Microelectrode study of high grade block in canine Purkinje fibers

Previous reports from this laboratory described an electrotonic mechanism for simple impulse transmission through blocked segments of canine Purkinje tissue with slow diastolic depolarization assuming a vital role in second degree block. Utilizing an electrical blocking current, a blocked segment of canine Purkinje tissue was produced. Transmembrane events were recorded from blocked segments during higher grades of block (3:1 to complete) to delineate further mechanisms responsible for a periodic distal boundary response. Our results confirm that slow diastolic depolarization is an important determinant in sustaining periodic impulse conduction. Its importance is related to (1) progressive decrease of the resting membrane potential toward threshold at the distal block boundary, and (2) augmentation of the transmitted electrotonic potential in accordance with voltage dependent changes in membrane resistance. These data further lend definition to the distinction between electrotonic, partially active, and active transmembrane potentials. Impulse transmission through a segment of inactivated tissue is electrotonic and slow diastolic depolarization plays an important role in the maintenance of periodic impulse transmission.     

Wedensky facilitation in canine right bundle branch

The phenomenon of Wedensky facilitation was investigated in canine specialized conduction fibers. A segment of block was produced by an electrical depolarizing current of sufficient intensity to result in non-conduction of impulses. A subthreshold stimulus was applied to the preparation distal to the segment of block with a bipolar stimulating electrode. Electrotonic potentials which originated at the proximal block boundary and traversed the segment of block were demonstrated with an intracellular microelectrode. Synchronization of the previously subthreshold distal stimulus with the peak of the transmitted electrotonic potential demonstrated facilitation by conversion of the distal stimulus to a 1:1 response. Temporal variation of the distal stimulus to coincide with different portions of the electrotonic potential demonstrated loss of facilitation when the stimulus preceded, or followed the electrotonic peak voltage.     

Ouabain-induced Wenckebach conduction block in canine Purkinje fibers: The role of cycle length and time dependent changes in membrane potential

The purpose of this study was to determine the mechanism for digitalis-induced Wenckebach conduction block. Canine Purkinje cells were exposed to ouabain (2.0 × 10^?7 M) and studied with conventional microelectrode techniques. When trains of stimuli were interrupted by a 5 second pause, restoration of stimuli resulted in successive action potentials showing an increasing slope of phase 4 depolarization which was expressed after the last beat as a delayed afterdepolarization. For any given state of ouabain toxicity, a beat-to-beat reduction in maximal diastolic potential could be induced by shortening the basic cycle length. If basic cycle length remained constant, continued exposure to ouabain would increase the net voltage reduction in membrane potential occurring during the train of ten beats. During the 5 second pause, an increase in membrane potential was observed and this hyperpolarization was of the same magnitude as the depolarization occurring during stimulation. With successive beats as membrane potential was reduced, action potential amplitude and $\text{dV}\text{dt}$ were concomitantly reduced and conduction slowed. Intracellular current threshold measurements showed that the reduction in membrane potential initially was associated with decreased current threshold requirements, but later in toxicity current threshold was markedly increased for beats occurring late in the train. These data suggest that (1) the beat-to-beat reduction in membrane potential is due to both an increase in the height of the delayed afterdepolarization and a reduction in maximal diastolic potential; (2) trains of beats are associated with progressive prolongation of activation time with concomitant reduction in $\text{dV}\text{dt}$ and membrane potential; and (3) failure of conduction is probably related to Purkinje segments showing decreased excitability.     

Electrophysiologic studies on atrioventricular nodal Wenckebach cycles

Wenckebach cycles with a 4:3 ratio, produced by rapid atrial pacing, were studied in 27 anesthetized denervated dogs using programmed stimulation. A test stimulus (S') could be inserted after any preselected beat of the Wenckebach cycle. An on-line computer measured the atrial (A) to His bundle (H) intervals. In all dogs a progressive increase in atrioventricular (A-V) nodal refractoriness was seen in the effective refractory period for each beat and a rightward shift of the A'-H' relative to the A-A' refractory curves. Atypical Wenckebach cycles could be produced by small changes in the basic cycle length. No evidence for reentry was found from the refractory curves of Wenckebach cycles and by interruption of stimulation after the third stimulus of a 4:3 Wenckebach cycle. Analysis of the A'-H' relative to the H-A' refractory curves did not confirm a positive feedback mechanism. In order to mimic a Wenckebach cycle, a blocked premature beat was inserted during stressed 1:1 conduction. The changes in the refractory curves for successive beats after the premature beat were rate-dependent and similar to those in Wenckebach cycles but smaller in magnitude. In Wenckebach cycles there is a progressive increase in refractoriness, caused by cumulative effect similar to that seen after a blocked beat during stressed 1:1 conduction, until block occurs and the cycle resets.     

