Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome.
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BACKGROUND: Loss-of-function mutations in SCN5A have been associated with the Brugada syndrome. We report the first Brugada syndrome family with compound heterozygous mutations in SCN5A. The proband inherited 1 mutation from each parent and transmitted 1 to each daughter. METHODS AND RESULTS: The effects of the mutations on the function of the sodium channel were evaluated with heterologous expression in TSA201 cells, patch-clamp study, and confocal microscopy. Genetic analysis revealed that the proband carried 2 heterozygous missense mutations (P336L and I1660V) on separate alleles. He displayed a coved-type ST-segment elevation and a prolonged PR interval (280 ms). One daughter inherited P336L and exhibited a prolonged PR (210 ms). The other daughter inherited mutation I1660V and displayed a normal PR interval. Both daughters had a slightly elevated, upsloping ST-segment elevation. The parents had normal ECGs. Patch-clamp analysis showed that the P336L mutation reduced I(Na) by 85% relative to wild type. The I1660V mutation produced little measurable current, which was rescued by room temperature incubation for 48 hours. Sodium channel blockers also rescued the I1660V current, with mexiletine proving to be the most effective. Confocal immunofluorescence showed that I1660V channels conjugated to green fluorescent protein remained trapped in intracellular organelles. CONCLUSIONS: Mutation P336L produced a reduction in cardiac I(Na), whereas I1660V abolished it. Only the proband carrying both mutations displayed the Brugada syndrome phenotype, whereas neither mutation alone produced the clinical phenotype. I1660V channels could be rescued pharmacologically and by incubation at room temperature. The present data highlight the role of compound heterozygosity in modulating the phenotypic expression and penetrance of Brugada syndrome. (+info)
Syncopal monomorphic ventricular tachycardia with pleomorphism, sensitive to antitachycardia pacing in a patient with Brugada syndrome.
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Polymorphic ventricular tachycardia and ventricular fibrillation are the most common arrhythmias in Brugada syndrome, causing syncope or sudden death. Sustained monomorphic ventricular tachycardias are rare in this context. We report the case of a 41-year-old man with repetitive syncopal episodes and an ajmaline-induced characteristic Brugada ECG pattern, in whom episodes of monomorphic ventricular tachycardia with pleomorphism and response to ventricular pacing were documented. (+info)
Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
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BACKGROUND: Brugada syndrome is an arrhythmogenic disease characterized by an increased risk of sudden cardiac death (SCD) by ventricular fibrillation. At present, an implantable cardioverter-defibrillator (ICD) is the recommended therapy in high-risk patients. This multicenter study reports the outcome of a large series of patients implanted with an ICD for Brugada syndrome. METHODS AND RESULTS: All patients (n=220, 46+/-12 years, 183 male) with a type 1 Brugada ECG pattern implanted with an ICD in 14 centers between 1993 and 2005 were investigated. ICD indication was based on resuscitated SCD (18 patients, 8%), syncope (88 patients, 40%), or positive electrophysiological study in asymptomatic patients (99 patients, 45%). The remaining 15 patients received an ICD because of a family history of SCD or nonsustained ventricular arrhythmia. During a mean follow-up of 38+/-27 months, no patient died and 18 patients (8%) had appropriate device therapy (10+/-15 shocks/patient, 26+/-33 months after implantation). The complication rate was 28%, including inappropriate shocks, which occurred in 45 patients (20%, 4+/-3 shocks/patient, 21+/-20 months after implantation). The reasons for inappropriate therapy were lead failure (19 patients), T-wave oversensing (10 patients), sinus tachycardia (10 patients), and supraventricular tachycardia (9 patients). Among implantation parameters, high defibrillation threshold, high pacing threshold, and low R-wave amplitude occurred, respectively, in 12%, 27%, and 15% of cases. CONCLUSIONS: In this large Brugada syndrome population, a low incidence of arrhythmic events was found, with an annual event rate of 2.6% during a follow-up of >3 years, in addition to a significant risk of device-related complications (8.9%/year). Inappropriate shocks were 2.5 times more frequent than appropriate ones. (+info)
Atrial electrophysiological abnormality in patients with Brugada syndrome assessed by P-wave signal-averaged ECG and programmed atrial stimulation.
