Comparative neuropsychiatry: white matter abnormalities in children and adolescents with schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder.

BACKGROUND: There is considerable evidence that white matter abnormalities play a key role in the pathogenesis of a number of major psychiatric disorders, including schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder. Few studies, however, have compared white matter abnormalities early in the course of the illness. METHODS: A total of 102 children and adolescents participated in the study, including 43 with early-onset schizophrenia, 13 with early-onset bipolar affective disorder, 17 with obsessive-compulsive disorder, and 29 healthy controls. Diffusion tensor imaging scans were obtained on all children and the images were assessed for the presence of non-spatially overlapping regions of white matter differences, a novel algorithm known as the pothole approach. RESULTS: Patients with early-onset schizophrenia and early-onset bipolar affective disorder had a significantly greater number of white matter potholes compared to controls, but the total number of potholes did not differ between the two groups. The volumes of the potholes were significantly larger in patients with early-onset bipolar affective disorder compared to the early-onset schizophrenia group. Children and adolescents with obsessive-compulsive disorder showed no differences in the total number of white matter potholes compared to controls. CONCLUSIONS: White matter abnormalities in early-onset schizophrenia and bipolar affective disorder are more global in nature, whereas children and adolescents with obsessive-compulsive disorder do not show widespread differences in FA.

Fatal methylene blue associated serotonin toxicity.

This is the first report of a fatal outcome from serotonin toxicity, precipitated by an interaction between methylene blue and venlafaxine. Methylene blue-associated serotonin toxicity has been described before but usually as mild toxicity. Its presentation after general anaesthesia may be atypical and therefore more difficult to diagnose. However, the syndrome is completely preventable if serotonin re-uptake inhibiting agents are stopped beforehand.

Molecular dynamics simulation of structural and dynamic properties of selenium structures with different degrees of amorphization.

We investigated Se structures of different degrees of disorder ranging from a 5% up to a 95% degree of amorphization. Starting from a trigonal crystalline structure we applied different strategies to introduce disorder into the Se configurations by irradiating atoms from their crystalline equilibrium positions. According to the symmetry of the trigonal phase, we introduced three types of disorder, i.e. the first type where only atoms forming layers of complete helical chains are shifted from their original positions (the thickness of these layers is chosen to represent the chosen degree of amorphicity), the second type where only atoms in planes-of respective thicknesses-lying perpendicular to the chains are displaced and the third type where only randomly chosen atoms are shifted from their crystalline equilibrium positions. After a thermal treatment of these disordered starting configurations, we calculated structural and dynamic properties (i.e. pair-correlation function and vibrational spectrum) and compared the results to both the original crystalline data and results obtained from corresponding glass structures.

[Eyelid drooping: diagnosis on the basis of an algorithm]. / Een hangend ooglid; diagnostiek op basis van een algoritme.

Five patients presented with eyelid drooping (blepharoptosis). A 26-year-old man with oculomotor disorders without anisocoria and a slow progressive course without fluctuations had a myogenic condition. His diplopia was alleviated by prism glasses. Surgical correction of the ptosis was planned. An 81-year-old man in whom the symptoms showed a course that varied over time had a disordered neuromuscular transmission that responded well to pyridostigmine. A 57-year-old man with oculomotor disorders and a dilated pupil on the affected side had an injury to the oculomotor nerve (and other cranial nerves), which remained stable after endovascular treatment of the causative aneurysm. A 22-year-old man had a constricted pupil (Horner's syndrome) and pain in the head and neck due to dissection of the internal carotid; his symptoms disappeared spontaneously. A 34-year-old woman had an isolated ptosis due to detachment of the aponeurosis of the M. levator palpebrae superioris following the chronic use of hard contact lenses; she was advised as to how to remove the lenses cautiously, to prevent further detachment. Eyelid drooping can have many causes. A systematic arrangement of the information gathered by a careful medical history and neurological examination often provides a reasonably accurate indication of the possible causes of the complaints.