Effects of proximal intra-atrial Wenckebach on distal atrioventricular nodal, and His-Purkinje, block with special reference to the theory of alternating Wenckebach periods

Intra-atrial Wenckebach patterns of stimulus-to-response intervals coexisting with distal, A-V nodal, and His-Purkinje, blocks occurred in eight patients during high right atrial stimulation at rapid rates. In two patients with 2:1 St-H block and in two patients with 4:1 St-V block, an increase in the degree of block occurred when the proximal intra-atrial Wenckebach cycle was completed with the stimulus which otherwise would have been propagated to the distal levels. However, the degree of block did not increase when the intra-atrial Wenckebach terminated in distally blocked stimuli. In one patient progression of 4:1 into 5:1 St-V block was due to the association of intra-atrial Wenckebach with alternating 2:1 block at the A-V nodal, and His-Purkinje, levels. Contrasting with most reports dealing with the mechanisms of alternating Wenckebach in a single structure, this study permitted the determination of the boundaries between proximal and more distal levels. It also showed that alternating Wenckebach cycles (of St-H intervals) ending with two consecutively blocked stimuli could result from the association of proximal intra-atrial Wenckebach with distal, A-V nodal Wenckebach, or abortive AW, cycles. The electrophysiology of documented two, or three, level block in different structures has validated previously made assumptions regarding multilevel block in a single structure.     

Wenckebach periods with repetitive block: evaluation with His bundle recording

Two patients are reported in whom repetitive block of two consecutive P waves occurred during Wenckebach beating induced by atrial pacing. His bundle recordings revealed block proximal to H in the first case, suggesting inhomogeneous conduction in the A-V node. In the second case, long cycle lengths were produced in the His-Purkinje system due to A-V nodal Wenckebach periods. The long cycles prolonged refractory periods in the His Purkinje system so that subsequent beats (short cycles) were blocked distal to H.The repetitive block of consecutive multiple atrial impulses could result in unexpected degrees of ventricular asystole during usually benign Type I second-degree A-V block.     

Electrophysiologic observations in a patient with bradycardia-dependent atrioventricular block

In a patient with atrioventricular (A-V) block distal to the His bundle (H), 1:1 A-V conduction with right bundle branch block and an H-V interval of 70 msec was established with atrial pacing at rates of 120 to 150/min, suggesting that the A-V block was bradycardia-dependent. Advanced second degree A-V block distal to the H deflection occurred with atrial pacing at 160/min after completion of A-V nodal Wenckebach periodicity proximal to the H deflection because of the long H-H encompassing the blocked P wave. Atrial extrastimulus testing coupled with sinus rhythm (with A-V block) demonstrated that critical H₁-H₂ intervals of less than 545 msec allowed conduction to the ventricles. The H₂-V₂ interval shortened progressively from 290 to 70 msec with shortening of these critical H₁-H₂ intervals. Atrial extrastimulus testing coupled with an atrial driven cycle length of 500 msec (with intact A-V conduction) revealed block of the H₂ deflection with an H₁-H₂ interval longer than 540 msec.In conclusion, at critical diastolic intervals, impulses were blocked, creating a state of decreased responsiveness. If a cycle length of subsequent impulses was shorter than the critical diastolic blocking interval, membrane responsiveness gradually improved and conduction resumed. If a cycle length of subsequent impulses was longer than the critical blocking diastolic interval, A-V block was sustained. Blocked impulses continually penetrated to the site of block and reset the state of membrane responsiveness.     

