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Biomedical subjects

A L Wit

Publications and source records attributed to A L Wit.

At least 37 records · Page 2Linked to original sources
PubMed1995

Electrophysiological effects of flecainide on anisotropic conduction and reentry in infarcted canine hearts.

BACKGROUND: The class IC antiarrhythmic drug flecainide has been shown to be ineffective for the treatment of ventricular arrhythmias in some patients who have had a prior myocardial infarction and sometimes even provoke arrhythmias (proarrhythmic effect). Since some ventricular tachycardias may be caused by anisotropic reentry, we determined the effects of flecainide on this mechanism for reentry in infarcted canine hearts in order to determine possible causes for its clinical effects. METHODS AND RESULTS: The effects of flecainide were determined on ventricular tachycardia induced by programmed electrical stimulation in dogs with healing myocardial infarction 4 days after coronary artery occlusion. Activation in the reentrant circuits causing tachycardia was mapped with a 196-channel computerized mapping system. We found that flecainide converted inducible unsustained ventricular tachycardia to inducible sustained ventricular tachycardia by modifying conduction in the reentrant circuit. In general, by slowing conduction, the reentrant wave front did not block after flecainide, leading to perpetuation of reentrant excitation. When sustained ventricular tachycardia could be induced before the drug, flecainide prolonged the coupling interval of premature impulses necessary to induce tachycardia by lengthening the line of block and slowing conduction around it. Flecainide also slowed the rate of the tachycardia but did not terminate it. The anisotropic reentrant circuits were modified so that the central common pathway of "figure-of-eight" circuits was narrowed and lengthened due to extension of the lines of block that bounded the pathways. Extension of the lines of block resulted from depression of conduction in the direction transverse to the long axis of the myocardial fiber bundles caused by flecainide. Flecainide also slowed conduction in the longitudinal direction in part of the circuits. The depressant effects of flecainide on both longitudinal and transverse anisotropic conduction were quantified by pacing from the center of the electrode array and it was found, contrary to predictions, that transverse conduction was depressed as much as longitudinal conduction. CONCLUSIONS: Flecainide slows conduction in both the longitudinal and transverse direction relative to the orientation of the myocardial fibers. This enables sustained reentry to occur more easily. Flecainide does not cause conduction block in crucial regions of reentrant circuits (central common pathway) and therefore does not prevent reentrant tachycardia in healing infarcts.

Animals↗
PubMed1995

Prediction of the location and time of spontaneous termination of reentrant ventricular tachycardia for radiofrequency catheter ablation therapy.

Ventricular tachycardia caused by reentrant excitation can lead to cardiac arrest and sudden death. Drug treatment and surgical procedures have been used with limited effectiveness. Catheter ablation methods are more promising because they are less invasive than surgery. Although ablation has come to be highly effective in the treatment of supraventricular tachycardias, the overall success rate remains low for ventricular tachycardias, which may be due in part to an inaccurate localization of the reentrant pathway. The authors hypothesize that a site in the myocardium exists that is critical for the maintenance or reentry and that when ablated, will result in permanent cessation of the tachycardia. The authors also hypothesize that this is the same site where the reentrant impulse blocks during spontaneous termination of tachycardia. A series of experiments has been designed to determine if there are specific properties of extracellular electrograms recorded from reentrant circuits that would enable the circuits to be identified without activation maps and, more specifically, allow the site of block causing spontaneous termination to be localized. For quantitative analysis of electrograms, a paradigm is developed to characterize electrogram morphology using a canine infarct model. Changes in morphology (shape, size, and location of signal deflections) can be considered (1) motions of a coordinate system and/or (2) conformational changes of shape. To a first approximation, stationarity over short time segments is assumed so that the motions and conformations can be parameterized. These parameters were extracted for 50 cardiac cycles during an episode of nonsustained ventricular tachycardia, in which 196-bipolar electrode pairs were positioned in an array format across the epicardial surface of the heart. The results of these studies of changes in electrogram morphology suggest that during cycles 5 to 49 of ventricular tachycardia, in many electrograms near the circuit, the cycle length increases linearly, the amplitude increases, and the duration of activation decreases. During cycles 50 to 54, the cycle length increases much more markedly, the amplitude decreases, and the duration of activation increases. These observations suggest that cycle lengthening may be an important property of some spontaneous terminations, and moreover that other morphologic characteristics are affected differently at different stages of cycle lengthening. Further, all motion parameters tended to oscillate from cycle to cycle in either an alternans pattern or longer oscillation. The variations in morphology were typically only a few percent from cycle to cycle. Such variability would not be evident using only ruler-and-caliper measurements made by hand because of the lack of precision and the sheer volume of data. It is expected that this approach for characterization of electrogram morphology will be extremely useful clinically to (1) increase speed and accuracy of ablation site selection and (2) reduce multichannel electrogram recording complexity during ablation site selection.