Treatment of chronic subdural haematoma with percutaneous needle trephination and open system drainage with repeated saline rinsing.

Fifty three patients with symptomatic chronic subdural haematomas were treated with single needle trephination followed by open system drainage with repeated saline rinsing for two days. After single trephination good outcome was achieved in 84% of the patients. Early recurrence was found in 11.3% of the cases. After a second needle trephination good outcome increased to 89%. Mortality rate was 4%. Long term follow up (mean 30 months) showed 6.7% recurrence rate. There were no complications. Single needle trephination with open system drainage and repeated rinsing is an effective and safe minimal invasive procedure for patients with chronic subdural haematomas.

Tachycardia induced electrical remodeling of the atria and the autonomic nervous system in goats.

Atrial fibrillation (AF) shortens the atrial effective refractory period (AERP). To investigate the role of the autonomic nervous system during this so-called electrical remodeling of the atria (ERA) and during recovery from ERA we analyzed heart rate variability (HRV). In 12 goats atrioventricular (300:150 beats/min) pacing was performed for 24 hours, interrupted at 4, 8, 16, and 24 hours for recording of 500 atrial (AA) intervals during sinus rhythm and measurement of the AERP(430ms) at 7.4 +/- 0.6 sites. After 24 hours, pacing was stopped and the electrophysiological study and recording of the AA intervals was repeated at 4, 8, 16, and 24 hours after cessation of pacing. Time- and frequency-domain parameters were computed from each 500 AA interval recording. After 24 hours of rapid pacing the AERP had shortened significantly (147 +/- 5.6 to 102+/- 6.4 ms, P < 0.0001). No significant changes in HRV and dispersion of refractoriness (AAERP) (47 +/- 7.1 to 44 +/- 4.2 ms) were observed. After cessation of pacing, the AERP prolonged again (102 +/-6.4 to 135+/-8.8 ms, P < 0.0001) and was paralleled by a significant increase in AAERP (44 +/- 4.2 to 63+/- 7.1 ms, P = 0.01). Furthermore, HRV increased significantly. At each time point an inverse relation between the logarithmically transformed vagal parameter HF (InHF) and AERP was observed. We calculated the mean InHF for each goat using all time points and used the median value to divide the 12 goats into high and low vagal tone groups. We compared the degree of ERA and recovery from ERA for both groups. The AERP shortened 47.4 +/- 6.5 versus 43.0+/-5.0 ms (NS) for goats with high and low vagal tone, respectively. During recovery from ERA the AERP lengthened 23.6 +/- 4.0 versus 42.5 +/- 1.7 ms (P = 0.001) for goats with high and low vagal tone, respectively. Multivariate regression analysis indicated a short AERP as the single independent determinant of the inducibility of AF during ERA and recovery from ERA (P < 0.0001). During recovery from ERA, the AERP prolonged and vagal tone and AAERP increased. A high vagal tone during recovery from ERA was associated with a short AERP and an attenuated recovery of ERA.

Digoxin delays recovery from tachycardia-induced electrical remodeling of the atria.

BACKGROUND: Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. METHODS AND RESULTS: We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. CONCLUSIONS: Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Prediction of lesion size through monitoring the 0 degree C isothermic period following transcatheter cryoablation.

A prototype steerable 8.5 F bipolar catheter fitted with a feedback thermocouple was tested in 7 anaesthetized pigs (30 kg) guided by the electrocardiogram in order to modify the AV nodal and His-Purkinje system conductive properties. Thermal energy was delivered by a pressurized N2O tank (> 650 psi) via a cardiac cryo unit (Spembly, Hampshire, UK) into the catheter wherein gas expands resulting in a tip temperature as low as -70 +/- 2 degrees C within 10 seconds. Cryoablation under fluoroscopic and electrocardiographic guidance was applied at distinct sites in both ventricles for 60 or 120 seconds. After a follow-up period of 6 weeks, the ablation lesions found were well demarcated with small margins of hypertrophy of myocardial cells. With respect to lesion volume variability (8-207 mm3) and geometry, a relationship between the 0 degree C isothermic period and cryolesion volume was found. Results of an in vitro model corroborated this relationship. Therefore, an isothermic period probably can predict the lesion size and its geometry in terms of lesion depth. This potential therapeutic mode of transcatheter cryoablation deserves further investigation.

