Masonic Medical Research Laboratory, Utica, New York
This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and ...disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death.
long QT syndrome; short QT syndrome; Brugada syndrome; polymorphic ventricular tachycardia; electrophysiology
Address for reprint requests and other correspondence: C. Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501-1787 (e-mail: ca{at}mmrl.edu )
An early repolarization (ER) pattern in the ECG, distinguished by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation has long been recognized and considered to be a ...benign electrocardiographic manifestation. Experimental studies conducted over a decade ago suggested that some cases of ER may be associated with malignant arrhythmias. Validation of this hypothesis was provided by recent studies demonstrating that an ER pattern in the inferior or inferolateral leads is associated with increased risk for life-threatening arrhythmias, termed ER syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BS) and ERS, these syndromes have been grouped under the term "J wave syndromes". ERS and BS share similar ECG characteristics, clinical outcomes and risk factors, as well as a common arrhythmic platform related to amplification of Ito-mediated J waves. Although BS and ERS differ with respect to the magnitude and lead location of abnormal J wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression. Although most subjects exhibiting an ER pattern are at minimal to no risk, mounting evidence suggests that careful attention should be paid to subjects with "high risk" ER. The challenge ahead is to be able to identify those at risk for sudden cardiac death. Here I review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes. (Circ J 2012; 76: 1054-1065)
Brugada Syndrome ANTZELEVITCH, CHARLES
Pacing and clinical electrophysiology,
10/2006, Letnik:
29, Številka:
10
Journal Article
Recenzirano
Odprti dostop
First introduced as a new clinical entity in 1992, the Brugada syndrome is associated with a relatively high risk of sudden death in young adults, and occasionally in children and infants. Recent ...years have witnessed a striking proliferation of papers dealing with the clinical and basic aspects of the disease. Characterized by a coved‐type ST‐segment elevation in the right precordial leads of the electrocardiogram (ECG), the Brugada syndrome has a genetic basis that thus far has been linked only to mutations in SCN5A, the gene that encodes the α‐subunit of the sodium channel. The Brugada ECG is often concealed, but can be unmasked or modulated by a number of drugs and pathophysiological states including sodium channel blockers, a febrile state, vagotonic agents, tricyclic antidepressants, as well as cocaine and propranolol intoxication. Average age at the time of initial diagnosis or sudden death is 40 ± 22, with the youngest patient diagnosed at 2 days of age and the oldest at 84 years. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of the Brugada syndrome, incorporating the results of two recent consensus conferences. Controversies with regard to risk stratification and newly proposed pharmacologic strategies are discussed.
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.
This lecture 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 often is secondary to preferential prolongation of the action potential duration of M cells, whereas in Brugada syndrome, it is thought to be due to selective abbreviation of the action potential duration of right ventricular epicardium. In the short QT syndrome, preferential abbreviation of action potential duration of either endocardium or epicardium appears to be responsible for amplification of TDR. In catecholaminergic polymorphic ventricular tachycardia, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. Thus, the long QT, short QT, Brugada, and catecholaminergic ventricular tachycardia syndromes are pathologies with very different phenotypes and etiologies. However, these syndromes share a common final pathway in their predisposition to sudden cardiac death.
Objectives The aim of this study was to test the hypothesis that late potentials and fractionated electrogram activity are due to delayed depolarization within the anterior aspects of right ...ventricular (RV) epicardium in experimental models of Brugada syndrome (BrS). Background Clinical reports have demonstrated late potentials on signal-averaged electrocardiography (ECG) recorded in patients with BrS. Recent studies report the appearance of late potentials and fractionated activity on bipolar electrograms recorded in the epicardium of the RV outflow tract in patients with BrS. Methods Action potential and bipolar electrograms were recorded at epicardial and endocardial sites of coronary-perfused canine RV wedge preparations, together with a pseudo-ECG. The transient outward potassium current agonist NS5806 (5 μM) and the Ca2+ -channel blocker verapamil (2 μM) were used to pharmacologically mimic the BrS genetic defect. Results Fractionated electrical activity was observed in RV epicardium, but not in endocardium, as a consequence of heterogeneities in the appearance of the second upstroke of the epicardial action potential, and discrete high-frequency spikes developed as a result of concealed phase 2 re-entry. In no case did we observe primary conduction delay as the cause of the BrS ECG phenotype or of late potential or fractionated electrogram activity. Quinidine (10 μM) and the phosphodiesterase-3 inhibitors cilostazol (10 μM) and milrinone (2.5 μM) restored electrical homogeneity, thus abolishing all late potentials and fractionated electrical activity. Conclusions These data point to an alternative pathophysiological basis for late potentials and fractionated electrical activity recorded in the right ventricle in the setting of BrS. We demonstrate an association of such activity with abnormal repolarization and not with abnormal depolarization or structural abnormalities.
