Reflection as a mechanism of reentrant cardiac arrhythmias.
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Animals↗
Biomedical subjects
G K Moe
Publications and source records attributed to G K Moe.
Effect of external potassium and acetylstrophanthidin on conduction velocity of isolated canine Purkinje fibers.
Isolated long Purkinje fibers were perfused in oxygenated Tyrode's solution. The conduction velocity of action potentials driven from one end of a fiber at cycle lengths of 300 and 1000 msec was measured using silver wire surface electrodes. Action potentials were recorded using glass microelectrodes. Tyrode's solutions of different potassium concentrations were used, and preparations were equilibrated for 10 min. Prior to acetylstrophanthidin, maximum conduction velocities reaching 2.3 m/sec were recorded at (K)o = 6 mM. The conduction velocity was not directly proportional to maximum dV/dt or action potential amplitude at (K)o between 2 and 6 mM; maximum dV/dt and action potential amplitude were greater although conduction velocity was decreased. In this range of (K)o, membrane excitability may be an important factor. Acetylstrophanthidin (10(-7) and 5 X 10(-8) g/ml for slowly and rapidly driven preparations, respectively) diastolic depolarization and slowed conduction at (K)o less than 6 mM, but it did not increase automaticity or decrease conduction at (K)o over 6 mM. The added effect of high potassium on digitalis-induced slowing of conduction, reported in whole animal experiments, was not observed.
Action Potentials↗
Oscillating concepts in arrhythmia research; a personal account.
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Arrhythmias, Cardiac↗
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.
Action Potentials↗
Determinants of postrepolarization refractoriness in depressed mammalian ventricular muscle.
Functional determinants of postrepolarization refractoriness were studied with microelectrodes in isolated cat and dog ventricular muscle preparations mounted in a three-chambered bath. Frequency-dependent conduction delay and block were readily manifested when the central segment (1 mm) was superfused with high potassium (20-30 mM) Tyrode's solution. Conduction disorders were attributed to postrepolarization refractoriness involving slow recovery in the amplitude of elicited subthreshold depolarizations in depressed fibers distal to the central blocked zone. Investigations of subthreshold phenomena in homogeneously depressed tissues indicated that a relatively large local response participated in the voltage displacement induced by subthreshold depolarizing currents. The local response was blocked by tetrodotoxin (10 micrograms/ml) or verapamil (2 micrograms/ml) when resting membrane potential was near -70 or -50 mV, respectively. At either level of reduced membrane potential, gradual recovery in diastolic excitability correlated closely with time-dependent recovery of the local response, the rate of which was also proportional to the current intensity applied. Thus, postrepolarization refractoriness in depressed ventricular muscle fibers is a function of the time for recovery of active subthreshold properties (the local response), as well as intensity of excitatory current input. These factors may play a role in the development of delayed conduction and reentry that occur at faster heart rates under ischemic conditions.
Action Potentials↗
Electrotonic inhibition and summation of impulse conduction in mammalian Purkinje fibers.
Models of electrotonically mediated transmission were created by superfusion of the central fiber segment of a three-compartment Purkinje fiber preparation with either an "ion-free" or "ischemic" solution or by localized application of pressure. The frequency-dependent impairment of impulse conduction across such inexcitable gaps was found to be the result of influences exerted not only by impulses transmitted across the area of block but also by impulses blocked at the proximal border of the inexcitable zone. The electrotonic image of a nonconducted response was observed to exert an important inhibitory effect on the electronically mediated transmission of a subsequent impulse, thus causing block or delay. This phenomenon, which we have termed electrotonic inhibition, shows both time and voltage dependence. The related phenomenon of electrotonic summation describes the facilitation of conduction that occurs when two subthreshold potentials occur close enough in time to fuse. These data provide a demonstration of Wedensky inhibition in heart tissues and point to electrotonic inhibition as a mechanism of concealed conduction. Electrotonically mediated phenomena may explain both temporal and spatial inhibition and summation previously described in nodal or depressed tissues and ascribed to partial active invasion of intermediary tissue.
Action Potentials↗
Rate-dependent changes in excitability of depressed cardiac Purkinje fibers as a mechanism of intermittent bundle branch block.
