BACKGROUND L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. OBJECTIVE The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. METHODS/RESULTS Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. CONCLUSION The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Cav genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

Sudden cardiac death † J wave † Brugada syndrome † Early repolarization syndrome † Cardiac arrhythmia † Ventricular fibrillation † Inherited cardiac arrhythmia syndrome The consensus conference was organized with the assistance of the Chinese Heart Rhythm Society and funded by an unrestricted educational grant from Buchang Pharmaceuticals.

To the Editor: Early repolarization, consisting of an elevation of the QRS-ST junction (J point), QRS notching or slurring (J wave), and a tall, symmetric T wave, is generally considered to be benign. 1 On the basis of preclinical experimental evidence, it has been suggested that some forms of early repolarization seen in the clinic may not be benign, especially when associated with the occasional appearance of J waves or ST-segment elevation. 2 Sporadic case reports and basic electrophysiological research have suggested a critical role of the J wave in the pathogenesis of idiopathic ventricular fibrillation. 3,4 Clinical evidence in support of an association between early repolarization and idiopathic ventricular fibrillation was previously reported in preliminary form by Haïssaguerre et al. and is fully disclosed by these researchers in this issue of the Journal. 5 However, direct evidence of a relation between early repolarization and the appearance of accentuated J waves in idiopathic ventricular fibrillation has been scarce.We evaluated the incidence of early repolarization among 1395 controls who were representative of the general population and 15 patients classified as having idiopathic ventricular fibrillation, excluding patients with long-and short-QT syndromes, the Brugada syndrome, or catecholaminergic polymorphic ventricular tachycardia. Among the 15 patients with idiopathic ventricular fibrillation, 4 presented with electrical storm (four or more episodes of ventricular fibrillation in 1 day). Continuous electrocardiographic monitoring of the patients with electrical storm was performed in the coronary care unit.The incidence of early repolarization among controls was 3.3%. In contrast, the incidence of early repolarization among patients with idiopathic ventricular fibrillation was 60% (9 of 15 patients). All four patients with idiopathic ventricular fibrillation and electrical storm had early repolarization. These four patients, whose hearts were apparently structurally normal, had a unique electrocardiographic signature consisting of a baseline early repolarization pattern; dramatic but transient accentuation of J waves across the precordial and limb leads before the development of electrical storm, which was precipitated by relatively short-coupled premature ventricular contractions; and suppression of the accentuated J waves and ventricular fibrillation with the administration of quinidine and isoproterenol and with pacing at increasingly rapid rates. In these patients with idiopathic ventricular fibrillation, unlike patients with the Brugada syndrome, the electrocardiographic and arrhythmic abnormalities could not be provoked with intravenous flecainide, were not limited to the right precordial leads, and were not accompanied by abnormalities on the signalaveraged electrocardiogram. Our observations suggest that an early-repolarization pattern is not always benign, as was previously thought, and that the transient appearance of global J waves in this setting is indicative of a highly arrhythm...

Our study provides additional evidence in support of the hypothesis that ER pattern in the ECG is not always benign. Transient augmentation of global J waves may be indicative of a highly arrhythmogenic substrate heralding multiple episodes of VF in patients with ER pattern. Ventricular tachycardia/VF initiation is more commonly associated with an SLS sequence, and PVCs display a shorter coupling interval in patients with ER pattern compared with those with BrS.

Background and Purpose— Limited data are available describing the relative effectiveness, safety, and optimal dosing of non–vitamin K antagonist oral anticoagulants (NOACs) for treatment of nonvalvular atrial fibrillation in East Asian patients. We tried to compare effectiveness and safety outcomes of standard- and low-dose NOACs and warfarin in this population. Methods— Using nationwide administrative claims-based datasets from the Korean National Health Insurance Service Database (July 1, 2015, to December 31, 2016), this study comprised 56 504 anticoagulation-naive nonvalvular atrial fibrillation patients with high thromboembolic risk (CHA 2 DS 2 -VASc score, ≥2) treated with oral anticoagulants. Main study outcomes included thromboembolic events (ischemic stroke or systemic embolism), major bleeding, and mortality. Results— Among the study patients, 10 409 (18.4%) received warfarin and 46 095 (81.6%) were treated with NOACs: dabigatran (n=12 593; 22.3%), rivaroxaban (n=21 000; 37.2%), and apixaban (n=12 502; 22.1%). Low-dose NOAC (75.1% dabigatran, 59.7% rivaroxaban, and 62.7% apixaban) was more frequently used than standard-dose NOAC. During median follow-up of 15.0 months, each NOAC was associated with significantly lower risk of thromboembolic events (hazard ratio [HR], 0.76; 95% CI, 0.75–0.81 for dabigatran; HR, 0.74; 95% CI, 0.65–0.83 for rivaroxaban; and HR, 0.68; 95% CI, 0.59–0.78 for apixaban). Regarding safety outcomes, dabigatran (HR, 0.81; CI, 0.69–0.95) and apixaban (HR, 0.67; CI, 0.56–0.79) were associated with lower risk of major bleeding but not with rivaroxaban (HR, 0.96; CI, 0.84–1.11). Among adults <75 years of age without chronic kidney disease, use of low-dose apixaban did not demonstrate clinical benefit over warfarin with respect to thromboembolic events (HR, 0.99; CI, 0.76–1.28) and mortality (HR, 0.85; CI, 0.62–1.16). Conclusions— In this cohort of East Asian patients with nonvalvular atrial fibrillation, NOACs were associated with better effectiveness and safety outcomes versus warfarin. Lower NOAC doses were more often used, but an unjustified underdosing of apixaban seems to result in lower clinical benefit.