Algorithms↗
PubMed1993

Role of alterations in refractoriness and conduction in the genesis of reentrant arrhythmias. Implications for antiarrhythmic effects of class III drugs.

Despite the fact that a number of different electrophysiologic mechanisms are capable of causing cardiac arrhythmias, reentrant excitation has emerged as the most important mechanism causing life-threatening arrhythmias that arise in the ventricles. Pharmacologic therapy of arrhythmias caused by reentry is aimed at preventing the conditions that either facilitate the initiation of the circulating reentrant excitation wave or the conditions that permit its persistence. This involves alterations in either refractoriness or conduction by the drugs. Both atrial and ventricular tachyarrhythmias may follow premature depolarizations that occur at a critical coupling interval to a previous excitation. One desirable property of antiarrhythmic drugs might be to prevent the initiation of reentrant excitation by the triggering premature impulse. Mechanisms are described to show how drugs that prolong the action potential duration (class III antiarrhythmic drugs) might have this effect. It is, however, emphasized that drug effects that have been documented in electrophysiologic studies on normal myocardium might not occur in an arrhythmogenic region that has pathologic alterations, because of changes in the properties of ion channels of the diseased myocardial cells. Antiarrhythmic drugs might also terminate ongoing reentrant excitation by causing block of conduction in the reentrant pathway, at least for one beat. Class III drugs are expected to stop the perpetuation of reentry by prolonging the action potential duration and the refractory period of myocardial fibers in the reentrant circuit to such an extent that the propagating reentrant impulse no longer finds excitable myocardium but blocks in refractory tissue. Therefore, the effectiveness of this drug class to terminate reentry should depend on at least 2 factors: the size of the excitable gap as the reentrant impulse moves around the circuit, which may be related to the mechanism that causes reentry, and the degree to which the drugs can prolong the action potential duration and refractory period at the rapid rates of tachycardia. Each of these factors is discussed with relation to the proposed mechanism of action of drugs that prolong repolarization.

Animals↗
PubMed1993

Reentrant circuits and the effects of heptanol in a rabbit model of infarction with a uniform anisotropic epicardial border zone.

INTRODUCTION: The purpose was to study reentry in a rabbit model of infarction. METHODS AND RESULTS: A model of an infarct epicardial border zone was produced in Langendorff perfused rabbit hearts by freezing the inner two thirds of the left ventricular wall, allowing only a thin epicardial muscle layer to survive. Reentrant circuits causing stable ventricular tachycardia occurred in the surviving rim of epicardial muscle as shown by mapping impulse propagation with a 196-electrode array. The circuits were functional, and reentry did not occur around an anatomical obstacle. Slow conduction in the circuits was caused by the anisotropic properties of the epicardial muscle. Activation in the circuits was slow transverse to the long axis of the fiber bundles and rapid parallel to the long axis. Other features of the circuits, including orientation of the central functional line of block parallel to the fiber long axis, and an oval shape are also characteristic of anisotropic reentry. Since the slow conduction causing reentry is a result of poor transverse intercellular coupling, we determined whether the "uncoupler" heptanol would cause block in the circuits and terminate tachycardia. Heptanol in concentrations up to 1.2 mM slowed conduction in the transverse and longitudinal directions in the circuits and sometimes extended the central line of functional block. It did not, however, stop reentry because the reentrant impulse was still able to conduct around the ends of the block line. CONCLUSION: Drugs that decrease intercellular coupling may not be effective antiarrhythmic agents when uniform anisotropy causes functional reentry.