When the heart rate is accelerated, rate-dependent intraventricular block may occur. This block has been attributed to abnormal action potential prolongation in a diseased conducting pathway. Less often, intraventricular block develops during slowing of the heart rate and has been explained in terms of phase 4 depolarization in potentially automatic cells within the diseased fascicle. We tested these hypotheses in isolated bundles of Purkinje fibers placed in a three-chambered tissue bath. In one group of experiments, conditions of localized injury and depressed excitability were mimicked by superfusing the central segment with sucrose solution. Action potentials were initiated in the proximal segment while the slope of phase 4 of cells in the distal end was controlled by intracellular ramps of current of either polarity. In these preparations, phase 4 depolarization facilitated rather than retarded propagation across the depressed segment, even at takeoff potentials as low as -45 mV. In a second group, depressed excitability was induced by exposing the three fiber segments to Tyrode's solution that contained high concentrations of KCl and CaCl2 or isoproterenol (0.1 microgram/ml). Under these conditions, Purkinje fibers did not undergo phase 4 depolarization and did not generate abnormally prolonged action potentials. These preparations showed a biphasic time dependence of conduction during premature stimulation or in response to changes in the basic cycle length. Conduction impairment and block were manifest at either side of an optimal interval or cycle length. Our results suggest that phase 4 depolarization and abnormally prolonged action potentials are not necessary conditions for intermittent block. Both tachycardia and bradycardia-dependent intraventricular conduction abnormalities may be associated with time-dependent variations in the excitability of depolarized conducting fibers as well as in the amplitude of the slow responses generated by these fibers. These alterations can be explained in terms of regulation of slow inward current by the intracellular calcium concentration.
Action Potentials↗
Parasystole, reentry, and tachycardia: a canine preparation of cardiac arrhythmias occurring across inexcitable segments of tissue.
A protected ectopic focus created in tissue excised from one heart was allowed to interact with the activity of the intact heart of another animal. The protected focus consisted of a Purkinje fiber in which a narrow central zone was rendered inexcitable. The model permitted us to study parasystole, modulated parasystole, reentry, and tachycardia in the same preparation. At moderate levels of electrotonic influence across the region of block, frequency scans revealed wide zones of pacemaker entrainment. The incidence and pattern of premature ventricular contractions generated were always a sensitive function of heart rate. Parasystolic patterns could be converted to apparent reentrant patterns by simple alteration of the atrial driving rate or the level of block. Suppression of pacemaker automaticity converted a modulated parasystole model to one of pure reentry. Reciprocation of the impulse across the inexcitable tissue segment generated a ventricular tachycardia that could be initiated and terminated by a single properly timed event. Our observations suggest that ectopic activity that behaves like parasystole and activity characteristic of what is commonly diagnosed as reentry, including tachycardia and idioventricular rhythms, may be a manifestation of a common mechanism whose arrhythmic expression differs as a continuous function of heart rate, level of block, or level of automaticity.
Animals↗
The case for modulated parasystole.
Several recently published tracings of parasystolic rhythms with unusual features were studied to determine whether the biphasic response curve characteristic of modulated parasystole could be extracted from the patterns of arrhythmia. Even in cases in which the possibility of modulation had been rejected, the phase response curves could be derived by inverse analysis of the ectopic intervals. When the derived curves were inserted into the program of the computer model, almost exact matches for the clinical patterns were recorded. In one case, in which the right atrium was driven at increasing rates, the patterns of manifest ectopic ventricular responses appeared to be re-entrant rather than parasystolic. In this case, similar patterns as a function of heart rate were recorded from a mathematical model of reflection.
Arrhythmias, Cardiac↗
Electrotonic metabolism of pacemaker activity. Further biological and mathematical observations on the behavior of modulated parasystole.
An in vitro biologic model of parasystole and a mathematical model of parasystole based on the phase-response relationships derived from the biologic model were used in tandem to further develop our understanding of the patterns of ectopic activity that might arise as a consequence of the interaction of two pacemakers across a zone of block. Superfusion of the central segment of a dog Purkinje fiber with an ion-free isotonic sucrose solution provided a narrow region of block. The modulation of pacemaker activity by electronic potentials transmitted across the area of block was shown to be importantly influenced by the position of the "ectopic" pacemaker relative to the site of block. Effects of repetitive electrotonic influences on a single pacemaker cycle, the degree of entrance block and capture of the pacemaker during a phase of supernormal excitability were also studied in both the biologic and mathematical models. Our results indicate that marked shifts in the incidence and pattern of manifest ectopic activity can occur as a result of slight changes in heart rate, ectopic pacemaker rate, level of block and the position of the parasystolic pacemaker relative to the block border.
