Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures.

BACKGROUND: Currently, there are no published randomized controlled trials evaluating the efficacy and safety of adjunctive antiepileptic therapy in idiopathic generalized epilepsy with myoclonic seizures. METHODS: This randomized, double-blind, placebo-controlled multicenter trial assessed the efficacy and tolerability of adjunctive treatment with levetiracetam 3,000 mg/day in adolescents (>or=12 years) and adults (or=8 days during a prospective 8-week baseline period, despite antiepileptic monotherapy. The 8-week baseline period was followed by 4-week up-titration, 12-week evaluation, and 6-week down-titration/conversion periods. RESULTS: Of 122 patients randomized, 120 (levetiracetam, n = 60; placebo, n = 60) were evaluable. Diagnoses were either juvenile myoclonic epilepsy (93.4%) or juvenile absence epilepsy (6.6%). A reduction of >or=50% in the number of days/week with myoclonic seizures was seen in 58.3% of patients in the levetiracetam group and in 23.3% of patients in the placebo group (p < 0.001) during the treatment period. Levetiracetam-treated patients were more likely to respond to treatment than patients receiving placebo (OR = 4.77; 95% CI, 2.12 to 10.77; p < 0.001). Levetiracetam-treated patients had higher freedom from myoclonic seizures (25.0% vs 5.0%; p = 0.004) and all seizure types (21.7% vs 1.7%; p < 0.001) during the evaluation period. The only adverse events more frequent with levetiracetam were somnolence and neck pain. CONCLUSION: These results suggest that levetiracetam is an effective and well-tolerated adjunctive treatment for patients with previously uncontrolled idiopathic generalized epilepsy with myoclonic seizures.

Actions of lidocaine on reentrant ventricular rhythms in the subacute myocardial infarction period in dogs.

The actions of lidocaine were studied in 18 dogs, 4 days after ligation of the left anterior descending artery, by computerized mapping. Lidocaine only occasionally suppressed the induction of reentry. At fast heart rates, lidocaine actually facilitated the induction of reentry. The effects on conduction and refractoriness of normal and ischemic myocardium were measured using high-resolution techniques. Lidocaine promoted reentry by a rate-dependent increase in refractory gradient, resulting in additional block, and a selective decrease in conduction velocity in ischemic tissue, resulting in additional conduction delay. Lidocaine could prevent reentry through a rate-independent differential increase in refractory period gradient at the entrance to the common pathway of the circuit, causing block of the reentrant impulse. We conclude that the proarrhythmic effect of lidocaine is due to increased conduction delay and block while the antiarrhythmic effect is due to block of the reentrant impulse by prolonged refractoriness in the common pathway.

The effect of a cyclodextrin vehicle on the cardiovascular profile of propofol in rats.

We studied the aqueous solution of propofol dissolved in hydroxypropyl-beta-cyclodextrin (HP beta CD) 20% to determine whether the cardiovascular profile differed from that measured for propofol prepared in Intralipid 10% (Diprivan). Conscious male rats were given an intravenous bolus of propofol, 5.0 mg/kg, the minimum dose that induces a loss of righting. Immediately severe bradycardia occurred which was the result of a combination of sinus arrest and atrioventricular block; a significant decrease of blood pressure resulted. A bolus of HP beta CD produced no significant changes in heart rate rhythm. The severe bradycardia produced by propofol in HP beta CD was blocked by both atropine and bilateral cervical vagotomy. Therefore, the effects of propofol in HP beta CD are cholinergic and neurally mediated. These results are consistent with the hypothesis that propofol reduces sympathetic tone prior to reduction in vagal tone, and thereby produces a period of time during which vagal tone is dominant.

Circus movement atrial flutter in the canine sterile pericarditis model. Cryothermal termination from the epicardial site of the slow zone of the reentrant circuit.

