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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, α-adrenergic agonists, β-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

Brugada Syndrome: Report of the Second Consensus Conference Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association

Ventricular fibrillation causes more than 300,000 sudden deaths each year in the USA alone. In approximately 5-12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation

The single most common cause of the withdrawal or restriction of the use of marketed drugs has been QT-interval prolongation associated with polymorphic ventricular tachycardia, or torsade de pointes, a condition that can be fatal. This review summarizes the current knowledge about molecular and clinical predictors of drug-induced QT-interval prolongation and torsade de pointes and discusses how new molecular predictors of drug action might be incorporated into drug-development programs and clinical practice. A general approach to drugs suspected of causing this problem is presented.

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Drug-induced prolongation of the QT interval.

HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.

Background—The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome. Methods and Results—Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 μmol/L), a K+ channel opener, or the combination of a Na+ channel blocker (flecainide, 7 μmol/L) and acetylcholine (ACh, 2 to 3 μmol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 μmol/L) restored the epicardial dome, thus reducing...

Cellular Basis for the Brugada Syndrome and Other Mechanisms of Arrhythmogenesis Associated With ST-Segment Elevation

Background—This study probes the cellular basis for the T wave under baseline and long-QT (LQT) conditions using an arterially perfused canine left ventricular (LV) wedge preparation, which permits direct temporal correlation of cellular transmembrane and ECG events. Methods and Results—Floating microelectrodes were used to record transmembrane action potentials (APs) simultaneously from epicardial, M-region, and endocardial sites or subendocardial Purkinje fibers. A transmural ECG was recorded concurrently. Under baseline and LQT conditions, repolarization of the epicardial action potential, the earliest to repolarize, coincided with the peak of the T wave; repolarization of the M cells, the last to repolarize, coincided with the end of the T wave. Thus, the action potential duration (APD) of the longest M cells determine the QT interval and the Tpeak–Tend interval serves as an index of transmural dispersion of repolarization. Repolarization of Purkinje fibers outlasted that of the M cell but failed to r...

Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome

Background The J wave is a deflection that appears in the ECG as a late delta wave following the QRS or as a small secondary R wave (R′). Also referred to as an Osborn wave, the J wave has been observed in the ECG of animals and humans for more than four decades, yet the mechanism underlying its manifestation is poorly understood. The present study investigates the cellular basis for the J wave using an isolated arterially perfused preparation consisting of a wedge of canine right or left ventricle. Methods and Results A 12-lead ECG was initially recorded in vivo. After isolation and arterial perfusion of the right or left ventricular wedge, transmembrane action potentials were simultaneously recorded from epicardial, M region, and endocardial transmural sites with three floating microelectrodes. A transmural ECG was recorded concurrently. A J wave was observed at the R-ST junction of the ECG in 17 of 20 adult dogs, usually in leads II, III, aVR, and aVF and the mid to lateral precordial leads. The J wave...

Cellular Basis for the Electrocardiographic J Wave

The discovery and characterization of the M cell, a unique cell type residing in the deep layers of the ventricular myocardium, has opened a new door in our understanding of the electrophysiology and pharmacology of the heart in both health and disease. The hallmark of the M cell is the ability of its action potential to prolong much more than that of other ventricular myocardial cells in response to a slowing of rate and/or in response to agents that act to prolong action potential duration. Our goal in this review is to provide a comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart, in the inscription of the ECG (particularly the T wave), and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes. Our secondary goal is to address the controversy that has arisen relative to the functional importance of the M cell in the normal heart. The controversy derives largely from the failure of some investigators to demonstrate transmural heterogeneity of repolarization in the dog in vivo under control conditions and after administration of quinidine. The inability to demonstrate transmural heterogeneity under these conditions may be due to the use of bipolar recording techniques that, in our experience, seriously underestimate transmural dispersion of repolarization (TDR). The use of sodium pentobarbital and alpha-chloralose as anesthesia also is problematic, because these agents reduce or eliminate TDR by affecting a variety of ion channel currents. Finally, attempts to amplify transmural dispersion of repolarization with an agent such as quinidine must take into account that relatively high concentrations can result in effects opposite to those desired due to drug inhibition of multiple ion channels. These observations may explain the inability of earlier studies to detect the M cell.

The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart.

https://www.heartrhythmjournal.com/article/S1547-5271(09)01377-0/pdf

Gan-Xin Yan

Papers

Cellular Basis for the Brugada Syndrome and Other Mechanisms of Arrhythmogenesis Associated With ST-Segment Elevation

Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome

Cellular Basis for the Electrocardiographic J Wave

The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart.

J Wave Syndromes