Yukei Higashi

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-induced Long QT Syndrome

Background—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions—dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial.

AIMS Most of recurrent atrial tachyarrhythmias after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are due to reconnection of PVs. The aim of the present study was to evaluate whether elimination of adenosine triphosphate (ATP)-induced dormant PV conduction by additional energy applications during the first ablation procedure could reduce the incidence of recurrent atrial tachyarrhythmias. METHODS AND RESULTS We randomly assigned 2113 patients with paroxysmal, persistent, or long-lasting AF to either ATP-guided PVI (1112 patients) or conventional PVI (1001 patients). The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at 1 year with the blanking period of 90 days post ablation. Among patients assigned to ATP-guided PVI, 0.4 mg/kg body weight of ATP provoked dormant PV conduction in 307 patients (27.6%). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4%). At 1 year, 68.7% of patients in the ATP-guided PVI group and 67.1% of patients in the conventional PVI group were free from the primary endpoint, with no significant difference (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.74-1.09; P = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the 1-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; P = 0.16). CONCLUSION In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.

Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial

AIMS Substantial portion of early arrhythmia recurrence after catheter ablation for atrial fibrillation (AF) is considered to be due to irritability in left atrium (LA) from the ablation procedure. We sought to evaluate whether 90-day use of antiarrhythmic drug (AAD) following AF ablation could reduce the incidence of early arrhythmia recurrence and thereby promote reverse remodelling of LA, leading to improved long-term clinical outcomes. METHODS AND RESULTS A total of 2038 patients who had undergone radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF were randomly assigned to either 90-day use of Vaughan Williams class I or III AAD (1016 patients) or control (1022 patients) group. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of class I or III AAD at 1 year, following the treatment period of 90 days post ablation. Patients assigned to AAD were associated with significantly higher event-free rate from recurrent atrial tachyarrhythmias when compared with the control group during the treatment period of 90 days [59.0 and 52.1%, respectively; adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.73-0.96; P = 0.01]. However, there was no significant difference in the 1-year event-free rates from the primary endpoint between the groups (69.5 and 67.8%, respectively; adjusted HR 0.93; 95% CI 0.79-1.09; P = 0.38). CONCLUSION Short-term use of AAD for 90 days following AF ablation reduced the incidence of recurrent atrial tachyarrhythmias during the treatment period, but it did not lead to improved clinical outcomes at the later phase.

Mechanism of decrease in the atrial potential after implantation of a single-lead VDD pacemaker: atrial histological changes after implantation of a VDD pacemaker lead in dogs.

HIGASHI, Y., et al.: Mechanism of Decrease in the Atrial Potential After Implantation of a Single‐Lead VDD Pacemaker: Atrial Histological Changes After Implantation of a VDD Pacemaker Lead in Dogs. The single‐lead VDD pacemaker system (VDDPS) enables atrial synchronous ventricular pacing with only one lead in patients with an atrioventricular block. There are some cases in which the atrial potential decreases after implantation of a VDDPS, making physiological pacing difficult. The mechanism of this decrease has not been elucidated yet. To elucidate the possible relationship between the decrease of the atrial potential after implantation of a VDDPS and histopathological changes of the atrium. We implanted a VDDPS from the jugular vein under anesthesia in 10 adult dogs. The tip of the pacing lead was fixed in the right ventricular apex of the heart under fluoroscopic guidance. Then, the lead was ligated and fixed to the jugular vein at a point where a favorable atrial potential was obtained. The end of the lead was passed from the neck to the back subcutaneously; then pulled outside and fixed there to measure the atrial potential. The atrial potential was measured using a pacing system analyzer under anesthesia on days 3 (n = 9) and 7 (n = 8) , as well as on weeks2 (n = 6), 3 (n = 4), and4 (n = 3), after the implantation. The heart was removed from the dogs on day3 (n = 2), day7 (n = 2), week2 (n = 2), and week4 (n = 4)to examine the atrial histological findings. The atrial potential was2.7 ± 0.7 mVat the time of the implantation,1.7 ± 1.1 mV (P < 0.05)on day 3, and1.7 ± 0.7 mVon week 4 after the implantation. Macroscopically, the pacemaker lead was covered with thrombus, and adhered to the atrial wall in 80% of animals. Microscopically, the endocardium was hypertrophic due to fibrous tissue; besides RBC extravasation, inflammatory cells infiltration and degeneration of myocardial cells, were observed under the endocardium. Inflammatory changes developed in the atrial wall after implantation of the VDDPS, and this seemed to be one of the mechanisms for the decrease of the atrial potential of the VDDPS. (PACE 2003; 26:685–691)

