Overdrive suppression of antegrade conduction over the accessory pathway.

In a patient with Wolff-Parkinson-White syndrome whose accessory pathway was primarily capable of bidirectional conduction, antegrade conduction over the accessory pathway was transiently inhibited after rapid atrial or ventricular pacing or after spontaneous termination of atrioventricular reentrant tachycardia. Pacing rate and duration of tachycardia were related to the duration of the suppression of preexcitation, while the coupling interval of the first sinus beat to the last driven or tachycardia beat was irrelevant to the phenomenon. Thus, overdrive suppression of conduction may be the most likely mechanism of this phenomenon.

A wide "gap" in retrograde conduction through a concealed accessory atrioventricular pathway depending on ventricular pacing sites.

We present a 57-year-old man with Wolff-Parkinson-White syndrome who exhibited a wide "gap" in retrograde conduction through a concealed atrioventricular accessory pathway. The appearance of the wide "gap" depended on the ventricular pacing sites. While ventricular extrastimuli at a basic cycle length of 600 msec from the right ventricular outflow tract consistently conducted to the atria, retrogradely through the accessory pathway, those from the right ventricular apex repeatedly revealed disappearance of the retrograde conduction at the wide coupling intervals from 550 to 380 msec. The mechanisms of this rare "gap"-like phenomenon are discussed in this paper.

Augmentation rhinoplasty using an L-shaped auricular cartilage framework combined with dermal fat graft for cleft lip nose.

We prepared an L-shaped framework using autogenous auricular cartilage and combined this with dermal fat, according to each patient, to graft it in 12 patients with cleft lip nose. Although auricular cartilage is weak on its own, by our method we obtained a strong columella strut and nasal dorsum augmentation at the same time. Dermal fat graft provided camouflage for cartilage irregularities and was useful for increasing the graft volume. Although absorption caused a decreased volume to a certain extent, there were no other complications such as cyst formation, and a natural nasal contour was achieved in all patients.

Is ventricular fibrillation interval an indicator of electrical defibrillation threshold?

To clarify whether peak-to-peak interval of the fibrillation wave (VF interval) during VF is an independent indicator of defibrillation efficacy, we measured the transcardiac DFT, VF intervals of the surface and local ECGs (lead II and the right ventricle), and the ERP in 82 open-chest dogs. Both VF intervals showed a negative correlation with heart weight (surface: r = -0.358 [P < 0.005]; local; r = -0.349 [P < 0.005]). DFT was 2.0 +/- 0.7 A and positively correlated with heart weight (r = 0.453 [P < 0.0001]). ERP did not show a significant correlation with heart weight. DFT was negatively correlated with VF interval (vs surface VF interval: r = -0.568 [P < 0.0001]; vs local VF interval: r = -0.504 [P < 0.0001]), but showed only a weak negative correlation with ERP (r = -0.314 [P < 0.005]). Even after allowing for the dependency of DFT and VF intervals on heart weight (normalized to a 100-g heart), the correlation between VF interval and DFT was still significant (vs surface VF interval: r = -0.487 [P < 0.0001]; vs local VF interval: r = -0.414 [P < 0.0002]). These results suggest that VF interval is an indicator of DFT in intact hearts that have not received pharmacological intervention.

Relation between aging and circadian variation of paroxysmal atrial fibrillation.

The purpose of this study was to determine whether aging influences the circadian variation of nonvalvular paroxysmal atrial fibrillation (AF). Among 31,200 consecutive Holter monitorings recorded between January 1988 and March 1997, we detected 212 patients who had paroxysmal AF in a drug-free state. These patients were divided into 2 groups according to their age: < or = 60 years old (94 patients) and >60 years old (118 patients). In each group, the sum of the duration of each AF episode and the probability of onset, maintenance, and termination of AF were determined as hourly data and compared between the 2 groups. The time distribution of AF showed remarkable age dependence, with a well-modulated and monophasic circadian rhythm in the younger group in contrast to a toneless triphasic rhythm in the older group. Among the onset, maintenance, and termination of the arrhythmia, the most obvious age-dependence was observed in the circadian variation of onset. In the younger group, there were triple peaks with the highest one in the night, whereas the older group exhibited a single peak in the daytime. In contrast, the probabilities of maintenance and termination showed similar circadian patterns between the groups, although their amplitudes were significantly reduced in the older group. Thus, aging significantly influenced the circadian variation of paroxysmal AF, with the most prominent effect on its onset, leading to more random time-distribution of AF with increasing age. These results extend to paroxysmal AF the concept that aging disrupts rhythmicity, suggesting age-dependent differences in its pathophysiology.