BACKGROUND: We have shown that atrial flutter (AF) in dogs with sterile pericarditis is commonly due to a single-loop reentrant circuit in the lower right atrium comprised of a functional or functional/anatomic obstacle and a slow zone of conduction (SZ) between the central obstacle and the atrioventricular (AV) ring. The goals of the present study were 1) to establish that the epicardial SZ is the critical component of circus movement AF and 2) to identify the optimal site within the epicardial SZ at which interruption of circus movement can be accomplished by ablative techniques. METHODS AND RESULTS: We analyzed the atrial activation patterns during epicardial cooling of the SZ with as N2O-cooled probe in eight dogs (five with clockwise [CW] reentrant circuit, one with counterclockwise [CCW] reentrant circuit, and two with both CW and CCW reentrant circuits around the same pathway). In all eight dogs, cooling (-5 to +5 degrees C for 5-20 seconds) the narrow isthmus at the inferoposterior part of the SZ between the central obstacle and the AV ring reversibly terminated the reentrant circuit, whereas cooling outside this area failed to terminate the reentrant circuit. The circus movement was not observed to continue along alternate pathways when conduction in this critical zone was interrupted. Both CW and CCW reentrant circuits could be terminated from the same site within the SZ. Cooling resulted in slowing of conduction in the SZ (55 +/- 15 msec) in both CW and CCW reentrant circuits. Cooling-induced termination of CW reentrant circuits was characteristically associated with oscillations of conduction in the cooled zone of the last three cycles before termination and conduction block occurred within the cooled zone. The last "manifest" reentrant cycle was associated with the longest conduction delay in the cooled zone. However, this delay was not necessarily reflected in the length of the last reentrant cycle because of compensatory acceleration of conduction in the rest of the pathway. On the other hand, in CCW reentrant circuits, conduction block occurred abruptly at the distal border of the SZ and without significant oscillations of conduction. CONCLUSIONS: The present study provides convincing evidence that single-loop circus movement in this model is critically dependent on an obligatory conduction in a SZ in the inferoposterior portion of the free right atrial wall between a functional obstacle and the AV ring. Because the atrial myocardium behaves electrophysiologically as a two-dimensional surface, the results of this study may help to guide the endocardial electrode catheter ablative technique for treatment of clinical AF.

A unified functional/anatomic substrate for circus movement atrial flutter: activation and refractory patterns in the canine right atrial enlargement model.

OBJECTIVES: This study was designed to test the concept of a functional/anatomic interaction in a canine model of reentry based on right atrial enlargement and to elucidate the electrophysiologic basis for functional conduction block. BACKGROUND: The monotonic feature of atrial flutter suggests a uniform substrate for the arrhythmia. Atrial flutter in the sterile pericarditis model is due to single-loop circus movement around a functional or a functional/anatomic obstacle near the atrioventricular (AV) ring. Sustained circus movement requires a critical interaction of a functional arc of block, a natural obstacle, the AV ring and a zone of slow conduction. The location of the inferior vena cava predisposes the lower right atrium to single-loop reentry. METHODS: In 11 dogs with right atrial enlargement, 127 bipolar epicardial electrograms were obtained during atrial flutter. For correlation of activation and refractory maps, the effective refractory period under each electrode was determined using the extrastimulus technique. RESULTS: Atrial flutter was due to single-loop reentry around functional arcs of block near the AV ring (n = 2) or around functional/anatomic obstacles (n = 8) involving the inferior vena cava. A slow zone was located between the arc and the AV ring and between the inferior vena cava and AV ring, respectively. During initiation, the arc joined the AV ring, forcing activation to proceed around the free end of the arc before breaking through the arc near the AV ring. Arrhythmia termination required the arc of block to rejoin the AV ring. Inducibility of sustained atrial flutter was associated with a marked spatial dispersion of refractoriness. The configuration of the functional arc of block was critically dependent on the spatial pattern of refractoriness. CONCLUSIONS: Atrial flutter requires a similar functional or functional/anatomic substrate independent of the underlying etiology. The spatial distribution of refractoriness in enlarged canine atria provides an adequate substrate for the development of functional conduction block.

Adrenergic effects on reentrant ventricular rhythms in subacute myocardial infarction.