Alcohols↗
PubMed1993

Spontaneous activity in transgenic mouse heart: comparison of primary atrial tumor with cultured AT-1 atrial myocytes.

INTRODUCTION: We have generated transgenic animals that heritably develop atrial tumors composed of differentiated proliferating cardiomyocytes. Experiments were initiated to characterize the electrical properties of these cells. METHODS AND RESULTS: We show that the primary atrial tumors are composed of discrete foci that exhibit spontaneous automatic activity. A direct correlation was observed between tumor size and firing rate of these foci. In addition to the primary atrial tumors, we examined the properties of cultured cardiomyocytes isolated from a transplantable transgenic tumor lineage (designated AT-1 cells). Cultured AT-1 cells are also spontaneously automatic. The action potential configuration from these preparations is similar to that observed in nontransgenic atrial cardiomyocytes, albeit somewhat more depolarized and of longer duration. As would be expected for cardiomyocytes of atrial origin, the transgenic cardiomyocyte preparations hyperpolarize during muscarinic stimulation due to increased K+ conductance mediated by a pertussis toxin sensitive G-protein. Assessment of pharmacologic blockage of the "if" pacemaker current suggests that the automaticity of both transgenic cardiomyocyte preparations may be of novel origin. In this context, the cultured AT-1 cells showed spontaneous behavior that was clearly of cellular origin; this activity was manifest as transient bursts of electrical activity followed by periods of electrical quiescence. This bursting pattern is unusual for normal adult cardiomyocytes, but has been observed in several other cell types. In the primary tumors, automatic behavior may arise from a similar cellular origin or alternatively from a microreentrant phenomena. CONCLUSION: Primary tumors and AT-1 cells show essential atrial electrophysiology with important novel features.

Acetylcholine↗
PubMed1993

Effects of overdrive stimulation on functional reentrant circuits causing ventricular tachycardia in the canine heart: mechanisms for resumption or alteration of tachycardia.

INTRODUCTION: The purpose of the experiments described in this article was to investigate the effects of overdrive stimulation on functional anisotropic reentrant circuits causing ventricular tachycardia in infarcted canine ventricles. We determined how overdrive stimuli affect reentrant circuits to alter characteristics of the tachycardia. METHODS AND RESULTS: Activation patterns were determined by mapping excitation with a 192 bipolar electrode array. We found that overdrive stimuli could activate the circuits with the same pattern as the reentrant wavefront and that after overdrive stopped either the last or the next to last stimulated wavefront continued propagating through the circuit as a new reentrant impulse and tachycardia continued. When the circuit was not altered after overdrive, the exit route that the stimulated wavefront took from the circuit to activate the rest of the ventricles was also not altered and the tachycardia after overdrive had the same cycle length and QRS morphology as prior to overdrive. In some experiments, however, the overdrive stimuli did not follow the original reentrant pathway but led to the formation of a different circuit with a different exit route to the ventricles. As a result, after overdrive stimulation tachycardia had a different QRS morphology and cycle length than prior to stimulation. When the new circuit after overdrive was small and the revolution time of the reentrant impulse around the circuit was short, fibrillation occurred. CONCLUSION: Functional reentrant circuits can either be maintained or altered after a period of overdrive stimulation. The results explain many of the effects that have been seen during overdrive stimulation of clinical ventricular tachycardia.