Uniqueness of pilsicainide in class Ic antiarrhythmics.

Pilsicainide, a class Ic agent, is known to be an effective drug particularly for treating atrial tachyarrhythmias. However, its electrophysiological effects on the atrium have not been well studied. To characterize the electrophysiologic effects of pilsicainide on atrial myocytes in class Ic drugs, we examined the effects of this drug on membrane currents in single rabbit atrial myocytes using the tight-seal whole cell voltage-clamp technique. Under the current-clamp condition, pilsicainide did not affect the action potential duration at therapeutic ranges (< or = 3 microM) and slightly shortened it at higher concentrations (> or = 10 microM). These observations were quite different from those with other class Ic agents including flecainide and propafenone which prolong the atrial action potential duration. The drug did not affect the resting membrane potential. Under the voltage-clamp condition, pilsicainide inhibited the transient outward current (Ito) that is more prominent in the atrium than in the ventricle in a concentration-dependent manner. However, in contrast to other class Ic agents, the inhibition to Ito by pilsicainide was observed only at much higher concentrations (IC50-300 microM) and did not affect the inactivation time-course of Ito. Moreover, the drug (10 microM) did not significantly affect the Ca2+, delayed rectifier K+, inward rectifying K+, acetylcholine-induced K+ or ATP-sensitive K+ currents. From these results pilsicainide could be differentiated as a pure Na+ channel blocker from other class Ic agents with diverse effects on membrane currents and should be recognized accordingly in clinical situations.

Ostensible day-night difference of QT prolongation during long-term treatment with antiarrhythmic drugs: reappraisal of the law of "regression to the mean".

This study was designed to test whether the law of regression to the mean explains the diurnal variation in the modulation of electrocardiographic variables during the treatment with antiarrhythmic agents. In part 1, in 34 subjects, ambulatory ECG monitorings were repeated twice, and the corrected QT interval (QTc) at a heart rate of 60 beats/min was calculated separately for the daytime and night. The individual diurnal QTc variation (day-night difference) of the first recording (4.4 +/- 3.3%) was significantly correlated with that of the second recording (5.0 +/- 3.1%; r = 0.61; p < 0.0001), and naturally, the second measurement tended to be lower than the first value in those with relatively greater baseline diurnal QTc variation and vice versa (p < 0.005). In part 2, 30 subjects undertook ambulatory ECG recordings before and during treatment with class Ia antiarrhythmic drugs. Mean QTc changes in the daytime and in the night with the drugs were comparable (18 +/- 17 ms and 19 +/- 15 ms). However, the day-night difference of postdrug QTc changes in each subject was inversely correlated with baseline diurnal QTc variation (r = -0.64; p < 0.0001). These observations in part 2 were comparable with those in part 1, and individual day-night difference in QT prolongation with antiarrhythmic drugs seemed to be a chance occurrence. It was suggested that the law of regression to the mean is appreciably reflected in the ostensible intraday variation of pharmacologic modulation of electrocardiographic variables.

Postshock recovery interval of relatively refractory myocardium as a possible explanation for disparate defibrillation efficacy between monophasic and biphasic waveforms.

We investigated the electrophysiological background for the waveform related variability of defibrillation efficacy. In 22 open-chest dogs, a localized potential gradient was created using an 8-V or 16-V field stimulus across a pair of plate electrodes separated by 5 mm. The post shock recovery interval of the nondepolarized myocardium adjacent to the excited area was estimated by the residual refractory period after an appropriately timed field stimulus. The postshock recovery interval and the defibrillation threshold were compared among six different waveforms but with the same total duration of 12 ms (n = 11) or 16 ms (n = 11). Six defibrillation thresholds in individual hearts showed a significant inverse correlation with postshock recovery intervals in most dogs (8/11) tested with a total pulse duration of 12 ms (8 V stimulus: r = -0.80 +/- 0.20 [n = 11]). In contrast, waveforms with a total duration of 16 ms failed to reveal this distinct relationship. We conclude that the waveform related variability of defibrillation efficacy is associated with the refractoriness of relatively refractory myocardium when the total pulse duration is within a certain range. However, the mechanisms responsible for waveform performance may vary as the total pulse duration changes.