BACKGROUND: Reentry has been shown to be a mechanism of ventricular arrhythmias elicited by programmed premature stimulation in the subacute ischemic period of dogs subjected to myocardial infarction. The spatial distribution of refractoriness in these hearts has been shown to play an important part in the formation of functional arcs of conduction block during programmed ventricular stimulation. Because the adrenergic nervous system influences cardiac arrhythmias and myocardial infarction can directly affect sympathetic innervation in the heart, we investigated the role of the sympathetic nervous system on reentry in the canine heart 4 days after infarction. METHODS AND RESULTS: The influences of adrenergic stimuli on the initiation of reentrant ventricular excitation were studied using a 128-channel computerized recording system in the canine heart 4 days after ligation of the left anterior descending coronary artery. Bilateral stimulation of the ansae subclavia preferentially improved conduction of premature beats in the normal zones. This corresponded to an improvement in excitability, as measured by a decrease in stimulus strength at the same premature coupling interval as control. Consequently, the effective refractory period was preferentially shortened at normal sites but not at ischemic sites. Both of these changes contributed to a shift of the arc of functional conduction block toward more normal tissue. As a result, sites proximal to the arc of functional conduction block had more time to recover excitability and thereby were available to be reexcited by the distal activation wave front. Conversely, intravenous infusion of norepinephrine preferentially shortened the effective refractory period of sites in the ischemic zone, thereby indicating that denervation hypersensitivity had occurred at these sites. The spatial dispersion of refractoriness and the arc of functional conduction block were significantly reduced in size. As a consequence, previously inducible reentrant rhythms were no longer inducible. CONCLUSIONS: Sympathetic stimulation can be considered an arrhythmogenic intervention, whereas norepinephrine infusion may be considered antiarrhythmic in this experimental model.

Circus movement atrial flutter in canine sterile pericarditis model. Activation patterns during entrainment and termination of single-loop reentry in vivo.

BACKGROUND: Recently, we used a custom designed "jacket" electrode with 127 bipolar electrodes in a flexible nylon matrix to map the total atrial epicardial surface in the in situ canine heart. Atrial flutter in dogs with sterile pericarditis was shown to be due to a single wave front circulating around a combined functional/anatomic obstacle, with the arc of functional conduction block contiguous with one or more of the atrial vessels. METHODS AND RESULTS: In the present study, this model was used to analyze the activation pattern during pacing-induced entrainment and termination of single reentrant loops in a syncytium without anatomically predetermined pathways. Sustained atrial flutter was induced in five dogs with 3-5-day-old sterile pericarditis. Atrial pacing at a cycle length 5-30 msec shorter than the spontaneous cycle length entrained the arrhythmia and could result in a "classical" activation pattern, characterized by an antidromic stimulated wave that collided with the reentrant orthodromic wave front of the previous beat at a constant site. However, two variations of this classical activation pattern were also observed: 1) Pacing at short cycle lengths could lead to localized conduction block in antidromic direction, forcing a change in the pathway of the antidromic wave front. This could prevent the expected shift of the site of collision in antidromic direction. 2) The stimulated orthodromic wave front could also use a pathway different from that of the original reentrant impulse, so that a different circuit was active during the pacing period. Termination of atrial flutter by rapid atrial stimulation was associated with progressive slowing and finally blocking of the paced orthodromic wave front and a progressive shift of the site of collision in antidromic direction. The occurrence of conduction block was determined by the cycle length of stimulation and the number of stimulated beats. A longer train at the critical cycle length or the critical number of beats at a shorter cycle length could reinduce the same reentrant circuit or a different reentrant circuit, respectively, during stimulated cycles following the beat that terminated reentry. CONCLUSIONS: The epicardial activation sequence during entrainment of reentrant arrhythmias does not necessarily follow a standard activation pattern. Instead, the stimulated orthodromic as well as the antidromic wave front might use a pathway different from that of the original reentrant wave front. The mechanisms of termination, failure of termination, and reinitiation of single-loop reentry are similar to those in the "figure-eight" reentrant circuit.

Circus movement atrial flutter in the canine sterile pericarditis model. Differential effects of procainamide on the components of the reentrant pathway.

