Kazunori Sezaki

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.

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.

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.

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.

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

Summary: 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.

Prolongation of intraventricular conduction time associated with fetal impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents

Summary To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be 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 μg/ml)]. Mexiletine tended to increase DFT [from 4.6 ± 1.2 to 6.1 ± 2.0 J (1.8 ± 0.6 μg/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 μg/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.

Effects of a Class III Antiarrhythmic Drug and Biphasic Shocks on the Postdefibrillation Refractory Period of Relatively Refractory Myocardium

Refractory Period and Defibrillation. Introduction: This study was designed to test whether the refractory state of nondepolarized myocardium is a major determinant of electrical defibrillation.

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

Summary 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 anti-arrhythmic 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-μg/kg bolus at the beginning of the third stage of the study, followed by constant infusion at 2 μg/kg/min. Eight dogs completed the study. Although the energybased 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 E403I on the DFT, suggesting the possible clinical usefulness of class III agents for facilitating defibrillation even in the presence of augmented sympathetic activity.

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 postshock recovery interval of the nonde‐polarized 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 defibriliation threshold were compared among six different waveforms but with the same total duration of 12 ms (n = 11) or 16 ms (n = 11). Six defibriliation 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.