High-frequency powers hidden within QRS complex as an additional predictor of lethal ventricular arrhythmias to ventricular late potential in post–myocardial infarction patients

BACKGROUND Ventricular late potentials (VLPs) have been known to be a predictor of lethal ventricular arrhythmias (L-VAs); however, detection of other arrhythmogenic signals within the QRS complex remains obscure. OBJECTIVE The aim of this study was to evaluate whether abnormal intra-QRS high-frequency powers (IQHFP) within the QRS complex become a new predictor of L-VAs in addition to VLPs. METHODS Both 12-lead electrocardiograms (ECG) and VLPs were recorded from 142 subjects, including 37 patients without heart diseases, 97 patients post-myocardial infarction (MI), and 45 post-MI patients with L-VAs. Time-frequency analysis of ECG (leads V(1) or II) using wavelet transform with the Morlet function was performed. After the time-frequency powers were calculated, the ratios of the peak of signal power during the QRS complex in high-frequency bands against the peak power at 80 Hz (b/a ratio; P100, P150, P200, P250, or P300Hz/P80Hz) were measured. Abnormal IQHFP was defined when the b/a ratio exceeded the optimal cut-off values estimated by receiver-operator characteristic curves. RESULTS The combination of abnormal IQHFP appearing at 200, 250, and 300 Hz with positive VLPs increased the sensitivity for prediction of L-VAs from 53.3% by VLPs to 89.5%, and the negative predictive value from 74.7% by VLPs to 87.7%. CONCLUSION The combined use of VLPs and IQHFP hidden within the QRS complex improved the prediction of L-VAs in post-MI patients.

Pulmonary vein isolation under direct visual identification of the left atrium—pulmonary vein junction using intra-cardiac echography

Introduction: Intra-cardiac echocardiography (ICE) which has some benefits, can be used to obtain detailed anatomy of the heart chambers or large vessels, and the catheter positions, and it has been considered useful for improving the outcome of the ablation. In the present study, we performed pulmonary vein isolation (PVI) under real time monitoring of ICE imaging utilizing an ICE catheter placed at the junction of the left atrium (LA) and PVs (LA-PV junction).Methods: PVI for atrial fibrillation (AF) was performed in 30 cases with drug-resistant AF (mean age: 66-years-old; including 22 males). An ICE catheter utilizing a 9 MHz frequency was inserted into the LA via the atrial septum, and placed at the LA-PV junction. Circumferential ablation was performed in the LA outside of the PV ostium, encircling both the superior and inferior ostia together under ICE imaging.Results: The anatomy of the LA to the PVs and catheter sites were clearly identified by the ICE during the procedure, which enabled a precise and safe catheter manipulation with minimal fluoroscopy. Further, the wall thickness of the PV and LA, and position of the esophagus could be obtained by ICE, facilitating care in adjusting the power and/or duration of the current delivery.Conclusion: ICE imaging of the LA-PV junction permitted real time monitoring of the target sites for PVI during the ablation procedure, and was considered a useful technique for performing PVI.

A Case of Transient Rise of Pacing Threshold during the Chronic Phase of Pacemaker Implantation

We experienced a case of pacing failure with transient rise of the pacing threshold more than one year after implantation. Neither the generator nor lead system was found to be defective. During the antibiotics therapy to treat cholecystitis, which was found on admission, pacing failure was improved. The clinical course suggested that the infection was related to the improvement, although accurate mechanisms were unknown.

Direct action of angiotensin II on the conduction through papillary muscle preparations of rat heart immediately after reoxygenation

We investigated the direct action of angiotensin II (Ang II) on myocardial conduction and transmembrane action potential immediately after reoxygenation.