Microelectrode study of Wenckebach periodicity in canine Purkinje fibers

Electrophysiologic mechanisms responsible for Wenckebach periodicity produced experimentally in a segment of blocked canine Purkinje fibers were investigated with multiple microelectrode recordings. Transmission through the zone of block was electrotonic. The Wenckebach mechanism was related to a progressive decrease in the efficacy of the transmitted electrotonic potential as a stimulus for the regenerative response at the distal block boundary with successive impulses of the cycle. This was manifested in the transmembrane potentials as a progressive decrease in upstroke velocity and a voltage change that caused the electrotonic potential to become progressively removed from the threshold for stimulation. The immediate cause of this phenomenon was a progressive increase in the voltage level (more negative) from which the electrotonic potential originated and a resulting change in voltage-dependent membrane resistance that further attenuated the signal with successive impulses of the cycle.Two main mechanisms appeared to be responsible for these phenomena: (1) a progressive increase in maximal repolarization voltage (more negative) of the transmembrane potential, and (2) a progressive decrease in the diastolic interval that, in the presence of enhanced phase 4 diastolic depolarization, caused the voltage level from which the electrotonic potential originated to become further removed from the stimulation threshold with successive impulses of the cycle.     

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.     

Electrotonic Inhibition and Active Facilitation of Excitability in Ventricular Muscle

Inhibition and Facilitation in Cardiac Muscle. Introduction: The effects of subthreshold electrical pulses on the response to subsequent stimulation have been described previously in experimental animal studies as well as in the human heart. In addition, previous studies in cardiac Purkinje fibers have shown that diastolic excitability may decrease after activity (active inhibition) and, to a lesser extent, following subthreshold responses (electrotonic inhibition). However, such dynamic changes in excitability have not been explored in isolated ventricular muscle, and it is uncertain whether similar phenomena may play any role in the activation pal-terns associated with propagation abnormalities in the myocardium. Methods and Results: Experiments were performed in isolated sheep Purkinje fibers and papillary muscles, and in enzymatically dissociated guinea pig ventricular myocytes. In all types of preparations introduction of a conditioning subthreshold pulse between two subthreshold pulses was followed by a transient decay in excitability (electrotonic inhibition). The degree of inhibition was directly related to the amplitude and duration of the conditioning pulse and inversely related to the postconditioning interval. Yet, inhibition could be demonstrated long after (> 1 sec) the end of the conditioning pulse. Electrotonic inhibition was found at all diastolic intervals and did not depend on the presence of a previous action potential. In Purkinje fibers, conditioning action potentials led to active inhibition of subsequent responses. In contrast, in muscle cells, such action potentials had a facilitating effect (active facilitation). Electrotonic inhibition and active facilitation were observed in both sheep ventricular muscle and guinea pig ventricular myocytes. Accordingly, during repetitive stimulation with pulses of barely threshold intensity, we observed: (1) bistability (i.e., with the same stimulating parameters, stimulus: response patterns were either 1:1 or 1:0, depending on previous history), and (2) abrupt transitions between 1:1 and 1:0 (absence of intermediate wenckebach-like patterns). Simulations utilizing an ionic model of cardiac myocytes support the hypothesis that electrotonic inhibition in well-polarized ventricular muscle is the result of partial activation of I_k following subthreshold pulses. On the other hand, active facilitation may be the result of an activity-induced decrease in the conductance of I_K1. Conclusion: Diastolic excitability of well-polarized ventricular myocardium may be transiently depressed following local responses and transiently enhanced following action potentials. On the other hand, diastolic excitability decreases during quiescence. Active facilitation and electrotonic inhibition may have an important role in determining the dynamics of excitation of the myocardium in the presence of propagation abnormalities.     

The influence of atrial systole on ventricular capture by failing artificial pacemakers. II. Experimental observations

The mechanism by which atrial systole influences the efficacy of ventricular capture by a failing pacemaker was investigated in 12 dogs with atrioventricular heart block. Atrial systole caused facilitation of ventricular capture in eight dogs, and inhibition of capture in 10 dogs. Interpolating atrial extrasystoles caused an enhancement or depression of the hemodynamic performance of the atrial systole that affected the efficacy of the pacemaker stimulus. These interpolation experiments showed that atrial systole influenced the efficacy of capture by a mechanical mechanism and not by an electrotonic mechanism. Atrial systole probably caused motion of the endocardial pacing catheter and/or ventricular myocardium. This motion increased or decreased the contact between the pacing electrode and the endocardium with subsequent changes in the efficacy of capture. In three dogs with pacing through epicardial electrodes, atrial systole had no effect on the efficacy of capture.     