The J wave, also referred to as an Osborn wave, is a deflection immediately following the QRS complex of the surface ECG. When partially buried in the R wave, the J wave appears as J-point elevation ...or ST-segment elevation. Several lines of evidence have suggested that arrhythmias associated with an early repolarization pattern in the inferior or mid to lateral precordial leads, Brugada syndrome, or arrhythmias associated with hypothermia and the acute phase of ST-segment elevation myocardial infarction are mechanistically linked to abnormalities in the manifestation of the transient outward current (I(to))-mediated J wave. Although Brugada syndrome and early repolarization syndrome differ with respect to the magnitude and lead location of abnormal J-wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression that we propose be termed J-wave syndromes. This review summarizes our current state of knowledge concerning J-wave syndromes, bridging basic and clinical aspects. We propose to divide early repolarization syndrome into three subtypes: type 1, which displays an early repolarization pattern predominantly in the lateral precordial leads, is prevalent among healthy male athletes and is rarely seen in ventricular fibrillation survivors; type 2, which displays an early repolarization pattern predominantly in the inferior or inferolateral leads, is associated with a higher level of risk; and type 3, which displays an early repolarization pattern globally in the inferior, lateral, and right precordial leads, is associated with the highest level of risk for development of malignant arrhythmias and is often associated with ventricular fibrillation storms.
: One hundred years after Willem Einthoven first recorded the electrocardiogram (ECG), physicians and scientists are still debating the cellular basis for the various waves of the ECG. In this ...review, our focus is on the cellular basis for the J, T, and U waves of the ECG. The J wave and T wave are thought to arise as a consequence of voltage gradients that develop as a result of the electrical heterogeneities that exist within the ventricular myocardium. The presence of a prominent action potential notch in epicardium but not endocardium gives rise to a voltage gradient during ventricular activation that inscribes the J wave. Transmural and apico‐basal voltage gradients developing as a result of difference in the time course of repolarization of the epicardial, M, and endocardial cell action potentials, and the more positive plateau potential of the M cell contribute to inscription of the T wave. Amplification of these heterogeneities results in abnormalities of the J wave and T wave, leading to the development of the Brugada, long QT, and short QT syndromes. The basis for the U wave has long been a matter of debate. One theory attributes the U wave to mechanoelectrical feedback. A second theory ascribes it to voltage gradients within ventricular myocardium and a third to voltage gradients between the ventricular myocardium and the His–Purkinje system. Although direct evidence in support of any of these three hypotheses is lacking, recent studies involving the short QT syndrome have generated renewed interest in the mechanoelectrical hypothesis.
A prominent J wave is encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada syndrome and early repolarization syndromes. Brugada syndrome and early ...repolarization syndromes differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J-wave syndromes. Despite two decades of intensive research, risk stratification and the approach to therapy of these 2 inherited cardiac arrhythmia syndromes are still undergoing rapid evolution. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, and molecular, ionic, cellular, and genetic mechanisms underlying these 2 fascinating syndromes that have captured the interest and attention of the cardiology community in recent years.
Ranolazine is a Food and Drug Administration-approved antianginal agent. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria. In the ...ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT syndrome, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and atrial fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazine's antiarrhythmic actions is thought to be primarily via inhibition of late I(Na) in the ventricles and via use-dependent inhibition of peak I(Na) and I(Kr) in the atria. Short- and long-term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiologic actions and antiarrhythmic properties of ranolazine in preclinical and clinical studies.
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