Animals↗
PubMed1993

Overdrive stimulation of functional reentrant circuits causing ventricular tachycardia in the infarcted canine heart. Resetting and entrainment.

BACKGROUND: Clinical electrophysiology studies have used, for the most part, models of anatomic reentrant circuits to explain entrainment of ventricular tachycardia. Our studies use activation maps to directly determine mechanisms of entrainment of functional circuits that cause tachycardia. METHODS AND RESULTS: Electrograms were recorded from 192 sites on reentrant circuits in the epicardial border zone of canine myocardial infarcts during sustained ventricular tachycardia. Overdrive stimulation from different sites and at different cycle lengths was investigated. The reentrant circuits were shown to be functional, yet stimulated impulses could enter and repetitively reset the circuits (entrainment), demonstrating the presence of an excitable gap. Entrainment could occur from different stimulation sites with the stimulated impulses from each site activating the circuit with a different pattern. Entrainment, however, did not occur when the stimulated wave fronts obliterated the lines of functional block in the circuit. Fusion on the ECG occurred during entrainment when the stimulated impulses activated the ventricles concurrently with a previous stimulated impulse leaving the reentrant circuit at a different site. The first postpacing QRS was captured but not fused because it was caused by the last stimulated impulse emerging from the circuit. The first postpacing cycle length on the ECG was either equal to or longer than the overdrive cycle length depending on whether there was a fusion QRS during overdrive. The first postpacing cycle length at sites in the reentrant circuit equaled the pacing cycle length. At an appropriately short overdrive cycle length, stimulated impulses blocked in the circuit to terminate reentry. CONCLUSIONS: Functional reentrant circuits causing ventricular tachycardia can be reset and entrained. Activation maps directly show the mechanisms.

Animals↗
PubMed1992

Time course of changes in intracellular K+, Na+, and pH of subendocardial Purkinje cells during the first 24 hours after coronary occlusion.

We investigated the basis for the alterations in the intracellular potassium and sodium activity occurring in subendocardial Purkinje fibers surviving in 24-hour infarcts by examining ion activities in these Purkinje fibers removed from infarcting hearts at earlier times. Specifically, we examined intracellular potassium activity, sodium activity, and pH at 1 and 3 hours after ligation of the left anterior descending coronary artery, and we correlated the changes in ion activity with changes in maximum diastolic potential. We tested various mechanistic hypotheses relating to how the ion activity changes develop and how they affect membrane potential. We found that intracellular sodium activity in tissue removed 1 hour after ligation was on average already maximally elevated by a factor of 2 over control (19.2 +/- 2.0 mM [mean +/- SEM] versus 9.4 +/- 0.4 mM). Potassium activity diminished progressively over the first 24 hours (from normal of 112.0 +/- 2.7 to 61.6 +/- 2.8 mM), although half of the decrease occurred during the first hour (to 86.8 +/- 4.1 mM). Intracellular pH did not change at either 1 or 3 hours. Whereas maximum diastolic potential depolarization exceeded the calculated depolarization of the potassium equilibrium potential by a factor of 2 in 24-hour infarcts, the depolarization at 1 and 3 hours could be more nearly attributed to the loss of potassium. The change in the dependence of maximum diastolic potential on potassium equilibrium potential may be due to changes in membrane conductance caused by ionic or biochemical factors. The changes in ion activity continuously develop during the first day after ligation and may be due to multiple factors and mechanisms.

Animals↗
PubMed1992

Experimental models of ventricular tachycardia and fibrillation caused by ischemia and infarction.

Experimental animal models of ventricular arrhythmias have been developed to elucidate mechanisms of arrhythmogenesis in humans. Studies of animal models have enabled the vulnerable period of the ventricles to be discovered and characterized and should eventually lead to improved techniques of defibrillation. Animal models of ischemic heart disease and myocardial infarction have also helped investigators elucidate the mechanisms of arrhythmias occurring at each stage of infarct development and healing. Data obtained from the experimental studies have been shown to apply to the clinical situation.

