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Biomedical subjects

C Antzelevitch

Publications and source records attributed to C Antzelevitch.

107 records · Page 6Linked to original sources
PubMed1986

Mechanisms underlying the antiarrhythmic and arrhythmogenic actions of quinidine in a Purkinje fiber-ischemic gap preparation of reflected reentry.

The effects of therapeutic levels of quinidine were studied in an ischemic gap preparation of reflected reentry. The preparation consisted of a Purkinje fiber mounted in a three-compartment chamber. A narrow central compartment was perfused with a solution prepared to mimic the extracellular milieu at a site of ischemia. Quinidine in concentrations that exert little effect on normal Purkinje tissue, 1 to 2 micrograms/ml, greatly impaired conduction and markedly prolonged refractoriness across the ischemic gap. The drug effected these changes by (1) extending the inexcitable zone within the depressed region, (2) decreasing the amplitude of the input signal entering this zone, and (3) decreasing the excitability of the tissue beyond the depressed zone (evaluated by current clamp techniques). These actions of the drug produced both antiarrhythmic and proarrhythmic effects. When the initial level of conduction impairment was high, quinidine totally suppressed reflected reentry at all frequencies by precipitating complete anterograde conduction block. At intermediate levels of block, the drug generally caused a prominent shift of the frequency dependence of reentrant activity to lower stimulation rates. Finally, when conduction was relatively less impaired, quinidine created the conditions for reflected reentry to occur. Our results suggest that the heart rate dependence of reentrant arrhythmias might be of prognostic value in the administration of antiarrhythmic drugs.

Action Potentials↗
PubMed1986

Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depressed canine Purkinje fibers. The characteristics of post-repolarization refractoriness.

Tissues from diseased hearts are known to exhibit post-repolarization refractoriness and rate-dependent changes of the refractory period that are often inconsistent with changes in action potential duration. To examine the electrophysiological mechanisms responsible for such rate-dependent changes of the refractory period, a narrow inexcitable zone was created by superfusing the central segments of Purkinje fibers with an "ion-free" isotonic sucrose solution. The degree of conduction impairment could be finely regulated by varying the resistance of the extracellular shunt pathway. At intermediate or low levels of block, the refractory period remained unchanged or decreased, respectively, as the rate was increased. At relatively high levels of block, however, we observed marked increases of the refractory period in response to increases in the stimulation rate. The disparity of refractoriness between normally conducting fibers and fibers exhibiting discontinuous conduction characteristics and post-repolarization refractoriness increased dramatically as a function of increasing stimulation rate. With the aid of current clamp techniques, we demonstrate that the differential behavior is due to the interplay between rate-dependent changes in the restitution of excitability at the site beyond the depressed zone secondary to changes in passive and active membrane properties and in the intensity of local circuit current provided to that site by activity generated in the segment proximal to the zone of block. Our data suggest that rate-dependent changes of refractoriness in Purkinje tissue are principally governed by attendant changes in membrane resistance.

Action Potentials↗
PubMed1985

Phase resetting and annihilation in a mathematical model of sinus node.

A mathematical model of primary sinoatrial pacemaker activity was developed using modifications of Hodgkin-Huxley type equations of voltage- and time-dependent membrane currents. The computer simulation of action potential activity incorporates the results of several existing cardiac models and recent biological data in an attempt to generate a model that more closely approximates the phase-resetting behavior of sinoatrial pacemakers observed biologically in response to subthreshold or electrotonic stimuli. The model was also used to study annihilation, i.e., the cessation of rhythmic activity induced by a critically timed subthreshold stimulus. Perturbation analysis performed by scanning the pacemaker cycle with 50-ms subthreshold current pulses yielded biphasic phase-response relationships that closely resembled the biological data. The pacemaker current, although relatively unimportant in determining the degree of phase 4 depolarization in the simulated sinus nodal pacemaker, was nevertheless prominent in determining phase-resetting behavior. The characteristics of annihilation were studied in normal, "depressed," and hyperpolarized states. In all cases, successful annihilation depended in large part on the dynamic interaction between the slow inward and delayed rectifier outward currents. The annihilation point was found to be an unstable singularity point in which a critical combination of stimulus intensity and timing could cause the pacemaker to approach but never achieve a state of complete quiescence. The model provides the basis for further investigation of complex arrhythmias that may arise as a consequence of multiple-pacemaker interaction within the heart.

