Atsuyuki Watanabe

Atrial Fibrillation in Patients With Brugada Syndrome : Relationships of Gene Mutation, Electrophysiology, and Clinical Backgrounds

OBJECTIVES The goal of our work was to examine the relationships of atrial fibrillation (AF) with genetic, clinical, and electrophysiological backgrounds in Brugada syndrome (BrS). BACKGROUND Atrial fibrillation is often observed in patients with BrS and indicates that electrical abnormality might exist in the atrium as well as in the ventricle. SCN5A, a gene encoding the cardiac sodium channel, has been reported to be causally related to BrS. However, little is known about the relationships of atrial arrhythmias with genetic, clinical, and electrophysiological backgrounds of BrS. METHODS Seventy-three BrS patients (49 +/- 12 years of age, men/women = 72/1) were studied. The existence of SCN5A mutation and clinical variables (syncopal episode, documented ventricular fibrillation [VF], and family history of sudden death) were compared with spontaneous AF episodes. Genetic and clinical variables were also compared with electrophysiologic (EP) parameters: atrial refractory period, interatrial conduction time (CT), repetitive atrial firing, and AF induction by atrial extra-stimulus testing. RESULTS Spontaneous AF occurred in 10 (13.7%) of the BrS patients and SCN5A mutation was detected in 15 patients. Spontaneous AF was associated with higher incidence of syncopal episodes (60.0% vs. 22.2%, p < 0.03) and documented VF (40.0% vs. 14.3%, p < 0.05). SCN5A mutation was associated with prolonged CT (p < 0.03) and AF induction (p < 0.05) in EP study, but not related to the spontaneous AF episode and other clinical variables. In patients with documented VF, higher incidence of spontaneous AF (30.8% vs. 10.0%, p < 0.05), AF induction (53.8% vs. 20.0%, p < 0.03), and prolonged CT was observed. CONCLUSIONS Spontaneous AF and VF are closely linked clinically and electrophysiologically in BrS patients. Patients with spontaneous AF have more severe clinical backgrounds in BrS. SCN5A mutation is associated with electrical abnormality but not disease severity.

Longer Repolarization in the Epicardium at the Right Ventricular Outflow Tract Causes Type 1 Electrocardiogram in Patients With Brugada Syndrome

OBJECTIVES We examined the relationship between repolarization abnormality and coved-type ST-segment elevation with terminal inverted T-wave (type 1 electrocardiogram [ECG]) in patients with Brugada syndrome (BrS). BACKGROUND Recent experimental studies have suggested that accentuation of the right ventricular action potential (AP) notch preferentially prolongs epicardial AP causing inversion of the T-wave. METHODS In 19 patients with BrS and 3 control subjects, activation-recovery intervals (ARIs) and repolarization times (RTs) in the epicardium and endocardium were directly examined with the use of local unipolar electrograms at the right ventricular outflow tract. Surface ECG, ARI, and RT were examined before and after administration of pilsicainide. RESULTS Type 1 ECG was observed in 10 of the 19 BrS patients before the administration of pilsicainide and in all of the 19 patients after the administration of pilsicainide. We found that ARI and RT in the epicardium were shorter than those in the endocardium in all 9 BrS patients without type 1 ECG under baseline conditions and in all control subjects regardless of pilsicainide administration. However, longer epicardial ARI than endocardial ARI was observed in 8 of the 10 BrS patients manifesting type 1 ECG under baseline conditions and in all of the BrS patients after the administration of pilsicainide. Also, epicardial RT was longer than endocardial RT in all patients manifesting type 1 ECG regardless of pilsicainide administration. CONCLUSIONS Our data provide support for the hypothesis that the negative T-wave associated with type 1 BrS ECG is due to a preferential prolongation of the epicardial AP secondary to accentuation of the AP notch in the region of the right ventricular outflow tract.

Clinical significance of macroscopic T-wave alternans after sodium channel blocker administration in patients with Brugada syndrome.

