Atul Bhatia

Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

Background— Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results— Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Cav&bgr;2b), CACNA2D1 (Cav&agr;2&dgr;1), and CACNA1C tagged with enhanced yellow fluorescent protein (Cav1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals ≤360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the &agr;1- and &bgr;2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Cav1.2 channels but normal trafficking of channels containing G490R Cav1.2 or S481L Cav&bgr;2b-subunits. Conclusions— This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome

BACKGROUND BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart. OBJECTIVES The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

Computed Tomography‐Fluoroscopy Image Integration‐Guided Catheter Ablation of Atrial Fibrillation

Introduction: This study examines the feasibility of atrial fibrillation (AF) ablation using registered three‐dimensional computed tomography (CT) images of the left atrium with fluoroscopy.

Electroanatomically Guided Catheter Ablation of Ventricular Tachycardias Causing Multiple Defibrillator Shocks

SRA, J., et al.: Electroanatomically Guided Catheter Ablation of Ventricular Tachycardias Causing Multiple Defibrillator Shocks. With conventional techniques, RF catheter ablation is difficult in patients with unstable VT or with multiple VTs. The feasibility of RF catheter ablation guided by three‐dimensional electroanatomic mapping technique in patients whose implanted ICD continued to deliver multiple shocks due to VT despite use of antiarrhythmic medications was assessed in 19 patients (15 men, 4 women; mean age [± SD] 70 ± 7 years). All had a prior history of MI and subsequently had received an ICD due to VT. During the 12‐week preablation period, these patients received 31 ± 15 shocks (range 4–62 shocks) due to refractory monomorphic VTs. An electroanatomic mapping technique using the CARTO system was performed to delineate scar tissue. RF catheter ablation was then performed at appropriate sites identified by pacemapping and by substrate mapping. Seventeen patients were on amiodarone at the time of ablation. Twenty‐seven VTs were documented clinically, and 45 were induced during electrophysiological evaluation. Of the 45 tachycardias induced, 38 VTs were targeted for ablation. Catheter ablation was performed during sinus rhythm in 31 episodes and during VT in 7 episodes. During a mean follow‐up of 26 ± 8 weeks (range 18–48 weeks), 13 (66%) patients had no recurrence of VT (P < 0.0001) and antiarrhythmic drugs were discontinued or the number of medications reduced in 17 patients (P < 0.0001). Electroanatomic mapping is helpful in identifying sites for catheter ablation in highly symptomatic patients with refractory VT associated with myocardial scarring.

Periprocedural anticoagulation for atrial fibrillation ablation.

Background: Catheter ablation for atrial fibrillation (AF) can increase risk of left atrial (LA) thrombi and stroke. Optimal periprocedural anticoagulation has not been determined.

Noncontact Mapping for Radiofrequency Ablation of Complex Cardiac Arrhythmias

Radiofrequency (RF) catheter ablation is the current treatment of choice for several cardiac arrhythmias. The conventional approach utilizing intracardiac electrograms during sinus rhythm and during tachycardia has inherent limitations, including limited two-dimensional fluoroscopic imaging and limited ability to evaluate several potential sites for ablation then go precisely to the most suitable site. Recently, a noncontact mapping system has been developed that can be used to perform single beat high resolution mapping of cardiac arrhythmias. In this report, we describe the advantage of utilizing the system in facilitating a successful outcome in 5 patients with different complex arrhythmias.

Driving safety among patients with neurocardiogenic (vasovagal) syncope.

The purpose of this study was to evaluate the risk of injury due to syncope while driving and the driving habits of patients with neurocardiogenic (vasovagal) syncope. Neurocardiogenic syncope is one of the most common causes of syncope. However, the important issue of driving related injury due to syncope in this population is not well defined. Risk of injury due to syncope while driving and driving behavior was evaluated in 155 consecutive patients (92 women and 63 men; mean age 49 ± 19 years) with history of syncope in whom hypotension and syncope or presyncope could be provoked during head‐up tilt testing. Patients with syncope and positive head‐up tilt table test were treated with pharmacological therapy. All participants were asked to fill out a detailed questionnaire regarding any driving related injuries and their driving behavior before tilt table testing and during follow‐up. Prior to head‐up tilt testing two patients had syncope while driving, and one of these patients had syncope related injury during driving. The mean duration of syncopal episodes was 50 ± 14 months (range 12–72 months). Of the 155 patients, 52 (34%) had no warning prior to syncope, while 103 (6%) had warning symptoms such as dizziness prior to their clinical syncope. Following a diagnosis of neurocardiogenic syncope established by head‐up tilt testing, six patients stopped driving on their own. During a median follow‐up of 22 months recurrent syncope occurred in five (3.2%) patients. No patient had syncope or injury during driving. In conclusion, syncope and injury while driving in patients with neurocardiogenic syncope is rare. The precise mechanism of this is unclear but may be related to posture during driving. Consensus among the medical community will be needed to provide specific guidelines in these patients.

Electroanatomic Mapping to Identify Breakthrough Sites in Recurrent Typical Human Flutter

SRA, J., et al.: Electroanatomic Mapping to Identify Breakthrough Sites in Recurrent Typical Human Flutter. The accuracy of conventional techniques in localizing previous radiofrequency (RF) ablation sites and thus breakthrough sites of recurrent atrial flutter is somewhat limited. We investigated the role of electroanatomic mapping for identifying breakthrough sites or “gaps” at the tricuspid annulus and inferior vena cava (IVC)/eustachian ridge isthmus to help RF ablation in patients with recurrent typical flutter. Twelve patients (8 men, 4 women, age 63 ± 10 years) with recurrent typical atrial flutter were included in the study. An electroanatomic mapping system (CARTO) was used to create a voltage map and activation and propagation patterns in the right atrium. Detailed voltage, activation, and propagation mapping of the tricuspid annulus and IVC/eustachian ridge isthmus allowed precise identification of gaps in all 12 patients at the tricuspid annulus (eight sites), IVC ridges (two sites), mid‐isthmus region (one site), and tricuspid annulus and IVC ridges (one site). Radiofrequency energy directed at these sites eliminated atrial flutter in all 12 patients, confirmed by noninducibility of atrial flutter and demonstration of conduction block during atrial pacing on either side of the lesion lines. During a mean follow‐up of 14.8 ± 3.5 months (range 8–19 months), paroxysmal atrial flutter recurred in only one patient and was subsequently treated with amiodarone, although this had been ineffective prior to ablation. Electroanatomic mapping can precisely identify gaps in the lesion line responsible for breakthrough of recurrent typical atrial flutter at the tricuspid annulus and at the IVC/eustachian ridge isthmus. These sites can be targeted with RF ablation with a high degree of success.

Endocardial noncontact activation mapping of idiopathic left ventricular tachycardia.

Mapping of Idiopathic Ventricular Tachycardia. Idiopathic left ventricular tachycardia with a right bundle, left‐axis deviation is thought to originate from posterior fascicles. Recently, there has been considerable interest in the anatomic and mechanistic basis of this arrhythmia. We report our experience with a 26‐year‐old man in whom new noncontact mapping technology was used to acquire detailed data from the left ventricle, identify the mid‐diastolic potential and part of the ventricular tachycardia circuit, and perform successful ablation. This information helped define the physiologic aspects of this unique tachycardia.

Biventricular Pacing and QT Interval Prolongation

Introduction: The purpose of this study was to examine BiV pacing‐dependent changes in QT interval and the related potential for proarrhythmia. Biventricular (BiV) pacing has emerged as a promising therapy for patients with advanced congestive heart failure (CHF) and bundle branch block (BBB).