Mathematics↗
PubMed1984

The effects of milrinone on conduction, reflection, and automaticity in canine Purkinje fibers.

Milrinone is a newly developed analogue of amrinone possessing potent positive inotropic action. Electrophysiologic actions of the drug have not been reported. In this study microelectrode techniques were used to assess the electrophysiologic effects of milrinone in canine false tendons homogeneously superfused with either normal or high-K Tyrode's solution and in Purkinje fibers mounted in a three-compartment chamber in which the central segment was depressed with an "ischemic" solution. Milrinone (0.2 to 20 micrograms/ml) caused no major changes in the action potential characteristics, refractoriness, or conduction velocity in fibers exposed to normal Tyrode's solution, but markedly improved conduction and abbreviated or eliminated postrepolarization refractoriness in the ischemic gap preparations. The drug also exerted important effects on reflected reentry generated in these preparations. Depending on the initial level of block, milrinone (1) suppressed the arrhythmia, (2) shifted its frequency dependence, or (3) created the conditions that allowed reflection to occur. Similar results were obtained in homogeneously depressed fibers. At similar concentrations, milrinone caused a relatively small enhancement of automaticity. Thus, in addition to its inotropic actions, milrinone produces important electrophysiologic effects. By restoring or improving conduction through areas of depressed conductivity, the drug may exert either antiarrhythmic or arrhythmogenic effects.

Action Potentials↗
PubMed1983

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↗
PubMed1983

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↗
PubMed1983

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1981

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↗
PubMed1980

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↗
PubMed1979

Phase resetting and annihilation of pacemaker activity in cardiac tissue.

Spontaneous rhythmic activity in isolated cardiac pacemaker cells can be terminated by a brief, subthreshold, depolarizing or hyperpolarizing perturbation of the proper magnitude applied at a specific point in the pacemaker cycle. Evidence is provided in support of a topological theory of the existence of a "singular" point in cardiac oscillators.

Action Potentials↗
PubMedDate not supplied

The effects of milrinone on action potential characteristics, conduction, automaticity, and reflected reentry in isolated myocardial fibers.

Milrinone, a newly developed analogue of amrinone, possesses potent positive inotropic effects. Electrophysiologic actions of the drug have thus far been reported in only one study conducted on canine Purkinje fibers. The present study used microelectrode techniques to evaluate the electrophysiologic effects of milrinone on normal and depressed isolated ventricular myocardial fibers. At apparent therapeutic concentrations (0.1-0.2 microgram/ml), milrinone abbreviated action potential duration and refractory period in normal myocardial fibers, but caused no significant changes in any other parameter. At similar concentrations, the drug markedly altered the electrical activity of K+-depolarized preparations, producing an increase in action potential amplitude, duration, and dV/dtmax. Milrinone also restored regenerative activity in K+-inactivated ventricular fibers. The drug exerted important effects on conduction velocity, refractoriness, and reflected reentry generated in fibers mounted in a three-compartment chamber in which the central segment was depressed with an "ischemic" solution. Depending on the initial level of block, the drug concentration, and the segments of the preparation exposed to the drug, milrinone (a) suppressed the arrhythmia, (b) shifted its frequency dependence, or (c) induced reentry. Similar results were obtained in homogeneously depressed fibers. The drug produced no major changes in depolarization-induced automaticity. Thus, in addition to its inotropic actions, milrinone produces important electrophysiologic effects. By restoring or improving conduction through areas of depressed conductivity, the drug may alter the manifestation of arrhythmias.

Action Potentials↗