Differential inhibition of plasma versus tissue ACE by utibapril: biochemical and functional evidence for inhibition of vascular ACE activity.

Utibapril is an angiotensin-converting enzyme (ACE) inhibitor with a proposed tissue-specific inhibitory profile. This implies that at a certain dose, utibapril should be able to inhibit tissue ACE activity without affecting plasma ACE. Moreover, if tissue ACE activity is rate limiting, functional conversion of angiotensin I should be decreased. Accordingly, we studied the dose-dependent effect of long-term treatment with utibapril on plasma and tissue ACE. Normal Wistar rats were randomly allocated to oral treatment with different doses of utibapril (0, 2, 10, 50, or 250 micrograms/kg/day) for 30 days. Tissue inhibition of ACE was assessed biochemically, whereas functional conversion of angiotensin I was determined in the isolated organ. Utibapril significantly inhibited plasma, renal, and vascular ACE but not ventricular ACE activity. Notably, however, only treatment with the highest dose of utibapril resulted in a significant inhibition of plasma ACE, whereas vascular ACE activity was already significantly inhibited after treatment with a lower dose of utibapril. In accordance, utibapril dose-dependently inhibited the contraction of isolated aortic rings to angiotensin I. Furthermore, angiotensin I-induced decreases in coronary flow in the isolated heart were significantly inhibited after treatment with the higher doses of utibapril. These data suggest the preferential inhibition of vascular ACE by utibapril in normal rats. Furthermore, the dose-dependent inhibition of the functional conversion of angiotensin I indicates that the tissue ACE activity may be rate limiting in vascular beds in rats.

Verapamil reduces tachycardia-induced electrical remodeling of the atria.

BACKGROUND: Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time. METHODS AND RESULTS: To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms, P < .001, P < .01, and P < .01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments, P = .03). CONCLUSIONS: Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.

Effects of beta-blockade on atrial and atrioventricular nodal refractoriness, and atrial fibrillatory rate during atrial fibrillation in pigs.

Despite their widespread use in atrial fibrillation, the effects of beta-adrenoceptor blockers on atrial and atrioventricular (AV) nodal refractoriness, and atrial fibrillatory rate during atrial fibrillation have been incompletely characterised. In particular, it is unknown whether additional sodium channel (class I) blocking effects play a role. Effects of bisoprolol (no class I effect) and metoprolol (mild class I effect) were therefore compared in 12 open-chest pigs. Atrial and AV-nodal effective refractory periods were determined at pacing cycle length 500 ms and 300 ms. Atrial fibrillation was then induced by premature stimulation and topical application of metacholine, and atrial fibrillatory intervals and ventricular intervals were recorded. After resumption of sinus rhythm, bisoprolol 0.1 mg/kg or metoprolol 0.3 mg/kg was administered, and measurements were repeated. Also, effects on plasma catecholamines and signal-averaged QRS duration were determined. Both bisoprolol and metoprolol prolonged atrial and AV-nodal effective refractory periods at both pacing cycle lengths, however, no differences were noted between the two drugs. No significant effects were observed on atrial and ventricular intervals during atrial fibrillation. Plasma catecholamines were low and unaffected by either drug, as was the QRS duration. It is concluded that the mild class I effect of metoprolol does not play a role in atrial fibrillation. Also, the results confirm the clinical notion that beta-blockers exert insignificant effects during atrial fibrillation in the setting of low sympathetic tone.