Circadian variation of paroxysmal atrial fibrillation.

BACKGROUND: Circadian variation in the incidence of acute cardiovascular events is well known but has not been extensively investigated in paroxysmal atrial fibrillation, although the significance of this arrhythmia is growing in our society with the increasing number of aged people. METHODS AND RESULTS: We detected 150 patients with paroxysmal atrial fibrillation in a drug-free state from among 25,500 consecutive Holter recordings. To determine whether the onset, maintenance, and termination of paroxysmal atrial fibrillation were random events, we analyzed the total recorded duration of arrhythmia and the incidence of and number of patients with the onset, maintenance, and termination of this arrhythmia as hourly data and as hourly probabilities. A prominent circadian rhythm of the total duration of atrial fibrillation, approximately 90% of which was well explained by a single cosinusoidal function, was detected with a nadir around 11 AM. Because the onset of the arrhythmia had little or no circadian rhythm, this finding was due to a diurnal pattern of maintenance and termination, both of which were well expressed by a double-harmonic density function. Maintenance showed a trough at 11 AM, and termination showed a peak at the same time, leading to the nonuniform duration of single episodes of atrial fibrillation throughout the 24-hour day. CONCLUSIONS: Paroxysmal atrial fibrillation showed a unique circadian variation that differed from the well-known pattern for acute cardiovascular events, a point that should be kept in mind when antiarrhythmic therapy is evaluated. Identification of factors that regulate the circadian pattern of the maintenance and termination of paroxysmal atrial fibrillation may lead to better chronotherapy for preventing perpetuation of this arrhythmia.

Three-dimensional activation sequence of cesium-induced ventricular arrhythmias.

To investigate the electrophysiological and electrocardiographic characteristics of ventricular arrhythmia due to abnormal repolarization, we studied the three-dimensional activation sequence of cesium-induced ventricular tachycardia (VT) in 10 anesthetized dogs using a 384-channel recording system. Seventeen monomorphic VT (mVT) and eight polymorphic VT (pVT) episodes induced by cesium chloride (2 or 3 mM/kg) were analyzed. Only a single arrhythmogenic focus was detected in most beats of VT, whereas two competing foci were temporarily observed in two episodes of pVT. The site of arrhythmogenic focus of mVT was the endocardium (5 of 17), the midmyocardium (4 of 17), or undetermined (8 of 17). Both endocardial and midmyocardial arrhythmogenic foci were also found in pVT, and most pVT (6 of 8) were associated with the transition of the site of arrhythmogenic focus. These results are consistent with the view that both myocardial muscle fibers and Purkinje cells can cause ventricular arrhythmia due to abnormal repolarization and that changing the site of arrhythmogenic focus is the main mechanism of pVT.

Is ACE gene polymorphism associated with lone atrial fibrillation?

ACE (angiotensin converting enzyme) gene genotypes have been shown to be a risk factor for development of left ventricular hypertrophy and cardiomyopathy, upon the assumption that the DD genotype is linked to higher cellular ACE activity leading to myocardial fibrosis. To test an analogous hypothesis that the DD genotype favors myocardial fibrosis in the atrium and thus promotes atrial fibrillation without any structural heart diseases, we determined the distribution of the ACE gene genotypes in 77 patients with lone atrial fibrillation and investigated the effects of the ACE genotypes on the clinical characteristics of atrial fibrillation. The distribution of ACE genotypes was not significantly different between the patients and healthy volunteers. Also, the ACE gene genotypes did not affect the types of atrial fibrillation and the age at the onset of atrial fibrillation. Thus, these results refuted the hypothesis of possible relationships between ACE genotypes and lone atrial fibrillation through myocardial fibrosis, and indicated some unknown differences between the atrium and ventricle.

[Successful repair for concealed Wolff-Parkinson-White syndrome with atrial septal defect in infancy: a case report].

