Takeshi Yamashita

Circadian Variation of Paroxysmal Atrial Fibrillation

BACKGROUNDnCircadian 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.nnnMETHODS AND RESULTSnWe 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.nnnCONCLUSIONSnParoxysmal 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.

Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria

Background—Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF. Methods and Results—The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analysis revealed that TM and TFPI were expressed predominantly in the endocardial cells of the normal atrium, presumably preventing local blood coagulation, and that rapid atrial pacing induced the loss of TM and TFPI expression in the endocardium, leading to deficiency in anticoagulant barriers between the atria and the blood. Conclusions—Rapid atrial pacing acutely downregulated the gene expression of TM and TFPI in the atrial endocardium, thereby inducing local coagulation imbalance on the internal surface of the atrial cavity. These results would support the validity of supplement of anticoagulant molecules deficient in AF.

Short-term effects of rapid pacing on mRNA level of voltage-dependent K(+) channels in rat atrium: electrical remodeling in paroxysmal atrial tachycardia.

BACKGROUNDnAtrial fibrillation causes electrophysiological changes of the atrium, thereby facilitating its maintenance. Although the expression of ion channels is modulated in chronic atrial fibrillation, it is yet unknown whether paroxysmal atrial fibrillation can also lead to electrical remodeling by affecting gene expression.nnnMETHODS AND RESULTSnTo examine the short-term effects of rapid pacing on the mRNA level of voltage-dependent K(+) channels, high-rate atrial pacing was performed in Sprague-Dawley rat hearts. Total RNA was prepared from the atrial appendages from 0 to 8 hours after the onset of pacing, and mRNA levels of Kv1.2, Kv1. 4, Kv1.5, Kv2.1, Kv4.2, Kv4.3, erg, KvLQT1, and minK were determined by RNase protection assay. Among these 9 genes, the mRNA level of the Kv1.5 channel immediately and transiently increased, with bimodal peaks at 0.5 and 2 hours after the onset of pacing. Conversely, the pacing gradually and progressively decreased the mRNA levels of the Kv4.2 and Kv4.3 channels. The increase of Kv1.5 and the decrease of Kv4.2 and Kv4.3 mRNA levels were both rate dependent. In correspondence with the changes in the mRNA level, Kv1. 5 channel protein transiently increased in the membrane fraction of the atrium during a 2- to 8-hour pacing period. Electrophysiological findings that the shortening of the action potential produced by 4-hour pacing was almost abolished by a low concentration of 4-aminopyridine implied that the increased Kv1.5 protein was functioning.nnnCONCLUSIONSnEven short-term high-rate atrial excitation could differentially alter the mRNA levels of Kv1.5, Kv4.2, and Kv4.3 in a rate-dependent manner. In particular, increased Kv1.5 gene expression, having a transient nature, implied the possible biochemical electrical remodeling unique to paroxysmal tachycardia.

Autonomic Nervous System Activity in Idiopathic Dilated Cardiomyopathy and in Hypertrophic Cardiomyopathy

To assess autonomic nervous activity in patients with cardiomyopathies, analysis of heart rate variability was performed using 24-hour ambulatory electrocardiograms in 14 patients with idiopathic dilated cardiomyopathy (IDC), 15 with hypertrophic cardiomyopathy (HC) and 18 healthy subjects. Heart rate variability during the night and daytime was calculated using fast-Fourier transform, and power spectra were quantified in 2 frequency bandwidths: 0.00 to 0.15 Hz (low-frequency power [LF]) and 0.15 to 0.50 Hz (high-frequency power [HF]). Log(HF) was used as an index of parasympathetic nervous activity, and log(LF/HF), of sympathetic nervous activity. Log(HF) was significantly lower and log(LF/HF) was significantly higher in IDC. These changes were related to ejection fraction. In HC, lower log(HF) and higher log(LF/HF) were recognized only during the night, and these changes were independent of the degree of myocardial hypertrophy. Our results indicated attenuation of parasympathetic activity and enhanced sympathetic activity in HC during the night, and also in IDC. Assessment of autonomic imbalance by analysis of heart rate variability may be useful for understanding the pathophysiology of cardiomyopathies.