Mechanism of the Wedensky phenomena in the left bundle branch

In a man with acute myocardial infarction, second degree atrioventricular (A-V) block with the Wenckebach phenomenon was observed. Paradoxically, only the first sequence beat showed left bundle branch block; beats conducted after shorter R-R intervals had normal intraventricular conduction. The most likely explanation of this, and of 2 earlier similar cases, is that Wedensky facilitation follows the beat that terminates a long R-R interval and allows the passage of the next descending impulse through the left bundle branch; the Wedensky effect allows the conduction of any further impulses that pass the A-V node to arrive at the depressed zone while the enhancing mechanism is still operative.

An extrapolation of certain properties of conduction in nerve allows this hypothesis: electrotonic (physical) potentials spread through and beyond the depressed zone in the wake of the blocked, propagated (biologic) impulse. Further electrotonic potentials invade the depressed area from the antidromic invasion of the distal left bundle, and also from nearby fibers. These potentials summate to raise the resting potential of the zone of block nearer to threshold, and thus facilitate conduction. Conditions most provocative of this phenomenon would appear with a small patch of disease in a bundle branch. This is consonant with previous clinical, pathologic and electrocardiographic experience.     

Absence of slow channel-dependent conduction within the His-Purkinje (bundle branch) reentrant circuit: a clinical and experimental study of the effects of verapamil

The effects of intravenous verapamil on intraventricular conduction and reentry within the His-Purkinje system were studied in 10 patients and 8 dogs using His bundle electrograms and the ventricular extrastimulus method. In the clinical study, ventricular stimulation was performed by applying stimuli of two times diastolic threshold current strength and in the dog study by applying stimuli ranging in strength from two times diastolic threshold strength to 40 mA. In the clinical study, verapamil was given intravenously as a bolus injection (0.075 to 0.15 mg/kg body weight) and in the dog study as a rapid infusion (0.7 to 1 mg/kg) over 10 minutes followed by continuous infusion at a rate of 0.014 mg/kg per min. Plasma verapamil concentrations ranged from 91 to 173 ng/ml (mean ± standard deviation 138 ± 27) in the clinical study and from 103 to 638 ng/ml (mean 459 ± 174) in the dog study. In both studies, verapamil produced no change in latency and intramyocardial (duration of QRS complex) and His-Purkinje (V₂-H₂ interval) conduction of even the earliest premature impulses delivered before the repolarization of the His-Purkinje system or ventricular muscle, or both, was completed; that is, some fibers might have been at the level of membrane potential at which conduction becomes wholly or in part dependent on the current flowing through the slow channel. Verapamil did not change significantly the determinants of reentry and did not abolish or modify the zone of reentry in any of the 10 patients.These results show that in patients with normal intraventricular conduction, slow channel-dependent conduction plays no role in the propagation of even the earliest premature impulses through the His-Purkinje reentrant circuit. In the absence of any evidence of slow channel-de-pendent conduction, one must assume that the slow propagation of very early premature impulses was mediated by incompletely reactivated rapid inward current system. These observations suggest that the system responsible for slow conduction cannot be recognized from the magnitude of conduction delay.     

Alternating reversed wenckebach periodicity: Concealed electrotonic conduction as a possible mechanism

Electrocardiograms were taken from a 67-year-old man with 2:1 atrioventricular block in whom alternating reversed Wenckebach periodicity was found. Long PR intervals of alternately conducted P waves progressively shortened until an alternate P wave was blocked. After an alternate P wave was blocked, the next alternate P wave was conducted to the ventricles with a markedly long PR interval. Then long PR intervals of alternately conducted P waves progressively shortened again until an alternate P wave was blocked. This is the first report on alternating reversed Wenckebach periodicity. It seems that concealed electrotonic conduction of alternately blocked impulses occurred as a possible mechanism.     