Reflected reentry in nonhomogeneous ventricular muscle as a mechanism of cardiac arrhythmias

Arrhythmogenesis in ventricular muscle exhibiting nonhomogeneous excitability was studied in isolated tissues from feline and canine hearts. Longitudinal bundles were mounted in a three-chambered bath and simultaneous transmembrane recordings were obtained from fibers in each chamber. Nonhomogeneous excitability was established by depressing only the central segment (1 to 2 mm wide) with high-K+ Tyrode's solution, which induced discontinuity of propagation associated with step delays mediated by electrotonic current flowing through the depressed zone. When transmission delays were long, activity distal to the site of block returned to proximal tissue as one of two forms of reflected reentry, each elicited by a different mechanism. Type I reflection, occurring with antegrade delays of 30 to 60 msec, was characterized by an early secondary depolarization due to electrotonic spread of currents from delayed responses in the depressed segment. Type II reflection evolved with delays greater than 90 msec and was manifest as a closely coupled regenerative action potential that developed independently of a pacemaker mechanism and of slow but continuous conduction. We conclude that delayed activation of excitable elements, which occurs when propagation is discontinuous, may lead to rhythm disturbances of focal origin that are mediated by electrotonic interactions across a zone of depressed tissue.     

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.     

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.     

Wedensky facilitation. Electrotonic potentiation during complete A-V block

The electrocardiogram recorded from a patient with third degree A-V block reflected almost regular A-V junctional escape rhythm. Some of the R-R cycles were slightly shorter than the basic escape cycle. A QRS complex ending such a relatively short R-R interval was always preceded by a sinus P wave, and had a QRS configuration which was minimally different from that of the escape complexes. The His bundle recording demonstrated that these minimally premature complexes were associated with an H-V interval which was shorter than that of the escape complexes. This indicates that the premature QRS complex could not be a capture beat. The relationship between the slightly premature QRS complex and the preceding sinus P-waves is explained on the basis of electrotonic potentiation or modulation to due Wedensky facilitation.     

Order-sensitive plasticity in adult primary auditory cortex

The neural response to a stimulus presented as part of a rapid sequence is often quite different from the response to the same stimulus presented in isolation. In primary auditory cortex (A1), although the most common effect of preceding stimuli is inhibitory, most neurons can also exhibit response facilitation if the appropriate spectral and temporal separation of sequence elements is presented. In this study, we investigated whether A1 neurons in adult animals can develop context-dependent facilitation to a novel acoustic sequence. After repeatedly pairing electrical stimulation of the basal forebrain with a three-element sequence (high frequency tone--low frequency tone-- noise burst), 25% of A1 neurons exhibited facilitation to the low tone when preceded by the high tone, compared with only 5% in controls. In contrast, there was no increase in the percent of sites that showed facilitation for the reversed tone order (low preceding high). Nearly 60% of sites exhibited a facilitated response to the noise burst when preceded by the two tones. Although facilitation was greatest in response to the paired sequence, facilitation also generalized to related sequences that were either temporally distorted or missing one of the tones. Pairing basal forebrain stimulation with the acoustic sequence also caused a decrease in the time to peak response and an increase in population discharge synchrony, which was not seen after pairing simple tones, tone trains, or broadband stimuli. These results indicate that context-dependent facilitation and response synchronization can be substantially altered in an experience-dependent fashion and provide a potential mechanism for learning spectrotemporal patterns.     

Effect of electrotonic potentials on pacemaker activity of canine Purkinje fibers in relation to parasystole.

Isolated false tendons excised form dog hearts were mounted in a three-chamber tissue bath. Isotonic sucrose solution was perfused in the central chamber to provide a region of depressed conductivity between the fiber segments in chambers 1 and 3, which were perfused with Tyrode's solution. The electrotonic influence of spontaneous or driven responses evoked in chamber 3 during the first half of the spontaneous cycle of a chamber 1 peacemaker delayed the next spontaneous discharge. This effect changed to acceleration when the chamber 3 segment fired during the second half of the spontaneous cycle. We found that subthreshold depolarizing current pulses 50-300 msec applied across the sucrose gap caused similar degrees of delay or acceleration. Furthermore, hyperpolarizing currents caused the reverse pattern. The results indicate that the discharge pattern of a parasystolic focus may be altered by the electrotonic influence of activity in the surrounding tissue. The significance of these findings is considered in relation to the mechanism of production of parasystolic rhythms.     