Introduction: Macroscopic T‐wave alternans (TWA) is sometimes observed after sodium channel blocker administration in patients with Brugada syndrome (BS), but little is known about the association between occurrence of TWA and clinical characteristics in BS patients. We investigated the association between spontaneous ventricular fibrillation (VF) occurrence and TWA after pilsicainide, a sodium channel blocker administration in BS patients.

Abnormal restitution property of action potential duration and conduction delay in Brugada syndrome: both repolarization and depolarization abnormalities

AIMS This study sought to examine the action potential duration restitution (APDR) property and conduction delay in Brugada syndrome (BrS) patients. A steeply sloped APDR curve and conduction delay are known to be important determinants for the occurrence of ventricular fibrillation (VF). METHODS AND RESULTS Endocardial monophasic action potential was obtained from 39 BrS patients and 9 control subjects using the contact electrode method. Maximum slopes of the APDR curve were obtained at both the right ventricular outflow tract (RVOT) and the right ventricular apex (RVA). The onset of activation delay (OAD) after premature stimulation was examined as a marker of conduction delay. Maximum slope of the APDR curve in BrS patients was significantly steeper than that in control subjects at both the RVOT and the RVA (0.77 +/- 0.21 vs. 058 +/- 0.14 at RVOT, P = 0.009; 0.98 +/- 0.23 vs. 0.62 +/- 0.16 at RVA, P = 0.001). The dispersion of maximum slope of the APDR curve between the RVOT and the RVA was also larger in BrS patients than in control subjects. The OAD was significantly longer in BrS patients than in control subjects from the RVOT to RVA and from the RVA to RVOT (from RVOT to RVA: 256 +/- 12 vs. 243 +/- 7 ms, P = 0.003; from RVA to RVOT: 252 +/- 11 vs. 241 +/- 9 ms, P = 0.01). CONCLUSIONS Abnormal APDR properties and conduction delay were observed in BrS patients. Both repolarization and depolarization abnormalities are thought to be related to the development of VF in BrS patients.

Clinical characteristics of responders to treatment with tolvaptan in patients with acute decompensated heart failure: Importance of preserved kidney size

BACKGROUND Recent clinical trials have demonstrated the efficacy of short-term treatment with tolvaptan, an oral vasopressin V2 receptor antagonist, in patients with heart failure. However, the response to tolvaptan varies among patients. The aim of this study was to determine factors associated with response to tolvaptan in patients with acute decompensated heart failure (ADHF). METHODS The Tolvaptan Registry, a prospective, observational, multicenter cohort study performed in Japan, aims to determine factors affecting the responsiveness of tolvaptan in patients with ADHF. We enrolled ADHF patients treated with tolvaptan and they were divided into two groups: responders and non-responders. Responders were defined as subjects who met all of the following three conditions: (1) increasing urine volume during a 24-hour period after the start of tolvaptan treatment; (2) improvement in New York Heart Association functional class; and (3) decrease in cardiothoracic ratio assessed by chest X-ray on day 3 of tolvaptan administration. RESULTS Among the 114 patients, treatment with tolvaptan improved three conditions of heart failure in more than half of all the cohorts (71 patients, 62%). As for baseline characteristics, estimated glomerular filtration rate, urine osmolality, and kidney size were significantly greater in responders than in non-responders. Multivariate logistic analysis revealed that kidney size was independently associated with responders (odds ratio: 1.083, p=0.001, 95% confidence interval 1.031-1.137). CONCLUSIONS The main clinical characteristic of responders to treatment with tolvaptan is that kidney size is preserved.

