Noriyuki Hayami

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.

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

BACKGROUND Atrial 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. METHODS AND RESULTS To 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. CONCLUSIONS Even 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.

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.

His‐Bundle Parasystole Masquerading as Exercise‐Induced 2:1 Atrioventricular Block

His‐Bundle Parasystole. We describe a case of symptomatic pseudo‐AV block due to His‐bundle parasystole masquerading as exercise‐induced 2:1 AV block. Electrophysiologic study revealed the presence of His‐bundle parasystole, and the fluctuation of parasystolic cycle length could be explained by the concept of modulated parasystole. Modulated parasystole is a possible explanation for maintenance of stable 2:1 AV conduction at an atrial rate of specific range during exercise.

Successful Treatment of Refractory Electrical Storm With Landiolol After More Than 100 Electrical Defibrillations

Electrical storm (ES) was observed in an 82-year-old man with recent myocardial infarction. Conventional therapy, including amiodarone, could not suppress the ES. After more than 100 electrical defibrillations, we were finally able to control the ES with the administration of landiolol. It is known that landiolol can inhibit ES. However, we hesitate to use landiolol in patients with low cardiac output. We would like to emphasize that careful use of landiolol should be considered in patients with refractory ES after myocardial infarction, although cardiac output is severely reduced.

Surgically repaired delayed mitral regurgitation after radiofrequency catheter ablation for Wolff-Parkinson-White syndrome

OHTSUKA, T., et al.: Surgically Repaired Delayed Mitral Regurgitation After Radiofrequency Catheter Ablation for Wolff‐Parkinson‐White Syndrome. This report describes a male patient with WPW syndrome who underwent surgical repair of sudden, severe mitral valve regurgitation through the posterior leaflet 20 months after successful RF catheter ablation for Kent bundle at the age of 14, and discusses the problem of valvular damage caused by this technique.

No Additional Effect of DPP-4 Inhibitor on Preventing Atrial Fibrosis in Streptozotocin-Induced Diabetic Rat as Compared With Sulfonylurea

Chronic inflammation is known to occur in diabetes mellitus (DM) and contributes to atrial fibrosis, possible substrates for atrial fibrillation. We tested the hypothesis that dipeptidyl peptidase (DPP)-4 inhibitors prevent the formation of atrial fibrosis through their anti-inflammatory activity, beyond the effects of controlling blood glucose.DM models obtained by administration of streptozotocin (STZ) were divided into 3 groups: with PKF275-055, a DPP-4 inhibitor in group D, glibenclamide in group SU, and no additional drug in group P. At 8 weeks after STZ administration, the heart was subjected to Masson trichrome staining and immunohistochemistry with anti-ED2, ED3, and smooth muscle actin antibody.The % area of fibrosis in atria of group P accounted for 14.7% ± 4.1%, showing a significant increase in fibrosis when compared with the control group. In group SU, the % area accounted for 7.9% ± 2.9%, indicating significant deceased fibrosis by sulfonylurea. Meanwhile, we could not find significant differences in group D when compared to group P or group SU. While ED3-positive cells increased in group P (1.12% ± 0.24%), they were significantly decreased in groups D and SU (0.41% ± 0.22% and 0.55% ± 0.29%, respectively). Between group D and SU, however, there were no significant differences in the amount of cells positive to ED2, ED3, and smooth muscle actin antibodies.In STZ-induced DM rats, administration of sulfonylurea and DPP-4 inhibitors inhibited inflammation and fibrosis of the atria. However, no significant differences were observed between the 2 antidiabetic drugs.

Importance of Pulmonary Vein Preferential Fibrosis for Atrial Fibrillation Promotion in Hypertensive Rat Hearts.

BACKGROUND Hypertension is one of the independent risk factors for atrial fibrillation (AF). Pulmonary veins (PVs) play an important role as the substrate for AF and triggers of AF. The purpose of this study was to determine the structural remodelling of the PVs and its effect on promoting AF in hypertensive (HT) rat hearts. METHODS Eighteen-week-old Dahl salt-sensitive HT rats and their controls were used for histological and immunohistological analyses, and electrophysiological studies were performed in Langendorff perfused hearts. RESULTS Masson-trichrome staining revealed that hypertension significantly increased the fibrosis in the PVs, particularly in subendocardial and perivascular areas, compared with that in control rats, however, at this early stage of hypertension, left atrial fibrosis was not prominent. In the HT rat hearts with PVs, electrical stimulation significantly increased the number of repetitive atrial firing and atrial tachycardia inducibility, which significantly diminished after the excision of the PVs. An immunofluorescent analysis revealed that HT rats had PV specific endocardial smooth muscle actin (αSMA)-positive cells with remarkable proliferation of platelet-derived growth factor (PDGF)-C and vascular endothelial growth factor (VEGF), which was lacking in the left atrial structures of the control and the HT rats. Pretreatment with imatinib, a PDGF receptor activity blocker, in HT rats reduced the αSMA-positive cell proliferation and fibrosis in the PVs and also induced a significant reduction in VEGF expression. Also, the drug pretreatment effectively prevented repetitive atrial firing promotion without affecting the blood pressure. CONCLUSIONS PV preferential fibrosis might play an important role in the arrhythmogenic substrate of AF in HT rat hearts.

Site of the Arrhythmogenic Focus and Cardiac Vulnerability to Ventricular Fibrillation

MURAKAWA, Y., et al.: Site of the Arrhythmogenic Focus and Cardiac Vulnerability to Ventricular Fib‐rillation. The aim of this study was to test the hypothesis that a subendocardial arrhythmogenic focus makes the heart more susceptible to VF due to electrical interaction with the Purkinje network. Monofocal ventricular tachycardia (mVT) was created by injecting 5‐μg aconitine into the left ventricular subepicardium (EPI‐mVT, n = 8) or subendocardium (ENDO‐mVT, n = 13) in anesthetized dogs. Despite the similar cycle length of mVT, the incidence of VF was significantly different between EPI‐mVT and ENDO‐mVT (100 [8/8] vs 46% [6/13], P < 0.05). VF was invariably preceded by hemodynamic deterioration. Three‐dimensional cardiac mapping (n = 10, 221 ± 11 recording sites) revealed that VF was triggered solely by focal firing unrelated to the primary arrhythmogenic focus in both mVT models. No interaction between the primary focus and adjacent endocardial tissue was indicated. These results suggest that the proximity of the arrhythmogenic focus to the Purkinje network has little role in cardiac vulnerability to VF, and that progression of mVT to VF is largely caused by sporadic focal firing regardless of the site of the arrhythmogenic focus in the present animal model.

Hydralazine inhibits ventricular tachyarrhythmias in an acquired long QT rabbit model

Some cardioactive vasodilating agents inhibit ventricular tachyarrhythmias (VT) associated with acquired long QT syndrome (LQT). We tested whether a vasodilator without direct cardiac effect can eliminate abnormal repolarization‐related VT.