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Charles Antzelevitch

Publications and source records attributed to Charles Antzelevitch.

83 records · Page 5Linked to original sources
PubMed2002

Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome.

BACKGROUND: Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood. METHODS AND RESULTS: The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (n=14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7 plus/minus 0.9 ms/mm (controls) to 12.2 plus/minus 2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits underlying TdP. CONCLUSIONS: These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role for M cells in the development of reentrant TdP arrhythmias in LQTS.

Action Potentials↗
PubMed2002

Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.

Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST-segment elevation in leads V1-V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome. Ten families were enrolled, and screened for mutations using single-strand DNA conformation polymorphism analysis, denaturing high-performance liquid chromatography and DNA sequencing. Mutations were identified in SCN5A in three families. One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III. Analysis of these mutations in Xenopus oocytes showed that the R367H mutant channel did not express any current and the likely effect of this mutation is to depress peak current due to the loss of one functional allele. The A735V mutant expressed currents with steady state activation voltage shifted to more positive potentials. The R1192Q mutation accelerated the inactivation of the sodium channel current. Both mutations resulted in reduced sodium channel current (I(Na)) at a time corresponding to the end of phase 1 of the action potential, as described previously in the Brugada syndrome. Based upon these observations we suggest that SUNDS and Brugada syndrome are phenotypically, genetically and functionally the same disorder.

Alleles↗
PubMed2002

Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3.

BACKGROUND: The electrocardiographic pattern of right bundle-branch block with ST-segment elevation in leads V1 to V3 is increasingly recognized among patients who have aborted sudden cardiac death, but also in asymptomatic individuals, raising questions about its prognostic significance. METHODS AND RESULTS: The clinical, electrophysiological, and follow-up data of 334 patients with the Brugada phenotype were analyzed. A total of 79 women and 255 men with a mean age at diagnosis of 42+/-16 years were studied. The abnormal ECG was recognized after a resuscitated cardiac arrest in 71 patients (group A), after a syncopal episode in 73 patients (group B), and in 190 asymptomatic individuals (group C). Sustained ventricular arrhythmias were inducible in 83%, 63%, and 33% of patients in group A, group B, and group C, respectively. During 54+/-54 and 26+/-36 months of follow-up, respectively, 62% of patients in group A and 19% of group B patients had a new arrhythmic event. Inducibility of ventricular arrhythmias was the only predictor of arrhythmia occurrence in both groups. During a mean follow-up of 27+/-29 months, 8% of group C individuals had a first arrhythmic event. In these individuals, inducibility of ventricular arrhythmias and a basal abnormal ECG were predictors of arrhythmia occurrence. CONCLUSIONS: An ECG showing right bundle-branch block and ST-segment elevation in the right precordial leads is a marker of malignant ventricular arrhythmias and sudden death. Recurrence of malignant arrhythmias is high after the occurrence of symptoms. Among asymptomatic individuals, those with a spontaneously abnormal ECG and inducible to ventricular arrhythmias have the poorer prognosis.

Adult↗
PubMed2002

Novel mutations in domain I of SCN5A cause Brugada syndrome.

Brugada syndrome, an autosomal dominantly inherited form of ventricular fibrillation characterized by ST-segment elevation in leads V1-V3 and right bundle-branch block on surface electrocardiogram, is caused by mutations in the cardiac sodium channel gene SCN5A. Patients with Brugada syndrome were studied using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing of SCN5A. Mutations were identified in SCN5A in two families and one sporadic case. In one family, a missense mutation leading to a glycine to valine substitution (G351V) in the pore region between the DIS5 and DIS6 transmembrane segments was detected. Biophysical analysis demonstrated that this mutation caused significant current reduction. In the other family, a 20-bp deletion of the exon 5 splice acceptor site was identified; as exon 5 encodes part of the intracellular loop between DIS2 and DIS3, this portion of the channel is disrupted. In the sporadic patient, a missense mutation resulting in the substitution of lysine by glutamic acid (K126E) in the intracellular loop at the boundary with DIS1 was identified. These three new SCN5A mutations in Brugada syndrome patients are all located within domain I of SCN5A, a region not previously considered important in the development of ventricular arrhythmias.