Wenckebach periodicity in single atrioventricular nodal cells from the rabbit heart

Previous studies have suggested that Wenckebach periodicity in cardiac tissues may occur because of discontinuous propagation across junctional areas in which there is high intercellular resistivity or different cell types. Under these conditions, the impulse may stop altogether at a given junction, or may renew its propagation but only after a step delay imposed by the diastolic time-dependent recovery in the excitability of cells distal to that junction. Accordingly, Wenckebach periodicity in the atrioventricular node may be explained in terms of electrotonically mediated delay in the activation of the nodal cells. To test this hypothesis, we have studied recovery of excitability, and susceptibility to rate-dependent activation failure in single myocytes isolated from the adult rabbit atrioventricular node. Recordings were obtained by using the patch technique in the whole-cell, current clamp configuration. Repetitive stimulation of single atrioventricular nodal myocytes with depolarizing current pulses of critical amplitude yielded frequency-dependent stimulus response patterns that ranged from 1:1, through various Wenckebachlike periodicities (e.g., 5:4 and 4:3) to 2:1 and 3:1. Both typical and atypical Wenckebach structures were demonstrated, as well as "complex" patterns (e.g., reverse Wenckebach or alternating Wenckebach) previously ascribed to multiple levels of block. The diastolic recovery of excitability curve, determined by application of repetitive stimuli at cycle lengths that were longer than the action potential duration, showed a monotonic function with a refractory period outlasting the action potential duration (i.e., postrepolarization refractoriness). Abbreviation of the stimulation cycle length to values below those of the action potential duration revealed the existence of a period of supernormal excitability during the repolarizing phase of the action potential. In either case, the stimulus response patterns obtained were a direct consequence of the shape of the recovery of excitability curve. The monotonic portion of the recovery curve was fitted to an empirical equation that when iterated reproduced the stimulus response patterns observed in the atrioventricular nodal cell. Our data demonstrate that recovery of excitability after an action potential is indeed a function of the diastolic interval, and that this slow process sets the conditions for the development of Wenckebach periodicity in the atrioventricular node.     

Reverse alternating Wenckebach periodicity

An atrial pacing-induced reverse conduction pattern of the alternating Wenckebach periodicity was observed in 5 of 42 children (12%) during electrophysiologic study. This conduction pattern is a reverse of the usual alternating Wenckebach periodicity: During an underlying 2:1 atrioventricular conduction block there is progressive shortening of the conduction time of the conducted impulses with termination in a lower degree of block. This reverse alternating Wenckebach periodicity may be caused by a mechanism similar to that in other Wenckebach phenomena.     

Atrial pacing-induced alternating Wenckebach periodicity and multilevel conduction block in children

Multilevel block within the atrioventricular (AV) node has not been previously described in children. Six children with atrial pacing-induced repetitive block are presented. The conduction patterns satisfy the requisites for alternating Wenckebach periodicity or multilevel AV block. In 2 patients the block is documented in the AV node and infra-His region. In 4 patients multilevel block within the AV node is postulated by deductive reasoning. In this study, 2 patterns of alternating Wenckebach periodicity are reported for the first time: sequences of 3:1 block with progressive prolongation of the conducted impulses terminating in 4:1 block; and sequences of 2:1 block with progressive prolongation of the conducted impulses terminating in 2 series of 3:1 block, in which the first conducted impulse following the first 2 blocked beats is not the shortest one, whereas that following the second 2 blocked beats is the shortest.     

AV nodal dual pathway electrophysiology and Wenckebach periodicity

Dual Pathways and Wenckebach Periodicity. Introduction: The precise mechanism(s) governing the phenomenon of AV nodal Wenckebach periodicity is not fully elucidated. Currently 2 hypotheses, the decremental conduction and the Rosenbluethian step‐delay, are most frequently used. We have provided new evidence that, in addition, dual pathway (DPW) electrophysiology is directly involved in the manifestation of AV nodal Wenckebach phenomenon. Methods and Results: AV nodal cellular action potentials (APs) were recorded from 6 rabbit AV node preparations during standard A1A2 and incremental pacing protocols. His electrogram alternans, a validated index of DPW electrophysiology, was used to monitor fast (FP) and slow (SP) pathway conduction. The data were collected in intact AV nodes, as well as after SP ablation. In all studied hearts the Wenckebach cycle started with FP propagation, followed by transition to SP until its ultimate block. During this process complex cellular APs were observed, with decremental foot formations reflecting the fading FP and second depolarizations produced by the SP. In addition, the AV node cells exhibited a progressive loss in maximal diastolic membrane potential (MDP) due to incomplete repolarization. The pause created with the blocked Wenckebach beat was associated with restoration of MDP and reinitiation of the conduction cycle via the FP wavefront. Conclusion: DPW electrophysiology is dynamically involved in the development of AV nodal Wenckebach periodicity. In the intact AV node, the cycle starts with FP that is progressively weakened and then replaced by SP propagation, until block occurs. AV nodal SP modification did not eliminate Wenckebach periodicity but strongly affected its paradigm. (J Cardiovasc Electrophysiol, Vol. pp.1‐7)     

