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Biomedical subjects

C Antzelevitch

Publications and source records attributed to C Antzelevitch.

At least 19 recordsLinked to original sources
PubMed2006

Therapy for the Brugada syndrome.

The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type 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. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).

Anti-Arrhythmia Agents↗
PubMed2006

Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes.

This review examines the hypothesis that amplification of spatial dispersion of repolarization in the form of transmural dispersion of repolarization (TDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies including the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia. In the long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada syndrome, it is thought to be because of selective abbreviation of the APD of right ventricular epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, the reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic VT syndromes are pathologies with very different phenotypes and aetiologies, but which share a common final pathway in causing sudden death.

Arrhythmias, Cardiac↗
PubMed2005

The Brugada Syndrome.

In 1992 a syndrome was described consisting of syncopal episodes and/or (resuscitated) sudden death in patients with a structurally normal heart and a characte ristic electrocardiogram (ECG) displaying a pattern resembling a right bundle branch block with ST segment elevation in leads V1 to V3. The disease is genetically determined with an autosomal dominant pattern of transmission in 50% of the familial cases. Several different mutations have been identified affecting the structure, function and trafficking of the sodium channel. The syndrome is ubiquitous. Its incidence and prevalence are difficult to estimate, but this disease may cause 4 to 10 sudden deaths per 10,000 inhabitants per year representing the most frequent cause of natural death in males younger than 50 in South Asia. The disease has been linked to the sudden infant death syndrome (SIDS) and to the sudden unexpected death syndrome (SUDS) by showing that the electrocardiogram and mutations are the same as in Brugada syndrome. The diagnosis is easily made by means of the ECG when it is typical. There exist, however, patients with concealed and intermittent electrocardiographic forms that make the diagnosis difficult. The ECG can be modulated by changes in autonomic balance, body temperature, glucose level and the administration of antiarrhythmic, neuroleptic and antimalaria drugs. Beta adrenergic stimulation normalizes the ECG. Loss of the action potential dome in right ventricular epicardium but not in endocardium underlies the ST segment elevation. Electrical heterogeneity within right ventricular epicardium leads to the development of closely coupled extrasystoles via phase 2 reentry that precipitate ventricular ,fibrillation. Antiarrhythmic drugs do not prevent sudden death in symptomatic or asymptomatic individuals. Implantation of an automatic cardioverter-defibrillator is the only currently proven effective therapy. Patients with frequent electrical storms may even need cardiac transplantation as last resort.

Bundle-Branch Block↗
PubMed2003

Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of I(Ks) in canine hypertrophied hearts.

OBJECTIVE: In animal models of hypertrophy, electrical remodeling giving rise to QT prolongation occurs rapidly and is associated with the development of torsade de pointes (TdP) arrhythmias and sudden death. Chronic AV block (CAVB)-induced hypertrophy in dogs has been associated with a reduction in the slow component (I(Ks)) of the delayed rectifier potassium current (I(K)), which contributes to a prolongation of ventricular repolarization, the development of an acquired form of long QT, and the substrate for triggered activity and TdP. The present study was designed to probe the molecular basis for the decrease in I(Ks) by studying the characteristics of KCNE1 and KCNQ1, the putative genes responsible for formation of the channel. METHODS AND RESULTS: Using a combination of Northern blot, competitive multiplex PCR and immunoblot assays, we found that CAVB reduces KCNE1 and KCNQ1 RNA in the canine ventricles by 70 and 80%, respectively. Protein levels of KCNE1 and KCNQ1 were reduced by 60 and 50%, respectively. We also demonstrate at the molecular level the basis for inter-ventricular difference in I(Ks) density previously reported in hearts of normal dogs and show the basis for reduction of this difference in the CAVB dog. CONCLUSIONS: Our results indicate that the CAVB-induced reduction in I(Ks) is due to a down-regulation of KCNE1 and KCNQ1 transcription. The data suggest that electrical remodeling of the cardiac ventricle during hypertrophy involves regulation of the gene expression through modulation of transcriptional and translational regulatory pathways. The reduction in KCNE1 and KCNQ1 expression increases the dependence of ventricular repolarization on the rapid component of I(K) and may potentiate the action of Class III antiarrhythmic agents.

Animals↗
PubMed2002

Brugada syndrome: a decade of progress.

