Kimie Ohkubo

Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization

Background— Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear. Methods and Results— This study included 50 patients (44 men; age, 45±17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels. Conclusions— We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

Impact of Biomarkers of Inflammation and Extracellular Matrix Turnover on the Outcome of Atrial Fibrillation Ablation: Importance of Matrix Metalloproteinase‐2 as a Predictor of Atrial Fibrillation Recurrence

MMP‐2 Predicts the Outcome of AF Ablation. Introduction: Although catheter ablation can effectively eliminate atrial fibrillation (AF), the progression of atrial remodeling increases the risk of recurrence. AF is associated with inflammation and subsequent myocardial fibrosis. We therefore examined the possibility of determining the postablation prognosis of patients with AF using biomarkers of inflammation and collagen turnover.

Programmed ventricular stimulation for risk stratification in the Brugada syndrome: A pooled analysis

Background— The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results— We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44–4.92, P<0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05–0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01–2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58–3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98–9.58 for induced arrhythmia). Conclusions— In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.

Does Location of Epicardial Adipose Tissue Correspond to Endocardial High Dominant Frequency or Complex Fractionated Atrial Electrogram Sites During Atrial Fibrillation

Background— Although increased epicardial adipose tissue (EAT) volume is known to be associated with increased prevalence of atrial fibrillation (AF), the exact mechanisms are unclear. Therefore, we investigated whether EAT locations were associated with high dominant frequency (DF) sites or complicated fractionated atrial electrogram sites during AF. Methods and Results— Three-dimensional reconstruction computed tomography images depicting EAT volumes (obtained by 320-detector-row multislice computed tomography) were merged with NavX-based DF and complicated fractionated atrial electrogram maps obtained during AF for 16 patients with paroxysmal AF and for 18 patients with persistent AF. Agreement between locations of the EAT, especially EAT surrounding the left atrium, and of high DF or complicated fractionated atrial electrogram sites was quantified. In addition, serum biomarker levels were determined. EAT surrounding the left atrium volumes was significantly greater in patients with persistent AF than in patients with paroxysmal AF (52.9 cm3 [95% CI, 44.2–61.5] versus 34.8 cm3 [95% CI, 26.6–43.0]; P=0.007). Serum high-sensitivity C-reactive protein and interleukin-6 levels were significantly higher in persistent AF patients than in paroxysmal AF patients (median high-sensitivity C-reactive protein, 969 ng/mL [interquartile range, 307–1678] versus 320 ng/mL [interquartile range, 120–660]; P=0.008; median interleukin-6, 2.4 pg/mL [interquartile range, 1.7–3.2] versus 1.3 [interquartile range, 0.8–2.4] pg/mL; P=0.017). EAT locations were in excellent agreement with high DF sites (&kgr;=0.77 [95% CI, 0.71–0.82]) but in poor agreement with complicated fractionated atrial electrogram sites (&kgr;=0.22 [95% CI, 0.13–0.31]). Conclusions— Increased EAT volume and elevation of inflammatory biomarkers are noted in persistent AF rather than paroxysmal AF patients. High DF sites are located adjacent to EAT sites. Thus, EAT may be involved in the maintenance of AF.

Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics

Background—Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results—We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). Conclusions—The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.

Prediction of the efficacy of pulmonary vein isolation for the treatment of atrial fibrillation by the signal-averaged P-wave duration

Background: The noninvasive methods for predicting a successful pulmonary vein isolation (PVI) have not been well described. The aim of this study was to assess the usefulness of the P‐wave signal‐averaged electrocardiogram (P‐SAECG) in predicting the chance of a successful PVI in patients with atrial fibrillation (AF).

Intravenous Administration of Class I Antiarrhythmic Drug Induced T Wave Alternans in an Asymptomatic Brugada Syndrome Patient

A 53‐year‐old man with an abnormal ECG was referred to the Nihon University School of Medicine. The 12‐lead ECG showed right bundle branch block and saddleback‐type ST elevation in leads V1–V3 (Brugada‐type ECG). Signal‐averaged ECG showed positive late potentials. Double ventricular extrastimuli (S1: 500 ms, S2: 250 ms, S3: 210 ms) induced VF. Amiodarone (200 mg/day) was administered for 6 months and programmed ventricular stimulation was repeated. VF was induced again by double ventricular stimuli (S1: 600 ms, S2: 240 ms, S3: 170 ms). Intravenous administration of class Ic antiarrhythmic drug, pilsicainide (1 mg/kg), augmented ST‐T elevation in leads V1–V3, and visible ST‐T alternans that was enhanced by atrial pacing was observed in leads V2 and V3. Visible ST‐T wave alternans disappeared in 15 minutes. However, microvolt T wave alternans was present during atrial pacing at a rate of 70/min without visible ST‐T alternans. (PACE 2003; 26:1900–1903)

Differential Pacing for Distinguishing Slow Conduction from Complete Conduction Block of the Tricuspid-Inferior Vena Cava Isthmus after Radiofrequency Ablation for Atrial Flutter—Role of Transverse Conduction through the Crista Terminalis

Background: Partial conduction block has been suggested a predictor of recurrence of atrial flutter (AFL).Aim: The aim of this study was to assess transverse conduction by the crista terminalis (CT) as a problem in evaluating isthmus block and the usefulness of differential pacing for distinguishing slow conduction (SC) and complete conduction block (CB) across the ablation line.Methods: We assessed 14 patients who underwent radiofrequency catheter ablation of the eustachian valve/ridge–tricuspid valve isthmus for typical AFL. Activation patterns along the tricuspid annulus (TA) suggested incomplete CB across the isthmus. In these patients, atrial pacing was performed from the low posteroseptal (PS) and anteroseptal (AS) right atrium (RA) while the ablation catheter was placed at the ablation line where double potentials (DPs) could be recorded. The pattern of activation of the RA free wall was assessed by a 20-pole catheter positioned along the CT during pacing from the coronary sinus (CS) ostium (CSos) and low lateral RA (LLRA).Results: Faster transverse conduction across the CT resulted in simultaneous or earlier activation of the distal halo electrodes than of the more proximal electrodes, suggesting incomplete conduction block across the isthmus. CB (13) and SC (1) were detected as changes in the activation times of the first and second components of DPs (DP1, DP2) during PS RA pacing and AS RA. Similar changes in the activation times DP1 and DP2 during AS RA pacing as compared to PS RA reflected SC through the isthmus, whereas increased DP1 activation time and decreased of DP2 activation time reflected complete conduction block across the isthmus.Conclusions: Transverse conduction across the CT influences the sequence of activation along the TA after isthmus ablation. Differential pacing can distinguish SC from complete conduction block across the ablation line in the isthmus.

A Nonsynonymous Polymorphism in Semaphorin 3A as a Risk Factor for Human Unexplained Cardiac Arrest with Documented Ventricular Fibrillation

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67–5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A I334V, VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A I334V (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A I334V. Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A I334V genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A I334V in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.

Relation Between Left Atrial Wall Thickness in Patients with Atrial Fibrillation and Intracardiac Electrogram Characteristics and ATP-Provoked Dormant Pulmonary Vein Conduction

Atrial remodeling plays a key role in development of the substrate for atrial fibrillation (AF). Whether the wall thicknesses of the left atrium (LA) and pulmonary vein (PV)–LA junction affect remodeling and AF ablation is unknown. We investigated the relationship between wall thicknesses, electrogram characteristics, and adenosine triphosphate (ATP)‐provoked dormant PV conduction as they pertain to AF.