Slow recovery of excitability and the Wenckebach phenomenon in the single guinea pig ventricular myocyte

The cellular mechanisms of Wenckebach periodicity were investigated in single, enzymatically dissociated guinea pig ventricular myocytes, as well as in computer reconstructions of transmembrane potential of the ventricular cell. When depolarizing current pulses of the appropriate magnitude were delivered repetitively to a well-polarized myocyte, rate-dependent activation failure was observed. Such behavior accurately mimicked the Wenckebach phenomenon in cardiac activation and was the consequence of variations in cell excitability during the diastolic phase of the cardiac cycle. The recovery of cell excitability during diastole was studied through the application of single test pulses of fixed amplitude and duration at variable delays with respect to a basic train of normal action potentials. The results show that recovery of excitability is a slow process that can greatly outlast action potential duration (i.e., postrepolarization refractoriness). Two distinct types of subthreshold responses were recorded when activation failure occurred: one was tetrodotoxin- and cobalt-insensitive (type 1) and the other was sensitive to sodium-channel blockade (type 2). Type 1 responses, which were commonly associated with the typical structure of the Wenckebach phenomenon (Mobitz type 1 block), were found to be the result of the nonlinear conductance properties of the inward rectifier current, IK1. Type 2 sodium-channel-mediated responses were associated with the so-called "millisecond Wenckebach." These responses may be implicated in the mechanism of Mobitz type 2 rate-dependent block. Single-cell voltage-clamp experiments suggest that variations in excitability during diastole are a consequence of the slow deactivation kinetics of the delayed rectifier, IK. Computer simulations of the ventricular cell response to depolarizing current pulses reproduced very closely all the response patterns obtained in the experimental preparation. It is concluded that postrepolarization refractoriness and Wenckebach periodicity are properties of normal cardiac excitable cells and can be explained in terms of the voltage dependence and slow kinetics of potassium outward currents. The conditions for the occurrence of intermittent activation failure during diastole will depend on the frequency and magnitude of the driving stimulus.     

Influence of pacemaker-induced tachycardia with A-V block on left ventricular blood velocity in man.

Phasic instantaneous left ventricular blood velocity was measured by radiotelemetry in 28 subjects with a Doppler ultrasonic flowmeter catheter during atrial pacing and induced A-V block Type I Wenckebach A-V block with conduction ratios of 9:8 or lower generally produced a stepwise reduction of peak left ventricular blood velocity in relation to shortened R-R intervals. Longer Wenckebach periods resulted in little or no blood velocity alteration during 1:1 A-V conduction. Those beats following a blocked atrial depolarization were associated with augmented blood velocities. In three subjects, bigeminal periods of 3:2 A-V block resulted in larger left ventricular blood velocities when compared with 2:1 A-V block, despite identical R-R intervals following the blocked P wave. This latter phenomenon was attributed to diastolic augmentation of left ventricular contraction following the second and hemodynamically ineffective beat during 3:2 A-V block. Three patients manifested true blood velocity alternation during second-degree A-V block and changing R-R intervals. The variations in peak left ventricular blood velocity observed during atrial pacing and A-V block are related to changing inotropic state and cycle length dependent alterations of left ventricular diastolic filling.     