Observations during clinical 2:1 and 3:1 A-V block below the A-V node. Evidence of partial penetration of atrial impulses into the His bundle

A clinical His bundle recording during 2:1 A-V block below the A-V node displayed RBBB, a prolonged H-V interval, and alternating amplitude and duration of the His potentials. The reduced amplitude of the non-conducted His potential suggests a lesser depth of penetration into the His tissue with subsequent block. The reduced His potential amplitude may be due to decremental conduction within the His bundle and/or prolonged refractoriness of the His tissue following atrioventricular conduction of the preceding atrial impulse.During 3:1 A-V block progressively deeper penetration of the atrial impulses into the His-Purkinje system occurred. Progressive penetration into the more proximal His-Purkinje system may have permitted recovery of a more distal area of refractoriness with subsequent atrioventricular conduction. This mechanisms appears similar to one of the mechanisms of 3:1 A-V block demonstrated experimentally, except that in this clinical record the major site of impaired conduction and progressive penetration is within the His-Purkinje system rather than within the A-V node.     

Rate-related suppression and facilitation of conduction in isolated canine cardiac Purkinje fibers

Previous studies have shown that antegrade conduction through damaged His Purkinje tissue may be suppressed following rapid ventricular pacing (overdrive suppression of conduction). We studied this phenomenon using isolated Purkinje fibers placed in a three-chamber bath. Superfusates for the left, middle, and right segments of the fiber were altered to produce action potentials that resembled those of normal bundle branch, damaged His bundle, and normal His bundle, respectively. To produce anisotropic conduction, the left segment of the fiber was adjusted to be three to four times longer than the right segment. Pacing the right segment at intermediate rates produced maximal action potential amplitude in the middle segment and 1:1 right-to-left conduction, whereas pacing at faster or slower rates reduced action potential amplitude and produced block. Pacing the left segment at fast or slow rates also reduced action potential amplitude in the middle segment, but conduction was maintained (anisotropy). After rapid or slow left segment pacing, action potential amplitude in the middle segment remained low during subsequent right segment pacing at intermediate rates, and transient block occurred (overdrive or underdrive suppression of conduction). With time, action potential amplitude normalized and conduction resumed. In other more severely depressed preparations, conduction block occurred even at intermediate right segment pacing rates prior to left segment pacing. Under these conditions, pacing the left segment at intermediate rates increased action potential amplitude in the middle segment and temporarily permitted 1:1 conduction at intermediate right segment pacing rates (overdrive facilitation of conduction).(ABSTRACT TRUNCATED AT 250 WORDS)     

Conduction of early afterdepolarizations in sheep Purkinje fibers and ventricular muscle. An in vitro arrhythmia model.

To establish an arrhythmia generator model, a double-chambered bath was used in which sheep Purkinje fibers (PF) and ventricular muscle (VM) were placed. The conduction patterns of early afterdepolarization-induced triggered activations (TAs) were examined between normal segments bathed in unmodified Tyrode solution and abnormal segments bathed in ethylenediaminetetraacetate (3.3-5.0 mmol). Three types of preparations were used: PF-PF (n = 10), VM-VM (n = 5), and PF-VM (n = 13). Two types of spontaneous TAs appeared. One type was conducted to normal segments, inducing activations over the entire preparation, while the other type was not conducted. The conducting TAs had significantly more rapid mean dV/dt, larger amplitude, and higher peak transmembrane voltage as compared to nonconducting TAs. While conduction occurred in all PF-PF, VM-VM, and PF-VM preparations, conduction of TAs from abnormal segment VM to normal segment PF was impaired. A low plateau resulting from electrotonic transmission of depolarizing current from abnormal segments was recorded in normal segments near the border. This low plateau probably facilitated the transmission of TAs. In addition to spontaneous TAs, stimulated or spontaneous action potentials from NL were conducted to the not yet fully repolarized ABN and induced activations resembling TAs. These results may be relevant to clinical arrhythmias due to action potential prolongation. The arrhythmia may occur directly as a result of triggered activity or indirectly via slow conducting TAs, creating the possibility for reentry. This type of model may be useful for intervention studies, for example, by identifying agents that block abnormal segment to normal segment conduction.     

