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Charles Antzelevitch

Publications and source records attributed to Charles Antzelevitch.

At least 37 records · Page 2Linked to original sources
PubMed2005

Brugada syndrome.

The Brugada syndrome is an autosomal dominant disease with incomplete penetrance that may cause syncope and sudden cardiac death in young individuals with a normal heart. It is characterized by an electrocardiographic pattern of complete or incomplete right bundle branch block and ST segment elevation in leads V1-V3. One of the genes linked to this syndrome is SCN5A, the gene encoding for the cardiac sodium channel. Mutations in SCN5A cause a functional reduction in the availability of cardiac sodium current in Brugada syndrome. However, only 20-25% of patients affected by this syndrome have mutations on this gene. A novel gene locus on chromosome 3, distinct from SCN5A, has been identified recently. The relative male preponderance of the phenotype, despite equal inheritance of the gene in males and females, has led to the speculation of a role for testosterone in the phenotype. The disease could manifest at first time as cardiac arrest without any previous symptom, and the electrocardiographic pattern could be intermittent, requiring a pharmacological challenge with Class I antiarrhythmic drugs to unmask ST elevation. Several conditions producing Brugada-like electrocardiographic patterns should be borne in mind and excluded while making a diagnosis of the Brugada syndrome. The management is difficult as pharmacological agents are not universally effective. The mode of treatment recommended by the majority of cardiac electrophysiologists is the implantation of a cardioverter defibrillator. Symptomatic patients with inducible ventricular arrhythmias and a positive family history should be considered for prophylactic implantation of a cardioverter defibrillator.

Bundle-Branch Block↗
PubMed2005

Cellular mechanisms underlying the development of catecholaminergic ventricular tachycardia.

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 micromol/L) or a slight abbreviation (300 micromol/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 micromol/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 Tpeak-Tend 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 micromol/L) or verapamil (1.0 micromol/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 catecholamine-induced 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.

Action Potentials↗
PubMed2005

Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Brugada syndrome: from cell to bedside.

Since its introduction as a new clinical entity in 1992, the Brugada syndrome has attracted great interest because of its high incidence in many parts of the world and its association with high risk for sudden death in infants, children, and young adults. Recent years have witnessed an exponential rise in the number of reported cases and a striking proliferation of articles serving to define the clinical, genetic, cellular, ionic, and molecular aspects of the disease. A consensus report published in 2002 delineated diagnostic criteria for the syndrome. A second consensus conference was held in September 2003. This review provides an in-depth overview of the clinical, genetic, molecular, and cellular aspects of the Brugada syndrome, incorporating the results of the two consensus conferences, and the numerous clinical and basic publications on the subject. The proposed terminology, diagnostic criteria, risk stratification schemes, and device and pharmacologic approach to therapy discussed are based on available clinical and basic studies and should be considered a work-in-progress that will without doubt require fine-tuning as confirmatory data from molecular studies and prospective trials become available.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Cardiac repolarization. The long and short of it.

Heterogeneity of transmural ventricular repolarization in the heart has been linked to a variety of arrhythmic manifestations. Electrical heterogeneity in ventricular myocardium is due to ionic distinctions among the three principal cell types: Endocardial, M and Epicardial cells. A reduction in net repolarizing current generally leads to a preferential prolongation of the M cell action potential. An increase in net repolarizing current can lead to a preferential abbreviation of the action potential of right ventricular epicardium or left ventricular endocardium. These changes can result in amplification of transmural heterogeneities of repolarization and thus predispose to the development of potentially lethal reentrant arrhythmias. The long QT, short QT, Brugada and catecholaminergic VT syndromes are all examples of pathologies that have very different phenotypes and aetiologies, but share a common final pathway in causing sudden death via amplification transmural or other spatial dispersion of repolarization within the ventricular myocardium. These same mechanisms are likely to be responsible for life-threatening arrhythmias in a variety of other cardiomyopathies ranging from heart failure and hypertrophy, which may involve mechanisms very similar to those operative in long QT syndrome, to ischaemia and infarction, which may involve mechanisms more closely resembling those responsible for the Brugada syndrome.