To evaluate the mechanisms of action of procainamide on the components of the reentrant pathway, drug-induced changes in activation patterns, effective refractory periods (ERPs), and stimulation thresholds were analyzed in nine dogs with sterile pericarditis and sustained atrial flutter. Activation maps were based on 127 close bipolar recordings from a special "jacket" electrode. From the control map, 22 +/- 2 sites covering the slow zone and the normal zone of the reentrant circuit were selected to measure ERPs and thresholds. The excitable gap was estimated from the longest ERP during pacing at the tachycardia cycle length. During atrial flutter, epicardial activation proceeded as a single wave around an arc of functional conduction block in the proximity of the atrioventricular (AV) ring or around a combined functional/anatomic obstacle, with the arc being contiguous with one of the venae cavae. An area of slow conduction, which accounted for 53 +/- 15% of the revolution time within 35 +/- 15% of the total length of the reentrant pathway, was bordered by the arc of block and the AV ring or a caval vein and the AV ring, respectively. Procainamide (5-10 mg/kg i.v.) prolonged the cycle length of atrial flutter from 144 +/- 17 to 190 +/- 24 msec (p less than 0.05) and then terminated the arrhythmia in all studies. The increase in cycle length was due to an increase in conduction time in the slow zone by 37 +/- 11 msec (86 +/- 17% of the total cycle length increase). During the last reentrant beat, conduction failed in the slow zone, with the arc of block joining the AV ring. At termination, procainamide had prolonged conduction time, stimulation threshold, and ERP in the normal zone by 11 +/- 18%, 40 +/- 80%, and 5 +/- 15%, respectively, compared with 51 +/- 16%, 86 +/- 93%, and 14 +/- 21%, respectively, in the slow zone (p less than 0.05 for all three parameters). The duration of the excitable gap did not change significantly. We conclude that procainamide preferentially affected the slow zone of single loop reentrant circuits. The drug terminated circus movement atrial flutter without abolishing the excitable gap, and its effect on conduction seemed the major determinant of the antiarrhythmic action.

Reentrant ventricular arrhythmias in the late myocardial infarction period: mechanism by which a short-long-short cardiac sequence facilitates the induction of reentry.

The electrophysiological mechanism by which a short-long-short stimulated cardiac sequence facilitates the induction of ventricular tachyarrhythmia was investigated in dogs 4 days after ligation of the left anterior descending coronary artery. In these dogs, reentry develops in the surviving electrophysiologically abnormal epicardial layer that overlies the infarct zone when premature stimulation results in a critically long arc of functional conduction block. The activation wavefront circulates around both ends of the arc, coalesces, and conducts slowly distal to the arc before reactivating sites proximal to the arc to initiate a figure-eight reentrant circuit. Epicardial isochronal activation maps and effective refractory periods (ERPs) were determined during three different stimulation protocols: A, a basic train of eight beats at a cycle length of 300 msec followed by a single premature stimulus (S2); B, a basic train of eight beats at a cycle length of 300 msec with abrupt lengthening of the last cycle of the train before S2 to 600 msec; C, a basic train of eight beats at a cycle length of 600 msec followed by S2. Protocol B was found to result in a differential lengthening of ERP at adjacent sites within the border of the epicardial ischemic zone, whereas protocols A and C induced, respectively, comparable shortening and lengthening of ERPs at the same sites. The differential lengthening of ERPs at adjacent sites resulted in an increased dispersion of refractoriness so that a premature stimulus induced functional conduction block between those sites. The development of a longer arc of conduction block and, hence, a longer reentrant pathway as well as slower conduction of the circulating wavefront during protocol B allowed more time for refractoriness to expire proximal to the arc and for the circulating wavefront to reexcite those sites to initiate reentry. The lengthening of ERP, associated with a single long cycle (protocol B), ranged from 44% to 79% of the total increase in ERP after a series of eight long cycles (protocol C). Epicardial sites with longer ERPs located close to the center of the ischemic zone showed more lengthening of refractoriness during protocol B compared with more normal sites near the border of the ischemic zone. This strongly suggests that the increased dispersion of refractoriness during protocol B is caused by the shorter memory of ischemic myocardium to the cumulative effects of preceding cycle lengths.

Electrophysiological basis of ventricular late potentials.