Animals↗
PubMed1990

Proliferation in vivo and in culture of differentiated adult atrial cardiomyocytes from transgenic mice.

Transgenic mice expressing atrial natriuretic factor-SV40 T-antigen fusion genes (ANF-TAG) developed unilateral right atrial tumors composed of differentiated dividing cardiomyocytes. The atrial tumors could be propagated as transplantable tumor lineages in syngeneic animals. Cardiomyocytes derived from ANF-TAG atrial tumors did not proliferate in tissue culture. However, cardiomyocytes derived from the transplantable tumor lines proliferated in culture, and these proliferating cardiomyocytes could be passaged in culture and recovered from frozen stocks. Cardiomyocytes from either tumor source were highly differentiated as determined by diverse functional and structural criteria. The cells continued to express numerous cardiac-specific proteins and retained ultrastructural features characteristic of cardiomyocytes including well-formed myofibrils, transverse tubules, and intercalated disks. In addition, the cultured cells displayed spontaneous electrical and contractile activities. These atrial tumor cardiomyocytes are a novel experimental resource for the identification of genes regulating the cardiomyocyte cell cycle.

Animals↗
PubMed1990

Cellular electrophysiologic mechanisms of cardiac arrhythmias.

Cardiac arrhythmias result from abnormalities in the initiation of impulses or in the conduction of these impulses through the heart. Arrhythmias caused by impulse initiation may be caused by either automaticity or triggered activity. Arrhythmias caused by abnormalities in conduction are often the result of reentrant excitation. These arrhythmogenic mechanism arise because of alterations in the transmembrane potentials of cardiac cells that are often caused by disease. These cellular mechanisms causing arrhythmias are the subject of this article.

Animals↗
PubMed1989

Intracellular pH of canine subendocardial Purkinje cells surviving in 1-day-old myocardial infarcts.

A large reduction of intracellular potassium activity in depolarized subendocardial Purkinje fibers 24 hours after coronary artery ligation is accompanied by a much smaller increase in intracellular sodium activity. Similar intracellular ionic changes also occur during acute ischemia in ventricular muscle and are consistent with mechanisms based on intracellular acidification, which is known to occur in acutely ischemic muscle. To determine if canine subendocardial Purkinje cells 24 hours after myocardial infarction are also acidic, their intracellular pH, surface pH, and maximum diastolic potential (MDP) were measured with double-barrel pH-sensitive microelectrodes and compared with control fibers in noninfarcted hearts. In 12 mM bicarbonate Tyrode's solution (5% CO2-95% O2), the average intracellular pH was not significantly different (p greater than 0.25) for normal tissue (6.83 +/- 0.08, SD, MDP = -83.5 +/- 3.2 mV), for depolarized Purkinje fibers in infarct preparations during the first hour of superfusion (6.88 +/- 0.11, MDP = -47.8 +/- 11.8 mV), and for partially recovered Purkinje fibers in infarcts averaged over the third to sixth hours of superfusion (6.85 +/- 0.12, MDP = -74.5 +/- 9.6 mV). In 24 mM bicarbonate Tyrode's solution, infarct intracellular pH during both the first hour of superfusion (7.08 +/- 0.13, MDP = -57.6 +/- 15.7 mV) and during the third to sixth hours of superfusion (7.06 +/- 0.15, MDP = -76.5 +/- 9.6 mV) was significantly alkaline (p less than 0.0005) compared with average control pH (6.92 +/- 0.12, MDP = 82.1 +/- 3.7 mV). In 24 mM bicarbonate Tyrode's solution, the intracellular pH did vary with MDP (0.0032 pH units/mV). During superfusion of normal Purkinje fibers with hypoxic Tyrode's solution, intracellular pH acidified by 0.22 pH units as they depolarized. Therefore, intracellular acidification does not seem to be a cause of the depolarization of subendocardial Purkinje cells 24 hours after myocardial infarction.