Comparison of longevity and clinical outcomes of implantable cardioverter-defibrillator leads among manufacturers

BACKGROUND An early failure of the Biotronik Linox S/SD implantable cardioverter-defibrillator (ICD) lead has been reported. We have also experienced several cases with early failure of Linox leads. OBJECTIVE Our aim was to assess the longevity of Linox S/SD (Biotronik, Berlin, Germany) compared with Sprint Fidelis (Medtronic, Minneapolis, MN), Sprint Quattro (Medtronic), and Endotak Reliance (Boston Scientific, Natick, Massachusetts) leads. METHODS We retrospectively reviewed patients who had undergone implantation of Linox S/SD (n = 90), Sprint Fidelis (n = 37), Sprint Quattro (n = 27), or Endotak Reliance (n = 50) leads between June 2000 and December 2013 at our hospital. Variables associated with lead failure were assessed by the Kaplan-Meier method and Cox survival modeling. RESULTS Failure rates of Linox, Sprint Fidelis, and Endotak leads were 3.2%/year (7-year survival rate, 81.0%), 3.4%/year (7-year survival rate, 77.2%), and 0.61%/year (7-year survival rate, 95.8%), respectively. No lead failure was found with Sprint Quattro leads. The survival probability of Linox leads was significantly lower than that of Endotak leads (P = .049) and comparable to that of Sprint Fidelis leads (P = .69). In univariate analysis, age was the only predictor of Linox lead failure. Patients <58 years old were at significantly increased risk of lead failure compared with patients ≥58 years old (hazard ratio, 9.0; 95% confidence interval, 1.13-71.3; P = .037). CONCLUSION In our single-center experience, the survival rate of Linox leads was unacceptably low. The only predictor of Linox lead failure was age at implantation. This is the first description of a lower survival rate for Linox leads in an Asian population.

Left atrial thrombus formation and resolution during dabigatran therapy: A Japanese Heart Rhythm Society report

Protocols on the use of novel oral anticoagulants for stroke prevention in patients with atrial fibrillation (AF) undergoing electrical cardioversion (ECV) are lacking.

Distribution and prognostic significance of fragmented QRS in patients with brugada syndrome

Background— Fragmented QRS complexes (fQRS) in the right precordial leads are associated with occurrence of ventricular fibrillation (VF) in Brugada syndrome. Recently, epicardial mapping has revealed abnormal electrograms at the right ventricular (RV) outflow tract and inferior region of the right ventricle. fQRS may reflect the extent of the area of abnormal potentials, but whether the distribution of fQRS has prognostic value is not known. Methods and Results— We evaluated the existence of fQRS in 456 patients with Brugada syndrome, including 117 patients with syncope and 23 patients with VF. The region of fQRS was defined as inferior (II, III, and aVF), lateral (I, aVL, and V5 and V6), anterior (V3 and V4), RV (V1 and V2), and RV outflow tract (V1 and V2 at the third intercostal space). fQRS were present in 229 patients (RV outflow tract in 175, inferior in 135, RV in 90, and lateral in 16 patients). During follow-up (mean 91 months), 39 patients experienced VF. In univariable analyses, fQRS in any distribution and fQRS in each region excluding the RV were associated with VF. Multivariable analysis showed that fQRS in the inferior (hazard ratio, 3.9; confidence interval, 1.9–8.5), lateral (hazard ratio, 3.5; confidence interval, 1.2–8.2), and RV outflow tract (hazard ratio, 2.5; confidence interval, 1.2–5.6) were associated with VF events. The presence of multiple regions of fQRS was associated with worse prognosis. Conclusions— The distribution of fQRS is associated with prognosis in Brugada syndrome, further supporting the association of fQRS and arrhythmia substrate.

Identification of electrocardiographic risk markers for the initial and recurrent episodes of ventricular fibrillation in patients with Brugada syndrome

New onset of ventricular fibrillation (VF) in asymptomatic patients with Brugada‐type ECG is not frequent, but it cannot be negligible. Risk markers for predicting VF are usually based on results of analysis in symptomatic patients, and they have not been determined for asymptomatic patients. We analyzed ECG markers in patients with Brugada syndrome to differentiate the risk factors for VF in both symptomatic and asymptomatic patients.

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost) -incorporated nanoparticles and imatinib (a PDGF-receptor tyrosine kinase inhibitor) -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of pulmonary arterial hypertension (PAH) and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for the treatment of PAH.