A 7-month-old girl weighing 5.3 kg, presented with atrial septal defect (ASD) and paroximal supraventricular tachycardia (PSVT). The preoperative electrophysiological study could not be performed because of the severe heart failure. On suspicion of a concealed Wolff-Parkinson-White (WPW) syndrome, whose accessory pathways conduct in the retrograde direction only, the operation was performed. The intraoperative epicardial and endocardial mappings revealed the presence of a left-posterior retrograde accessory pathway. This accessory pathway was successfully ablated by a cryoablation using transseptal superior approach. The postoperative course was uneventful without a permanent heart block. We report a successful surgical repair for an infant with concealed WPW syndrome, who revealed severe heart failure because of PSVT and ASD.

Electrophysiological background of individual variability in electrical defibrillation efficacy.

This study was performed to test whether heart-to-heart variability of defibrillation efficacy is attributable to differences in postshock refractory state of nondepolarized myocardium. In 30 anesthetized dogs, a localized potential gradient was created using 1-16 V of stimulus across a pair of platinum plate electrodes on the right ventricle (5-mm interelectrode distance). The postshock recovery interval (PSRI) of the relatively refractory myocardium directly adjacent to the excited area was estimated by measuring the recovery interval after an appropriately timed field stimulus. The transcardiac defibrillation threshold (DFT) was also determined. The results showed that DFT normalized by the weight of the heart was inversely correlated with the PSRI measured with a field stimulus of 6 V (local shock intensity approximately 5 V/cm) or more (6 V: r = -0.502, P < 0.005; 16 V: r = -0.635, P < 0.0005). This observation suggests that variability of defibrillation efficacy in intact hearts is largely due to differences in the postshock refractory state of the nondepolarized myocardium.

Effects of a class III antiarrhythmic drug and biphasic shocks on the postdefibrillation refractory period of relatively refractory myocardium.

INTRODUCTION: This study was designed to test whether the refractory state of nondepolarized myocardium is a major determinant of electrical defibrillation. METHODS AND RESULTS: Postshock recovery interval (PSRI) was estimated by measuring the residual refractory period after an appropriately timed field stimulus (1 to 16 V). The PSRI and transcardiac defibrillation threshold (DFT) were compared before and during the administration of E-4031, a new Class III antiarrhythmic drug (group 1, n = 10), or between monophasic and biphasic shocks (group 2, n = 14) in anesthetized open chest dogs. Group 1: E-4031 reduced the DFT from 2.6 +/- 0.6 J to 1.8 +/- 0.6 J (P < 0.01). The PSRI increased with the increase of the applied voltage and was almost always greater during E-4031 infusion than at baseline. There was an inverse correlation between the changes of DFT and PSRI measured with a 14-V stimulus (r = -0.80, P < 0.01) and a 16-V stimulus (r = -0.80, P < 0.01). Group 2: Mean DFTs were not statistically different between the two waveforms (3.3 +/- 1.0 J vs 2.9 +/- 1.4 J). However, there also was an inverse correlation between the differences in individual PSRIs and DFTs of the two waveforms (10-V stimulus: r = -0.62, P < 0.05; 16-V stimulus: r = -0.75, P < 0.01). CONCLUSIONS: Modulation of defibrillation efficiency by E-4031 infusion or by changes of the shock waveform was related to the effect of these interventions on PSRI. These results suggest an independent role for the refractoriness of nondepolarized myocardium in the mechanism of defibrillation.

Nonreentrant supraventricular tachycardia due to double ventricular response via dual atrioventricular nodal pathways.

Narrow and wide QRS tachycardias associated with various rhythm disturbances were recognized during 24-hour ambulatory eletrocardiographic monitoring in a 65-year-old man with coronary artery disease. Laddergram analysis revealed the presence of dual atrioventricular nodal pathways. Non-reentrant supraventricular tachycardia due to simultaneous fast and slow conduction through the dual atrioventricular nodal pathways was confirmed by electrophysiologic study. The atrial rate determined the occurrence of simultaneous conduction, and extrastimulation failed to induce a double ventricular response. Enhanced vagal activity was thought to play a critical role in provoking this phenomenon. Radiofrequency catheter ablation of the slow pathway eliminated the arrhythmias.

Effect of isoproterenol on facilitation of electrical defibrillation by E-4031.