Electrophysiological, rate dependent, and autonomic effects of the class III antiarrhythmic almokalant after myocardial infarction in the pig.

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 mumol.kg-1.min-1, continuous infusion: 0.0025 mumol.kg-1.min-1) from 292 +/- 25 to 308 +/- 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 +/- 19 to 261 +/- 16 ms (PCL 400 ms +1ES), and from 209 +/- 18 to 219 +/- 18 ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 +/- 27 to 186 +/- 29 ms (P < 0.05) and at PCL 300 ms: from 150 +/- 29 to 174 +/- 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 +/- 2.5 ms to 5.4 +/- 4.2 ms (P = NS). After programmed stimulation, it further decreased to 2.8 +/- 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 +/- 2.2 ms before stimulation and 3.3 +/- 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.

Rate-dependent effects of the class III antiarrhythmic drug almokalant on refractoriness in the pig.

The electrophysiologic effects of intravenously administered almokalant, a new class III antiarrhythmic drug, in 7 isoflurane-anesthetized pigs after low and high dose were investigated. Low-dose almokalant included bolus infusion of 0.05 mumol/kg/min for 5 min followed by a continuous infusion of 0.0025 mumol/kg/min for 40 min. Thereafter, a high dose of 0.2 mumol/kg/min for 5 min and 0.01 mumol/kg/min for 40 min was given. PR, QRS, AH, and HV intervals did not change during almokalant administration. The QT interval increased dose dependently from 337 +/- 17 to 442 +/- 20 ms at high dose (p < 0.05). Atrial refractory periods (AERP) were prolonged dose dependently at a 500-ms pacing cycle length from 178 +/- 15 at baseline to 227 +/- 27 and 253 +/- 23 ms during low- and high-dose almokalant infusion, respectively. For pacing cycle lengths of 400 and 300 ms, these values were 180 +/- 11, 207 +/- 25, and 259 +/- 34 and 157 +/- 12, 193 +/- 21, and 234 +/- 28 ms, respectively. At a pacing cycle length of 500 ms, mean ventricular effective refractory period (VERP) was 270 +/- 25 ms as compared with 306 +/- 24 and 337 +/- 17 during low and high dose, respectively. A similar pattern of VERP changes during both low- and high-dose infusion was noted at the shorter pacing cycle lengths, with an increase from 240 +/- 23 to 274 +/- 22 and 279 +/- 24 ms during a 400-ms cycle length and from 210 +/- 17 to 235 +/- 19 and 234 +/- 21 ms during a 300-ms cycle length. The ratio of the VERP and ventricular monophasic action potential duration (VAPD) did not change significantly. The Wenckebach cycle length increased by 36 +/- 36 and 83 +/- 37 ms with low- and high-dose almokalant infusion, respectively. The percent increase of AERP at pacing cycle lengths of 500, 400, and 300 ms during high-dose almokalant was 42, 44, and 49%, respectively; these increases for VERP were 25, 16, and 11%, respectively. In conclusion, prolongation of refractoriness by almokalant was more pronounced at the atrial than the ventricular level. Prolongation of refractoriness was maintained at short pacing cycle lengths especially in the atrium, indicating absence of reverse-use dependence of almokalant in the porcine heart. The marked atrial effects, paralleled by atrioventricular conduction slowing, and the absence of reverse use-dependence all contribute to the feasibility of use of almokalant, in particular in the treatment of supraventricular tachyarrhythmias.

Analysis of randomness of atrial and ventricular rhythm in atrial fibrillation.

The aim of the present study was to examine the relationship between randomness of atrial and ventricular rhythm during atrial fibrillation. Atrial fibrillation was induced in 10 open-chest pigs by application of metacholine on the surface of the right atrium followed by incremental pacing. Local atrial rhythm (AA intervals) was recorded with a bipolar epicardial electrode, and episodes of atrial fibrillation corresponding to 500 ventricular (RR) intervals were selected for analysis. Randomness of the distribution of AA and RR intervals was assessed by autocorrelation. Pearson's test was used for statistical analysis. Random AA and RR interval distribution was observed in nine pigs (P > or = 0.05). In the remaining pig, atrial fibrillation had changed to atrial tachycardia. This was associated with immediate transition of a random to a non-random ventricular rhythm. These findings provide strong circumstantial evidence in support of the contention that randomness of ventricular rhythm during atrial fibrillation is due to randomness of atrial rhythm.