The presence of late potentials on the body surface recording was correlated with ventricular activation maps of reentrant circuits in the postinfarction canine model of reentrant excitation. Late potentials were found to correlate with delayed myocardial activation. However, during a reentrant rhythm complete diastolic activity on the body surface could not be detected if the mass of electrically active cells was too small and/or if very slow conduction in part of the reentrant circuit generated low amplitude extracellular potentials. Myocardial zones responsible for late potentials during a basic rhythm (e.g., sinus rhythm) may not necessarily be part of the critical zone of slow conduction during reentrant activation. Dynamic changes in late potentials are not amenable to temporal signal averaging techniques but could be detected by a high resolution beat-to-beat recording. A thorough understanding of the electrophysiological limitations of late potentials in the signal-averaged ECG could result in better utilization of the technique in clinical practice as well as in the development of new approaches for the detection of the arrhythmogenic substrate.

Electrophysiological effects of a chemical defibrillatory agent, dibenzepin.

STUDY OBJECTIVE: The aim was to study the cellular cardiac electrophysiological effects of the antifibrillatory drug, dibenzepin. DESIGN: Standard microelectrode techniques were used to measure the effects of dibenzepin (3 microM, 9 microM) on conduction time, Vmax and input resistance in canine papillary muscles, in vitro, at three paced cycle lengths (1000, 400, 200 ms). Results were compared when adrenaline (0.5-5 microM) or propranolol (0.2 microM) were present. EXPERIMENTAL MATERIAL: Papillary muscles (n = 25) from hearts of adult mongrel dogs, weight 13-18 kg, were used. MEASUREMENTS AND MAIN RESULTS: Dibenzepin, at 3 microM, caused significant reduction of Vmax at cycle lengths less than or equal to 400 ms. Paradoxically, the conduction time decreased at all three cycle lengths when measured along the longitudinal axis of the fibre between two microelectrodes spaced 2 mm apart. Superfusion of dibenzepin (3 microM) and propranolol (0.2 microM) significantly reduced Vmax and lengthened conduction time at all cycle lengths. Dibenzepin reduced input resistance from 1.45 to 0.76 M omega, thereby suggesting that improved coupling may occur between cells to account for the shortening of conduction time. Propranolol blocked these results. CONCLUSION: The defibrillatory action of dibenzepin may be related to a decreased intercellular resistance caused by increased catecholamine availability during fibrillation. This would result in improved conduction and, thereby, a decrease of the critical number of asynchronous re-entrant circuits necessary to maintain fibrillation.

Circus movement atrial flutter in the canine sterile pericarditis model. Activation patterns during initiation, termination, and sustained reentry in vivo.

The mechanisms of single-loop reentry in a syncytium without anatomically predetermined pathways have not been shown. Using a "jacket electrode" with 111 bipolar electrodes in a nylon matrix, we mapped in situ the atrial epicardial surface during atrial flutter in dogs with sterile pericarditis. Of 21 episodes of reentrant atrial flutter, only four showed double-loop ("figure-eight") reentry, whereas in 17 episodes a single loop was present. During initiation of single-loop reentry, an arc of functional block extended to the atrioventricular (AV) ring. This forced activation to proceed as a single wave around the free end of the arc, before breaking through the arc close to the AV ring. Activation continued as one loop around an arc close to the AV ring (in eight episodes) or around a combined functional and anatomic obstacle (in nine episodes) when the arc joined an atrial vessel. A zone of slow conduction was consistently bordered by the arc of block and the AV ring or by the anatomic obstacle and the AV ring. Spontaneous termination occurred when conduction failed in this area and the arc rejoined the AV ring. High-density recordings (2 mm) along the arc of block showed double potentials separated by an isoelectric interval, interpreted as local activation and electrotonus due to activation on the opposite side of the arc. Histologically, a diffuse inflammatory reaction involved 50-80% of the atrial wall. A transitional layer of myocardial bundles with preserved cross striation, but separated by edema and inflammatory cells, was enclosed between an epicardial layer of fragmented myocytes and an endocardial layer of grossly intact myocardium. There were no distinctive features at sites of functional conduction block or slowed conduction. In conclusion, single-loop reentry is the common pattern during atrial flutter in this model. Its induction depends on an interaction of the AV ring, a functional arc of block, and a zone of slow conduction. The location of the inferior vena cava predisposes the lower right atrium to this type of reentry.