The Brugada syndrome has gained wide recognition throughout the world and today is believed to be responsible for 4% to 12% of all sudden deaths and approximately 20% of deaths in patients with structurally normal hearts. The incidence of the disease is on the order of 5 per 10 000 inhabitants and, apart from accidents, is the leading cause of death of men under the age of 50 in regions of the world where the inherited syndrome is endemic. This minireview briefly summarizes the progress made over the past decade in our understanding of the clinical, genetic, cellular, ionic, and molecular aspects of this disease.

Arrhythmias, Cardiac↗
PubMed2001

Molecular basis for the transmural distribution of the transient outward current.

Regional differences in electrical properties of cardiac cells contribute to the normal function of the heart as well as to the inscription of the J wave and T wave of the ECG. Amplification of these electrical heterogeneities can lead to the development of life-threatening cardiac arrhythmias and sudden death. A number of ionic distinctions have been shown to contribute to the different action potential morphologies of epicardial, M and endocardial ventricular cells as well as to the distinctive responses of these three cell types to pharmacological agents and pathophysiological states (for reviews see Antzelevitch et al. 1999; Antzelevitch & Dumaine, 2000).

Action Potentials↗
PubMed2001

Electrical heterogeneity within the ventricular wall.

Recent studies have established the presence of three distinct cell types in the ventricular myocardium: epicardial, M and endocardial cells. Epicardial and M cell action potentials differ from endocardial cells with respect to the morphology of phase 1. These cells possess a prominent transient outward current (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 slowly activating delayed rectifier current (I(Ks)), but a larger late sodium current (late I(Na)) and sodium-calcium exchange current (I(Na-Ca)). These ionic distinctions underlie the longer action potential duration (APD) and steeper APD-rate relationship of the M cell, which is more pronounced in the presence of antiarrhythmic agents with class III actions. The preferential prolongation of the M cell action potential results in the development of a transmural dispersion of repolarization (TDR), which can be estimated from the electrocardiogram (ECG) as the interval between the peak and the end of the T wave (QTpeak-QTend interval). Using the canine arterially perfused ventricular wedge model, transmembrane action potentials of the various cardiac cell types can be correlated to the waveforms of the ECG, providing insight into the cellular etiology of ECG abnormalities. Two congenital syndromes of sudden cardiac death that have been modeled using this technique are the long QT and Brugada syndromes. The long QT syndrome has been linked to 5 gene mutations on chromosomes 3, 7, 11, and 21. Mutations in the cardiac sodium channel SCN5A have been linked to families with a history of the Brugada syndrome. Although the etiologies of these two syndromes are different, lethal arrhythmias in both are thought to arise due to amplification of intrinsic electrical heterogeneities. Similar mechanisms are likely responsible for life-threatening arrhythmias in a variety of other cardiomyopathies ranging from heart failure and hypertrophy, which involve mechanisms similar to those operative in LQTS, to ischemia and infarction, which may involve mechanisms more closely resembling those responsible for the Brugada syndrome.

Animals↗
PubMed2001

The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities.

The Brugada syndrome is an arrhythmic syndrome characterized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these patients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator.

Action Potentials↗
PubMed2001

Divergent expression of delayed rectifier K(+) channel subunits during mouse heart development.

The repolarization phase of the cardiac action potential is dependent on transmembrane K(+) currents. The slow (I(Ks)) and fast (I(Kr)) components of the delayed-rectifier cardiac K(+) current are generated by pore-forming alpha subunits KCNQ1 and KCNH2, respectively, in association with regulatory beta-subunit KCNE1, KCNE2 and perphaps KCNE3. In the present study we have investigated the distribution of transcripts encoding these five potassium channel-forming subunits during mouse heart development as well as the protein distribution of KCNQ1 and KCNH2. KCNQ1 and KCNH2 mRNAs (and protein) are first expressed at embryonic day (E) 9.5, showing comparable levels of expression within the atrial and ventricular myocardium during the embryonic and fetal stages. In contrast, the beta-subunits display a more dynamic pattern of expression during development. KCNE1 expression is first observed at E9.5 throughout the entire myocardium and progressively is confined to the ventricular myocardium. With further development (E16.5), KCNE1 expression is mainly confined to the compact ventricular myocardium. KCNE2 is first expressed at E9.5 and it is restricted already to the atrial myocardium. KCNE3 is first expressed at E8.5 throughout the myocardium and with further development, it becomes restricted to the atrial myocardium. The fact that alpha subunits are homogeneously distributed within the myocardium, whereas the beta subunits display a regionalized expression profile during cardiac development, suggest that differences in the slow and fast component of the delayed-rectifier cardiac K(+) currents between the atrial and the ventricular cardiomyocytes are mainly determined by differential beta-subunit distribution.