Semi-automatic external defibrillation.

Malignant arrhythmia, which is responsible for most of the out-of-hospital cardiac arrests, is ventricular fibrillation (VF). The best treatment of VF is a controlled electric shock on the chest administered in a short delay. The emergency medical technicians (EMTs) qualified to carry out this treatment in Belgium and in districts often succeed in arriving on the spot 8 minutes earlier than the people of the Service Mobile d'Urgence et de Réanimation (SMUR). The delegation of defibrillation to ambulance crew members however implies a specific teaching, training and a medical control. The Brussels experience shows that semi-automatic external defibrillation by EMT-Ds (SAED) is feasible when criteria for applying SAED in the pre-hospital phase are applicable.

Late potentials, QTc prolongation, and prediction of arrhythmic events after myocardial infarction.

In a series of 171 consecutive survivors of acute myocardial infarction, the predictive value of late potentials and QTc prolongation was prospectively assessed. QT intervals were measured in lead V2, corrected QT (QTc) was calculated using Bazett's equation (cut-off value 440 ms). Late potentials were considered to be present when all of the three signal-averaged electrocardiographic variables were abnormal (i.e. QRS > 114 ms, D40 > 38 ms, and V40 < 20 microV). Complete follow-up was obtained (mean 13 +/- 6 months, range 6-24 months). Six percent of the patients had an arrhythmic event (i.e. sustained ventricular tachycardia or sudden death). The relative risk of late potentials for arrhythmic events was 7.7 (P < 0.02). The relative risk of QTc > 440 ms was 1.1 (NS). In a multivariate analysis, the addition of QTc prolongation did not significantly improve the prognostic value of late potentials alone. It is concluded that late potentials are predictive of arrhythmic events after myocardial infarction, but the presence of concomitant QTc prolongation does not worsen the prognosis.

Effect of metoprolol on atrial fibrillatory rate, atrioventricular nodal concealed conduction, and ventricular response during atrial fibrillation in pigs.

We wished to elucidate the effect of beta-blockade on fibrillatory rate and atrioventricular (AV) nodal concealed conduction during atrial fibrillation (AF). Subsequent to determination of the effect on atrial functional refractoriness with the extrastimulus technique (basic cycle length 400 ms), the effect of metoprolol (0.3 mg/kg) on atrial fibrillatory rate was determined in 8 open-chest pigs with metacholine-facilitated AF. Once stable AF was established, fibrillatory rate was recorded with a bipolar epicardial electrode, together with the ventricular response during 500 ventricular intervals. For each episode of AF, three indexes were calculated to determine the degree of concealed conduction: the ratio of the longest to the shortest ventricular interval, the ratio of the median ventricular interval to the median atrial interval, and the coefficient of variation of the ventricular intervals. Metoprolol decreased fibrillatory rate (571-432 beats/min, p < 0.01), suggesting a proportionate increase (+32%) in atrial functional refractoriness during AF that far exceeded the increase (+7%) during sinus rhythm (217-233 ms, p < 0.05). None of the indexes of concealed conduction was affected by metoprolol. Metoprolol decreases fibrillatory rate in AF, possibly due in part to its class I effect, causing rate-dependent prolongation of atrial refractoriness. Despite reducing fibrillatory rate, metoprolol does not affect AV nodal concealed conduction measurably. Our results support the assumption that the reducing effect of beta-blockers on ventricular rate during AF is due to direct prolongation of AV nodal refractoriness.