Ventricular arrhythmias in the subacute myocardial infarction period. High-resolution activation and refractory patterns of reentrant rhythms.

Patterns of activation, functional conduction block, and effective refractory periods during reentrant activation were investigated in a 4-day postinfarction canine model using a 64-channel high-resolution (1 mm) bipolar electrode array. Lower resolution (3-10 mm) isochronal activation maps of the entire epicardial surface were constructed from 126 sites during the initiation and sustenance of reentry and showed reentrant wave fronts that circulated around arcs of functional conduction block. During initiation of reentry by premature stimulation, high-density recordings from these same regions showed that conduction block occurred abruptly, within 1 mm, and without prior decrement of the impulse. Electrograms recorded in proximity to the arc of block were comprised of two deflections: a local activation potential and an electrotonic potential reflecting activation 1 mm away; the reverse order of activation and electrotonus was observed on the opposite side of the arc of block. The occurrence of functional conduction block during premature stimulation in this model was correlated with abrupt increases in effective refractory periods of 10-120 msec (27 +/- 24 msec; mean +/- SD) within 1 mm or less. Neither the abrupt change of refractoriness nor functional conduction block appeared to depend on differences in excitability, the geometrical characteristics of the surviving epicardial layer, or the orientation of the myocardial fibers. During sustained reentrant activation, high-density recordings along the arcs of block showed split electrograms comprised of local activation and electrotonus, which were identical in morphology to those recorded during the initiation of reentry. The interval between the deflections was shorter at the ends of the arc and increased to a maximum value at the center of the arc. The activation potentials corresponded in time with activation of large isochronal regions on either side of the arc of block. There was evidence that at least part of the arc of block during sustained reentry represented thin discrete zones of constant block due to electrotonic influences of impulse penetration from both sides of the arc. Our results strongly suggest that continuous arcs of functional conduction block are a necessary prerequisite for both the initiation and the sustenance of reentrant activation in subacute canine myocardial infarction. Functional conduction block during the initiation of reentry was due to abrupt changes in refractoriness, within a distance of 1 mm or less.

Reentrant ventricular arrhythmias in the late myocardial infarction period: 17. Correlation of activation patterns of sinus and reentrant ventricular tachycardia.

The relationship between myocardial sites with late activation during sinus rhythm and sites critical for the initiation and sustentation of reentrant ventricular tachycardia was systematically examined in the 4-day-old postinfarction canine heart. The critical sites for prevention of the initiation of reentry and for termination of sustained figure-of-8 reentrant tachycardia by cryothermal techniques were correlated with the last 20 msec isochrone during sinus rhythm. In 12 experiments, 20 critical sites were examined. The mean distance between sites critical for reentry and the latest isochrone during sinus rhythm was 26.7 +/- 13.3 mm. Only five sites (25%) were within a 12 mm distance, which corresponded to the diameter of the cryoprobe. Nine sites (45%) were within a 24 mm distance (twice the diameter of the cryoprobe), while 11 sites (55%) were separated by more than 24 mm. In three experiments the sites of latest activation during sinus rhythm represented areas showing Wenckebach period or 2:1 conduction block. These sites became dissociated and did not participate in the reentrant excitation induced by premature stimulation. Poor correlation was explained by the fact that sites critical for reentry were intimately related to the location and extent of the arcs of functional conduction block while sites of delayed activation during sinus rhythm were not.

Effects of glyburide on ischemia-induced changes in extracellular potassium and local myocardial activation: a potential new approach to the management of ischemia-induced malignant ventricular arrhythmias.