Action Potentials↗
PubMed2005

Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes.

Torsades de pointes (TdP) is a potentially lethal arrhythmia that develops as a consequence of 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 inscription of the ECG T wave. Antiarrhythmic agents with class III actions and/or the various mutations and cardiomyopathies associated with the long QT syndrome reduce net repolarizing current and amplify the intrinsic spatial dispersion of repolarization, thus creating the substrate for the development of reentry. The result is prolongation of the QT interval, abnormal T waves, and development of polymorphic reentrant ventricular tachycardia displaying characteristics of TdP. Prolongation of the QT interval apparently is not the sole determinant of a drug's potential to cause TdP. Agents that do not increase transmural dispersion of repolarization have little or no potential to induce TdP despite any ability to prolong the QT interval. In addition, drugs such as amiodarone and sodium pentobarbital can cause large QT prolongations but, by reducing transmural dispersion of repolarization, may reduce the likelihood of TdP. Arterially perfused wedge preparations of canine left ventricle can be used to explore the role of transmural dispersion of repolarization in the genesis of TdP. The purpose of this article is to review recent advances that have improved our understanding of these mechanisms, particularly the role of transmural dispersion of repolarization, in the genesis of drug-induced TdP and to examine how these advances can guide us toward the development of safer and more effective drugs.

Animals↗
PubMed2005

Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.

OBJECTIVES: The purpose of this study was to compare the effect of intravenous flecainide and ajmaline with respect to their ability to induce or accentuate the typical ECG pattern of Brugada syndrome. BACKGROUND: Brugada syndrome is associated with a high incidence of sudden cardiac death. The typical ECG pattern of ST-segment elevation in the right precordial leads often is concealed, but it can be unmasked with sodium channel blockers such as flecainide and ajmaline. Little is known about the relative effectiveness of these provocative agents in unmasking Brugada syndrome. METHODS: Intravenous pharmacologic challenge with flecainide and ajmaline was performed. Whole-cell patch clamp techniques were used to assess the relative potency of ajmaline and flecainide to inhibit the transient outward current (I(to)). RESULTS: A coved-type ST-segment elevation in the right precordial leads was induced or enhanced in 22 of 22 patients following ajmaline administration. Among the 22 patients, only 15 patients showed positive response to flecainide, resulting in a positive concordance of 68%. Both drugs produced equivalent changes in QRS and PQ intervals, suggesting similar effects on sodium channel current. Whole-cell patch clamp experiments revealed a reduction of the total charge provided by I(to) with an IC(50) of 216 and 15.2 microM for ajmaline and flecainide, respectively. CONCLUSIONS: Our data demonstrate disparate response of Brugada patients to flecainide and ajmaline, with a failure of flecainide in 7 of 22 cases (32%). Greater inhibition of I(to) by flecainide may render it less effective. These observations have important implication for identification of patients at risk for sudden death.

Ajmaline↗
PubMed2005

Brugada syndrome: report of the second consensus conference.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Is there an overlap between Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy/dysplasia?

The Brugada syndrome is a congenital syndrome displaying an autosomal dominant mode of transmission in patients with a structurally normal heart. The disease has been linked to mutations in SCN5A , a gene located on the short arm of chromosome 3 (p21-24) that encodes for the alpha subunit of the sodium channel. The syndrome is characterized by a dynamic ST-segment elevation (accentuated J wave) in leads V 1 to V 3 of the ECG followed by negative T wave. Right bundle-branch block of varying degrees is observed in some patients. The syndrome is associated with syncope and a relatively high incidence of sudden cardiac death secondary to the development of polymorphic ventricular tachycardia that may degenerate into ventricular fibrillation. An acquired form of the Brugada syndrome is also recognized, caused by a wide variety of drugs and conditions that alter the balance of currents active during the early phases of the action potential. Among patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia, there is a subpopulation with a clinical and electrocardiographic pattern similar to that of the Brugada syndrome. These cases of arrhythmogenic right ventricular cardiomyopathy/dysplasia are thought to represent an early or concealed form of the disease. This review examines the overlap between these 2 syndromes.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences.