Action Potentials↗
Effects of lidocaine on conduction through depolarized canine false tendons and on a model of reflected reentry.
Reflected reentry was produced in canine false tendons, mounted in a three-chamber bath, in which the central fiber segment was partially depolarized with an "ischemic" solution to provide an area of impaired conduction. Lidocaine (3-5 mg/l) added to the central chamber further impaired conduction; consequently, reflections were obtained at lower frequencies and over a wider range of stimulation cycle lengths. Complete block followed drug exposure in some preparations. At moderate stimulation rates, the drug-induced shift of the frequency-dependence of manifest reflected reentries was either arrhythmogenic or antiarrhythmic. The action of lidocaine can be explained on the basis of effects on depressed fast or slow response activity at the boundary regions of the ischemic gap. Under slow response conditions, in false tendons homogeneously exposed to a solution containing 20 mM K+ and 9 mM Ca++, lidocaine delayed propagation or induced complete block. In fibers mounted in a single sucrose gap, the drug increased the current required to reach threshold without significant changes in resting potential, threshold voltage or input resistance. The effect of lidocaine on threshold current was lost in Na+-deficient solutions. Thus, lidocaine impairs conduction through K+-depolarized false tendons, an effect that may be related to the Na+ background current.
Animals↗
Models of parasystole and reentry in isolated Purkinje fibers.
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Animals↗
Excitation, conduction, and reflection of impulses in isolated bovine and serum cardiac purkinje fibers.
When an impulse arrives at an area of impaired conductivity, a slowly rising electrotonic potential may bring the distal tissue to threshold after a delay imposed by the passive electrical properties of the system and by the time-dependent changes of these properties during diastole. This phenomenon can be demonstrated in Purkinje strands in which an area of depressed conductivity has been induced by the impedance of a sucrose gap and can be mimicked by the application of relatively long current pulses of low amplitude. The functional refractory period, defined as the shortest interval between two distal responses both propagated across the gap, was determined by the application of premature stimuli at progressively earlier intervals. The time course of the recovery of excitability as well as the conduction intervals could be varied almost at will by manipulating the electric impedance between proximal and distal ends of the fiber. When the time of activation of the distal end across the gap exceeded the absolute refractory period of the proximal segment, the impulse reflected back as a closely coupled premature beat. Time-dependent changes in the passive electrical properties of the depressed segment may set the conditions for reflection. The results suggest the possibility of reflection as a mechanism for premature beats and demonstrate obligatory shifts in the patterns of premature reentrant activity accompanying changes in basic cycle length. These experiments provide important clues for the distinction between reentrant and parasystolic mechanisms.
Action Potentials↗
Electrotonically mediated delayed conduction and reentry in relation to "slow responses" in mammalian ventricular conducting tissue.
A narrow zone of block in isolated false tendon preparations was created by perfusion of the central compartment (gap) of a three-compartment tissue bath with either an isotonic sucrose solution or a solution designed to mimic the extracellular milieu in ischemic tissue. Driven responses on the proximal side of the gap were transmitted to the distal side after long delays. The characteristics of the "ischemic" gap model were found to be qualitatively similar to those of the sucrose gap model in which impulse transmission is electrotonically mediated. In both models, the effects of driven action potentials were mimicked by electrotonic displacement of membrane potential by current pulses passed across the gap. Foot-potentials representative of electrotonic potentials bringing the distal membrane to threshold were present in all cases and were found to be largely unaffected by the slow channel-blocking agent, verapamil. Transmembrane activity recorded from the central portion of the gap segment was shown to be electrotonic in nature. Ectopic activity in the form of reflected reentry was readily demonstrable in the ischemic gap model in the presence or absence of verapamil as well as in the sucrose gap model. When propagation across the gap was mediated by "slow" responses, transmission was relatively prompt and reentry did not occur. Our observations suggest that very slow conduction through ischemic areas may result from step delays imposed by electrotonic transmission of impulses across inexcitable segments of cable rather than from uniform slow conduction of propagated action potentials with slow upstrokes.