To determine whether isoproterenol could reverse enhancement of electrical defibrillation effectiveness by class III antiarrhythmic agents, we measured the internal defibrillation threshold (DFT) in 12 anesthetized dogs during infusion of (a) saline (baseline), (b) isoproterenol, (c) isoproterenol + E4031 (a new class III antiarrhythmic agent), and (d) E4031 alone. The isoproterenol infusion was adjusted so that heart rate (HR) was at least 30 beats/min greater than baseline. E4031 was given as a 40-micrograms/kg bolus at the beginning of the third stage of the study, followed by constant infusion at 2 micrograms/kg/min. Eight dogs completed the study. Although the energy-based DFT was not affected by isoproterenol (from 6.1 +/- 1.5 to 6.0 +/- 1.7 J), it was decreased to 3.7 +/- 1.6 J in the third stage by infusion of E4031 and isoproterenol (p < 0.01 vs. baseline and vs. isoproterenol). After the discontinuation of isoproterenol in the fourth stage, i.e., during infusion of E4031 alone, DFT was 3.4 +/- 1.6 J (p < 0.01 vs. baseline and vs. isoproterenol). Therefore, isoproterenol did not antagonize the effect of E4031 on the DFT, suggesting the possible clinical usefulness of class III agents for facilitating defibrillation even in the presence of augmented sympathetic activity.

Prolongation of intraventricular conduction time associated with fatal [correction of fetal] impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents.

To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 +/- 1.5 to 4.4 +/- 1.6 J (3.1 +/- 1.2 micrograms/ml)]. Mexiletine tended to increase DFT [from 4.6 +/- 1.2 to 6.1 +/- 2.0 J (1.8 +/- 0.6 micrograms/ml); p < 0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 +/- 3%). Flecainide increased DFT from 4.2 +/- 1.3 to 6.1 +/- 1.5 J at a plasma level of 1.04 +/- 0.37 micrograms/ml (p < 0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 +/- 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.

Shock-induced refractory period extension and pharmacologic modulation of defibrillation threshold.

Shock-induced refractory period extension (RPE) has been suggested as a mechanism of electrical defibrillation. We measured RPE caused by localized field stimulation measured before and during infusion of disopyramide (n = 5), flecainide (n = 5), or E-4031 (n = 5) in anesthetized dogs and determined the effect of the drugs on the internal defibrillation threshold (DFT). In the baseline state (n = 15), 16 V/cm S2 field stimulation prolonged the effective RP by 36 +/- 15 ms (22 +/- 12% of RP without S2), whereas 4 and 8 V/cm S2 stimuli did not cause marked RPE. The RPE normalized by the RP without S2 was not significantly influenced by any drug (16 V/cm: disopyramide 30 +/- 11 vs. 27 +/- 11, flecainide 25 +/- 5 vs. 19 +/- 12, and E-4031 18 +/- 13 vs. 22 +/- 14%). Disopyramide did not alter the defibrillation threshold (4.2 +/- 0.6-4.4 +/- 0.6 J). In 2 dogs given flecainide, ventricular fibrillation became refractory to defibrillation. In contrast, E-4031 lowered the threshold from 4.5 +/- 2.4 to 2.2 +/- 1.2 J (p < 0.01). The results suggest that flecainide and E-4031 do not modulate defibrillation efficiency through their effects on RPE.

Studies on immunoglobulin and immunoglobulin-forming cells in Heterodontus japonicus, a cartilaginous fish.

Immunoglobulin (Ig), lymphoid tissues and Ig-forming cells of the Japanese bullhead shark, Heterodontus japonicus were analyzed biochemically, histologically and immunocytochemically. The serum of Heterodontus contains two Igs with different molecular weights one with 900 K and the other with 180 K daltons. Heavy chains of the two Igs showed an identical molecular weight of 68 K and the same antigenicity, indicating that the two Igs belong to the same class with different molecular structure. Light chains of Heterodontus Igs showed two distinct bands using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, one with the molecular weight of 25 K and the other with 22 K daltons. The latter finding indicates the possible existence of two light chain types in the Heterodontus Igs. White pulp of the spleen appeared as a well-developed lymphoid tissue accompanied large number of Ig-forming cells especially around blood vessels. Massive lymphocytic aggregations were found in the central area of the intestinal valves and certain lymphoid cells were demonstrated to be Ig-forming cells. Ig-forming cells were also observed in the epigonal organ, although the frequency was much less than in the former two tissues. Although the spleen is the major Ig-forming organ in Heterodontus japonicus, the valvular intestine and the epigonal organ also appear to share the function of Ig production.