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BACKGROUND: There is evidence that some patients with Brugada syndrome (BS) exhibit atrial tachyarrhythmias including paroxysmal atrial fibrillation. We investigated whether BS associated not only with vulnerability to ventricular fibrillation, but also with vulnerability to atrial fibrillation. METHODS AND RESULTS: In 15 patients with BS and Brugada-type electrocardiogram (ECG) (14 men, 1 woman; age 52.8+/-12.9 years) and 15 age-matched control patients (12 men, 3 women; age 50.9+/-18.9 years), the P-wave signal-averaged ECG was recorded, and the filtered P-wave duration was derived from the vector magnitude obtained by X, Y, Z leads. In 11 of the 15 patients with BS and Brugada-type ECG, invasive electrophysiologic testing was conducted. Filtered P-wave duration was significantly increased in patients with BS and Brugada-type ECG in comparison with control subjects (143.2+/-12.9 vs 129.6+/-10.1 ms, p<0.001). Ventricular late potential (root mean square voltage <20 muV in the last 40 ms and <40 muV at a low amplitude signal duration >38 ms) was present in 10 of the 12 BS patients in whom a QRS wave signal-averaged electrogram was also recorded. In all 11 patients with Brugada-type ECG who underwent electrophysiologic testing, sustained atrial fibrillation (>5 min) was induced by 1 or 2 atrial extrastimuli. In 10 of these 11 patients, ventricular fibrillation was also induced by 2 or 3 right ventricular extrastimuli. CONCLUSIONS: The electrical abnormality in BS is not limited to the ventricular level; similar changes occur in the atria. Such abnormal conduction properties could be a substrate for re-entrant atrial tachyarrhythmias. (+info)
Brugada-like early repolarisation pattern associated with acute pericarditis.
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Two cases of acute pericarditis presented with interesting electrocardiograms resembling Brugada-like or early repolarisation patterns. This report emphasises that proper interpretation of the electrocardiogram in patients with ST-segment elevation assists the clinician in arriving at the correct diagnosis in making appropriate diagnostic and therapeutic decisions, and also that the saddleback-type ST-segment elevation cannot be a sensitive finding for the Brugada syndrome. (+info)
Syncope due to Brugada syndrome in a young athlete.
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A 30-year-old male athlete with exercise-related syncopal symptoms spontaneously exhibited a type 1 Brugada ECG and was inducible during electrophysiology study. He was diagnosed with symptomatic Brugada syndrome and deemed at high risk of sudden cardiac death. Thus, he received a cardioverter/defibrillator and was advised to abstain from further competitive sports activities. This case points to a role of the ECG in pre-participation screening. It also demonstrates that, in athletes with Brugada syndrome, repolarisation anomalies may be markedly attenuated during vigorous exercise and considerably increased immediately after exercise. The observed J-wave amplitude dynamics suggests enhancement of pre-existing autonomic dysfunction through heavy exertion. (+info)
Brugada-like electrocardiographic changes induced by fever.
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As "time is myocardium" in the settings of acute myocardial infarction, it is important to make the diagnosis as quickly as possible, and a high clinical suspicion is needed to avoid missing the diagnosis, resulting in unwarranted interventions. The electrocardiogram is a crucial tool in the identification of acute chest pain, enabling a detailed analysis of patterns of ST-segment elevation. We describe the case of a 22-year-old man who presented with fever, with dynamic electrocardiographic changes similar to the Brugada syndrome. These electrocardiographic anomalies disappeared when the temperature returned to normal. (+info)
Different effect of the pure Na+ channel-blocker pilsicainide on the ST-segment response in the right precordial leads in patients with normal left ventricular function.
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BACKGROUND: The response of the ST-segment in the right precordial leads to Na+ channel blockers in patients without structural heart disease and a typical Brugada-type ECG has not been fully elucidated. METHODS AND RESULTS: A pilsicainide challenge test was performed in 161 patients and according to recently established ECG criteria and an organized computer algorithm, the ST morphology was classified and the maximum increase in the J wave amplitude (maxDeltaJ) from the standard and high right precordial leads V1-3 was examined. Before the test, subjects exhibiting type 1 ECG in the standard leads were excluded. After administering pilsicainide, type 1 ECGs in the standard leads were observed in 31 cases and a maxDeltaJ of >or=200 microV was observed in 29 cases (23 type 1, 2 type 2/3 and 4 normal ECGs). In the additional higher right precordial leads, type 1 ECGs were observed in 55 cases and a maxDeltaJ of >or=200 microV was observed in 45 cases (42 type 1 and 3 type 2/3 ECGs). CONCLUSIONS: A maxDeltaJ>or=200 microV induced by pilsicainide, including that measured in the high right precordial leads, was associated with a change mainly to a type 1 ECG. (+info)