Action Potentials↗
Effects of current flow on pacemaker activity of the isolated kitten sinoatrial node.
The dynamic behavior of the cardiac pacemaker in response to single or to periodically repeated perturbations was studied using kitten sinoatrial (SA) nodal strips mounted in a sucrose gap. Sustained stepwise applications of current across the gap produce lasting variations in pacemaker cycle length that depend on current magnitude and polarity, but not on the phase of the pacemaker period at the time of the input. Brief current pulses, whether hyperpolarizing or depolarizing, may abbreviate or prolong the immediately affected cycle depending on their timing. These changes result in phase shifts of the subsequent discharges, but they do not alter the pacemaker period permanently. The phasic effects of brief current pulses can be described by a phase response curve (PRC), which is a plot of the phase shift as a function of the position of the stimulus in the pacemaker cycle. PRCs were constructed for inputs of different polarity and several strengths and durations. The behavior of the sinus nodal pacemaker when interacting with period perturbing inputs, such as vagal stimulation or electrotonic depolarization, can be predicted on the basis of the phase response curve.
Action Potentials↗
Desensitization of the cholinergic receptor at the sinoatrial cell of the kitten.
The hyperpolarizing effects of long periods of vagal stimulation were studied in kitten sinoatrial node-vagus nerve preparations. Verapamil (2.2 x 10(-6) M) was used to arrest spontaneous pacemaker activity, thus permitting uninterrupted observation of the time course of cholinergically mediated hyperpolarizations. With progressively longer vagal trains the hyperpolarization was not maintained but decreased, rapidly at first, and then more gradually despite continuous vagal stimulation. Similar decay of the cholinergic effect was also observed during continuous iontophoretic application of acetylcholine (ACh) or carbamylcholine (CCh). The results show that, for the most part, the decay of the hyperpolarizing response cannot be due to "fatigue" of nerve terminals, to a gradual reduction in the driving force for K+, or to hydrolysis of ACh by cholinesterase. These experiments demonstrate the development of desensitization of the cholinergic receptor at the sinoatrial cell membrane. The data fit the "cyclic reaction" model proposed by Katz and Thelsleff (J. Physiol. London 138:63-80, 1957) for the neuromuscular junction.
Acetylcholine↗
Characteristics of reflection as a mechanism of reentrant arrhythmias and its relationship to parasystole.
A model of "reflection" was developed in a sucrose gap preparation of Purkinje fibers. In this preparation, a driven impulse on the proximal side of a sucrose gap is electrotonically transmitted after a delay to the tissue distal to the gap. When the delay is long enough, electrotonic transmission in the reverse direction over the same blocked segment can reexcite the proximal segment. Frequency-dependent alterations of patterns of ectopic activity were qualitatively similar to those of a parasystolic model and to those described in previous in vivo demonstrations presumed to represent circus movement reentry. Moderate changes of frequency or in the degree of block were shown to convert a manifest bigeminal rhythm to a trigeminal or more complex rhythm with or without intervening periods of silence. Our observations suggest that reflection and parasystolic pacemaker activity are examples of a continuous spectrum of ectopic impulse generation.
Animals↗
A biologic model of parasystole.
The electrotonic interactions of a parasystolic pacemaker with ventricular responses to the normal pacemaker across an area of depressed excitability were simulated in a model consisting of strands of canine Purkinje fibers mounted in a sucrose gap preparation. Experiments were conducted to study the patterns of ectopic activity that result from entrainment of the "ectopic" pacemaker (EP) on one side of the sucrose gap by evoked responses (sn) on the other side of the gap. When one-way conduction ("entrance block") was established, manipulations of the SN frequency and of the impedance between the two outer chambers resulted in periods of silence, concealed or manifest bigeminy, trigeminy and quadrigeminy, and periods of more complex patterns of group beating as the entrainment ratios changed. The results confirm the predictions of the previously described mathematical model that these patterns depend on the magnitude of the electrotonic influence of SN on the EP cycle length and also on the ratio of the intrinsic frequencies. These studies should help to distinguish between reentrant and parasystolic mechanisms in clinical arrhythmias.
Animals↗