Circadian variation of cardiac K^+ channel gene expression

Background—Many cardiac arrhythmias have their own characteristic circadian variations. Because the expression of many genes, including clock genes, is regulated variably during a day, circadian variations of ion channel gene expression, if any, could contribute to the fluctuating alterations of cardiac electrophysiological characteristics and subsequent arrhythmogenesis. Methods and Results—To examine whether cardiac K+ channel gene expression shows a circadian rhythm, we analyzed the mRNA levels of 8 Kv and 6 Kir channels in rat hearts every 3 hours throughout 1 day. Among these channels, Kv1.5 and Kv4.2 genes showed significant circadian variations in their transcripts: ≈2-fold increase of Kv1.5 mRNA from trough at Zeitgeber time (ZT) 6 to peak at ZT18 and a completely reverse pattern in Kv4.2 mRNA (≈2-fold increase from trough at ZT18 to peak at ZT6). Actually, along with the variations in the immunoreactive proteins, the density of the transient outward and steady-state currents in isolated myocytes and the responses of atrial and ventricular refractoriness to 4-aminopyridine in isolated-perfused hearts showed differences between ZT6 and ZT18, a circadian pattern comparable to that of Kv1.5 and Kv4.2 gene expression. Reversal of light stimulation almost inverted these circadian rhythms, although pharmacological autonomic blockade only partially attenuated the rhythm of Kv1.5 but not of Kv4.2 transcripts. Conclusions—Among all the cardiac K+ channels, Kv1.5 and 4.2 channels are unique in showing characteristic circadian patterns in their gene expression, with Kv1.5 increase during the dark period partially dependent on &bgr;-adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

Can a Class III Antiarrhythmic Drug Improve Electrical Defibrillation Efficacy During Ventricular Fibrillation

OBJECTIVESnWe tested whether a new class III drug (MS-551) administered during ventricular fibrillation (VF) could decrease the defibrillation threshold (DFT) in anesthetized canine hearts.nnnBACKGROUNDnPretreatment with class III antiarrhythmic agents is known to enhance electrical defibrillation efficacy.nnnMETHODSnIn a preliminary study (n = 10), we ascertained the validity of DFT determination by a sequence of incremental defibrillation shocks in a single fibrillation/defibrillation episode. We then compared the DFTs after 130 s of VF with and without administration of MS-551 (2 mg/kg body weight) at 10 s after the onset of VF in 12 open chest dogs and 8 closed chest dogs.nnnRESULTSnMS-551 decreased the DFT in both experimental models (open chest [mean +/- SD]: from 416 +/- 106 to 318 +/- 92 V, p < 0.05; closed chest: from 714 +/- 75 to 615 +/- 112 V, p < 0.05). The change (delta) in DFT in each heart was inversely correlated with the drug-induced prolongation of VF cycle length before the defibrillation attempt (delta DFT vs. delta VF cycle length 10 s before the first discharge: r = -0.58 and -0.81, p < 0.05).nnnCONCLUSIONSnMS-551 given after the induction of VF improved defibrillation efficacy. Class III antiarrhythmic agents deserve consideration when VF is resistant to electrical defibrillation during cardiopulmonary resuscitation.

Effects of antiarrhythmic drugs on canine atrial flutter due to reentry: Role of prolongation of refractory period and depression of conduction to excitable gap☆

Antiarrhythmic drugs prolong the effective refractory period and depress conduction. To determine the exact role played by these two electrophysiologic effects in the termination of reentry, the effects of disopyramide, flecainide, propafenone and E-4031, a new class III drug, were examined in a canine model of atrial flutter (cycle length 120 +/- 4 to 131 +/- 3 ms) caused by reentry. Atrial flutter was induced in 32 anesthetized open chest dogs after placement of an intercaval crush. The excitable gap ranged from 9 +/- 2% to 11 +/- 4% of the basic flutter cycle length. The effective refractory period in the reentrant circuit during atrial flutter was estimated by subtracting the excitable gap from the basic flutter cycle length. Prolongation of flutter cycle length by the test drugs was proportional to the interatrial conduction time (r = 0.87, p less than 0.001). Atrial flutter was terminated by each test drug in all dogs except for flecainide and propafenone in one dog each. E-4031 prolonged the refractory period during atrial flutter to 129 +/- 6 ms, which did not differ significantly from the flutter cycle length immediately before termination (134 +/- 4 ms). The refractory period during atrial flutter after injection of the other drugs was shorter than the flutter cycle length before termination of atrial flutter (for example, flecainide 126 +/- 5 vs. 179 +/- 11 ms, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of anatomic architecture in sustained atrial reentry and double potentials

To determine the role of anatomic architecture in atrial flutter, electrophysiologic findings were correlated with anatomic features in a modified model of atrial flutter with ligation of the crista terminalis. Crista ligation in the middle right atrium prolonged intraatrial conduction time in a rate-dependent manner in 12 dogs, particularly in the low right atrium. With burst atrial pacing, unidirectional block occurred either in the low right atrium or in the interatrial septal region near the superior vena cava, leading to initiation of atrial flutter. Atrial activation mapping revealed a slow conduction area in the low right atrium where conduction had been delayed by crista ligation. On the intact tissues between the venae cavae, double potentials were recorded, a finding indicative of functional block in the center of the reentrant circuit. The interdeflection time of double potentials changed with the activation sequence of atrial flutter. This change could be explained by assuming that the functional center of the reentrant circuit leaned on the right atrial free wall side. Anatomic study demonstrated that areas of slow conduction, unidirectional block, and functional block in the center of the reentrant circuit were closely related to the location of the intact crista terminalis. In conclusion, the intact portion of the crista terminalis played an important role in the genesis of atrial flutter after blockage of longitudinal conduction through the crista.

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.

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.