INTRODUCTION: ST-Segment elevation is a common electrocardiogram (ECG) manifestation of acute transmural myocardial ischemia in leads facing the injury. Acute myocardial ischemia involving the right-ventricular (RV) outflow tract is known to induce a Brugada-like ECG. In this paper, we examined the electrophysiological bases for the similarities between the ECG characteristics of the Brugada syndrome model induced by terfenadine (5 mumol/L) and the ECG manifestations of the acute transmural no-flow ischemia model. METHODS: For both experimental simulations, we used isolated arterially perfused canine RV wedge preparations to record transmembrane action potentials (AP) from endocardium and epicardium together with a transmural pseudo-ECG (ECG); basic cycle length=400 to 2000 ms. RESULTS: In the presence of a prominent Ito-mediated AP notch, no-flow ischemia causes true ST-segment elevation because of selective depression and loss of the AP dome at some epicardial sites. In the absence of a prominent AP notch, ischemia ultimately produces an apparent ST-segment elevation, which is secondary to a prolongation of the R wave caused by marked transmural conduction delays. Similarly, in the Brugada syndrome model generated in preparations displaying a large epicardial Ito, ST-segment elevation was due to loss of the epicardial AP dome at some sites but not at others. Transmural conduction delay giving the appearance of ST-segment elevation is also observed in the Brugada model in preparations exhibiting smaller AP notch. In both models, propagation of the dome from the site at which it is maintained to a site at which it is lost may result in closely coupled phase 2 reentrant extrasystoles. CONCLUSION: Our results suggest that Ito can modulate the electrocardiographic manifestation of acute ischemia as well as that of the Brugada syndrome, and that both clinical entities are the result of a similar electrophysiological substrate.

Action Potentials↗
PubMed2005

Short QT syndrome. Genotype-phenotype correlations.

The short QT syndrome is a new congenital entity associated with familial atrial fibrillation and/or sudden death or syncope. Three different gain-of-function mutations in genes encoding for cardiac potassium channels (KCNH2, KCNQ1, and KCNJ2) have been identified up to now to cause short QT syndrome. The syndrome is characterized electrocardiographically by a shortened QTc interval less than 300 to 320 milliseconds and a lack of adaptation during increasing heart rates. During programmed electrical stimulation, atrial and ventricular effective refractory periods are shortened, and in a high percentage, ventricular tachyarrhythmias are inducible. Sudden cardiac death occurs in all age groups and even in newborns. Therapy for choice seems to be the implantable cardioverter-defibrillator because of the high incidence of sudden death. However, ICD therapy may be associated with an increased risk of inappropriate therapies for T wave oversensing, which, however, can be resolved by reprogramming ICD detection algorithms. The impact of sotalol, ibutilide, flecainide, and quinidine on QT prolongation has been evaluated. But only quinidine effectively suppressed gain-of-function in IKr, along with prolongation of the QT interval. Furthermore, in patients with a mutation in HERG (SQT1), quinidine rendered ventricular tachyarrhythmias noninducible and restored the QT interval/heart rate relationship toward a reference range. It may serve as an adjunct to ICD therapy or as possible alternative treatment especially for children and newborns.

Anti-Arrhythmia Agents↗
PubMed2005

Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG.