Animals↗
PubMed2001

Chromanol 293B inhibits slowly activating delayed rectifier and transient outward currents in canine left ventricular myocytes.

INTRODUCTION: Drugs that selectively inhibit the slowly activating component of the delayed rectifier potassium current (I(Ks)) are being considered as possible antiarrhythmic agents, because they produce more prolongation of action potential duration at fast rates with less transmural dispersion of repolarization compared with blockers of the rapidly activating component (I(Kr)). Although the chromanol derivative chromanol 293B has been shown to be relatively selective in blocking I(Ks) in some species, its selectivity is far from established. METHODS AND RESULTS: The present study uses whole-cell, patch-clamp technique to examine the selectivity of this compound for inhibition of I(Ks) in comparison with other repolarizing ionic currents, such as I(Kr), inward rectifier potassium current (I(Kl)), transient outward current (I(to)), and L-type calcium current (I(Ca-L)) in canine left ventricular mid-myocardial and endocardial cells. Chromanol 293B blocked I(Ks) with an IC50 of 1.8 microM and I(to) with an IC50 of 38 microM. Concentrations as high as 30 microM did not affect I(Kl), I(Kr), or I(Ca-L). Higher concentrations of chromanol 293B (100 microM) caused a slight, but statistically insignificant, inhibition of I(Kr). CONCLUSION: Our results indicate that chromanol 293B is a relatively selective blocker of I(Ks) in canine left ventricular myocytes.

Animals↗
PubMed2001

Cellular basis for complex T waves and arrhythmic activity following combined I(Kr) and I(Ks) block.

INTRODUCTION: A growing number of cardiomyopathies have been shown to result in a reduction in both I(Kr) and I(Ks) yet little is known about the electrophysiologic and ECG characteristics of combined I(Kr) and I(Ks) block. METHODS AND RESULTS: To address this gap in our knowledge, transmembrane action potentials (APs) from epicardial, M, and endocardial cells were recorded simultaneously, together with a transmural ECG from arterially perfused canine left ventricular wedge preparations exposed to combined I(Kr) (d-sotalol; 100 micromol/L) and I(Ks) (chromanol 293B; 30 to 60 micromol/L) block. Under baseline conditions, the T wave was typically upright; epicardium repolarized first, coinciding with the peak of the T wave, and the M cells repolarized last, coinciding with the end of the T wave (T(end)). Complex (inverted, biphasic, and triphasic) T waves developed following combined I(Kr) and I(Ks) block. M and epicardial APs prolonged dramatically, so that the endocardial AP was now the earliest to repolarize, coinciding with the first nadir of the complex T wave. In the case of biphasic/triphasic or inverted T waves, Tend coincided with repolarization of either M or epicardial cells, whichever was the last to repolarize. QT intervals prolonged from 286+/-13 msec up to 744+/-148 msec and transmural dispersion of repolarization (TDR) increased from 33+/-10 msec up to 244+/-71 msec. Early afterdepolarizations (EADs) developed in M and epicardial cells, evoking extrasystoles that precipitated polymorphic ventricular tachycardia. Acceleration-induced EADs and T wave alternans also were observed. CONCLUSION: Combined I(Kr) and I(Ks) block gives rise to inverted, biphasic, and triphasic T wave morphologies, a dramatic increase in TDR, and a high incidence of EADs. The diversity of T wave morphologies derives from a preferential AP prolongation of different transmural layers leading to variation in the predominance of voltage gradients on either side of the M cell region. Our study provides direct evidence linking EADs that arise in ventricular epicardial and M cells to the triggered beats that precipitate polymorphic ventricular tachycardia. Our results also suggest possible guidelines for the estimation of TDR from complex T waves appearing in the precordial leads of the surface ECG.

Action Potentials↗