ABSTRACT
BACKGROUND: Long QT syndrome (LQT) is a pro-arrhythmogenic condition with life-threatening complications. Fifteen genes have been associated with congenital LQT, however, the genetic causes remain unknown in more than 20% of cases. MATERIALS AND METHODS: Eighteen patients with history of palpitations, pre-syncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole-exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from 16 subjects with no identifiable cause of LQT. RESULTS: Deleterious and novel SCN10A mutations were identified in 3 of the 16 patients (19%) with idiopathic LQT. These included 2 frameshifts and 1 missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified 2 damaging SCN10A mutations with allele frequencies of approximately 0.2% (p.R14L and p.R1268Q) in 2 independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H and p.R485C) were also identified in the 2 subjects on QT prolonging medications. CONCLUSION: Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss-of-function as the underlying disease mechanism. The common association with atrial fibrillation suggests a unique mechanism of disease for this LQT gene.
Subject(s)
Arrhythmias, Cardiac/genetics , Long QT Syndrome/genetics , NAV1.8 Voltage-Gated Sodium Channel/genetics , Syncope/genetics , Adult , Aged , Arrhythmias, Cardiac/physiopathology , DNA Mutational Analysis , Female , Frameshift Mutation , Gene Frequency , Genetic Predisposition to Disease , Genetic Testing , Humans , Long QT Syndrome/physiopathology , Male , Middle Aged , Pedigree , Phenotype , Syncope/physiopathologyABSTRACT
OBJECTIVES: This study assessed the coexistence of intra-atrial re-entrant tachycardia (IART) and isthmus-dependent atrial flutter (IDAF) in patients presenting with supraventricular tachyarrhythmias after surgical correction of congenital heart disease (CHD). BACKGROUND: In patients with CHD, atrial tachyarrhythmias may result from IART or IDAF. The frequency with which IART and IDAF coexist is not well defined. METHODS: Both IDAF and IART were diagnosed in 16 consecutive patients using standard criteria and entrainment mapping. Seven patients had classic atrial flutter morphology on surface electrocardiogram (ECG), whereas nine had atypical morphology. RESULTS: A total of 24 circuits were identified. Three patients had IDAF only, five had IART only, seven had both, and one had a low right atrial wall tachycardia that could not be entrained. Twenty-two different reentry circuits were ablated. Successful ablation was accomplished in 13 of 14 (93%) IART and 9 of 10 (90%) IDAF circuits. There was one IART recurrence. The slow conduction zone involved the region of the right atriotomy scar in 12 of 14 (86%) IART circuits. No procedural complications and no further recurrences were seen after a mean follow-up of 24 months. CONCLUSIONS: Both IDAF and IART are the most common mechanisms of atrial re-entrant tachyarrhythmias in patients with surgically corrected CHD, and they frequently coexist. The surface ECG is a poor tool for identifying patients with coexistent arrhythmias. The majority of IART circuits involve the lateral right atrium and may be successfully ablated by creating a lesion extending to the inferior vena cava.
Subject(s)
Atrial Flutter/diagnosis , Heart Defects, Congenital/complications , Tachycardia, Supraventricular/diagnosis , Adolescent , Adult , Aged , Atrial Flutter/complications , Atrial Flutter/epidemiology , Catheter Ablation , Child , Electrocardiography , Electrophysiologic Techniques, Cardiac , Female , Fluoroscopy , Follow-Up Studies , Heart Defects, Congenital/diagnostic imaging , Heart Defects, Congenital/surgery , Humans , Male , Middle Aged , Prevalence , Recurrence , Tachycardia, Supraventricular/complications , Tachycardia, Supraventricular/epidemiologyABSTRACT
BACKGROUND: We hypothesized that frequency domain analysis of a wide bipolar interatrial electrogram describes the global organization of atrial fibrillation (AF) and should vary over time. By timing shocks to periods of high organization of AF, cardioversion efficacy should improve. METHODS AND RESULTS: A total of 15 dogs (weight, 28.2+/-3.4 kg) were rapidly paced for 48 to 72 hours to induce AF. Coil electrodes with a surface area of 1.80 cm(2) were then placed in the left and right atria to form a wide bipole. Wide bipolar electrograms were digitally filtered, and a fast Fourier transform was performed over a sliding 2-s window every 0.5 s. The organization index (OI) was calculated as the ratio of the area of the dominant peak and its harmonics to the total area of the magnitude spectrum. The atrial defibrillation threshold (ADFT(50)) was determined using a 3-ms/3-ms biphasic shock and an up-down-up protocol. Additional shocks with higher and lower energies were delivered in a random sequence to develop a distribution curve. The OI varied over time, with a mean of 0.42+/-0.03, a maximum of 0.65+/-0.07, and a minimum of 0.20+/-0.06. The OI changed rapidly, with durations of high organization (OI>0.5) ranging from 1 to 5 s. The ADFT(50) for QRS complex-synchronized shocks was 183+/-56 V, versus 142+/-49 V for shocks synchronized to an OI>0.5 (P<0.001). The distribution curve shifted leftward when shocks were synchronized to an OI>0.5. CONCLUSIONS: AF signals show a high degree of variability. Shock efficacy is increased when shocks are delivered during periods of high AF organization as determined by the OI method.