Effects of streptokinase during acute myocardial infarction on the signal-averaged electrocardiogram and on the frequency of late arrhythmias.

Although a number of studies have shown that the incidence of late potentials is lower after thrombolytic therapy, it is not known whether this is paralleled by fewer arrhythmic events during long-term follow-up. In patients with first acute myocardial infarction, filtered QRS duration was significantly shorter when treated with streptokinase (95 +/- 11 ms, n = 53) than when treated with conventional therapy (99 +/- 12 ms, n = 77, p < 0.05). The low-amplitude signal (D40) was shorter after thrombolysis (28 +/- 11 vs 33 +/- 12 ms, p < 0.02). Terminal root-mean-square voltage did not differ significantly (41 +/- 24 vs 35 +/- 23 microV). Irrespective of treatment, late potentials were predictive in the complete group (n = 171) for arrhythmic events during follow-up (13 +/- 6 months, range 6 to 24) (hazard ratio 7.7, p < 0.02, Cox proportional-hazards survival analysis), but treatment (streptokinase vs conventional) did not significantly affect outcome when added to the model. It is concluded that thrombolysis prevents the development of late potentials. However, this study does not confirm the hypothesis that prevention of late potentials leads to a decrease in arrhythmic events.

Sequential bilateral bundle branch block during dofetilide, a new class III antiarrhythmic agent, in a patient with atrial fibrillation.

INTRODUCTION: The mechanism of wide QRS complex tachycardias during dofetilide infusion was studied in a patient with atrial fibrillation. METHODS AND RESULTS: Endocardial recordings from the intraventricular conduction system showed that dofetilide caused "classic" aberrant conduction (Ashman phenomenon, typical QRS morphology) at high prematurity ratios (preceding interval = 1.78 x coupling interval--290), thus mimicking ventricular ectopy. In addition, there was frequent sequential bilateral bundle branch block, caused by a significant difference in preceding bundle-to-bundle intervals (mean difference +/- 1 SD: 74 +/- 26 msec). CONCLUSION: The present findings may prove helpful in the clinical assessment of wide QRS complex rhythms after dofetilide and possibly other "pure" Class III antiarrhythmics.

Sustained atrial flutter around the tricuspid valve in pigs: differentiation of procainamide (class IA) from flecainide (class IC) and their rate-dependent effects.

The wavelength theory considers two determinants of reentry, i.e., refractoriness and conduction velocity. It does not take excitability into account primarily. We evaluated frequency-dependence of excitability and refractoriness before and after flecainide or procainamide administration in relation to termination of reentrant atrial flutter. After making a Y-shaped lesion in the right atrium, we induced 62 flutters (cycle length 171 +/- 15 ms) by electrical stimulation in 15 pigs. Strength-interval curves were determined to assess excitability and refractoriness. Multiple cycle lengths were used to establish rate-dependent changes. Flutter cycle length increased after flecainide (to 290 +/- 67 ms) or procainamide (to 295 +/- 54 ms). The flutters always terminated abruptly (flecainide dose 103 +/- 104 mg, plasma concentration 370 +/- 21 ng/ml; procainamide dose 1,150 +/- 686 mg, concentration 51 +/- 24 mg/l). Flecainide caused an increase in diastolic thresholds from 0.3 +/- 0.2 to 0.8 +/- 0.5 mA (p < 0.006) and procainamide from 0.5 +/- 0.3 to 0.9 +/- 0.5 mA (p < 0.02). The increase in threshold was frequently dependent. Procainamide increased refractoriness at longer cycle lengths (> or = 250 ms), but this effect was abolished at shorter cycle lengths, indicating that only after significant slowing of the rate, prolongation of refractoriness may appear. Thus, both drugs interrupt reentrant flutter mainly by reducing excitability. Subclassification into IA and IC may be less relevant at high rates. Construction of strength-interval curves and assessment of rate-dependent "postrepolarization refractoriness" should be considered when one studies drugs that influence excitability.