INTRODUCTION: The principal aim of this study was to assess the efficacy of quinidine in suppressing IKr in vitro and in modulating the rate dependence of the QT interval in the "SQT1" form of the short QT syndrome. METHODS AND RESULTS: Graded-intensity bicycle exercise testing was performed off drug in three patients and during oral quinidine in two patients with short QT syndrome and compared to a control group of healthy normal subjects. The in vitro effects of quinidine on currents in patch clamp technique were investigated. Off drugs QTpV3/heart rate correlation is much weaker in patients with short QT syndrome, and QTpV3 shortens less with heart rate increase compared to normal subjects. In addition to prolonging the QT interval into the normal range, quinidine restored the heart rate dependence of the QT interval toward a range of adaptation reported for normal subjects. Data from heterologous expression of wild-type and mutant HERG genes indicate the mutation causes a 20-fold increase in IC50 of d-sotalol but only a 5.8-fold increase in IC50 of quinidine. CONCLUSION: Oral quinidine is effective in suppressing the gain of function in IKr responsible for some cases of short QT syndrome with a mutation in HERG and thus restoring normal rate dependence of the QT interval and rendering ventricular tachycardia/ventricular fibrillation noninducible.

Adolescent↗
PubMed2005

Role of repolarization restitution in the development of coarse and fine atrial fibrillation in the isolated canine right atria.

INTRODUCTION: Although the role of action potential duration restitution (APD-R) in the initiation and maintenance of ventricular fibrillation (VF) has been the subject of numerous investigations, its role in the generation of atrial fibrillation (AF) is less well studied. The cellular and ionic basis for coarse versus fine AF is not well delineated. METHODS AND RESULTS: We measured APD-R during acetylcholine-mediated AF as well as during pacing (standard and dynamic protocols) in crista teriminalis, pectinate muscle, superior vena cava, and appendage of isolated canine arterially perfused right atria (n = 15). Transmembrane action potential (TAP), pseudo-ECG, and isometric tension development were simultaneously recorded. Acetylcholine flattened APD-R measured by both standard and dynamic protocols, but promoted induction of AF. AF was initially coarse, converting to fine within 3-15 minutes of AF. Coarse, but not fine AF was associated with dramatic fluctuations in tension development, reflecting wide variations in intracellular calcium activity ([Ca(2+)](i)). During coarse AF, APD-R data displayed a cloud-like distribution pattern, with a wide range of maximum APD-R slope (from 1.21 to 0.35). A maximum APD-R slope >1 was observed only in crista terminalis (3/10). The APD-R relationship was relatively linear and flat during fine AF. Reduction of [Ca(2+)](i) was associated with fine AF whereas augmentation of [Ca(2+)](i) with coarse AF. CONCLUSIONS: Our data indicate that while APD-R may have a limited role in the maintenance of coarse AF, it is unlikely to contribute to the maintenance of fine AF and that [Ca(2+)](i) dynamics determine the degree to which AF is coarse or fine.

Acetylcholine↗
PubMed2005

Modulation of transmural repolarization.

Ventricular myocardium in larger mammals has been shown to be comprised of three distinct cell types: epicardial, M, and endocardial. Epicardial and M cell action potentials differ from endocardial cells with respect to the morphology of phase 1. These cells possess a prominent I(to)-mediated notch responsible for the "spike and dome" morphology of the epicardial and M cell response. M cells are distinguished from the other cell types in that they display a smaller I(Ks), but a larger late I(Na) and I(Na-Ca). These ionic distinctions underlie the longer action potential duration (APD) and steeper APD-rate relationship of the M cell. Difference in the time course of repolarization of phase 1 and phase 3 are responsible for the inscription of the electrocardiographic J wave and T wave, respectively. These repolarization gradients are sensitively modulated by electrotonic communication among the three cells types, [K(1)](o), and the presence of drugs that either reduce or augment net repolarizing current. A reduction in net repolarizing current generally leads to a preferential prolongation of the M cell action potential, responsible for a prolongation of the QT interval and an increase in transmural dispersion of repolarization (TDR), which underlies the development of torsade de pointes arrhythmias. An increase in net repolarizing current can lead to a preferential abbreviation of the action potential of epicardium in the right ventricle (RV), and endocardium in the left ventricle (LV). These actions also lead to a TDR that manifests as the Brugada syndrome in RV and the short QT syndrome in LV.

