallstandige Storung der Erregungsuberleitung zwischen Vorhod and Kammer des menschlichen Herzens. Z Ges Exp Med 41:180-237, 1924 Scherlag BJ, El-Sherif N, Lazzara R: Experimental model for study of Mobitz type II and paroxysmal atrioventricular block. Am J Cardiol 34:309-3 17, 1974 El-Sherif N, Scherlag BJ, Lazzara R, et al: The pathophysiology of tachycardiaand bradycardia-dependent block in the canine proximal His-Purkinje system following acute myocardial ischemia. Am J Cardiol 33529-540, 1974 El-Sherif N, Scherlag BJ, Lazzara R: Conduction disorders in the canine proximal His-Purkinje system following acute myocardial ischemia. I. The pathophysiology of intra-His bundle block. Circulation 49:837-847, 1974 El-Sherif N, Scherlag BJ, Lazzara R: Conduction disorders in the canine proximal His-Purkinje system following acute myocardial ischemia. II. The pathophysiology of bilateral bundle branch block. Circulation 49:848-857, 1974 El-Sherif N, Scherlag BJ, Larzara R, et al: The pathophysiology of paroxysmal A-V block after acute myocardial ischemia. Experimental and clinical observations. Circulation 50:5 15528, 1974 El-Sherif N, Scherlag BJ, Lazzara R, et al: The evolution of second degree block in the canine proximal His-Purkinje system (abstr). Am J Cardiol 33:135, 1974 Lazzara R, Scherlag BJ, El-Sherif N: Transmembrane potentials in the His bundle after coronary occlusion (abstr). Am J Cardiol 33: 150, 1974 Lazzara R, Scherlag BJ, El-Sheril N: Cellular electrophysiology of the ischemic His bundle. Circ Res, in press

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Lazzara R, Scherlag BJ, Robinson MJ, et al: Selective in situ parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circ Res 32:393-401, 1973 Scherlag BJ, Helfant RH, Damato AN: Catheterization technique for His bundle stimulation and recording in the intact dog. J Appl Physiol 25:425-428, 1968 Scherlag BJ, Abelleira JL, Samet P: Electrode catheter recordings from the His bundle and the left bundle in the intact dog. In, Research in Physiology (Kao FF, Koizumi K, Vassalle M, ed). Bologna, Italy. Aulo Gaggi Editore, 1971, p 223-238 Scherlag BJ, Kosowsky BD, Damato AN: Technique for ventricular pacing from the His bundle of the intact heart. J Appl Physiol 221584-587, 1967 Elizari MV, Bailey JC, Greenspan K, et al: A simple dissecting technique of the A-V canine conducting system for electrophysiological studies (abstr). Circulation 4: Suppl II: 11-149, 1972 Katz LN, Pick A: Clinical Electrocardiography. The Arrhythmias. Philadelphia, Lea & Febiger, 1956, p 540-658 Hoffman BF: Electrical activity of the atrio-ventricular node. In, Specialized Tissue of the Heart (Paes de Carvalho A, deMello WC, Hoffman BF, ed). Amsterdam, Elsevier Publishing, 1961 Mendez C, Moe GK: Some characteristics of transmembrane potentials of AV nodal cells during propagation of pacemaker beats, Circ Res 19:993-1010, 1966 Cranefield PF, Klein HO, Hoffman BF: Conduction of the cardiac impulse. 1. Delay, block and one-way block in depressed Purkinje fibers. Circ Res 28:199-219, 1971 Fabiato A, Fabfato F: The two components of the human atrial action potential. Circ Res 29:296-305, 1971 Churney L, Oshima H: Is the fundamental electrical response of the single heart muscle cell a spike potential? J Gen Physiol 46: 1029-1046, 1962 Lieberman M, Kootsey JM, Johnson EA, et al: Slow conduction in cardiac muscle. A biophysical model. Biophys J 13:37-55, 1973 Reuter H: Dependence of the slow inward current in Purkinje fibers on the extracellular calcium-concentration. J Physiol (Lond)