Coexistence of left branch block and ectopic rhythm simulating alternating block

During the acute phase of diaphragmatic myocardial infarction with septal extension, the ECG of a patient with a chronic left bundle branch block changed in a period of seconds from complete left bundle branch block to incomplete right bundle branch block then to narrow QRS complexes followed by incomplete and then complete left bundle branch block: the same QRS changes then occurred in reverse order; the atrial rhythm was absolutely stable during the recording. These appearances are explained by fusion of sinus and of an ectopic rhythm arising distal to the zone of block, the rate of which (sometimes faster and sometimes slower than the sinus rhythm) could have been influenced by an electrotonic effect after retrograde activation of the right bundle and concealed conduction in the left bundle. Appearances of bundle branch block may be recorded when the ventricle is partially activated from the point of breakthrough of the blocked branch.     

Tachycardia- and bradycardia-dependent atrioventricular block: observations regarding the mechanism of block

A case of paroxysmal bradycardia- and tachycardia-dependent atrioventricular (AV) block is described in a patient with right bundle branch block. The His bundle recordings demonstrated the site of the AV block to be distal to the His bundle recording site (probably in the left bundle branch). Whereas AV block distal to the His bundle occurred at an atrial paced cycle length of 700 ms, intact ventriculoatrial (VA) conduction was present up to a ventricular paced cycle length of 400 ms. Resumption of AV conduction was dependent on a critical HH or RH (in case of escapes) interval. These findings suggest that the bradycardia-dependent block is related to a time-dependent decrease in the amplitude of the current intensity of the proximal segment during late diastole. Spontaneous diastolic depolarization during late diastole resulted in impaired anterograde (AV) conduction but facilitated retrograde (VA) conduction. These findings are consistent with experimental "in vitro" observation in the sucrose gap model of AV block.     

Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons

Members of the Kv7 family (Kv7.2-Kv7.5) generate a subthreshold K(+) current, the M- current. This regulates the excitability of many peripheral and central neurons. Recent evidence shows that Kv7.2 and Kv7.3 subunits are targeted to the axon initial segment of hippocampal neurons by association with ankyrin G. Further, spontaneous mutations in these subunits that impair axonal targeting cause human neonatal epilepsy. However, the precise functional significance of their axonal location is unknown. Using electrophysiological techniques together with a peptide that selectively disrupts axonal Kv7 targeting (ankyrin G-binding peptide, or ABP) and other pharmacological tools, we show that axonal Kv7 channels are critically and uniquely required for determining the inherent spontaneous firing of hippocampal CA1 pyramids, independently of alterations in synaptic activity. This action was primarily because of modulation of action potential threshold and resting membrane potential (RMP), amplified by control of intrinsic axosomatic membrane properties. Computer simulations verified these data when the axonal Kv7 density was three to five times that at the soma. The increased firing caused by axosomatic Kv7 channel block backpropagated into distal dendrites affecting their activity, despite these structures having fewer functional Kv7 channels. These results indicate that axonal Kv7 channels, by controlling axonal RMP and action potential threshold, are fundamental for regulating the inherent firing properties of CA1 hippocampal neurons.     

Dopamine enhances both electrotonic coupling and chemical excitatory postsynaptic potentials at mixed synapses.