The increase in extracellular potassium [K+]o levels during the early phase of myocardial ischemia may result in part from activation of adenosine triphosphate-sensitive K+ channels. Glyburide, a second-generation hypoglycemic sulfonylurea, is a potent blocker of these channels. We studied the effects of glyburide on [K+]o and on intramyocardial conduction delay during a 10-minute occlusion of the left anterior descending artery in the dog. K(+)-sensitive electrodes and bipolar plunge electrodes were introduced to record, respectively, [K+]o and local electrograms from close sites in midmyocardial regions in normal, border, and ischemic zones. Recordings were obtained before (control ischemia [CI]) and 20 minutes after intravenous administration of 0.15 mg/kg of glyburide (glyburide plus ischemia [G + I]). During G + I the extent of the increase in [K+]o was less compared to that during CI, and the difference was statistically significant during the first 7 minutes of ischemia in the ischemic zone and during the first 4 minutes of ischemia in the border zone. On the other hand, the degree of local intramyocardial conduction delay was significantly reduced during G + I compared to CI during the entire 10 minutes of ischemia in both the ischemic and border zones. In summary, our results have shown that glyburide significantly reduced the rise of [K+]o and intramyocardial delay during the early phase of acute ischemia and could thus attenuate the electrophysiologic consequences of ischemia that underlie the initial phase of malignant tachyarrhythmias. Although the effects of glyburide may result in part from a direct action of the drug on cardiac adenosine triphosphate-sensitive K+ channels, other metabolic antiischemic effects cannot be ruled out.

A logical state model of reentrant ventricular activation.

The ventricular surface of the heart was modeled as two-dimensional, 4096 element, network of cells connected logically to each other. An ischemic area was represented by a central core of prolonged refractoriness, distributed into eccentrically-layered elliptical contours such that refractoriness declined along varying gradients to the surrounding normal area. Propagation of cardiac action potentials was stimulated by five sequential states ranging from activation to inactivation. Reentrant activation was induced by premature stimulation of the network and resembled a "figure 8" type reentry seen experimentally. Activation patterns of reentry appeared as two propagation wavefronts which traveled around the ends of a continuous line of functional conduction block, merged into a single wavefront, then conducted slowly along a retrograde path to reactivate a region proximal to the block. Reentry could be prevented by modifying the distribution of recovery of excitability through stimulation at two strategically located sites during basic rhythm. Prevention occurred when the second site was situated in an area of prolonged refractoriness, just distal to the line of block. These simulations indicate that reentrant activation is characterized by the formation of long lines of conduction block which occur along a border of steeply graded refractoriness, and retrograde slow conduction which occurs along a more shallow refractory gradient. The occurrence of reentry is dependent on: 1) the coupling interval of the premature stimulus, 2) the location of the stimulus relative to the maximum refractory gradient, and 3) the activation sequence of the basic paced beats. Thus, this paper presents an efficient logical state model of cardiac activation which simulates experimentally observed activation patterns of reentry and its prevention.

Effects of caffeine and ryanodine on delayed afterdepolarizations and sustained rhythmic activity in 1-day-old myocardial infarction in the dog.

Caffeine and ryanodine are known to modulate oscillatory release of Ca2+ from the sarcoplasmic reticulum. The effects of caffeine and ryanodine on delayed afterdepolarizations (DADs) and sustained rhythmic activity in subendocardial Purkinje fibers surviving 1-day-old myocardial infarction in the dog were studied with standard microelectrode techniques. In preparations that showed sustained rhythmic activity, a high concentration of caffeine (10 mM) and ryanodine (10(-7) and 10(-6) M) slowed and terminated the sustained rhythmic activity and markedly suppressed DADs. An increase in the temperature of the tissue bath from 37 degrees to 39 degrees C did not change these results. In quiescent normal and infarcted preparations, a low concentration of caffeine (0.5 mM) differentially induced DADs in ischemic but not in normal Purkinje fibers, increased the amplitude of existing DADs, and brought subthreshold DADs to threshold potential that caused triggered activity. Our results are consistent with the hypothesis that triggered activity arising from DADs characterizes the sustained rhythmic activity in endocardial preparations 1 day after infarction and indicate an important role for the sarcoplasmic reticulum in the genesis of DADs and triggered activity in this model.

Dependence of delayed afterdepolarizations on diastolic potentials in ischemic Purkinje fibers.