Background: Due to the absence of differential guidelines for heart failure with tachyarrhythmia, it is difficult to diagnose tachycardia-induced cardiomyopathy (TIC) at the initial visit. Furthermore, clinical outcomes of rate versus rhythm control in TIC are unclear. Hypothesis: Because the etiology of TIC is different from dynamic cardiomyoplasty (DCMP), differential parameters may be present. Methods: We assessed 21 patients with TIC (15 men; mean age, 50 ± 14 years) and 21 control patients with idiopathic DCMP. We assessed clinical courses, echocardiographic parameters, as well as outcomes by treatment.Results: In the TIC group, the related tachyarrhythmias were atrial fibrillation (n = 12), atrial flutter (n = 5), atrial tachycardia (n = 3) and paroxysmal supraventricular tachycardia (n = 1). After treatment, all patients became asymptomatic and the ejection fraction (EF) improvement ( EF 15%) was observed in all patients (left ventricular ejection fraction [LVEF], 30 ± 11% initial versus 58 ± 6% last ). In the idiopathic DCMP group, no patient showed EF improvement (EF increase 5%), and 4 patients (19%) underwent heart transplantation. Left ventricle (LV) mass indices, volumes adjusted by BSA, and dimensions were smaller in the TIC group than in the idiopathic DCMP group. Of those, LV end-diastolic dimension was the only independent predictor of TIC in multiple regression analysis (odds ratio [OR] 0.742 per 1 mm, 95% confidence ratio [CI] 0.618 to 0.891, p = 0.001). The Association of University Cardiologists (AUC) was 0.908 on receiver-operating characteristic (ROC) curve analysis and LV end-diastolic dimension 61 mm could predict TIC with a sensitivity of 100% and a specificity of 71.4%. After restoration of sinus rhythm (n = 8), one experienced recurrent TIC after discontinuation of amiodarone. After control of heart rate (n = 13), one experienced recurrent TIC due to poor control of heart rate (log-rank test, p = 0.808). There were no differences in the echocardiographic parameters between the 2 groups before and after treatment except for the larger initial LV volumes in the rhythm control. Conclusions: In patients presented as heart failure with tachyarrhythmia, initial echocardiographic parameters, especially LV end-diastolic dimension, help to differentiate TIC from idiopathic DCMP. Rate control was as effective as rhythm control for EF improvement and prognosis.

Ventricular tachycardia (VT) is a potentially fatal tachyarrhythmia, which causes a rapid heartbeat as a result of improper electrical activity of the heart. This is a potentially life-threatening arrhythmia because it can cause low blood pressure and may lead to ventricular fibrillation, asystole, and sudden cardiac death. To prevent VT, we developed an early prediction model that can predict this event one hour before its onset using an artificial neural network (ANN) generated using 14 parameters obtained from heart rate variability (HRV) and respiratory rate variability (RRV) analysis. De-identified raw data from the monitors of patients admitted to the cardiovascular intensive care unit at Asan Medical Center between September 2013 and April 2015 were collected. The dataset consisted of 52 recordings obtained one hour prior to VT events and 52 control recordings. Two-thirds of the extracted parameters were used to train the ANN, and the remaining third was used to evaluate performance of the learned ANN. The developed VT prediction model proved its performance by achieving a sensitivity of 0.88, specificity of 0.82, and AUC of 0.93.

Background-Mutations in the ryanodine 2 receptor (RyR2) gene have been identified in patients with catecholaminergic polymorphic ventricular tachycardia. We examined the cellular basis for the ECG features and arrhythmia mechanisms using low-dose caffeine to mimic the defective calcium homeostasis encountered under these conditions. Methods and Results-A transmural ECG and action potentials were recorded simultaneously from epicardial, M, and endocardial cells in arterially perfused canine ventricular wedge preparations. Caffeine alone produced no change (10 to 100 mol/L) or a slight abbreviation (300 mol/L) of the QT interval and no change in transmural dispersion of repolarization. Isoproterenol (100 nmol/L) alone induced sustained monomorphic ventricular tachycardia (VT) that originated in the epicardium in 3 of 14 wedge preparations. Isoproterenol in the presence of caffeine (100 to 300 mol/L) induced epicardial VT in 9 of 16 wedge preparations. Delayed afterdepolarization-induced triggered beats that originated in the epicardium were associated with an increased T peak -T end interval and transmural dispersion of repolarization. Bidirectional VT developed in 11 of 16 wedge preparations as a consequence of alternation in the origin of ectopic activity between endocardial, M, and epicardial regions. Single extrastimuli delivered during sustained epicardial VT induced a rapid polymorphic VT/ventricular fibrillation (VF) in 3 of 9 wedges. Spontaneous polymorphic VT was observed in 3 of 16 preparations. Propranolol (1.0 mol/L) or verapamil (1.0 mol/L) completely suppressed ectopic activity that arose from the epicardium and prevented induction of polymorphic VT. Conclusions-Our data suggest delayed afterdepolarization-induced extrasystolic activity serves to trigger catecholamineinduced VT/VF under conditions of defective calcium handling. Epicardial origin of the ectopic beats increases transmural dispersion of repolarization, thus providing the substrate for the development of reentrant tachyarrhythmias that underlie rapid polymorphic VT/VF.