Showing papers by "Charles Antzelevitch published in 2009"

A Mutation in the β3 Subunit of the Cardiac Sodium Channel Associated With Brugada ECG Phenotype

Abstract: Background— Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene. Methods and Results— A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B , the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A /WT+ SCN1B /WT+ SCN3B /L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a −9.6-mV shift of half-inactivation voltage compared with SCN5A /WT+ SCN1B /WT+ SCN3B /WT. Confocal microscopy revealed that SCN5A /WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B /WT and SCN3B /L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium. Conclusions— Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype. Received October 15, 2008; accepted April 20, 2009. # CLINICAL PERSPECTIVE {#article-title-2}

Is there a significant transmural gradient in repolarization time in the intact heart? Cellular basis of the T wave: a century of controversy.

Abstract: The ECG is one of the oldest and most versatile noninvasive cardiac diagnostic tests. It has remained in use essentially in its original form despite dramatic advances in cardiac electrophysiology. In May 1887, Augustus Desire Waller recorded the first human Electrogram using a primitive instrument called a Libbmann capillary electrometer. It had 2 deflections corresponding to ventricular depolarization and repolarization.1 In 1903, Willem Einthoven invented the String Galvanometer—a more sophisticated voltage recording instrument and recorded an Elektrokardiogramm with 5 deflections that he named PQRST.2 Response by Opthof et al p 80 Since its initial invention, the body surface ECG has become a commonly used and extremely valuable test for the diagnosis of a variety of cardiac conditions. Despite a century of prolific use and intensive investigation, the cellular basis of ECG waveforms, particularly the T wave, remains a matter of debate. The saga of the T wave began in 1856, when 2 German physiologists Kolliker and Muller attempted to explore the electric activity of the heart using frog sciatic nerve attached to gastroenemius muscle as a voltage recording instrument and observed 2 contractions (see review by Noble and Cohen3). In retrospect, the second “contraction” probably reflected a voltage gradient related to the T wave of Einthoven. In 1883, Burdon-Sanderson and Page4 were the first to demonstrate that in the frog’s heart, the wave of excitation spreads from the base to the apex of the ventricle. The record was diphasic, with the first positive (R) wave followed by a negative (T) wave. They also demonstrated that the T wave corresponds to repolarization of the ventricle. Similar series of experiments by Bayliss and Starling in 18925 in the canine heart showed that the T waves are usually upright in mammals. This was followed by Mines6 on …

Atrial-selective sodium channel block for the treatment of atrial fibrillation.

Abstract: The pharmacological approach to therapy of atrial fibrillation (AF) is often associated with adverse effects resulting in the development of ventricular arrhythmias. As a consequence, much of the focus in recent years has been on development of atrial-selective agents. Atrial-selective sodium channel blockers have recently been shown to exist and be useful in the management of AF. This review summarizes the available data relative to current therapies, focusing on our understanding of the actions of atrial selective sodium channel blockers in suppressing and preventing the induction of AF and electrophysiological properties that confer atrial-selectivity to these antifibrillatory drugs.

New Pharmacological Strategies for the Treatment of Atrial Fibrillation

Abstract: Atrial fibrillation (AF) is a growing clinical problem, increasing in prevalence as the population of the United States and countries around the world ages. Intensive research aimed at improving prevention, diagnosis, and treatment of AF is ongoing. Although the use and efficacy of catheter ablation-based approaches in AF treatment have increased significantly in the last decade, pharmacological agents remain the first-line therapy for rhythm management of AF. Currently available anti-AF agents are generally only moderately effective and associated with extracardiac toxicity and/or a risk for development of life-threatening ventricular arrhythmias. Included among current investigational strategies for improving the effectiveness and safety of anti-AF drugs is the development of (1) Agents that produce atrial-specific or predominant inhibition of I(Kur), I(K-ACh), or I(Na); (2) "Upstream therapies" that effect nonion channel targets that reduce atrial structural remodeling, hypertrophy, dilatation, inflammation, oxidative injury, etc; (3) Derivatives of "old" anti-AF drugs with an improved safety pharmacological profile; and (4) Gap junction therapy aimed at improving conduction without affecting sodium channels. This review focuses on new pharmacological approaches under investigation for the treatment of AF.

Potent antiarrhythmic effects of chronic amiodarone in canine pulmonary vein sleeve preparations.

Abstract: Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation. Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF). Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks). Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD90) and a significant use-dependent reduction in Vmax leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 μM), high calcium ([Ca2+]o= 5.4 mM), isoproterenol (Iso, 1 μM), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. Vmax, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals. Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog.

Genetics and Sinus Node Dysfunction.

Abstract: Sinus node dysfunction (SND) is commonly encountered in the clinic. The clinical phenotype ranges from asymptomatic sinus bradycardia to complete atrial standstill. In some cases, sinus bradycardia is associated with other myocardial conditions such as congenital abnormalities, myocarditis, dystrophies, cardiomyopathies as well as fibrosis or other structural remodeling of the SA node.1-8 Although there are many etiologies for symptomatic slow heart rates, the only effective treatment available today is the implantation of a pacemaker. The predominant ion channel currents contributing to the pacemaker activity in the sinoatrial node (SAN) include currents flowing through hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels,9 Ltype Ca, Ttype Ca,10 delayed rectifier K,11,12 and acetylcholine (ACh)-activated13,14 channels. However, their relative contribution remains a matter of debate and the cellular mechanisms contributing to abnormal sinus node function leading to bradycardia are not fully elucidated. Sodium channel current (INa), encoded by SCN5A, is responsible for the cardiac action potential (AP) upstroke and therefore has an important role in initiation and propagation of the cardiac action potential. Although it is largely absent in the sinus node, it plays an important role at the periphery of the sinus node in transmitting electrical activity from the sinus node to the rest of the atria. Mutations in genes encoding structural anchoring proteins (ANK2, Caveolin3, AKAP9) have been associated with the development of atrial as well as ventricular arrhythmias.15, 16, 17 Sinus node dysfunction has been associated with a variety of atrial tachyarrhythmias, atrial fibrillation (AF) in particular. In recent years, numerous publications have focused on the genetic basis for ion channels and structural protein remodeling, providing further insights in the mechanisms of sinus node dysfunction and its role in AF. In this review, we will focus on the genetic aspects of the various forms of sinus node dysfunction and their relation to AF.

Abstract 1929: Mutations in the Cardiac L-Type Calcium Channel Associated With Four Sudden Cardiac Death Syndromes

Abstract: Mutations in the Cardiac L-Type Calcium Channel Associated with Inherited Sudden Cardiac Death Syndromes Background: L-Type Calcium Channel (LTCC) mutations have been associated with Timothy (LQT8)...

The role of spatial dispersion of repolarization and intramural reentry in inherited and acquired sudden cardiac death syndromes

Abstract: The cellular basis for intramural reentry that develops secondary to the development of transmural dispersion of repolarization (TDR) is examined in this review. The hypothesis that amplification of spatial dispersion of repolarization underlies the development of intramural reentry and lifethreatening ventricular arrhythmias associated with inherited ion channelopathies is probed. The roles of TDR in the long-QT, short-QT, and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia are critically examined. In the long-QT syndrome, amplification of TDR is generally secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada syndrome, it is due to 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. The available data suggest that the longQT, short-QT, and Brugada syndromes are pathologies with very different phenotypes and etiologies, but which share a common final pathway in causing sudden cardiac death.