The transmitter dopamine reduces electrotonic coupling between retinal horizontal cells and increases their sensitivity to glutamate. Since in other systems single afferents establish mixed electrotonic and chemical excitatory synapses with their targets, dopamine might be expected there to depress one component of excitation while enhancing the other. This hypothesis was tested by applying dopamine locally in the vicinity of the lateral dendrite of the goldfish Mauthner cell (M cell) and monitoring the composite electrotonic and chemical excitatory postsynaptic potentials and currents evoked by ipsilateral eighth nerve stimulation. Dopamine produces persistent enhancements of both components of the postsynaptic response while it also increases input conductance. All these dopamine actions are prevented by superfusing the brain with saline containing the dopamine D1 receptor antagonist SCH-23390. Postsynaptic injections of the cAMP-dependent protein kinase inhibitor (Walsh inhibitor, or PKI5-24) block the dopamine-induced changes in synaptic transmission, implicating a cAMP-dependent mechanism. Furthermore, there is a dopaminergic innervation of the M cell, as demonstrated immunohistochemically with antibodies against dopamine and the rate-limiting enzyme in its synthetic pathway, tyrosine hydroxylase. Varicose immunoreactive fibers lie in the vicinity of the distal part of the lateral dendrite between the large myelinated club endings that establish the mixed synapses. As determined with electron microscopy, the dopaminergic fibers contain small vesicles, and they do not have synaptic contacts with either the afferents or the M cell, remaining instead in the synaptic bed. Taken together, these results suggest that dopamine released at a distance from these terminals increases the gain of this primary sensory input to the M cell, most likely through a phosphorylation mechanism.     

The influence of atrial activity on ventricular capture by failing artificial pacemakers. I. Report of two new cases and review of the literature.

Atrial activity can influence the ability of a failing artificial pacemaker to excite the heart. An appropriately timed atrial beat may cause failure in excitation by pacemaker stimuli which are usually successful in ventricular capture. Conversely, stimuli which usually fail in excitation may be made to succeed by an appropriately timed atrial beat. Two case reports and a review of the literature are presented. Alternative mechanisms for this influence of atrial activity are electrotonic effects (Wedensky facilitation or inhibition) and mechanical effects (motion of the pacing catheter or ventricular myocardium). The authors consider the latter mechanism preferable.     

Cellular electrophysiological effects of fulguration by low energy shock

In spite of the increasing use of catheter ablation in the treatment of refractory ventricular and supraventricular arrhythmias, little information is available on the basic electrophysiological effects of the treatment. Although high-energy shocks are still usually delivered, the current trend is toward lower energies. We studied the electrophysiological effects of non-deflagrating anodic shocks of 2 joules on preparations of sheep ventricular myocardium and Purkinje's fibers. The shocks were delivered by a standard defibrillator between a small-area catheter electrode and a wide-area inert electrode. Action potentials were recorded by the standard microelectrode technique. After the shocks were delivered, the Purkinje's cells that were 5 mm distant from the shocked area on either side were depolarized in the -30 to -40 mV zone, but they progressively reverted to an almost normal resting potential. Recovery was bi-exponential, with time constants of about 1 min and 10 min respectively. Similarly, the conduction block induced by the electric shock in 100% of the cases was reversible in 50%. It must be noted that at the time of conduction recovery the pattern observed was that of electrotonic conduction where the distal action potential conducted was preceded by a pre-potential. This pattern always regressed progressively, with gradual disappearance of the pre-potential in the distal cells, suggesting that the unexcitable area had vanished or become smaller. Although a normal 1/1 conduction and normal action potentials returned in the cells that were 5 mm distant from the shocked area, recordings performed at a distance of 1 to 4 mm from that area disclosed alterations of action potentials that were usually irreversible.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alternating Wenckebach periodicity: A common electrophysiologic response.

Alternating Wenckebach periods are defined as episodes of 2:1 atrioventricular (A-V) block in which conducted P-R intervals progressively prolong, terminating in two or three blocked P waves. In this study, His bundle recordings were obtained in 13 patients with pacing-induced alternating Wenckebach periods. Three patterns were noted: Pattern 1 (one patient with a narrow QRS complex) was characterized by 2:1 block distal to the H deflection (block in the His bundle) and Wenckebach periods proximal to the H deflection, terminating with two blocked P waves. Pattern 2 (four patients) was characterized by alternating Wenckebach periods proximal to the His bundle, terminating with three blocked P waves. Pattern 3 (eight patients) was characterized by alternating Wenckebach periods proximal to the His bundle, terminating with two blocked P waves. Alternating Wenckebach periods are best explained by postulating two levels of block. When alternating Wenckebach periods are terminated by three blocked P waves (pattern 2), the condition may be explained by postulating 2:1 block (proximal level) and type I block (distal level). When alternating Wenckebach periods are terminated by two blocked P waves (patterns 1 and 3), the condition may be explained by postulating type I block (proximal level) and 2:1 block (distal level). Pattern 1 reflects block at two levels, the A-V node and His bundle. Patterns 2 and 3 most likely reflect horizontal dissociation within the A-V node.