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192:479-492, 1967 26. Rougier 0, Vassorf G, Garnier D, et al: Existence and role of a slow inward current during the frog atrial action potential. Pfluegers Arch 306:91-110, 1969 27. Carmeliet E, Vereecke J: Adrenaline and the plateau phase of the cardiac action potential: importance of Ca++, Na+, and K+ conductance. Pflueger Arch 313:300-315, 1969 28. Pappano AJ: Calcium-dependent action potentials produced by catecholamines in guinea pig atrial muscle fibers depolarized by potassium. Circ Res 27:379-390, 1970 29. Beeler GW Jr, Reuter H: Membrane calcium current in ventricular myocardial fibers. J Physiol (Lond) 207:191-209, 1970 30. Vltek M, Trautweln W: Slow inward current and action potential in cardiac Purkinje fibers. Pfluegers Arch 323:204-218, 1971 31. Shigenobu K, Sperelakls N: Calcium current channels induced by catecholamines in check embryonic hearts whose fast sodium channels are blocked by tetrodotoxin or elevated potassium. Circ Res 32:932-952, 1972 32. Weidman S: The effect of cardiac membrane potential on the rapid availability of the sodium carrier system. J Physiol 127: 213-224. 1955 33. Paes de Carvalho A, Hoffman BF, dePaula Carvalho M: Two components of the cardiac action potential. I. Voltage-time course and the effect of acetylcholine on atrial and nodal cells of the rabbit heart. J Gen Physiol 54:607-635, 1969 34. Cranefleld PF, Wit AL, Hoffman BF: Conduction of the cardiac impulse. Ill. Characteristics of very slow conduction. J Gen Physiol 59:227-246, 1972 35. Cranefield PF, Hoffman BF: Conduction of the cardiac impulse. II. Summation and inhibition. Circ Res 28:220-233, 1971 36. Lazrara R, El-Sherlf N, Scherlag BJ: Electrophysiological properties of canine Purkinje cells in one-day-old myocardial infarction. Circ Res 33~722-734, 1973 37. Harris AS: Potassium and experimental coronary occlusion. Am Heart J 71:797-802, 1966 38. Grlfflths J, Leung F: The sequential estimation of plasma cate-

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cholamines and whole blood histamine in myocardial infarction. Am Heart J 82:171-179, 1971 Rosenbaum MB, Ellzarl MV, Lazrari JO, et al: The mechanism of intermittent bundle branch block. Relationships with prolonged recovery, hypopolarization and spontaneous diastolic depolarization. Chest 63:666-677, 1973 Myerburg RJ, Stewart JW, Hoffman BF: Electrophysiological properties of the canine peripheral A-V conduction system. Circ Res 26:361-378, 1970 Langendorf R, Pick A: Atrioventricular block, type II (Mobitz)its nature and clinical significance. Circulation 38:819-821, 1968 Langendorf R, Cohen H, Gozo EG Jr: Observations on second degree atrioventricular block, including new criteria for the differential diagnosis between type I and type II block. Am J Cardiol29:111-119, 1972 Narula OS: Conduction disorders in the A-V transmission system. In, Cardiac Arrhythmias (Dreifus LS, Likoff W, ed). New York, Grune & Stratton, 1973, p 259-291 Anderson GJ, Greenspan K, Flsch C, et al: Electrophysiological studies of Wenckebach structures below the A-V junction. Am J Cardiol 30:232-236, 1972 Anderson GJ, Bailey JC: Conduction delay and block within the peripheral Purkinje system. In Ref 43, p 203-215 Spear JF, Moore EN: Electrophysiological studies on Mobitz type II second degree heart block. Circulation 44:1087-1095, 1971 Rosen KM, Loeb HS, Gunnar RM, et al: Mobitz type II block without bundle-branch block. Circulation 44: 111 l-l 119, 1971 Yeh BK, Tao P, DeGuzman N: Mobitz type II A-V blocks as a manifestation of digtalis toxicity. J Electrocardiol 5:74-44, 1972 Watanabe Y, Drelfus LS: Second degree atrioventricular block. Cardiovasc Res 1: 150- 158. 1967 Dreifus LS, Watanabe Y, Halat R, et al: Atrioventricular block. Am J Cardiol 28:371-380. 1971