Action Potentials↗
PubMed1988

Action potentials of cardiac muscle in healing infarcts: response to norepinephrine and caffeine.

Previous studies have shown that the muscle fibers that survive on the epicardial surface of a 5- or 14-day-old infarct in canine hearts have reduced or absent plateau phase during repolarization. Since the absence of a plateau phase could be related to a decrease in the slow inward current, we determined whether norepinephrine (NE) (3.13 x 10(-5) M) or caffeine (2.5 to 5.0 mM) restored the reduced plateau phase of action potentials of fibers from the 5- to 14-day infarct (4 mM K+). In addition, we compared the slow inward current-mediated slow response action potentials induced by NE or caffeine in K+ depolarized fibers from the 5- and 14-day infarcts to those induced in control fibers. Our results show that NE and caffeine had little or no significant effects on repolarization or the plateau area of action potentials of fibers from infarcted preparations. In addition, NE and caffeine both induced slow response action potentials in normal fibers, but in some fibers from infarcts, these agents failed to elicit slow responses. In other fibers from infarcts, NE and caffeine induced slow response action potentials but they had reduced mean areas when compared to the control potentials. In conclusion, the alteration and absence of slow responses in fibers from infarcted preparations suggest that there may be a chronic abnormality in the slow Ca current channel in fibers from the 5- and 14-day infarct.

Action Potentials↗
PubMed1988

Influences of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts.

Excitation in the epicardial border zone of 3-5-day-old canine infarcts was mapped with an array of 192 bipolar electrodes during sustained ventricular tachycardia. Reentrant circuits were found in which activation occurred around long lines of apparent conduction block based on the criterion that excitation on opposite sides of the lines occurred with marked disparity in time. When the lines of apparent block were functional (i.e., occurred only during tachycardia and not during sinus rhythm or ventricular pacing) they were oriented parallel to the long axis of epicardial muscle fiber bundles. Isochrones distal to the lines were oriented parallel to them because widely separate sites within these isochrones were activated nearly simultaneously. This suggested that excitation not only occurred around the lines of block but also slowly across them. This slow activation occurred transverse to the long axis of the myocardial fibers and therefore might result because of the anisotropic tissue properties. To test this hypothesis, the epicardial border zone was stimulated during sinus rhythm through electrodes around its margin and at the center of the recording array. Activation transverse to the myocardial fibers in regions where lines of block occurred during tachycardia was slow, whereas it was rapid parallel to fibers' orientation. During tachycardia electrograms along the lines of apparent block had long durations and were fractionated, a characteristic that can also result from activation transverse to the myocardial fiber long axis. Therefore, we propose that the parallel orientation of the muscle bundles in the epicardial border zone is an important cause of ventricular tachycardia because activation transverse to myocardial fibers is sufficiently slow to permit the occurrence of reentry.

Animals↗
PubMed1987

Impulse propagation from the SA-node to the ventricles.

Normally the pacemaker of the mammalian heart is located in the sinus node. In the rabbit the sinus node can be subdivided into two regions, the center of the node where the impulse originates and the border zone through which the impulse is conducted towards the atrium. Conduction properties of both regions were investigated. It appeared that conduction velocity increases and refractoriness decreases when one goes from the nodal center towards the atrium. The tissue mass of the atrium is large in comparison to the sinus node and normally the resting membrane potential of atrial fibers is more negative than that of nodal fibers; consequently, a potential difference exists causing a current flow between both areas. Evidently this hyperpolarizing current flow depresses impulse formation in the border zone fibers which have better intrinsic pacemaker properties than fibers in the nodal center. If the impulse has reached the atrium it is conducted with a relatively high safety factor and will reach the AV node in principle without difficulty. The AV node, if deprived of sinus nodal dominance, develops spontaneous activity originating from the lower nodal fibers. Also in this structure, electrotonic depression by surrounding tissue causes deceleration of the pacemaker.

Action Potentials↗