Atrioventricular alternating Wenckebach periodicity: conduction patterns in multilevel block

Atrioventricular (A-V) conduction patterns were analyzed in three patients with atrial pacing-induced alternating Wenckebach periodicity. These cases were unique because in each (1) separate levels of block responsible for the conduction disturbance were located above and below the His bundle recording site, and (2) there were several departures from the simple alternating Wenckebach pattern. Apparent supernormal conduction, temporary 1:1 conduction and a specific form of gap in A-V conduction resulted from the interplay of many factors including a simple mathematic relation of the blocking ratio at the two levels, the characteristics of the Wenckebach cycles, and the cycle length-dependent features of refractory periods at the different sites. The findings indicate that (1) delay in proximal impulse transmission is usually the critical factor in overcoming prolonged distal refractoriness and producing variable conduction patterns during the course of alternating Wenckebach periodicity; (2) many irregularities in alternating Wenckebach periodicity can be explained by known electrophysiologic mechanisms; and (3) simple mathematic equations alone are too rigid to reflect properly the dynamic process underlying this conduction disturbance.     

Mechanism of tachycardia-dependent appearance of ventricular extrasystoles in concealed bigeminy

A case of concealed ventricular bigeminy is reported in which the number of sinus QRS complexes intervening between two successive noninter-polated extrasystoles was always uneven. Coupling intervals of manifest extrasystoles to the preceding sinus QRS complexes were almost fixed and much longer than sinus QT intervals. Bradycardia-dependent disappearance of manifest bigeminy and tachycardia-dependent appearance of extrasystoles occurred in this case. Apparently, 2:1 block of sinus impulses occurred in the reentrant pathway, with markedly depressed conductivity. Concealed electrotonic conduction of blocked sinus impulses in the pathway of extrasystoles may have favored the appearance of the subsequent manifest extrasystoles without concealed conduction owing to two-level block. A possible explanation for the mechanism of such concealed bigeminy is presented, which uses the concepts of longitudinal dissociation and electrotonic inhibition in the reentrant pathway with markedly depressed conductivity.     

Concealed intraventricular conduction in the His bundle electrogram.

Multiple areas of concealed intraventricular conduction are deduced on the basis of aftereffects observed in His bundle recordings. Electrocardiograms and His bundle recordings are presented from two patients with unstable bilateral bundle branch block, the instability of which depended on the interval at which ventricular depolarization was initiated by sinus or paced impulses. This circumstance allows postulation of 1) concealed transseptal retrograde penetration of the left bundle branch system; 2) concealed transseptal retrograde penetration of the right bundle branch system; 3) alternate beat Wenckebach phenomenon with two areas of block in the bundle branch system with concealed penetration of the proximal area; 4) concealed re-entry in the right bundle branch system during an H-V Wenckebach cycle with resetting of the sequence of 2:1 H-V block and return of the re-entry wave to the A-V node causing subsequent A-H block; 5) proximal 2:1 block and distal Wenckebach block producing only two consecutively blocked beats; and 6) infrahisian Wenckebach block with changes both in A-V conduction and QRS contour.     

Factors related to the induction of ventricular fibrillation in the normal canine heart by programmed electrical stimulation

Programmed electrical stimulation was performed in eight normal dogs using a stimulator and endocardial electrode catheters identical to those used in human studies. The right and left ventricular apex were paced at a drive cycle length of 400 ms and, in some cases, 500 ms, with a pacing sequence of single (S1S2), double (S1S2S3) and triple (S1S2S3S4) premature impulses introduced after eight paced complexes. Pacing sequences were performed using combinations of pulse width (1, 2 and 4 ms) and current strengths of 2, 5 and 10 times diastolic threshold, and in three dogs, 15 times diastolic threshold. Twenty-two episodes of ventricular fibrillation were initiated in five dogs in 170 pacing sequences using current strengths up to 10 times diastolic threshold, and six episodes of ventricular fibrillation in the two of three remaining dogs tested at 15 times diastolic threshold. Ventricular fibrillation was reproducible on seven of nine occasions. Ventricular fibrillation was never induced by S1S2 at up to 15 times diastolic threshold; it was induced by S1S2S3 in 3 (1.8%) of 170 sequences, but only at 10 times diastolic threshold. It was induced by S1S2S3S4 in 19 (11.4%) of 167 sequences using 2 to 10 times diastolic threshold, although 20 of 28 episodes only occurred with S1S2S3S4 at 10 or more times diastolic threshold.(ABSTRACT TRUNCATED AT 250 WORDS)