Animals↗
PubMed2002

Prominent I(Ks) in epicardium and endocardium contributes to development of transmural dispersion of repolarization but protects against development of early afterdepolarizations.

INTRODUCTION: Previous studies from our laboratory demonstrated (1) a much larger I(Ks) and (2) inability to induce early afterdepolarization (EAD) activity in epicardial and endocardial cells versus M cells. This study tests the hypothesis that these two characteristics are interrelated. METHODS AND RESULTS: Standard and floating microelectrode techniques were used to record transmembrane activity from the canine left ventricular epicardial, M, and endocardial regions in isolated tissue slices and arterially perfused wedge preparations. The I(Kr) blocker E-4031 (1 to 10 microM) caused prominent prolongation of action potential duration (APD) and induced EADs in tissues isolated from the M region, but not those from epicardium or endocardium, causing a large transmural dispersion of APD. In contrast, the I(Ks) blocker chromanol 293B (10 to 30 microM) produced moderate prolongation of APD without EADs in all three tissue types. The combination of E-4031 (1 microM) and chromanol 293B (30 microM) resulted in profound prolongation of APD and the development of EADs in all three tissue types. In the perfused wedge, neither E-4031 nor chromanol 293B alone could induce EADs. In combination, the two drugs caused significant prolongation of APD and EADs in all three transmural regions. CONCLUSION: Our results support the hypothesis that a prominent I(Ks) is responsible for the ability of epicardium and endocardium to resist some but not all of the arrhythmogenic effects of I(Kr) block. The data highlight the critical importance of I(Ks) in the canine heart and the significant role of electrotonic interactions in minimizing the development of an arrhythmogenic substrate when repolarization reserve is reduced.

Action Potentials↗
PubMed2002

The Brugada syndrome.

The Brugada syndrome describes a subgroup of patients at risk for the occurrence of ventricular fibrillation who have no definable structural heart disease associated with a right bundle branch block conduction pattern and ST-segment elevation in the right precordial leads. This syndrome is caused by genetic defects in the alpha subunit of the sodium channel. This defect causes a reduction in the sodium channel current, which accentuates the epicardial action potential notch leading to ST-segment elevation. Sodium channel blockers can potentiate these findings and screen for patients with intermittent baseline electrocardiographic findings. Because of the poor prognosis of such patients, symptomatic patients should be treated with an implantable cardioverter-defibrillator.

Bundle-Branch Block↗
PubMed2002

Molecular mechanisms underlying the long QT syndrome.

Recent studies of the molecular basis of the long QT syndrome (LQTS) have advanced our understanding of the mechanisms responsible for the abnormal prolongation of ventricular repolarization and revealed associations between LQTS and other primary electrical diseases of the heart such as Brugada syndrome. The role of DNA single nucleotide polymorphisms in acquired LQTS and differences between the Romano-Ward and Jervell-Lange-Nielsen forms of congenital LQTS are gradually coming into focus. In this brief review, our goal is to summarize the molecular mechanisms proposed to underlie the susceptibility to arrhythmias in LQTS and discuss the direction of current and future research.

Family Health↗
PubMed2002

Cellular mechanisms underlying the long QT syndrome.

QT prolongation is commonly associated with life-threatening torsade de pointes arrhythmias that develop as a consequence of the amplification of electrical heterogeneities intrinsic to the ventricular myocardium. These heterogeneities exist because of differences in the time course of repolarization of the three predominant cell types that make up the ventricular myocardium, giving rise to transmural voltage gradients and a dispersion of repolarization responsible for the inscription of the electrocardiographic T wave. Agents and conditions that reduce net repolarizing current amplify the intrinsic spatial dispersion of repolarization, thus creating the substrate for the development of re-entry. The result is a prolongation of the QT interval, abnormal T waves, and development of polymorphic re-entrant ventricular tachycardia displaying characteristics of torsades de pointes. These conditions also predispose M cells and Purkinje fibers to develop early afterdepolarization-induced extrasystoles, which are thought to trigger episodes of torsades de pointes. Agents that prolong the QT interval but do not increase transmural dispersion of repolarization are not capable of inducing torsades de pointes. The available data suggest that that the principal problem with the long QT syndrome is not long QT intervals but rather the dispersion of repolarization that often accompanies prolongation of the QT interval.

Animals↗