Action Potentials↗
PubMed2005

Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome.

Seven forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes have been identified. Genotype-phenotype correlation in clinical and experimental studies involving arterially-perfused canine left ventricular wedges suggest that beta-blockers are protective in LQT1, less so in LQT2, but not protective in LQT3. A class IB sodium channel blocker, mexiletine, is most effective in abbreviating QT interval in LQT3, but effectively reduces transmural dispersion of repolarization (TDR) and prevents the development of Torsade de Pointes (TdP) in all 3 models, suggesting its potential as an adjunctive therapy in LQT1 and LQT2. High concentrations of intravenous nicorandil, a potassium channel opener, have been shown to be capable of decreasing QT and TDR, and preventing TdP in LQT1 and LQT2 but not in LQT3. The calcium channel blocker, verapamil, has also been suggested as adjunctive therapy for LQT1, LQT2 and possibly LQT3. Experimental data using right ventricular wedge preparations suggest that a prominent transient outward current (I(to))-mediated action potential (AP) notch and a loss of AP dome in epicardium, but not in endocardium, give rise to a transmural voltage gradient, resulting in ST segment elevation and the induction of ventricular fibrillation (VF), characteristics of the Brugada syndrome. Since the maintenance of the AP dome is determined by the balance of currents active at the end of phase 1 of the AP, any intervention that reduces the outward current or boosts inward current at the end of phase 1 may normalize the ST segment elevation and suppress VF. Such interventions are candidates for pharmacological therapy of the Brugada syndrome. The infusion of isoproterenol, a beta-adrenergic stimulant, strongly augments L-type calcium current (I(Ca-L)), and is the first choice for suppressing electrical storms associated with Brugada syndrome. Quinidine, by virtue of its actions to block I(to), has been proposed as adjunctive therapy, with an implantable cardioverter defibrillator as backup. Oral denopamine, atropine or cilostazol all increase ICa-L, and for this reason may be effective in reducing episodes of VF.

Adrenergic beta-Antagonists↗
PubMed2004

Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome.

BACKGROUND: The short-QT syndrome is a new clinical entity characterized by corrected QT intervals <300 ms and a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Gain-of-function mutations in the gene for outward potassium currents have been shown to underlie the congenital syndrome. The present study examined the cellular basis of VT/VF in an experimental model associated with short QT intervals created with a potassium channel activator. METHODS AND RESULTS: Transmembrane action potentials from epicardial and M regions, 4 transmural unipolar electrograms, and a pseudo-ECG were simultaneously recorded in canine arterially perfused left ventricular wedge preparations. At a basic cycle length of 2000 ms, pinacidil (2 to 3 mumol/L) abbreviated the QT interval from 303.7+/-5.4 to 247.3+/-6.9 ms (mean+/-SEM, P<0.0001). The maximal transmural dispersion of repolarization (TDR(max)) increased from 27.0+/-3.8 to 64.9+/-9.2 ms (P<0.01), and an S2 applied to the endocardium induced a polymorphic VT (pVT) in 9 of 12 wedge preparations (P<0.01). Addition of isoproterenol (100 nmol/L, n=5) led to greater abbreviation of the QT interval, a further increase in TDR(max) (from 55.4+/-13.7 to 69.7+/-8.3 ms), and more enduring pVT. TDR(max) was correlated significantly with the T(peak)-T(end) interval under all conditions. The effects of pinacidil were completely reversed by glybenclamide (10 micromol/L, n=4) and partially reversed by E4031 (5 micromol/L, n=5), which prevented induction of pVT in 3 of 5 preparations. CONCLUSIONS: Our data suggest that heterogeneous abbreviation of the action potential duration among different cell types spanning the ventricular wall creates the substrate for the genesis of VT under conditions associated with short QT intervals.

Action Potentials↗
PubMed2004

Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.

BACKGROUND: The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial. METHODS AND RESULTS: We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier. CONCLUSIONS: In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.

Ajmaline↗