The mechanism of focal rhythms 1 day after myocardial infarction has been ascribed to both abnormal automaticity and triggered activity arising from delayed after-depolarizations (DADs). During the course of superfusion in vitro, diastolic potentials repolarize to more negative resting potentials. The dependence of DADs and triggered activity on diastolic potentials was studied using extrinsic currents. During sustained activity (maximum diastolic potential = -61 +/- 7 mV), hyperpolarizing current decreased the DADs, rendered them subthreshold, and terminated triggered activity. During the quiescence caused by constant hyperpolarizing current, a stimulated train of action potentials produced DADs. Decreasing the current permitted augmented DADs. In quiescent preparations (resting potential = -68 +/- 7 mV), a train of stimulated action potentials was followed by subthreshold DADs. Depolarizing current increased the DAD amplitude. To exclude depolarization-induced automaticity, constant currents were applied without a previous train of stimuli. Neither DADs nor triggered activity were evoked. Therefore, DADs and triggered activity, postinfarction, depend on the diastolic potential. There is a continuity between subthreshold DADs and sustained activity. DADs may reach a magnitude in which extrinsic interventions may not adequately terminate sustained triggered activity.

The differential response of normal and ischaemic Purkinje fibres to clofilium, d-sotalol and bretylium.

To determine whether ischaemic tissue is more sensitive than normal tissue to class III anti-arrhythmic agents, we studied the effects of the class III agents clofilium, d-sotalol and bretylium on normal and ischaemic Purkinje fibres one day after ligation of canine left anterior descending coronary artery. In ischaemic Purkinje fibres superfused with normal Tyrode's solution (4mM K+, 2.7mM Ca+2) clofilium produced early afterdepolarisations at 10(-7)M and 10(-6)M, d-sotalol at 10(-5)M to 10(-3)M, and bretylium at 10(-3)M. The early afterdepolarisation response of ischaemic tissue, which in some cases prolonged action potential duration to beyond 10 s, was significantly different from the simple prolongation of action potential duration seen in normal Purkinje fibres at the same concentrations. Clofilium and d-sotalol differentially produced early afterdepolarisations at or very near "anti-arrhythmic" doses. Therefore, class III anti-arrhythmics produced early afterdepolarisations differentially in ischaemic tissue at concentrations which did not produce early afterdepolarisations in normal tissue.

QTU prolongation and polymorphic ventricular tachyarrhythmias due to bradycardia-dependent early afterdepolarizations. Afterdepolarizations and ventricular arrhythmias.

Polymorphic ventricular tachyarrhythmias occurred spontaneously during bradycardia in dogs given the inotropic polypeptide anthopleurin-A (AP-A). The arrhythmia was investigated in in vitro and in vivo experiments. In in vitro experiments, AP-A (50 micrograms/l) produced bradycardia-dependent prolongation of action potential duration that was more pronounced in Purkinje than in muscle fibers. Only Purkinje fibers developed early afterdepolarizations (EAD) and triggered activity. These effects could be abolished by rapid pacing, lidocaine (4 mg/l), or tetrodotoxin (1 mg/l). In vivo experiments were conducted in anesthetized healthy dogs with simultaneous recording of surface ECG, monophasic action potentials from the endocardial and epicardial surface of the left ventricle by contact electrode catheter technique, and transmembrane action potentials from the epicardial surface of the left ventricle with a floating microelectrode technique. AP-A in a dose comparable to that used in vitro (4 micrograms/kg, i.v. bolus) resulted in bradycardia-dependent marked prolongation of both monophasic and transmembrane action potentials. An EAD gradually appeared on both recordings but was more marked in endocardial monophasic action potentials. Eventually, a premature ventricular depolarization arose from or very close to the peak of the EAD. The prolongation of action potentials was associated with similar prolongation of the QTU interval in surface ECG, and in some experiments, the EAD corresponded to a distinct prominent U wave. A ventricular premature depolarization arose from the U or TU complex and initiated polymorphic ventricular tachyarrhythmias that terminated spontaneously or degenerated into ventricular fibrillation. These effects were reversed by rapid pacing or lidocaine (1 mg/kg). The present study provides evidence in support of the hypothesis that AP-A-induced ventricular tachyarrhythmias are due to bradycardia-dependent EAD and triggered activity.